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·LUPUS
NEPHRITIS
By
Robert C. Muchrche, MS, MD
Putrict ral I be lealth Fell in l, lernen Ved me Resen han
Educational Horp tals linerally Illino (llege ( Vel
1onstant (x*(nljllospital I csearch Fell
lalyle an
Hoxpital (Airago
al
Robert M Karh, FRCP, FACP
Prnjertor / Veicine Internly Illan ini lleue !
Phyncion Research an! Fl ral eno nepsfula esi(
Innociate itten lg l hysician I realleria frosp tal (h 19
(
Conrad L Pirani, MD
Pr fener slithology I nuternity Illin e Il ge VI
Victor E Pollach, MB, MRCPE
Pesearch bell rin lelere I rexbyteria Il ep lal Inst
In rersity of Il in 1 College of Helme (hiragn
SANS
ACNE
PEN
es
BALTIMORE
THE WILLIAMS & WILKINS COMPANY
1957

·Repunted from VEIKIAF
Volume 36 \umer 1 Varch 1937
Copyright 1957
THI WILIS WILLIS COMPANY
Made in the Intel States of interien
Tilrary of Congre
Citilag Curd Mumt er
58645
CourOSFI) AND PRINTED AT TUT
HALFRLY PRENS. Ic
BA TISTORF 2 )

·LUPUS NEPHRITIS ·2 VLFHRCKI" KRK PIRAVI, AND TOLL th (2) Cereje lup is nephra11s (glomerulonephritis) 16 (3) Nephrotic and pseudonephrotic syndrome in SLI 5.2 2 l'athologic literal 66 Criter for histologic analisis and definition of terms 66 3 The renal lesions in Cases studied by biopsy ES ( Tlie chatacter nnil dlstribution of renal lesions 77 D The renu lesions in cases of SII studied post mortem 79 I The renul lesions in cases of subacute klomerulonephritis studied post mortem 82 Evolution of the renal lesions of lupus nephritis 8+ 3 The Relationship of Structuril(hanges in the hidnes to Henal Function 6 1 Viacroscopic inn il sis 87 B Protein Iria S Toats of renal function 92 VII The Clinicopathologie Features of Lupus Nephritis 97 1 The incidence of lupus nephritis in patients with clinically diagnosed SLI 97 The time of onset of lupus nephritis 95 3 The clinical features of lupu, nephritis 93 + Vephrotre ind pse donephrotic sindrome 100 5 Discussion of patholog! 102 VIII 1reatment of I up 13 Sephritis 100 1 General me isures 100 2 The effects of corticotrophin and cortisone on lupus nephritis 109 I\ l'rognosts 110 1 Prog1098 in STI 110 2 Prognosis in 1 pus nephritis 112 The Relationship of SIT ind I upus Nephritis to Other Diarisce 113 1 Glomerulonephritis 113 2 Poli Irteritis nodlogi 115 3 Rheumatoid arthritis 119 + Sclerodermi ani dermatomi 091119 123 5 I broil otic thrombocitopenic purpura 120 o ancordosis ind Wegener s granulomatosis 12) v lhe tural History of I uue lephritis 131 I INTRODUCTION Lupus Nephritis describes succinctly and graphuc illy involvement of the kney intenc Lupus Erythemitosus (SI E) Fty mologically, the term lupus nephritis is far from perfect, since is combines a Latin and 2 Greek Word to describe a clinical and pathologic entity Descriptncly it in inaccurate for the fact and skin of those who are all with lupus nephritis lu e neither the nature nor the qualities of a scurred wolf-bitc Although we have coincd ponderous but precise plira-cs to describe the grate but common renal complications of SLE the words "lupus" and "nephritis live the virtue of common yenge, and this con-deration ou crrtles all other aspects of nomenclature Lupus nephritis, thus naned, series to focus attention on a specific discase of the kidney which is at present tlie nyjor com plication and the most pressing problem in patients ill with SLE Tic clinical course of the disease was different fifteen years ago when Keith (140) wrote, renal insufficiency docs not play an important role in causing death" At that time patients usually died of a "lupus crisis' or as a result of infection ·LUPUS NEPHRITIS 3 92 176) However tle introduction and liberul use of antibiotics I looil trins fusions balanced water and electroly te therapy and corticotrophıın (ACTH) and stcroid hormone therapy lare apparently prolonged life in those afflicted hy SI E With present metho ls of care many patients with SLE can usurlly be kept frec of symptoms for a consderable length of time only to cuccumb to a progresive renul failure Becau c of the problems used by the increased incidence of lupus nephritis i stu ly of the ren al ons oli ement in SLE was undertaken Tlc use of serial per cutaneous renal hiopies (133 199) cnabled us to follow the lustological evo lution of kiIner inyoli cment The changing clinical status laboratory data an i renal function tests werų correlated with the scrial pathological clanges Tl us a continuing study of the pithophysiology and natural Instory of lupus nepl ritis was posible Preliminary observations have been reported ciscw hure (201 202 2261 This communication outlines observations on thurty thirce na tients studied intensively during the past two years and was supplemented by a retrospective stu of twenty one cases collected from the pot inortom na terial in the hospitals Departments of Pathology I REVIEW OF CLINICAL FEATURES 1 INTRODUCTION Lupus erythematosus was first recognized oscr 120 yells ago In 1827 Per (236) de cribed it as a rare form of flux sebrce Lleien years later Biett (27) writing in Cazenare and schedel s textboch called it try theme centrifuge and described Dartre rongente que detruit en suince In 1863 Fuchs (83) called it cborrhagi adultorum There scems little doult that these diseases are identical sath what we hnos tolay as lupus irythenatosus I olate i ob servations were reported by other authors It was named hypertrophı tollicu lorum by Robert Willis (302) inflammatio folliculorilin by Ernsmus Val on (303) stearrhoea flavescens by Meligan (205) and aent acacia by Erich sen (76) F Hebra (116) Ind Cazenute (49 50) first outline 1 the disease clearly and distinctly In 1845 Hebra (115) described it under tl nume sel orrhoen con gestite in 1856 in his cl2« ic Atlas der Hautkrankheiten (116) he depicted two forms of the disease an i used the term lupus erythematodes ---first coined by Cazenare (48) in his fundamental work of 1851 \cum inn (206) in 1863 de scribed tle pathology of the skin lesion in this disc 1°C haros (132) in 1872 suggested that t} ere were two forms of the disease and named them lupus erythematosus discoiles and lupus erythematosus dis cretus et aggregatus In the course of his patl ologic stules (117 1321 he ob served specific changes in the connective tissue of the papillary layer of the sl in These changes he called hy aloid degeneration Five years later Neuniann (207) introduced the term fibrinoid degeneration to describe the ch inge in the collagen fibers hich assumed the same staining and structural qualitics as fibrın ·1 VLEIRCLE KARK PIRAVI AND POI LAN 2 REVAL INTOLI ENCAT N SLL At the turn of the century renal in olsement was recognized in cases reported by Hallopcau (106) Crafy (47) Gallon ay in MacLeod (86 175) Littlc (171) and Short (261) In 1899 Brooke (3G) found all thic signs of soft white kidneys it the post mortem evamination of pomin ill with lupus erythema tosus and proteinuria Sequeria and Balcan (256) reported ten cases of lupus eri thematosus and noted involvement of the kidneys in fise Gullon ay and VacLeod (86) in 1903 and Indy ohn (122) also stressed the frequent fiction of tl e hidneys wir William Osler in ? number of publications (213 214 215 216 217 218) described the systemic manifestations of a group of diseases which involved the skin and joints His first papers in 1888 (213) and 1893 (214) described cases of Flenoch Schonlein purpura By 1904 (216 217) he hud described twenty ninc patients Only onc casc a fifteen ycar old girl fulfilled our criteria for SI E She died an ur mı? (Casc 19) This is the first Aincrican descrition of a chc of SI E lloncer O ler did not di tinguish this case from others with the Eri themi Group of Skin Diseases (214) and it is incorrect to attribute to bum ecognition of SI E as Tumults ind Harveg 1 ne donc (291) In 1 1 revich of lenoch Schontein purj ura Guudner (84) correctly pointed out that in tl cse papers Osler had delineated the clinical features of Honoch Schonlein purpuras In 1908 Pernet (222) de crilci r case of lupus crythematosus with 1 7911 and fatal course Protein was found in tl e prticnt s urinc He collected ning similar cases from the literature and called this group lupus cryti emateux ugu demblec In 1922 heith and Ron ntrec (141) reported four patients with lupus (rythematosus ani nephritis and stressed that nephritis 1 15 1 common com plication of disseminated lupus erythemntosus Tno jerrs later Libman and macks (167) reported tl c clinical yndrome roduced by t! e atyrıcıl verrucous en locarditis of SLE "hich bears their name They found that there was l isto logie cudence of renal disease in three of their four patients one of whom dicu in uremia Bachr (8) in 1931 reported renal complientions in seventeen cises of Libman Sachs discnsc IIe concluded thnt tl e le ions were an cypression of om ortance of renal ini oli emcnt in lupus erythematosus and stated that there peutic measures bate had no beneficial ctfect Daugi erti ani Bagger sto s (83/ rej ortel esencnscs of Libman Sacl s disease tho had nepl rotic cdoma ar thritis of varying duration and a rapidly progressive course Thesc patients none of whom had a face rasi died in renal failure In 1971 preliminary studies of serial renal biopsies in SLC scre reported by Afuchrche hark and Piradi (201 202 226) and Lister and Baker (170) reported a case of SLE diagnosed by renal biopsy *lles ! to thank Dr T IV Francis and Dr Lloyd Stevenson of the ler Lib ary MII Un crsty Montreal for access to O ler s personal papers manuscripts and looks ·LLPLS NEPHRITIS 3 LRIMARY FINDINGS Protein and formed clements may appear in tle urine in patients with SLE nl en they are acutely all dchy drated and febrile (110 269) As in other condi tions these abnormal urinary findings muy be transitory For this reason the exact interpretation of data on urinary finding reported by previous authors is difficult as one is often uncertain as to the permanency and significance of tl eir ob criations on the urine On the basis of abnormal urinary findings Viontgomery and McCreight (191) reported renal irritation nephrosis or nephritis in 100% of thirty two ciscs of acute SLE and in 69 of scienty seven cascs of subacute SLE Other autl ors reported tl at abnormal urin uy findings scre usually tr ins tory during acute cxacerbations The abnormalitics disappeared cither when spontaneous remis sion occurred 12731 or as a result of therapy (42 110 209) Honever if urinary al normalities persisted during the stage of remission then renal d'image usually w is permanent Ross and Wells (218) wlo studied thirty four patients with SLL wrote Abnorm ul urinary findings are so common that in their absence we may justifiably question i diagnosis of lupus erythematosus However Harvey and his colleagues (110) found no en lence of renal discase in 26% of tl cır 138 patients with SLE Considerable amounts of protein may be found in tlc urine during acute exacerbations of SLF (110) an 1 Madden (176) felt that persistent proteinuri i was of prognostic value as it was found more frequently in the fatal cases Gross heniaturzi was observed in 6% of 34 cases reported by Shearn an? Pirof shy (2091 and Soffer (269) reported that microsropic 1 emnturia was often found during acute exacerbations Cry throcytes leucocytes and casts nero found in the urinent some stage in the core of VI Ein 61% of 44 cases obscried x Jeswar and his colleagues (127) and in 56 of 279 cases reviewed by them Fisl berg (78) ob cruel that clumps of leucocytes were common this finding Tas led clinicians to make an crroneous diagnosis of pyelonephritis Krupp (158) found 1 tell coping of the urinary sediment in four patients with lupus ery thematosus Tlne telescoped urinary sediment containel elements representing the three stages of glomerulonej hritis--thie erythrocyte and erythrocyte casts found in the ncute stage tłe ou al fat bo lies and fatty casts of the subscute stage and the broad casts found in chronic glomcrulonephritis hrupp s obscrvation was confirmed hy Mile (185) Iut Cole (56) reported identical urinary findings in a case of polyarteritis nodosa and Schreiner (235) notel telescopud urinary findings in three pror en cases of chronic glornerulo nephritis He pointed out that although the fin ling of telescoped urinary Tural (102) attempted to correlate urinary findings with renal pathology in a retrospective study of 20 patients who died of SLE They found no correlation of urinary abnormalities suth the histologic appearance of the kidneys ·0 VLHRCKFIR PIRAVI AND I OLLA 4 REAL ILCTION Ad quate studies of renul function have been made but ruch (190) Sofier, Iucemann und Brill (269) studied rennl function in slightly more than half of their 55 patients with acute SLC and considered that the urine concentra tion test was the least sensitive of the renal function tests that und They stated that the 15 minute excretion of phenolsulphonpithalain and the urca clerince test jielded the most useful information in 79-ing the function of the hidncy in SLL Azotcmia was present in 16% of their patients and 119 al o found in 16 of 216 215C revien ce by Tessar et al (127) Soffci and his colleagues (269) observed an elevation of the blood tirea nitrogen licin oncr ont third of patients in u liom protein or cry throcytes were found in the urine Azotemi nas usually progresive and death from renal insufficiency resulted They believed that persistent azotemi " ? 4 serious prognostic sign (266) 5 EDEVA IND THE EPIIROTIC S7 \DROVI Jessa: ind his colleagues (127) reviewed the literature on Sir which was published between 1948 and 19,2 They fourd reports of 279 patients an i arkied 44 of their own wluch had been studied by tween 1937 and 1952-1 total of 323 czucs Edema was noted in proximitely 16%, wule Soffer, I udem inn ind Brill (269) found cdemu in 22, of the 55 patients they stuclied In 1939 Reifenstein and is colleagues (237) revicu el 17 cases of SLE rc ported in the literature and added one of their own Retrospecti cly they di ignosed the nephrotic syndrome in tuo of the c patients We cannot agree that there w119 sufficient etxlence in either casc to warrant dugno-13 of nephrotic my ndiome Thic first patient had been reported by Belote and Ratner (21), who found protein and costs in the urine The patient 11 as not clematous and the levels of scrum albumin and cholesterol were not recorded! Tubular nephro 18 dugno-cl at lutop Thu nccond cusu Wa reportul originally by Tremo uno (289) and although the patient lind features of the nephrotic syndroine (cdem prot inurin lypoalbumiinomi il the scum cholesterol level was not cleated 511 weeks after the onset of clemn the paticnt died Histologic cumminution rosenied severe glomerular and tubular damage Shearn and Prrofsky (259) noted that four of their patients hud a clinic al munt of the nephrotic syn drone A post-mortom ei bination of two disclosed chronic glomerulonephri ti Three of the four patients had scrum cholesterol levels within the range of normal and in the fourth an initial level of 420 mg/100 ml later decreased to 250 ing This patient is reported in full by Brunner ind us colle gues (35) as a cic of nephrotic syndrome Daugherty and Baggenstoss (63) ob scried seien 0758 with nephrotic odema arthritis of varying duration murhed proteinuria and with a rapidly progresic course Subacute glomerulo nephritis was found in tłuct and chronie glomerulonephritis in one of the four 0986» on » liom autopsis scri dong Bocak and Adlersburg (33) studied the biochemical features of the nephrotic ni ndlroing in a patient ill with SLT. They found azotem lon crum protein normal alphı 2 globulin ruled! buti globulin and a mishal ri e in gamit globulin less The lad of total lipid and neutral fat the greatly increase!

·LUPUS VEPIIRITIS 7 the beta lipoprotein was decreased and the cholesterol and phospholipid les cls were slighth cleated 6 HYPERTENSION Hypertension is suid to appear late in the course of SLC-usually in the presence of advanced renal discase (102 110) The inculence of hypertension associated with SLE varic from 9 to 214 cises (127) to 12 of 138 c15cs (110) In inore thin half of Hariey s ritients (110) who had hypertension rennlin olvement was so sei ere that nitro.cn retention hnd developed On the other hand blood pressure had always been norinal in five patients w lio dicd in urem Soffer and lus colleagues (269) reported hypertension in 13 of 55 patients and foun 1 tlint treatment with cortisone and ACTH mas not cffcctic in reducing blood pressure levels 111 REVIEW OF RFVAI PATHOLOGY 1 INTRODUCTION In the past twenty years Ilemperer Bachr and tl cir collcagues have made the inost thorough ratl ologic studies of SLE In 1941 they thought (151) that the changes occurring in collagenous tissues were primarily degenerative in nature Tlicy observed differences between SLE and rheumatic fever In rheu matic fesor proliferation of fibroblasts ss is the main feature frequently result ing in Aschoff body formation In SLC on tlic other land degeneration of collagen was the predominant histologic finding and the cellular reaction was not a prominent feature (141) In distinguishing between SLC and polyarteritis nodosa they pointed out that in SLC degeneratic changes appeared in the small se scls and capillarice lule rossels of a larger caliber were usually affected in polyarteritis no lost The changes in the connectic tissues in polyar teritis nodosa were also accompanied by an inflammatory reaction Associated with an infiltration of cosinophilic polymorphonuclear cells These changes were not acen in SLE It is apparent from reading their publications that Klemperer and his col league, modlified their opinions in tlic course of their studies on the so called systemic 'collagen diseases Thes came to regard the widespread alterations in the connectic ti sues is 1 manifestation of a single process involving not co! lagen but the ground substance of the heart glomeruli the skin and the blood vessels (148) Histocytoclicmical studies by Klemperers associates Gueft and I nufır (101) indicated that the fibrinoid material scen in tl c ground substance in SLF includes an unusual protein deri ed from tlc degradation of nucler proteins Tlus protein wae later characterized as a paraprotein which appeared as a result of the metabolic defect in SLE (147 148) Klemperer and lus co sorhers suggested tlıt the paraprotein impregnated the ground substance by translation froin the bloodstream into the resscl will (101 146) 2 GROSS RENAL PATHOLOGY llith regard to thic pathologic changes in the huncy, lupus nephritis was found in 28 percent (130) to 100 percent (193 246) of autopsy studies of pr ·8 VLEIIRCKE KAR PIRAVI AND POLLAK tients dying of SLr Ilarvey and his collcagues (110) found some degree of renal molt ement in 34 of the 38 patients with SLL on whom autopsies were made In most large series of autopsy reports glomerular insolvenient was found in or cr 75 percent (9 246 269 272) At autopsy the hidneys were usually somewhat larger than normal (12 151) Their surfaces i cre smooth and in comc cases were diffusely mottled suth minute petechial hemorrhages (3 151 261) They rescinblcd grossly the appearance of the kidney in acute diffuse glomerulo nephritis or malignant nephrosclerosis (151) Contraction of the kidney is un common in lupus nephritis (193) but was noted in cases of SLL dying with chronic glomerulonephritis (193 272 277) 3 WIRE LOOP LFS10\S FIBRIVOID ID IIS ALINE THROVIBI In 23 patients with florid SLE on whom postmortem eviminations were donc Baelir Klemperer und Schnfrin (9) foun i renal involvement in cgl tien Thuy found glomerulonephritis in tko glomerulitis in tl rec und in thirteen they found that the glomerular loops were stiff and thick These lc ions were the most impressite microscopic abnormalities encountered in tle kidney Baehr and his colleagues coined the term are loop to describe ti e lesions because the rigid walls of the glomerular capillaries resembled rather distinctly loops of bent wire The lesions were characterized by a patchy briglt cosinophilic thuchening of one or more segments of the glomerular capillarzes near the pe riphery of the glomerulus llith cosin stains the wire loop naterial resembled amyloid but did not stain with Congo red or take a metachromatic stain with crystal solet (151 272) Tie sie loop material was shown to be fibrinoid in Neumann s sense (207) It stained red with Azan decp inahogany brown with Bielschon sky silver stain (151) and red with tle pcrio lic acid Schilf reagent (1831 When stained suith Mallory Heidenl in stan tl e color varied from red to orange to blue and shades of purple were scen depending on the amount of fibrinoid swelling of the capillary tuft (3) The pure loop material did not glie the collagen reaction with lon Giesons or the Vasson s triclorome stain (151) The exact location of the fibrinoid wire loop material in the glomerular tufts has bech a matter of controu ersy It will probably remun an unsettled prol lem as long as the exact lustology of the normal gloincrular tuft is in doult Klemperer Pollach and Bachr (151) dissolved wire loop material out of the glomerular tufts with trypsin and found an cinpty space between the endothe Dum und epothelium Recently Churg and Grishman (51) lime studied thic locus of glomerular fibrinoid by phase microscops and the Mallory Gallego stan Their findings also indicate that wire loop material lics between the epithelial and endothelial basement membranes Thus far electron microscopy (80) has not soli cd this problem Although it has been emphasized that nire loop lesions were pathognomonic for SLE (9) Klemperer also obecried sic loop lesions in five of 43 cases of subacute and chronic glomerulonephritis (151) In addition lesions resembling mirc loops have also been observed in cclamp ia (3 232) scleroderma (3) dermatomyositis (3), malignant hypertension (3 151) and renal rein thrombosis (231) ·LUPES NEPIJRITIS 9 Another lesion observed in the kidney in SLE is the hyaline thrombus Hyaline thrombi were found in a small percentage of those cases in which Wire loop involvement of the kidncy was demonstrated They were seen within the capillary lumen and appeared to blend with the walls They were refractile homogeneous and cosinophilic and liad the same appearance and staining qualities as wird loop material Klemperer and his colleagues (151) originally believed hynline thrombi to be an extreme development of the fibrinoid alteration of the capillary wall but Allen (3) considered tl cm to be verrucal stellings of the glomerular capıllary wall 4 FOCAL NECROTIZING GLOVERULITIS AND LADOTHELIAL CELL PROLIFERATIOV Bizarre and pyknotic glomerular cell nuclei scre noted in association with evere wire loop changes In some areas of groas fibrinoid change obvious necrotic lesions were seen (151 264) Tlcse changes in the glomerular tufts presented 1 pathologic pieturi termod focal necrotizing glomerulitis Ti cac le cons resembled those seen in the local embolic glomerulonephritis first described by Loblein (11 172) in patients who died of subacute bacterial endocarditis Klemperer (151) believed that focul glomerular Decrosis and the are loop lesions were different grades of the same procese He related the des elopment of the lo ions to the intensity of the process and noted that focal necrosis of the capulları tufts might occur in the absence of wire loop change However Klemperer pointed out that the development in SLE of focal necrotizing glo merulitis is not relate to the presence or absence of verrucous endocarditis of Libman Sachs Stickney (272 274) studied the kidneys of 15 prtients who died of SLE He observed that the most common pathologic lesion in lupus nephritis was an in crease in the number oi endothelial cells in the glomerular capillaries Prolifera tion of the c cells was found in seven of the fiftcen cases He also observed hya line thuicl ening of the capillars walis in five of the cases but noted the wire loop lesion in only one 5 HEVATOXILIN STAINED BODIES Hematoxy lin stunel bo lies were first obscrı cd in the heart valves and salve pockets in patients with atypical verruco is endocarditis (103) These «mudgy diffuse lavender staining amorphous bo les have also been found in the kidneys of patunts all with SLE (149) They were seen lying free in the lumen of the glomerular capıllarıcs (149) in the intertubular capillaries (104) and rarely within the substance of l yalınc thrombi in the glomerular capillary lumen (51) Tiey were ensili distinguishable from pknotic or lysed nuclei (kary or rhexas) hlemperer found 1 cmatory lin bodies in the kidneys from 41 of 45 cases of SLE (140) He and his colleagues did not find hematoxylın bodies in acute or chronic diffuse glomerulonephritis rheumatic or bacterial endocar d ·10 VUETIRCLE LARK PIRAVI AVD TOLLAK them in patients with hyperglobulinemia (66) Hokes er most authors believe thnt hematory lin bodies constitute a reliable criterion for the diagnosis of SLE in butopsy material (104 150) The hematous lin bodies were thought to be derived from the nuclei of fibroblasts macrophages lymphocytes and poly morphonuclear leucocytes (101) They were found to be Feulgen positive methyl green negine and strongly ab orbent in the ultraviolet spectrum at 2337 Angstroms 17 en they were treated with trichloracetic acid they cre found to lose the ability to ab soib ultraviolet rus of the wine 171c length and to become Fculgen negatic (150) The above stuning reactions suggested that hematowy lin bodies w crc composed of depoly mcrized desoril onucleic acid (150 233) Speeral studies Tare shown progressive degradation of the desoxyribose nucleic acid of the nucleoprotein and ultimate disappearance of the nucleic acid molecule (104) Morphologically (25) and listochemically (104 150) they were found to be similar to the smudgy purple glomerular liyalıne thrombi (31) and to the phagocytized musscs sccn within the Hargruvcs s cells (109 149 150) 6 SUBACUTE 1D CHIROVIC GLOVERULONEPHRITIS Typical subacute glomerulonephrits with cpithelial crescents has been ob served in SLE by numcrous investigators (63 151 167 272) Daugherty and Baggenstoss (63) associnted the histologic cudence of typical glomeruloneplını tic renal lesions with the clinical des clopnient of the nephrotic syndrome in their patients with SIT In this type of glomerulonephritis ticy foun 1 prolifera tion of the endothelial cells of the capillaries In some instances they also noted fibrinoid necrosis of the basement membrane and mirc loop changes 7 INT OLIEVEVT OF TUBULES INTERSTITITY AND VESSELS Tatty degeneration of the tubular cpit elium is seen in the lidneys of p3 tients who lind the nephrotic syndrome due to lupus nephritis Tle fatty vacuo lization was associated with changes in the glomeruli (35) In reviewing the literature we noted that interstitial edema w9s rarely mentioned Focal inter stiral infiltration with lymphocytes plasmı cells and ) istiocytes occurred fre quently (151) but this findmg carried no more significance tl an in general autopsy material The renal arterioles i cre not infrequently involved ind the lesions of SLE uere reported to have been similar to those seen in inalignant nephrosclerosis or polyarteritis nodosa (12) Pyelonephritis (180 277) renal ab cesscs (126 269) renal infarcts (272) and chronic arteriolo nephrosclerosis (245) have been described in 25 ociuton with SLI 11 REVIEW OF TIC LTIOLOGY AND PATITOCENT'SIS OF THE REVIL LESIONS IN SYSTFMIC LUPUS ERYTHEMATOUS The ctiology of systemic lupus erythemato us remuns un olied T1 corick regarding the nature of SLE hare follon cd fashionable trends in medical thouglt In turn drithesis tuberculo i syplulis and other infectious diseases focal in fection auto intoucrtion from the putrid proclucts of digestion ind allerg ·LUPUS NEPHRITIS 11 have been blamed In recent years it has becoine popular to incriminate lıyper immune reactions to the streptococcus dysfunctions of the pituitary adrenal axis and stressful life situations More recently it was postulated that in patients all with the collagen diseases the proliferation of plasma cells in the tissucs and the elevation of gamma globulin in the serum had pathogenetic Significance The cffcct of tl e elevated gimma globulin would be to produce systemic injury of the connective tissues For tlus reason the collagen diseases have been classificd as dysg immaglotulinemias (69) Early observers suggested a varicts of local and traumatic causes for the ap pearance of skin lesions in lupus erythematosus (143) French (53 221) German and Viennese (70 105 157 2771 intestigators supported the theory that lupus crythematosus was of tuberculous origin hcl (136) in a comprehensive re Viens of this subject s) owed that this view was untenable He investigated the po tmortem reports in the literature and determined that in only 20% was there any posibility of actie tuberculosis an l in some of these cases the disease was probably inactic prior to the onst of SLE Four years later he was the first to use the terın ystemic lupus erytl cmatosus (137) In 1919 Bart cr sugge ted that streptococcal infections might be the cause of lupus erythematosu (15 16) Since then miny cases lave been reported in which streptococci scemed to play a prominent etiological role (173 193 203) Blloto conserc 1 tl at the disci e was due to an ultramicroscopic agent (20) and Voolton and Clark claime i to have i olated virus from the blood of pr tients witl SI E (194) This has not been confirmed by other ins estigators heith and Row ntre (141) (mphasized the danger of removing or disturbing foci of infection if there were signs of activity in the disease Although positive blood cultures have been ohtunce in the terminal etages of the disease (176)-espe cially when seconlarly invading organisins may be expected to have been present-recent bacteriological studics have not supported the view that orgin isms cuuse SLL (1013 Crocher (61) suggested a possible endocrine ctiology The preponderance of SLL in women luis been attributed to ovarian dysfunction and to prugnancy (157) From a questionnaire submitted to 100 dermatologists it was concluded that pregnancy and no significant effect on the clinical course of lupus erythe matosus (73) Rose an? Pill bury (246 247) ol served a high incidence of acute disseminated lupus erythematosus in women during hetne menstrual life and emphasized the occurrence of premenstrual cracerbations of the disease Cas tration (209) and testosterone therapy (11) have liad no beneficial effects on SIE CI nical and laboratory findings consistent with SLE were noted in 15 percent of 128 patients with rheumatoid arthritis and lypercortisonism Half of these patients 1 ad euadence of renaliny ok cment as indicated by a bloo l uren lcu el in excess of 40 mg/100 ml cylindurii persi tent microscopic lemuturi or albuminuri3 or come combination of these findings (80) Klinge (153) was among the first to suggest that allergic or hypersensitivity reaction played an important role in the etiology of a number of diseases char acterized by fibrinoid degeneration of connective tissue Fox (79) ob erved the ·12 MUEHRCHE, LARK, PIRAVI, AND POLLAK onset of SLC follon ing administration of foreign protein Stoke Beerman and Ingraham (276) suggested that infectious allergic agents produced vascular allergic manifestations leading to lupus erythematosus Since then many authors (108 124 239 242 286 298) huc stressed that an antigen antibory reaction may cruse SLE and other collagen diseases or discases of reaction A po sible relationship to the Shu artzman reaction has been suggested by the recent studies of Brunson and bis colleagues (38 39 40) and of Booth Muirhend and Vontgomery (32) The widespread use of chemotherapyutic and antibiotic igents has been correlated with an apparent increase in the incidence of SLI and other collagen diseases —in particular, polyarteritis nodon For examplc Gold (96) stated that in approximately 87% of his patients sulfonimide or penicillin therapy preceded the onset of SL Houcier Bachr and Pollack (11) found no valid esidence to support this concept and concluded that the de clopment of SLC was coincidental to chemotlıcrapy or antibiotic therapy Teilum (281) suggested that the features of focal glomeruloneplıritis in SLE sere analogous to other changes which could be interpreted as part of an al lergic reaction—similar to the Arthus phenomenon He suggested thie possibility that the hypergammaglobulinemia of SLE may be the cause of the renal lesions Teilum also obscri cd certain similarities between SLE and sarcoidosis (285 286) and stressed the relationslup between the two Recently Kurnick (159) ) as studied the mechanism of t1 c Hargravers cell pole nomenon Hc concluded that an abnormal factor in the gamma globulin altered the cell membrane This allowed a protcolytic cnzyme in Fruction III of scrum to enter the cell 1 here it destroyed the protein inhibitor of deoxyribo nuclease The uninhibited desoy ribonuclea e attachel chromosomal de oxy ribonucleic acid which in turn changed into the depolymerized nuclear ina** *0 characteristic of fibrinod hy alınc thrombi and the Hargruvess ceil Jadra sol n (122 123) Stickney (272 274) Montgomery (190) and others (193) cup ported the view that some touc irritating substance produced renal damage (81) lo such substance has been isolated Vany other ctiological factors have been implicated these include nervous fatigue (74) the pleuropineumonia group of organisins (37) hereditary syphilis (221) lend intoxication (174), and a special affinity of the 19-cular system for the ferments of lymphocytes (87) The reports (68 119 223 238 257) of a syndrome indistinguishable clinically from SI E occurring during the treatment of hypertensi e patients with hydral izinc re of some interest to those who believe that SI E15 1 discree of renc tron intoling ground substance and connective tissue T) esc reports strengthen the hand of those who belicve that the upsurge in the diagnows of SI L is the result of a renction in certain sensitiie individurls to antobiotics and can be related to the widespread use of these agents The fact that the SLT like aj ndrome subsides completely when hy dralazine tl crapy is stopped indicates that the reaction docs not produce the discase SLE de nouo It mar unmı h subclinical SLE It may provide a clue to the etiology of SLL but it is quite posible that it is producing ? syndrome aluch ne classify as SI C I ccausc of our impcrfect knowledge of the clinical spectrum of the disease and even mort ·LUPUS NEPHRITIS 13 because of our profound ignorance of its cause Nevertheless, Reinhardt and 1 aldron (238) found acute collagenous necrosis in the skin biopsy of one of these patients and Dammin et al (62) reported a case with LE cells ante mortem and postmortem in whom they found renal splenic and other lesions consistent with SLL Comens (57) h is produced a syndrome rescmlling SLE by the administration of hy ciralazine to doge Hargarses s cells were demonstrated in the periph eral blood of the e animals Ho conclu led that pathologic specimens of the kidneys revealed changes consistent with those found in disseminated lupus crythematosus Altl ough fibrinoid degeneration was found in tuo specimens we cannot agree with this conclu ion The wire loop lesion demonstrated does not resemble that seen in biopsy or autopsy specunens from patients with SLE and the lesions morc pecul ir to lupus nephritis did not occur in the lidneys of these hydralazine treated dogs In recent years clinicians have become aware of a new organ system in the body-the ground substance (substance fondamentale or grund substanz) and its associated connective tissues The dc clopment of new tests for the study of diseases involving the ground substance does not mean that we have the right to «cparate etiologically discases of this organ on the basis of these tests The presence of the Hargraves s cell and its associated phenomena implics to many people a definitive diagnosis of lupus erythematosus but tlus may not be the case We do not as yet recognize the limitations and usefulness of any single one of the miny LE cell tests presently being used and it would be unwisehistorically speaking and at the present time—to classify cieryone with a posz tre LE cell test is having systemic lupus erythematosu (129) All of us who are old enough recognize that we treated many patients with poutne 1944cr mann tests for syphilie despite their set ement denials that an opportunity had ever arı en for them to contract this vencrable discase llc non recognize to our clismuy that 30 years after Wassermann described his te toc were treating un necessarily patients u lio suffcred sth infectious mononucleosis SLE and other discascs in which the Wassermann reaction was positie Altlıough new instru ments an i new tests u uy alluminate a discase process the physician produces jatrogenic diseascs wien he uses them to make injudicious deductions there from-deductions which are invalid because the test is not understood or bccausc its limitations have not been worked out Unfortunately there is no such thing as a pathognomonic sign or test for any disease There are always exceptions which prove the rule Some now consider that dyogainmaglobulinemia is the cause of discases which aftcct the ground substance Two hundred years ago it was popular to think of fevers as being tie cause of a variety of infectious diseases We now understand that fevers are the result and not the cause of infectious diseases and it may well be that dysgammaglobulinemias are the result and not the cause of diseases of the ·14 VUEJIRCKE, KARK PIRANI AVD POLLAX ogs distinct from that of SLC need be invoked to explain lupus nephritis Serial biopsy studics of the kidncy provide a sure and simple method to clarify the his togenesis of the renal lesions It is our hope that in the future the application of play sıcal and chemical methods to renal biopsy specimens may further eluci date the reactions of the ground substance in tlus discasc V METHODS OF STI DY 1 SELECTION OF PATIEVTS Systemic lupus erythern atosus presents itself in mans a bizarre guise Its course is variable and is usually characterized by acute or chronic episodic all nes followed by partial or complete remmissions There are no clinical or labora tois findings peculiar only to this discase In cach patient the diagnosis was made on the basis of 1 broad spectrum of clinical and laboratory findings in which the clinical history was most important Thirteen clinical and nine Inboratory cuteria were used to validate the selection of patients for this study Ticy are set forth in Tables I to III Tlurts thrcc patients were carefully selected on the medical scrvices of three hospitals (Table 1) Fourteen Negrocs and nineteen Whites were studied at the timc of their entry into the study, the ages of tlıc 28 females varied from 11 to 61 years (nerage agc 28 9 years), and the ages of the five malcs varied from 15 to 47 y cars (21erage age 32 2 years) (Fig 1) Of the thirteen symptoms and signs consulered by us to be important clinical characteristics of SLT nine or mort were found in 30 patients and in no patient were fewer than sesen noted (Table I and Fig 2) At least five of the nine laboratory criterin ucrc ob cried in 32 of the 33 patients (Tables II and III and Figure 3) Thirty tno patients had a face rash and 31 suffered from insolvcment of their joints Every patient had recurrent bouts of fever and in all the clinical course is characterized by clacerbations and remissions Evidence of involvement of the cerous membranes either of effusions into thic scrous culties or of recurrent pleuritic and abdominal puns was noted in all patients Enlargement of the lner sploen or lymph nodes as found at some stage of the illness in every paticnt Characteristically these ucre quociated with exacerbations of the clinical illness and the size of the affected organs returned towards normal as the clinical state of the patient improved The cry throcyte sedimentation rate (ESR) was in ariably elevated Anemia or leucopenia was observed in 28 patients In 31, the scrum globulin level is el 1 ted and in cery patient the thymol turbidity te t was positic Har griics s cells were found on examination of the bone marron or periplieral blood in 26 patients 2 THE STUDY OF RF AL FICTION After the diagnosis of SLL had been made the patients crc studied in hos pital and were followed in a special clinic The function of the kidneys 11 18 14 ·LUPUS NEPHRITIS 1s sessed by the following tests Unalysis In ery asc cu ly mo n ng epe mens of ne were exam ned slo tls nf er colection by one of us (RCM or EP) Cean vo dcd spec mons from ma e pat ents and cathe er spec mens from female patents were exam ned A po ton of eacl sse men s subm tted for ba ter olog c culture Flu ds were re cted fo 19 hou s befo e tl e col le ton of the spe men for ur dalyss The spec fic gruty of the u ne as te ed at room nperatu cs the stanla iz 1 non p er Tie poen was est matcl scm - ont ut ely u ng te u fosal cylc ac d S per n nute and he on entra ed scd m nt resu I ended by agt ng a a fe drops of ur ne It ist on exam neł mcro or alls w th lo and ) gh power m gn fin on Polar ze 1 Ight vas u d for he den ficat on of an so rop lipods b Tess of Renal Funct on ) The spec fi gauty of te ne tas measu ed fol on ng a 1 od of 14 hou s of Ad lp at on l'or spe mens of u ne we e collected and the max mum spec fic ga ty eo led Uca clac (188) se e determ ned for a sngle ttro l our pe od in a erage u ne flow of at least 2 ml per ma te as atta ned a most p ents Te esults re e rejo el a 2 pe centage of a e age no mal enal fun ton ( 5 ml mn 100 wh n tl e ur ne for 39 er n 2 nmn 51 ml mn 1000 when the r De Mo $1 thun ml mn) ) PSP CE e on 6 ms of phenolsulfoon tale . I'SP) as oe ed a ra eno af a wa er lo lb d been g ven 219) The bla ller was empt ed ompletely 15 m nu e li er and he ex eon of PSP as meas el on a Coleman Juno spect opl otometr In a fe ns an s meas emen s of effe t e renal pl ma flo (ERPT) glon eri a fil nt on (GIR) and t bular ex re o y mas Tn) cem de bv ng nu1 h and -nữ ad (P4H) od ng to the me hods of Gold ng and Chis (98) Bolcm al Eram nat ons of the Bloot In all ca es the follow ng bo hem lex m na tons of the blood ee done blood c eat n ne b ti e me hod of pc ers (" bool u nog n b thc Con av me hod (58) blood non pote n n trng nb the me hod deser bed blond McMeeh n 155) se um pot ns b the Coln mc hol (121 305 Teto 1 SC uim hol eo wa de emned by a mod fi at on of e Boo netlo!? 0) the th mol thit a od ng to the me hod der bei hy si nk and Hong ol 8) Wen ad d le serum bod um and po a s um were measud) an nerals nu d Aame plo ome C od swee measu elb the me bo i of Shales and S Iles (254) and the CO om bong po e ky he me hod o Van Sze and Ne 1 (999 The so um ho ne se 196 Iete mn innt nepb o cand pe donephrot csnl ome PP t 3 IE LATOLOGIC METHOD 5 ml s mple of enou boot vas ob nel s ng po a man anmon um oxala e or n as an co gul The lemo 2 est ma ed n and I 1 robe he a oct and the ers hro te sedimenta on rate was meas odb en ethodo Woby 301) IU es ve e oun ed n both chambe 8 of an mpo ed Neuba c ) ema tom The og lat on mes fc e mersu ed by the mod fied method of Lec anl he 220 anl the 11 ed og t mes by the me od of Duke The po homb atne nc ed by Q & one tage method (235) Dect and nd et Coombss tess we e pe fo mel on all pa ents (59) Ica non lo lla g aves Cells Clo ted bloo l nr Lone marron was ncubate 1 fo one halt to toho The clo was bohen up and the le oytes were conced a cd and smea ed OD les and ta ncus thrght as an T cold s se e se hd fo ati ast 5 m nute oder ·TIBITI Clinical data on 33 patieni: ill with systemic lupus erythematos is on whom renal brop81c8 uere lone Durat on of D sea e Enlargement of Seros tis Skole ons Case Patents Int als No Sex Age (Yrs) T'athologs Diagnos's' Date ol Pre Post B opses study sudyll (sr) (Mos Remarks Rem tent Cun cal Course F1 st renal b opsy normal 1 NIF 23 2 8 1/ 0 55 N + + + 0 + 0 0 0 + + 0 0 0 Onset Acute lemolyt c anem 2 D MeK 29 15 3 6/18 65 N + + + + 0 + 0 D + + 0 + D + Mixedema Vague as mptoms for 10 years 3 YW F31 9 13 9/3 51 N 1 25 53 N + + + + 0 0 + 0 + + 0 D SL n bopey post e 1 EDF 24 11 18 12/17/511 9 B 34 N + + + 0 0 + + 0 + + + + + Thrombophleh tas Raynaud phenomenon for 8 years before otler symptoms 3TH F 19 110 + 8 1/12 55N S/19 S5 N + + + + E + + + D + + + D) #IJST 21 1}s + + + + + + + + + + + + + + 11 7/14/5+N 11/21 34 VGN (1) 5 27 53 VG N (1) Skn lopsy Ispertyto duom poste 7 VT F 39 23 + + + 0 + + 0 + + + + 10 17/53 N 9 9 54 N 8 5 55 N + 0 + SL a bogey pou ti e BMW F 31 11 9/14 54 1/10 55 + + + + + + + + 0 + + + N + 0 Ded Acute exacerbat on wth throm Locytopenis and convulsiotu JAV 15 9 53/1 65 + + + 0 0 0 0 + + + + 0 race Taah for 9 years before other symptom Two pisodes of hem Tileg a Thrombop! lebt.

·Fural renal bropny normal + 13 10 0 + 0 Ver 61 + + 0 2312 + + no Sjøgren syndrome ance 1939 Poly arterit. noda on muscle to ay 19 S1 6 17/55 + + LDF 3 + 0 + D ed of poliomyelitis + 0 + 14 5 3 51 V 1121 51 N 7/27/55 VGV) 4 FREE Fırat biopsy prolurratze plomerultus + 12X KF 30 + + 12 + + 0 0 + + + U + + + 1% 2/28/54 IMG (1) 0/29/84 IMG (1) S 25/55 MPG (1) Skin ROMY poet ve Il matro fever Ar caldmatol a mirmus VWF 21 2113 + 13 + + + + ++ + + + D + + 0 23 9/29 53 PVG (18) 2,1/51 PVC ) 5/10 51 | PUG N ( 18) 5,716 55 TVG Nx) 1 14MY F 17 + + + + + + + + + 11 10/15 54 PVC ? x) 1/31/55PVC (x) 0 + + + D Tulere lejn link abaceas developed te (ni cortione F1 st dropay mabanovo plomerul 118 15MT F11 11 + + + + + 0 + 15 5/17/541 3/19 35 MG () + + + + + + + Fuce rash for 8 years before other mptoms Shan bropy po 1995 16 CKY 32 111) 15 + + + + 0 0 6/12 54VG () 0/17/55 MC (0) c + + o 0 17 FWF 48 1313 26/20 55 WG (*) + + D 0 + 0 + a 0 + ++ 18 D F 31 1713 + + + + + + + + + D + 0 8 11/11 55VC 18) 5/11/55MG N (13) 19 BJ F 11 a т + + + + 14 6/15 51 MPG ( LR) 2/10/56MPG N( x) + + + + + 0 0 ·TABII Kontinued Duration of Disease Fnlargement of Serositis Skin Lesions Case Patient Initals Vo Ser Age (rs) Tathologic Diagnosis Date of Pre Post Biopeses tudy study (7)(mos Rem flent Cinca! Remarks asino Lymph Dodes Raynauds Phenomenon Myocarditis Spleen Live Pleura tirel biopay membranous glomerulut15 OPY 31 1 3 55 VG. (1) + + * + + + 0 + + + 0 + + 0 21 D 11 T 11 + + + 7 2/26 55 MIG (16) 1 55 MON (8) + + + + 0 + + + + 0 0 Firat bonny membranova plomerulonephrite 18 22 V V 17 11 + + + + + + 0 + + + 0 + + 0 92/28 55 VG N (18) 8/16 55 VG NR 11/11 55 MG NOR) Arthritia for 10 years before ut er man restations of SLI 23 ES F 33 6 + + + + + + 0 + + + 0 + 0 + Nephrotic drome D ed in renul failure 18 7/11/51 VG N (R) 10 5 51 SONOR) 2/17/55 CC NOR) 9/10/55 CG N (da) i 11/56 CC. V(dr4 21 W 11 16 1117 3 16/7 55 VON (1 x) + + + + 0 + t + + + 0 0 0 0 Ne; 1 rotic by odrome 25 RVF 99 13 12 5 6 51 50 55 VPG VIR M N (1 41 + + + + + + + + + + 0 + + Died with convulsione an1 coma urems and electrolyte 1 sturbance 21 2 10 1753 YIK V (1 x} 14/12 53 SON(R) + + + + + + + + 0 + + 0 I) ed in renul futuro + + 27 M127 1 1 55 VIGN (1 x) S/18 55 MICR) + + + + + 0 + + 0 0 Nephrotic syndrne Dedremia Electrols te distrulunce and lemor rlingCherputiti ·+ 0 11451 MPG N g& 11 26 6 + + + + + + + + 0 + Pseudonepl rut ca ndrome WR + 3 yeur's earl er Dedi myocardit. + first dropsy rukarude or cronie glomerulonephrt. RC 29 31 Nepl rotic an Irome To Akin + + + + 0 + + + + D 15 6 7 51 SC NR 9/27 51CGNOR) 6 21/55 CG NOR) hnny 30 A4 27 + + + + + 1 1/18 55 SO, V(B) 11/10 55 SG V (d ) { + + + + Pseudoner lur tic androne D ed in O + 0 0 +1+ uren 31 RZ V 21 2413 + + + + + + + + + + + + 0 0 21 918 53 SG V (dB) + 23 51CGV (dk) 9/10/55 CG N (d & Nephrotic syndrome Dud in renal failure 32 BD) FB 0 | TS 5 SGN 1 %} + + + + 0 + + + + + + + 0 + Faudonephrotic oyndrome Died with Duria and utem 33 D. 38 15 2 2 18 55 CG N ( 1) + + + + 0 + + + + + 0 0 + 19 • N N TITANI Innlequate SON-Silurite al mer lonephritis. IC-Proliferative glomerult. VC CO N-Chronie glomerulonephritua Ven runo 18 kl mer litis () Zocal (1) Local I N-rol feralne glomerulonej i ritua MC N-Membranous xlor verulonej na (d)-Diffuse (x)-Generalized na-Vept roscleron 4-Autowy ·TABLI II Unnary fin lings and tests of renal function in 33 patients with systemic lupus erythematosus Macroscopic Urinalys s Creat. Sn Grt Durat no of Sex Disease and Date ol Age Pre Tost Bior sy (study study (yrs) (6) Case I'at ents Mo Int als Pro te nur a (Plus Un ts or Patholog Dagnost Non Urea Conc Nitrogen Protein Stroken, Dune (mg/100 (mg/100 Test ml) m!) Max Sp GT 15 Min Fx PSP (Total Dose) Urta Clear ance Text ( ANRF) EI/24 (mg/100 Hrs) RBC 11 BC Casts Farat renal biopey normal NK T 23 1 2 8 11/20/55 N 0 0 0 28 09 3 I 021 31 51 2 D Vek 5 29 15 8/18/3SN + D Occus onal ng 10 10 1 036 23 56 3 VWd F 31 12 973 34 N 1/"5 65 N 13 0 0 ܘ ܗ 3-5 5-8 Oreasonal WBC (few) 3+ 27 11 10 1 028 1 026 33 27 A9 103 4 PD F 24 11 JB 2/17 541 9 & 04 N 0 0 3 0 or 26 31 8 11 11 09 1 0989 1 032 25 22 100 110 Ocrsonal 5 T 11 T 19 Na 8 11/12/55 N 5/19 65 N 0 9 11 02 0 53 i Occasional Ocras ona) 31 26 1 028° 1 030* 17 41 8 19 F 20 111 0 D 14 7/14 51 N (1/21/5 so N a f| 5/27/55 VG V (1) 0 15 5 0 Vany gran las both on i cellular Cecation 23 17 10 1 D 1 032• 120° 38 32 28 21 17 91 02 09 0 10-12 7 MT 3 0 0 0 O 08 23 10 17/53 N 199 31 N N 27 29 17 1 034 1 022 1 0"0 Occasional Ocensonal 50 25 24 72 76 9/5/55 04 5 3 09 % VW T 31 0 12 11 9/14 31 V 1/10 55 N 8 23 55 ) D 3 5 1 2 Orcus on I Occuen! {ranular 32 24 31 10 | 3 ! 1 01 1 021" 1 020 3+ 31 76 112 +++ 15-0 9 IA M 15 O 5 3/21 55 N D D 27 10 08 1 025 1025 32 115 19 VIS 2962 13/19 51 ts 8/17 351 06 0 Cronular ranular os al fat bod 39 37 15 19 09 1 3 100 1 0169 "T 11 53 38 11 11) L 13 Siz O 0 Occns opal 25 08 18 1 5 8 54 N (11/21 51 N 7 2/55 10 VODA 1 020 1 020* 1 015 6 150 + ·F 9 y DT plomer 09 1 K F30 0 51 9 B5 5 5 PG PA PC 05 OS 05 :) 3 4 2 3 30 2 0 3 9 20 MO ปี 6 dea 2 ec F 3 R9 * 29 5 29 PG + 23 5 9 0 9 0 030 B 2 B 8 5 PG 8 5 PN 3 5 26 55 PGN X 0 3 90 0 0 2 02 8 02 0 D 0 3 5 3 9 0 55PV 1 6 38 K ce 02 02 ܚ ܟܕ 99 0 26 80 CO DP mbre 5 P 0 0 Оссан 3 0 25 090 090 55 > 08 0 0 0 09 G C 2 5 16 5 که 0 29 0 OS 21 3 B 9 030 00 no 7 C F 8 2 6 0 55 25 2 0 36 3 0 T 8 0 35 50 5 5 55 010 G GN 0 0 9 28 3 3 0 3 G 0 0 50 R 90 3 B 6 55 0 0 6 PG PC N 3 60 35 2 U 0 0 0 55 8 9. 8 3 07 20 F 3 9 8 G 0 8 3 3 0 0 80 2 7 2 26 55 2 32 2 0 PG GN & R 3-4 0 07 00 57 2 + 2 0 r ado tab 2 me 5 DS 9 고 | 1 8 55 GN 8 55IGN GN 8-0 - 5 08 06 +++ 80 0-30 2 9 YEn la and ya & an & ea da 08 3 2 25 26 2 52 3 103 ·TIBII 12ontin ie! Pro te nura croscopic Ur nalyss (asc Patents Vo In i als her And AC (45) Durat on of D) wave Date of Pre- Tostvi phony study (yrs Patholog bagainst plus Un ts or Km/24 Jins) Non Urca Creati Sort1 13 W Urca ons Clent 1 xc 1P I'rolet kennt trogen Teat ICC 1". Total img 100 RONax Test ml) Dose) Spar AVRI) mos RBC 11 BC Casts b pay memil ano 18 giu ne ulanes 5 23 r33 6 15 7/11 5 N (& 1C 5 SINON (IR 2/17/55 V (1 x) 9 10 55 (G VIR 1 23 76 ++++ #10 25 40 50 40-50 25-50 Meer seorc Wony 35 35 17 56 Vanylsi e ka ins fatty Vany 1yal no futty cell lat disny sal ne granular Vanylyal ne kran lar cellular OFB 10 17 27 69 13 28 13 47 78 I CIR 1 014 I 012* 1 010 0 $ 11/56 (GN (DKA ++++ Sany Vany Il ne pran lar cel Iur 119 74 13 0 1 010 24 W 11 V 45 3 4 7 65 NIB D2 -- 3 Iyul ne grupular celular 38 20 1018 16 35 25 F 29 17 15 26 51 5 9 55 SONIA) MCV (1 x) 8-10 0 40-50 15 39 &!D (ranular le cry to Hvalne zrunulur os al fut tulee 1 028 100 2R 25 US 4R 150 1 22 21 3 10 17 33 VIN(lx) 12 12 53 N (1 x) ++ 5 ++++ 15 15 Crah Jar el lar Cronular Iyul ne elular 08 08 5 1 00 I 014 28 29 27 MI + 27 Miz 1/4/55 VION ( k) 5/19 % VIC V W k) +++ ++++ 35 JIyal ne grun Inr cell Ihr 209 1 010 29 I 28 6 0 11 24 51 VISN (1 x) ++++ 15-70 Cronular -] iar ksal ne osat fat 43 20 09 1012 40 #b pay anba ir or ch on cglomerulonephria ng RC 31 6 15 16 7 51 SON ( IR) 9/27 51 CCN (1 x) 6 21/55CC (1) ++++ +++ 23 25 33 D 5-8 0 Iyul ne kranulur oxsl fut lod co 11yal no kranular ou al fut lois Ilyal ne pranulat fatty 80 59 31 37 36 31 17 1 7 1 018 101B 1 011 22 7 15 10 27 #2 301 27 1 1/18 55 C (x) * *186 X xl 1 2 +++ 10-50 Vony 40-50 Veny Haty bylne Kran lur ell lar 39 17 *1 31 Vany 1010* 1 007 31 K 7 V 21 21 19 16 53 SC (I * 23 51 CC (I => 10 10 20 10-15 6-10 10-13 06 101 Iyul ne granular 01 u fut I do ron af Alular RBC Exd Cran Jar REC sal ne 14 09 3 2 81 1 020 1 013 13 17 55 COY (1 e) { ++++ 40-50 B- 216 23 S I 011 ·5 11 32 BD 54 1 015 15-10 15 51 AN(BA 18 16 8-10 12 (ranu sr yalne RBC o al fat tod es 4 ! 012* 2 IB 3915 3! DJ 18 55 Ndf 40-50 ++++ 78 83 97 la troud (ran ar Iyal ne cc leucoeste S to ma PG Pol ferat e gl ner 1 Inade i ate VG emira gle ur N Membrano , glomeru ones ir tu ts PGN It ferat ex neruloner, ((N Clone glomerulo epirty (1 & Nute glome I ne Foc ! Lo a (11 ff ye ( enera re 1 as Neph one proga Autorey D Ded NO to ay Inn #nwlch tepec fic gras ty once trut n test was done are marked wth an asterisk In utier nstances the f gweg en teh luat recorded apec fic flats 33 ·TABLE III Other pertinent laboratory dala on 59 patients with systemic lupus erythmalosus on whom renal bropsies were done 21 Duration of Disease Case Patents Sex and ARE (11) Cholia Thymol in tuls Date of Biopsy Pathologic Dagnosis sm/ Serum Serum (ho Senin Serum sterol Albumuo Globulin ester ase (mg/ (gm/ 100 ml) 100 ml) capit 100 ml) units/ hour) ESR Coombs & Test Wasser- Har man graves $ Test Cells Direct Indirect Turbid Test Ilemsa tocrit HBC Post study study (mos) [/mma) men hour) First renal biopsy normal 1 NI F23 2 8 1/20 55 N 28 23 12 7 + 0 0 + 42 3500 35 2 Dve 2915 3 9/18 53 N 419 49 62 58 Q 0 {{01 31 VW F 31 4 12 V 9 3/54 125 $5 332 308 si 21 31 47 0 0 0 0 097 39 10 4000 29 1 LD r 24 11 2/17 34 9 8 SI 179 159 29 3 2 70 + D 46 34 40/10 41 37 + 5 FI F 19 8 V 1/12 35 5 19 55 217 210 36 37 3 0 51 88 + 0 0 + MUEHIRCKE, KARK, PIRANI, AND POLLAK 40 40 8600 5800 24 34 8 r24 134a 36 + 0 0 + T/14 55 N 11/94 35 VIC V (f) 5 27 35 MG V (1) 392 312 33 20 32 31 143 11 0 30 22 11 5100 3100 5000 34 34 15 0 0 7 VT F39 3 23 10 17 339 9/9 54 N 8 5 35 0 0 0 240 258 *50 43 38 29 23 36 12 0 13 8 + 35 41 40 8350 5000 900 24 31 46 Mir r31 447 11 240 390 29 36 0 60 9/14 54 1/16 55 831/35D 34 35 27 B D N 0 0 + 32 4D 25 12000 J 1300 20000 13 13 39 V 15 9 5 3 21/35 240 30 37 22 0 0 D 19 8900 30 50 MS 13 ns 8/19 54 6 17 $5 290 308 3 2 33 31 0 12 7 98 0 0 + 39 6000 5.300 15 15 11 LD r 11 14 200 150 10 5 18 55 11/21 54 7/12/65 VGN (1 x) 1: 13 3 13? + 0 + D 23 31 31 ·Fabopsy polvere 3 2 I K F 30 18 2 28 51 f 0 0 D + PMG PMG MPC 9 28 54 5 25 55 25 227 24 4 6 +7 51 3 B 30 3 2 19 5 10 3 12 7 36 12 40 7000 7900 0300 39 38 3 M I 2 2 23 22 3 + 0 U T 7800 9 29 53 21 3+ 8 10 5! 3 26 55 PIC& PMG I) PMG N15 PMG NI 8) 220 30 392 38 31 3 2 +1 4 3 2 3 4 3 34 36 32 11 7 14 WEM r 17 35 48 D 0 0 15 34 31 55 0 PIG IM 5000 + 37 230 3 5 47 22 5 32 Fb pay mo anous y Ma 5 MVP IVF 1 5 30 5 7 51 3 955 76 185 MG (1 G 37 12 4 136 3 36 4700 5000 0 0 + 6 Ск V 32 5 30 6 12 55 6 17 55 MC (11 VG (If 0 0 0 15 0 + 57 81 97 57 12 12 35 LUPUS AEPIIRITIS 17 F +9 12 3 2 5 20 55 VG (L & 37 31 37 0 99 4 B 0 0 0 U 39 3900 38 8 VD F 31 1AZ 8 1 11 55 NO 18 19 40 43 6 0 0 + 35 4100 12 64 Kuhn u 32 Kahe 5 1 55 NG N 316 4 12 * 4400 13 19 BJ F 11 Ma 14 & MPC MPC N 38 10 6 15 31 2 10 55 + + + 0 216 125 12 57 31 30 8 0 $2 3 00 6500 20 PM г 34 912 8 1 3 55 MG ( 185 30 43 94 0 0 + 35 5000 36 21 DB F 44 2 226 55 7 1 55 19 + MPG (8 VG N 8 07 21 38 39 0 0 36 50 4000 49 34 5 38 F stó pey m n bra noua ome u on ph JV M 4711 9 32 D 2 28 55 8 6 55 11 4 55 + MG VIR VC NIB GNIS 251 281 210 02 16 4 39 38 46 0 45 38 37 31 5100 4100 3700 54 43 30 20 ·Durat on of Discase Serum Case Patents No Initials Sex and ge () Date of Biopsy Fatholog Dagnos so Serum Cho lesterol img/ 100 ml Hema ESR HBC Coombs s Test lasser Har mann gravess tocrt Test Cells Drect Ind rect Serum Serum Chon Th5 mol Albumia Globul nesterase Turbd km/ gm (srk 100 ml) 100 ml) unts/ Test hour) Pre study (13) mim'mm/ rost study (mos) hour) Forstb opey memb anous plomerulonephrutu 23 IS r33 18 2 27 2 2 17 + 0 0 0 1/11 51 VON ( 18) 10 5 31 SC (1 x) 2/17 55 CV ( 2 9/10 53 CGN () 1/11/564 CGN (d g) 595 306 36 315 251 090 0 75 DR3 6 20 25 25 23 1000 7100 1:00 1100 8000 5+ 0 29 17 2 3 12 32 5 3 17 - 21 W 11 148 15 3 8 7 55 VG N() s) 450 26 36 32 + 3 D 1c D 30 2800 25 RN F 29 1142 12 5/26 51 5 9 554 MPCN (1) HGN (18) 232 110 35 27 39 9 0 12 3 12 3 + 10 50 14600 30 39 31 26 28 FV T 27 2413 2 215 10/17 $ 3VIGNOR) 12 12 53 | SGV 8) 19 7 + 0 + 35 4500 12 25 39 27 MP 112 1 55 VPG N (18) 5/16 554 Wrc (1 x) 319 20 37 11 2 0 0 0 + 7 1110 99 41 126 6 0 LUPUS VUPIIRITIS 11/°4 SLA VPG N (1 x) 165 28 31 50 + + + 50 31 Iroopey wacale or diren e plomer dokopi (o 29 RC 1 34 6 15 112 D 67/54 9 27 58 5 21 35 29 31 D U + BCN g) CGV (g) CC ( 18) 12 420 306 300 13 29 23 38 34 37 3500 4500 31040 1 17 30 BS 27 912 1 38 55 SGV (tg) 2/10 554 SC (1 x) 136 17 30 D 39 93 3 2 21 0 0 + 4310 13300 8 31 31 RZ V 21 2013 21 O 0 0 + 9 19 53 SGV (DK) 4 23 64 CGN (8) 8 17 554CC V (d ) 100 3431 52 13 1 2$ 31 8 30 18 18 31 5 19 3400 6000 5X0.0 36 7 7 32 BD 19 92 0 11/15/5+41 SGN) ) 132 23 12 8 + 24 35000 20 31 DJ 13815 2 7/18 55 CCN() 123 35 65 o 0 + 0 23 DI 30 Nrnal of Innpirto Vollra I-Inaler ute ING-Ir 1 ferat se al merul 1 a SEN-hne te glorier foretr1 CV - Aut 1 11-Denaulose -Sea Tano aner tas ICV I rol ferat se gluw.sul tert. ve V-Verol ruhoun met 1 harts (1)-Focal {I)-lah (1) ff we (R) (rneral z ·LUPUS NEPHRITIS 27 the los poner objectic and suspicio cells were cymuned under the high do oljeetne A preparation was not called positive if only one or two al normal cells were found The Hargravess cell wie defineil 18 n rol moiphonucleur neutroplal with one or more Jirge inclusion bodies cionding the lies to the edge of the cell The typical inclusion boily vos as lugea n nomni acutrophil It was homogenous unstructured without a sharply defined border and st uncu a reddisls-11011t to purple coloi with Wights stain ke dard not coouer related phenomena adequate for digo-13 although they may have been suggestive These phenomena nerc frce bodies of Use same type as the oclusion matenal, come types of Lodies stirrounded by sci cru neutrophils smallei inclusion bodies in neutrophile, inclua on lodies in leucocitos other thin acutrophils inclusion Lohips apy (Duing to lic within a vacuole or showing lolulition OLCHA #5 12 9- Number of patients 3- 0 H 20 21 30 31 40 41 50 Over 50 Age in years ra 1 Age distuibution of 33 pntants all with SLI studied by cn il bioput Remien! clinical tourse Fevr lymphadenopathy Face rash Arthritis ond orthralg10 Affection of noils ond hour Hepatomegaly Ches1 pain Plevral effusion Pericardiol eftusion Splenomegoly Abdominal pain Ascites Sensitivity 10 hfوrاما؟ oynouds chernomenon O 20 40 60 BO 100 Percent of patients Fra 2 Percent incidence of symptoms and signs in 33 patients ill with SLE and studied by regal biopsy ·28 MUCHRCKE KARI PIRINI AND POLLAK Sad mentat on rotera sed Thymol turb dty ro sed Hyperglobulinem a Urno y abnormalt es Anemia Hargraves's cells Leucopen a Coombss test WR + T 0 20 40 60 80 too Percent of potents I'ra 3 Percent inc dence of abnormal laborntory tests in 33 patients ill mith SLE ho were studied by ronal b opsy 4 RENAL BIOPSY AND REVAL PATIOLOGI After the preliminary studies had been made 1 rưnıl biopsy was done using the technique previously described The cylinder of renal tissue as fixed im mediately in 10% neutral formalın in sılınc After fixation the specimen was embedded in parnffin and sections were cut at five microns In all cascs sections were stained sth hematoxy lin ind rosin (IICC), with Mallory anılınc blue (177) and with the periodic acid Scliff reagent (168) A minimum of five II CC sections and one each of Vallory anılınc blue and PAS was studied in cach csc In some cascs frozen sections acre styined with Oil red O for lipids (168) and in others paraffin scctions were stained by the short Foot method for reticu lum (168) In a few cases y portion of 1 idney tissue was fixed by the freczing drying method of Gersh (88) and stuned for athaline phosphatrusc by the Go mori technique (168) The criterii commonly in use in patl ologic studies were applied to the cvalua tion of the histologic lesions obsersed in biopsy and autopsy material Tlie rela tirely limited amount of material available for study presented non problems which have been discussed in previous papers (133 135 200) Only those biopsies which included adequate amounts of renal tissuc were analyzed The tissuc was considered to be adequate when five or more glomerult and their adjacent tubules were present in tlic sections in fact most of the biopsies contained ten or more glomeruli YI RESUITS 1 CLINICAL VATERIAL Data on 33 selected patients ill with SI L have been summarized in the tables and charts In general the patients huel ecn classified in the tables on the basis of the renal pathology as this provides the most objectue basis for study However it has been impossible to dit orcc entirely the clinical from the patio ·LUILS NEPIIRITIS 29 logic features, and for this reason the data will be discussed on a clinicopathologic basis The criteria for selection of patients for study have been outlined in the sec tion on method The criteria used for selection and an analysis of the signs, synıptoins, and laboratory investigations are set forth in Figures 2 and 3 and in Tables I to 11 alich also gn e details of the clinical features, urinary findings tests of renal function, and laboratory and pathologie data of all patients Definitions of the pathologic terms used tre given at the beginning of section VI (2) (page 67) One-tlord of the patients were found to hwe normal kidneys or minimal renal change when first studied, although they had systemic manifestations of the disease This group of 11 patients provides controls in the study, and it is ob Sious that some time must elipse before we will have an opportunity to report on the development of their disease Alrendy in this group are 2 patients ($6, ¥11) hoc renal discasc has progressccl--In one can considerably A Patents uith normal renal bropsies Eleven patients (cases *1-11) have been classified as having normal kid neys-o far as Lupus Nephritis is concerned-at the time of the first biopsy One of these patients, a 61 year old ladı (*10) had benign nephrosclerosis, but no other lesion in the hidney Another (83) had had several attacks of acute pyelonephritis Abnormalities were found in the urint of both these patients In three patients the renal biopsies were unquestionably normal, and in five (including X3) minimal changes were detected (Sec Section VI(2)—Pathol ogs) These were so mild, howcver that the hidneys have been classifieci as being normal In three of the patients with essentially normal kidney s bloglit changes were found in the urinary sediment-usually a few erythrocytes or an excess of leucocytes These findings were usually transient The history of the following case illu-trates this point Crest ED (R&L 0712) an intelligent 26 veu old housewife had had multiple jo nt pains and Ray nuuds phenomenon since 1914 In July 1952 she des eloped severc swelling of the left following exposure to the sun in Tugust 1953 her joints became swollen She had a fever lost her appetite and 119 short of breath Thc h mph nodes were enlarged The laser and spleen were not enl irged She had a jericardual effusion The direct and indirect Coombs tests were positive and the seruin globul n was elevated Hargravess cells were found the bon marrow After treatment with ACTH 78 started her clinical condition improved She was disel arged from lo pital and maintained n health » th cortisone Before treat ment 3+ protein leucous tes and casts were found in the uring after her temperature Was normal and no abnormality was found in the wine Friso lcs of arthralgia plcuritic pun and low grude fever occurred in February 1954 the skin of the foieums and fingers was red tense and arreared atro huic There was a dffuse alupecia of the scalp The lymph nodes were again enlarged A renal biopsy * 18 clone on Tebruary 17 A few leucocy tes were found in the urine tl e GIR (CINULIN) was 114 ml/min anul thic RPT (CAE) was 533 ml/min 8 months later she developed gastro enteritis due to Simonella panama hut made an uneventful recovery after treatment with cl lorimp caicol ·TABLC IV Pathologie analysis of biopsy ani autopsy specimens of kidneys from 38 patients all wrth SLE Glomerula Tubules Interstitium Vessels Case patients Shalogen Pathologic Dias Cello Hyalune thrombi hary orrhexis Ploid Jematoxylın bodies Ischemia bolic Adhes Cres - Clone ions cents alimlar. Tophy Dilata Pro Tubular Bowmans Degeneration From Casts damage Ldema I bross Inflammation Sclerosis First renal biopay normal 7 F 0 0 0 - " 0 0 # 0 0 0 e 0 0 0 o 0 + 0 0 + + 0 0 0 0 0 0 o + 0 0 0 0 z zzzz # ++ Oo OO ++ IH OO SO ao 30 lo 0 0 0 ö # 1 :: 1 :: 1 8 8 8 ö lot öltö 7 7 7 7 7 7 7 1:1::::::::::::::: 1 + - joll + S Tort +II+II++ 4Z 6 z z Es Ooo Oo +++10+ OOO OOO ++| 7 VT ololo ofcopoteles 20110|--|--0lcocols bolol -- OOO 777 77 0 los ool olcool + + + pool OOO oo + + + + + + + Qoc OOO o + col 土土土 + + + Oo OOO M O - O O Ho ## + 4 ++ OD So N It H 0 0 0 0 + 0 + 0 0 0 M + 1 #1 -- 1 +1 + 1 - .) ++ ·OH + + OH + ++ # + + # # + Go + 10 +++ +0 H + +to + + + + 0 o+1 + + + od O + + + + + + + + + + + + + + + + ++ + + + + +++ +0. .. + Oo C+ Oo . . + . + + # # + + + + + ++ + -- +++++ + ++++ GOO + + + + + + +o +++ 1 II+ + + ++ # # + • + + ++ ++ ++ 1 Ho See --++ I + #1 + @ I + . + + + + + OF ++ + # + I + + + + + + + ++++'+ + + + + # + + + + + +++ 1 ### + + + + III + I ++ +I+ + S + + + + + + + + - Il + +o +o + + ec OOC OOO e ce Oo ++ Po 6 mouduqunu Ardo + + r. buy mim! aneus glo a wom pris OO ood .++ +o Q o + + #+ de a + oH # # + #I++++ # # h + + I + + It + + + - e o + DD | H + + ee ++ OO + + + + + + + + Io + + + ++ + o G DOO + ++ I + + + + + + + + + + o + + + + +++ 0 + # # + + II ++ # # + + + + 0 ++ + + + # # +++++ III + I ++ ++ ++ ++ +++ ++ TTT ++ # Nn N&A -- MICI re IMG PVC (X 7) Old IMONI PVG N 8) I VE & PVG ( 8 ( MC (11 MC ( 8 MC Ng VIG) MPC NIR 1170 (5) MNO) TG NI MG YMPI IN 11 LD 1 1 MM 18 CI CW 19 BI 21 DB 22 JU or 31 ·TABLE IV-Continued Glomerus Tubales Interstitium Vreels Case Patients NO Initials Pathologic Diagnosis Base ment mem trzne Cellu ſarily Ischema ly aline thrombi Wore Loop les- BOTAS kary orrhexis Hematoxylin bodies Fabri noid Ein bolic | Adhes Cres les jons certs 1003 Clome rtlar damage AL rophy Dlata tion Pro teia Cases Tubular lamage Fitri poid Ederna Inflammation Fibrosis Sclerosis * 17 biopsy membranous plomerulonephritis -Continued 23 EB 0 0 0 0 + VG N (8) SG N (16) CGN (K) CON ( ) CG N ( k) 4 ++ +++ +++ +++ ++++ 0 + ++ +++ + +++ ++ +++ + +++ ++ ++ ++ + 0 0 0 D 0 0 0 0 0 0 0 ++ + + + 0 + o + 0 + ++ ++ F + ++ ++ +++++++++ + +++++++++ ++++++ ++ ++ 0 ++++++++++ ++ + 0 ++ + + + ++ + ++++++++ ++ ++ ++ +++++++++++++++++++++ + +++ + + + + + + + ++++++++++ +++++++++ 0 + ++ 0 + + 0 + 24 W11 MONO) +++ + +++ 0 +++ 0 ++ 0 0 0 ++++++ ++ ++ + +++++++ ++ + + + 25 RN MICN (8) VG N d x) ++ +++ ++ 0 + ++ + # + 32 ++ 0 ++ + ++ +++++ ++ 0 ++ 0 D + + + 0 ++ + ++++++ 0 + ++ ++++ + c 0 ++ + + 7 + 0 + t I F 26 CV, SIGN SON (1&A +++ +++ + ++ +++++ 0 0 ++ +++++ + +++ +++ D + +++++ +++++++++++ + ++ + ++ ++ + ++ ++ +++++++++++++++ + +++ + 0 F ++ H + 27 M1 VIGN (1) MPG V (1 x) TT ++ + +++ +++ + +++ ++++++++++ ++ ++ ++ 0 0 0 ++ क ++ +++++++ + ++++++++++ 0 ++ +++ + +++++ + +++++ ++++++ + + + 2B A# MIG NAR) 4 +++ +++ ++ +++ ++ 0 0 ++++++ + + + + ++ + + Firat biopay subacvle or chronse glomerulonephritt 29 RC + ++ SGN (1) CG N 1 ) CGN (6) F ++ ++ +++ + 0 ++ ++ + 0 0 +++ +++ ++ - + + + 0 0 0 0 0 0 + 0 ++ ++ ++ ++ +++ ++ ++ 0 0 + + ++ +++ ++ ++ ++ + + + ++++++++++++ ++ ++ ++ ++ + + D 0 + ++ + ++ + ++ + 8 a oe SG N (IR) SG Y () +++++++++ +++++++++ 0 + +++ ++ ++ ++ ++ +++++++ +++ +++++++ ++ +++++++++++|+++ + o ++ +++ + + I+ +++++ ++ +++++++++ + +++++++++ 31 RZ 0 ++ + NO V(de) CG N ( DE) CG N OA ++++++++++ +++++++++ ++++++ ++ ++ + OHH ++ + 0 + D 0 F +++++ + +++ +++ +++++ ++++++++++++ +++ ++ +++++++++++ + 0 + ++ +++++++ ++ ++++++++ +++++++++ + +++ ++ + ++ ++ st ++ 0 ·37 B ) SGV (1 x) +++ ++ +++++++++++++++++ + ++ 0 ++++++++ +++++ +++ +++++++++ 31 DJ CG V dn +++ + 0 + + 0 0 ++++ ++ + + +++ ++++++ ++ N Nrnal Taipale SO V Suhacute glomerulonephr tus If I rol le at cgl n prults CGV Chronc glomerulonepirtis Ven runo a glon ul tia (0) Focal (1) Local PC N-I fernt e klone I nel t. VON Ve un # me u (d) Difuse (8) General zed De Ney buroeclerus 1 A-Anutey ilria 33 ·31 JL ENRCKE, RA, PIRT, AND FOLLAK In June 1951 she had 1 thromlxoplulebitis of tlie left leg Three months later she was rendmitted to hospital for study butterfly face tash was noted The Impla nours were enlarged and there was srlerodactyl There was no peripheral edemi and the blood pressure was pormal renal biopsy was done on September 8 I fex eri throci tes leucoes tex and cellular casts were found in the urine Since thint time she has been kept relatively free of symptoms with small doses of cortisone Framination of the urine has been normal First Biopsy The first biopsy contained normal renal nedulli but 18 inadequate for dignons Second Biopsy (September 1954) Adequite renal cortex (12 glomeruli) ond meclulla were included in the sections The glomeruli were eventually normal Bow mans spices contained a molerate amount of proteinaceous material The consoluted tubules al o contained proteinaceous material and were lined by a slighth sirollen and degenerated epithelium The interstitial fibrous connective tissue and the small arteries were normal very small mount of gi inulnr lijd material was seen in the cells of the convoluted tubules in sections stuned with Oil Red-o Gomori preparations for all alınc phosphatase di oscil the presence of abundant enzymatic tettsits in the cells of the con oluted tubules Dingos rexentually normal renal truc The renal histology from two of the patients (X6 11) s as normal at the time of the first biopsy and urinalysis and renal function were not disturbed Lupus nephritis de cloped and was found 10 months and 14 months after the first study Onc patient died as a result of poliomyelitis, and the others alle and reasonably well The histories of these two patients are gn en belon Case JS (R & E 417655) a nervous apprehensue 21 year old housewife lind had rheumatic fever in childhood She enjoyed good health until June 1953 when she des eloped an er thicmitous ruh insolving the face and upper chest following exposure to sunlight Slim hrane rute Jl I skin biopes *9done its histologic aproerince we consistent with lupus erythematosuy In My 1951 she was short of breith on exertion and des cloj ed Rninud s phenomenon One month later she had migmton joint pains and was a Imiterd to howptul She was febrile scutels ill anemic and had a butterfly face mish nod alopecia of the scal; There is tachycardut electrocardiographic evdence of my or arditis and poucandal friction rub The blood pressure was 140/60 mm Hg There was a pleural effu sion and 1 pleural friction rub was heurd The thyroid glind was diffusclt calarged and norint was leaid over at ll lymph nodes were enlarged Unaal sis and tests of renal fupc tion were normal Mans Hargraves s cells were found on examination of the bone marrow SI E int hyperthyrouliem were dignosed The BVR and 1” ug cake confirmed the litter dignore he was treated with ACTH and methimazole and her condition improved dra mitacills 1 renal biopsy was done on July 14 Slue guncu 21 jounds in wright and when discharged from lio pital she *123 free of symptoms ind 114 being treated with small do of (ort i one In ovember 1954 she 8 reidmitted for stuch i funt face rah was seen The shin over the fingers was thickened but the lymph nodes Iner and sy ken were not enlarge 1 There was a trier of protein many leucocy tes and mini granular and leucory te casts in the urine Renal function w13 lights impused 1 ccond renal loopt was done 10 Januari 1955 tretimazole was chiscontinued hut she continuer to the rortor Four months later she is again studied in the hospital There were areas of atro; luc khin The sh n of the forearm and fingers was tense and atrophic The I lood pressure glamriuli) ucre included in the section Swe tor question JP Chene MILIK UI ·LUPUS VEPIIRITIS 35 membrane the glomerul appearid essentially normal There was a minimal increase in cellularity of the glomerular tufts and Bowman s spaces contained some proteinaceous material The convolute 1 tubules were normal an sze Tler lining epithelium was some bat swollen and their lumina containe 1 & moderate amount of proteinaceo is material The interst tial tissue was not remarkable Minimal tl ickening was seen in the walls of the small arteries Dugnons Essentially normal renal tissuc Questionable localized glomerulit s was seen Second Bropsy (November 1954) Adaquate renal cortex (8 glomerul) but no medulla was included in the sections The glomeruli were shghtly ischemic Minimal local hyper cellular ty was noted and there was moderate local thickening of the hacement membrane in several glomeruli Bowman s spaces containe la mo lerate amount of proteinaceous raa teral The convoluted tubules Frere normal ia s ze and were lined by a sl ghtly degenerated ep thel um In several areas the tubules were atrophıç Their lumina contained a moderate amo at of proteinaceous maternal There was a slight increase of nterstitial trgue and foci of chronic inflammatory cells were seen Mild thickening and sclerosis was seen in the walls of the small arteries Mallory and PAS preparat ons confirmed the above finings Dragnosis Mild local and local membrano is glomerulonephritis Therd Biopsy (Vay 1955) Small fragments of renal cortex (4 glomerul) and medulla were included in the sections The glomerul were slightly ischemic and a slight but ds tnct local th chen ng of their basement membrane was noted There was no definite hyrer cellular ty and Bowman s spaces contained no proteinareous material M nimal degenerı tive changes were seen in the i ning epithelum of the convol ted tubules wli h contained a small amount of moteinaceous materiał Mild th ckening and filerosis were seen in the walls of the small arteries Diagnosis Vild lo al and focni mew branous glomer lonez hrulis Case 11 LD (R & E 41424) a 13 year ol l negro high school student enjoyed good health until January 1954 when she developed migratory arthritis of tle ankles and knces One month later sl e had anorexia way co igł ng was short of breath and had lost 16 po nds in weight A d agnos s of tuberculos mas made and streptomycin and 1soniazid prescribed In March she was feverish and a butterfly rash appeared across the face A diagnosis of erysipelas was made by a physician On admiss on to the University of Illino s Hospitals in Warch 1954 she was anemic febrile lethargie acutely all and complained of pain in the abdomen The blood pressure was 80/0 There was tachycardia a protodiastolic gallop rhythm and electrocardiographic evidence of myocardit s There was an erythematous rash over the face ears and distal phalanges The conjunctivae were injected anl the gims bled easily The cervical lymph nodes and liver were enlarged There were pericardial and pleural effusions There was a trace of protein and several lencocytes erythrocytes and by alıne casts in the unipe Many Hargraves a cella were found on examination of the bone marrow She was treated with ACTFI and a remarkable clinical improvement took place She became afebrile the pleural an i pericardial effusions decreased the gallop rhythm disappeared and the FCC returned to normal Unin ilysis an I hematocrit becamı normal A renal biopsy was done on vaj 8 The GFR (CINOLIN) was 117 ml/mn the RPF (Ceaa) was 668 ml/min and the TMPAI was 76 mg/min She was discharge 1 from hospital on maintenance doses of cortisone Io Sc tember she had a cough mild dyspnea pleuntic pan and a sore throat Tender cystic nodules appeared on the dorsal surface of the interp) alangeal joints There were pericar hal anl pl i ral effus ons There was miched improvement of symptoms wlen ) dosage of cortisono as in reased Except for muld dy sprea ant pericardial rain sle was ·36 VLEHRCHE, LIRh, TIRANI, AVD 1OLL Ik free of symptoms when admitted for study in October, 1931 Save for a butterfly face raslı slight alorecir of the scalp and cervical Imphadenopathy the shysical examination w19 normal The direct Coombs s tot was po itse 1 second renal biopy was donc when the urinnly se NPN and te-ts of ren ul function were bormal In June, 1955 she becime lethargic complained of headache ani de elored over a stiff nech agıl a flaccid paralysis of her legs On admission to the hospital her neck wus ftaff There was ucahness of arms anel legs and the face and ankle jerks neic absent Tic CSI pressure was increased the protein was elcz sted and 225 lcucocy tes ($0% polymorphonu. clears) were found in the spinal flurl Poliomyelitis #94 dngnoeeil She desclosci a scuori bilateral pocumonia became comatose and died scien days after admission l'ost morten crimination confirmed the diagnosis of poliomyelitis First Bopy (ay 1954) Adequrte renal cortex (6 glomeruli) but no me lulls were in cluded in the sections The glomeruli were essentials normal except for slight 1-chemia an! questionable local thickening of their brement membrane There was slight degeneration of the lining epithelium of the consoluted tubulee uliose lumini contained froteinaccoue material The interstitial tissue and small arteries were normal Diagnosis Fesentinlly normal renal tissue Second Biopsy (Vocember 1953) (Fig 1) Adequate renal corter (8 glomerul) an! medulla were included in the mal local thiel ening of the man s spaces did not contain, diluted They were lined by low cuboidal epithelium in which minimal legenerutne changra TIG 4 Patent 11 Second Bropy October 19); The glomerulus sewentualis norus.) Tirpitrent fa 1 been uil with SLL for ne months (H&T X 620) ·LUPUS EPHRITIS 37 FIG 5 Patrent 11 Autopsy June 1956 Note the marked and rather diffuso smudg, thickening of the glomerular berment membrinc-suggestive of Sibrinoi! The tubular cpithelium is somewhat degearrated (H&E X 400) were noted The tubular lumini contained a small amount of proteipaccous murrial The interstitial tive was normal Comparison with the previous biopsy disclourd no changes of note Dungnosis Essentially normal renal tissur Iutopsy Specimen (July 1935) (TUR 5) The glomerult were slightly lolulitel od 1 distinct but mild to moderate local tlachening was seen in the breement membrune Minimal local hypercellularity was also noted in tle glomerular tufts In place the tl: koori glonjeru lır basement meml rane was smudgy in character suggestie of fil rino1 chingne A few wire loop lesions were noted 'Hematox; lin bohre were not scen B mins arts con lained little or do proteinaceous material Moderate degeneration of the living epithium of the convoluted tubules w19 noted Thry contained proteinaceous interul The capil larics and small sein, were congeatru The interstitut tis-ue contained foci of clironie in fummaton celle especully numerous asound some of the glomeruli an la few stall arteries Vallory and PAS preparations confirmed these hoding lo lipad 19 sren within the sprchebum of the convoluted tubules with Oil Rel O rrepintions of frozen sctions Com- 1 arison with the previous biopsles indicated a deforte inrrente in the fient of the glomerular changes and an addition the presence of fit rinoi! degromiton Dingnouis Lucal and Dez prakzed membrano is glomerulonephritis B Patients uith abnormal renal biopsies When the first hopes are mule, thic luetology of the kidneys x is abnormal 11 22 6144 At that time the urme of all Irut thru of the patient. (*12 16, 19) 175 abnormal In general, renal function was not affected until the degree of ·38 VLFHRCAŁ KARK, VIRATI, "\D POLLA kidney damage was severe In some of these patients the renal lesions and clini cal status have changed little during the period of study In others the renal lesions have progressed and the clinical status hus deteriorated of the ten pa tients who died, sny died of renal disease (X23, 25, 26, 30, 31, 32), one of renal diseasc and acute pancreatitis (827), one during in acute exacerbation of SLE with myocarditis and seiere renal damage (†28) One patient died of anterior poliomy clitis (11) Her kidneys, a hich liad been normal when first studied were the seat of moderate membranous glomerulonephritis at the time of her death The tenth (*8) died of an acute clacerbation of SLE, terininally there were abnormalities in the urine, but the last hustologie study, made seven months previously, was normal The clinicopathologic fentures of the patients who c kidneys were abnormal will be discussed below under the following headings (1) Mild Lupus Nephritis (Glomerulitis) (2) Severe Lupus Nephritis (Glomerulonephritis) (3) Nephrotic and Pseudo nephrotic Syndrome in SLE (1) Mild lupus nephritis (glomerulitis)- Ten of the patients had mild involvement of the kidney shon first «tudied Enght patients were studied on subsequent occasions and a total of 21 studies was made Initially local membranous glomerulitis was found in the kidneys of seven patients (*15-21) and prolferatac glomerultis in the hidneys of three ($12-14) In some of these ten patients mixed membrinous and proliferativo changes were found but the cases hue been classified according to the pre dominant pathologic lesion Clinically none of these patients had severe renal dumage when first secn (Tables II und III), and at the time of their last studs only one patient (X19) was ill with chronic real failure Her renal fustology is described below The remaining nine patients had relatively good renal function after a period of study varying from 2 to 23 months but lustologically a severe degree of dım ngo is present in at least two (X18 21) Since they have been under observa tion all these patients hue had symptoms and signs of SLE with a varying clinical course The discase las been characterized by severe acute exacerbations in three patients ( 14 18 19) and has been more chronic in character in 4x (X13 15 16 17 20, 21) One patint (13) lind number of acute errcerba trons when first scen but the discuse has now settled down To predict renal involvement from the overall clinical course of the patient les proved imposa ble Below are recorded the histories of two of these patients, one (813) whose renni di case has changed but slowly the other (#19) x hose course has been more rapidly don nhill Case 18 In De umber 1951 1! ( RF 303019) a 23 year oll negro factory worker deseloper in erythematous skin al on terre ci est ani estett or surf ter of the fore rms su intermittent m gratory dont ring A dugnges of SIF - made In lug t 1932 ale leycloped marke ! pip:lledlem ao 1 diplopia a cerebral tumor was suspected and a craniot ·LUPUS NEPHRITIS 39 omy nas done No tumor as found It was tho ght that br symptoms had been due to nvol ement of tlel an b SLE Later a pleural effus on Fag a 1 rated She was sl ghtly Anem c and had a le ory to s Ur only $ 9 and blood NPV were normal In lo ember there 119 electro a d og uph celne of myocard t s and per card to The 1 er and spleen were enla g d Tl ree montls later sl e de eloped sell og of the f ce fe er anorex a st ffness of her finge s and abdon nal pa . She became ery tort of breat! and was readm tted to loptal n February 1953 There were bla ral pleural effus ons and nfiltrat on n the r glt lo r r lobe The e was a m culr fa e ra h a c tes and enlargement of the l er and lymph rode D fu e alapec of tle s alp as noteu Proten leuco y te and cast appear d trans to lyn the ur ne The thymol turb dty was cle ated and many larg a ess cells were found on eram dat on of the bone nar ow Tl ere was a post es hle cell phenomenon Treatment h ACTH re ulted a clin cal mpro ement and she was d scharged from ho r tal on da ly nject ons of ACTI Later se 9 g en co one In Sep ember sl e wat eated a the ho p tal 1 pen c ll n for a pneumococcal pneu mona A ren i boreyras done on September 30 1953 at a t me when r Daly blood NPV and tess of enal funct on see normal Tour months later she had an exacerbat on of symptoms She was fe eh had marked dyspnea na sea and vom t ng The pleural cav t es were asp aed on se cral o cus ons ACTH Wing en and her cond on aga a m roved A sp on renal hursy was done on r b uary 1 1954 Urinalyss blood NPV and tests of en 1 fun ton e normal Pero tal e leme was noted n July 1951 Slewa adm tted to tle hosp tal for std She had a moon fa e and a b te fly face rh The f nd were normal and the blood p es ure was 128 104 mm Hg Thes 1 en was no enl ged Prote a vas not found n the ur ne but many l u oe te were seen a tle snary sed ment The blood PN and tests of enal fun ton were normal A renal bors was lone on Augu t 10 1954 Co t cone an! nterm ttent ACTH tle apy wee g ven wien she as d scł arged f om lo p tal In May 1950 the plys al examination was normal e for a m 11 conjun tvts and the pgmented btterfi fece ra h Urnalys blood NPV and tests of renal funct on we e no mal A fou t renal bor y was done on May 23 1935 F st B op v (s pten er 1963) A small fragment of nel cor er (5 glomeruli) but no medul a mas de ud d n the sect ong The glomer 1 wee sl ghtly s bem and mn mal to slglt rregulril kemag of the r basement membrune was seen Tiere was sigit local 13 per ellulr ty b to a lhes ons veed tecte ! between the glomer lart fts and Bowman end le Bowmans spaces conta ned a small amount of prote a ceous mate al The on olu ci tubules were rregular a sze they conta ned a mod rate amo nt of p ote na eo mater al and se e Ined by a slightly degenerateep hel um Tiere as a mid ncrease of nterst t il fibrous connect ve t ssue wh h con 1 ned a few small foc of cl on nflan mator cells In a few tub les hyal ne casts were present Ti e small arter es rere not rema kable Dvignosus a la local and gene al zcd p ol ſe ate and nemb anous glon e ultrs Se ond B op v (rcbruary 1964) (F & 6) Adequate ren I cor er (18 glome ul) and med 1 ere nclud d the sect ons In general th glome ul appeared s leme ani gltl lobula el aul there was a dst act local 1ypercellular y de to endothel al el! prolien u The was tom mal local en knng of the b sement memb ane lu pics thes ons see no ed between the glomeru ar tufts and Bonman s carsi le bt no ep the al rescents ere p event Ti e con olute l tubules conta aed a small amount of pote na eous ma c al and the ring ep theil m was m ldly legenera ed The erst t al fibo s con nectetue as sl ghtly ncreased and onta ned oc as onal I on ni mmatory ells The soull bloo! es els tere congested and a few red blood cells had a d fin te kle slape No defin e changes were detected the alls of tl e small a ter es Duagnosis Lo al and gene al 2 d polfe a cand ne b anous plome 1* Ingnose of schle cell tra t was made T! s confirmed by labo atost d es ih dB opsy ( lug ( 13 ) Idequate renal cortex (16 glomerul ) and medulla were n cl ded n the set oue Tiere 19 m n mal sel emia and slglt lolul on of the glomer!

·OF ·LUPUS NEPHRITIS 11 Color PLATE-IG 1 Paluent X12, First Bropy, rebruary 1954 Note the sinall areas of local reicellularity the periphery of the glomerular tuft In these areas there us also mild smudg thickening of the basement membrane (H&E X 400) COLOR PLATE-I'c 2 Patient $19, Forst Biopsy, June 1954 Note there is an irregular rather suvere fibrinoid thickening of the glomerul ır basement membrane This is particularly prominent in the area of local necrosis seen on the right thin this area the capillaries are obliterated, and hypercellularity and hary orrhexis are present (H&E X 430) Compare Color Plate-Tag 3 COLOR PLATE--IC 3 Patrent $19, Sccond Biopsy, February 1955 Note the fairly severe irregular smudgy thirhening of the basement membiane Ibove the glomerulus is adherent to Bowman s capsule, near the base of the adhesions poorly defined 'hematoxylın' bodies can be seen (H&E X 430) Compare Color Plate-Iug 2 COLOR PLATE-I'TG 4 Palient *19 Fourth Biopsy, May 1965 Numerous areas of lochi lny percellularity can be scen throughout the glomerulus There 19 a slight to moderate iniegular tluckening of the basement membrane (H&E X 470) See aleo Tag 6 ·42 VUEHRCKE, KARK, PIR4NI, AND POLLAK Fra 6 Patient #19 Second Biopsy, February 1954 There is slight lobulation of the glomerul ir tuft Note the emudgy basement membrane thichening and hy percellularity in local areas at the periphery of the glomerulus (H&E X 450) See also Color Plate-Fg 4 Many glomerulı were large and a distinct local hypercellularity was seen Their busement membrane was only slightly thichened in some areas No distinct "vire loop lesions were noted In a few areng within the glomeruli the hy percellularity was very marhed and hnu caused complete obliteration of the capillary lumina hans orthevis tas noted in these areas To adhesions were seen between the glomerular tufts and Bowmans capsules and no epithelial crescents were noted No hem alory lin" bodies were seen the convoluted tubules contained a moderate amount of proteinaceous material Their lining epithelium was mil ils degenerated A few hy alıne cists were noted within the collecting tubules There was a mild sclerosis of the walls of all the arteries and arterioles when compared with the prowous biopsies there 19 a distinct increase in the severity of the glorderular damage Dagnosis Local and generalızcd prohferattte and membranous glomerulonephritu Fourth Biopsy (Vay 1955) (Color Plate-Fig 4) Adequate renal cortex (13 glomeu ılı) 11. +1 in places but only minimal harz orrhevig and no hematovy lin' bodies were seen There cre no adhesons betreen the glomerular tufts and Bowman 8 capsule, nor were epithelial cres ccnts detected There were mild degenerative changes of the epithelum of the consoluted tubules whose lumini contained a moderate amount of proteinaceous material A few hyaline casts were noted within the collecting tubules The interstitial fibrous connectic tieue 13 slightly increased and contained a few scattered inflammatory cells There was a minimal degree of thickening of the wall of the small arteries and mild degenerative changes were seen therein but no fibrooid was noted Comparison with the preu que biopes showeil do differences in the severity of the lessons ·LUPUS NEPHRITIS 13 Dugnose Local and generalized prolferative and membranous glomerulonephritis Case 19 In July 1953 B.J (R E 40019") & cheerful 12 year old negro school grl developed pneumonia and a pericardial effus on The pneumobid improved on treatment with peni cilla but the pericardial effusion pers sted There as a h story of intermittent episodes of fever and st ffness of the fingers and tocs In August she was referre 1 to the University of Ill nois Flogp tals She was anemie a utely ill and had a h gh fever i dark scaly eruption covered the whole thorax The blood pres ure was normal The heart rate was rapid and there was electrocardiographic eviden e of myocarditie There were effus ons loto peru card al pleural and peritoneal cavities Ti e liber spleen and lymph no les were all enlarged Urinaly 818 was natural The leucocy te count was normal The thymol turb dty was 25 units thu cephal n flocculat on was 4+ in 48 hours and many Hargraves s cells were found on examinat on of the bone marro Y SLE was diagnosed and treatment with ACTH was startel She had a prompt cl a cal response became alebo le and the ple ral and pericarlal effusions decreased Cortisone was given after I er discharge from hosp tal In December 1953 her symptoms returned she was dehydrated had lost weight and 1 was 33 6 units and the cephalın flocculation was 4+ in 48 hours The blood NP was nor mal Tl GFR (CINELIN) was 9x ml per m nute the RPF (Cras) was 514 ml per minute and the TMPAK Was 73 mg per minute A renal biopsy was done on June 14 1951 Over tle next seven months increasing amounts of protein were found in the urine In January 1955 she was anorexic and lost 15 pounds in teght The arterioles in the fundi were narrowed The Iver was enlarge there was ascites and some peripheral edema Viany 1 mph nodes were evlarged The serum album n was 22 gm and the serum globulin 57 gmn/100 ml The blood cholesterol was 123 mg/100 ml Gross proteinurn was noted and many leucocytes and granular and hyal de casts were found in the urine Tests of renal funct on and medulla were included in the sections Most glomeruli were definitely altered they Nele somewhat lobulated there was local and smudgy inegular ticken ng of their base ment membrane suggest ng fibrooid changes Wire loop lesions were potest in miny t U gu tuonepi rits of Lohlein In these areas lary orrbes s was noted but no hematory lin Lod es were seen There were few adles ons between the glomerular tufts and Bowmans capsules but no epithel al crescents were seen The convoluted tubules varied somewhat in size their lo ng ep tl elum was sl ghtly degenerated and their limina contained a small amount of prote naecous matern! There was a sight increase in interstitial connect re tesue rith min mal cim and infiltrat on of chronic infimulatory celle Mld scleros 9 and 1 sectional le fibrinoid changes were seen in tl e small arteryea Mallory gud PiS preparations confirmed these findings ·張 ·LUPUS NEP IRITIS 45 e COLOR P E-FG5 Pa n *2 BPYO b 1753 Fb no 4 h kem ng of h Bom ru b men mnb De nominn hro ghout he gom ulus Th e a e no d nt OOP HAF X 500) S e al o Co o P-F8 6 COLOR P E-F061a py D mb 1953 Gomerulu f om the au opsy mn of me a a Coo Pl_Ig 5 No c the 1 ge fbro p hel al co nt o up ng mm h of Bo mn $ e The gome ul s omp e ed Hype ellul y and regu h Dng of homerula b mn memb ane 19 p esen No e the bu oo of he edema ous ne al se (HLE X 430) Co OR PLA E F G 7 Paven *91 F Bopy spmbe 1953 The glome u us obu ed an ith ea e many a e sof endo b 1 al ell p o fe at on The bement membran s ma hedly hned and mudgy No the eph lal cell p olfe a on at the pe pherv e of ea ly resc nt fo ma on The ate s al t ssue 9 edema ous H&E X 430 Compa e Coo P4--Fg 8 and Fg 8 and 9 COLOR PLATE-FG 8 Ta * *31 ond Bop y Ap 1 195 Noe he se e e gul th i n ng of h g on eru a b sement memb ane ob 2 on of nd ea ya nz on r b nod hang Feos dnoh gom u No the fib op he en anl heed me and fib 0313 of he erst al t ssue (H&E X 430 Compa e Coo Pe-Fg 7 and Fg 8 an 19 sugg th ·46 MUELIRCKF, KARK, PIRASI, AND POLL 4X Dagnosty Local and generalized membranous and proliferatie glomerultus Seco: I Biopsy (February 1905) (Color Plate-Fig 3) Ide juite ronal cortex (five glomeruli) but no medulla sere included in the sections The glomeruli were schemic and slightly lobulitrd There were locul are 19 of hy percellularity an 1 of thickening of the b1cment membrine with the formation of wire loop lesions and in plices obliteration of the capillary lumini In some glomerul tle breement membrane was not only thickened but oprcared smudgy and granulir-suggestive of fibrinord tiangcs In other glomerult there was harz orrhexis and a few mother poorly defined hematorylin bodies were scen I few adhesions were noted between the glomerular tufts and Bowman s circules in which a mild degrce of fibroblastic proliferation was scen a pliccs There were moderate degenerative changes in the lining epitlielium of the convoluted tubules whose lumini contained some proteinaceous material A fes hyaline cists were noted in the somewhat dlated collecting tubules and in the descending portion of Henle loops The interstitial tresue #18 nornal Minimal sclerosis of the walls of the small arteries was seen These findings were confirmed in Mallory and l'AS preparations Dragnosts Local and generalized membranous and p olfcrative glorrerulonephritis (2) Severc lupus nephritis (glomerulonephritis)— Twelve of the patients lid sciere involvement of the kidney when first stud ved Eight patients were studied on subscqucnt occasions and a total of 26 studies was made Initially local membranous glomerulonephritis was found in the kidneys of seven patients ($22-28), some of these liad prohfcrative changes in addition Subacute glomerulonephritis was found in the hidneys of four ($29- 32) and chronic glomerulonephritis in one (*33) Clinically eight (X23, 24 27, 29, 30 31, 32 33) lad evidence of sei cre renal discase when first, seen, and five have died, the other tliree are ill with chronic renal failure Three of the remaining patients (X22, 25, 26 28) liad some evidence of impairment of renal function Two died (X25, 26) of rapidly progressing renal failure tro and tuckie months after they were first seen A third (28) died of SLL witlun ten days The fourth patient (X22) is chronically ill Nine of these patients had general ized edema, and their illnesses are discussed in detail in section (3) Nephrotic and Pscudo nephrotic syndrome in SLE Below is recorded the history of one patient who died of chronic glomerulonephritis Case 31 tory unt 1951 greatly but subsequently be had bouts of ſever and arthritis Sue for moon 14t de mu all ht Antil Three months later while still taking cortisone he developol chest pain 18 11 of pe was increased Betncen September 1951 and his admission to the University of Ill dos Jospitals in Vny 1953 he had received approximately 7o gm cortisone en 1 23 g {CTII Large purple ·LUPES VERBRITIS 17 23 yrs RZ Hct 30 20-3 A Dumn 6 -400 cholesterol gm./ICOM - 0 Co cum mg/100ml 9- 0_0 30 COM MM/L 300 mg/100m -200 Inorganc phosphate mg/00 ml 120 Ch or de meg/L 1025 Prote nur a gm/24 hou s U ne Spec gray OIS 100 60 cearance ANRF 0- NPN 2503 Urea -15 PSP Excerion (5 m nute) mg 100m 1507 C24 Creat nine 12 mg/100ml 00 20 H stological Domage 2 իր o Glome vio domago Tubular damago Interst ta nflam. Vessel (broid dengan nters that brost 1953 und Jean- 1958 Tuo 7 Patient *31 Chart illustrat ng the histologic changes in two hiops specimens and one as topsy specimen and the changes in renal function and biochemical findings over a period of 26 months (see text) TT +8tu om 10 ital he was checo Ersting of a high protein low salt die (alcium gluconate and sodium bicarb Stj vomiting abdominal pun and d breathing gran i mal scizuies 1ypertension gn1sures and positive Cl zostel s siga The Iner and lymph nodes were enlarged He was dehydrate l and suserely acidotic He was treated with blool and satravenous fluids and grilually imposed 10 April 1931 bewRendnutted to buspital for study Neither effugioi s into the serola rat po nary not 1 1118 diet wag altered to provide 2 000 eulones and was low in potassium and protein He *19 also given so lium bearboorte aluminum hydroxile gel calcium glu opate oral pen - 10 ani multivstamins lle nas eticourage i to drink large quantities of water especially

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·LUPUS VEPIIPUTIẾ 19 COLOR PLATE-T 9 Patient 439 Postmortem Bropey Photomicrograph of a portion of a glomerulis Note that the glomerular basement membrine is thickened and mudgy TIe cop llary lumini are almo tolliteratrd in the central area ote tie lemntorslin bo lirs in 1 slight hiry orrhexis in this arcr Below and to the right n small hy ning thrombus can be seen (IXE X 1100) COLOR PLATF-FIG 10 Patient ** Autopsy December 1993 This sertion way staine ! with Mallory-az in which colors the normal or hyalinized glomerul ir basement membrane blue In th 19 glomerulue note that the busement membrane 19 smudge and stained a reddih Color The 19 typical of fibrinoi! In the night loker gun frant small Invalinc tliromli are prrent within the lumina of the capillaric (Mallory nz"ın 430)

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·LUPUS NEPHRITIS 51 before bed time on this regimen 7 daily urine output of between 1500 and 2300 ml was maintained From April 1951 to July 1955, his renal function steadily worsened and severe azotemia developed During this period there were no clinical manifestations of SLL Hargraves's cell, were not found in the bone marrow or peripheral blood, the serum globulin and scdimentation rate fell to normal, and the thy mol turbidity derreiscd After sun bathing on July 4 1955, he developed a butterfly face rash fever and swelling of his cyelds, and was aclmitted to hospital Purpura uremic frost hypertension and enlargement of the spleen were noted He had sucre anemia and leucopenia On y ray of the abdomen the kidneys were small and appeared contracted He was agun given transfusions of whole blood, and his clinical state improved When readmitted to hospital on August 8 he was slıort of breath and had been vomiting for three days The blood pressure was 185 115 mm Hg Thr herrt was enlarged and there was a systolic murmur over the prccordium The liver ? CODsiderably enlarged, the spleen was palpuble and there is a generalized lymphadenoj athy He was lethargic and restless The hematocrit was 19 There was oligum and the urinary findings were unchanged He dicd following two epileptiform ron ulsions The NPV before death was 212 mg/100 ml Post-mortem examination revealcd the following Icsions fibrinous pericarditis and picuritis perihepatitis and periplenitis an old mitra) val ulitza and fibrinoid degrneration of small arteries in the omentum and wall of the esophagus There is no perurterial fibrosis in the splcen Forst Biopsy (September, 1953) (Color Plate-Iug 7) 4dcquite ronal cortex (12 glomeruli) and medulla were included in the sections The glomerula wele ischemic and lobu- Izted Marhed diffuse and generalized hvpercellul inty was seen in the glomerular tufts Their basement membrines were thickened and in some areas cre smudgy and granular in appearance and the capillary lumina were obliterated Epithe hal crescents were present in many of the glomeruli in others extensive adhesions were seen between the glomerular tuſt and Bowman's capsule A few small areas of hars orrhexis were noted but hematorilon bodies were not found The convoluted tubules were moderately atrophic They contained A small amount of proteinareous material A few large pale blue-staining hyaline casts Welc maen in soine of the collecting tubules The interstitial tissue was edematous and miny Chronic inflammatory cells were scattered throughout it There was a marked increase of fibrous connective tresue fibrinoid material was seen in the small arteries and arterioles whose walls were somewhat thickened These findings were confirmed in Mallory and PAS Preparations Diagnosus Late subacute proliferatic and membranous diffusc and generalızed glomerulonephritza Second Bropey (aprel 195,) (Tg 8 and Color Plate-F1g 8) Idequate renal cortex (20 glomeruli) and medulla wcie included in the sections There was profound ischemia and marked lobulation of the glomeruli Most of the glomeruli were either partially or completely fibrosed to some castines thuis was due to marked thickening at the basement membranr Loral hypercellulirts was seen in most of the glomeruli Epithelial crescents were seen in many la places fihrosis of Bon man s capsule was marked The basement membrane w 18 thu honed, smudgy and granular, and in places its appearance nas suggestive of fibrin. old The convoluted tubulcs vele atrophic They were small, lined by a low cuboidal epithelium, and contribcd little or do proteinaceous material A few rather large hy aline 1 preparations confirmed these findings ·52 WESIRCKE, LARK, PIRINI, AD POLLAK Dragnosis Chronic prokferatile and membranous, diffuse and generalized glomeruloneph- Tits Autopsy (August, 1955) (Fig 9) Minns glomerulı were partially or completely hyalin ized In others there was muhed thickening of the basement membriac which obliterated the capillary lumina in many places are loop' lesions were seen in a few glomeruli In mint there was considerablc proliferation of epithelial cells in both vecernl an ! parietal 1.13 ers of Boxmın s capsule I few fibrorpithelui crescents serc son ind adhesions between Bowmans cupules and glomerular tufts were common The breement membrane in many glomeruli urcared smudgs and granular, but Mallory preparations did not confirm the pre cnce of fibrinord There is slight kenorrhexis lo hematous lın' bodies were soca Mot convoluto tulsules were markedly atrophic, some were molerately dilated and filled with proteinaceous maternel or hu line cists There were advanced degenerative changes in the lining epithelium of these tubules and in Oil-Red O preparations abundant granular lipid wis scen in the cells There were similur changes in the loops of Ilenle and in the collecting tubule. There was marked fibrosis of the interstitial tisuc which wie infiltrated with chronic inflammatory cells The walls of tlic small arteries and arterioles were severely sclerotic and hyalinized and their lumina were narrowed No definic fibriboid changes were sccn in the vesscl walls Dragnosts Chronic membranous and proliferature, difuse and generalized glomerulonephrodis (8) Nephrotic and pscudo-nephrotic syndrome in SLE. The criteria we hnie used for the diagnosis of the nephrotic syndrome in patients with SLE n ore the positive criteria of Leiter (166), namely, edemu, massne proteinuria, lon scrum albumin, raised serum cholesterol, and an abnormal urinary sediment By virtue of these criteria and clinical course, seven patients were diagnosed as having the nephrotic syndrome (X19, 23, 24, 25, 27, 29, 31- and Table V) Among the cuscs from the Pathology filcs, studied retrospectively, there was onc (GB) in whom the clinical data fulfilled all criteria for the diag nosis of the nephrotic syndrome In contrast to this group of patients there are three cdematous patients (X28, 30, 32-and Table VI) whose clinical course progressed rapidly to termination They also fulfilled Leiter's criteria, save for the fact that their serum cholesterol lezcls u ere lou To characterize this group of patients whosc illness was so acute and whose prognosis as co grave, nehue coined the term "pseudonephrotic syndrome" (202) Onc other case (NO), t ho dicd with the pseudonephrotic syndrome, iras found among the cascs studied retrospectncly from the Pathology files A VEPIIROTIC ST\PROVE Among the patients with the nephrotic syndrome, five were women and three were men Tieir ages ranged from 13 to 46 y cars. In two the blood pressure was significantly clev ated Three had persistent gross hematurin, and all the others had microscopic hematuria IIy alınc and granular casts were found in all, and fatty casts, doubly refractile bodies, or oval fat bodies in five In general, proteinuria persisted, but the quantity paused varied day by day The nitrogenous constituents of the plasmi slowly increased, the concentrating pow cr of the kidney decreased, and there was a parallel deterioration of the urca clearance and PSP excrction The scrum cholesterol ringed between 369 and ·LLPLS VEPHRITIS 53 Fra 8 Patient *31 Secon 1 Biopsy April 195, Low power vice late edema fibrosis and infiltration of chronic inflammatory cells in the interstitial tigue The tubules are atrophic There is increased cellularity of the glomeruli Epithelial crescents are alo seen (II&E X 180) Compare Tug 9 and Color Plate-Tag 7 and 8 FIG 9 Potrent 31 Jutopey August 1955 Yote the severe thickening of the glomerular basement membrane and the regular dastnbution of endothenal and epithelial cell pro- Isferation The adjacent convoluted tubules are atrophie and the interstil tisue is infiltrated by chronic inflammatory cells in other areas fibrosis and hyalinitation of the glomerul were prominent (llar x 30) Compare Fig 8 and Color Plate-Fig 7 ani 8 ·YLFURCHE LAR, PIRAVI, AND POLL 4K TIBLFI Climcal and laboratory data from eight patients tuith SLE and the nephrotic syndrone Urne Serum Patent ARE Sex Edema BP Present Status Onset of Ederna Pa tenº Red ces Casts esterase Fatt Abduran š523 | Cholesterol er lure 27 S DIT 100 101 ME! $19 1 13 T +++ 110 80 ++++ Hero Hyal ne N! 2 2 425 -- January AL e Azoth cranulus 1955 mind hs *23 IS 33, T ++++ 360/90 17 6-23 0 Cross bertena on Pyal ne crats 27 +2390 Verch ID od January Cronular DRB 1951 1958 Hena) BBC 21 W IT 46 +++ 150/50 92 11yaline M 26460 092 June 1953411 Chro Cranular < renal Cellular ta! re *"5 RN ng +++ 180 120 39 Cross 11yal ne Casts 3 4440 Apr 1955) D cd May Grapular DRB 1933 Reval tu lure *27 VP 27 r ++++(132/ 8 ++++ Cross N: 20369 - Jan Hry Ded May Cranular 1955 1955 Renal Cellular Dura Inilure and prek acute pan nancy cre i tu #29 RC 31 I ++++1141/99 ++++ Vco 11yal na Costa 2.9 420 1 17 Septem Ale Cbro Granular DRB ber 198 be tena! Coulure 3) Z V ++++110 1082 4-10 7) Wacro a) De Costa 2 +150 - May 1952 Died Angust, Granular (DRB 19.53 Renal RBC Tulure GB 22 M++++110 3++++ V TO Ilyal ne Casts 21471 Apr 1 1951 Dod June Granular DRB 1954 Renal RBC falure WBC I cro yal ne 1 (ms per 24 hours or pl MB doubly refrece le bodes Case studed postmo tem only 471 mg/100 ml and in none did it exceed 500 mg/100 ml As we shall show be low the development of the renal lesions in this group of patients--as in other patients with lupus nephritis—was associated with a suppression of many of the manifestations of SLE In particular we have confirmed Brenner s observation (35) that skin lesions may be absent in the presence of the nephrotic syndrome Thircc of these patients are alue (three months to three y curs after the onset) and two are slowly becoming increasingly azotemic The other four died from two months to three years after the onset of cdema All died as a result of their kidney discase, except patient X27 n ho suddenly developed acute pancreatitis when she was already sci crely ill from renal failure At the time of the initial lustologic study, membranous glomerulonephritis was seen in four subacute glomerulonephritis in three Case #19 de cloped the nephrotic syndrome at the time of her second biopsy which showed mem branous and proliferatue glomerulonephritis When serial histologic studies were donc (X23 25 27 29 31) the lessons acre found to lure progressed in all ·LL PLS VEPHRITIS TABLF 12 cinal and labo ato y data fro for patents oth SIE and the pse lo nephrol synd o e 53 Lrine Pa Age Se Edema Serom BP Pro Red Ce s Onse of 28 AW Edma 28 Ft +++ Da e and Cause of Desh 2 80 ++++S o 30 B) 2 F +++ 10 +++ Ceux DRA Ilya ne JOFI Cron L 65 No em Novem 951 32 BD Grus Hyu pe Haxy anuCana Ce A DRB 95 19 F +++ 17 Lu 8 0 38 Octobe 10 90 Cros 2951 Feruary 10: Hlya Be DRD G anul OFB RAC 23132 953 Rens OS +++ Jy 1954 No era ca Granu a Hy ne 1951 20 (ams pp 21 h sur pun. DRB = doub y rel se e hotes OFB-ofa beds Curetud rd pow mp en on y 08 Rens fs ure Tay 19 June 9-10 Rena re cases In cascs 23 an 127 membranous glomerulonej ! ritis rogressed to sub acute glo ierulonepl ritis The points leserled above are allu trated in tlc following cases Snc 1919 FSI VE 195 1) (1 810) a ple nt al rooper e 33 year oli louse w fe had ha! Rtyn do plenon enon In m ! De e nber 1933 ele leveloped an cry tema to y ra b of the fe e and er cnsor surf e of the forcims Tisd sappeared "thn two wechs Later that nonti e le clopta se ere sore throat ani fe er and general zed Iym; ad nopit! was note! Theer & gas anl gmrtons sub led spontabcou ! + 1 = two works in F brurn 19 sollag of the Irft anklc occ rel and there we crins n te sho 11 rs elbo s and knces Edema arreared and progressed to avol e feet ft e ani Ind Om Nr 23 seier me ucly Hand was adn tied to ano ler ho tal selal fe er general 7041 cl m antan enl rgri spl en Tle blood pres ure nas 1200 mm Ilg The Ien ocrt wa 3 and the le corite count 4000 m TI ere mas g oss po nur 201 m ovog да rn T! е ne spe fic gra! *13 1 02 Tle total rum proten was 40 kn 100 n Tieren un test was negat elo Targra ess cils cre found on er un 01 op of the lone ro Selad pools of pleunt c pin The fe cred 1801 s no galy s ici montaneous! She was sent lome to rt in bed Goes hematur 1 lope ant n Junc sie not I titler I was full ng ot One ao th later she was a Inttel to the lovers t of Ill no s llors tals Senas a p me there was nese nder the eyes the lympl no les were sl ght! enlarged but the Iver anleen aere not palj ble Tle blood pres ure and opt e fund were normal ! sto em *4learl at the app Crous ! em tuna & nofel and 7 gra profe n was ·VUEHIRCLE, LARK, PIRANI, AND POLLAK TABLI Clinical and laboratory data from eight patients with SLE and the nephrotic syndrome Lt ne Serum Patient Age Set Edema BP Pro tent Present Status Onset of dema Red cells Casts Fatt Cl olesterol Cholin * L Albumja #19 BJ #23 IS me/ 1 pll 100 100 mil's m! 13 F +++ 110/80 ++++ Slucro Hyalıne NL 22425 January Alise Arnte Granglar 1955 mia und hy pertension 31 F ++++160 00 17 6-23 D GTORA Hyalne Custs 27 425 0 90 Varel Died January Granular DRB 1931 1956 Rena RBC failure 46 +++ 150/90 93 Micro Hyalino Nil 26 460 02 June 1955A1ye Cbro Granular mic renat Cellular Failure 29 F +++ 180/190 Groas Hyalone Casts 3 410 - Apl 1955 Died May Granular DRB 1955 Renal #24 WII *25 RN fa lure prte Tena! #27 \ I 127 F ++++ 132/78 ++ ++ Crons Hys) de Vil 20369 - January Thed Slay Granulur 1955 1935 Renal Cellular During failure and atute TN nancy creatitis * 29 RC 34 r ++++ 141/92 ++++ Micro Ifyaline Casta 20401 17 Septem Alive Chro Grapular DRB her 1952 me fasure 31 RZ 21 * ++++ 110/109 2 4 10 7 Stero Hyaline Casta 2460 May 1952 Died August Granular DRB 1955 Rena! RBC failure OB 22 V ++++ 110/75 ++++ Viero Haline Casts 21 471 Apnl 1951 Died June Granular DRB 1956 Real RBC failure WBC Grams per 24 hour or plus onits 1 PRB - doubly refractile bodies i Case studied post mortem only ta manifestations of SLL In particular we have confirmed Brenner's observation (35) that shin lesions inay be absent in the presence of the nephrotic syndrome Three of these patients are aluc (three months to three years after the onset) and two are slou ly becoming increasingly azotemic The other four died from two months to three years after the onset of edema All died as a result of their kidney disease, except patient #27 who suddenly des cloped acute pancreatitis when she was already scr crcly all from renal farlure At the time of the initial histologic study, membranous glonteruloncphritis was seen in four, subacute glomerulonephritis in thrce Case $19 des eloped the ncplırotic syndrome at the time of her second biopsy which show cd membranous and proliferative glomeruloneplıritis When serial histologic studies were done (*23, 25, 27, 29, 31), the lesions scre found to have progressed in all ·LUPUS VEPIIRITIS 27 sy stol c murm roer the precord m The I er spicen and lymph nodes were not enlırged Ur paly & was unchange! The ur ne spec fic gray ty tras fixed at 1010 The blood and blood creat n ne had increased to 41 and 47 mg/100 ml respect els Ste bad hyper c lorem e ac do s (CO 16 mV/L cl lor de 12 meq/L) Tic serum albm 1724 36 and uc glolul n 1.8 m/100 ml The ser m cl oles erol was 376 mg 100 ml Vany E col an! h olyt cc (cooCac cultured i om te urne I renal b ong was done on February 7 1955 Foth al u on to the hosp tal In July 1925 ) or el cul cond ton cas unchanged. She 1 ad azotem 1 and hypercl lo em c ne do s The lyer and spleen were agin cnlarged Cross hematuria pere sted Sle became short of breath and compl ned of tredness and was ad mtted to hosp tal th a l cmatocrt of 190 These symptoms o ed after trin fus on of one I ter of I lool Tl e ur pary fiud ngs ere uncl anged but the blood creat o ac lalrun to -9 mg/100 ml antic non prote ant ogen to 61 mg/100 ml A fourth renal b op *18 made on Septetober 10 Flihald on to the losptal From September to no ember 1955 she had to cre menor rh ag aandag se rly anem c She hal dyspnca on crert op parory stoat Docturnal dyspnea an I complı nrl of sc ere lead ches On exam nat on the blood presue was 210/110 mn IIg the le rt wa enlarged I rudates and I emorrhages and sl g! t rap lledema were noted a the opt e fun! Tle hematocr t was 20 the bleed ng t me was prolonge 1 to 10/2 mn tes ani de protam net mt no was in ren ed nd cut as the pre ence of a pose ble 1 eparn lhe rulat ng ont oagul nt Ti e bloo I creat n ne * 997 mg 100 ml and the CO omb n ng rower #19 17 mWIl er sc was treated » th a low so I um low protendct pentol n um reerspine an I cl lorpromaz ne Final an on to the hosp lal was n December 1930 Schui been om t ng for onc neck Tiel er and sl en were no longer palpable The ur ne conta ned proteo 4+ miny ery hocytes 5 8 le o cs and many granular and cellular cats Pote all and on c ococe were ul ulf om at The blood creat n ne tras 11 8 mg 100 ml and the Lloor! NP was 10 mg 100 m Sic had an ep ode of acute lus g per ton is with ady nım c lcus (29) Ti s re ponderi ell to treatment motra enous I, Irocort sonc 600 mg daily Tiereafter I er copd t on g a lually deter orated and she d ed on January 110/ 1906 It the pot mo ten crim nat on there tras serofih nous per cards and picur 8 gen cral zed c len a and anscurca The left cptr cle ras enlarged an il cr an 1 spleen were both enl rgel Thch loc s were moderately contractel and there was a b lateral p clonephr 19 and cyst ty FB op v (July is ide uate renal co tex (5 glomerul ) and medulla were acl lcd n the sect ong 1 lo mo lerate th ken ng of the bu çment membrane of te glomer 1 was seen TI ; rear d some hat smudg in pl ces 11 te loop lesions were boted but there was no leur te dence of fibnno d el ange in the basement membranc Nether Iypercell la ty of the glomerul Doradles ons were noted 1 small amount of prote nacro & material » 9P went th n Bowmins spaces The lang ep the) um of the consol te! tblcs 19 mot rately leg neratel and a stal amount of pro e Daceous material ras roon ntlerlno In er tal fibro 9 and edem trere siglt omal h al ne ch 10gc9 were seen the walls of the snall Llood vessels Du ono Iocal and gen al zod m mbao aglun lonephnis $ cond Bop y (October 190) (Fg 11) Adequate real cortex ( glomerul ) an! moduli were 1 del in the act ons The glon en lncre profound! alteret #th rather or crecen a lob lat on and hyj ercellular ty The basement metnbrane was moderately th Leocl ani sm lg & Eget Dg * e loop Ics ons There were a few adir ons between the glon eri!rtis ant Bowman s cars les but no cp tlel nl cres ents were noted In an o ci onal glo crulu kary orr) er 3 #18 soen but no hematoryl n bod cs were present very binall amount of prote onceous material was present a some of Bowman & spaces Tl re was a nther markel atroply of the con oluted tubulce boce ln ng ep the m noir 1 to incre lrk er rl Thetlat Im on 1 Ded a molerate amo at ·56 VUEIRCHE, KARK, PIRAVI, AVD POLLAK 40, ES 32 years HCH 2011 A bumn 6 on/100 ml 500 Cholesterol 400 mg / 100m 200 pinong Phos mg/100 ml Colc um mg/100 ml ៩៩៩។ co MM/L 120 Cho de F110 meq/l 100 -25 Prote nuro 90 12 m/241 O Ur ne 1020 SD Gr 1015 1o Urea 60 40- Clearance 20 % ANRF 0 NPN 757 25 PSP 123 Excre on 15 m LO -45 Creatine mg/100 ml 60 monoc 25 LU = H Glomeru or O damage H stologkol 2 Tubular dam damage 0 Intersttol edema Intersti al 1 boss wy Sept Nov Jon Feb Mb Apr May J Jury Aus Sep +--/994-------1955 - FIG 10 Patient *23 Chart illustrating the histologic changes in four biopsy sperimens and the changes in renal function and Liochemical findings over a period of 15 months The patient died in January 1996 (sce text) found in a 24 ho ir urine specimen Many leucocytes and numerous hyaline granular and fatty casts were seen in the sediment The hematocrit was 21%, the leucocy te count was normal and the ESR was raised The blood NI \ and BUV were 41 and 21 mg/100 ml rabant at TI. 1 r 197 ml/min, and the TAPAR 1997 mg/min She was kept in bed the sodi im in her dict wag restricted but she received no sterous A renal biopsy was made on July 11 Gross / ema turia persisted Second admission to the hospital In September she became fes crish lad abdominal pain and a recurrence of ankle ciema On readmission to the hospital anasarei and pallor were noted The bloo 1 pressure was 160/90 mm Hg There was a right pleural effusion and ascites The liver was tender and both later and spleen screenlarged The left ankle was painful red and swollen The hematocrit was 20% There was gross hematuria and proteinuria Many Icucocy tes doubly refractile bodics hy alınc granular fatty and erythrocy te casts acre found in the urine Renal function as ses erely impaired The NPN and BUN were slightly raised The total serum protein was 54 gm/100 ml (albumin 35 globulin 19 gm/100 ml) The serum cholesterol 529 375 mg/100 ml The Coombs and Il assermann tests were negatie The ths mol turbidity ras 47 units p coh and an hemolytic enterocorcus were grown from the urine She was kept in bed, the sodium in her diet was restricted and tetracycl dc was given Marhed improvement followed Her temperature became normal The spleen and liver were not palpable The edema subsıded and the urine became sterile A renal biops wis done on October 5 Third admission to the hospital At the time of the third admission to hospital in Tebruary 19.5 she had malaise and persistent gross hematuria There was periorbital edema but no anlle edema She ris pale The blood pressure and optic fupdı merc normal There was a ·LUPUS NEPHRITIS 59 11 12 Patient #03 Third Bropsy February 1955 The glomenilir basement mcrabrane 19 d ffusely thickened and "stre loopg" Rre seen in places There is no glomerular hypercellularity Note the fibroep thelinl crescent in the glomerulus on the night The interstitial connective to Ica edematous fibrosed and infiltrated by numcrous chronic inflammatory celle The tu bulcs orc atiophie (11&L X 225) FIG 13 Paturnt '3 Forth Bop v September 1935 The glon rrulus 19 lot late lote 11 c smudgy thickening of the glomerular basement membrane an the clumping of endo thelial celle The interstitial true is fibrotic ani edematoug The tubules are atrophic (II (E X 430) ·58 VUEHRCKE, MARK, PIRLVI, AVD POLLAK Fio 11 l'alucnt *99 Second Bropsy, October 1954 The glonicrulus is lobulnted Note the endothelial cell prolferation and smudgs basement membrane thrchening in areas throughout the glomerulus The interstitial tissuc 19 edematous and the tubulcs are somewhat atiophuc (H&E X 430) of proteinucous material lynline casts were noted within some of the collecting tubulos The interstitial fibrous connectne te 1995 rather marked) inccred and edematovy and w98 infiltrated by a consı lerable number of chronic inflammatory cells in places changes suggestive of fibrinoid were scen in the small arteries Dragnosis Subacute local and generalzed, membranous and proliferatuc gloriculo nephritis and superimposed interstitial nephritis Third Biopsy (February 1995) (Fig 12) A sınall fragment of renal cortes (3 glomerula) but no medulla was included in the sections The glomeruli scre somewhat lobulated and markedly ischemic A diffuse somewhat smudg thickening of the basement membrane degenerative changes of the lining epithelium were scen They contained a relitnely small amount of proteinaccous material and in places a few liyalınc chats The interstation fibrous connective tissue as markedly increased and dematous It was jpfiltrated by a Jurge number of chronic ind immatory cells There 19 moderntc thu honing nn sclerosis of the walls of the small blood vessels Diagnosis Farly chronic diftise and ocneralized membranous glomerulonephr/14 ruth superimpo ed interstitial nephritre Fourth Biopsy (September, 1955) (Tig 13) Adequate redal corter (7 glomeruls) and medulli were included in the sections The glomerul were 18clicmic and lobulated and mther sei ere and diffuse thickening of their basement membrane was seen There was local hypercellularity Wire Joop' lesions and question ble fibrinoid changes were seen No proteinaceous material was seen in Bowmans spicce Many Bon man's capsules were ·LUPUS NEPHRITIS 61 Dragos Chronic diffuse and generalzed membranous glomerulonephries, superimposed acule 8 ippurative and chroni pyelonephritus Case 29 RC (RCE 415-95), a 31 year old housewife had migratory arthritis intermittent fever, and anorexia since 1919 For the next two years she suffered from pleuritic pain In August 1952 while vacationing in Floridi she developed an erythematous rash of the face nech and clbows Lesions of lupus erythematosus were found in a section of a biopsy of skin and Hargraves a cclls were seen on exam nation of the blood The following month swelling of the ankles appeared In May, 1951 she was admitted to hospital and found to have the nephrotic syndrome due to SLE The eyelids were puffy and there was much pretibial edema bilateral pleural cffusions and ascites The liver was enlarged the blood pressure was 153/98 mm Ilg but the optic fundi were normal The urine contained considerable protein and many hyal ne granular fatty and ery throryte casts Renal function was impaired The blood NPN was 69 mg/100 ml The brrum albumin was 29 g/100 ml and the serum cholesterol was 380 mg/100 ml Treatment with hydrocort sone resulted in clinical improve ment an ithe edem subsided The dosage nas reduce I when he developed a toxic pe closis In Jult she had rcrurrence of arthritis and picurit c puin She complained of a diffuse alopecia of the scalp On admission to the University of Illinois Hospitals for study in September the blood pressure was 141/72 mm Hg and there was no edema There was much protein in the urinc and leucocytes and many hy al ne granular and fatty costs were soen in the sed ment There was impairment of renal function A renal biopsy was done on September 28 Scaly erythematous lesions developed on the skin and regressed following trentment with chloroquin In Iebruary 1953 she had 4 streptococcal phary ng ts and fever arthritis and pleurisy Penicillin was gien an 1 resulted in an aprovement of her symptoms Two weeks later she was adm tted for at lds The blood pressure was 130 84 mm Hg Urinalysis was unchanged The bloort NP is 45 mg/100 ml Later the liver and spleen bee me çnlarged She tas rendmitted to hospital in June There was no peripheral edema The blood pressure was 160/90 mm Hg and grade II hypertensive retinopathy was found on funduscopic cramına tion I third repal biopay nas done on June 21 Urinals sis 1128 unchanged at this time First Ruopsy (1 inc 195,3 Adequate renal cortes (5 glomeruli) and very little medulla trere included in the sections The glomerul were markedly schemic and somewhat lobulated Tiere was dst nct local hy perccllularity due to endothelial cell proliferation and a loc ut irregular thickening of tle basement membrane in a fen glomerul. In these same 2rcns there was slight harvorrhexis Lut no hematory lin bodies were seen There were numerous adhcona 1 ctucen the glomerular tuits and Bowman s capsules no epithelial cresrents wcie Dotel Bosman s spaces contained a small amount of proteinaceous material an Bow mans capsules were shghtly fibrotic TI e roni oluted tubules were atroplic an placca an! tl ri lin ng crithelum ras moderately degenerated Their lumina contained snall amounts of proteinaceous material The interstitial fibrous connective tissue was moderately increased and si ghtly edematous with moderate infiltration of chronic inflam matory culls Tiere was all th chening of the walls of the small arteries and changrs sug gestive lut not lignostic of fibrino d degeneration nere seen therein Mallory and PiS preparat ons conbrmed these findings In Oil Red-O preparations of frozen sections a ron siderable amount of fnrly granular l pid maternal 29 noted within the cells of the convoluted tubiks Gomoris pepirations for alkaline phosphatase in frozen dried material disclosed the ITC score of sery small amounts of the enzy me with the cells of the convoluted tubules Dupnosis Late sibacute local and generalized membranous and prolferatue glomerulonephritus Srcond Bwpsy (e plomber 1954) Aurquate reund cortes (8 glomerult) and medulla were included in the sections The glomeruli were ischemic and somewhat lobulated Parlial 11 alinization *03 scer in many due to fusion of thickened busement membres ·60 VUEIRCKE, KARK, PIRANI, AND POLLAK Fra 14 Patient #23 Autopsy January 1956 Note the sercre diffuse thickening of the glomerular biscmcnt membranes Tibrinoid changes and hyalinization are present in the glomerulus on the right Slight local hy percellularity is scen The tubules are atrophic and the interstitial connective tissue is fibrosed Cisen here there was cuidence of acute sup purative and chronic pielonephritis (H&E X 310) thick and fibrotic neither epithelial crescents nor glomerular adhesions were accn The interstitial fibrous connecte tissus was markedly increased and slightly edematous and there is a diffuse infiltration of chronic inflammatory cells The tubules were mirkedly atrophic and contained ocensional hy aline casts but little or no proteinaccous material The tubular epithelium #18 slightly degenerated The small arteries were sl ghtly to moderately sclerotic In O i Red O preparations only minimal fatty degeneration of the tubular epithelium tras noted Diagnosis Farly chronic diffusc membranous and local proliferalıc glomerulonephritu uith superimposed interstitial nephritis Autopsy (January 1950) (Fig 14) Many glomeruli wcre part ally or completely hy alinized others were aschemic and lobulated There was a severe diffuse thickening of their basement membranes which in places appeared smudgy and granular suggestive of mild aceous material hyaline casts and many polymorphonuclear leucocytes were found within the dilated tubules There were considerable degeneratic changes of and abundant granular lipid was seen within the lining epithelium of the convoluted tubules Tiere was fibrosis and but po fibrinoid changes ·LUPUS NEPHRITIS 03 and lympl podes were enlarged The left w st left elbon and left apkle tere pa af 1 red and s oll Tiere was 3+ pro en n the unne and erythrocytes a few leucocy es and many hyal ne and granular casts in thesd ment The blood APN was 34 mg/100 ml the serum cholesterol ras 10?mg 100 ml the albumin was 30 gm/100 ml and the globulin 1930 gin/ 100 ml The serum sod um was 12 meq/L and the chlor de was 96 meq L The Wa ermann test was po ve Vany Hargra esa cells were found on eram nat on of the per rheral blool There was x ray cdence of r ght pleural effu on SLE was d agnone Sympto matc mpro ement followed on treatment with 100 mg cort one d ly On December 15 she became feverish and acutely ill and was readm tted to ho ptal The e was cdema of the eyel ds and legs a macular face rash and enlargement of all the lymph nodes The bloo 1 pressure was 150 90 min Hg B lateral pleural effus ons were found There was a ta hy ad and ev dence of myocard ts on the electrocard ogram Protein many 1 ucocytes a fer erz throcytes and muy granular and hy al ne ca ts were found in the u ne The serum albim was 2 6 g/100 ml The hemoglob n was 8 4 g/100 ml and the \PV was 49 mg 100 ml When treat oth tetracycl De and ncreased doses of ot one she mpro ed remarh hly and be ame asymptomat c The do gp of cort cone was reduced to 75 mg da ls on ds large f om tlc hosp al One cekl or she was realm tted wh acute ab lom nal pan an 1 anusar? The rash was st Il pre ent and the ret nal arter oles ro in spasm The bloo 1 p essure was 190/100 mm Hg Tl e abdomen was rąd There was rebound ten lerness and hyperact ve bowel sounds The 1 and lymph nodes ne e enla ge There was gos pop pur a and g 099 hematur 1 The ur nary spec fic gra tv as fixed at 1 010 Many lcu ocy tes and hy al de gran lar and leucocy tc casts and doubly refract le bod es were seen the ur ne The blood NPN was 110 mg 100 ml R nal funct on wag s crely mpe od The serum album was 1 7 gm/100 ml the scr m chole terol ras 13 mg 100 ml and the serum chol nesterase was 038 A pH un ts per hour Tle Wassermanu te t was negat e Many larg aves s cells we e found on pran nat on of the bone marrow The dosage of co t sone was ncreased to 75 mg day She became afebr e and the I ematuria ceas d The bloo I NP fell to 47 og 100 ml On Jan vry 19 1955 1 renal lopsy nas done and subucute glomerulonephrts vas dgnosed E col was gonn r peatedh from the unne but cultu e of the renal «e ster le Sło as ds larged I om tle hosp tal and cont nucd to take ort one at lome Hos two weehs later on r bruary 7 she was re dm tted with pulmonary edem Ti e blood gres u e was 195 110 mm Hg the pulse as rap d and a gallop rythm was foun! So was Ancm canl was p og Trinh blood n the ur ne Thc bloo 1 \P\ was 81 mg 100 ml Sle was ac lot il e serum potass u n was 7 5 meq I She expr da coma tl ree days later Renal Ropay (Ja Q v 1005) (Tg 15) S et ons nclude 1 a small fragment of renal rotor (6 glomer 1) but no medulla The glomerul were is bem e some hat lob 1 ted and I jer cllul r Tico $95local rregular th chen ng of the basement membrane In somo glomen ! part al hy u n zit on of the tuft was noted In plares the th chened basement mrmbrane was sm dgy and granular strongly sugge t og fibrino d la o ler glomerular tufts we loop les ons ere scen Bowmans c pils were th honod and fill o cd Łp thel al cll prol fc at on formed cre cents a Bonman s spuccs a cl conta and a mo lern c amount of ote naceo e nate al There was cons derable at oply and deg nc a on of the In ng er helm of the con o te tubules Ther lum 11 conta ned much prote on cous mater 11 H al ne css tere noted n . fen of the collect og t Lules There was rather mu kod nterstt 1 fib os h some edema and considerable afiltrat on of chron c nflam maton cell Sgh ¢ to mo lerate th chen ng and sclerose of the fall of the sinall arter es el ADR 9 yg te of fib bod Mallory and PAS preparat ons confirmed the poene of fibr no d mater al n the glomer1 WYSON Duigno, Lale s ha te lo al ani o meral ze! poll of ead men branous plome loneph tus Tutor y (Februa y 1950) (I gs 16 an 117) The glon eral were moderately as percellular loh I tel anl ischem In man the tufts were compres 1 by Inrge fib oep th el 1 ·62 VIL EKRCKF, KRK, PIRAVI, AD POLLAK and obliteration of capillary lumina 1 few areas of hypercellularity were present There nere many adhesions between the glomerular tufts and Bowman's capsules which were thickened and fibroscd few "sare loop lesions were seen, but no definite fibroinoid changes were detected within the glomeruli either epithelial crescents nor'hematovy lin" bodies were scen Marked atrophy and rather severe degenerative changes were seen in the lining epithelium of the convoluted tubules Their lumini contained a modernte amount of proteinaceous material There is a marked increase of the interstitial fibrous connective tissue whuch was slightly cdematous and contained numerous areas of cl ronic inflammatory cells A few tubules contained hyaline casts Slight sclerosis and some fibrinoid changes were boted in the walls of the small arteries Mallory and PAS ricparations confirmed these findings Comparison with the previous biopsy revealed a marhed increase in the scverity of the lesions Interstitial fibrosis and atrophy of the tubules was more marked and the fibrosis of the glomeruli hnd progressed Diagnosis Chronic local and generalized membranous and proliferative glomerulo nephritis superimposed interstitial nephintus Therd Bropsy (June, 1955) Adequate renal cortes (11 glomeruli) and medulln were included in the sections Some of the glomeruli were completely hyalınızed In others there was a rather diffuse and screre thickening of the basement membrane and wire loop Irsions were scen There was little or no evidence of glomerular hy percellularity Bowman 8 spaces were free of proteinaceous material and contained no epithelial crescents There was either modernte atrophy or some dilation of the convoluted tubules They contained a small amount of proteinaccous material and were lined by a slightly degenerated epitheinum A few hynline casts were noted in the collecting tubules The interstitii fibrous connective trasue was moderately increased in areas and iras infiltrated by chronic inflammatory cells Slight to moderate sclerosis 1:15 noted in the walls of the small arteries but no definite fibrinold changes there seen Diagnosis Chronic local and generalized membranous glomerulonephritis B PSEUDO-WEPHROTIC SI \DROVE The four patients who died of SLE with lupus nephritis and the pseudonephrotic syndrome were all young women who were critically all throughout their discasc (Table VI) None of them lived longer than five months, and tuo (case X28 and MO) died muathin a few wechs of their first symptoms Two cases (x28 and 30) cre treated with ACTH and cortisone, but to no nvail One patient (casc 28) died of myocarditis and renal disease The other three patients died in renal failure and uremna Oliguria was present, but none was anuric ll ben first admitted to the hospital, all these patients were edematous and looked "nephrotic" They were pule, their fees yere sollen, and their cyes were puffy It was, therefore, with some confidence that a clinical diagnosis of the nephrotic syndrome was made, and the finding of abnormally lon ecrum cholesterol levels occasioned some surprisc However, the other laboratory dat1--sase for the low serum cholinesterasc lccl in case #30--were consistent with that is usually found in the nephrotic state Casc SO BS (R & E 494717), a 27 year old negro factory worker enjoyed good health until July 1954 when she had supraorbital headaches and was found to be anemic One month later r r ·LUPUS VEPIIRITIS 65 Fra 17 latent #30 Ai topy February 1965 Ti e glomerulus 18 adhereat to Bowman's capsulc m a few places Note the sudgy thickening of the glorcrular basement motobrane and a small area of hary orrhexis The vascular spaces around the glomerulus are copgested (IT&C X 310) crescent. In others there was irregular local thuchening of the busemoot menbrane al though no typical mirc loop lesiong scre noted In a fer smudgy granulir fil rinod changes were not in the basement membrane In a ſes glomerul conderable har or thesis was sent but no hematory lin bodies were detecter! There was a mo lerate to sovcre interstitial fb10914 with cons lerablc edema and infiltration of Chiropue inflummatory cells Ti e consoluted tubulcs were either atroplac or dilated Their epithelium w33 low cuboil an degrnerite! Their Jumana contained proteinaceous material and occasional hyaline casts TI c small blood vessels were congestel Occasional focal fibrinoid changes *ere noted in the slightly thickened walls of the ema!) arteries Mollory ap 1 PiS prepara- Lions confirmed the presence of fibrinoid material in the glotterul anl in the walls of the artenolog Oil Rell-o preparations disclosed the presence of fairly abundant granular I pid materinl in the epithelium of the convoluted tubules Comparison with the biopo revealed some increase in the severity of the leaons partorularly in the degeneration of the cubule, Duonos Lnte subacute defusc ani generalized proliferatie an I membranous plomerulonrphilus This case presents rather strikingli the severe insolvement of the kidneys text in the patients ll sath the preudo seplyotic sy mume aml lappure tutis The clinical state and course of the patients parallcis in severity the degree of renal dunge The type of lesions seen in these patients 19 also shonn in Color Plate-Fus 9 (Case X32) Asses-nent of the histologic analyes gn en in Table IV indicated that prohleratne and basement membrane changes were not strikingly different in the nephrotic and reudo nephrotic groups Moncler with respect to 'hy aline' thromb "uire loop lesions, harsothers and the presence of hematory lin" ·F10 15 Patient X 30 Blops, January 1955 Note the epithelial an 1 fibroep tl el nl crescents Ti ere is partial lyalinization of some glomerul Come hypercellulrity and irregular thickening of the glomerular basement membrane is also present Mote the interet tilf brosis and edema ani tie atropl y of tlc tubulcs in many arcae (HCL X 200) 11G 16 I altent *30 Autopsy February 19,5 Bormans space is almost filed by a fibroep tl el il crescent wh ch completely surroun is the glomerulus The glomerular basement mcnbrane is em dgs and irregularly thickened Tie per glomerular ti je s infil trated ly arge number of cl ron c inflammatory cells (H&E X 310) 61 ·LUPUS NEPHRITIS 07 TABLE VIT An analyms of the nature and severity o the Tenal lenons in 40 abnormal hopy and 9 autopsy specimens from $3 pahent teith SLE (4) Biopsies (40 specimens) (B) Autopsies (9 specimens) Histologic Features Analyzed Grades of damage Grades of damage Total number ab Domial Total fium berab 4+ 3+ 2+ 1+ 4+ 3+ 2+ t+ Dormal 7 0 10 3 2 0 17 10 8 9 Glomerul Bisement membrane thickening Ware loop" lesions Fibrinoid Typercellularity Focal neer0919 kary orcheria Hematoxilin' bodies Hy aline" thromul Capsular udlesions Crescent Ischem Protein in Bon mans Bhicc 200 30 20 0 0 0 1 0 0 0 0 1 13 16 21 15 10 6 2 I was 0 5 2 0 4 Mo 10+ 2 1 3 0 13 & 0 18 0 LE 3 39 0 0 0 0 7 0 0 4 26 311 0 0 6 7 Total glomerular dam ap 1 12 16 11 40 6 2 1 0 6 8 1 31 2? Tubulca Degeneration Atrophy Dilatation Protein in tubular lumina (as in tubular lumina OO-iso 15 7 15 15 6 16 12 8 23 14 0 1 0 0 1 3 9 7 4 9 0 0 5 1 2 3 3 4 3 30 23 0 2 8 Total tubular damage 1 10 9 16 36 2 5 2 0 0 4 Interstitial este I dem Il 0415 Indammation 3 4 2 7 6 5 10 29 23 3 2 18 16 4 2 2 3 0 1 0 1 1 Arterie Sclerose Fibrinord 0 0 3 0 0 5 4 20 | 13 23 17 3 2 0 * Cance au lied dini ilts and pathologicalls of the lesions enuncrated abouC was grauded from normal) to 4 plue (ex. treneli setere and affecting all or almost all of the appropriate structures, The details of the analyses 10 et forth in Tables Il and VII (2) Terminology- The pleomorphi-m ind patchy character of the lessons oí lupus nephritis inade ·G6 MUEIRCKE, KARK PIRANI, AND POLLAK bodies and fibrinold degeneration the affection of the glomeruli was more common and more severe in the peeudo nephrotic group (Color Plate-F1g 9) 2 PATHOLOGIC NATERIAL A Criteria for histologic analysis and definition of terms In diffuse disorders of the hidneys such as diabetic glomerulosclerosis or prohferatie glomerulonephritis it 18 upusual to find that all nephrons are af fected by the disease process Many are spared and even in those nephrons that are involved the glomeruli are not damaged in a uniform manner The histologic picture is une cn and the lesions can be seen to be in different stages of des clopment This was also found to be true for lupus nephritis In the carly stage of the disease at least three glomeruli out of every five were seen to be damaged but they were not affected to the same degree As the dıseasc pro grossed more and more glomerult were involved and the lesion became more diffuse but still unci cn in its de clopment The irregularity of the process made careful evaluation of the sections most important lest the degree of damage be assessed incorrectly or erroncous interpretations arise For these reasons among others a finc systematic analysis was made of each biopsy or autopsy studied Details of the analysis and grading are given belor In essence this is a scmai quantitatic histologic study which allon ed us to reduce inherent errors to a minimum It permitted us to make a nice assessment of the type and degree of structural damage in cich section it allow ed us to comprre-in dctul—the findings in serial studies of the saine patient and siis to prove useful in com paring the degree of structural change with data from tests of renal function In this study of patients with lupus nephritis it was apparent that an adequate renal biopsy reflected accurately the type and degrec of pathology in the hidncys In the nine cascs which were studied both by biopsy and at postmortem excel lent correlations were noted between the detailed analyses of the histology in the biopsy and in the utopsy specimens (1) Vethods of analysis On each specimen observations and assessments cre made with respect to the following structures and pathologic cntitics Glomerular damage was assessed as a whole and the following glomerular structural changes were assessed in dividually thickening of the basement membrane increase in cellularity of the tuft (endothelial or epithelial) hyaline thrornbi wire loop lessons harz or rhexis heinatory lin bodies fibrinoid changes in the glomerular basement membrane local necrotic lesions adhesions of the glomerulus to Bowmans cap sule and fibroepithelial crescents The congestion or ischemia of the tuft were also et aluated Tubular damage sas al o assesced as a wliole and the tubular changes observed and evaluated sere degeneration atrophy, and dilatation The number of casts in the tubular lumini was also noted The presence of pro tein.ccous material was sought both in Borman s spaces and in the tubular lumını In the interstitial tissue the changes er aluated acre the presence of edema of fibrosis and of infiltration with inflammatory cells In the vessel walls sclerotic changes and fibrinoid degencration were noted In each case the severity ·LUPUS VETHRITIS TABLI III in analjalt of the nature and sterity of the renal lesions in 10 abnormal biopsy and 9 autops / specimens from $3 patients utth SLE (4) Bop es (40 specimens) (B) Autores (9 specimens) I stolng Featured Analyzed Grades of damage Total nomber ab normal Grades of damage Tota! ber 16. ++ 2+ 1+ DOTTES 3+ 2+ 1+ 1+ 7 0 10 3 Glomeruli Bisement mirmbrano tlichening Hire loop lesions Fibroid Hypercellularity Local necrosis har orrhexis Hematovylın bodres Ilialınc throm! Capsulu adhesions Croucenta Lechemia Protein Bon min 0 0 0 1 0 0 0 0 1 0 0 17 10 8 9 2 5 13 16 1 15 10 6 2 1 10 23 30 2 13 11 CO-OOOOOOOO 2 0 0 0 3 0 4 3 7 0 16 3 35 0 13 0 JS + 9 מן #jice 0 0 4 26 30 0 0 1 6 7 Total glomerulardan app 1 12 16 10 6 0 & Tubulra Degeneration Atrophy Dilatation I'rotein in tubufar lumay Casts in tubular lumina 1 0 6 1 0 1 3 2 1 0 0 15 7 15 15 6 16 12 8 23 11 37 22 21 39 23 a 5 1 0 0 O 0 3 2 Total tubul ir damage 1 10 9 16 36 2 5 2 0 0 1 Interstatnl tigste I dem Fibrous Influtnimatron 0 0 0 7 6 5 + 2 . IS 16 19 20 23 3 2 2 2 2 3 4 1 2 + Arteris Sclerova Fibrino 0 20 0 0 3 2 0 4 3 3 $ Casek etu biet cmniealls an i pathologically of the lesions numcrited above was graded from (normal) to 4 p tremely severe an affecting all or almost all of the appropriate struct details of tlic anak ses are set forth in Tolles II and III (2) Terminology- The pleomorphu-m and patchy character of the lesions of lupus nep- ·68 MUEHRCKD KARK, FIRANI AND FOLLAK the selection of precise and descriptive diagnostic terms quite difficult Nonethe less in this study it was imperative to use accurate albeit cumbersome terminol ogy The following terms were chosen because they seemed to us to represent more accurately the character and degree of the histologic changes Glomerulitis tras used to indicate a proliferative and/or 1 membranous lesion of the glomerular tuits in the absence of any significant tubular damage or changes in the interstitial tossue Glomerulonephritis was used to indicate a proliferative and/or a membranous lesion of the glomeruli associated with tubular and/or interstitial tissuc changcs In both glomerulitis and glomerulonephritis the distribution and degree of lesions was specified by adding one or two of the following descriptive terms 1) Local referring to a glomerulitis or glomerulonephritis characterized by lesions affecting one or morc arcas within each glomerulus 2) Diffuse referring to le sons affecting diffusely cach involved glomerulus 3) Focal referring to lessons either local or diffusc affccting only some glo merul 4) Generalized referring to lesions eitl er local oi diffusc affccting all or al most all glomerul: (3) Material In the present study are included 57 biopsy and nine autopsy specimens from 33 patients The detailed histologic analysis for each specimen from cach p3 tient is set out in 1able It A summary of the histologic findings is set forth in Table VII A and B The slides from 21 cases of SLE in the files of the Pathology Departments have also been retien cd and the same methods of analysis described above were used to study them (Table I\) In addition 15 autopsy cascs of glomerulo nephritis were studied by the same methods (Table 1) These analyses were compared with those from patients with lupus nephritis (Table VI) B The renal lesions in cases studied by bropsy (1) The glomerular lesions- Thickening of the glomerular basement membrane The glomerular basement membrane is normally a thin delicate cosinophilic structure which is colored purplish red with the PAS technique and blue with the anılınc blue of the Nal knon n that the thickness of the basement membrane may vary within a muncu range in perfectly normal glomeruli Tlus is probably the result of distention or retraction of the basement membranc resulting from congestion or ischemia of the glomerular tuft and was taken into account before establishing the de grce of basement membrane thickening especially in the carly stage of lurus nephritis Thickening of the glomerular baseinent membrane was present in all 40 ab ·LUPUS NEPHEITIS 09 Tig 18 Patri #1' Scond Borey May 1955 Tote the local ti henng of the glomert lar b soment membrano especially at the perplers of the glomeruli tuft The smudgy appearance of the ti hen og is suggest ve of fibr no i stange In the areas of tl chering note the sl git but defin te Isperrellularity due to clump ng an i/or rol foration of endo thel al cells (IISC X 500) normal bio sy and in all ninc lutop specimens It 12 more sciere in the autopsy specimens as inglt be expected Tlc thickening of the basement rem brane 1 1s usually local rat) er than difiu e the peripheral portions of the glo merular tuft being more commonly affected (Fig 18) Won present at least 50 per cent of the glomeruli xerc usually afiected A diffuse regular thichcoing of the glomerular basculent membrane similar to tl at scen in membranous glo merulonepl ritis 1128 observed only very late in the disease The scs crity of the thickening varied considerably in difierent are 19 of the same glomerulus (Fig 19) and from one glomerulus to another As it inerczecd around various capillary loops the capillary lumen proportionately decreased in size and contained fewer red blood cells In some cases the capillary lumina became completely obliter ated in patches (Tug 20) No cvaluation of basement membrane thickening was made when the glomeruli scre partially or completely hy alınızed Complete hyalinization was most unusual and was seen only twice (Fig 21) Il tre loop lcs ons were seen in 29 biopsy and all nine autop 3 specimens The incidence and sei crity of nire loop lesions # is greater in the autopsy material Tic c lesions were usualls not observed unless the thickening of the glornerudhr bi cinent membrane 19e at least of modernte ses critz (2+ or greater) Tl e insolied capillary loops aj perred stiff and rigid (Fig 22) Early in tlc drence they were seen in the peripheral portion of the glordcruli, later, ·70 MUEHRCHE LARK, PIRANI, AND POLLAK I'c 19 Patre 1 #29 Second B opsy June 1905 Notc a fairly diffuso but irregular thick.cn ing of the glomerular basement membrane and narrowing of the capillary lumina Mote also on the left the well organ zed adhesion between the glomerulır tuft and Bowmans capsule (HCE X 480) although they were more common at the periphery, they 31 cre scen in some cases throughout the glomerular tuft Slight to moderate fibrinoid chinnges were found in all but four of the scctions in which "wire loop 'lesions were scen Fibrinoid changes The presence of fibrinoid changes in the glomerular basement membrane and in the walls of the small arteries was recognized or at least suspected by the smudgy granular strongly cosinophilic appearance of the involved structures in II&E stanned sections (Color Plat-Fig 2 und 5) The affected areas appeared more irregular and less dense or stuff than com parable lesions resulting from hyalınc or amyloid deposition Confirmation of the fibrinord change was obtained in Mallory preparations in which the in volved basement membrane stained a reddish color contracting with the blue of the uninvolved connectic tissue (Color PlutoFig 10) In the PAS prer arations fibrinoid stained 2 particularlv intense red purple color With milder changes (+) the special staining reactions were not as specific Fibrinoid changes were found more commonly in the glomeruli than in the small arteries and ar terioles and were scen in 30 biopsy and in ciglt autopsy specimens Proliferative changes in the glomerular tuft Varying degrees of hy percellu larity acre noted in 29 biopsy and nine autopsy specimens Es aluation of pro liferntre changes presented considerable difficulty cspecially in the early stages of the discase when the degree of hy percellularity was slight Sections cut abole or below 5 microns--the section thickness used consistently in this study-mu ·Foc 20 Patient ** Autopsy Vay 1970 Note in one arct that the thickening of die glomerulur bneement membrie 19 severe there is complete obliteration of the capillaries And early by el Dizition [schere in the glomerulus the luis mrnt membrane 14 only moderatelsthickened (II&E X 500) 1.c 21 I atient 93 Rtopsy, July 1953 Parual and coinplete hyalinization of glomerul in advanced lupus nephritis In the glomerulus at the left si cre diffuse basement membrane thirkonior cin still br rrengoizel The degree of hu alihuzation of glomerult is unusual even in a lansat lurus orylintis (114! 230) 71 ·72 VUEURCLE ARK PIRAVI AND TOLLAK Fia 22 Pat ont * Bop y June 1955 Note thc d ffuse b t irregular th cen ng of the glomer ilar basement membrine Distinct wire loops can be seen especially at tlc per ph ery of the glomerular tuft Note that the involved cap llary loops appear st if an Ist ghtly smudgy (HLE X 400) lead to over or under evaluation of tl c degree of glomerular cellulırıty When hypercellularity was present in the milder lesions it was almost cxclusrely noted in the peripheral portion of the glomerular tuft (Color Plate-Fig 1) as it increased in severity it tended to become more diffuse (Fig 23) and was often associated with varying degrees of glomerulır lobulītion Local thichening of the baccment membrane or fibrinoid changes or both were observed frequently in the areas of hy percellularity In almost all cascs tl e increnscd number of cells in the glomerular tufts aprerred to be due to endothelial rather thin epithelial proliferation It was only in the more advanced stages of lupus nephritis that epithelial cells appeared to have increased in number cither in the visceral or in the parietal layer of the glomerulus Reduction in the size of glomerular capil laries due to hyaline or fibrinoid changes led to a conglutination and apparent increase of endothelial cells in some arens Tlus vas taken into account before determining the degree of hypercellularity Local necrosis of the glomerular tuft A small local arer of necrosis in the peripheral portion of the glomerulus was one of the lesions considered strongly suggestive and almost prtl ognomonic of lupus nephritis (Color Platc Fig 2 and Fig 38 and 40) This lesion was seen in one or more glomeruli in 13 biops) and five autopsy specimens It was characterized by local areas of basement membrane thickening with obliteration of capillarics fibrinoid changes and early necrosis a few lymphocytes and occasionally polymorphonuclear leuho ·LUPUS VEPIIRITIS 73 110 23 Pat 16*', Propsy June 195, Note the marked by percellular ty of the glomerulus due to prol ferat on of the endothel al cells The breement membrane tl chening is m ld and 13 obsc red except in a fun arcis by the cellular prol fcrat on Th s type of d ffuse glomerul tis is not common in lupus nephrts (II&E X 370) cytes were seen harjorrhcus of endothelial cpithelial and inflammatory cells was an almost constant feature of the lesion and hematowy lin bodies were observed in about one third of them These local necrotic lesions resembled closely those which orcur in embolic glomerulonephritis of Lohlein By contrast with einbolic glomerulonephritis necrosis was not is prominent inflammatory cells were less numerous and micro organisins cre ncier observed cien in sections especially prepared to demonstrate bacteria harz orrhexis was common to both embolic glomerulonepl ritis and lupus ne diratis but the presence of hematory lin bodies mas con viered quite characteristic for lupus nephritis The nature of the local and focul glomerular necrosis in lupus nephritis is not well understood Ilematox jlın bo les were observed in only four biopsy and three autopsy specimens They were found only within tl c glomerul) in as ociation invariably with hary orrhexis and u willy with fibrinoul changes (Color Platc-Fig 9 and Fig 10) They were rounded or oral structures of approumately nuclear size or smaller they stained dark lascnder to purplish red with hematovy lin in contrast with the blue black color of the nuclei Additional stains used for the identification of heinator; lin bodies included iron hematory lin (blach) and pyronine (purple red) These speeral stoning reactions were not found to be essential for their identification Hyalınc thromł z which occluded the lumni of the glomerular capillaries ·74 MULTIRCLE KIRK PIRAVI AD POLLAK were observed in threc qutor sy specimens and were not scen in the biopsy specimens They were rounded or elongated cylindrical structures homogeneous and strongly cosinophilie (Color Plate-Fog 9 and 10) They filled more or less completely the lumina of the capillaries and frequently were attached to the capillary wall These thrombı ieacted in a strongly positive minner in PAS preparations and stained red in Mallory Azan preparations No red blood cells were seen within them nor were they thought to participate in their constitution The staining properties and general appearance of hy alıne thrombı made differentiation from superficially similar enpillary lesions such as tose ob served in diabetic glomerulosclerosis quite easy Ti e material constituting hya line thrombı although not exactly identified lustochemically, was certainly morc closcly related to fibrın or fibrinoid than to hy alınc It appears to us that in this context the term hyalınc should be abindoned in favor of fibrin or fibrinord Capsular adhesions Adhesions between the glomerular tufts and Box mans capsules were observed in 16 biopsy and in seven uutopsy specimens In the carly stage of their des elopment thin strands of smudgs or smooth hyaline material ucre seen As thcsc synechae became larger they involved progressively larger areas of the surface of the glomerular tuft and eventually formed well developed fibrous adhesions (Color Plate-Fig 3) Frequently the process 179 accom panied by a certain degree of retraction and distortion of the glomerulus Ad hesions des cloped particularly in relation to areas of local hy percellularity or necrosis of the glomerular tuft (Tig 39 and 40)-evidently as a result of in flammatory alterations at the periphery of the glomerulus Fibro cp thelial crescents were noted in three biopsy and in tlorec autopsy specimens (Color Plate-Fig 6 and Fig 15 and 16) They were always asso ciated with capsular adhesions Thcy di l not differ significantly from the fibro epithelial crescents scen in the common variety of subacute glomerulonephritis Glomerular ischemia The number of red blood cells present in the capillaries of the glomerular tuft was evaluated Our criteria in thus evaluation were based on our experience of approximately fifty biopsy specimens of cssentially normal hidneys Grades from 0 to 4+ indicate progressively sci crc degrees of glomerular ischem It was seen in 38 abnormal biopsy specimens and in hinc autopsy specimens The presence of ischema was thought to be significant only when associated with other lesions of the glomerulus Overall glomerular damage After cach element in the glomerulus had been analyzed independently an estimate of total glomerular damage was made The degree of glomerular dumage was graded in ti e usual manner taking into considerntion not only the severity of the lesions but also the proportion of af fected glomeruli Various degrees of glomerular damage were found in 40 biopsy and in nine autopsy specimens As expected the incidence and severity of the glomerular lesions was greater in the autopsy specimens (2) Tubular lesions- The state of the renal tubules as also et aluated As in many renal discases the changes observed in the tubules in the various stages of lupus nephritis nere ·Llet's \FPIRITI> 75 not specific An accurate analy is was made onls of the changes scen in tlic proximal and dental consoluted tubules ance renul medulla nas present in approximately fifty per cent of the biopsies In biopsy material the appearance of the tubular epithelium, cien in the normal hidncy was different from that usually scen postmortem A. n rule in bop specimens the free margin of the cpithelial cells was more irregul ir and there 119e greater variation in the height of the cells As a result the size of the tubul ir luncn al o izried The cause of the irregularity of thic frce margin is not known It may be the result of the trauma of the biopsy needle Another po--lele explanation is that it is duc to the varying activity of the ecil and represents ab-option of protein and solutes The varying lierglit of thic epithchum nay represent varying states of diureis (28 135 181) These features peculur to brop material made the cu aluation of tubular dam ige inore difficult Degeneration of the tubular epithelium was found in 37 biop- and nine au topsy specimens Various features 11ere then into consideration The following features cre commonly found swelling of the cells with or without vacuolization of their cytoplasm ind un ciconi e irrigul irits and frying of the frec margin of the cells with loss of the bru- border (Fig 39 and 40) In a few cases in which Oil-Rod O prep ir itions for lipids were made vacuolization ans soon to be due to ſat droplets Occasionalls fincly disided lipid material was observed in tubular cells in thich vacuolization was not cudent in H&L preparations At times the cytoplam) of the tubulai cells containel co-inophilic hyalinc' granules These rirely gue a strongh poutre reaction in PAS preparations These granules may reprevent the results of tubul ir protein reabsorp tion (210 211) In a fox cisc thc Gomori teclinique was used to stain alkuinc phosphitise in the tubule- It appeared to us that the concentration of this enzyme was decreased proportionately to the degree of tubu) or degeneration Laluation of this feature 1198 difficult Iecause of the lack of a sufficient nuinber of normal control biopsy specimens and because of the observation that even in normals there was 1 considerable iriation in the concentration of alkalinc phosphintase in the tubular cells trophy of the conı oluted tulules was judged by the reduction in the size of the tubules and in the number and size of their cellular componente Pyknosis of nucle was frequently fociated with cellular itrophy 19 a rule the tubular biscinent membrane was tluckened in those cu-in wluch atrophs 1199 sciere Tubular atrophy was observed in 22 biopsy and even autopay specimens (Fus 12 14 and 151 Dilatation of trimis 15 Olenalm 1 loop- ind m four au DOC)- mens As a rule dilat ition 176 found only in some groups of nephrony while others were ntropheud (Fig 8 and 211 It never reached the proportions sein $0 conmonly in chronic renul de particularis pisclonephriti Proteinaceous material utprent in Bou minap ICT (I 18 40) ind in the luming of the convoluted tubules in uning atiounts eren in renal tis-ue from patients whose urine 1199 (ret of ramtlic int amounts of protein it tiine the tosinophilie aniorphous or granulat protein irony- miterial app and to be in ·76 VUEIRCKE KARK PIRAVI AVD POLL 4K direct continuity with the irregular free border of the tubules and with the cytoplasm of the cpithelial cells of Bow mans capsule end of the tubules Ilow ever in many cases the protein precipitate appeared to be free in the lumen and its amount was roughly proportional to the degree of proteinuria (sce also Table XIII) Casts The casts seen within the tubules were usually liy alıne less commonly granular ind infrequently cellulır i type Try throcy to casts were seen in only one case (X23) As a rule the casts stuned a deep red purple color with PAS Occasionally they were quite large and hid 1 595appetrince They seemed to be more numerous in the collecting tubules Occasionally casts cre observed in biopsy specimens which were otherwise entirely normal Overall tubular damage The estimate of totul tubul ir dumage was made after the above features were analyzed The tubules were damaged in varying de grees in 36 biopsy and nine utopsy specimens and were significantly more severe in the latter (3) Interstitral tissue The appearance of the interstitial tissue recen cd considerable attention It is in our opinion the forgotten tissue component of ti e hidncys and abnormalities therein may have greater functional significance than is generally thought (5 89) The three basic abnorinaltics obsericd in tl e interstitial fibrous connective tissue were cdemi fibrosis and inflamination Edema nas found in 19 biopsy and in all nine nutopsy specimens It 198 clivracterized by a swelling of the connective tissue with resulting separation of fibrillar and cellular elements and often a change in stuning qualities The normal cosinophilia was usually decreased and in patchy vrt of several biopsies a pale gray bluc color was noted suggestive of alterations in the mucopoly caccharides of the ground sub stanco (Color Plate-Fig 6) In gencr il cdemu was noted in the relatively carly stages of lupus ncplırıtıs and reached its maumum in the subacute stage of the diseisc (Fig 8) larying degrees of fibrosis were noted in 28 biopsy and in eight autopsy specimens Ti e degree of fibrosis wis related to the chronicity of the disease As the disease process become morc clironic 7 greater density and occasionally hyalınızntion of the fibrous connective tissue was observed (Fig 12 and 14) PAS and Mallory preparations were useful in er aluating these changes more accurately Il lien present both interstitial cdema and fibrosis were pately in distribution especially in the corter and as a rulc were seen in areis where the glomerul were more severely damaged Interstitial infiltration of mfummatory cells 17 18 noted usually in the moder ately advanced or advanced stages of tl e disc9cc and was found in 23 biopsy and cight autopsy specimens It is characterized by relaticly small numbers of lymphocytes plusmn cells and histiocytes located is a rule in the areas of fibrosis and cdema (Fig 8) Peru ascular di tribution of interstitial edema fibrosis and inflammatory cells was not a striking feature Occasionally large infiltrates were observed which were often periglomerular especially when acute lesions were present in the glomeruli (1 18 16) In a few chocs a super imposed infection was suggested by the large number and distribution of 10 ·LUPUS VEPIIRITIS 77 flammatory cells and by the presence of neutrophils and co inophile This interpretation was reinforced on occasion by positive bacterial cultures obtained from renal tissue at the time of biops! Neither definite fibrinoid changes nor hematoxylın bodies acre obscried in the inter titial fibrous connective tissue (4) Tessels As a rule a few emull arteries and interioles could be recognized in cach biopsy specimen In general the vascular changes were not impres lle The most common arterial lesion 1 is fibrol of the wall with or without halınızation and mild narrowing of the lumen clerosis of the vessel all was present in 23 biopsy and six autopsy excimens A significant degree of a cular scleros19 was seen only in the more unced and chronic stages of lupus nephritis Fibrinoid changes in the really were e irefully scarched for and were observed in 17 biopsy and se autopsy sprcimens Joker they were of significant de grec (2+ or 3+) in only four biopes and three autopas specimens (F1s 24) The presence of fibrinod in these cases is confirmed by the staining properties of this material in PAS and Vallory propritions In general fibrinoid was less commonly observed in the walls of smilt arteries and arteriols than in the glotncruli (The character and distribution of real lesions When the detailed analy is * as completed a pathologic dignosis was made for each biopsy and each autopsy speeimen using the decriptic termunology FIG 21 Case of SLF from po mortem series (RSE futon 130/129) Small renal arter Sole revere fibrinoi i chioges in olying most of ulc sesi ll There are a few Infum ator cells in the perirternal trsucs (IAT X 330) ·78 ML FIIRCLF MARK PIRAVI, AD POLLAK TABLE VIII The type and distribution of the renal lesions au lupus nephrttra in 40 abrormal biops, and 9 autops / specimens Clomenul tas Glomerulonephritis H stology of Lupus Nephrts 15 b opsy and no (0) autopsy speramens 25 b opsy specimens 9 autopsy specimos 6 G 9 3 12 1 Type of lesion (a) Membranous (b) Proliferative and membranous (c) Vembranous and proliferative (d) Subscute (e) Chronic 2 Distribution of lesions in glomerulus (a) I ocal (b) Difuse 3 Distribution of lesions throughout section (a) Focal (b) Generalized 2 0 7 3 2 0 0 6 5 15 0 20 5 5 10 3 22 0 9 defined above In Table VIII are grouped the various dingnoses according to the character and distribution of the lessons Glomerulitis was found in 15 biopsy specimens but was not seen in any autopsy specimen The lesions within cach glomerulus were local in all cases with glomerulitis, and in most of those with glomerulonephritis Diffuse lesions were noted late in the course of the discase only in fire biopsy and four autopay speciinens Focal lesions affecting a few glomeruli were found only in five sections with glomerulitis and in three with glomerulonephritis Thus in the majority of cases the lessons affected all or almost all thic glomerul-even when the renal lesions were in an early stage In all abnormal sections examined glomerular basement membrane thichening was scen Associated proliferative changes were noted in 25 biopsy and seven autopsy specimens Proliferative changes were slightly more predominant among the biopsies wath glomerulitis, changes in the basement membrane predominated among the biopsy and autopsy specimens wath glomerulonephritis In 15 of thc 31 specimens dingnosed as lupus glomerulonephritis the histologic picture was either subacute (scien cises) or chronic lupus glornerulonephritis (eight cascs) The histopathologic criteria used to diagnose the subscute and chronic glomerulonephritic stages of lupus nephritis were not significantly dif ferent from those used to diagnose the common types of subacute and chronic glomerulonephritis In the subacute stage, honescr, the glomerular changes of lupus nephritis were still prominent in most case In the chronic stage the changes were less suggestive of Jupus nephrits, and in some cases the changes of lupus nephritis could not be recognized When the histologic findings were analyzed for severity and type of lesions no differences were noted with age, sex, or racc No relationship was noted betn ecn the duration of symptoms and signs of SLE and the ses erity of the ·LUPUS NEPERITIS 79 renal lesions Honcier, once the renal lesion was established it was progresse in most instances D The renal lesions in cases of SLE studied postmortem In order further to es aluate the findings in the renal biopsies the hidney 8 of 21 autopsy cis, from the files of the Departments of Pathology were studied These cases were selected because they had had the characteristic clinical features of SLE during life, and because there une pathologic evidence of SLC in orgins other than the kidneys The findings are set out in Table Il Vany TABLT I in analysi8 of the natire and severity of the renal lesions in 20 autopsy specimens from patients with SIF Grades of Dainage 11 stolog c Features Analyzed Total \umber Abnormal 4+ 3+ 2+ 1+ 7 6 5 2 1 1 2 2 9 2 Clomerul Basement membrane thichening Wirel op 'truong Hibrinoid Ilyporecllularity I ocal necrosis hary orrhevig Hematorylin' bodies IIyaline' thrombs Capsular adhesions Crescents Ischemin I'rotein in Bou min 8 space 20 12 J 19 0 7 5 6 0 0 0 5 6 8 19 0 0 5 7 Total glomerular damage 1 8 $ 0 6 8 Tubules Degeneration Atrophy Dilatation I'rotein in tulular lumina Casta in tubular lumin3 4 12 S 7 0 0 1 ? 18 13 11 20 13 0 Total tubular damage 3 10 0 1 4 Interstitial ties le slenen Hidrox19 Taflammation 10 13 10 15 13 16 3 3 Irene Sclerosis Hibrino 0 0 1 10 11 3 1 * Cancs stu lied from the files of the Departments of Pathology 1913 1936 ·80 VILEHRCHE KIRK PIRIVI AD POLLAK of the cases in this group had died sth clinical cuidence of severe renul involc ment It is apparent (Tables VII Il and \1) that the incidenct and severity of the renal lesions was considerably greater in the nutopsy than in the biopsy specimens This was true of almost all features anak zed Lesions such as hematoxylın bodies and hyaline tlırombi sere definitch more common in the autopsy than in the biopsy specimens T) is 171.23 perlaps be cxplained by the fact that a far larger number of glomerult was available for study in autopsy slidcs On the other hand le sons such as local necrosis vcrc only slightly more frequent in qutopsy specimen In one instance tlc hidies w28 listologically normal Seycn bad lupus glo merulitis and thurteen wcrc digno cd 25 pus glomerulonephritis of the lat ter group cycn lind subacute lupus glomerulonephıritis and in no case was chronic lupu glomerulonephritis found Basement moint rane cl anges and cellular proliferation were noted in 12 cnscs chinges in thc bi cment membrane without proliferatic changes were seen in ught As 1194 cupected the hi to Fig 25 (a) Pat ene *30 A lopsy February 1955 Port on of external surf ce of a h dney in severe subacute lupus glomerulonephrit: The capsule has been remos cu Note the wo! len appearance and the d stinct mottling of the organ A few punctate / emorrhagcs can be Seen ·LUPUS NEPHRITIS 81 + Fru 2. (B) Talent 9.30 Atlopey brinty 1995 Section 11 rough 11e same kidoey Tote the mottling of the suollen corter Ti e corturomed vir jonction is detinet logic abnormalities in the hrdnesu progreed to in udi inced stage in a large proportion of the who had der Grossly the hidnets were heavier than normal and appeared sn ollen pale and mottled (Fig 25) A mild contraction of the bidnes 1595 son in ser, few specimens (Fig 26) Tlus 14 in Agreement with the cyprience of other investi gators who have ronarhed on the rarity of contraction of the hidness in SLE Ten of the 21 autoputes were done between 1943 and 19,0 the reinander from 1931 to 19,6 TIC lesions were distincth mori sestre in the later group This may be related to prolongation of life due to treatment of patients with ICTII anil steroid hormone A separate compari on 95 al o made lutscen the nine auto specimens from 49 clinically tudiet and trented by us and the 11 autopay specimens from patients who died between 1951 and 1950 and ho nere not tudied clinically by ue The inculenec anul scrits of the runnl lesions nas komen hnt more sciere in the group studied lng us (ur patients sere studied more clocts were treatel inore intensek and lito longer than the 11 p ·82 VLEIIRCHE KARL PIRINI AND POLLAK Ire 26 Patent*03 Autopsy January 1956 Chron c lupus glomerulonephrit , an gurer imposed ps clonephritis Sect on of kidney Note that the cortex is narros Tle rad at ng pattern of the pyramids us abnormally prominent Small interst tial abscese can be scen at tl c upper and lower poles tients in the post mortem group 1951 1956 Therefore the increased severity of the renal lessons in the group of patients studied by us may be related to prolongation of life I The renal lesions in cases of subacute glomerulonephntıs studied post mortem Because of the morphologic resemblance of the lesions of tle advanced stages of lupus nephritis to tho c of the common type of glomerulonephritis a com parative analysis was made of the histologic features in the two discases In Table are set out the histologic findings in the kidneys of 15 autopsy casca of subacute glomerulonephritis These were consecutive cases in the period 1952-1955 taken from the files of the Department of Pathology in all the clinical and pathologic features were considered to be typical of subacute glo merulonephritis and in none * ?s there clinical or pathologic eudence of SLE A comparison of these findings (Table 1) with those of the autopsy checs of lupus nephritis (Tables VII and IV) rciciled that although many features were common to both diseases there were also many differences (Table XI) Certain features considered characteristic of lupus nephritie such as local ne crosis kary orrhexis hematory lin bodies and hy alıne thrombı did not occur or were very rarely seen in subacute glomerulonephritis lire loop leciong and fibrinoid degeneration were far less commonly found than in lupus nephritis Mild degrees of glomerular hy perccllularity were common in Jupu nephritis but ·LE PLS NEI TIRITIS 83 TABIL in analysis of the nature and seterity of the renal lesions in 15 autop/ specimens from patients with subacute glomerulonephritis Cra les of Damage fustolonic catures Analyzed Total Wumber Ibnomat ++ 3+ 2+ 3 II 3 0 0 0 . 15 Glomerulo 119ement memhrane thickening Ware loop' lesions Fahrinoid IIy percell ilants local necrosis har orrhexin Ilemnitoxylon bolies alıne' thromby Capsular adhesions Crescenta Ischemia Protein in Bow in s space 0 0 1 0 1 10 0 0 0 0 5 5 10 0 0 - 0 15 10 15 + 0 3 Total glomerular damage 8 + 3 0 15 0 0 0 0 Tulules Degeneration Atrophy Dintation I roten in tublar lumina Chats in tubulir lumini 15 3 3 15 14 12 15 14 7 10 0 3 Total tubular dimage 2 13 0 0 15 9 Interstil tusele 1 dema Fibrosis Inflammation 0 0 0 5 10 15 15 11 3 Arleries Sclerosis Fit rund 0 9 0) 0 -- Cars studied from the files of the Department of l'athologs (niversity of lint 14 1932 1955 the incidence and mierity of the feature were definitely greator in ulricute glom rulonephritis Fibrocpithelial cre-cents and glomerulorup-ular arthe wonin Here toore cominon in subacute glomerulonepluritas Tubular dinage 143 definitely nore scsere in cubicute glomeruloneplerstin Th14 x 15 capaci uls true of atrophs and dilatation, and pointed to a more chrono di-case process This interpretation * as confirmed by the luglier incidence and Feater scients of inter-titsal fibrosis among the 29-y of rulmeute glom rulo- ·84 MUEIRCKF, LARA, PIRANI, AND POLLAK TABI EU 1 comparison of the incidence of histologic abnormalities in biopsy anl autopsy specimens of lupus nephrit18, with autopsy specimens of glomerulonephritis Percentage Incidence of Abnormalities in Histologie Features Analyzed Lupus nephritis Glomerulo nephritis 40 biopsy specimens 9 autopsy specimenst 20 autorsy specimensi 15 autopsy Apecimen 100) 74 20 13 100 74 34 28 10 0 41 8 95 75 100 100 69 100 56 78 33 33 78 33 100 78 100 60 15 90 30 35 25 30 55 30 95 35 7 0 7 100 67 100 27 Glomeruli Bisement membrane thickening Wire loop 'lesions Fibroid IIs percellulity Local necros13 har orrhexis Hematori in bodies Ilvaline" thrombi Capsular adhesions Cescents Ischemia Protein in Bowman's space Tubules Degenerition Atrophy Dilatation Protein in tubular lumina Casts in tubular lumina Interstatul tissue Edema Fibrosis Inflammation Arteries Sclerosis Fibrinoid 100 7S 93 56 GO 97 58 90 65 50 100 65 100 93 SO 100 93 100 89 100 75 100 19 70 58 so 03 63 + 55 25 60 7 * Sce Table II 1 thee 1 able VII B I See Table 1 $ See Table 1 nephritis Fibrinold changes in the arteries were definitely more common in the cases with lupus nephritis, while the incidence of sclerotic changes 1125 similar in the two series F Erolution of the renal lesions of lupus nephritis (1) Inalysis of the findings- In 21 patients two or more specimens were studied by biopsy or autopsy at intert als varying bets cen sit wechs and sixteen months Seven of these patients died, and the analysis of their autopsy studes is included in this discussion ·LUTUS VEPHRITIS 83 In most cases the inters al between studies we four to cight months Two specimens were studied from each of tuche patients, thru specimen- from each of seien patients, and four and five specimene froin one patient ech The shortnat puriod between the first and 12-t hrtologic tudi nas sis weche (27), the longest wa- 23 month- (X31) The fir-t biopsy was normal in fix patients In four (A3 3 1 8) the second or thurd biop“ tnhen at interi als up to 22 months remained normal In the other two (X6 11/ repcat studies disclo-od tlic development of a nıld to modcrate membranous glomcruloneplıritis in four and fourteen inonths respectacks Glomerulitis 19s found in the first biops of seven patient. In ont 1x 16) thic Icon 3 19 unchanged on sear later wlight progression of the I(-on or curred in tno patients 1* 12 14) in fifteen and four months respectisch In four cases (13 18 19 21) the lesion pogrend froin glonicrulit- to glon rulonephritis during a periol of ob criation ringin; from four to ten months Glomeruloneplisitis was observed in the first biopus in cight instances In one (29) there was slight progression in the first three months but sub c quently thic changes lind not progrcnud nine months Inter" In ssen 1*22 23 25 26 27 30 31) considerable progression of the alreadı -(Icre renul le-jon was ou (ned in a period ranging from 6 seeks to 23 months (2) Reconstruction of the histologic cu olution of lupus nephrts- From our studies it is cu adent that the renal lesions of lupus nephritis ont they had developed inevitably progressed the morphologie appearance of the lesion changed with the progression The Funnu pathologic pxecimens lullable in thus study liste pirmutted an accurate reconstruction of the histologic cio lution of lupus me puliratis fron the curcat to the most advanced stiges T! c carlient ind milder lions of lupus nephritis were confined to the glo merul it this mange an irregular loc il thehening of the basement member inc in small areas at the periphery of the tuft was frequently found it b*s a sume What smudgy appearence Ilthough strongly sugge-tive of fibrinord this ap pearence could not definitely be attributed to deportion of fibrinoul 14 the PiS and Vallory stains did not u-u111 give the cracters-tu tuning renctions In almot all in-tances a milu loc al proliferation of endothac dzal cells # 19 noted in a cornition with the thickening of the basement meniuran. This u-uill ap peared to be clue in pirt at kant to clumping of calls the so-ult of narrowing and of conglutination of capillars loop. In some ca diffuse proliferatne glomerulati 14 noted This suggested thit the art is of loc ut liv prallularity were not duc only to clumping of culs bout that there *}* trix local prolifer tion of endothelial cells The importance of these eitli gloinerul ar le ions of lupus neplintis 111* not been cinpiha-ized crcpt bi tichnes and Keith (272 274) and in amtlis recent tuds (261) Morcover the fuse detected and we huic confirmed that these le tons are present in autopes sfxecimens side by sy lewith more ad mead and typicalchinges Thes probably represent glomerult recenth affected in a fresh criccrbation of E "The potentiis since bern metuled twelve month later to further progres on of the tenal trgon his orcure ·86 VLERCKE KARK PIRAVI AND POLLAK Some cases of glomerulitis progressed slow ly during the period of obscrvation In many cases the local and focal glomerulitis progressed gradually and th following features morc peculi ir to lupus nephritis appcrred the narrow in and conglutination of expıllary loops became more marked in local areas untu the local necrotic le sons des cloped within these lesions harsorrlieus henn tory lin bodice fibrinoid changes and occasional liyalınc thrombı were ob seriod In other case, the local hy percellularity was loss ohu rous as tlucl ening and fibrinoid changes of the glomerular basement membrine became the pre dominant feature At first this 11.75 observed at the periphery of the glomerulus latır areas throughout the glomerulus icre nioliad llarc loop lesions vi ere note 1 at this stage This was the membranous form of lupus nephrits which Was found erther alone oi in combination with local necrosis Frequently in the areas of local necro is te glomerulus becime adherent to Bowman & cap ule The e local 2dl csions grad 19lly underwent organization and evcntually became fibro od l hen adhesions between the altered glomerulu tuft and Box mans cap ule were more exten ne prolferation of epithelial cells W ile observed and epithelial crescents and later fibrocpithelial cre cents atro formed At this stage which we have called subscute lupus glomerulonephritis tlıc histologic features peculiar to lupus nephritis were less prominent in some cines but cre still pre cnt Evolution to chionc glmorulonephritis with 6 brosis and hyılınization of many glomeruli u as uncommon in both bioj sy and autopsy specimens In the carly stages no tubular 19-cular or interstitial to sue changes were ob cried As the glomerular lesions become more pronounced tubular degenera tive changes appeared the interstitial tissue I ecunc odematous at first in focal arcas and later throughout the sections Interstitial fibro is wis ob crid later th'ın interstitial edema in tic course of the disci e Small interstitial infiltratos of cl ronic inflammatory cells began to appear with the development of inter stitil edema and fibro is Initially foci of inflammatory cells were often located around the glomeruli only later were they observed in other areas of ti e cortex and medulla A superimposed pyelonephritis was ob ersciin tl e subacute and chronic glomerulonephritie stages in three instances Vascular changes occurred only late in the diso9se Fibrinoid changes were obscried in the walls of smil arteries and arterioles in some cases these preceded the appearance of mild sclerosis The rapidity of evolution of the renal changes in luy us nephritis varied greatly from casc to czse In our opinion the presence of severe fibrinoid changes locul necrosis hematory lin bodies and hy alıne thrombu must be considered as evidence of marked actrity of the lupus nephritis they were observed more coinmonly and were more sciere during acute clinical exacerbations of SLE 3 THE RELATIONSHIP OF STRUCTURAL CHANGES IN THE KIDVEY TO RENAL FUNCTION Addis introduced quantitative erumination of the urinary sediment as an indirect mea of ob crying the nature and extent of lesions affecting the kidney ·LLPLS FPHRITIS 87 TABLF VII Kesalta of wrinalyses inade ist prior to hist logir stud) (6' studies made) Kkney Glomerultus Clomerulonephritas Lone Mem bran อบ Sorma? Total Vem bran ous Hiem bra OUS Vem bran aus and rol fera ITE Suta ute Chro ac pro liera tit 12 + 0 0 - 1 3 0 0 2 2 0 0 0 2 0 1 0 19 2 3 $ 0 0 0 0 0 0 0 0 ? 0 1 2 3 Sormal Night crooke RBC onl (3 12/11PF ) light recena WBC onl (5-15/11PF) light rrey RDC and WBC Ixcess WC (5 15 IIMH) Volerate numlor (fanta I reesy NBC and moderate numer of cast I arge number of casts with or with out exce4 RBC WBC 0) 0 1 1 1 0 5 0) 0 0 5 6 7 Totale 17 6 } X 7 7 621 One patient (*3) had hal attacks of pielitas Tiroler (10) l ad nephrouclerosis 1 locule atahes mide just before death (1) Iloweser lic recognized the cligno-tie lmoititions of this method of study (21 The technique of seri renal biopic has offered us i unique opportunity to staily directly to nature and extent of leon uffisting thi hines and to compare and relate the pathology to the findin on urinals ds and to non function asennel at the time of biop Thex interrelationship will be din cunc primarily from the point of view of the titus of the urine and of renal function 1 vurovome urinalyys (1) Tormol urinalysis From Tail VII it will be noted that the microscopic analı ve of the urinir seulement #14 normal 19 tnine In tnelie instances the hunes cre Intolog call normal and in maten there was mild lupus nephritis glonc rulitı In trombiente (46 111 urinis «ze and the renal Intolon were normal at the two 19 first stuch usuaris both ducopou meinbranous glomerulo nephrite and lcucocites and molerite numbers of conta were found in thur urine Four patients 1812 18 19 21, had glomerulits shen fint tudiel but no alınormality ana found on me roscopie urin dy 4 Wilhin tudied later three of tl tr palenta di col de veloped glonu ruloneplıratis nad the urinals se hulle comme alınormal in all four (1) Ibnormal analysis in 13 ore t-ions the urinal * 118 abnormi! (Tihle VII) In nine crum ·SS VILEIRCLE IR PIRAVI AYD L'OLLAK nitions there 175 a slight excess of leucocytes of cry throcytes or of both in the urine but not more than occasional hy alıne or granular casts were found The honeys of three of these patients were normal but when one ($11) sub sequently developed 1 local ind generalized membranous glomerulonephritis the urinaly eie had become abnormal One patient in this group (X13) had four biopsics there was only a slight change in the renal lesion such progres cd from glomerulitis to muld glomerulonephırıtıs but leucocytes and cry throcytes were the only abnormality found on microscopic cuzininition of the urine On 14 occasions moderate number of casts 11?found on examination of the urine All these urines contained 5-15 leucocytes, and five had 3-12 eryth rocytes per high pox cr field One of tl ese patients (3) ] ad huil acute py chitis and another (10) hnd benign nephrosclero is neither had lupus nephritis In tro X12 14) membranous and proliferative glomerulite nas found on cach of two examinations in one evrnunation (X26) subacute glomeruloneplırıtıs was found meinbranous or proliferative and membrinous glomerulonephritis was diagno ed in the other ses en biopsies On twenty occasions in clccn patients large numbers of casts ucre found in the urinary sediment All these patients had lupus glomerulonephritis mem branous in five membranous and proliferatıc in two sub cute 11 air and chronic gloinerulonephritis in sci en Mine of the ele cn patients had neplerotic or pesudo nephrotic syndrome due to lupus nephritis All had excess numbers of erthy rocytes in the urinary sediment and on mine occasions there were 40 or more crt throcytus per luigh pol cr field There were less than 5 leucocy tes per high power fiel in six cases -15 in ten cises and more tl an lo leucocytes per luigh power field in four cases Hyalınc and granular casts were cach found on nineteen occasions cellula casts (lcucocy te or epithelial) on thirteen cry thro cy te cists on four occ1-100s and fatty casts or oval fat bodies on fourteen oc casions Fatty cast ind os il fat body were found on thirteen out of scienteen claminations in patients who had nephrotic and p cudonephrotic syndrome and in onc patient (*33) who had chronic lupus glomerulonephritis On 21 occasions an increased number of lcucocytes was found in urines which contained no casts or 1 modernte number of casts In munt of these urines the Jcucocytes were clumped and in a few, leucocy to casts were found this finding was reminiscent of the urine in 13 cionephritis and in patients with clumps of leucocy tes in the urine the diagnosis of lupus nephritis must be considered (78) Organisms were cultured from the urine of many of these patients but froin one biop-3 specimen only In only one patient (#3) as there clinical or histo logic cuidence of pyelitis or pyelonephritis Others de cloped cudence of infec tion later in the course of their disease when their kidneys i cre scierely involved by lupus nephritis As we are dealing with a single disease wc en compare tlic relationship of abnornialities in the urinary sediment to the degree of histologic changes in the kidney From a study of Table XII it is clear that urinalysis is of value in as speeing the extent of the renal ni ok cment in lupus neplıritis In the fifteen? Two other patients lnd no evilence of lupus neprits One (3) laill attacks of velitis the other (10) had nephrosclerosis TI ese crees are crel, les from this anales ·LUPI TEPHRITIS 89 instances withi norinal kidney sincro copie avamination of the urine 1195 normal in trekt and in thirce there is only a light increase of leucocy tes cry throci tes or both Filteen 1995 nere diagnosed for-tologirallı as mild lupus neplinitis (glomerulitrs) Urinaly si ti is normal in een there were slight abnortunities but no cists in four and there were ? moulurite number of costs in four c16 Thus in most c750 with renal involcmi nt confined to the glomeruli there were no ca te in tlic urine and in none of the car is there 1 Tirge number of casts In 30 instances biopo ncctions were interpreted 1- con- stent with lupus glo merulonephritis In all but troinstinccs cist-lae found in the urine and scre present in large numbers in (Henty The fire ince of many cats in the urine was a definite indication of gloincrulone pliritin-tint of structural damage to both glomcruli and tubulce B Proteinuriat The amount of protrin in tlu urint a in masured citic - quantitative (0 to 4+ ) on merly morning peremen of urine or quantitativck on 1 2 1 hour urine specimen Hi-tologie obrtntions on the presence or absenre of protein accous mnterial in Box man puces incl tubules were made in it and the care cumnitized in Table VIII In thirts (ikht instance, the patient bud proteinuris at the time of the biopsy Protein iceous material was observed in the tubules of clusan in Bonmin pris only in one (in and in Bosmin Apraces and tubulex of the remaining toents In minteen antince the 17- tient dul not has protonuria when the hop"? 14 215 con Proton ire oux materi was found in Bowman Spices and tubulis in ten ind in the tubules only in Six Protein is not found in other Bon mın p194* 01 tubule in only three patients the presence of protein accou- maternt in Boni in prosind tubules of patients ulio hue no measurable juotu smurni constitute - addition il ruch net for the vien tut protein is normally filtered in that Llornc rulus and restorbed by the tubules (2135) Proteinuria i comnion finding in those condition in which the glomerulir brument meinbrine is thickene lor this reason an int14 114 m de not only of the total glomerular i mig but it o of the ch ingrs in cellularity of the glomerulus and in the thichnis of it-basenu nt member in the rolutionship letneen on the one liane proteinuri (pire al quintatatud or miq tunti tatisch and on the other bind kidney dum ibi glomerul ir dimiga 113 per- TIBIL 111 1 alition of proteinuria to the present proteinareu el in vr an. #prire and in rengli lilar linini in sºl. pty xperiment Prote put froican Roth Hathanne 49 Iubular Luma Protes Ta Proieren Bowman. See forens Tubular la kwa Lum na (nly Ur lutilat Luma Total I'trecht Hisent 21 10 11 6 34 19 3

·BD WDP
He
Proto nura (un
.
B
39
5 6
Proteinur a lom / 24 hours)
Fra 27 (a)
TG 27 The relationship bets cen the degree of proteinurn and the degree of (a) total
kidney damage (b) glomerular basement membrane thicken ng (c) hyrcrccllularity of the
glomerulus and (d) tubular dimage in patients all with SIC who were studied by renal
biops The amount of protein in the urine is expressed either in plus units or in grams per
24 I ours Note that there is good correlat on between the amount of proten in the ur DC
and total kidney damage thichening of the glomerular basement membrane and tubular
damage There is poor correlation between the amount of protein in the urine and glomerultr
hy percellul rity
...
4.4
Glomerulor basement membrane th cken ng
Prote nuro (+ un 13)
2
7
8
►9
3 4 5 6
Proteinuro (gm/24 hours)
l'ic 27 (b)
90

·LIPUS YEPHRITIS
91
cellularity of the glomerulus, thickening of its basement membrane, and tubular
changes, is shown in Figure 27 Study of the charts indicates that there was no
correlation between hypercellularity of the glomerulus and proteinuria There
was good correlation between the total didney damage, glomerular damage or
tubular damage and the amount of protein in the urine And there was ob3 10us
Hypercelularity of glomerulus
++
Prote nuria (units)
2
4
Ź
6
►9
3
Proteinuro gm / 24 hours)
To 27 (6)
Tubulol domage
...
Proteinuria ( units)
.
2
6
7
8
3 4 5
Prote nurko igm / 24 hours)
DG (d)

·92 VUEHRCKE KARK, PIRINI, AVD POLLAK correlation between the changes in the glomerular basement membrane and the quantity of protein in the urine (Tests of renal function In their studs of hypertene patients before and after sympathectomy Tulbott and his colleagues first demonstrated the value of studying the relationsluip between renal function and renal structure in the living patient Their studies were niade usmg renal tissue removed at operation (281) The adient of 1 technique for percutaneous biopsy of the kidney has immeasurably widened the scope of such studie Our patients like been studied over periods of time up to two scars Studies of renal function were made just before each biopsy was then and, in those who died within few sechs of death Frequently studies were also made at 1rying intervals between biopsies During the tho years of tle study serial changes in the clinical and laboratory data were observed and compared with the l-tology on fire and four occasions in cases $23 and 13 respectivels, on three occasions in checs X6 7,11 12 22 29 and 31, and on tno occisions in tu che other ciues Eximples of the c changes is observed scrmally are gren in Figures 7 and 10 The methods uscd for the renal function studies and for the scmi quantitative 9sement of histologic changes are de cribed in Section For each biopsy the appropriate function is compared with the degree of orcrall hidney dimage with the degree of glomerulır damage, and with that of tubular damnge Degrees of structural change were plotted on the ordinates of the graphs the function test on the ab ciesne (1) Brochemistry of the blood The blood creatinine leic 1118 mensured on 58 occncions nt the tinic of the renal biopsy (Fig 28) It was 14 mg/100 ml or less in all sixteen checs with normallidneys in sitcon of the sci enteen cuscs in which kidney dinge was estimated as 1+ and in seien of the ten cases in which the damage 94 2+ In K dney domoge 6 7 1 2 3 4 5 Blood creatinine (Mg / 100 mi) FiG 28 The relatioaship between the blood crcatınıne levels an 1 the degree of Lidoey damage in patients all with SLE who were studied by renal biopsy (sce text) ·LUPCS VEPIIRITIS 03 . Kidney demago O 30 45 60 75 90 JOS 120 150 Boos U 40 Trogen (DOM FG 29 Titolationship tcts on the land urri nitrok al ves sal the degre of dinos Himige in patient all with LI no nire xtu ind in noul (* tex two tlekscius 16 and 17 mg 100 ml ul in the third 1.3 biops 11 the creatinine kid to 26 : 100 mil epite the fart that the br-tologie change u ne not grow wie il sith the nephrotze auront and there 174 considerable of the interattad tant of the hidnry Vorderat us atson of tlc blood creatinine lascists buen olersed in other patient math nephrotic anilrorocthntever the underlying patholo) In the patients win the adnan of the interstitial touches denred after uses the creatinine lucis In fallen tonirls norm) The chitmine ked so lon- than 4 m, 100 15 in three of 940419 wes thesiva 3+ mal di Medpad and between 1 anul 20 in. 100 ml in the rain unmg tin les greater than 30 mg 100 ml in all mine e1-py with 4+ renul de Thus the boot un ato me besar 32 snest schis nors 35 heute until the bus worstereit stunniger and farveru creatinin level reflected onls -48 degree of his domime The lloont una nitrogen ne me i ured on 2101* F 29. Tu kuel of the BUS 173 14 mg 100 sul or dous in filtean of the date 2019 with formal hilnej intin of swinteen 0744 in a liom tu rond 1714 tynnu at 1+ in four of cluson cups satls 2+ rentadural e{ima md in one CINC with 3+ dunina Ti lesc! is txtween land 30 111 100 ml in one rise with normal hulness in seson with it tructural change in fost susth 2-4 d unge ind in file with more usare chang Blocks of more than 30 mg/100 ml urre encountered twice in patient with ? dimogy and in an nere the Iron 11 more need The Ulo« non prolci nitrojen * e* tur atrezi on 63 (ISON F1x 30. The loud of the Ws3i me 100 mil or Bios m tifteen of the filters escrz Uite nurtual kulcs saalis sght of the fourteen ( 14* in when the renul Ohing sisestatuntet at 1+ and in seien of fifteta cu* in u kuni at 12+ In twelve Case with 1+ or ?+ renal dinge the VP ku *** in the range 3.270 mlo ml anel in two it ur. 60 mg 100 ml In only ino of the phot141 intimne in wlucl the rem pathology 17 3+ us *+ *7. tht VPX {** thi en 3i 114 ml Tendente hodnejskere lu-toloit normal the loss of stuum containe *** (un formal fint in all rise and shares of Xindl X in 1}} ·91 MLEHRCKE, KARK, PIRANI, AVD POLLAK Normal Kidney damage O 125 175 25 35 00 75 100 150 200 Non Protein Nitrogen (mg/100 ml) Tic 30 The clationshup between the blool non protein nitrogen descls and the degree of hidacz damige in patients all with SLE ho were sterlied by renal biopsy (soc text) but one instance With slight to moderate structural damage (1+ to 2+) tho les els of BUN and NPN were raised slightly above the norinal of 14 mg/100 ml and 35 mg/100 ml respectively in 43 and 41% of casc, and were considerably above normal values in 7% of cascs By contrast the level of creatınınc was raised slightly above the normal of 1 4 mg/100 ml in only 11% of cases with slight to moderate structural damage, and was considerably clevated in 47 Thus with slight to moderate structural damage thio BUN and NPN were pierhaps more sensitic indicators of the change in renal function than was the creatinine, on the other hand both BUN and NPN are subject to greater variation as a re-ult of extrarenal factors such as dehydration and variations in the protein intake When the renal damage was more adı anced (3+ to 4+) Iittle difference was observed in the proportion of cascs with elevated blood creatinine, BUN or NPN levels As was cxpected the levels of urea nitrogen, non-protuin nitrogen, and of creatinine in the blood did not reflect accurately the degree of underlying renal structural damage glomerular, tubular or both They were raised only when the damage was severe, and were not sensitive indices of loss of renal function (2) Specific tests of renal function Specific gravity concentration tests were done within a few days of the renal biopsy on 43 occasions The results are shown in Figure 31 In general as thic renal damage became more sci cre, the concentrating power of the kidney dlecrcasc, and this was found to be cqually truc en relation-lups with glomerular dan age or tubular damage were accessed independently The figure 1 022 was taken as the lower limit of the concentrating power of the normal hidney The concentrating power was 1 022 or greater in nine of tuchsc cases with normal kidneys, in tschic of fourteen ca-ts vith 1+ kidney damage, and in four of scien cases with 2+ damage It was 1 020 in the case with normal kidney s and in two with 1+ damage, and 1 018 to 1 020 in three with 2+ damage ·LLOCS FIRITIS 93 --- Abnormal Normal .. K dney domoge .. 1003 TOID 1015 1020 025 1030 1035 1040 Spet ic Grovity Concentrat on test (Maximum spor) 17 31 TI e relation bip between the marmum urinary i kraut ani the Igre of lors dlamike in patients all with Iulo were studied in real 1971 (err tru) In all ten casca in whom there is 3+ to 4+ dag the 11.juimum pecific frivity of the urine was le than 1 020 and it 11010 or la in fiic of the 8IX case with 4+ duage Irea clearances were made in ul in tince (Fig 32) in the re ults were expressed 14 8 percentage of average norm i renul function \RFThe normal clerance was issumed to ix 70 c or more Fruin Figure 32 it is seen tiat there we a clo e correlation lxtween the area ele irine in the degree of renal image Values of 70 o or fruitor ce found mushtuen instance with normal hulness or 1+ damage in tro with 2+ climate ind in non where the dumage 1179 mort sovere glues of 50 to 70 AVRF were found in two in Atances with normal kulnoys in eight with 1+ dimive in three with 2+ danske ani in one with more advanced ksion Ilukthan were not found until there win 2+ damage fire occ 1-ons) and were olin siin tuolit of the tisrtcencies with more advancul ke ion Thu tlic ura Juarance to the a furly accurate estimate of the degru of ourul Jante to the kidni in to od tistologir alls u ar results in obtinud u het Glomerular dange an I tutular dannage were ed independently - Dnormal Normal . K dney damage .. . ... 45 60 75 90 109 20 135 30 Ureo Clearonce (% Average normal rengl funcion) 13 Turniej lrtments the urca cleaniner (coprevod na pamet 98 of alcman monal tenul fuprten) and the degree of kiin, domage in to sito ut at , fte s r* *text) ·96 MUEHRCKE, KARK, PIRAVI, AND POLLAK - Abnormal - --- --- Normol ---- --- . + Kidney damage 5 10 5 20 25 30 35 40 45 PSP (% excret on in 15 m nutes) I'ra 33 The relationship between the amount of phenolsulphonphthalein cxcreted in fifteen minutes and the degree of kidney damage in patients ill with SLE who wcro studied by renal biopsy (sec text) The excretion of phenolsulphonphthalein was measured fifteen minutes after intru nous injection The results of 59 studies are set out in Figure 33 Twentyfive per cent or more was excreted in 26 of 34 ciscs with normal kidneys or 1+ damige, in three of eleven with 2+ damage, in three of seven where the damage was 3+, and in none where it was 4+ It was betwcen 15% and 25% in fourteen of the remaining sci enten in ulom renal damage was 1+ to 3+ In all seven cascs with 4+ damage thic cicrction of PSP was less than 15 in 15 minutes and in it was below 86 Thus the 15 minute cicretion of PSP 8110 an accurate estimate of the degree of ren al damage Conclusion In Tablc XIV the renal damage, estimated histologically, has been compared with the results of the specific gravity concentration, urca TABLE VIV The relationship betucen the degree of histologic damage and the number of abnormalities found uhen patrents with SLF ucre studied by means of three simple tests of renal function One of Three Tests Abnormal Renal Damage Number of Cases All Three Tests Normal Two of Three Tests Abnormal All Three Tests Urca Spec Abnorma! clear conic Total PSP PSP Urea clear Sp gr CONC PSP Total 1 0 0 8 5 0 2 1 0 + ++ +++ ++++ 2 3 2 1 2 14 13 9 6 6 1 5 6 4 0 0 0 0 1 1 0 2 3 0 3 3 6 0 0 0 * Only cases in bich all three tests were made are included in the table ·LUPUS VEPIIRITI clearance, and phenosulphonphthalei eserctron tets It can be seen th it alen tle kidneys were norinal histologically, all three te-ta of renal function ere norinal in cight of the fourteen crimination that one test only 1, almormal on five occasions and that both the ure i clearinct and P-Pcrcrction were low on one occasion It should be emphasized that although tent of function were abnormal in six instances the degree of diminution in function is licht In 0969 with minunnl lustologic changes in the hidnas (1+) all three to the of function were normal on fire of the thirta n (13NNN trois and 1!! three were abnormal in only one Igun the degree of commution of function is slight in repet of ench test llatha moderate degree of kidnes dim 12+1 there is no in-tince in ucli all three tests were normal Onc ! almorin 1 on jour ou non tro were abnormal on tuo occ 1490114 and all tlinie were abnormal circ time 01 the mill in tincc in bich the hidnu duge te maled - 3+ tno ti to were abnormal on three oce on ind thru ter were norm ui on the other thrce With the nioat sccre (UILE (4+1 ill thru tests went abnormal on all Si occa10n It has been shown above thit thu apar citu All the intratron ure i clearinct, and P P tests cach reflected the underlink steru ot hilna dimige Adverthelens for each test there is a con- lurable blind perimental Variation I roni Iuble \It it in abort that one of these three tists may Ic abnormal when thic bidnii were 11-tole al 107121 but that the direc of abnorinalitu nis slight Inase in the limpe o haina mags it is also Fean that no single tout au spurior to the other two But , combination of all thirce tests gaic an cicellent overall impri (1) of the underlying dari better goue inent, in fact thun uden in ons af flu t-tn 1 und aloni W ben the functional ump urment Basistomit si boy in - Hent of all throu simile tents taken together an icur ite impronil: lot of hi toluir dange 1199 ohtuncit VII TIF CINNICOPATHOLOGIC FEATURE OF 11 INFIIRITIS 1 THE INCIDE vr Of LitNDRIUS N 1471F\TS HITUL (HIVIC ILLI DI AVON.D) L The criteriul by differunt iniciators for the a--2110 nt of renal in Foliement in lart omhli that it is diflicult to rompi one such with anotlır Vany reports and bice on sunori il urati in findings and interpreta. tion of their clita mu-t de pend on dether the proteinurnian Islandari mere primanent or u bither they appeared t115 for during a corbution of SI E. This ron uertion apples to the sits reportellos dema br 1 mont-Il mars an 1 Rngin (127) The wthor found at norui urinirs seulement in bor of ther series of 44 usatz in 56, of the 270 C3 Pixelthen Vont- Somety more accurately diagnose renul insols Teni! the prince of perphrit The ·98 MUETTRCKE KARK PIRANI AND POLLAK 1938 and 1947 (191) Using these criteria 64% of the second series had evidence of renal intolsement but only 13% of the first series It is difficult to account for this discrepancy It will be noted that the second series antedates the use of cortisone and corticotrophin therapy Thus increased longevity as a resu! of successful steroid therapy cannot explain the increased incidence of lupu nephritis from 1938 to 1947 These patients may have lived longer because of treatment with transfusions blood plasma, sulfonamides and penicillin In Harvey s series only 26 per cent of 138 patients had no signs of renal involve ment Thus there was some cvidence of affection of the kidney in 74% of his patients The 33 patients reported here have not been followed for as long a time as those observed by Montgomery (190 191), Jessar (127) or Harvey (110) Despite this 24 of 33 patients had renal molement on histologic erzdence (10 73%) Using the criteria of Montgomery, 21 patients have had persistent proteinura or cylinduna due to lupus nephritis (1 € 64%) in one additional case (X10) persistent proteinuria and cz linduria sere the result of benign nephrosclerosis As our clinical interests have covered the field of diseases of the kidney as well as that of SLE we considered it possible that our selection of cases may have been based in favor of cases of SLE with renal involvement However it will be observed that the incidence of renal involvement in our patients was similar to that in other large series in which this bins did not exist Haricy and his colleagues (110) have also observed that structural damage to the had ncy by SI E is more common thin urinary findings and tests of renal function would have led them to believe The assessment of rennl involvement from post mortein material 1199 been subject to considerablc crror for there are few studies in which the particular orientation of the authors has not played a part in the selection of their material Ten of our patients died and post mortem cxaminations were made on the kid ncys of nine All had a glomerulonephritis These results are comparable with others For example Mook and his colleagues (193) cxamined the kidneys of 9 patients who died with SLE and found evidence of kidney involvement in all Baehr (9) found glomerular lesions in 78 of 23 post mortem criminations and Harley (110) found some degrec of involvement of the kidneys by SE in 89% of 38 cases lle may therefore conclude that the kidney is invoked by SLE in a high proportion of patients on clinical grounds about tro tlurds to three quarters of patients with SLC huse lupus nephritis and on pathologic grounds an em higher proportion shou euidence of kidney intoli cient 2 THE TIVE OF O SET OF LLPLS VETHRITIS The time of appearince of the first significant symptom has been taken as the time of onset of the disease In some cases a single sign or symptom (eg Raynaud s phenomenon polyarthralgia biologic false posti e test for syphilis) occupied the stage for a long period of time and the duration of the disease ·LUPUS NEPIIRITIS 99 was interpreted in this light In four patients (X24, 27, 30, 32) edema was the presenting symptom and made its appearance at the time of or shortly after the onset of other symptoms of SLE Seren other patients (#22, 23, 25, 28, 29, 31, 33) presented to us with renal symptoms Hon ever, all of these patients had had other symptoms or signs of SLE for from two to ten or more years Wicn first seen, all of these eles en patients had severe lupus nephritis (glomeru lonephritis) By contrast, in elesen patients renal ini olvement pas initially discovered by urinalysis, by tests of renal function or by renal biopsy (#12-21 and *26) All had come to hospital primarily because of non renal manifestations of SLE Only one of these patients had scsere lupus nephritis hen first studied (426), and she died a few months later Symptoms of SLE had been manifest for periods of from three months to clev en years in this group of patients Eleven patients (*1-11) had no evidence of renal affection by SLC after periods of time which covered from 11 months to 9/2 years Two of these patrents (#6 111 subsequently descloped lupus nephritis 17 months after the onsct of their disease Meagree, therefore with Hamburger and his colleagues (107) that the time of appearance of renal affection bs LE 13 variable the hidney may become involied at the onset of the dien or at ans time there after until just before death 3 THE CLINICAL FEATURES OF IUIVE PIIRITIS Mild lupus nephritis Ten patients had mikl lumus ne plirits when first scen The glomeruli were affected but there is no significant involvement of the tubules In none of the patunts were renal manifestations 1 proininent feature of the clinical picture in three no abnorm dites were found in the urine, two cxcreted excess anjounts of protein but no calls or formel clements two had a slight cxcess number of erythrocytes to exerted crcc-s protein red and white cells and in only one patu nt were there one in the urine in acklition to protein and culs There was a very slight incrore of the blood \PX in two and a slight decrease in rural function in ont Three hul portantly clerated blood pressures in two lis perten-lon pp rol only during (1704rb1 tions of SLI Thus in the early stage of road in olscent there was little to be found on clinical and itboritori cximin itron Eight of these 10 patients with muld lupu- nephriti line been studied serialls Iny renal bioping and four linte developed ance-both clinical and patho logie-of progression of their rend le von Von fis 1 died in none of tfice (ight patients his there been an definite relationship between the frequency and ricrits of the exaculations of it and the program of thus runal leons Scucre lupus nephritis Tuche patients bil este lunes nephritis tulen first xeen and their hidnes lesions en cinefiel a glomerulonej linii Bi contrat with the ten patients with nult lup** Delirita renal shiftentions were a rominent feature of the clinte il picture and in it in the wore the domu mint feature line of the prints 11 nephrots op 1139 ·100 VUEIRCLE, KARK, PIRAMI, AND POLL 4K In all twele patients definite abnormalities were found lien the urine was first examined Proteinuria was found in all, eles en lid cry throcytes in the urinary sediment and these cre present in large numbers in four, lcucocytes nere seen in the sediment of all but two and large numbers of casts mere al o observed in the urine of all patients Ninc had azotemia and in two the APN was at the upper limit of normal Renul ſunction as decreased in nine and at the lower limit of normal in three Light of these patients harc dhed, seven of them in uremia The disersc is progressing ripidly in tho and more slonly in the other two fue patients in this group had hypertension, but in two it de veloped only within three months of death Chronic lupus glomerulonephritis This has been an uncommon pathologie finding The lesions in thice ($23 29 31)—diagnosed histologically as sub ucute glomerulonephritis plien first scen--progressed to chronic glomerulone phritis and contraction of the kidnet In addition to these three patient #33 had chronic glomerulonep! ritis when first studied The clinical course of these four patients progressed more slowly than that of those who died in the sub acute stage of glomeruloncpi ritis The blood pressure was permanently elevated above 150/90 mm Hg in scsen patients Onc (#10) 1 woman of 62 hod nephrosclerosis but no cudence of lupus nephritis Case X16 i!l with glomerulitis was the only patient with mild lupus nephritis who had an elciated blood pressure This may have been duc to coincident essential hypertension Another (*29) 1128 had 1 blood pressure of 160 90 mm Hg for about two years In the other four patients the blood pressure was raised for from two to twelve months beforo denth in renal failure Excluding the prtient with nephro clerosis the blood pressure was clevated in 911 (1e 187) This incidence is slightly higlier than that ieported by others (110 127) Hypertension was as ocrited with advanced renal discise in four of the sn patients and with moderateli adı anced renal disease in one On the other hand the blood pressure was normal in four patients who died in uremun These observations are similar to those of IIarscy et al (110) 4 YEPIIROTIC AND PUEL DO VEPHROTIC SI \DROVE By the nephrotic syndrome we mcan that clinical state-regirdless of its causc luch is characterized by celema musite proteinuria hypoalbumine mı and hyperchiolesterolenı1 The urinary sediment contains granular and liz alını casts and if they are carefully sought fatty casts and doubly refractile bodies are almost insariably found Allen (4) whose definition of nephrotic an drome is essentially similar to ours states It is well known thint in ingl percentage of cascs of disseminated lupus erythematosus with clinically sig nificant renal involvement (approximately 33) nephrotic androme desclops Many authors liale inderd mentioned the occurrence of nephrosis in SLE but the blood cholesterol values are often lacking in their reports and few harc published all tl e es ential data on their patients ll chaic been able to find but seien reports of cases of SLE in which all the above clinical enters of the nephrotic syndrome are fulfilled The first is the case of Brenner I elf and ·LUPUS \EPIIRITIS 101 Hochstein (35) reported in 1948 Two years later four cases were reported by Daugherty and Baggenstoss (63), another by Hamburger and his colleagues (107), and in 19.3 Dubois reported a seventh (case $7) (66) In reports of several large series of patients we have been unable to find cases of the nephrotic syndrome with SLE Jessar, Lamont Havers, and Ragan (127) reviewed 279 published cases of SLE and added 44 of their onn Although a number of these patients had proteinuria, hypoalbuminemia and cdems there is no mention whether or not these findings were present in combination nor is there any reference to the levels of serum cholesterol In an extensave review of the litera ture on SLE Ross and l ells (248) do not mention tle nephrotic syndrome and Kushniruk (160) lıkesi i did not ob eise it in his series of 75 cases of lupus erythematosus Of the 138 cascs of SLE recentis reported by Harvey and his colleagues (110) only one case *39) ma bave had the nephrotic syn drome and in tłu-patient the cholesterol lest I was not recorded Vuch to our surpri e seven of the 33 patients in our clical study manifested all the criteria of the nephrotic yndrome at some time during thi period of study We have uued serial renal biopass as a tool in the studv of the nephrotic syndrome (134 203) as well as in the study of the kidney affection in SLE This Very fact may explain the large proportion of cases with nephrotic syndrome in our scric An alternative explanations more likely Vost reports of luge series of cases of SLE with nephritis have been made iiy retrospertize studies of post mortem material and ho pital records which may have been incomplete When We analyzed the available data on patients with 'I E who diut in our hospitals prior to 19,2 ne found that for our purpo-es adequate clinical and biochemical observations had not been recorded during the course of the patients illness Therс nere several -uch cases hich imght have been diagnosed SLE with the nephrotic syndrome but in only one of them (GB) are the data adequate to diagnose neplerotic syndrome in retrospect In three of 33 patients in our clinical study all the criteria of the nephrotic syndrome were fulfilled sare that the serum cholesterol lez el uas lov or within the normal range (Table VI) These three patients were all acutely ill and in all three the clinical couree was one of rapid progra- to death all three died within five months of the onset of edema Because these patients were similar clinically sc coincil the term p.cudo nephrotie (2021 to describe the syndron. Since these observations were made we have found a fourth cre in our post mortem series (110) sho also had the pecudo nephrotic syndrom she died within onc month of the onset of edema Shearn and Profsky (259) called attention to a clinical var int of the ne phrotic syndrome which occurred in patients ill mith SLE Three of their four patients had cholesterol levels within the normal range and a fourth patient had an in Sachs dise had the ic was 125 mg/100 ml, she died six months later In 1940 hel (139) had written Extreme hypercholesterolemia I have but ·100 MUEIIRCKC KARI PIRAMI AND POLLAK In all thelie patients definite abnormalities vere found klica the urine tas first clamıncd Proteinuril is found in all eler en had cry throcytes in the urinary sediment ind these were present in large numbers in four leucocytes vcre seen in the sediment of all but two and large numbers of casts were al o observed in the urine of all patients Nine hnd azotemii and in the the NPN was at the upper limit of normal Renal function was decreased in nine and at the lower limit of normal in three Eight of these patients have died seien of them in urcmia The disease is progressing rapidly in two and more slowly in the other tro Five putients in this group had hy pertension but in two it de veloped only within three months of death, Chronic lupis glomerulonephritis This lias been an uncommon pathologic finding The lesions in three (X23 29 31)-diagnosed listologically as sub acute glomerulonephritis when firet scen-progressed to chronic glomerulone pliritis and contraction of the kidncy In addition to these thrce patient #33 ind chronic glomerulonepłıritis when first studied Tlic clinical course of these four patients progressed more slon is than that of those who died in the sub acute stage of glomerulonephritis The blood pressi re was permanently clcuated above 150/90 mm Hg in seven patients Onc (10) & woman of 62 hnd nephrosclerosis but no evidence of lupus nepl ritza Che 16 all with glomerulitis was the only patient with mild lupus nepl ritis who hnd an elevated blood pressure This may 1 arc lscen due to coincident essential liy pertension Another (X29) hus liad 2 bloo l pressure of 160 90 mm Hg for about two years. In the other four patients tic blood pressure 11 18 raised for from tro to escle months before death in renal farlure E\cluding the patient with nephrosclerosis the blood pressure was eles ated in !! (10 184) This incidence is slightly higher than that reported ly others (110 127) Hypertension was associated with ndvanced renal discasc in four of the six patients and with moderately adı anced renal disease in one On the other I and the I lood pressure as normal in four patients wlo died in uremin These observations are sınılar to those of Harvey et al (110) 4 VEPIIROTIC AND PELDO CPIROTIC SYNDROVE By the nephrotic syndrome we mean that clinical state-regardle of its cu which is characterized by cdema massive proteinuria hypoall uninc mil and livpercholesterolem. The uriniry sediment contains granular and hyaline casts and if t1 ey are carefully sought fatty casts and doubly refractile bodies are almost insariably found Allen (4) whose definition of nepl rotien drome is essentially similar to ours states It is noll knonn tl at in 1 Jogh percentage of cases of disseminated lupus erythematosus with clinically sig nificant renal intolsement (approximately 33m) nephrotic syndrome de elops Many a thors have indeed mentioned the occurrence of nephrosis in SIE but the blood cholestcrol values are often lacking in their reports and few have published all the essential data on their patients Te hue been able to find but seven reports of cases of SLE in which all the above clinical criteria of ti e nephrotic syndrome are fulfilled The first is the case of Brenner Leff and ·LUTLS NEPHRITIS 101 Hochstein (35) reported in 1918 Two years later four cases were reported by Daugherty and Baggenstos (63) another by Hamburger and his colleagues (107), and in 1953 Dubois reported a sei cnth (casc #7) (66) In reports of seterul large series of patients we have been unable to find cases of the nephrotic syndrome with SLE Jessar, Lamont Hivers and Rigan (127) reviewed 279 published cases of SLE and added 44 of their own Although a number of these patients had proteinuria, hypoalbuminemır and cdema there is no mention whether or not these findings scrc present in combination nor is there any reference to tlc les cls of scrum cl olesterol In an exten ive review of the litera ture on SLC Ross and Il ells (248) do not mention the nephrotic syndrome and Kushniruk (160) likewise did not obscrie it in his series of 73 chocs of lupus erythematosus Of the 138 c?cy of LE recently reported by Harvey and luis colleagues (110) only one line *39) may have had the nephrotic syn drome and in th patient the cholesterol lese) 11 is not croriled Vuch to our surpri e seren of the 33 patients in our clinical study manifested all the criteria of the nephrotic syndrome it some time during the period of study lle harc uscd scrial renal biopsy 1s 1 tool in the study of the nephrotic syndrome (134 203) as well as in the study of the kidney affection in IT This very lnct may aplain the Inrge jioportion of cats with neplu otic syndrome in our serica An alternative explan ition is most likel vostre ort of large scries of cats of SI r with ne plritis has been in de bu retrospecture studies of post mortem maten and hospital records which may have been incomplete 11 hen we annlyzed the nailable dat i on patients with SIE who diei in our liospitals prior to 1902 wc found that for our purposes adequate clinul ind biochemical observations ld not been recorded during the cour e of the patient illness There icre severn! uch cascs which might have been diagno «d SLE with the nephrotic syndrome but in only one of the in ( Bisere the date arlequate to diagnose nephrotic syndrome in ictro pect In three of 33 patients in our clinical studs all the criteria of the neplırotic syndrome were fulfilled save that the serum cholesterol level u as low or ithin the normal ringe (Table VI) Tlcse thirce patients were all acutely ill ind in all three the clinical co rac was one of rapid pio rosy to death all three died within five months of the onset of cdema Becau e these patients nere similar clinically sc coined the term pocudo nej) rotic 2021 to deseribe the syn drome Since these ob criations u ere made chwe found a fourth casc in our post mortem scries (VO) who also bad the pseudo nephrotse sindrome she died with in one month of the onset of edemn Slearn and Pirofsky (259) called attention to a clinical variant of the nephrotic stodrome sluch occurred in patients all sath SLE Three of their four patients had cholesterol levels within the normal lange and a fourth patient had an init Sacks disc had the fc mas 12 mg/100 ml she died six months later In 1910 heil (139) had written Extreme hypercholesterolemia I hnic but ·102 VILEHRCHE KARK PIRAVI, AD POLLAK rarely obscried in cases of systemic lupus cry thematosus In otlıer instances the cholesterol valuc is normal or cren diminished 'The explanation of thesc los serum cholesterol levels is quite obscure As in otler patients with SLE the serum globulin level was raised and the thymol turbidity test was abnormal The cephalın flocculation and prothrombin times vcrc norinal The scrum cho lincstcrasc level was lon (0 38 ApH units/hour) in the one patient in whom this obscrvation is made This contrasts with the abnormally high levels of scrum cholinesterase usually found in the nephrotic syndromc (295) In tlirce cases the Incr as crimined post mortem and no histologic damage was ob served It is nei crtheless possible that SLE could produce some liver damage not detected histologically or by the limited tests of liver function performed in thesc patients Such undetected lucr damage might depress hepatic synthesis of cholesterol but as Gould has pointed out the plasma cholesterol level falls only with sei cre luer insuficiency and cholesterol synthesis may be increased in the presence of slight lucr dunnge (100) Squirc has noted that the more sei cre degrees of hypercholesterolemia in tlic nephrotic syndroine crc qeso ciated with extremely lon lesels of serum albumin (271) No "ignificant differ ence was noted between the scrum albumin les cls in the tuo groups of patients with nephrotic or pecudo nephrotic syndrome Careful inzlysis of the pathologic changes between the two groups revealed that the proliferative ind basement membrane changes were of sinılır degree Howeverly aline thrombi wire loop lesions hary orrlicus hematoxy lin' bodies and fibrinoid degeneration were obseried more frequently and were more soi cre in the pscudo nephrotie than in the nephrotic group of patients Tous morphologic difference is surely the expression of a more acute and sexere in volvement of the glomeruli of the patients all with the pseudo neplırotic syn drome Cantaron and Trumpei (41) state that a low plasini colesterol level occurs in the terminal stages of n vriety of disenses and that fall from a previously elevatod or normni les cl is of scrious prognostic significance particularly if 7sociated with increasing nitrogen retention It must be emphasized that in the pet udo nephrotic group the cholesterol levels were los ab imtro Tl is lon cho lesterol level with other features of the nephrotic syndrome in a patient ]] sath SIE 1924 in our cyperience plud 7 grave prognosis and rapid demi e 5 DISCLS10V or I ATIIOI OCI In the previous ecction the lustologic fcatures and evolution of lupus nephritis were set forth in detail It remains non to discuss the significance of the lesions their specificity and posible pathogenesis Lupus nephritis is a diseise wuch affects predominantly the glomerular capillaries and their constituent clements In the carlier and milder stages of the discuse the morphologic abnormalitas are confined to the glomeruli, the tubules and interstitial ti «ue are intoked later in the course of the disease Honever in a few cases which clinically are severe at the outeet the tubules and interstitial to sue may be inlokal from the lic ginning ·LUPUS EPHRITIS 103 Clinically lupus neplıritis does not run a protracted chronic course This may be due to one or more of the following reasons 1 The renal lesions progress more rapilly than those of most other renal diseases 2 Exacerbations are more closely spaced 3 Retersion to normal of glomerular lesions docs not occur In many in tances the systemic nature of SLE contribute to the dcath of the patient before the renal levons l we evolved to a more clironic and les, ac tive form Our studies indicate that the course and charactei of SLE ind lupus neplinitis m11 have changed during the past several years Tl ce is no doubt that the life span of the c patients 1 as becn prolonged by ticatment da result renal changes tend to be more by cre and chronie und le specifie in character Cer tain changes have been produced in the kidneys of permental animals by the admin tration of cortisone (30 240 241 287 301) and it is possihle that treat ment with corti one could produce similu changes in min However the lesions seen in patients with lupus nephritis treated with cortione art very different froin those seen in the experimental animals and in the pre umably normal kirlneys of patients with rheumatoid arthrztos treated for long periods of time with cortionc we have observed no abnorinalitics (230) Tevertheles it is conceivable that cortisone might modify the couse and c ai ac ter of previously existing renal lesions and this treatment at lave been a factor in lonering the incidence and decre 24ing the severity of certain changes such as wire loor lessons fibrinoid and lienintory lin bodies I nfortunately corticosteroid ther apv does not present the progresion of the icnal di cat Our study again emphasizes the pleomorphic nature of the icnal lesions in SLE (3 19 151) Because they are no plonoi shie it is misleading to cla-sify lupus nephritia as a varity of membianous glomerulonephritis 13 41 An ir regular loral touchening of the glomerular baseinent membrane is the most con sistent teature (19 1511 and varying degrees of thickening cre found in all Specimens studied hy us Meiertheless proliferatne changes are common in the glomeruli and many other features are more typical of lupu- nephritis than 15 thuckening of the glomerular basement membr inc Vany observers have stated that wird loop jesions are onc of the most characteristic fentures of lupus nephritis but they line been noted in many other renal diseases (3 151 231 232) Il ben they occur only in local areas at the periphery of the glomerulus and sy dien they are associated with fibrinoid changes were loop lesions are more strongly ruggestive of lupus nephritis Moreover we wish to emphasize that are loop lesions are not observed in the carliest stages and may disappear in the inost adv {nced stages of the disease then wir loops are present they are not diagnostic of lupus nephritis unless Az ociated with other features more specific to tłus disease on the other hand tl er absence does not exclude the cagnosis As reported by others fibrinoid cl angrs were frequently observed in lupus nephritis They were not universally prevent and in most in-tances e-pecially ·101 MLEIRCHE, LARK, PIRAMI, AND POLLAK in the biopsy spccumons, they ucre of mild to moderate sei erity The relatie scarcity of severe fibrmoid changes may be due to the fact that many biopsics were studied in in carly or mild stage of the di-erce, and to the fact that most specimens were obtained during periods of relative clinical rcnussion Fibrinoid changes were more common and more sciere rhon rinal invoks cment as well established clinically, or when the biopsies had been taken from patients with ncutc clacerbations of SLC The stunning properties of fibrinoid suggested that it is closely related to but not identicul with fibrın (7,198 296) With the methods used in this study we could not detect any differences between glomerulır and arterial fibrinoid-differences wluch has been suggested by recent studies (32, 192) In a few instances fibrinox was noted along in csscntually normal glo mierului baecment membr ine Tlus strongly uggests the posstbility that circulating protlıc matural as deposited from the blood onto the membrane It is not clear « lietlicr tlus deportion is iclated to the quantitative and quitative changes in tlic serum proteins which occur in SLL Tht occurrence of local and focal glomerular nccronis has been reported by several investigators (19 131) Although Lleinperir and his associates de cribed thus lesion in detul its importance and frequent occurrence sert overlooked until Sunitha recent study (264), its nature, honesci, 18 not well understood Morphologically it is similar to the lesson of embolic glomerulonephritis de scubed by Lohlein (172), and the possibility of an embolic etiology cannot be cicluded cntirely cien in the absence of microorganisms in the blood and tissues In none of the patients studied 1 is a definite diagnosis of Libman Sachs endocarctis mue, moreover it is unlihels that the firm, icrrucous vegetations of Libman Sachs endocarditis could be responsible for embolic manifestations & Therefore it is pobible that the glomerul ir necrotic lesions are primarily the result of local a chemia from colescence of capillara, basement membrane tluckening fibrinoid changes and endotheinl cell proliferation This leuion, which is unusual in other renal dicases with glomerular inclema may be duc to sercral factors including the rapidity of development of the capillary ob struction and the local release of abnorm it substances peculur to SLE (159) Hematoxy lin -or more accurately lemntowplul' (261) --bodies were found relatnely inírequently in our maten Tlu- 1195 probably a reflection of the high proportion of early lesions studied, and of thic fact that only a limited number of glomerul was tvailable for study in caclı biopsy specimen Nonethe less they were found in 1 feu biopsy specimens in which the immediate fixation of the living trsuc cicludes the possibility that the formation of hematoxylin' bodies results from agonal or postmortem changes Their common occurrence in areas where pyhno is kary orrleus and hari olsals are scen points to their probible origin from nuclear inaterial and to thivir close relationship to the Har- * It is of interest that es in only one of the thirty c of Gro (103) who found tion of Jessy (127) and Harscy (110) cach of hom obeeri ed this levon la aproximate onc tiril of tl elr pitients This difference in inci lence is the cult to cxplun but the recent experience of other pathologi ts hts beca simtir to ours (231 232) 1 ·LLLS VERJIRITIS 10 gratcs s cell phenomenon (2), 104 109 130 1621 It is not clair to lieingtoxy lin bodies should be specific for SLC e for tuo ei«8 (228 30G! ong of which might he had SLE, they hnie not been obenied in any other renal disca e including thoc quocinted with necrotizing le-ions of the glomeruli IIyalinc' thromb in the glomerular capillaries ne nually obscried in the advanced and active stages of lupus pephritis but aic not peculiar to lupus nephritis (128) Tliey appear to const primarılı of fibrin and platelets The mild to moderate bisoplulic eniu 1310g which is onrued in womt instances muy be due to the presence of material of nucle ir 011_n and the rentation form intraluminal' hematory lin' bodies may be difficult in the CILS Ilsalınc' thrombi must al o be differentiated from a centic fibrinui i tleheminof the capillary wall-the so called verucal ciputi 13 Their patho.cnc-is 18 obscure, wo agree with Jones (128) th it alterations in the frumg cells of the capillaries and cloning down of the circulation pot ibly sin role in their forination Clumping and proliferation of the endothelial cells of the glomerular tuft 18 coinmon in lupus neplirtis (19 272 274) Indi linnun (then anal dis casca In lupus ncplırıtıs this cellular prolitul itin u ulls iffat mall areas rather than the whole of the giomcrular tuft in I thi da tol u lothelul cell proliferation is not compirablc in severity to tu un in en lying of acute glomerulonephritic Our findings suggest th it endoth lilc 11 policiation follong the dev clopment of changes in the gloculu bu avent membrane By contra t proliferation of epithelial cells and the donation of filrocpithelial crescents is a late manifestntion of lupu nephritis Thus in otries of lupus nephritis proliferntive changes are found in the homenuli in ad htion to the membranous changes The lack of specificity and the difficultus of intermetation of the tubul ir changes in lupus nephritis lave been discu--cat in the previous station As in miny renal diseases hy aline droplets are close sed in the cytoplasm of the com Oluted tubular coils tlıcır reictruty sitli PAS not as muhed ns in the kidney of amyloidosis and of multiple nuy clom ito is The accumulation of byline' droplets is the result either of che ne rc-oiption by or of altered metabolism of the tubular cells (211) Infortun italy it was mopo sblc to carry out satıf actory mutochondrial stums on our natural better to cvaluate this process Flems of the interstitial tissue of the kidney is a frcquent finding This correlates well with the swollen gro - appearance of thic Lilney at autop ), and with the frequent occurrence of nephrotic and p cudo nephrotic syndrome Interstatul fibro is occurs even more commonli but is rare sufficiently cerere to cause gross contraction of the lidneju With the exception of hematoxylın' bodies no other single histologie ferture can be considered charreteristic or pathognomonic of this di-case lesertheless lc hi-tologie diagnous is relatnich, ein in mins cases as some lustologic features occur frequentls in a combination peculiar to lupus nephritis leg ** Loe loops , local necrosis fibrinold nad hematorslin bodies) lccurate ·106 MUEHRCKE LARK PIRANI AND POLLAK histologic diagnosis is more difficult in the early stages before these lesions have doveloped However, the local involvement of small arcas at the periphery of the glomerulus by membranous or membranous and proliferative changes was found to be of great value in diagnosis in the early stages Diagnosis is also more diffi cult in the late chronic stages when ti e typical lesions have become obscured by the chronicity of the process Licept for non specific glomerulonephritis differ ential diagnosis does not present a serious problem Ti e histologic differentiation from other diseases which may simulate SLE clinically is discussed in section (Y) below Although the systemic nature of the connective tissue changes in SLE 18 neil known it is not clear whether involvement of the kidneys in SLE is a primary or a secondary manifestation of the disease The kidneys are not always involved early in the disease but are affected ultimately in a very high proportion of patients It is possible that renal insolstment in SLE is a secondary mani festation such as a reaction to one or more abnormal circulating substances derived from either the connective tissue itself or from the reticulocndothelial system—both connective tissuc changes and reticuloendothelial hyperplasia are known to occur in SLE In our patients however the development of lupus nephritis was not specifically preceded by or related to any one or combination of clinical or laboratory abnormalities Thus it seems more probable tl at lupus nephritis is a primary manifestation of the generalized involvement of the connectit e tissue VIII TREATMENT OF LUPUS NEPHRITIS 1 GEVERAL MEASURES The treatment of SLE has been reviewed extensively in recent publications (55 67 110 267 269) and the therapeutic response of SLE to cortisone and corticotrophin is well known We will tl erefore limit this discussion to certain aspects of the treatment of lupus nephritis The prevention and treatment of acute exacerbations of the discase are of prime importance Intercurrent infections cepecially of the upper respiratory tract dental extractions (141) drug reactions (90 97) exposure to sunligit and other stimuli have been reported to precipitatc acute exacerbations of the di case One of our patients ($23) had an exacerbation of SLE a recurrence of nepl rotic syndrome and an increase of hematuria following an upper respir atory tract infection in another patient (30) »ho was severely ill further deterioration of SLE and of lupus nephritis occurred after dental extraction In two others (*21 31) the face rash became more prominent and the general symptoms and signs of SLE recurred after exposure to sunlight In one of tice patients there was an increase in the lustologic damage to the kidney but this may have been coincident al One patient ($18) whol ad many acute exacerba tions and was not free from symptoms despite large doses of prednisone (30 60 mg daily) became acutely 1l »l enes er she indulged in excessive physical er ertion All these precipitating factors must be avoided as far as possible ex acerbations should be anticipated after infections and during and after preg ·LUPI'S VEPIIRII 107 TABIT I Relalionship of pretious treatment uith 107 ll or ( ortisone to the degree of kidney pathology found at the time of the first histologic study Kidney Pathology at the Time of Furst Study ACTH Dr Cort sane Therapy Before First Study Total Cases Tormal Glomerulis Gl merulonephr tus cs lo 8 3 22 11 3 IALI \11 Efect of treatment with 10 and RIP n the progression of renal lesions IR 21 patients with SLE hidnes Damage Somone Therapy between 1 st And Last listalogic Study Improved Lo hanned Progressed + Progressed ++> 11 2 les lo 0 0 2 CYTT 41 nancy They must be treated vigorously and with a venit of urgeney if and when they arise Oncc clinical and histologie cadence of lupus nephritis had appeared, treatment was symptomatic 1 The prezention of lupus wephritis When the 33 patients in this series were first stuched hx un 22 or 676 had Istologic evidence of renal ini oleinent compatible with SLE, and two others (#6 11) subscquently developed renal lesions of SLE At present corticotrophın and an TCSU SLE suppress the clinical manifestations no effect of the steroids was demonstrable in presenting the des clopment of le-jons lle must conclude that there is at present no way in which the des clopment of lupus nephritis can be presented in the patient with SLL Blephrotic and pseulo nephrotic syndrome in lupus nephritis Tlic-c patients were kept in bed for varying lengtlis of time and in onc, diuresis ensued spontaneously 1$23) llig! protein feriling (up to 1 5 kg kilo/day) and ditars rolum restriction were amel at in all cases, but in almost all of these patients there was fairls 4 sere renal dam ge, and permanent azotenuia necessitate a lutation of the protein intake The patients with peculo nephrotic «yndrome ($28 30 32) sete 111 cxtremels all and required trs strict bed rest and meticulous nursing care one of them (28) necncd 300 mg hydrocorti-one eich day intruchously the second (830) was treated ·10S VUEURCLE MARK PIRAVI IND POLLAK with 75 to 100 mg cortisone daily, ind the third ($32) receiied no steroid In no ence was there any detectable effect of treatment on the outcome C Chronic renal failure in lupus nephntis In general the aim of treatment was to allow the patient to lend as norma a life is possible in all ca-ca thc dietary protein intake was limited unually to about 40 gm dul Thic patients were carefully instructed about the impor tance of an adequate fiud intrke and urinary output The fluid intake (2000 3000 ml 21 hours) was apre id ti rough the 24 lours and we insisted that they drink 2 to 3 glasses of water at night before retiring Thcsc tro mea ures ir combination wcie perhaps the mot important fnctors in presenting rapidls advancing azotemia in tho c with chronic ronal fuluro In patients who were treated with corticotroplun or cortisone the sodium intake was kept belon 2 gm (85 meq) duly, but sodium re triction has not proved necessary in patients receiving prednisone Patients with the nepl rotic or pseudonephrotic sy ndiomes and some of those with chronic ronal failure cre limited to 500 ing (22 meq) of sodium duls Patients with chronic renal farlure were closely ob-crved in the outpatient department Frequent electrolyte determinations enabled us to anticipate and treat scrious electrolyte imbalance in some ca es This was usually done by limiting the clectrolyte intake in the diet as the need aroc Pho phorus is on occasion limited to C00 800 mg/day ind potasyum to 1000 mg (25 mcg) or less Sudden and fatal hy perrotassemi ($32) cannot als ays be presented by dietary means mapecinlly when tre patient is ses crely ill and there is side proud tis ue breakdown Ion cxchange resins 50 gluco contra cnously with insulin and calcium ucre used to prevent sudden cardiac arrest due to liy perpotaszeni Calcium lnctatc in doses of 9 gru duly and vitamin D 10 000 units duly were given to patients in a hom the les cls of scrum calenin icre low Supplementary sodium bicarbonate was some times nece sars to combat hypochloremic acidosis lu ci und somiting were Well controlled by chlorpromazine Initially it was gi on in do cs of 20 mg 6 hourly by intramuscular injection When the vomiting 118 controlled the in tramuscular injections 1 cre stopped and the drug was given by mouth Anemia may be due to the effects of SLC on tl e bone marrow or to 1 hero lytic process (1) It uvually responds well to treatment of the sonce sath cortisone or corticotroplun (67) On the other hand of inemın was associated with significant azotemia steroids were of no value and transfusions of picked red cells were given As rections to blood transfusion are not uncommon in patients with SLC cro s matching should be meticulous and Coomlss teets should be done routinely Transfusions should lcgisen only as the general symptoms si artant for no improi cinent in renal function occurs in the patient those hoinoglobin is fused to normal (201) and Platt hus suggested that glomerular plasma flor mij be adier cly affected by a substantial increase in the heinatocrit (227) Transient livpertension occurred during acute einecrbations of SLE (A) anul usually responded to treatment of the esaccrbution sith corti one or corticotroplin Permanent hypertension occurred infrequently as patients tisu ·LLPL VEI TIRI1IS 109 alls died before the stage of chronic glomerulonephritis Tho-c with hyperten bion were treated with small docs of rescrpint and, or pentolinium Thư history of case X31 (Fig 7) illustrates the successful management of a patient with SLE un clironic renal failure In October 1953 this 23 cai old student 195 8Merely ill with grand inal seizures hypertension sus crc acidos tutiny ind anasarea After recovery from tlus heute prode he was treated us outlined above and was able to continue working aght lour- dak until thile naths hefore his death in August 1953 During the whole of this period lut was admitted to ho pital once at our request and once for blood tran-ſu ion 2 TINE EFFECTS OF CORTICOTROPIII AVD CORTIOVE U LLLS VEIKRITIS In 1931 Rich and lusco workers reported that the disclopmı nt of a jaman tal anaphylactic nephritis in rabbits 1242) was prevented by the administration of corticotrophın (ACTH) 123 241) Won conti one ? An Instead of ACTII anaphylactic neplıritis did not destlop loseva diftercut type of le ion appeared (240) Subsequently they shonu that the li tons Here pro duced by cortisone alone (2411 The lesions were chuctenzed by that ition of the glomerulur capillary loops focal neciouis of all of the loops and tlu forma tion of lirge hyaline nas es in the tufts Theit is frouent ruptust of the tufts and considerable hemorrhage in the tubule. The lesions not mm u in ap pearance to the glomerulai lesions in diabetes mellitus li cuba el hos himmel strel and Wil on (112) Bloods orth and HN (301 m Halens in i stumpf (3011 have also produced similar lions in i abluts with corto on Harvey and h14 colleagues (110) stated that they hail olacruel 2001 ir l-on- in on patient with SLF, but no hustologic de cription is given With out doubt corticotrophin and cortisone ure of glit i lui ind may be life saving in acute encerl,ations of SLL (42) 67 266 269The early ex crknees of numerous investigators (41 42 45 71 118 266 268 2881 kad then to conclude that the rennlleion of SLEwmc.cklom bu nefited by corticotrophin or corti one Dubois (671 and linserick (113) however noted a douers in tlic hematuria and proteinuria in some patients given large closes of cortisonc but in thirce patients with SLE treated with cortisone 1 inch ay (123) noted 1 murhed cracerbation of the renal picture is determined from the Iddis count Particuaris noticeable in the tremendous incre ist in albuminuria When these three patients were treated with ICTII there was scrs little alteration in the renal picture Soffer and Badır (216) obrued that hein aurii and a lindura persisted despite trı atment In five of their ten patients with azotemia the blool urca nitrogen returned to normu lesels when the patients 1 cre rehydrated and their clinical condition liud improved Harvey and his colleagues (110) made simular oberi ntion and at the post mortem cimination of scral patients treated with corticotrophin and cortisone for long periods of time thics founel no renal disease Recently Bollet egil ind Bunim (31) trented four matients with Sir and lupus neplacitis is its up to 30 mg of predmz one daily Thics found no mprovement in the rema status and no wgnificant chance in the quantity of proteinuri Dubois (16) reported that the curls wild nephropathy cleared with trent- ·110 MUCIRCHF KRK PIRAVAND POLLAK inent Two of hus patients improved after treatment with corti onc but cudence of renal involveinent apperid agun during exiccrbations a few months later Soffor and his co workers (269) did not ob eri e an increased rate of progression of the renal lessons 74 result of corticotroplan or corti one therapy in 50 på tients They also cmphı ized that hormonal tl craps had no effect on tl c hyper tension associated with underlying renal di case On the other hand Ilarity (110) observed cleuation of the blood pre cure and rapid accumulations of flur! in seven patients with SLE ind lupus nephritis who were treated with corti cotrophin und corti one In five the change 1179 so rapid that horinonal therapy had to be stopped In a small numbes of patients with SIP treated with hormones Soffor (269) observed a significant improvement in renal function Heller Jacobson in 1 Hammarsten (118) studied the protein C\cretion urinary scelament and tests of discrete renal functions in tuo patients with SLE and in four patients with glomerulonephritis They concluded that corti ond find no beneficial effects upon the basic pathologic process in the glomerular capillaries Of the pre-cnt series of 33 patint 22 had recen cd corticotro hin or cortisone before the fir t biopsy is made (Table 1) Scion had lustologic cu lence of set cre hrdney damage ind in eight the kidneys were norinal Eleven patients had recented no hormone therapy before the first biop , Tuse of this group hal pathologic evidence of severe hulney damage ind in three tichidncye weru normal in twenty one patients serial hi tologic examinations were made (Tahle 111) A decrease of Laney damage 78( ed Instologically was not obscried in any patient Set cntcen patients were treated with lormones between the time of the first and the last lustologie study The does used were those which were sufficient to suppress symptoins m in no cree did the maintenance dosc ex coed 200 mg of lydrocorti one daily Purtoen of the ca tients the renal lesion progre er in i in chiunge Tour patients were not treat tan 1 was the last lustologic studly Int noted whereas in the other logic materiale did not fi by cortisone in rabbits Tlic numbers of patients tion of patients Treatmen Infortunately did not to the hidney follon ingt we can find no cildenect of the renal lesion for 1128 tlie same in those pa who had never rucelled Its The literature on progn out seu herr (110 184) ·LtPL VETERITIS 111 starting point of tlic disease Until recently 7s considered to be an acute or subacute disease, and the less dramatic symptoms and sign- duch my have been present for cars were overlooked lith incrcaung interest in and experi ence of the disease it 119s pon been recognized that pist episodes such as Raynauds phenomenon arthralgia thrombocytopenic purpura and hemolytic anc mnia were not independent de cace entities but Kere due to activity of SLE (2901 Voreover as pointed out by Voore and Lutz (196! and hy Haerich and I ong (114), Lologic fal e positive serologic tests for plules may be observed for many years before the patient des elops symptoms or signs of SLE Thus it is apparent that it iniy be difficult or imposible to date the onset of SLE which does not necc sarily coincide with the appearance of the first florid attack of the disenec Fvidence that SLFs frecuently a chronie rather than an acute or eubacute t case was presented in 19351 Verrell and Vulman (1841 In their series of 99 patients the time between the timated onset and the date of chagnosis vaned from less than one month to 35 yeurs Any of thur data reveals that this latent perio? was over ten years in thelve patients it was from five to ten years 211 eetcnteen patients from two to five years in tuenti six patients and it was two years or len, in forts four pitunts Bathr Klemputer and chifrin (9) reported that the marurum surah al time is 41 jars from the time of on ct but this report is tn cnty years old and more recent reports contain numbers of cases in wlucit the disease lias been present for ininv years (22 110 111 127 290) As the course of the di esse mn be so prolonged and as the initial symp torns may be insidious and are extremely v riable it is often difficult to define exactly the date of onset The duration of the isset( from the appearance of the first symptoms to the time of our initial study as won n graphically in Figure 31 In most, but not all cases the time of our initial study corre ponded clonely with the time of dingnos from Figure 34 it will be note ? that in the majority of cares (57%) the duration was less than tho ears frut that in four cases (12) It was between five and ten vears and in five casey (156) it was Debrecn ton and fifteen years Because of the difficultı in &igning an exact Numbe of potent 20 B 2 1 24 30 38 42 48 54 60 Try from onset . Me of ydy (mons) HIC 31 Ilistogram dlouing the Imagth of time from the onset of the fret of mpton of SLI tatil the date of the first red l bony dore ja 33 pat cuts til et ·112 VLEIINCKE AR PIRVI AD POLL IN dute of onset in these patients, it is likely that these figures are comicult in. accurate If so they err in underestimating the duration of the discose Harvey and his colleagues (110 196) studied tua pecific factors with respect to their cffect on prognosis pumeks age at the time of diugno in and the dura tion of time from onxt to diagnoza Tl cv found no significant chfference be tween the surrorship curies of patients under 18 over 40 years of age and in respect of the second point, they concluded that the type of ch e that pre sents scrious enough az mptoms carly in its coure to Iring the patient to tic attention of the doctor and enable to male dugno im! 10ll be the type that progresnes morc rapidly t) ercuter' Our sucs is too small to analyze in respect of these two gener il points of age and duration of the scree but much can be gloined from a close study of the course of a single manifestation of the disease--namely the renal invols cincnt 2 ROCOSIS I LLLS VEPRITIS U dc по cicr protein and formed elements may appear in the urine of patients with SIL during ncute cacerbations (110 269) and thiese abnormalities muy (1971 perr either when spontaneous re mission occurs (273) or quart ult of therapy (42 110 269) Thus has been our experience heath (140) in 1940 did not belicic that ronal insufficiency played an im portant role in causing deutli but the orpoulte Vicw hnd leen ndi necu ly Sniper in 1930 (265) Hc drew attention to the importance of the roorl lesion picted below In Table WWII finding on 33 patients are prosented the patients will be discussed on the basis of the clinical and pathologic criteria previously discribed When first studied cleren lad normal hidneys Mine are still nung one (*8) died of an acute ciaccrbition of SI L and t/c other (811) of aruto anterior poliomy ciitis She 24 not azotemic at the tune of Icr death but a membranous lupus glomerulonephutis was found at post mortem eurminntion one of the ten patients with mill lupus nepliritis (glomerulitos) Dis dicit but four (14 18 19 21) luc de cloped clinical and pathologie endence of progreisc renal noli cment Tucle patients had sus cre lupus nephritis (glomerulonephritis) when first studied Dight have since died and only one ($29) enjoys moderate health despite a muld degree of zotemir Sur of these patients had the nephrotic syn drome ind four have died in uremia Oi the other two ($24 29) have mild azotomii and impurment of ren z1 function Thrçe patients bed the pseudo nephrotic syndrome (proteinur13 by poalbuminemia cdemi and lou scrum cholesterol) All died within nocks of the onsct of cdema The gravity of the ·LUPUS NEPHRITIS 113 TIBLI 1111 Duration of illness and clinicul si dy of 33 patients uit SLE a clinicopathologic presentation Number Lv ng Vode of Presentat on Number Durat on of of Illness Before Dunat on of Patents rst Study sau ly Sumber Mode TIL Dead Prok senal VO V Total healthyhealth II HS (3 180)11 7 (323) 6 3 0 9 2 . 5 + 10 I Jornal kidneys II Glomerultis III Glomerulonephritis (Illa ) \eplırotic syn drome (ITH ) Psrullo nel til syndrome 1026 (3 132112 2 13 23) 5 12 46 (3-150) 6 5 0 24) 7 30 (372) 12 0 1 241 1 1 1 . 8 4 2 3 3 6 (5-6) 05 0 0 0 0 3 • Average in months for the group Range nivel in parentheses prognosis in SLE with the nephrotic ind pecudo ne plırotic syndrome is thus clearly show n, and these results confirm the findings of Daughertsind Biggen sto s (63) and of Slicarn and Profek (239) In es ence tlurty-thru patients with SLE 71e been followed for periods of up to tuo vears Ten have died within tlus period flung an overall mortality rate of 30 Of those who died six died of sucre renal failure and one of cute pancreatitis due to fibrinord necrosis of pancro atic vessels This patient (*27) who had the nephrotic syndrome was suscreli uremie Anotlır dıcıl of in cuto attach of SIL and myocarditis (28) Shc lind picudo neplırotic sy ndiome azotema und severely damaged kidneys Patient $11 lied des cloped renal damage but was not in renal failure when slic did from intercurrent acute anterior polony chitis Patient X8 did from an inadequately treated wherba tion of SLE (cute lupus eris) She was the only prtient in whom there was no evidence of lupus nephritis Y THE RELATIONSHIP OF SEE AND LUPUS AFPIRITIS TO OTHER DISF ISES 1 CLOVERULONEPHRITIS Fes modern texts of medicine mention SLE as a possible cause of renal dis ea e simulating glomerulonephritze acute subcute or chronie As SLE has become a more common-or more commonly recognized---clinical entity its relationship to glomerulonephritis has assumer an increased import incc In recent years many authors have pointed out that the presence of a skin rash as not a sine qua non for the diagnosis of SIC and skin riches are not infrequently absent in patients wath lupus neplırıtı- This was fir-t reported by Brenner (35) and sul, equently stressed by Hamburger (107) Recently Varmont (178) reported five enses of SI E without a skin rash, tuo had proteinuria and the other three dicul in renal fulur.

·114 vurliRCHE KARI, PIRATI AND TOLI AR If no skin rash is present, other symptoms and signs may be oferlooked, if they are found their full importance may not be realized Milne (187) rightly stressed the necessity of a brou clinical perspective in arriving at the corriet diagnosis The following case lustory illustrates tlus point Case *3.9 BD ( RE 42,9') in attractive 18 your old lugh school student ind enjoyed gool henlth until June 1951 liter period of exposure to the sun she de eloped cry thematoris spots on the fort rms and fre In Juls chc hu trunyent anhle edema wh ch recurred one month Inter Grou proteinuria and hematuria apreuredi 1 dugnosis of Bright dirase as made and she was confined to boi! On November 1st slc is admitted to the Vancrsity of Illinois Hospitals where cuorbital and pretibul edema kas noted Vuch blood and pro tein was found in the urine n few leucorvtrs and many hyalinc granulir fatty and cry thro cy to casts were seen in the urinary seciment The serum albumin w is 23 gm/100 ml the serum globulin was 33 gm/100 ml the blood cholestriol was 132 mg/100 ml and the MI V was 98 mg/100 ml She was able to concentrate her urine to a specific gravity of only 1015 the ure i clearince was 11% of ANRF, and the exciction of PSP was 3 in 15 minutes A dgnose of sub cute glomerulonephrts was made However careful review of the histors resciled the following all I tionn! information it the beginning of the illness she was feverish and had noted arthritis of the interphalingral joints In October she had pun in the shoul ler joints and compluned of ; leuritic pun On crimination there was a persistent fever, a faint hutterfly face roshuis detecteil tlic liver was enluged, there were elusione into pericardıl pleural and peritoneal cauitars the li coc3 te count was 3500/mm and the thymol turbidity was 12 units This nuditional cvidence mide 1 diagnosis of SI E with lupus neplırıtis very probible and many Hargraves cells were found on eximination of the bone marrow She became comitone had several convulsions and died on November 15 Permis ion for 1 full postmortem evimaation was refuse 1 but kidney tissue was obtained post mortem with a biopsy necdle Postmortem Bropsy (Color Plate-Iug 9) The glomeruli were exhemic an I there were loc i rois of irregul ir smudgs thiclening of their basement membranos Loonl areas of Lay percellularity were also seen The lumını of a few glomerular capillaries cre filled by homogenous cosinophic material these cepill try thrombi were PIS postic and staine! red in Vallor preparations (Color Plite-Fig 10) Distinct wire loops han orrhevig and hematow lin bo lies were roen in a few glomeruli (Color Plate-lig 9) I few adhesions between glomerular tufts and Bowm in s (psule were noted Proteinaceous material x 13 obseriod in Boumn in sy uy in l in the convoluted tubules wlo«c lining clutclium showed considerible atrophy and degeneratie chinges Theic wis edema and fibrosis of the gater stitial tesue which 17 infiltr ned by Chironut infimators selle There wcie fil e nosi changes in the small arterice Diagno · Lupus nephriw subacute local and generalizeil membrano is and proliferatic glomer lonephrit The pathologic differentiation of lupus nephritis from glomerulonephritis my be difficult (Section VI (2E) and Table VI) In the early stages of the condition the local involvement of small areas of the periphery of the glomerulus by membrinous and proliferative changes (Color Plate-Fug 1) luas been, in our experit nec, peculiar to lupus nephritis, it here'is in glomerulonephritis the whole or almost all of thic glomerulus is usually involved Nonetheless we have seen lesions in the carly stages of glomerulonephritis, which lave been difficult to dı-tinguish from those oi kupus nephritis Tor example, in Entichnap and Joiners excellent clinical and pathologic study of Bright's disease (75) Figure 1 is taken ·I nt be 111 t! 1 - Toth discases IIargrates s cells vert found on c13mination of the peripheral LUI EPHRITI. from the hiddey of 1 paticnt diagno cd clinicalls as Cili tu pathologic diagnosis of Clits tipe II neplıriti sa made by the ta tlor B local area of necro se local hy percellulzrity and han orri en indle ening of the glomerulır ba cment membrane are prominent te sture tunately tlc clinical hi tons of this patient was not given but the poli features are more con i tent with the diagno i of lupu ni niti inte Croonian lectures in 1912 Arthur Elis wrote Vucl ott! #bich still exits in our knon ledge of the conditions group à undit Brights disca e arose from failure to study the natural li tort ditions--t er mode of incidence and subsequent cour e to ! 162) Casc 31 (page 42) is an eicellent illu tration of the valu in the study of the natural fustory of renal di c1 c 31 1 ani! tance in arriving at an exact pathologic dia,no is Insert tont developed symptoms and then een bi u for theft had the clasical clinical and laboratory picture of SLE IU his urine A renal biopsy made in September 1933 11 15 COM no is of lu us nephritis (Color Plate-Fig 7) Fibrinold I the glomerular basement membrane and in the artcriole areas of harz orrhexy A etcond biop y in pril 1931 rest 1 (Color Plate-Fg 8) In these biop 10 there were tatui chron c lupus glomerulonephritis respectack From the titur 1 pts clinical and laboratory cour e cime more ani 1.0ie to a case of chronic glomeruloneplıritis without SLE nd it roti ton in Augu t 1902 the renal lesion 111s quite indi tingui hidul > oi clio o pl ritis would undoubtedly have been made let tikin, into account t? no cul lat oratory and pathologic features studicu serialls over 1 p riui ut years there was no doubt that this 1118 a case of IL ut lupus ni! 2 POLY ARTERI IS NODOS 4 Polyarteritis nodo 2 miz run a prolonged remittent course and the wr affect many organs and 53 steins of the boda Conscquunthi the difi rental dngno mas be a dificult one is has been cuphasized by Banhs (14) him mir (131) Pagel (219) and others In 1928 olh (293) reportel a ? of tanical SI E in whom lesions characteristic of poliarteritis ne do a here found tinortem recentis Lincoln and Richer (169) and hofman Jolinson ud 2n derman (156) reported cases of hu tologically proven pols arteriti no lo . in a) om llargrates s cells were founi lle harc obeersed three patients in a hom the problem of the relationship be In een polyarteritis nodosa and SLE arose Case $10 had fertures common to Llood and polyarteritis nodosa s as found on examination of a muscle bio The follon ang case is presented because her clinical course wins typical of elint T ·118 MULHRCKE KARK PIRANI AND POLLAK nodosa runs a prolonged course characterized by exacerbations and reinisalons It is 1 recuirent progressive inflammatory di ease of the muscular type of ar teries Fibuinoid necrosis was a prominent pathologic feature and intolerant of the kidney almost universal (29 154 307) Renal infarcts here the prom nent pathologic ſesion but were not extensive enough to result in renal insufficiency A smlar pathologic picture was de cribed by Davaon Ball and Platt in five of their caves (their Group B) (64) Ti e lesions described in liy persensitivity angiitis hy the Cincinnati workers were very different (154) A necrotizing glomerulonephritis was found in ninu of their ten cases Exudation and necro is rat) er tl an proliferation of cpithelium nnd endothelium characterized ti e glomerular le ions pd as the process was acute no evidence of healing was such in any of the lesions Davson Ball ani Platt described a similar but not identical le on in eiglt cases (tl Car Group A) (64) There was patchy fibrinoid necrosis of the glomerular tufts but with Vuying umounts of epithelial crescent formation and partial fibrosis of the tufts Four similar cases were later added by Wainwriglt and Davson (297) Urınalysis is not helpful in differentiating the two diseases As has been shown by Sclireiner (255) and Hamburger (107) even the telescoped urinary sedi mcnt may be found in both conditions and in other forms of glomerulonephriti In these circumstances can renal biopsy be of assistance in the differential diag nosis of SLE and polyarteritis nodosa? The lesions described by Zeek us polyarteritis nodos1 are obviously very different from thio c of SLL and their focal distribution and nature makes at unlikely that a positie diagnosis could be made in all cases by renal biopay The necrotizing glomerulonephritis described by both the Cincinnati and the Vanchester workers honey er is very similar to the glomerulonephritis seen in some cases of SI E ind in one of her cases 7eck found some features of SLE (151) Patients with the necrotizing glomerulonephritis of hypersensitivity angntis are acutely ill and the course is a rapid one In those patients with SIE and lupus nephritio wo were rutely ill and in thon the clinical course was of te difficulties my oled in making an accurate histologic 110 is ale ted #cll in case 5 reported by Pagel and Treip (219) In this patient a 46 year ol! mun the clinical diagnosis was eit) er pols arteritis nodosa or SLE The patient died of rapidly progressive renal fulurema finding more in keeping with the diagnosis of livpersensitity ingutis On the basis of t) e di tinctive wre loor phenomenon Pagel and Treip concluded that tl e pathologic diagnosis was SLL no I ematory lin bodies were found We have shown that the wire loop losion occurs in a variety of diseases and in patients wath lupus nephritis running 60 fulminating a course hematoxylın bodies have been found in the areas of local necrosis (X28 30 32) 4s Smith (264) has also pointed out IVe conclude therefore that the diagnosis in Pagel s case was probably not SLE but Zreh hy persensitivity angutis ·LUPUS VEPIIRITIS 110 Fig 37 huinry from a patr nt ill urth long standı o hur mator l arthnts (R&F Autop 68/1915) Notu tle d ffuse by percellularity of the glomerular tufts due to en lottelualcll proliferation (H&E X 230) This type of Iffusc glomri ilitis sparmi les t it ob erve in some instances of furt nephrit (compare Fig 23) 3 RHEUMATOID ARTHRITIS Joint prins and arthritis are prominent features of the symptomatology of SLE Vald arthritis is common but more severe degrecs with marked deformi ties of the joints are unusual The kidney - arc frequently affected in SLE but clinical involvement of the kidneys in rheumatoid arthritis 15 not sigmficant Although fen putlologie studies have been made in rheumatoid arthritis Cobb Anderson and Buur (5+) observed that renal discuse was notably frequent Piram and Bennett (235) found a proliferatic glomerulitis in two of three 01-09 (Fig 37) and Baggenstoss and Ro cnberg (13) were impressed by a lugli inci dence in autopay mitcrial of 1 pecific diffusc proliferate glomerulitis They spy culated that tlic agent responsible for rheumatoid artlırıtıs mght al-o be responsible for a lon grade subclinical glomerulitis (13) That this may be a terminal phenomenon is suggested by our own loy studies in twenty two pa tients with rheumatoid arthritis in none of whom were the glonjeruli abnormal (230) Rheumatoid arthritis 1* 1 generalized di casc and on occasion needs to be differentiated from IC Lalor tory tests muy afford little help in both dis eases the globulins may be clerited the thymol turbidity and other flocculation tests may be postne (156 163 230) and Hargrales cells may be found on esminition of the bone murron or peripheral blood 182 120 182 208 2631 At the present time the cvact relationship betueen the two disenses is a matter for speculation Ilijmans and lus colleagues (1201 found Hargravess cells in 54 ·120 VUEHRCHE, KARK, VIRAVI, AD POLLAK of 455 cascs (12%) of rheumatoid arthritis, and have suggested that some cases of rheumatoid arthritis muy in fact be suffering from SLE The following patient had rheumatoid arthritis for ten years before develoring SLC and lupus neplıritis: Case 92 J.NI ( NE 497706), a 47 year old laborer, had hal intermittent attacks of conjunctivitis for 26 y curs In 1914 he first developed arthritis which involved symmetrically the interphalogeal, krist elbow and ankle joints He was treated for rheumatoid arthritis Apart from recurrent attacks of arthritis resulting in some deformits he had no symptoms uptil the full of 1951 when he complyined of pleuntıc pun and increasing shortness of breath la Junviry, 1955, he der cloped & fcvcr and 110$ admitted to hospital acutely ill and anemic There is much cdemı of abdomen, sacral region and legs and hic had ascites and bilateral pleural effusions The pulse 729 rapid, the blood pressure was 155/95 mm Ig the heart 18 enlarged a Grade III blowing systolic murmur is heard at the apex and there was clectrocardiographic evidence of myocarditis Lncr, spleen and lymph nodes were enlarge and on examination of the bone malow many Ilargraves s cells were foundl Ilis condition improved rapidly after treatment with digitals, los salt diet, and cortionc, but protein and hyaline cists were persistently found on the orde The maximum urinary specific grunts was 1 018, and the NPN was slightly clevated After leaving hospital on February 28 he was much improved, but still had intermittent clicet pain and prins in the joints I! June 1955, he had a funt face rush, was anemic and the white cell count w ny low 'The TIG 38 Patient 92, Forst Bropsy, February 1955 Note the smudg irregular thichenug of the glomerular basement membrane Thig is strongly suggestive of fibrinod In some areas there is obliteration of the cap:llaries, hypercellularity and slight karyorhexis (early local necrotic lesion). (H&L X 500) ·LUPUS NEPIIRITIS 121 Ficart was slightly enlarged Liver spleen ard lymph nodes were not palpable There was protein ++ in the unne, and many erythrocy tes leucocz tes and cellular, hyaline and fatty casts in the urinary sediment Tests of renal function were normal From July to November 1955 he had recurrent attacks of arthritis and purpura, Fas feverish, and had several small Demoptysca When admitted to hospital in lovember he was acutels !! feren hand complaibel of pain in the chest and in the joints There were many purpurc blotches on the skin of the arms and legs his legs were cdematous the liver was enlarged the heart was enlarged and the blood presure was 150/100 mm Hg The urine contained +++ protein and the microscopic urinalysis was unchanged His symptoms improsed after the dove of pre dousone was lucreased to 25 mg per das Renal biopsics were made on February 28 June 16 and November 14 1955 The first renal broray (February 1955) (Fig 38) contained tca glomerul their surround ing tubules and come medulla Most glomerul were slightly Ischemic and tobulated ind there was a local irregular thickening of their basement membrane This was smudgy in character suggesting fibrinord "tre loop Icsions were noted in a few places Mild local hy percellularity and occasional baryothers were observed in a few glomeruli In these areas the capillary lumina were obliterated and a fex adhesions beta cen the tuft an 1 Bowmans cap ule were noted no 'bem.tovy lin bodies were seen the convoluted tubules were slightly dlated in places and there were distinct degenerative changes of their lining epithelium Proteinaceous material was present in Bowmin 8 spaces and in the tubular lumina There was slight interstitial edema and fibrosis and a small number of chronic in Nammatory cells infiltrated the interstitial tissue Dugnosis Local and generalized membranous glomerulonephritis Second Renal Bopsy (June 1905) (Tug 39) I've glomeruli with their surounding Fig 39 Palant 4.2? Second Biopsy, June 1955 In both glomeruli note the irregular sinu lo thickening of the brement membrane It is local 19 the glomerulus on the left, diffuse in that on the right. A well organized adhesion can be seca beta een the glomerular tuft And Borman s capsule in the glomerulus on the right, this is probably the end result of local decrous in this area There is a moderate degree of interetitial edems an I tubular degeneration. (II&E X 350) ·122 VLFHRCKE, KIRh, PIRAVI, 41 POLLAX tubule were included in the sections The glomeruli cre ischemic and somethit olulited There was a rither mashed locul thickening of the basement membrine wuch 4 smudg and granulir in places suggesting fibrinoid In plıces this thickening 17 quite marked with oblicuation of the capillar lumini There were adhesions between the glomerular tufts and Bowmins cipsule There is minimul local hypercellularity, and occasion il kary orrhexis in these arens Ibundant protein iscous material is found in Boxmın s prccs and in the Sunun i of the consoluted tubulce which were diluted in fome place anel atropluie in otheis The tubules were lined by a low cuboidal epithelium in which distinct legcncrative chinges wcie seen A fex tubules were complctek filled by i de blush homogeneous cists wuch stained strongly positive with the PAS technique There ne celom i in l fil rosis of the interstitil tissue wluch " is infiltrated by a small number of chioni inflimmtory crlis The changes were more sciere than in the first biopsy Dingnor Local and generalızed membranous glomeruloncphnts Third Renal Bwpsy (\olomber 1955) (Fig 40) Telve glomeruli their sturouniling convoluted tulrules and a little medulla were included in the section. There w 14 irregular loc a thickening of the brement membrane of all glomerult It se muntg nail grinular in appearance resembling fibrinod, occasional wire loors' were con In some glomeruli thic cipilliry loops had collesced in rreis und sere necrotic, fibrinoul matemal nukir rists There were molete degenerative changes in the tubular epithelium Icre was much I IG 40 Patient $22, Third Bropsy ouember 1953 Note 7 tuucal Irsion of local nocios * uith whesions to Boxmins capsule Within this arcu note the sulgt fibrinand material 'Hematory lin" bodies are preerut but cannot be clearly seen in this sick and white photomicrograph In the remainder of the glomerulus slight thekening of the bnsement membrane is evident Bowman's space contains proteinu rous material Vote thic 1 scuolir degeneration of an adjacent convoluted tubule (HCC 500) ·LUPUS VEPIIRITIS 123 rately fibross of the interstitial tissue which was infiltrated with a moderate number of chron e inflammatory cells There was mild thickening and seleros 3 of the walls of the small arteries and arterioles in some there were changes suggestive of fibrmoid These fin! ogs wcre confirmed in Mallory and PAS preparations The lesions were more marked than in the second biopsy Dugno u Local and ger erol zed membranous glo nerulonephritis diagnostic of lupus nr plnit 4 SCLERODERYA AND DERMATOVYOSITIS According to hlemperer the morphologic evidence permits the conclusion that generalized scleroderma (progressive diffusc sclerosis) is characterized anatomically by 1 fundamental implication of collagenous tissues (144) The sclerotic process can be traced to the connective tissue framework of the organs and appears to be the result of an increase in collagen fiber formation despite widespread hyperplasia of the connective tissue fibers there is no concomitant fibroblz.tic activity in any phase of the morbid process (148) Neverthcless fibrinoid alterations have been observed in scocination with the progresive sclerotic transformation of the collagenous tissues and as Moore and Shechan (195) have shown hoth changes are commonly found togetlier in the kidney Klempcrer him clf points out that the sclerosing change obscried in scleroderma 18 Dot specific to that disease and is a common finding in the spleen pericardium and retroperitoncal tissues of patients with SIT (152) Thus it is not surprising on morphologie grounds to find that in some patients there may be no clear cut differences between SLE and scleroderint and that rigid classification may be impossible Recently Richards (243) reported patient in whom the clinical fentures were those of SLE but who hrad scleroderm of the fingers and Tumulty (290) also mentioned shin changes resembling those of scleroderma in patients all with SLE This problim also arose in the case reported by Volpe and Hauch (294) Their patient diagnosed by them as sufit ring from scleroderına nas diagnosed elsewhere as SLL when inany Hargraves scelis ncre repeatedly found on cxamination of the bone marrow From the clinical lu-tory it 18 perhaps more likely that the patient was suffering from SI C Surely we can admit that she presented features of both illnes es lle encountered a similar problem in one of our patients Cac In 19 0 1 7 (1 911) Iglt sk nnet cmot on 1 39 err old negro loufen tri migritory Jontyns affe ting the interpl alidgel louller and hacc jo nts Two Yours liter she suffet 1 from alle and more i3 ani rotopled of sl ortness of leath 111 lun pi bo lee are olarar i anl op stils of lymp noi lop ) perplastic Impl 11 en is uns found In July 193 a litterfy i ce cash aspred after expo ire to the sun semn a los fra le frer and e! mi of the face apl ptctib al reg oos nas note! The lymph nodes ant liner #ere nok enl rge ! The patent was anem c had a pericard 1 elusion and the rerum globu Inl el 101 LSR a.cre ta on Hurgmies cells were not found on crimination of the bone mirror but al 10 st from tle skin of the fice 883 cons tere i to or compatible with lusus er them to & When slc 7 treated with cort sone I er gmploms im; rose con deralls ·124 MUCIRCKE, KARK, PIRANT, AND POLLAK Following this honeser she continued to bue intermittent joint pains and recurrent pleural pain was troublesome She lost much hair from the scalp When seen again in July 1991 there was atrophy of the skin in patches in the butterfly area of the face The lymph nodes were enlarged and a pericardial effusion was found The thymol turbidity was 12 units and Hargraves s cells were found in the peripheral blood At this time honever a new and striking feature had appeared Tle skin of the forearms an! of the fingers was tence shiny atrophic and indurated and multiple parony chlae were prominent A skin biopsy revealed dermal fibrosis By August 1995 she had become very weak and fatigued easily ant she had develope 1 sei ere Raynauds phenomenon The skin had become thich and indurated Ircas over the Innds were white and tender and the skin was firmly bound down TI e lyer 19 endurged and tender and tests of luser function were abnormal Hargraves s cells were repeatedly found in the peripl er il blood On barium suallow ses cré csophageal changes typical of scleroderma were seen A skin biopsy showed changes characteristic of scleroderma Renal biopsies made in October 1953 September 1951 and August 1955 scre reported as essent ally normal The initial diagnosis in this patient was SIE This was made bccausc of the interınıttent febrile course, the development of a typical face rash the affection of lymph nodes and Inver, and of the joints pleurn and pericardiuin The serum globulin and thy inol turbidity were raised the skin biopsy was consistent with the drgnosis and Hargrazcy s cells were repeatedly found And yet at a later stage findings typical of scleroderma were rioted llc arc driven to conclude that this patient suffers from a diffuse collagen disorder with featurcs of both SLE and scleroderma The pathology of the kidneys in generalızcd scleroderma was described by Masugi and Y1 Shu in 1938 who were the first to point out that cutensive fibrinord changes could occur in the connective tısues of the arterioles and glomeruli (179) Two years later, Pollack described tho cascs of cleroderma with extensive fibrinoid clianges in the vessels (228) both had aetere renal in volvement and in onc the lesions re cmbled those seen in SLC In lus discussion of Pollach s paper Bachr stated that both patients had a long intermittent fcurile course persistent hematuria involucment of the synovial membrancs of the joints and involvement of pleura pericardium and peritoncum Leucopenia and depression of the hemoglobin were found in one On the other hand as a result of their experience of 150 cases of scleroderma Leinu and et al (165) have pointed out that hematuria docs not occur for long periods and usually de clops only in the terminal stage of the illness sliercas one of our patients ($23) wath SLC had prolonged hematuria for about one year Thue despite the typical skin lesion the clinical course of the patients described by Pollack more closely resembled that of SLE than that of scleroderma and it is probable that they had fcatures of both diseases The cli scleroderi ctidence velops ab 195 214) The prthology of the renal lesson has been described by Masuki asu Ya Shu (179), Bevans (27) Goetz (94), Moore and Shechan (196), Leinwand ·LUPUS NEPIIRITIS 123 Fin 41 Audney from a patient urth scleroderma who died with sciere and rapidly progressize renal farlire (R&E Autopsy 133 196) Note the market intimal thu hening in the small artery on the left and almost complete obliteration of the lumen The mucinous The character of this thichensog 13 not clearls demonstrated in the black and white , hotomicrograph Distinct fibrinoid changes are seen in the chickened wall of the Irteriole (arrows center and right) len ding into the glomerulus lote alºo the diffuse thickening of the basement membre in the glomerulus (HEX 150) (165), and recently by Rodnan and hus colleagues (244) The le son affects the origins of the intralobular arteries, where a concentric mucinous like thichening of the intimu may be « sci ere as to stretch the media of the sesac) (F18 41) 11 hen ses cre these lesions result in a widesprend focal cortical infarction which shes the le-on its patchy character Fibrinoid necrosis is often seen at the peripheral portion of the intralobul ır arteries and muy extend dutally from there into the gloinerular tufts (Fig +1) As not all arteries are affected the lesion in patch in its distribution and ens of norimul hidney are found letween areas which are grossly damaged Voore and Shechan rightly obserse that this lesion differs from that seen in the other so called collagen diseases Dermatomyositis has been considerer by some author to be akin to sclerodurma but others have regarded the two discascs as distinct clinical entities (63) In 1940 kcil described in detail file (nes which be considered showed transitional features between dermatomy out and LF (138) These patients 111 bud long and complicated clinical histories liut despite the completenes of the protocols it is impossible to be ccrtun that any of thoni nas suffering from SLC Postmortem ciiminations in tro of them did not reveal any lesions dignostic of SIT Renal dic15€ rare been reported in dermaton yositis Talbott and his collongues reported 1 single cise in 1939 (282) Originally the diagnosis was ·126 MUEHIRCHE, KARL, PIRANI, AND POLL 4X sclcroderma and a skin biopsy lnud slotn features "similar to those observed In some cases of muscular cances associated with arthritis and scleroderma' In the last week beforc this patient's demise there occurred a sudden dcteriora tion in renal function-which had previously been normal The postmortem diagnosis was "chronic diffuse dermatomyositis with sclerodermi The authors commented on the renal lesion as being in their experience, unique There was a widesprend focal cortical infarction, but the glomerul within these degenerating areas were prescried Thic medullary and arcuate branches of the renal artery were normal, but the intralobular arteries showed an infiltration of their subrntımal substance by 1 mucinous material, the-c lesions censed abruptly when the vessels assumed the caliber of afferent arterioles Fibrinoid necrosis was seen in a few arterics This renal lesion resembles very closely that described later in scleroderma, both clinically and pathologically (165, 19., 244), and cannot be considered to be due to dermatomy outis per se Keilre viewed the publislied cases of dermatoiny ositis (139) and concluded that the kidneys are, as a rule spared in dermatomy ositis," although he bumself had referred to the rare occurrence of gross hematuria azotemia and hypertension Recently Donzalski and Norgın were unable to adduce any further cuidence of kidney mrolvement in dermatomy ositis (65) 5 TIROY BOTIC TIIROVBOCYTOPEVIC PURPLR4 1 compo outcome within at most eight wecks (262) The clinical picture is usually cpi odic ind is characterized by thrombocytopenic purpura, severe bemolytic anemi and bizarre and transitory neurologic signs Thesc clinical findings may also occur as manifestations of SLC Thrombotic thrombocytopenic purpura is sometimes associated with other so cilled collagen diseases (262), and a number of cascs hale ben reported m which there were fentures of thrombotic thrombocytopenic purpuri ind of SLE (17 18 46, 161, 279, 280 299) The following case was diagnosed clinically as suffering from SLL At the postmortem camination Icarons of both SI E and thrombotic thrombocytopenic purpura icre found RS (R & E 40,015) a 31 ser olt television repur man hud ba! Sunt etes mellitus sinre 1900 leverthele<3 bus health ris goo I until 1932 loen snelling of the points of Is fingers occurred Thencefornard helal intermittent attacks of pun n stelling involving the fingers wrists elbows knees and anklee In Mai 1923 he halut) romlol lolutus of tłc right leg One year later a diagnoss of theumatoi! arthritis 195 made wen pun and swelling of the joints recurres! Beenue he had attacks of sciere pleuriti puo an/ tle Il assermann reaction was positive the diagnosis of SLT WAS con lerc ! but II nrgraves s cells were not found Subsequenth he had episodes of fever and letharg In Ocrober 1953 bc hyl chulle was fcverish and compl uned of sciere generalized abominal pun which persi te 1 until 115 a Imssion to hospital on November 14 1905 He sas acutch ! h19 temperature was 1019 anl the pulse rate was 120 per m pute with multiple extrasy stoles There # 13 1 general art ·LUPUS EPIRITIS 127 lymphadenopathy and bilateral picural effusions petechiae #crc found in the mouth and on the skin of the cliest and abdomen There was generalized abdominal tenderness and myrhed rebound tenderness but Lowel sounds were present The urine specific gruity 1$ 1031, the urine containeil protein ++ no bile and a trace of urohilinogen In the under) srdient there were many erythrocs teg 20-30 leucoey tes some of which were in clumps mapy byalınc and grinul ur and a few leucocyte (43t3 The hematoent was 30% the Irucocy te count was 2200/mm, and adequate numbers of platelets were sern on a blood smear The forum bilirubin u 0.29 mg/100 ml scrum albumin 31 g/100 ml, serum glotulin 20 km/100 ml (gamma globulin 105 gm/100 ml) Hle na dinynord as having an acute erarerbition of it with acute abdominal complications of lupus (229) and was therefore treated with intravenous hidrocortisone 500 mg dul Later as hu condition improyed Jic w 18 gi en hydrorortisone hy mouth Blood cultures and the lasermann renction were negative Thc leucory te count as persistently low Later he developed a pericardual friction rub and a systolr murmer #19 heard at the base of the heart In March 1956 lic complained of sciere headaches subsequently becimr comatosc hud fcicral (lonic Or ul tons on 1 diel He did not have purpura at this time At the post mortem camination a verrucat nonbacterial endocarditis of the mitralie *found There was molerate hypertrophy of the left vintric Je bulttrral a llicenc pleurite and acute bronchopneumonii There were multiple widespread platelet thrombi in the arterioles of myocardium ludz bruin spleen Iner and kincse There was grorralized lymph no lo hyreislisin and moderite splenomeguh Well marked jerurteruul fibrose was seen in the folcen (F1x 42) In the kidneis (Tug 43) the basement membrane of most glomerul was irregularly thickened the thickening W28 nere in ure is freulting in marked narrowing of the camllars lumina in places the thxhene! 1995 ment membrine aj pored emu igy and granulir suggesting the presence of filsonoid 1r Joop Jeons were forn 10 some glomeruli There was no erllular proliteration in the glomerul The consoluted tutmiles wcre atrophic in areas and drgcneratate bunges uery s40 in the lining Cynthelium FiG 42 Palunt, RS Autopsy Spleen from a patunt uthu is t of LF and thrombofir thrombocytopenic purpura Note the famounted periarterial filro-13 in te pedicu! or arteria This is typical of SLE Note that a small rubendothelial platelet thrombus enn le eren in the artery on the left (ILL X 170) ·128 MUEHIRCKE, KARK, PIR4\I, AND POLLAK IG 43 Patient RS Aulopsy Kidncy from a patient uho died of SLE and thrombotic thrombocytopenic purpura Note the severe and diffuse somewhat smudgy thicheating of the glomerular basement membrane and the wire loop lesions To tle right of the glomerulus a small artery is completely occluded by a fairly homogeneous pintelet thrombus (11&EX 230) There was consıderable fibrosis of the interstitial tissue in places and infiltration with chronic inflammatory cells A moderate degree of thicheping and hyalınızation of the walls of the small arteries and arterioles was noted The lumina of many were almost completely occluded by irregular smudgy eosinophilic thrombi-some of which were undergoing organization Dragnosis Diffuse and generalı cd membranous glomerulonephriw consistent with lupus nephritis Al ultiple arteriolar platelet thrombı A clinical diagnosis of SLL was made because the patient had a prolonged cpisodic illness with fever, maluse, arthritis, and evidence of involvement of pleura pericardium and peritoneum The leucocy te count was persistently low, the 11 qasermin reaction was positic transiently, and the findings in the urinary sediment were consistent with the diagnosis of SLE At the postmortem examination a pathologic diagnosis of SLE was made because there was peruirterial fibrosis of the spleen, crrucous nonbacterial endocarditis, and the renal lesions were compatible with lupus nephritis Save for the terminal episode of com and convulsions there was no clinical evidence to suggest thrombotic thrombocytopenic purpuri, yet arteriolar platelet thrombi were found postmortem widespread throughout the organs A similar case with Hargraves's cells in the peripheral blood and clinical and pathologic features of SLE and thrombotic thrombocytopenic purpura was reported recently by Laszlo, Alvarez and Friedman (161) ·LUTUS NEPRITIS 120 Sır years ago the opinion was expressed that the lesions of thrombotic thrombocytopenic purpura were "entirely different from those of periarteritis podosa, disseminated lupus erythematosus and of the usual infections diseases (43) Orbison coneidered it to be a variant of one of the presiously characterized collagen diseases stating that This stand is supported by the prominent aneurysms, large occlusne masies in the arteries and capillaries and the focal destructive lesions of the arteries which characterize this disca«e are not found in other members of the group (of collagen discases) (212) Nonetheless features of SLC or of polyarteritis nodosa have been found in ton percent of the reported cases of thrombotic thrombocy topenic purpura (262) and in one instance features of all three were noted (280) The exact nature of thrombotic thrombo cytopenic purpura and its relationship to the other collagen discascs needs clarification Capillary and arteriolar damage may be widespread in both SLE and throm botic thrombocytopenic purpuri Several obscrvcrs hanc prescatod evidence that the vascular damage actually precedes the formation of platelet thrombi in thrombotic thrombocytopenic purpura (6 99 212) In our opinion it would scem possible that widespread platelet thrombosis with or without thrombocytopenja and purpura might occur as a complication of the vascular dimage in SLE It 19 surprising that it is not seen more frequently The kidneys are affected often in thrombotic thrombocytopenic purpura The urine usually contains small amounts of protein gro<3 or microscopic hematuria and granular casts are frequently found renal insufficiency and moderate azotemia are quite common (262) Thus (lamination of the urmary sediment is not hclpful in differentiating this condition from lupus nephritis The differential bustologic diagnosis usunily pre ents little difficulty Eo-ino plule thrombi apparently consisting only of fibrin and platelets are found m the arterioles and locally within the glomerular capillaries in the pioni case of thrombotic thrombocytopenic puspurs glomerular changes are listed to the arcas immediately adjacent to the capillart thrombs and the remainder of the involved glomeruli is normal (10 2021 In contrast with lupus nephritis the only glomeruli affected are those in sluch the capillarics or arteriolis con tain platelet thrombi a large proportion of glomeruli is normal There are scieral reports of various forms of nephritis in cases duing of thrombotic thrombocytopenic purpura (60 99 201 299) it is not char from these report, » cthcr or not thic simultaneous occurrence of nephritis and of thrombotic thrombocytopenic purpura in these patients was fortuitous 6 ARCOIDOSIS AVD EGEVERS GRAIL LOVATOSIS Nelore Keils masterly analysis (136) shoking that the simultaneous occur rence of SLE and tuberculosis as fortuitous it was assumed especially in France and in Vienny that the two diseases are related intimatets, and that tuberculosis was the cause of dcath in patients all with SLC The association of cutaneous sarcoidosis and lupus erythematosus has boca reported and proven lustologically in four patients (93 189 275) In recent ·130 VUEBIRCKE, LARK, PRIVI, AVD POLLA years Teilum has advanced the opinion that there is a definite association be tw cen non tuberculous granulomatous lesions and systemic lupus erythema tosus He first described two cases in 1945 (283) In our opinion the findings given in the protocol of the sccond case are insufficient to warrant a definitie drgnosis of SLE The first casc, a twenty year old girl, had all the clinical features of SLE At the postmortem etamination the hidncy lcsions i cre compatible with lupus nephritis, and periarterzil fibrosis was noted in the splcen (286) In the lungs multiple nodular subserous gint cell granulomata Tere found there w18 focal fibrinoid necrotizing process in the interstitial connectne tissue and in the walls of vessels, both in the lungs and the lymph nodes No Schaumann bodies were found in the granulomatous lesions In a later paper Teilum concluded that the milzıry epithelod cell granuloinata in the ceros together with local ncerotizing and granulomatous proccesca have to be interpreted as tis ue injury specific to the drcise (SLC) (281) Flis pathologic findings Inve not been confirmed cither by oursche- or 1 numerous other investigator Teilum also considered that the hyperglobulinemia periarterial fibions of the spleen and wire loop lesions of the glomeruli in SLI were expresslyc of prinary allergic lay perglobuliosis in the reticulo endothelial system innlogous to the morphologic imunits reaction in Bocck streord (286) In our opinion the clinical and pathologic similarities between the two diecases are at best superficial Despite the relative frequency of SI E and sarcoidosis their aimultaneous occurrence in the same patient is so rure that it should be considered fortuntous Rechtly we live studied by serial ronal biopsies to patients in n hon it accueil possible at first that the two discases might be qesocated in the first patient the clinical features of SLE were observed Hargraves s cells were found and the kidney lesions were diagnostic ot lupus neplırıtıs The granulomatous lesions were at first thought to be due to sur coidosis but were later shown to be due to tuberculosis Tlie second patient had widespread granulomatous lesions for two years and a dingnosis of sarcoidosis was made by lymph node biopsy Hſc de cloped the nephrotic syndrome, and at the first biopsy renal lesions suggestive but not dignostic of lupus nephritis cre found Subscquentis lc has been obscried for tsche months and no other clinical or brochemical features huse suggested the diagnosis of SLE Thus we can assume that nerther prtient had both SLE and sarcoidosis Renal ini olie tally due a from that of lupus nephritis In llcgencrs granulomatosis the lungs and upper respiratory passages are involi cd by necrotizing giant ecll granulomis (77 91 164) Sooner or later in ino t patients eudarn of renal damage appears and about one half of the reported c19c8 hry almo t ini riably involsed by this por of capillars Joops and seants polymorphonuclear cell ciudation au ·LUPUS NEPIIRITIS 131 lesion is similar to the local necrotic lesion seen in lupus nephritis lowever, in Wegencr's granulomatosis more glomeruli are insolved, "hematory lin" bodies are not seen, and granulomatous lesions are found in the interstitial tissue (91) The Icesons in the lungs and in other organs bear no morphologic resemblance to those of SLE X THE NATURAL JISTORY OF LUPUS NFPIRITIS Lupus nephritis is a progres ise fatal glomerulonephritis, hichi at present, is the main cause of death and the most serious problem in patients all with SLE In lupus nephritis the glomerular tuít is damaged, and reacts to deposits of abnormal mucopolysaccharides and other proteinaceous substances, with the nppcarance of local basement membr ine thickening 'fibrinoid change,' hema toxy lin" bodics and endothelial cell proliferation At any moment in time the hidneys of two tlures of patients il) outh Ear insolied to a greater or lesser degree by these patlıologic abnormalities and their consequences The majority of patients ill with SLE dle of renal failure and lupus nephritis is found on post mortem examination in over 75 percent Its course may be fulminating and the patient may dic of renal farlure withun weeks of the clinical onset of the allocss On the other land lupus nephritie mai disclop slouk in ' patient si lo has been ill sath LE for months or Jurs or mas present with the gradunl onset of 4 classical nephrotic as ndrome-11 Juch may be the only onert manifestation of "LE Uxually it progresses slowly but incror ibli to death during a period of about one to four years Imul proportion of patients my live longer In general the rate of progre-op of lupus nepluati in mont rapid thin that reen in the common foriny of glomerulonephritis related to treptococcal illness The earliest lesjon of lupus nephrite consists of a local membranous glomeru litis involving small aicus at the periphery of the glomerular tuft Small areas of endothelial cell proliferation ure aluo commonly necn These early lessons have been found by renal biopsy in the ab-ence of signs symptoms or lalsoratory data indicating insolvement of the kidney Tile urine may be normal or it mon cont un protein lcucocytes in clumps and lcurou te catsfinding sluch oftca leads to the erroneous diagnosis of pyelonephritn" It the stage of the illness teste of renal function all of little value in making diagnos Renal intole ment thuch crin only be suspected clinicalls may be diagnosed by repal biopsy The rate of development of the glomerul ar changes ind the progress of the renal discque mu depend on the extent and suerit of the initial lesions in the kidney The progres-on of the lesion in the glomerulus 19 indicated by the up pearance or incrust of fibrinod material in the basement membrane by an in crease in prohferative lessons by the deselopment of adhe-jons between the tuft and Bonmin e capuk ind in some cpses by the des clopment of local areas of necrosis and harvorrhcus The-cle ons may mine the embolic glomerulo nephritis of Lohlen As the renal lt-ion progresses cry throcytes and granular casts appear in the "Vi tienta will acute SLI des clop trane tors urnın al normalities an. A ne in 11* !! ou non rol in milingon These patients do not pressar ne 12; no nephritie This an onls lives its ut clark when the unfar abnormalitiet popyt ·132 MUEIIRCKE KARK PIRANI AND TOLLAK urine of most patients, and epithelial cell casts fatty casts and oval fat bodies in the urine of some renal function decreascs azotemia increases, and the clin cal manifestations of renal involvement such as nocturuq polyuria and thirst make their appearancc From our experience wc suspect that--f they live long enough-almost all patients with progressive lupus nephritis will pass tlırough an edematous stage of nephritis associated with hypoalbuminemız h3 percholes terolemia and much proteinuria When this nephrotic syndrome appears the typical face rash of SLE may have disappeared and 18 usually abscnt once severc renal disc250 is established In other patients i!l with SLE as tre havo nen tioned above the nephrotic syndrome may be the presenting manifestation of the discase The diagnosis of SLE may be overlooked because the better knona symptoms and signs of SLE may be absent or minimal when cdema deyclops Usually a carefully taken history establishes the presence of symptoms of SLE in the immcdiatc or remote past Presumably lupus nephritis is t1 e causc of the nephrotic syndrome in adults in a significant proportion of cascs and the cxact diagnosis is best made by finding the characteristic histologic picture by renal biopsy In this form of the ncpl rotic syndrome spontancous or inducci di ircsis with rapid clearing of water logging is not commonly seen and the edema usually persists for months Usually tl c patient s diseasc slides imperceptibly from the edemantous phase into a slowly or more rapidly progressate chronic renal fuil ure During the edematous phase there may be histologic evidence of either membrinous or membranous and proliferative changes in the glomerular tuft and cpithelial crescents may be found the features morcjcculiar to lupus ne phritis are usually present at this stage Tubular degeneration is cuidcnt and fatty changes arc demonstrablc with special stains Interstitil cdcma and mild fibrosis are common and the vesscls of the kidney may contun fibrinoid At this stage of the illness the hidney may be prone to infection and secondary insolvement with inflammatory dı-cascs such as pyelonepl ritis may be evident clinically and histologically Progression to chronic glomerulonephritis with con traction of the kidney is rare and hy alınization of the glomeruli is unusual Tit 1 Ine brome atrop) ic or dilated but severe tubular atrophy is rarc ע all Proteinuria decreases and casts appear in incuba blu tante af renal finction become most abnormal Clinical and Inboratory or during an acutc exacerbation of SLE WIL Lulu al ju * no malowanesiscs Usually death 19 chronic renal failure and in many it. of any 1 the end the kidney may be indistinguisiti ·LUPUS NEPIEITIS 133 chronic glomerulonephritis of the common type and microscopically little or po evidence of the lesions typical of lupus nephritis may be found One other facet of lupus nephritis remains to be discussed In a few cases the di case may run a fulminating course (pseudo nephrotic syndrome) The glomerul: ate eeierely damaged from the outct Although a brief history of other symptoms of SLE may be elicited the onset may be sudden The patient is admitted with much protein in the urine and appears to have the nephrotic syndrome Honever the serum cholesterol level is low In our experience this pseudo nephrotic picture was usually complicated by the de clopment of other cvidence of acute SLC such as abdominal crises and myocarditis After a short stormy illness the patient dics in renal failure The cause in not difficult to find Renal function has been compromised by a most extensive and active glomerular disease in thich widespread local necrosis fibrinoid change, kary - orrhexis,'hematoxylın bodies and hyaline thrombi occupy the stage Serere tubular damage and interstitial edema fibrosis and inflanimation complete the picture ACKNOWLEDC FMENTS We would like to thank Dr James A Schoenberger for doing the tests of discrete renal function on six of our patients Dr Gcorge Hlass Dr Cecil A hrakower, and Dr Hans Popper for access to material in thcar Departments of Pathology Dr R A Clasen Dr Edwin Irons Dr Peter Pulo» and Dr Charles Wolle for their interest and help le rould like to thank Miss Loretta Cudnou sky and Viss Joan llalle for their untiring help with the nursing of these patients Mr Jackson Lucas, Mrs Myrtlc Petrunkewitch Mrs Polacck Viss Dolores Rix and the late Mrs Florence Ross for technical assistance Mrs Ruth Best and Mr Lawrence Toriello of the Illustration Studios University of Illinois made the charts and plotomicrographs We are indebted to the Upjohn Company Kalamazoo Vichigan for ar Tanging for the publication of the color plates In particular se would lic to thank Dr A G MacLeod and Miss Helen Burrell for their help The prednisone uscd in the later part of this study was kindly supplied as Meticorten by Dr George Babcock Jr of the schering Corporation Bloom ficld, New Jersey BIBLIOGRIPI 1 4DD3 T clinical chassification of Brights Dace JIVI 85 163 1925 2. 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·140 VUEHRCHE, LARS, PIRAVI, AND POLLAK 162 LEE, S L, MICHAEL, S R, AD TRAL, I L The LE (lupus erythematosus) cell Am J Mcd, 10:446 1951 163. LEFKOVITS, A M, AND FARROW, I J. The liver in rheumatoid arthritis Ann Rheuma Dis, 14: 162, 1953 161 LEGG4T, P 0, AND WALTOV, E W Hlegcner's granulomatosis Thorax, 11: 94, 1956 165 LELY AND, I, DLXIEE, W, AND RICHTER, MY Scleroderma (based on a study of oi er 150 cases) Ana Int Med, 41: 1003, 1951 166 LEITER, L Nephross Medicine, 10 135 1931 167 LIBYAN, E, AND SACKS, B A luth to undescribed form of als ular and mural endocarditis Arch Int Med, 33: 701, 1921 168 LILLIE RD Histopathologic Techniqur Philidelphn The Blinton Co, 1919 169 LINCOLY, M, AND RICKER, V A A Cise of periarteritis nodosa with L E cells, apparent complete remission with cortisone therapy Ann Int Mcd, 41: 639, 1954 170 LISTER L M , AD Bixer R D Necdie biopsy of the kidacy in the diagnosis of disserpinated lupus erythematosus Am J Med, 17:851, 1951 171 LITTLF G A casc of lupus erythicmatosus Brt J Dermat, 17. 101 1905 172 LÖNLEIN MUcber himorrhagische eranaflektionen bei chronischer ulzeruser Endo. karditis (Embolische nichteterige Heidaeplıritis) Med klin, 6 374, 1910 173 Low, R C,AD RUTIERFORD, Postmortem report of a cise of lupus erythemaotosus Brit J Dermnat, 32 362, 1920 174 LUDY, J B, AND Corsov, E F Lupus erythematosus Incrcscd incidence, licmatoporphyrinura and spectroscopic findings Arch Dermat Sypl, 37: 403 1938 175 MACLEOD J AH Case of lupus erythematosits associated with nephritis Brit 3 Dermat 20: 162, 1908 176 MADDEN JI Acute dissemianted lupus erythematosus Arch Dermat & Spli, 25, 851, 1932 177 MALLONI TB Pathological Tuhnique Philadelpl19 11 B Suundors Co 1942 178 MARVONT A Value and limitations of the LE cell test in the syndrome known as 11. 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(strict on an ganon rinn Fremont J Bol Clem 61: 523 19 m3 FOLK R Per rter! 4 nodosilci e acm Lupus n then atoles el ron cmeraccrhat one Dormit 7-!: 53 682 1999 201 TOP RIDICI JT of Bel rol mu th I L cells an i prolonge irem on on cort on tlcris Canal VI J 72 59° 19.00 20 Tartu I J 410 h RW Serum dl o ne pren lealth an icas Im J My 14 09 19.1 200 11 AG ER 13 VII stoel rmietl stad of fil no Isbet103 ani other al normal suc - 11 If tofflr not cnzt es IV I Il lat! 59 63 1902 Y IS IT JAND DIO J Tle renal ni pa ces in de murm op forn of 1 Irter inoxto JP Brt ( 199 1920 O ***11 1 Hap VIII Ti cant RO of oll krn J Imt nol 63: 427 1910 2001 ALLIC DC Dſuse I am natel pl telet thron box (thron lot c thrombocytopn In ) w l a report of two con Vial 2 9 1951 300 1LF AND STIGE PTI ombot thrombor toprac Im Ne ew of the * licet 14r fort of three css ucl lirca 1 tr 17.897 106 301 W11F* I * 13 F III Toll ani fritt glon enlir ons Drall is on enre wone in J Inth 31:25 120 30 TALLER III tr tons of Cneous D 614 London II B II re ISII 303 LX JI I prietal and trorect al treate on th d no. (atl olor and treatn en of 1-14 8 of the shn Afringe a oring to a natral As of chis fi Innsin I lbs an o t ne of the anton aniil ve olons of elcoh n Lop lon JC1 rib IS19 311 INTRE VIV up I ID BFR J11 stan land zcinic for the lost my! nt on 1 Im J V S 189 109 1930 20 HQ ( OC CLX BY E ANDI 1184 Stuice nam protens 1 1 ilirole for t] en at of total roten true all um n total glob in alpli plot un lato glol lo and gimmaglol in 10 ml of romm im J CI PIB 11 1915 3917 \ AXEN RAD I ORDIematoxin la obitel a tha all r8¢ ang is nalne nf luy senthenatons Irel lath 56 343 1923 30* 7or I les art rts no loss an 1 other forms of sectot ng ang to low I'nglo J Med 218 €61 193

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