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·לל
THE “NEURILITY” OF
THE KIDNEY
A MONOGRAPH ON NERVE SUPPLY TO THE KIDNEY
by
C. G. DE MUYLDER, M.D.
BLACKHILL
SCIENTITIC PUBLICATIONS
OXFORD

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Published simultaneously in the United States by
Charles C Thomas, Publisher, 301-327 East Lawrence Avenue, Springfield, Illinois
Published simultaneously in Canada by
The Ryerson Press, Queen Street West, Toronto, 2
First published March, 1932
Printed n rolland for BLACKWELL SOŁNTIFIC PUBLICATtons by
EREKICDE DRL KXI JEN HOITSEMA NV
GRONINGEN

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·TORENORD The application of modern methods of investigation to the study of renal function in normal and pathological conditions has elucidated a number of problems which were not well understood a few years ago, in particular the development of biochemical techniques has helped to advance the inter pretation of hidncy function in a way which would otherwise be lacking Nath the clearance methods the three assumed stages of urine formation, 10 filtration reabsorption and secretion, have been carefully analysed although there is still an amplc field open to speculation from these biochemical studies ind from other fields of approach one thing appears to be certain, nimely that the kidney has an almost unique capacity to adapt itself to the requirements of the body as a whole an exquisite adaptability which cannot be rcadily understood without accepting an equally rich innen ation of this organ The sensitivity of the kidney to nervous stimulation was in early finding of Claude Bernard which Vulpian confirmed and which has repeatedly been demonstrated But the finding that the denervated kidney also shows a certain cipacity for adaptation even iſ more limited or altered from the normal, sccms to indicate that the kidney possesses in autonomous innervation which can control kidney function independently from the higher centres A large number of accurately observed facts indicate that the unique and charac teristic behaviour of the kidnes depends upon its nens ous ind vascular com poncnts Some illustrative examples of this are i In monkeys and cats it has been found that during pressor responses evohed by electrical stimulation of some parts of the cerebral cortex the lomb volume usually increased while the kidney volume diminished the intra arterul injection of Indian ink during such experiments shows the virtual ciclusion of the ink from the vascular bed of the renal cortex Hacmorrh 16c in frogs and rabbits and asphy wn in frogs causes a marked constriction of renal cortical vessels but a splanchınıcectomy is previously performed such a constricting effect is always markedly decreased when not totally presented 3 Intra arterial injection of n lous concentration of phenol urethane which does not cause vasoconstriction in the legs docs constrict the renal arteries 1 Bilaterní renal cortical necrosis in human pathology is a measure of the duge that may follow alterations of blood flow within the kidneys Thus alteration is probably due to 1 spasm of the cortical artenoles Iven the interpretation of findings of the clearance method feeds to assume in independent and exquisitely fine response of small segments of the intrarenal arterial trec such as the afferent and efferent arterioles of the glomerulus It is a fact that thie profuse literature on the insestigation of renal function y ·Vi FORLIVORD by "clearance" methods has not been paralleled by comparable work on the detailed neuro-vascular architecture of the kidney, and in this sense this book by Dr De Muylder is a welcome contribution to the understanding of such minute intrarenal arrangements His personal work, both in America and in Belgium, has permitted him to incorporate into his methods that which he has found beneficial in both these schools As a Belgrın it is not only natural but indeed satisfactory, that he brings into his monograph 7 kcalth of information from the school to which he belongs, and in several instinccs his personal contributions serve to integrate previous work by some of his colleagues More than this, he brings forward data which, up to now, have not been sufficiently appreciated For instance, that neither the neries of the metanephric blastema nor those of the ureteral bud innervate thc mcdulla propria and he insists that the nephron must be considered as a neuro-vasculotubular unit He dismisses the existance of secretory nerves, pays due attention to the innervation of the intrarenal veins and suspects that the area between cortex and medulla (the juxta-medullary region) has a sensory nerve supply and that nerve endings may be found in the veins of the kidney, resembling the presso-receptors of the large veins of the cardio-pulmonary area On several points De Muylder's work is a challenge to accepted traditional views, but when findings give way to speculation this is not brought forward to claim new knowledge but to fill existing gaps until new data removes or confirms what he has tentatively put forward Having been personally engaged in an investigation of the role of the nervous and vascular systems in the conditioning of hidney function I am acquainted with the enormous difficulties of integrating data from fields so widely apart as those of biochemistry, radiology, histology, physiology, pathology and clini cal medicine four years ago, with some colleagues, I published the findings of the different behaviour and, not infrequently, oppositc response of many of the renal cortical vessels to those of the renal medulla, 7 finding wuch has been repeatedly observed in our experiments with rabbits and which has also been confirmed by a substantial number of other investigators working both with rabbits and with other species, including monkeys Some workers, however, claim they have been unable to confirm our observations and the facts are still under scrutiny If such an observation, which has been readily repeated and can be visually recorded, has not been confirmed by other research workers, it is not surprising that the integration of so much more complex and frequently conflicting data tahes such a long time and sustained effort Dr De Muylder's contribution will help to increase our knowledge and to focus the attention of many observers on the role of the ner ous system in controlling the blood flow through the different components of the nephron J TRUFTA ·PREFACE \BOUT fourteen years ago, when we began a study of the nerve supply to the idney, we did not fully realize the manifold possibilities of the subject, its in imate relationship to some pathological problems became obvious to us only We decided therefore to review available published data and to initiate a new examination of the anatomy of the renal nerves We soon became aware hat the argument mainly revolved about the microscopic anatomy of the in rarenal nerves, and we have concentrated on this subject Our line of approach to this problem may be summarized as follows first, we decided to use a tech nique for staining the visceral nervous system which would not be vulnerable to basic criticism at the present state of our knowledge, second, because the nerves in the adult kidney form very intricate plexuses, we chose to study them during development from early embryonic to adult stages, so that we could witness the constitution of the more elaborate picture displayed by the adult This policy proved to be a very gratifying one in various respects, the results of nervestaining are much more successful during early stages of life and we have been able to describe structures which have not previously been described During the course of these investigations, our attention was drawn to the juxtaglomerular apparatus The significance of some of the components of this apparatus became clear as we came to understand how they reacted under nephrosclerotic conditions and how they might be linked to a special type of neoplastic degeneration Comparative anatomy enabled us to understand various facts which would otherwise have remained obscure Comprehensively, our knowledge of the innervation of the kidney appears to fit very closely the more recent advances in renal physiology and experimental pathology We are acutely conscious of the fact that many important problems remain unsol ved, but it seemed advisable to summarize our present data and to make a general survey of the subject available to those who are interested in the role of the nervous system in the functioning of the kidney 11

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·ACKNOWLEDGEMENTS We wish to express our gratitude to those who helped us in the preparation of this monograph to Professor E VAN CAMPENHOUT without whose advice and criticism this work would never have been done, to Professor P LACROIX for his encouragement and for many photomicrographs, to Professor D H Barron who enabled us to study a series of sheep embryos, while being at the Uni versity of CAMBRIDGE to the department of Gynecology and Obstetrics of the University of LOUVAIN (Prof R&J A SCHOCKarRT) for kindly allowing us to use some of their embryonic material to the department of Surgery A of the University of LOUVAIN (Prof G DEBAISIEUX) for the opportunity to study surgical specimens, to Mr G lijns of the University of Brussels for the photomicrographs, to Mrs GEREBTZOFF, Miss Piotti and Mr BRULLEMANS who made our drawings and diagrams, to Dr R E LIVINGSTON for reviewing part of the manuscript, to Professor P GERARD and Professor A POLICARD for their permission to reproduce illustrations already published in the Archives de Biologie' and in the Bulletin d Histologie appliquee' respectively, to all those who helped us to carry on our work, were it but by not interfering with it CH DE MUYLDER

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·TABLE OF CONTENTS PACE Vi1 FOREWORD BY PROF J TRUETA PREFACE ACKNOWLEDGEMENTS TABLE OF CONTENTS LIST OF ILLUSTRATIONS 1X X1 X:11 CHAPTER I 1 Normal innerzation of the kidney A Technical remarks B Position of the problem C Microscopical data 4 I 2 CHAPTER II The normal juxtaglomerular apparatus 35 CHAPTER III Comparalue anatomy A Alligator luctus B Other vertebrates 12 44 CHAPTER IV Possible relationship betzeen nen ous elements and some aspects of renal pathology A Nephrosclerosis B The renal nerves in nephrosclerosis The juxtaglomerular complex in nephrosclerosis 1 The second convoluted tubele 2 The muscle cells of the juxtaglomerular arterioles D Neoplastic processes in the kidney and neurogenesis 50 51 51 52 56 60 CHAPTER V Significance of the nervous constituent of the kidney 68 BIBLIOGRAPHY 75

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·LIST OF ILLUSTRATIONS PAGE 2 3 4 5 13 13 I Digrammatic reconstruction of a medullated nerve fiber 2 Photomicrograph of a human semi lunar ganglion after reduced silver im pregnation 3 Photomicrograph of ganglion in the hilum of the kidney of a human newborn 4 Drawing of arterial nerve endings in the kidney according to VAN GEHUCHTEN 5 Photomicrograph of a microganglion deep in the hilum of a human kidney (MASSON S trichrome) 6 The same after silver impregnation 7 Drawing of periureteral plexus in a newborn mouse 8 Drawing of a bunch of arteriolar nerve endings in a mouse embryo 9 Photomicrograph of a periarterial nerve plexus in a mouse embryo 10 Photomicrograph of the nerves of an interlobular arteriole in a human foetus 11 Drawing of the nerves of the afferent arteriole in an adult mouse 12 Drawing of an intrarenal nerve cell in a newborn mouse 13 Drawing of an intrarenal microganglion in a newborn mouse 14 A & B Low and high manification of a photomicrograph of a nerve fiber enlargement in the kidney (pseudo nerve cell) 15 Drawing of the nerves at the vascular pole of the glomerulus on the base of the macular segment (Adult mouse) 16 17 14 15 16 17 18 19 20 21 22 23 18 ] mouse T 19 20 1 21 O lings of a 26 27 28 22 A B & C Photomicrographs of an intravenous nerve ending in the cortex of the kidney of a human foetus under low and high magnification and at two different levels of focus 23 Drawing of nerve ending under endothelium of subcardinal vein in a mouse embryo 24 Similar ending on the same vein 29 26 27 28 29 Drawing of the macula densa of a human embryo 30 Photomicrograph of juxtaglomerular complex in the kidney of a young girl 31 Photomicrograph of juxtaglomerular apparatus in the kidney of a young rabbit 32 A & B Photomicrographs of the renal hilum of Alligator Lucius showing the budding of modified myocytes (low and hugh magnification) 33 Photomicrograph of macula densa (Frogs kidney) 31 31 32 32 33 35 38 39 40 43 44 ·XIV PACF 45 46 of the carp LIST OF ILLUSTRATIONS 34 Photomicrograph of iron contuning cells in the kidney of the turtle 35 Photomicrograph of iron staining granules in paraganglionic cells in the renal hilum of rooster 36 Photomicrograph of nene cell in the hidney of the carp 45 37 Photomicrograph of modified muscle cells in the wall of an abdominal artery 47 38 Drawing of a free tubular segment in human nephrosclerosis 57 39 Photomicrograph of a medullated nerve fiber in a human atropluc kidney to show GOLGIS funnels 52 40 Photomicrograph of macula densı and glomerular hilum in spontaneous nephritis of the adult rabbit 55 41 Photomicrograph of macula densa and so called pscudo \feissnerIAN cor puscle in the kidney of a dog 42 A & B Low and high magnification photomicrograplis of vascular root of glomerulus to show micromuscular sphincter (human kidncy) 57 43 Diagram of the juxtaglomerular complex 60 44 Photomicrograph of piraganghonic cells in a human semi lunar ganglion 63 45 Semi diagrammatic drawing of relationship between intrni enous nenc endings and periarterial plexuses 68 46 Diagram of the changes observed in periarterial myocytes in Alligator and Mouse 69 56 ·THE NERVE SUPPLY TO THE KIDNEY ) CHAPTER I Normal innen atron of the kidney - A TECHNICAL REVARAS The microscopical innervation of the kidney in various species of mammals (mouse, rat, guinea pig, cat, dog, etc including man) appears to be remarkably constant, when examined by the same method, CAJAL's reduced silver technique, the specificity of which is well-known Recently, though, there has been some argument about the type of nerve fibers actually stained NoviDEZ (1939, '*), NovIDEZ & Hare (1942, 16) and Wrete (1950, 207) have claimed that the orthosympathetic postganglionic fibers remain unstained or take a light-brown colour Ranson and BILLINGSLEY (1918, 6) had already expressed similar views WEBER (1940, 409), BAUMANY (1941,'), ELFTHAN (1943, ® ), UNGEWITTER (1943, 189), HARMAN and Davies (1948, 92 9) have noticed significant differences between deepand light-staining fibers, the deep-staining ones generally being of the vagal' type and the light-staining ones of the "sympathetic" type It is difficult, however, to make a didactic statement beciuse of the rather common observation of varying darkness of the black colour from the periphery to the center of the specimen submitted to silver impregnation a nerve fiber may show different shades along its course through the tissues We agree that some fibers are darker than their neighbours, but we prefer to differentiate fibers by their structure, thickness and the degree of myelinizition Altogether, the various morphological characteristics, among which the quality of impregnation is the most obvious but not the most important, may have a special meaning (ortho or parasympathetic fibers, pre- or post-ganglionic or cerebrospinal fibers) and the observer is on more solid ground if he takes all of the characteristics of the fiber into account rather than rely upon the shade of brown or black to determine his classification The real nature of the morphological characteristics of the nerve fibers is not known NAGEOTTE (1922, 39) has published a reconstruction of a myelinated nerve fiber, which is classical, not unfrequently nerve fibers are seen showing various structures appearing in NAGEOTTE's general picture The appearance of the sheath of myelin itself varies considerably the same is true ·2 MAU RAN THE NERVE SUPPLI TO THE KIDNEY of the nerve fiber, the axoplasma, the neurofibrıls, and theso called MAUTIINER'S sheath We do not know to what extent the various aspects correspond to the structure of the living stage Various works, by J Z YOUNG SCH (1936, 208 209, 1937, 0) mainly, using giant axons MYE from Cephalopods, Crustacea and Annchids threw some light on that problem It may be AXO suggested for the time being that if neurofibrils do not exist in the axoplasm, at least there is some inner longitudinal organization of the molecules, there must be an interphase between the semi-fluid axoplasma and the sheath of myelın, the fatty layer is sandwiched between the fiber proper and the SCHWANN cells, un- NAG myelinated fibers seem to have a fatty layer obscured by the presence of proteins, a fatty layer may sometimes be present outside a fibrocytic layer, and so on Other aspects are accounted for by a variety of prthological and experimental phenomena For the purposes of this study we need not be concerned with all of the discrepancies between the nerves in vivo and on stained sections We require only a technique without too many artefacts, and producing them consistenly Our experience SCHM confirms that CAJAL's reduced silver impregnation fits these requirements This technique might not show all the finest nerve fibers but the fibers shown by the properly applied method are beyond any doubt nervous struc tures As mentioned above, there is more than one test for establishing the nervous nature of a fiber or a cell, among these "marks" of "neurılıty" are the shape or contour, the internal structure, the affinity for various stains and the lack of affinity for others Bearing this SCH» SCHMIDT LANTERN ANY incisure Rez network of RAZZONICO insidefunnel in mind at every stage of the researches, one of Golg The outer layers represented should not label "nervous' every black or by the PLENK LAIDLAW Sheath, the mesh brown fiber encountered in a section - even work of her and Ratzrus and epineurium are not pictured in this reconstruction if the tissue is supposed to be correctly im. too although it is sometimes very useful pregnated by cither one of the classical, or the without to ascertain the presence of myelu modern, fashionable, silver-stains REZ ·NORMAL INNERVATION OF THE KIDNEY first establishing the presence of typical SCHWANN-cells or their cytoplasmic syncytium, of myelin sheaths, of eventual MAUTUNER's sheaths, of axoplasma, axons and neurofibrils We controlled our results by various other techniques, such as the Rocers method (modification of BrelsCHOWSKY's siker-impregnation, for paraffine sections) , Massov's trichrome (iron hematoxylın, ponceau of xylıdın and acid 3 FIG 9 Human sema lunar ganghon after reduced silver im pregnation this technique was used for the majority of our specuens and fits the requirements referred to in the text fuchsın, anılın blue or light green) silver impregnation of reticulin (Foot), haemalun cosin, a so As the results of these different methods complemented each other, we were able to obtain an overall picture which we believe to be quite complete and comprehensive Great care should also be exercised in correlating structure and function K KURE, for instance, (1933, 10) concluded from his observations on the splanchnic nerves that the fibers with a visible myelin sheath and which were thicker than five micra were of a gustatue type (because they were never "We are indebted for these controls to prof E VAN CAMPENHOUT who applied Rocers method to some of our material B ·4 THE NERVE SUPPLY TO THE KIDNEY found in the splanchnic area and because such a sensivity was absent in the same area) and that the fibers which had a caliber of three to five micra conveyed the sensations of pain. Having demonstrated both types of fibers in the renal area, KUBO (1935,"9) denied Kure's hypothesis, because there are no gustative impulses arising from the renal area, and no painful stimul arising from the renai parenchyme (where the smaller fibers were seen). Fic 3 Photomicrograph of a ganglion in the hilum of the kidney of a human newborn such ganglions are very frequent in the location Masson's trichrome Because the main difficulty to the examination of renal nerves has always been the propre staining of nervous structures, we felt that technical discussions wluch might be helpful should be included. This view will be supported by a short summary of the published data B POSITION OF THE PROBLEMI Many communications have been devoted to the study of renal innervation. The majority of these are referred to in our previous publications and ne mention here only the most important historical features IVe give first a brief list of early textbooks where reference to renal innervation may be ·XORVAL INNERVATIO OT THE KIDNEY 5 found', but, as gross dissection of the renal hilum reveals the presence of many nerves and ganglons, we shall not make any particular mention of such descriptions, nor shall we discuss the significance of their variations 104 Drawuyg of arterial nerve endngs in the kidney according to VAN GEPECKTeX Silver impregnation Couch) LOLLIKER V, Handbuch der Genebelehre des Menschen, 1863-1867 Periarterial series are followed to interlobular arteries, no endings are demon strated LUDWIG, C, in STRICKER S Handbuch der Lehre von den Geweben des Menschen und der Thiere Periarterial plexuses with a few ganghons exist, but their endings are unknown FREY H Handbuch der Histologie und Histochemse des Menschen 1874 The structure and function of intrarenal nerves are unknown KRAUSE 1 Allgemeine und meroscopische Anatomie, 1876 The renal neries are probably exclusnely vascular TOLDT Lehrbuch der Gewebelehre, 1877-1888 There are perisascular renal nerves but their endings are unknown SCHAFER IN QUAIN s Elements of Anatomy vol 2, 1882 Renal nerves are small arsse directly from the reaal plexus and the small sympathetic nerve and contain fibers onginating as well from the sympathetic as from the cerebrospinal system They are followed up along the fine arteries but their eadings are still not known IAN GEHUCHTEN , Anatomie du système nerveux de 1 homme 1892 Sec fig 4 and summary table below This list not exhaustise the descriptors are quoted mostly from Rerzus (1892 164) more references to early scxtbooks are mentioned in D Events contribution to this subject {1899 13;

·TABLET Mamc and Year Material Methods Observations Vessels and connective tissue 2 Nephron itself PAPPENHEIM 1841 3 year old child 30 year old man Nerves Follow intrarenal arteries, they are demonstrated along arteries of in diameter (o 3 mm) No ganglionic cells HOLBROOK 1883 Pig, sheep ox, cat, CONHEI LOWITT Alany nen, cs, mainly non modul Non medullated periarterial nerves man (child) (chloride of gold) lated in periarterial layers and bund. give off peritubular plexuses on either les, they form the plexuscs of the side of membrana propria, with deliallerent vessels and reach the capil catc fibrils in the cement between lanics of the tuft, with nene fibrils epithelial cells, unosculating with interin the walls and between the strooth cellular spokes muscle cells Exceedingly scanty non medullated Small number of true ganglia nerves, apparently independent from artcries, in the pyramidal substance RETZIUS 1892 Young mouse and rabbit (11 days) GOLCI No tubular nerics Periarterial plexuses with knob like endings on smooth muscle cells, reaching vasa afferentia, ending where glomerulus begins (frec enda ings around arteries and in vascular hilum of glomerulus) No ganglionic cells THE NERVE SUPPLY TO THE KIDVEY Mouse and rat GOLGI VAN GENCHTEN 1892 1397 Free ending twigs in walls of blood. vessels (Sce ſig 4 ) BERKLEY 1893 (Dog), mouse Gorci (modified) Periarterial non medullated plexuses Arterial plexus gyyes off fibers to tubul: (some fibers are extremely fine, sotne contort wrapped in fibrils supplied are quite coarse and broad), giving with endings on and inside membrana off short branches with cnd bulbs propria Also fibers around and on smooth muscle cells, extending between collecting tubulus In purely to Bowman's capsule in a meshwork medullary areas nerve fibers arc icry surrounding the capsule without en rarely met with tering at and bearing round knob like endings No nenes connected with venous trunks nor on yasa recta Numerous ganglionic enlargements of the Sbris but no real nerve cells(?)

·Mouse (24 d old) GOLct (last) No neries on tubules themselves for in the medullary proper hoLLIKER 1893 Rich plex ses along arteries up to MALPIGIE corpuscle with end ngs upon corpuscle and fibers runn ng around it to oppos te pole to form a meshwork on efferent essel and send branches between tubules bran ches also reach renal capsule where they show endings AZOULAY 1894 Van human foe tus GOLCE Plexus of non medullated varicose fibers unfrequently around vessels No defnite nervous cells No interstitial nervous cells Plexus mostly, penetrating, through medullary renal substance where a few fibers stay while others reach the cor ter which exhsbits many free narrow fibers with knob like endings on the wall of tubular cells or glomerular epithelium (probably not yet true end ng CAJAL (fast) No tubular nerves 2 day old gu nea PS AZOULAY 1895 Strictly periarterial nerves with knob like endings turning around glomerulu to renal lobules giving off 1 or 2 small branches to the vas afferens entering the glomerulus where they gue 2 to 4 varicose branches to the inner aspect of BowMAN 5 capsule and between the cap llary loops sen sory branches regulat ng blood pressure through vasomotor nerves NORMAL INNERVATION OF THE KIDNEY PrN4 1896 GOLGI Rabbit gunea pie mou sc Arter al plexus gres off varicose fibers to tubules follow ng membrana pro pria ending on it or between epithelial cells Very rich periarterial plexuses with endings on smooth muscle cells and aricosit es forming a plexus around BOWMAN S capsule or more often sending fibers running around the capsule and end ng afterwards end ings on the capsule itself and very scarce fibers entering the tuft to end on capsular epithelium and capillary loops Ganglionic cells (?) and pseudo ganglionic cells belonging to con nective stroma") ·Namr and Year Ataterial Mcthods Observations i Vessels and connective tissue 2 Nephron itself D'EVANT 1899 llan (foetus, child, GOLGI CAJAL Rich periarterial plcxuses with knob- Periarterial plexus sends fibers ending adult) LOWIT-RANVIER, like endings, and others, on the vas on the wall of the tubules Vantmals Rabbi APATHY, EHRLICH, cular wall, and endings on glomerules Guinea pig, mouse. PALADINO Free nene endings between tubules rat, dog, cat, dor Nervous cells in parenchyme without mouse, newborn per cellular capsule puppy Reptiles, Amphibians, Fishes V SMIRNOW 1901 Endings on tubules, on membrana propria and between epithelial cells all along the nephron Embryos and newe- GOLGI born man, dog, EHRLICH cat, rabbit, mouse, white rat, guinea- Pig Adults man, dog, cat,mouse, guineapig, squirrel, hamster, bat, tamia (Hanephros) THE NERVE SUPPLY TO THE KIDNCY Fish, amphibians, rephiles and burds, incomplete results (pron and mesonephros) DIE 1898-1902 Adult mouse Golci Usual periarterial plexuses Arterial plexus gives off branches to tubules io form sketchy peritubular plexuses (tubub contor(1) with endings on membrana propria, and on Bow- MAN's capsule No medullary nerves RENNER 193 1920 (1931) (BIELSCHOUSKY, EURLICH) Penvascular plexuses to vasa affcrentra and efferentia with motor muscle endings Non medullaled fibers and scarse medullated ones No Intrarenal ganglion cell CHAMADAN 117 BA lihts Same raulu as SPANNRK בבאקווR4 ; A tr ·Brown Samc results as SPANNER CHARADASCIL 1927 Rana esculenta Rana temporaria Bufo vulgaris Perureteral plexus extending to pra tically all tubular segments but main ly to excretory system Tubular ner ves from arterial origin Vethylene-blue Pernascular plexus mainly periar terial forming a perscapsular (Bow MAN) net and extending to tubules Ganglia present Rana agilis and mostly Angus fra SPANYER 1928 Blis Vascular nerves send tubular nerves to form peritubular plexus branching with knob like endings outside the basal membrane and inside, in the basal part of the epithelial cells INIMOTO 1928 Frog toad turile pigeon cock duck mouse rat, guinea pig rabbit dog man CAJAL (mod fied) Periarterial nenes and plexuses (me dullated and non medullated) with end bulbs in the vascular wall and many terminal branches on Bow MAN S capsule and fbers inside glo merular tuft Vascular neries are clearer than tubular nerves Oedema and atrophy of neries in disease Pgcon n avita minos 5 B Tubular nervous net I rog Methylene-blue (nath critical re marks) Nervous vascular net giving antra glomerular nerves through hilum and capsule without truc visible cndformation Non medullated nerves HIRT 1930 NORMAL INNERVATION OF THE KIDNEY Rat guinea pig cat dog man From periarterial plexuses are build up peritubular plexuscs, in cortical as in medullary areas, on membrana propria with fine varicose branches and endings on membrana propria and between epithelial cells BIELSCHOWSKY (modified) EHRLICHT (with technical remarks) KAUFMANN and GOTTLIEB 1931 Non medullated periarterial ple xuses in adventitia and media of arteries plexuses on veins too nerve endings in arterial wall and in glomeruli along the cap llaries No orsginal microscopical rescarches id DAMBRIN 1932 CAJAL (modified) KUBO 1933 Mian dog rabbit horse rat pigeon chicken toad frog Periartenal plexus extending to pre Arising from periarterial plexus exists capillary vessel with endings inside a peritubular plexus outside membrana vascular wall and inside glomerulus propria with various endings (bulbs Majority of non medullated fibers twigs) even between epithelial cells except in buds where the medullated ones are the majority Normal ganglionic cells mostly in Microganglionic cells(?) 9 hulum ·TABLE I (Continued) Observations 10 Name and Year Material Vethods 1 Vessels and connective tissue 2 Nephron itself Spinal parasympathetic innervation KANDA 1933 KLBO and CITOJA Pageon, dog, rab- 1933 bit CAJAL (modified) Lxperimental study Medullated and non medullated Peritubular plexuses with endings on periarterial, and periurefcral neries membrana propria (?) No intracelluto pelvis and calyces Small number Jar endings, no secretory nenes of fibers inside BOWMAN'S capsule Coeliac plexus resected in dog alter 24h, nerve hypertrophy, after 72h nerve degeneration NADAL 1935 Injection of contrast substances into nerics THE NERVE SUPPLY TO THE KIDNEY KUBO 1935 I Various degrces of swelling, atrophy and disappearance II Neries intact I Experimental study of nervepoisoning II Unlateral cervical vagectomy, une or bilateral abdominal splanchnectomy III Excision of cochac plexus, with cocliac ganghon It Degeneration of series In renal hilum, thick medullated fibers larger than 6 micra In renal parenchyme, thiti medullalated fibers, between 3 and 5 micra MONTICONE 1910 No original microscopical researches TE VIUNI DER See text ·Man Gros SCHULTZE OBERLING 1914 Rich plexus along was aflerens (part No data on secretory neries of t coming from the nearby paren chyme with endings on cells of vascular wall (Possibilty of presence of medullated fibers) Th n fibers enter ng glomerulus and fibers to outer layer of BOWMANS capsule Bulk of fibers turn ng around glomerulus to end in near by paren chy me (by pass) EPSTEIN and SOTELO 1946 Van (human loe tus) Reduced silver um pregnation Periarterial plexuses Thin and thick fibers (receptor vasod lator and va soconstrictor) Free interstitial nerve end ngs in connectie t ssue arising from th ck fibers g ving off this branches (some of them for vascular channels) HARYAN and DAVIES BODIAN Catrat Nerye endings in epithelium of con voluted tubule (TCI) 1948 Periarterial nerves forming a com plex of nerve fibers per ad ng the perivascular space of the glomerulus endings in perivascular tissue of glomerular tuft Coiled vessels between arteries and veins with epitheloid mod fications in renal sinus richly suppi ed with nerves Many medullated nerves NORMAL INNERVATION OF THE KIDNEY d Mouse rat macaca cat 1948 KNOCHE H 1950 Man (foetus and adult) B ELSCHOWSKY GROS (th ck frozen sec tions) Terminal reticulum in outer layers Perivascular nervcs give off non of vessels and outs de BOMMANS medullated branches forming a ter capsule as 1 ell as on glomerular minal reticulum on the convoluted tuft tubules II ·12 THE NERVE SUPPLY TO THE KIDVES The other references are given in Table I This table shows that nearly every possibility has been described as a fact and that nenes haic been demonstrated at one time or another in every single part of the kidney Such a table demonstrates the widespread discrepancy among the various results and emphasizes the need for renewed investigation with a reliable histological technique The principal unsolved problems, for the time being, may be stated as follows 1 Are there intra epithelial nerve endings in the nephron, to which a secretory function might be ascribed? 2 Is there any special nervous device regulating the blood flow through the glomerulus, and, secondarily the blood supply to the tubules? 3 Is there any evidence of a connexion between the renal nerves and the source of hypertensive mechanism? These problems are closely related to various forms of pathology, including nephritis or nephrosis, nephrosclerosis, high blood pressure, crush-syndrome, eclampsia, and even neoplasms C MICROSCOPICAL DATA The embryology of the third, permanent renal organ of the higher vertebrates (metanephros) is well known, it develops from two "anlagen" a metanephrogenic blastema and an ureteral bud The ureteral bud arises from the pelvic portion of the wolffian duct and grows cephalad towards the lateral lumbar mesenchyme where the metane phrogenic blastema develops The blastema appears as a condensation of lumbar mesenchyme which the branching of the ureteral bud splits into small cellular masses, the spheric isolated masses assume early the shape of an inverted capital S while a lumen appears in their central part, they form thus a tubular sketch The half of the S directed towards the hilum forms BOWMAN'S capsule, while the peripheral half differentiates into the tubule itself, including the "pars intermedia" at the junction with the ureteral bud, the latter forms the "tubuh recti" and the excretory system proper These two "anlagen" have their individual blood supply Our studies show that they have also their individual nerve supply The nerves reach the kidney (metanephros) betueen the 38th and 43rd day (30 to 55 mm) in the sheep embryo, and before the 9 mm stage in the mouse cmbryo (personnal observations) According to PIRNER (1949,16) libers reach the kidney on the 5th day of incubation in the chicken embryo, on the 6th day of incubation, VAN CAMIPENHOUT (1931, '9) sau the renal plexuses around the origin of renal arteries, but no intrarenal fibers The nerves per ade the kidney along two different pathways They follow the blood vessels of the hilum, mainly the renal artery, or the ureter and ·NORMAL INNERI ATION OF THE KIDNEY 13

·THE NERVE SUPPLY TO THE KIDNEY
10u
Fic 7 High magnification of drawing of the nervous
plcxus applied on the wall of the uretero-peluc junc
fron of a newborn mouse Reduced silver impregnation
---
tou
FiG 8 Bunch of nerve endings in the outer layer of an intrarenal
artertole, in a 10 mm mouse embryo this drawing shows very
clearly the syncytial disposition of the fibers Reduced siks er im
pregnation

·NORMAL IN FRTATION OF THE KIDNEY 15 cventually its blood vessels In both cases, they finally arise from the plexus surrounding the aorta and the ilac arteries and the gangla spread along these vessels sometimes fibers arise directly from the ganglia of the lumbar sympathetic chain This set up becomes obscured as the embryo grows We never demonstrated nerve fibers entering the kidney through the capsule or tog Per arter al nerve plex is a mouse embryo the artery is betwech two lobes is wail bu ld of flat endothel al cells op het od mus le cells and a few (broblaste surround ng the nerve fibers 14 mramouse embryo MONIDEZ reduced sker mpregnat on the convexity of the organ If such fibers eust they are probably unimportant under normal conditions Entering the kidney through the hilum with the vessels and with the ureter, the series form plexuses is which it becomes difficult to recognize the fibers belonging to either group Thuis question though may be answered to a Certun extent by embryological studies at the stages where it remains possible to follow the ureteral nen es as such they do not extend any further than the insertion of the całyces on the papillae while the vascular neres branch all through the renul parenchyme along the vessels up to the outer limit of the cortex ·16 THE NERVE SUPPLY TO THE KIDNEY The "ureteral nerves” should be distinguished from the fibers supplying the ureteral vessels, although they have the same origin both arise from the plexus and ganglia surrounding the iliac arteries, where these are crossed over by the ureters, branches also come off other ganglions lying deeply on both sides of the rectum, the uterus and the bladder The "ureteral neries" form a loose FIG 19 The nerves of the interlobular artery of a 20 cm human foetus with the finest twigs extending along the preglomerular arteriole Reduced silver impregnation network in the outer layer of connective tissue surrounding the ureter, they reach downwards the outer layer of the bladder and upwards the renal pelvis From this plexus small branches and isolated fibers enter the muscle coat of the duct where they form very simple knob- or ring-like endings between or upon the smooth muscle cells, we never saw them entering the mucosa On their way towards the pelvis, and mainly in the vicinity of the uretero pehic junction they may come in close contact with cells which in the early stages resemble sympathoblasts, at later stages small islets of ganglionic cells may be found there although infrequently We saw, for instance, a typical micro ganglion in the outer layer of the pelvis of a young mouse, where the main nervous network is located, this network branches off and sends tiny fibers to form a much looser plexus closely applied to the muscle coat, with knob. or ring-like endings between the muscle cells or upon them In the renal parenchyme, the "vascular nerves" follow mainly the branches ·NORMAL INNERVATION OF THE KIDNFY 17 of the arteries, and the veins to a lesser extent Here again, the bulk of the nerve supply is to be found in the adventitia, it forms a well developed plexus from which smaller branches arise, entering eventually the media where they end always in the same fashion fan-like, knob-like, club or ring-like terminal en- 10_204 FIG 11 The nerves on the afferent arteriole different levels are drawn on the same picture Adult mouse reduced silver impregnat on largements upon the muscle cells Not a single fiber was ever seen coming in close contact to the intima In connexion with the periarterial plexus one may find intrarenal microganglia" We found them in young mice where they may be rather frequent in some individuals, and lack completely in others We found but one ganglionic cell in the renal cortex of an adult mouse, along a small artery In one case, in ·18 THE NERVE SUPPLY TO THE KIDNEY a young mouse, one of the little nests of nervous cells was accompanied by a few epithelioid cells, surto tiny paraganglionic body. Ganglionic sometimes in large numbers in birds a red to in due course. The existence of intrarenal nervous cells is thus a fact; its importance, 11. Fic 12 Nerve cell in the outer layer of an intrarenal arteriole. Newborn mouse RANSON'S silver impregnation Drawing oc 26, obj 100 mm of course, is open to discussion. As scveral authors reported their existence and other ones denied it, it may be of interest to point out that reviewing the literature on intrarenal nervous cells, and on innervation of the kidney as a whole, is a particularly trying experience and that care should be taken to find out what the authors report as actually seen by themselves or what they quote from other works; it is also of utmost importance to liare a precise idea of the material studied, the extent of the study and the technique used. We expressed our views on the technique previously. It should be borne in mind that the existence of one particular structure found only once, figured in an original paper and quoted or reproduced afterwards by the majority of the authors may outweight some other extensive and unsuccessful researchwork of ·NORVAL INNERVATION OF THE KIDNEY 19 long duration, and thus give the false impression that such a structure is frequent simply because it is oftentimes quoted Werhus underline the assertion that after an extensive search through the sections of several hundreds of kidneys in various mammals, we only found intraparenchymatous nervous cells in the conditions described above Some results raise the question as to whether 2 10 ber FIC 13 Intrarenai microganglion at the bifurcation of an interlobar artery Newborn mouse reduced siler impregnation Drawing op 16 Obg tog um the characterization of a neni ous cell in the kidney should be the same as anywhere else in the body To illustrate this point, we cannot do better than quoting first, one of the earlier works on the subject ganglionc enlargements, sometimes of considerable extent, occur among the libers adjacent to the blood vessels, or even separate from them, and on the whole, local enlargement of neries throughout the kidney is not infrequent Varicosities of the smaller fibers occur everywhere Owing to the intensely black staining no cell structure is visible in these local gangir , nor can nerse cells, strictly speaking, C

·20
THE NERVE SUPPLY TO THE KIDNEY
FIC 14A and B in the kidney of a dog, a nerve fiber entargement
among normal looking fibers, may be followed on a few serial sections
without showing any nucleus ?pseudo-nerve cell (low and high magnis
fication) ROGERS silicr impregnation on slide

·YORMAL INNERVATION OF THE KIDNEY be made out within the limits of the kidney". (BERKLEY, 1893,", p.410). W might also mention KuBo's (1933,"7) description of ganglionic cells in th renal system including a normal form which is found mostly in the hilum of the kidney, and microganglionic cells found in the pelvis and the calyces of all Fic 5 The nerves of the vascular pole of the glomerulus run on the base of the macula densa berween the glomerulus and a slightly oblique section of TCH Adult mouse reduced silver impregnation Drawing or 16 ob 100 mm 10 Lan animals, and in the medullary of the dog, KUBO states: "Über das Vorhandensein dieser Mikroganghenzellen wurde von jeher viel diskutiert, besonders sind es die Ganglienzellen in dem Mark die bisher von niemandem beobachtet wurden" We believe that similar criteria should be applied to cell bodies as to nerve ·THE NERVE SUPPLI TO THE KID\EY fibers one should recognize as nen ous cells only these which exlubit neil established marks of "neurility" Let us repeat that such cells are found scar cely and irregularly, in the vicinity of the main ntun Tot VALLS Iers may be obvious when they rench the media of the afferent artery, they become thicker, irre gular and even seem to branch off We never saw them entering the glomerular tuft, they always short circuit it and pass from the afferent to the efferent artery without exten ding along the capillary bed enclosed in BOWMAN's capsule, usually they cross the triangulur space bordered by the two vessels and the second convoluted tubule (T C II) We first noticed in mouse embryos the fact that nerve fibers followed the basal aspect ofT C II between the afferent and efferent glomerular vessels Later on, we had a good opportunity to study the structure of such fibers in one case which we published (1945, 58) In an adult mouse the juxtaglo merular complex, submitted to si! ver impregnation could be studied through a series of slightly oblique sections, the branching of two or three main fibers closely applied to 10M the differentiated segment of the Fic 16 The same on next serial section under a tubular epithelium called "macula higher magnification to emphasize the irregular densa" (ZIMMERMANN) (sce p 39), course of the fibers and the res It ni ance was obvious, with irre accounts partly for the me staining (MASSON's trichrumie, ior instance), another group of these fibrils shows up very clearly after silver impregnation for reticulin (Foot), the basal meshwork surrounding the tubule has a fan like dispersion towards the hilum of the glomerulus Sometimes, however, the course of the nerve fibers is different, instead of ·VORVAL INVERTATION OF THE WIDVEY 23 ·24 THE NERVE SUPPLY TO THE KIDNEY crossing over the vascular root of the glomerular tuft, they circle around the outer wall of BOWMAN S capsule, passing near the neck of the first convoluted tubule (TCI) and giving off an eventual twig to the capsule itself After. wards the fibers run along the efferent artery without any remarkable change in their morphology, they follow branches of the efferent artery supplying the renal cortex, where they thin out and fade off between the capillaries and tubules Between capillaries and tubules, the nerves are linked mainly to the former according to our repeated observations, this is in contrast with the situation at the glomerular root where the nerves are closely applied to the basis of the "macula densa" It should be pointed out that nenes are never found in the medullary arca proper, which they do not seem to enter, either from below upwards along the insertion of the calyces (ureteral nerves), or from above downwards with the capillarization of the efferent artery (vascular nerves) This point is remarkable it emphazıses the dual embryological origin of the metanephros The ureteral nerves correspond to the ureteral hud growing cephalad to meet the metanephrogenic blastema The metanephrogenic blastema recen es its nere supply from the bundles following the vessels and dividing up all through the cortex The ureteral nerves on one side do not reach the collecting tubules opening into the papillae, the medullary capillaries of the efferent artery, on the other side, do not appear to be followed by nerves Therefore, a sort of "no man's land" exists betueen the zones corresponding the two main com ponents of the kidney (ureteral bud and metanephrogenic blastema) This territory, apparently free of nerves, is the medullary area proper The nerve supply to the arteries is inseparable from the innervation of the nephron itself, as a matter of fact, a nephron cannot be considered as a mere tubule, but the neuro-vasculo-tubular unit should always be referred to as a whole From the first part of our description, it may be inferred that so called "secretory” nerves do not exist, in fact, we never saw fibers ending on or in the wall of the tubules, although we frequently demonstrated in our sections nene endings on the vessels, and on the walls of the pelvis, for instance Spread on the basis of the "macula densa", the nerves come in close contact to the renal epithelium, the same happens to a lesser degree when they circle around the glomerulus and pass in the vicinity of the neck of the TCI Oterhwise, whenever a nerve is seen close to a tubular epithelium, it may always be shown to be even closer to a vascular channel of some sort, again, ot, walls, ncri es, in our Other a relationship observers desco su plexus on each side of the basal membrane with perforating anastomosis, intercellular and intracellular nerve endings of a great variety of shapes, parti culary well shown by methylene-blue staining This method is apparently not a onc ·25 NORMAL INNERVATION OF THE KIDNEY reliable, and its results should not be accepted without checking them by other techniques (see for instance Hirt's criticism of the method) Very often after silver impregnation, an impression of intraepithelial nerve ending may be gained, but a closer study on serial sections reveals that the "ending" is but the cut end of a fiber running obliquely between the tubules One more word about the aglomerular arteries in the present state of our knowledge, it seems that they always are the result of atrophy of corresponding glomeruli, consequently their nerve supply is no particular problem We found the innervation of the veins much more interesting than expected The origin of the nervous meshwork situated in the adventitia is the same as the origin of the periarterial plerus, and both networks have such intimate con nexions that very often the venous nerves appear as mere twigs arising from more important arterial nerves The silver-impregnated fibers in the walls of the veins would not be worth any particular description, if their loose network would not be supplied with special endings С ps FC 18 A nerve end ng under the endothelium of a renal vein in a newborn mouse (so-called pressoreceptor type) Reduced siher impregnation Drawing of 16 oby 100 mm Nene endings, ring or pear shaped may be found on the outer surface of venous endothelium they may be isolated or form a sketchy corpuscle, Iou ·26 THE NERVE SUPPLY TO THE DIDNEY resemling one of these presso receptors described by NONIDEZ (1937, ", 1941, “s) in the large veins of the cardio pulmonary area Sometimes a nerve bundle comes iery close to the enous endothelium, sometimes it bulges into the lumen of large veins, covered by an endothelial sheath These pictures are scry clear and the nerve can usually be traced on a F16 19 Intravenous nerve bundle in the inferior vena cala of a romm mouse embryo Compare the irregular structure of the intravenous nerves to the smooth appearance of the extravenous fibers in the right lower corner Reduced silver impregnation Oc 16 obj 100mm few serial sections in new born animals, one wonders of the absence of such formations in adults is not due to the difficulty of following a much longer track in large vessels on a great number of serial sections Anyway, in young animals such a set-up undoubtedly exists Sometimes, the nerve bundle docs not cross the vein, but goes back to the same side of the wall after running parallel to it In embryos, an interesting modification appears in marked contrast with the surrounding nerves, the intravenous fibers are covered with spikes ending with a tiny knob on the inner wall of the sheath, the nene has the general appearance of a bundle of barbed wire The sensory value of such an apparatus seems obvious, as no other function may be considered Compared to other nervous apparatuses elsewhere in the body, it seems hard ·E E 2 N NORMAL INNERVATION OF THE KIDNEY 27 to believe that such a definite structure as this one would be without any function whatsoever The same applies to the more important structures that we shall describe and discuss now We were able to study extensively, in mouse embryos and young mice, intravenous nerve endings, we were fortunate enough to find them later in human embryonic material These endings are of two different types labelled A and B in our previous publications, when A and B are present together they form a complex which we called V C In order to give an accurate description of the type A and to make it readily understandable, we better follow its histogenesis as we reconstitute it from serial observations on mice A nerve fiber runs outside the wall of a V renal vein, along its course, on a E length of several micra, the fibers 3 enlarges and instead of being like a black stripe after silverimpregnation, it shows a bundle V of tiny neurofibrils loosened in a pale brown background surroun- E ded by a thin black sheath As N the loosening of the neurofibrils FIG 20 A diagrammatic reconstruction of histogenesis and the diameter of the main fiber of intravenous nerve endings in young mice For further increase, apparently a similar lumen of the rein Ecndothelium N nerve fiber phenomenon to that so obvious in arteriosclerotic vessels takes place the modified segment seems to increase in length between its two fixed extremities and it takes the shape of a horse-shoe that horse-shoe has always its convexity towards the endothelium, and it bulges into the lumen of the vein, covered by a thin layer of intima, no media being interposed between the intima and the nervous structure The two extremities of the horse-shoe come closer together while its main body bulges more and more in the lumen of the vein up to several micra, the whole horse-shoe undergoes then a process of approximation of its two branches which finally become fused together creating a pear-shaped mass, the dual origin of this mass is suggested by a small hole in its middle due to incomplete closure, or a dark avis running from the pedicle to the middle of the mass of neurofibrils where it enlarges a bit, there are the fused surfaces of N 4 comment sec text ·28 THE NERVE SUPPLY TO THE KIDNEY the inner part of the sheath of the horse-shoe At that time generally the bulging has increased and the pear-shaped corpuscle is now related to the main nervous fiber underlying the endothelium by two thin fibers which are sometimes twisted and always surrounded by a very thin film of cytoplasm The modified fiber forming the pear-shaped corpuscle may have a branche, ending FIG 21 A bunch of intravenous nerve endings in the kidney of a newborn mouse Another group of endbulbs on the lett is less clearly defined For relationship between these and the perivascular plexuses sec p 68 fig 45 Reduced silver impreg nation (MONIDEZ) by a little ring, included in the main body of the corpuscle and confusing the picture sometimes Corpuscles of the type A may be isolated but more frequ. ently are found in little bunches of a few units According to variations of silver impregnation or to hazards of orientation of the specimens before section, the type A may appear to differ from time to time from the description given above, although this picture represents the complete corpuscie as usually found under optimal conditions in human material and in mice The type B is very simple, a branch of a main nene fiber takes off, usually at right angle, and bulges in the lumen of a vein, covered by a thin film of cytoplasm, it ends by a small knob or ring and may well be the equivalent of ·VORILAL I NERVATION OF THE KIDVEI one of the appendages described with the type A Several B endings may be crowded on a small area of the vein, or may be mixed up with a group of A endings forming thus a C complex One more word should be added to this description in 1 C group one may find various aspects of the above described A formations so that by looking at one complex, one may get an idea of the 29 FC 22A An ntra enous nerve end ng atek dney of a 20 cn human foetus the low magn í cat on shows how the end corpuscles bud from the trunk of nerve fibers wlen tese cross a small cort calven the h gher man ficat on (fg 22B and C) focused on two different planes shows frst the nt matc s ructure of the corpuscles then of the pod cle the red blood cells are clearly seen on fg 'C Reduced s Iver mpregnat on process of differentiation of the whole structure then several fibers bulge into the lumen of the vein in the same area they generally are inclosed in one pocket of cytoplasm and the pedicle is broad the formation being sessile Otherwise as uc have said before the pedicle may be long and thin, and the question arises whether many of these endings are not torn from the vascular wall during the various stages of embedding or other stages of the histolo gical technique This may account for not finding sometimes the typical pictures or finding them very scarcely although one sees stumps of fibers crossing the level of the venous wall, and roundish or pear shaped reticulated

·30
THE NERVE, SUPPLY TO THE KIDNEY
FIC 22B
TIG 220
corpuscles free in the lumen of the vessels We must keep this in mind when we
state that we never found any intravenous endings in adults, and remember
that successful silver staining of nen es is very difficult to obtain, especially in

·T 11 G NORMAL INNERVATION OF THE KIDNEY 31 the kidney, after the first weeks of life On the other hand, the results are very gratifying during the embryonic stages and the only satisfactory pictures in human material were obtained at the stage of 20 cm Our series of silver stained mouse embryos being by far the most complete, we were able to study with accuracy on that materialwhat happened to these endings during the early stages of development They appear first in the main trunk of the renal vein and afterwards they bud all over the venous tree when the veins become gradually supplied with nerves Before that 10M renal stage, the nerve endings may be found in the main venous trunks of the abdomen, from which they seem to disappear while they get more and more numerous in the kidney, as if some function was taken over, step by step, by the latter organ Whatever this function may be, will be considered briefly later on, after reviewing data col lected on the juxtaglomerular apparatus We previously alluded to the difficulty of interpreting the nature of nerve fibers according to their greater or lesser affinity for silver salts, and stated that a good test was the existence of an important sheath of myelın or not The existence of myelinated fibers in the renal parenchyma has been a matter of some discussion, we are now defini- 104 tely convinced of their existence After birth one can find at least FIG 24 Another subendothelial ending on the one or two of them, even by such same vein the vein is cut obl quely and seems to end blndly on the drawing linn

·32
THF NERVT SUPPL) TO THE MIDVFI
$
FIG 25 Medullated nerve fibers in the k dney of a young grl in the case
the amount of nerve fibers is exceed ngly great and crcry myel n sheath
not stained MASSON s trichrome after 1 vat on in HOLLANDE S flud

·NORMAL INNERVATIOV OF THE KIDNEY 35 techniques as MASSON s trichromic stain in the large nerve bundles entering the hilum of practically every kidney Their course in the parenchyma has not been ascertained in every case but at least two features are firmly established i myelinated fibers follow the branches of the artery as far as the hilum of the glomerulus and may be found lying on the muscular coat of the preglomerular FG 27 A free nerve end ng in the connect ve tissue between the medulla and the cor ex of the k dney of a 20 cm human foetus The ma n fiber b anches off to the left of the p cture one of the branches (un een here) reaches a lymphat c channel Reduced sl er impregnat on arteriole 2 myelinated fibers end freely in the connective tissue between the medulla and the cortex of the kidney they loose apparently their sheath and branch off in every direction the last branches showing thickenings at their extremities These fibers are probably sensory carrying impulses from the kidney to the nervous centers The possibility of the preganglionic nature of the bloodflow throughout the kidney by means of short reflexes the so called axon reflexes in which the subendothelial venous nerve endings may act as receptor endorgans Wishing to have an over all picture of renal innervation in the classical ·34 THE NERVE SUPPLY TO THE KIDVES sense of the word, and taking into account only the observations which stand beyond any doubt, we are brought to the conclusion that the kidney is very well supplied with nen es, its "reactivity", especially as far as its vascular bed goes, must be a very important factor indeed This impression will be rein forced by the following chapter devoted to the juxtaglomerular apparatus a complex impossible to overlook in any study of renal inner ation

·CHAPTER II
The normal juxtaglomerular apparatus
Che data presented in this chapter were not collected in the same order as they
ire given here Study of pathological specimens and of some adult kidneys
nade it necessary to go back to early stages of development which will be
Myo.
SCLEROS
NEPHRO
A.
СС
FIG 28 A diagrammatic representation of the derivat ves of the neura!
crest_and the origin of the renal blastema From the neural crest derive
(2)
(par
ventral root and by (6) the migration of the presumpi se nephrogenous
material
Myo stands for myotomc SCLERO for sclerotome and NEPHRO for
nephrotome CNS Central nervous system Сн Chord Ao Torta
I'Intest ne
Сс
Coelomic car ty
described first
appear norma
are conscious
of our presentation
1
32
D

·36 THE NERVE SUPPLI TO THI LIDNEY A transverse section through the lumbar region of a mammalian embryo, before the first appearance of the renal blastema, shows the neural crests arısıng from the neuro-ectodermic angle and bulging ventrally Besides the ganglionic cells of the dorsal roots, the material of the neural crest grues rise to the sympathetic ganglia, the paraganglionic cells such as the medulla of the suprarenal, and SCHWANN-cells, but a close study of the lower limit of the neural crest reveals that some of its cells undergo a mesenchymatoid transfor. mation and become quite similar to pure young mesenchymatous cells present in that region This suggests the existence of an ectomesenchyme or mesectoderm, lateral and ventral to the spine, in the abdominal area, as e xists in the cephalic part of the embryo Definite proof of the existence of a cephalıc mesectoderm has been given by various authors, and its fate has been studied very accurately It is known to give rise to connective tissue, cartilage, etc (STONE, 1922--1929, Bad Boy) (VAN CAMPENHOUT, 1931-1937, º 199) HILBCR (1942, 100) demonstrated by liis experiments on amphibians (Trito, Bombinator) that the neural crest in the truncal area becomes mostly mesenchy matous and migrates caudally, giving rise to a typical mesectoderm of neurectodermic origin GRUENWALD (1939, % 1943, 88) concluded from his studies of the differentiation of the metanephros, that nervous tissue may induce a mesone phric-like differentiation of the metanephrogenic blastema in the chicken embryo VAN GEERTRUYDEN (1946,"") pointed out that nervous tissue muy induce the production of nephrons by the mesonephrogenous blastema in the absence of the ureter, (which induces it normally) He showed that the mesonephrogenous material migrates to and fro between the nephrotome and the mesenteric root, where the neurectodermic elements migrate at the same time The lumbar ectomesenchyme may thus contribute to the constitution of the renal blastema The induction by nervous elements of a differentiation in a renal anlage may be linked to the presence of a neurectodermic material In the lumbar region where ectomesenchyme would be present, the renal blastema appears at a later stage The ureteral bud growing cephalad out of the pelvis, encounters this mass of mescnchyme composed of young cells closely packed, and doides it up by brunching regularly in the same way as the hronchual tree (LUDWIG, 1949, 3) As we recalled previously (p 12) the small balls of blastema isolated on each side of the ureteral branches undergo several changes a lumen appears, to form vesicles wluch become rapidly S shaped, the lower curve of the S is the anlage of BOWMAN's capsule and its upper end includes the "pars intermedia" or junction between the nephron (or true renal unit) and the collecting system A close study of the differentlation of the nephron, points to two facts which are of definito importance very early a vascular lumen appears in the concavity of the lower branch, ·THE VORMAL JUXTAGLOMERULAR APPARATUS 37 1 1 L 1 La 1 j t 11 their prou enru, aliu those cells close lo the base stand on an early basal membrane by an enlarged foot While the tube stretches and becomes more and more twisted, the epithelium progressively gains its adult appearance, glomerulus, maintains its embryonic appearance, in contrast to the neighbouring segments It resembles a young neuro epithelium It is not unusual to find in relatively early stages a discrimination between two types of cells some are swollen, roundish and of a light shade of pink, others are red and taller, with an enlarged upper extremity bulging in the lumen of the tubule, with a narrow junction at its middle and lower thirds, and an enlarged foot resting on the base of the tubule These more or less hour-glass shaped, acidophilic cells, generally border on both sides a clearer cell, their curvatures fitting its ovale shape Differentiation will now proceed until it becomes very obvious in certain adults, where we nouced it first In the mean time, the glomerular tuft develops It has been shown by DE WINIWARTER (1943,9) and confirmed by us that the endothelial channel enclosed in the carly BOWAN's capsule becomes surrounded by mesenchymatous cells which very early assume an epithelioid appearance, this primary vessel is thus an artery, and the same appearance is easily found early in the development of any renal artery, as in arteries elsewhere The inner layer of Bowman's capsule, at this stage, is represented by a columnar cpithelium in striking contrast with the outer layer which is very early flattened out and endotheloid "The inner layer begins then to show folds, in which expansions of the primary artery grow, giving an early and sketchy picture of the glomerular tuft An interesting point is that the cpithelioid cells surrounding the primary artery maintain their appearance for a very long time while similar cells all over the arterial tree in the kidney gradually differentiate into smooth muscle cells, a process which eventually takes place in the glomerulus itself later on Undoubtedly, the muscular coat, or media, of these renal arteries is originally composed of cuboid cells appearing epithelioid in sections These cpitheloid cells of the glomerular artery remain embryonic and in close contact to the tubular segment which remains embryonic too Further differentration gnes every reason to believe that these embryonic looking structures represent the "anlage" of the juxtaglomerular apparatus which thus may be ·38 THE NERVE SUPPLY TO THE KIDNEY distinguished from surrounding material ever since the carly stages of desclopment. The full details of this process have already been published in a paper (1948, *), in which we pointed out how uneasy it was to give precise chronological landmarks for these phenomenons, as they happen over long periods of 1-ont time in the successive generations of nephrons which develop inside the kidney during foetal life Obviously they will be present more often at the periphery of the kidney than in the depths of the parenchyme where the older generations are located, this may explain, to a certain extent, the presence of the modified muscle cells, in the adult kidney, usually in the outer half of the cortex, although an alternative explanation may be afforded by relating their appearance to a peripheral decrease in blood pressure; (see p. 70 and s.). As we said before, the epithelioid cells of the glomerular artery finally become smooth muscle cells On the other hand, the juxtaglomerular segment of the renal epithelium may be found undergoing a more pronounced differen- ·THE VOR VAL JUXTAGLOVERULAR APPARATUS 39 tration By this time it is obvious that this segment belongs to the second con voluted tubule and represents the so called "macula densa' (ZIMMERMANN, 1929, 1933,2") Obviously the "macula densa' or 'palısadıc segment differentiates before the nerves reach its vicinity In the later half of foetal life and after birth very definite changes may be N Για young n the coated macula densa w th a vacuole under one of the dark cells the efferent arter ole is in the upper part of the p cture (WLASSONS trichrome) seen in the macular epithelium, although in some cascs they are not evident A remark should however be made in order to get the best results and the clcarest pictures, fundamental rules of a sound histological practice should be applied which are too often overlooked when surgical or pathological speci ·40 THE NERVE SUPPLY TO THE LIDNEY cells may extend beyond the limits of the macular segment, but it reaches its highest degree on this particular spot The presence of so called "vacuoles" makes the picture a bit more confused, these vacuoles appear in the basal part of the macular cells, and were noticed by various authors A close study on serial sections reveals, however, that if the existence of vacuoles is possible, it trichrome 15 also frequently possible to trace the origin of the so-called "vacuoles” to the lumen of the TC II, with which they are connected by small intercellular channels, being thus true diverticula of the lumen of the tubule These tubular processes are usually located between the main body of acidophilic cells and their basal expansions The narrow intermediate parts of the cell bodies are lateral to the diverticulum and the whole picture represents some sort of a bridge like structure which reminds us of the epithelium of Corti of the inner car Between the acidophilic cells (A) one finds ovoid cells (B), less slender than the previous ones, and resting in alveolı build by the fuchsinophilic elements Comparing further these two types of cells, the cytoplasm of the A cells with its closely packed, extremely fine, red granules looks more like an homogeneous mass, in the middle of which a dark staining nucleus assumes the same shape as the upper half of the cell In the B cells, the granules are coarser and diluted by a mass of clear watery fundamental substance in the middle of which floats the nucleus, this nucleus is generally round and clear, but ·41 THE NORMAL JUXTAGLOMERULAR APPARATUS sometimes sickle shaped on sections and excavated in the fashion of a bowl In this case, the concavity of the nucleus may be facing a vacuole, by far the most frequent in a basal corner of the cell (or between two cells) The study of various aspects of these clear cells conveys the impression that in some cases they leavi betw suggests that the B cells are only an oedematous form of the A type Mc MANUS (1943, 126 & 1944, ) clarmed that in the cat and rabbit's kidneys the Golgi structures seen as granules and short rods are on the side of the nucleus facing the attached pole of the cell, in the macula densa, although the usual position is immediately on the lumen side of the nucleus in the distal tubule This would be an useful indication of the individuality of this segment if JASSWOIN (1925, 156) and FISCHER (1938, 68) had not described variations of the Golgi apparatus according to temporary functional states, in various parts of the nephron, and if the process of differentiation described above did not precisely imply functional changes, in contrast to a resting stage where all the cells appear more or less the same It is not an artefact due to inadequate fixation and staining, because every cell in the vicinity looks perfectly normal in keeping with admitted standards of health Moreover this differentiation is prepared step by step throughout embryonic life It is more frequently found in cases where functional disturbances of renal hydro or hemo-dynamics may be suspected and it undergoes definite changes in pathology We may conclude this description While the nephron differentiates, two juxtaglomerular structures undergo particular changes the "macula densa” ܝܙ ܙ . become quite similar to components of a normal "media", but they remain capable of taking anew an epitheliord structure The macular cells show a definite tendency to divide up into two morphological types which may be only two different functional stages It should be remembered that these structures are in close contact with the nerves described in the previous chapter The relationship between artery, modified muscle cells and nerves has given birth to a new concept the "neuro myo arterial” juxtaglomerular apparatus (GOORMAGHTIGH 1932 76, 1914, 79) This apparatus with the macula densa forms the juxtaglomerular complex (Mic MANUS, 1942, 124 125) The arterial muscle cells and the macular cells derive from the mesenchymatous "anlage" of the renal blastema, which may have a neurectodermic component, or mesectoderm The chapters to come give us more information on a possible link between the juxtaglomerular complex and mesectoderm ·CHAPTER III Comparative anatomy We shall summarize here very briefly observations made on kidneys of various animals The facts thus pointed out have a direct bearing on our study A ALLIGATOR LUCIUS In the vicinity of the hilum of the kidney, the aorta the main renal arteries and some of their branches entering the parenchyme, show suggestive features The media of the larger vessels consists mainly of a circular coat of smooth muscle cells on the ventral side of the aorta and in the renalarea the myocytes on one side change their mun oricntation and instead of being concentric to the vascular lumen, take a stellate arrangement and bud into the outer layer of connective tissue While undergoing this change in position, they modify their structure and become larger, clearer and granular, where granulations appear myofibrıls vanish (fig 32, A & B) They assume thus a definite epıtlıclial endocrine appearance and form small islets in the outer layer of the adventice, resembling closely paragın glionic cells in the vicinity of the arteries where such a process takes place small groups of cells exactly similar to these come in close contact with other epithelial masses the cytoplasm of which is packed with tiny little granules giving a much darker appearance to the cell These complexes are surrounded and pervaded by nerve fibers and the darher epithelial cells may be found mixed up with typical ganglionic cells The significance of the whole process may be expressed as follows smooth muscle cells of the media migrate to the periphery and undergo an endocrine differentiation, exactly similar cells are found in the vicinity of these arteries as a component of epithelioneural complexes of a paraganglionic type Tlus strongly suggests that smooth muscle cells have a paraganglionic potentality, the question arises whether these cells have a mesectodermic origin (neural crest) which would be the only satisfactory explanation in the present status of our knowledge So far no experimental answer has been gren to this question but seseral observations are of interest and they all point to the same direction The existence of a lumbar ectomesenchyme in the renal area, is highly probable n mammals have shown that the muscle cont of Ae 44 glonierular apparatus or may be replouuu

·COMPARATIVE ANATOWY
43
ng 32The hilum of the kidney of Alligator Lucius showing the
budding of periarterial myocytes in the outer layer of the artery Low
magnification) Massov's trichrome
SIC 3,8 l he ne under buy 2710fcalion

·44
'THE NERVE SUPPLY TO THE KIDNEY
logical evidence of secretory activity such as that of the granular cells of the
renal arterioles of the mouse.
B. OTHER VERTEBRATES.
The hilum of the kidney of lower vertebrates (frog ', salamander, turtle, a.s.o.)
116 33 The macula densa in the kidney of a frog, at the
vascular polc of the glomerulus, with a definite palısadıc
arrangement MASON'S inchrome,
and its evnen.
number
-JUIC, HIUSt of them representing
the med
suprarenal, but some of them not (clear cells, when opposed
to dark ones filled with iron staining granules). There is nothing new about
* W4WIL
AIR
The frog kidney has typical macular strator **
MUYLDER, 1950, 431
with a meso. or m
relation
t

·COMPARATIVE ANATOVY
45
FC 31 Two groups of paraganglionıc cells along the intrarenal vessels
of the turtle the cells are overloaden with iron staining granules MASOV S
trichrome
FI 3, In the renal hilum of a ronster paraganglion cells with dark
iron stainit gran i accompany nerve cells along the renal vessels
Hrinalum Losin

·46 THE NERVE SUPPLY TO THE KIDNFI this observation (see, for instance, DA COSTA, 1939, and the monograph on the adrenal gland by HARTMAN and BROW NELL, 1949, 9) The same observation may be made in birds, as we did in the kidney of a rooster, typical paraganglionic neuroepithelial bodies were present even in FIC 36 A nerve cell in the kidney of the carp embedded in a nerve running alongside a large ven this is a very common feature in the kidney of old carps MASSON S trichrome the midst of the parenchyme along the renal arteries (dark granular cells), besides we found at least one picture suggesting the type of transformation described in the alligator The aorta and the kidneys of various fishes are of great interest GERARD (1943,?) reported on glomic structures in the aortic wall of various TELEOSTEI ·COMPARATIVE ANATOVI) 47 (Lepadogaster Gouanı, Lepadogaster Candollu, Callionymus Lyra) when it gives off the pronephretic arteries We described (1950, **) a neurovascular complex of a glomic type in the hidney of the carp (Cyprinus Carpio) a great many nerve cells may be found along the vessels (arteries and seins) (sce fig 36) Thc aortic Hall may show another type of glomus like structure which Tic 37 Viod fied muscle cells nested in the wall of an abdominal artery of the carp at the inlet of an arteriovenous anastomosus MASSON S tr chrome emphasizes the importance of this region for the general regulation of visceral blood supply There is a definite possibility that muscle cells of the arterial wall, in the renal area at least, have an endocrine potentiality and form epithelioneural bodies Their link with the sympathetic nervous system would be best explained by their mesectodermic (neural crest) ongin, and such an origin is, at least, possible from the morphological standpoint A nervous origin of muscle cells is not surprising as the muscles of the iris derne from the peripheral part of the retina which is an expansion of the central nervous system These muscle cells are smooth in the mammals and started in bırds They have been compared to the epitheliomuscular cells of thc Coclenterata From our viewpoint no difference should be made betucen striated muscle cells and smooth muscle cells as we remember the structure of the human oesophagus, or the smooth and strated muscle coats of the intestine of the perch, for instance One of the two types of muscle cells is not unſrequently found in close ·48 THC NERVE SUPPLY TO THE KIDVEY relationshup to nerve cells, as in cerebellar tumours, nerve sheath tumours and renal tumours where they would onginate from the same stem, in Massor's opinion "In so far as the reality of the genetic relationships between muscle and nerve tissue is concerned, different facts argue in its fasor in the same fashion as do the renal adenosarcomas There in first of all MARINESCO and GOLD. STEIV's myogenic "medullo-epithelionia" of the cerebellum, which could very well be a complex nervous tumor-at the same time medullo-epithelioma and neuro-epithelioma of the cranial crest-included within the cerebellum Next there are the observations made on rhabdomyomas of nerves (GRATIA, ORLANDI, P MASSON), whose striated cells come not from myotomes but from constituents of nerves originating from the neural crests” (MASSON, 1938, 3, p 31) SZANTROCH (1938, ...) in his studies on the development of the sympathctic nervous system expresses the opinion that one single blastema gives rise to the sympathetic ganglionic cells and the muscles to be innervated through the expansions of these cells, in the digestive and respiratory system and the abdominal blood vessels Alore recentls KEUNING (19.45,') admitted that the vegetative nerve plexus of the intestinal wall was of mesodermic origin WEBER (1940, 805) admits that the vegetative neuroblasts along the intestine are at the beginning undistinguishable from pure mesenchyme cells, but, among the anonymous mesenchyme cells, arc a great many ectomesenchy matous elements whose migration from the neural crest is indisputable l'an CAMPENHOUT (1931, 'ge) demonstrated by experiments on chicken embryos that no development of intravisceral (digestive) neric cells could be expected without migration of sympathetic neuroblasts originating from the neural crest Nerve cells seem to differentiate from mesenchyme in the lungs (BAUMANN, 1940,"), again, they may be mesodermic or mescctodermic, although we don't have any hint to the cuistence of an ectomesenchyme in this particular field The same general reasoning applies to the periarterial blastoma which wc are discussing now, not only does this blastema give rise to modified muscle cells which sometimes tahe a Neuroendocrine appearance, but cells have been described whuch extend in the arterial wall the nervous networks themselves (Cajal's interstitial cells, see the recent studies by Boene, 1940,", 1943, **, 1949, "), not to speak of their presence in intestinal musculature The main trouble with these cells is that their nervous nature or "neurord" quality still rests upon their silver impregnation more thin on their specific morphology, their true significance is controversia! Our observations on the arterial wall of Alligator are less open to discussion The modified muscle cells of the rena) artenes base been compared to the glomic cells described by Masson and even to the cells of the His-bundle ·COVIPARATIVE AVATOVY Both cells are in fart m specialized in the elements such as go relationship of the Lo pann! r uu muscle cells in the chain of events is a Helent, whether they secrete an hormone or pass over a ner vous impulse, has no bearing on our discussion The interpretation of our observations seems reasonable in view of the known facts myocytes of the arterial media become endocrine, and migrate to join neurocpithelial bodies A sensible way to explain this, is to postulate the presence of ectomesenchy matous cells in the periarterial blastemi as he said at the beginning of thus discussion An extensive review of glomic structures in the sense of Massov Anand specialized arteriovenous anastomoses 7s do (1938, ") would be out of nl bright-3 ant uns are not purely aca 12 terms of function (local regulation of bloc Herste for instance FRANKLIN and Mc LACHILI, 1936, 68 & 6s, BOVIVFVTO and MORIN, 1941,* TRUETA & al, 1947, 87) 2 f ·CHAPTER IV Possible relationship between nervous elements and some aspects of renal pathology A NEPHROSCLEROSIS A slow but continuous process of nephrosclerosis decreases the number of glomeruli ever since the first completion of development of the kidney Later on, in adult life, this process increases in actiyzty and may finally result in gross impairment of renal function, by this time it has become a chico pathological entity becausc its ill effects are obvious The picture of renal tissue undergoing sclerosis is very much confused We have studied it very carefully, and, after checking our observations by com paring them to several descriptions found in the literature, we think we rre on the way to the understanding of this problem To begin with, derivatives of the ureteral bud do not seem to plav any im portant role in the picture of nephrosclerosis We are thus left with the tubulo vascular unit to which we referred previously and which corresponds to the metanephrogenic blastema The scarring of the glomerulus seems to initiate the whole process The shrinkage of the glomerular tuft, surrounded later by a fibrotic capsule and finally replaced by it does not always result from a serious impairment of blood flow through the glomerular arteriole, this is shown by sei eral observations of aglomerular arteries, which are indeed nephronic vessels, the glomerule of which underwent sclerosis although the mun channel remained patent Such observations postulate an intraglomerular mechanism depriving the capillaries of their normal blood supply and producing their collapse We don t see any intraglomerular nervous penetration, but we know that the capillary channels are embraced and supported by a skeleton of ROUGET ter is ob c elements carp, its action may be compired, although in a more localized fashion, to the function of the muscular intraglomerular vessels of the SelAcuII (BARGMANN 1937,5) At the same time, the tubules do not disappear right away after their glome rulı have been reduced to an afunctional fibrotic mass, indeed they shou definite signs of hypertrophy and even increased cellularity (true hyperplasia) which gives the whole picture a tumor like appearance Related to the previous point is the fact that the surviving epithelial cells show signs of excretion or secretion, they hue intracytoplasmic granules and vacuoles, as active glandular cells do, also masses of an hyaline substance are 50 с ·POSSIBLF RFI TIONSHIP 51 enclosed in epithclium lined vesicles comparable to a thyroid like arrange ment Finally, debris are found apparently tripped in a tubular segment without connexion with the col lecting system Several observers enderroured to explain the signi ficance of these pictures according to a probablc function of the sclerotic kidney the endocrine C secrction of the kidney has tery often been referred to in connexion with these aspects One should not forget that two processes at least may be present and that the misse of secretion products surrounded by epsthelsal cells may well be rem nants of the excretory function of the tubules, whereas the etentually so important endocrine ſunchon may not be shown by any striking FG 38 tree tubular > garnt Tuns trepiros morphological changes The pro cleros s to show the collo dl ke substance n the lumen of the the socle V ASSOV cess of nephrosclerosis may liare I chrome Draw ng or 6 ob romm two different outcomes complete shrinkage of the kidney when atroplıy is predominant the other produces local hypertrophy and results in tumor like productions the so callcd Klenomas true adenomas and possibly, malignant tumors see § D B TE RENAL NERVES IN NEPIIROSCLEROSIS He have already mentioned the renal nerves and their centual action on micro muscular sphincters Tuo paints are of interest first, no more than in normal hidneys did see hidneys second As 1 rule always tration nor does the silver impregnation reveal an gross pathology (thic remarks mide pa should however be borne zu mind) Sometimes one gets the impression that the nerses incre ise in number this should be reltcu to a decreise in the mass of renal parenchyme which dilutes them \lanı normi nenes re thus seen in a fibrotic shrinking scar and thus might well be hept in mund bs plusiopathologists (fig 39) (Thit jI VACLOVERULAR COMPLEX IV NEPHROSCLEROSIS 1 shall consider the second com oluted tubule with the macular area und the muscle cells of the glomerular arterioles orte IS ·52 THE NERVE SUPPLY TO THE KIDNEY 1 The second cont oluted tubule We have already discriminated between the behavior of the glomerulus, the convoluted tubules with HENLE's loop, and the excretory portion proper In relation to the object of our study, it is, of course, interesting to try and find out whether the portion of the nephron extending between the glomerulus FIG 39 Medullated nerse fiber in a human atrophic kidney, to show the funnels of Golci (high magnifica tron) MASSON S Inchrome and the "tubuli recti, degenerates uniformly, or if some segments react in a more or less typical way, different from the neighbours There is some recent evidence that more segments should be individualized in the nephron (on various grounds, morphological and ſunctional) than the classical subdivisions 1 The first convoluted tubule with a neck, various loops and a terminal straight portion, 2 HENLE's loop ith a narrow and broad branch, 3 second convoluted tubule with a "macula densa" and a terminal "Spars intermedia" Turther subdivisions of this complex are suggested by researches pertaining, for instance, to the appearance and behavior of fat-free ·53 POSSIBLE RELATIONSHIP and fat loaded segments, to the shape of cell-borders, to the intensity of athrocytosis, to the capacity of iron storage, etc Whatever the final picture of the normal adult nephron will be, when the renal tubule undergoes sclerosis it does not react in the same way on its full length Very good evidence of this has been presented by several intestigators and we should like to quote here some results of OLIVER and co workers (1934, 5, 1950, 5) The first convoluted tubule (TCI) is subjected to great variations it may undergo atrophy and fatty degeneration, or become dilated, hypertrophic and hyperplastic with an increase in its length and its degree of convolution, between these two possibilities exist all transitional stages and, even more, marked atrophy and marked hypertrophy may be found alternating along the course of a single unit Hevle s loop is not the site of hypertrophy or hyperplasia The second convoluted tubule (TC II) is usually dilated and irregular enclosing in its lumen a coagulum, or fatty or granular “debris", it may also contain crystals (as the loop of Hevle sometimes does too) At the distal end of TC II, the 'pars intermedia' (connecting tubule or 'Schaltstuck' ) is usually empty and non dılated A very important point is that the renal unit undergoes fragmentation which is particularly obvious in certain regions "When the deeper layers of the cortex and the outer stripe of the outer zone of the medulla are dissected, imong the hypertrophied and hyperplastic terminal spiral portions of the proximal convolution, are found isolated segments of tubule, the external contours and general configuration of which resemble exactly those of the intact enlarged kinked spiral They are obviously interrupted or pinched fragments of this terminal portion of the proximal convo lution, for they may be found lying in situ arranged in a linear series, each unit closely following the other' OLIVER & LUEY (1934, p 807) The abnormal kidney may show glomeruli without connexion with the tubules and, in tubules separated from their glomeruli, tubular segments disconnected from each other, undergoing atrophic, hypertrophic or hyper plastic changes in their epithelium, with a normal, narrowed or enlarged lumen Cysts may be formed with a colloid like substance "Such vesicles and cysts are of course, functionless and in certain cases may comprise a con siderable part of the epithelial-tubular element of the diseased organ OLIVER & LUEY (1934, p 815) On the contrary tubular hypertrophy and hyperplasia may be related to a compensatory mechanism, the renal epithelium taking oner some functions of the glomerulus as in the aglomerular kidney of lower crtebrates Thuis phenomenon should be kept in mind while trying to understind such changes as described by SELYE and STONE in the so called en docrinc kidney of rats (1946, 7) The changes occuring at the level of T C II, with particular reference to its terminal portion, were the main object of our study The absence of spectacular cellular reaction may be due to either a ·54 THE NERVE SUPPLY TO THE LIDNEY disposition of vascularization protecting this area from the full impact of blood non-purified by a preliminary filtration through the glomerulus (this blood being partly purified by the compensating T C I), or by a special function of this segment which would not take up toxic constituents from the blood The latter hypothesis which suggests a special metabolism of this segment is supported by observations of elective lesions, in such cases as localized nephritis and crush-syndrome Both mechanisms may be involved Wherever the truc explanation lies, the epithelium of TC II remains fairly normal in nephrosclerosis and when other sections of the tubule eventually degenerate and disappear, the second convoluted tubule generally survives Though its epithelium does not undergo the changes quoted above, it is nevertheless subject to cytological modifications It should be remembered here that the TC II, particularly in its terminal portion is not homogeneous Several observers pointed out that the epithelium of the TC II shows tno types of cells, dark ones and clear ones One might suggest that these two types are basically similar, and represent only different stages of activity, but this does not lessen the importance of the difference which may be very striking indeed As said previously such a difference is more pronounced in the macular area The chief features of that heterogeneity were described in a previous chapter but we want to add here some more information WIGERT and EKBERG (1903, 206) demonstrated the existence, in the renal epithelium of the frog, of two different cellular types dark principal cells with a narrow base and a broad upper extremity, and clear intermediate cells nested in the alveoli formed by the dark ones, with an expansion of the lumen in their own cytoplasm With Da Fano's silver staining technique, ORKELS (1929, 5) demonstrated in a series of animals (rabbit, dog, rat, pigeon, frog) renal cells characterized by their affinity for the siler, and bulging into the lumen of the tubule FEYRTER (1940, 64, 1943,6) made a similar observation and extended it to other groups of cells found in the vicinity of the TC II These cells would be similar to the "Schaltzellen" (SCHACHOWA) which are the darker cells found in the end segment of the nephron extending under the base of the nearby clear cells, with their own broad base When the nephron disintegrates, the end segment and especially the macular segment survive thus for a long time The study of a series of human kidneys undergoing sclerosis established this fact Practically always nephrons can be found degenerating in otherwise healthy looking adult kidneys and portions of nephrons surviving between the normal tubules may account for these epithelial masses or vesicles eventually found scattered throughout the kidney Other cxplanations may account for the presence of such structures one is their differentiation from embryonic cells of the renal stroma, much in the same way as LEY DIC-cells do in the testicle, but our studies of histogenesis of the ·POSSIBLE RELATIO\SHIP 55 kidney never provided us with any evidence to support this hypothesis, another one assumes their origin to be in the wall of the arterioles which would be more or less the same hypothesis as the previous one (sec p 71), another hypothesis still sees their origin in detached appendages and diverticula of the renal tubule itself (PETER, 1907, '57, FEYRTER, 1910, 6, 1943,6»), here again, the سا histogenesis of the nephron does not give much support to this hypothesis, unless one admits that these appendages do not appcar clearly before the adult stige, at what time they may as well be considered as a first symptom of the hyperplastic reaction mentioned previously This relationship to the ageing of the nephron and its eventual breaking down seems thus to be probable Whatever their origin is, the most conspicious of these islets resemble closely the TC II and FEYRTER also de dropicts and sa self, he thought that these islets where a diffuse endocrine organ of the same nature is the corte of the suprarenal These islets are obviously the same as the cell masses described previously by BECIIER (1936,', 1937, , 1949, ), in the vicinity of the vascular pole of the glomerulus, although BECHER thought that these cells where more similar to the medulla of the suprarenal To sum up wc believe that these cells are mainly derivatives of the TC II and an expres sion of a slow process of breaking down increasing in intensity as time goes on 0 1 ·56 THE NERVE SUPPLY TO THE KIDNEY The segmental survival of the nephron is quite typical in thc macular area This has been noticed by GOORMACHTICH and the conclusions of our observations are in complete agreement with his, in cases of polycystic kidney and renal atrophy the few tubular remainders scattered through a fibrous mass had often the structure of the heterogenous macular segment, showing thus its definite tendency to survive while the rest of the kidney disappeared We made the same observation in the extratumoral zone of the renal parenchyme, in a mixed tumor of the kidney to which we shall refer later on These two last cases are good illustrations of what may happen in nephrosclerosis Of course if nephrosclerosis is bilateral, the patient will die before ultimate stages of fibrotic scarring occur, but unilateral cases give us the opportunity to observe a disease of long standing On the other hand the proliferative activity of the hypertrophic stage may increase and give rise to benign tumors (adenomas) and eventually malignant tumors (renal cell carcinomas) 2 The muscle cells of the glomerular arterioles We have already said a word about the origin of the aglomerular arteries and their relationship to a shrunk glomerular tuft A glomerular artery may also disintegrate the same way as any tıcd off artery does when no collateral channels FIC 41 In the kidney of a dog the juxtaglomerular complex is represert ted by a macular segment of TC II (above) and a pseudo-VEISSVERian corpuscle (below) thus corpuscle belong to the walls of the afferent and efferent artenoles where they give off their branches to the glomerular tuft M45504 $ trichrome ·POSSIBLE RELATIO VSHIP 57 ·58 THE NERVE SUPPLY TO THE KIDNEY develop But nowadays it is impossible to sum up so briefly the situation RUYTER (1925, 167) was the first to describe, with some details, the modified muscle cells of the media of the preglomerular arterioles in several animals they were epitheliod and characterized by the presence of granules staining black with iron hematoxylın, remaining unstained by the dyes for lipoids and glycogen, but being well stained by Van GIESON's technique after mitochon drial fixation Sometimes these granular cells contain myofibrils, proving their muscular nature Similar findings in the human kidney were described by OBERLING (1927, 147, 1944, 448 149) Since then several people have published the results of their researches on this subject Modified muscle cells were described by Onkels in the mesonephros of the frog (1929, 15) GOORMACHTIGH (1932,7 to 1944, *) made similar observations on the kidneys of human beings and a cat He mentioned the relationship of the modified cells with nervous fibers and gave a description of a "pseudocorpuscle of MeissNER” buried in the angle of the afferent and cfferent artery, this "pseudo-corpuscle of MEISSNER" has unfortunately been the source of much confusion, although it was said to be composed of more or less spindleshaped cells resembling the SCHWANN cells, piled up in the corner of the vascular root of the glomerulus Such an appearance is not unfrequently scen, but after observing it closely, times and again, we were absolutely unable to detect anything suggesting the nervous nature of this structure, on the contrary, it very closely resembles these micromuscular bundles that we observed along renal vessels of the carp Such micromuscular bundles exist also around the ampulla at the origin of the glomerular loops, a fact mentioned also by GOORMACHTIGII (1941,72) This author calls the complex "segment neuromyo arteriel” and suggests that it would act as a sensory zone from where vasomotor reflexes would originate regulating the blood flow through the glomerulus ZIVVERMAN (1933, 2-2) who was one of the authors who first described the macula densa, described also a "polkissen" which really seems to be the same thing as the modified muscle cells (see also HERINGA & RUYTER (1933,5), Matus (1934, 34), MONSERRAT (1934, "s), KAUFMANN, 1940, "}} BECHER (1936,", 1937, "", 1949, 2) found the modified muscle cells too, but his main interest was focused on small islets of clear epithelial cells in the vicinity of the afferent arteriole he thought these islets were endocrine, similar to the medulla of the suprarenal and secreting an hormone wich produces the congestion of the modified muscle cells of the arteriole He did not believe that these islets were deriving from the tubules themselves, he stated that these islets had not been described before ercept by GOORNAGITIGH who called them "pseudo-corpuscle of MEISSVER" not realizing their real nature ·59 POSSIBLE RELATIONSHIP CLARA (1936, 26), (1938, a) described also the modified muscle cells, the neighbouring epithelial islets and, in the hulum of the glomerulus, a sphincter of small smooth muscle cells APPELT made similar statements (1939,") More is to be said about the modified muscle cells of the media Although some pathologists believe that the epithelioid cells are a degenerative form, without function, of arteriolar myocytes, a large number think that they probably have a function related to the blood flow through the glomerulus, but how this works out is a matter for conjecture For some authors these cells represent the most peripheral link of a sensory mechanism such as in the glomic structures and are the origin of the afferent pathway of a reflex arch Some other observers think that these cells are apt to become oedematous and occlude the lumen of the afferent artery (QUELLZELLEN) Finally, GOORVAGHTIGH made an interesting contribution to this problem, he reproduced GOLDBLATT's experiment on several animals and noticed with the onset of hypertension an hypertrophy and hyperplasıı of the smooth muscle cells His observations suggested that the modified muscle cells are taking a definite secretory appearance He thus concluded that the hypertensive hormone was secreted by the modified muscle cells which he called CMA = "cellules musculaires afibrillaires" Several investigators undertool to verify this hypothesis by experiments on immals, or by observations of normal human kidneys and kidneys of patients suffering from high blood pressure Examples of such rescarches will be found in the papers Graef (1940, ' , 1943, 6-), Graef and PROSKAUER (1915, ºs), DUNIIVE and CANDOV (1910, **), DUNIHUE (1911,", 1976, 36 sz), KALFVAN (1941, °, 1942,""), Mc MANUS (1942, ', etc ), TRIEDYAN and KAPLAV (1942, , 1943, ”), FRIEDMAN, KAPLAN and l\ILLIAUS (1943, ?), OBERLING (1944, **), SCHLOSS (1945,', 1946,"", 1947, ", 1948, '), DE MUYLDER (1916,""), Des Prez (1918, “), Diva, BERNASCONI and MARTUZZI (1950, 56), etc The complexity of the problem will be appreciated by taking into account the hypertrophy of the modified myocytes after bilateral sino-carotidal denervation resulting in high blood pressure (ELAUT, 1934, 6), or by the administration of adrenotrophic hormone or desoxy corticosterone (DOUGHERTY, 1948,"") I or the time being it is very difficult to decide which hypothesis is the right one, and whether the CMA might not hue several functions altogether Thesc cells are undoubtedly present in nephrosclerotic kidneys but it is difficult to decide whether their number is significantly increased cien in some cases with definite high blood pressure To sum up this section on nephrosclerosis, we shall say that the glomerular lulum shows sanious structures, forming part of a juxtaglomerular complex, some of them getting conspicuous onk through senescence 10 70 7 ·60 THF NIRVE SUPPLY TO THE KIDNF) The afferent artery with normal smooth myocytes and modified epithelioid muscle cells 2 The efferent artery, the structure of which may approach that of the afferent artery 3 A micromuscular sphincter at the inlet of the glomerular tuft 4 Nerve fibers running along the arteries and crossing the space betwcen the base of the macula densa and the vascular root of the glomerulus 5 The macula densa of the TC II 6 Free epithelial islets, deriving apparently from the TC II TCI BOWMANIS CAPSULE M CROMUSCULAR SPHINCTER EP THEL OD CELLS NORMAL MyOCYTES TCI NERVE BIRST VAS OFFERENS FREE EP THELAL SLET FIG 43 Diagram showing the various parts of the juxtaglomerular com plex and their mutual relationship TCI and TC II stand for first and second convoluted tubule respec tisely The disappearance of the elastica interna where the cpitheloid cells are present has not been shown to avoid confusing the picture The next chapter will possibly enable us to go further and see whether there may be a relationship between 5 and 6, and the nervous system D NeoPLASTIC PROCESSES IN THE KIDVES AND NEUROGENESIS HYPERTROPIIY and hyperplasia accompany nephrosclerosis, mimicking thus closely hepatic cirrhosis In the same way as regeneration in cirrhosis produces adenoma-like structures, pictures are present in the nephrosclerotic lidney suggesting the production of renal adenomas True renal adenomas may also ·61 POSSIBLE RELATIONSHIP be found, and their growth may produce in the surrounding tubules nephrosclerotic changes The question whether true adenomas surrounded by nephrosclerosis, and nephrosclerosis producing adenomatous pictures are closely linhed, is open to discussion The relationship between true or pseudo-adenomas on one side, and malignant tumors of the kidney on the other side is also a matter of much disagreement Large series of cases, studied from that point of VICW, were published without presenting any clearcut evidence, however the general trend seems to be that an hyperplastic reaction mav gne rise to true adenomas and that true adenomas may undergo malignant changes, although adenomas may be found in normal looking kidneys and large adenomatous masses may be present without showing any malignant transformation All thuis, of course, concerns only the tumors arısıng from the nephron itself, exclusive of the collecting system (renal cell growth or metanephroma) They present various aspects and the pathologists experiences a lot of trouble in trying to classify some of them The possible relationship between free epithelial islets and hypernephroma should be closely investigated The following pages will show us that the typical hyperncpliroma is probably a well characterized, highly differentiated renal tumor We hnow that three types of cells are set free in the kidney to form adenom 2-lihe structures TC II cells, macular cells and modified muscle cells, they become endocrine-like and ſoamy, lying on capillaries, which is a structure of hypernephroma We recently studied what we think is an interesting tumor, from various view points It gives valuable information on the potentialities of renal tissue and the various ways these potentialities may become appearent A chnical diagnosis of Wily tumor was made in a young boy The left renal region was submitted to X-Ray therapy to reduce the size of the tumor Operation was postponed because of pulmonary infection, but after a while It was felt that a nephrectomy should be performed notwithstanding residual pulmonary discase because the tumor was increasing in size A left kidney was ihus remoied with a tumor like a goose-egg in its inferior pole The microscopical findings appeared unusual and a thorough study of the specimen was made, with various histological techniques on several hundreds of sections A basic feature was the presence of a ven young blastoma of sarcomutous appearance This blastema may be completely undifferentiated and gue risc to a lughly malignant strcoma, with many atypical cell divisions, it is also linked by every intermediate stage to more differentiated arcas of various types fibrosarcoma, mnosarcoma, lcio- and rhabdo-myosarcoma, it shows areas of curuliginous differentiation and even suggests the ci olution into ostcosarcom?

·62 THE NERVE SUPPLY TO THE KIDNEY It forms embryonic renal tubules, typical of Wilms-tumor Although we studied several such tumors in order to find neurogenesis, the present case is the first one in which we discovered an important nerous proliferation related to tubular formation The apperrance of neuroblasts in the tumor fulfills the requirements recalled in a previous chapter on technique (see p 2) the neuro fibrils are stained red by Massov's trichromic stain whereas the connective fibers stain blue with anılın blue, they are yellow after Van Giesov's stunning when collagen fibers are red, they are impregnated by Rogers' silver technique and remain unaffected by Foot's silver impregnation of reticulın Their morphology is similar to their structure in typical nervous system Such neuroblasts differentiate from a common blastema giving rise to tubular sketches to which they are linked by many transitional stages The tumor itself arises from the kidney in which neoplastic degeneration is seen It is not our purpose here to deal at full length with other particulars of this tumor, such as the relationship between various parts of the normal nephron and neoplastic disease The presence of hypernephroid tissue related to the above mentioned structures is of great interest for the discussion to follow Interpretation of these facts is insecure if one does not admit that the renal blastema contains neurogenic elements The existence of a lumbar ectomesenchyme arising form the neural crest and contributing to the formation of the renal blastema is the logical way to explain thisSo far we are in complete agreement with the facts described by MASSON (1938, "92) Masson thus recalled the existence of nervous elements in certain embryonal adenosarconas of the kidney and showed that the neuroblasts were closely linked to the embryonal renal cells, this led him to admit the contribution of the neural crest to the renal blastema The ectomesenchyme is capable of producing a great many tissues such as connective tissue, cartilage and muscle, as usual mesodermic mesenchyme does Hypernephroid tissue being present in a tumor with neurogenesis and being morphologically related to it, we wondered whether the ectomesenchyme would not afford a solution to the problem of the hypernephroma In other words, would not the ectomesenchymatous origin of renal hypernephroma clarify this whole field of research It should be noted here that Pick (1927, 's) described an unusual renal tumor, a peripheral hypernephroid growth surrounding a gangliocytoma In his opinion, this was a combined neoplasm, a typical hypernephroma arising from a “Struma aberrans suprarenalis renis" (GRAWITZ, 1883,"), from both elements of the ectopic suprarenal rest, “Nebennebennierchen”, the cortex * Unless one admits that there is no specificity in the production of nervous tissue (sec the historical surrey of the development of the sympathetic nens ous system by Vax CAMPENHOUT 1930 1901 ·POSSIBLE RELATIONSHIP and the medulla For him thrs was a capital sign in favor of Grawitz' theory, because neither chromaffin tissue, neither sympathetic ganglia are present in the kidneys "Da in der Niere weder chromaffines Gewebe noch sympatische Ganglien vorkommen, bleibe dann als wahrscheinlichster, man kann wohl sagen, einzig moglicher Schluss nur der auf die hypernephrogene Natur der 63 FIC 44 Human semi lunar ganglion showing a nest of para ganglionic cells in the midst of typical nerve cells (compare with the tumor in Pick 3 case referred to in the text) MASSOYS triclirome gesamten Blastombildung und damit im besonderen also auf die hypernephrogene Natur der hypernephroiden Geschwulstanteilc We know that nene cells may exist in the kidneys although they are scarce, we have indications of the existence of paraganglionic cells in close relationship to renal usuc The gangliocytoma in Pick's tumor muy thus be from renal origin, and the hypernephroid gronth may be of the same origin too But 11c do not even need the existence of truc nenous and paraganglionic cells in a gren normal kidney to explain the local origin of such growth The renal adenosarcoma produces sketchy nephrons and sympathogonic capsules The tumor described by Pick may well be a true renal tumor arising from one mescclodermic blastema gnung rise to ganglionıc cells and hypernephroid tissue as in our above mentioned case In Pick s case the ganglion cells are seen budding in the hypernephroid ussue and the two get very intimately fused We ·64 THE NERVE SUPPLY TO THE LIDNEY publish again a photomicrograph of paraganglionic tissuc enclosed in a sympathetic ganglion (a state of affairs which is not too unfrequent), the neurectodermic origin of both elements is fairly evident from the embryological viewpoint The similarity between this picture and the one published by Pick is striking If we believe that some hypernephroid tumors associated with neurogenesis are produced by a same blastema, potentialy nervous and nephrogenous, we are able to explain a great many observations, as we pointed out a few years ago This hypothesis is supported by early embryonic studies showing a mesen. chymatous transformation of the peripheral cells of the lumbar ganglionic crest in the presumptive renal area Histogenesis and histology of the kidney show the existence of a juxtaglomerular complex where modified muscle cells and modified tubular cells are in close relationship to nerves The modified muscle cells get the structure of endocrine, paraganglionic cells and this assumption is borne out very clearly by observations of comparative anatomy (epithelioneural complexes) The modified tubular cells assume the appearance of a neuro-epithelium of a sensory type Neurogenesis in renal tumors is another expression of the "neurility" of the renal blastema When the renal blastema undergoes neoplastic degeneration its possibilities are manifold it may produce more or less typical renal structures, renal cell carcinomas with or without tubule or gland formation, it may also produce various neural crest derivatives, connective tissue, cartilage, bone, muscle sympathoblasts and their derivatives and neuro endocrine cells (see p 12) Such a view would unify the problem of renal tumors, including the ever varying aspects of “hypernephromata” from renal-like structures to endocrine structures i The fact that these endocrine structures may mimic adrenocortical morphology is not a difficulty as there are reasons to believe that parts of the cortex of the suprarenal may arise from an ectomesenchy me as happens with the kidney This leads us to consider another spect of the same problem If the "neurility of the renal blastema is supported by the neural crest derivatives, is the neurectodermic contribution to the lumbar mesenchymc (ectomesenchyme or neurectoderm) exclusive to the kidney and renal area or does it show up somewhere else? The renal area proper is but a section of the urogenital fold which should be investigated thouroughly If in the course of our investigations we find that the renal area is but a part of the whole field where neurectoblastic material forms ectomesenchyme and endocrine cells, our hypothesis would gain strong support 1 The word nign Hyper caden ma nephroma that there nenh ·POSSIBLE RELATIO\SHIP 6, Neurility is present in the gonads As VAN CAVPENHOUT points out in a recent view of the subject (1919, '98), the testes have the usual nene supply and epithelioneural bodies These are of interest BERGER (1923,') was the first one to recognize the interstitial nature of what he called “sympathicotropic" cells, these being true LEYDIG-cells It is not our purpose to discuss the whole problem of the sympathicotropic cells, let it suffice to recall their cxistence in the testicle, in the ovary, and in the vicinity of the gonads of various mammals, their close resemblance to paraganglionıc cells although they lack chromaffinity and argentaffinity (Van CAMPENHOUT), the fact that they seem to be born on the spot mixed up suth nerve fibers or to invade nervous bundles later on Where do these special cells exactly come fromThe apparently conflicting opinions of DE WINIWARTER (1910,*) and Berger 1915, seem to support the observations made bs VAN CAMPENHOUT thus juthor (1917, 56) demonstrated in 1 series of human embryos the presence of argentaffine cells in the neries and ganglia near the testicle and the ovary up to the 10 cm stage, from this stage on, up to the 19 cm stage for the ovary, and 22 cm stage for the testis, the nerves do not show anything but fibers and SCHWANY as well as endoneural cells Later on cells make their appearance inside the hilar nenes and become similar to the interstitial cells proper of the testis and the orary such cells may well des elop from the neurectoderm ging risc to the neric sheath, the cells born in the gland itself (De WINIWARTER & SAINYONT, 1909, for the ovary) arise from young mesenchyme cells of the strom a much in the same way as the epitheloid cells of the primary arterial wall make their appearance in the lidncy In a study of the testis in infancy and childhood, GRUENWALD (1946, ) remarked, when many interstitial cells disappeared shortly after birth, the presence of cell forms which may be stages by which they are transformed into connective tissuc cells As it seems to happen with the kidney, do neoplastic processes tell us anything about the nature of these cells? The wholc subject of tumors in testes and ovaries is terribly confusing The LEYDIG-cell tumors are not usually difficult to recognize, typical malignant tumors are very scarce (Massov, 1913, "), typical benign tumors are more frequent It appears from a review of the liternture that some LEYDIG-cell tumors were labelled hs pernephroma As a matter of fact corticosurrenal rests or nests may be found in the vicinity of the gonads (SCHILLER, 1942, 63, O'CROWLEY & Rust, 1913, ', Harley, 1917,", VAN CAMPT VHOUT, 1947, 5 etc) On the other hand LEY DIG-cells may be found elsewhere than in the normally located testes and ovaries (ISBERI E, 1934, ", NELSOY, 1938, "and so forth) This led IyyFs (1942, 5) to the following conclusions, discussing neoplastic diseases of the testis in animals As is the case of true tumours of min, the cells of thc benign tumour of the call included in the present series show such a striking resemblance to ·The 11 66 THE NERVE SUPPLI TO THE KIDNEY normal interstitial cells that their origin seems fairly certain The concept that this type of tumour is "hy pernephromatoid" in nature is unnecessary tumour cells oft that ad responsible for the idei oi the existence ot an hypernepliroma testis It might therefore be suggested that the so called adrenal rests of the testis are in fact interstitial cells deposits Indeed the whole idea of an hypernephroma testis rests on a very insecure foundation For us the discussion would be useless if we admitted that the argentiffin and chromaffin cells, SCHWANN-cells, sympathicotropic cells and some at least of the LEYDIG-cells and adrenocortical rests, represent only tarjous aspects of a same fundamental material, the neurectoderm guving rise to an ectomesenchyme The coexistence in the testis of a newborn of intranerı ous sympathicotropic cells and a nest of pheochromic cells (BERGER, 1935, 's) is readily explained by the same hypothesis VAN CAMPENHOUT and WITSCHI state in 1948 (197) Adrenocortical, interstitial and thecalcells are closely related, embryologically and cytologically" This confirmed partly the view expressed by BERGER (1945, ") We therefore, concur on this point with yon TVINIWARTER, that the interstitial cells from the sixth month on become almost exclusively located in the theca interna of the deep atretic follicles > Can the link betueen adrenocortical rests and sympathicotropic cells be their common origin from ectomesenchyme if the corter of the suprarenal is of mesodermic origin? Recently, VELICAN (1950, 0) verified on 1 series of human embryos, foetuses, newborn and adults the ontogenic et olution of the cortex of the suprarenal He described a first plasmodial stage beginning after the 26th dar (5 to 6 mm embryo) and extending throughout the whole embryonic life coelomc epithelium starts budding along the mesenteric root and the cells in. sinuate betncen the aorta and mesonephros (Group I) The 7,5 mm embryo shows coelomic budding on the inner aspect of mesonephros (sexual germin. atre zone) (Groupe II), one portion of these cells coninbutes to the constitution of the gonads, another portion reaches the space between the aorta and mesonephros and forms the first "anlage" of the cortex of the suprarena) These cells form a coat to a vascular expansion in the same way as cpithelord cells coat the primary vessel pinched in BOWAN's capsule Around tlus portion the Group I cells form a second “anlage" (the adult cortev), the central zone (called androgenic zone by the author) is a temporary one, sts involution begins after birth and its place is finally taken by the concentration ·67 POSSIBIL REI ITIO\SHIP of chromiffin cells in the inner part of the suprarenal (the medullary) A thorough study of embryology (GRUENWALD 194?, ) shous 7 stage of anonymous mesenchyme between the coelomic proliferation of cords and the final differentiation of the cortex This may be the stage when ectomesen chymatous elements get mixed up with the purely mesodermic anlage as would happen with gonads The bulk of information we have seems to make our hypothesis worth in vcstig ating thoroughly It muy clarify greatly not only the embryology, histo logy and pathology of the lumbar area but also many problems of function It is an extended and more comprehensive version of the conclusion expressed by Aprrz (1943) fter a comparative study of renal and suprarenal tumors Die Gemeinsamkeiten beider Geschwulstformen werden am besten verstand lich wenn man eine gemeinsame Abstammung von Vesothel als Bildungs matcrial des Mierenblastems und der Vebennierenrinden anlage annimt He renched this conclusion after finally remarking the unduly high frequency of GRANITZ tumors in LINDAU S disease and tuberous sclerosis the bulk of his evidence pointed to a dysontogenic origin of GRAWITZ tumors but not due to embryonic inclusions in the sense of CONVIIEIS L ·CHAPTER V Significance of the nervous consiluent of the hidney THUSFAR we have mostly described morphological findings concerning the Intrarenal neurogenic elements We shall try to clucidate their possible signficance by comparing them to data provided by physiology and cxperimental pathology Summing up the various observations we are impressed by the special significance of the juxtaglomerular apparatus Our first conclusion however is that the kidney is closely linked to nervous elements it has a definite characteristic of "neurility" Such "neurility" is shown all over the organ by the extensive nerve supply to the vessels without which vessels the nephron is meaningless, in the kidney the vessels have particular importance because of the excretory function proper to this organ On the background of generalized "neurlty" no local. ized structures stand out the intra cnous nem e endings, 2 the juxtaglo merular apparatus As intravenous nerve endings seem to disappear after birth, and as the juxtaglomerular apparatus seems to acquire its extreme differentiation after birth, one wonders of these tho structures are not com plementary elements of a regulatory mechanism The analysis of each structure VEIN TRA BLOMERULUS Fic 45 Semi diagrammatic Jrawing to emphasize the relationship between the intrarcnous nerye endings, the perivascular plexus and a glomerulus New born mouse Sther impregnation seems to support this hypothesis In a previous discussion of the possible meaning of intravenous nene endings, we reached the conclusion that they 68 ·SIGNIFICANCE OF THE NERVOUS CONSTITUET 69 could not be anything but sensory organs reacting to the modifications of the blood flow and the chemical changes in the blood They would initiate reflex actions regulating the blood supply to the nephron, the effectors being the muscles of the vascular walls The analysis of the juxtaglomerular apparatus is more difficult If we first confine ourseli cs to the macula densa, uc may point ALLIGATOR 0 A. MOUSE AA AFFERENT ARTERIOLE 116 46 diagrammatic comparison between the changes occuring in the myocytes of the arterial media in the hilum of the kidncy of the alligator and along the afferent arteriole of the mouse out that it is nearly constant feature in the periphery of thic corter. It is always located in the same place in the wall of the T.C II, affi\cd to the sascular pole of the glomerulus It is in cry close connection with the urine (diverticula of the lumen) and the underlying structures (opening up of the basal reticular meshuork), for all c know it is quite similar to a sensory epithelium and the nenes running along its basis supply the wall of the glomerular arterioles I ·70 THE NERVE SUPPLI TO THE DIDNFY scems thus probable that it intiates short refles actions by influencing the arterolar walls, acting more or less like the intravenous nerve endings found at the earlier stages This possibility is emphasized by the definite local modıfications of the arteriolar walls suggesting a special function of the modified muscle cells (epithelioid cells and micromuscular sphincter) The epithelioid cells have an endocrine appearance, previous investigations (alligator) suggest that they belong to the neuro-endocrine group, they thus provide a mcchanism for changes in the glomerular vascular bed Such changes as vascular con striction of long duration may lead to nephrosclerosis Before reaching a nephrosclerotic stage, the kidney adapts its function to the needs of the whole organism It reacts to humoral and nervous stimuli or botlı, and its reaction is immediate We do not intend to review the renal physiology and physiopathology from the viewpoint of the nerve supply to the kidney We shall briefly mention HABIBURGER's monograph (1936,9") on "Physiology of renal innervation' A revien of the literature, and personal caperimental researches, lead this author to deny the existence of any secretory nerves the various reactions to interference with the nervous system are readily understood by purely vasomotor changes, some of these vasomotor changes, though, appear difficult to explain, such as difference in behavior of renal arteries on one hand, and arterioles and capillaries on the other hand, certain cases of anuria or oliguria, uremia, and high blood pressure, which are less mysterious to day The influence of the nervous system on renal pathology, which is secundary in HAMBURGER's study, is the main subject of the monograph by REILLY and co-workers (1942, 5), these authors succeeded in reproducing a large field of human pathology by their experiments of acute and chronic irritation of the renal nerves, they induced chronic glomerulo-nephritis with hematuria, uremia and high blood pressure leading to final nephrosclerosis TRUETA and co-workers (1947, '87) made a refined study of renal circulation which taught us the mechanism of the medullary shunt of renal blood and the direct bearing of nervous action on this shunt by way of the splanchnic nerves VAN GELDEREN (1949, 902) studied the physiology of kidney innervation on patients submitted to splanchnicectomy or enervation of the kidney He does not present a conclusive evidence of the existence of proper tubular nerves The extended conception of a neurogenic contribution to the hidney fits well in the picture and the notion of a juxtaglomerular regulating mechanism proves useful The way the glomerulus shuts off or opens may explain clinical pathology, a good example of this is the problem of renal hypertension The bearing of this reaction on the onset of high blood pressure is open to discussion We must consider a few points 1 The juxtaglomerular complex is usually more des eloped in the peripheral part of the renal cortex, than in its deep layers ·SIGNIFICANCE OF THE VERVOUS CONSTITUENT 71 . TRUETA and his co workers have shown that by a reflex action, ischemia of the outer layers of the renal cortex may be produced The reflex iisoconstric tron seems thus more severe where the juxtaglomerular complexes are more dercloped, which is in kecping with the view that these structures are reflex centers regulating the circulation through the glomerul: 3 Trueta's experiments where made in an attempt to reproduce the "cruslı syndrome' in which there is anura and high blood pressure 4 Ischemiz of the kidney produces high blood pressure (GOLDBLATT & (193-4,& sq)] Thus reflca ischemız of the renal cortex may well be the cause of high blood be of endocrine ongin (experiments with transplanted hidncys, isolation of renin, anciotonin, etc) The question immediately priscs where does the hypertensie hormone come from? We have no definite answer to this question yet Two poss! bilities are open The epithelioid cells of the arteriolar medu (GOORNACHTIGH), 2 Eprtliclial cells (rom the nephron, either in the normal nephron, or in the so called BECHER , FEYRTER , PETFR cells (free islcts cells) Morphological studies show no fundamental difference between the islct cells and some normal tubular cells Miodiſied muscle cells and tubuloid cells have both been supposed to sccrcre an hormonc modifying the tonus of the vascular walls Whichieser of these cells are endocrine, one supposes that under conditions of abnormal stimulation they secrete in excess of vasoconstricting hormone, thus producing a generalized fugh blood pressure (in the acule phase) Morcover are the tubular cells and cpstheloid cells so differene? 1 The muscular coat of the glomerular arterioles arises from the loose mesenchyme from which the S shaped tubular sketch also diferentiates Thuis mcscnchi mitous appearance, of course, may be a know a mask put on different celts 2 The curly muscular coat is cpithelord 3 It may become granular and secretory the 4 Smooth muscle cells of the media may bud and producc paraganglionic lihc structures which are closely related to nesses in cpitheloneural bodies On the other hand wc know the neurogenic potentiality of the nephronic anlage liter all the tubular cells of the macular segment and the epitheliod cells of thic juxtaglomerular arteriole mas both arise from an cctomesenchyme, and both secrete one or several formones regulating the blood flow through the ·72 THE NERVE SUPPLY TO THE KIDNEY glomeruli An exhaustive discussion of this subject would lead us much too fır, and is beyond the scope of our work The endocrine secretion does not explain the renal hypertension of long standing, although it explains the acute one, such as in cclampsia or nephritis (scarlet fever, etc) The removal of ischemic kidneys after a certın lapse of time does not cure hypertension, the mechanism of which seems different Knowing the extensive innervation of the blood vessels of the kidncy, we wondered if these vascular walls were not sensitive areas, like the carotid sinus and aortic areas regulating the blood pressure In the cardio-aortic and carotidal zones, a local decrease in blood pressure, initiates a reflex by which the inhibition of the centers in the brain stem is lessened and the systemic blood pressure elevated The reverse is also true, a local increase in blood pressure in the cardio-aortic and carotidal zones, stimulates the depressor nerves, in creases the inhibition of the centers, and decreases the systemic blood pressure The complete section of the depressor nerves produces a permanent luigh blood pressure in the kidney, the narrowing of the renal artery decreases the blood pressure in the renal vascular bed and is followed by high blood pressure Wc do not know the effect of increasing the blood pressure in the renal vascular bed On the other hand, we know that in parabiotic twin rats, a bilateral nephrectomy in one of the twins produces a high blood pressure in that twin exclusively, this postulates a non humoral mechanism and a purch nenous action “The effect of denervation of the kidneys on systemic blood pressure seems to amount to nothing “High blood pressure may be produced by narrowing the renal artery of a denervated or transplanted kidney These two propositions seem to ruin the comparison betucen the depressor arcas and the renal area The second proposition, as matter of fact, does not exclude the existence of renal depressor neries, the existence of an endocrme activity is demonstrated now, and if tuo mechanisms exist, it seems that the endocrine one is working in this case, the nerves being disconnected So we are left with the first objection Let us assume for the sake of argument that we have renal pressosensitive areas, working in the same way as the cardio aortic and carotidal zones What would one expect from a complete deneration of both kidneys? No depressor impulses will reach the centers from the renal arcas and the blood pressure should be elevated But, at the same time, if still ponerful impulses arise from the juxta-cardı?c zones the vasomotor centers are main tained at a low level of action The problem is thus a question of deciding wluch are the most powerful impulses If the cardio-aortic and sino carotidal ones are the most powerful, the negative result of denen ation of the kidney is well explained, but if this is the case how can one explain the hypertensic effect of 39 ·SIGNIFIC I\CE OF THF VERVOUS CO\STITUENT 73 prolonged ischemır of the kidney Two points must be taken into views I ischemia produces first endocrine hypertension, and the hormone may also modify the reactivity of the centers, which may become regulated to high ischemia, and low intrarenal blood pressure, produces a continuous decrease of the inhibitor impulses from the kidney, thus slowly upsetting the is established, the kidneys may be removed without relieving the disease of the central vasomotor areas The experiment on parıbiotic twins excludes an hor monal factor and postulates the existence in the hidney of some sort of a sensory zone producing depressor cffects the onset of high blood pressure makes one wonder what the activity of the juxta cardınc depressor nerves muy be in this case, the only possible answer being that they are overwhelmed by the pressor demand arising from the renal area Heymans and ROUCKAERT (1939) studied experimental high blood pres sure from both vicwpoints of renal ischemia and exclusion of cardio aortic and sino carotidal nerves Their very interesting results may be summarized as follows 1 Section of cardio aortic and sino carotidal nerves which by relies tonus action Acep the blood pressure at a moderate le cl, initiates ? severe hypertension of long duration by a ncurogenic, sympathetic mechanism The kidnev is apt to secrete in the circulating blood a vasoconstrictive sub stincc which at the same time, lessens the tonus of the nerves depressing the blood pressure it thus produces 1 high blood pressure 3 A By total sympathectomy (except of the kidneys and suprarenals) the not clisconnected sympathetic is hyperstimulated but docs not produce high blood pressure Section of cardio hortic and sino carotidal nenes in this case lets loose progressive hypertension of long duration although it is completely uneffective in totalls sympathectomized dogs C Renal sympathectomy exclustely reduces blood pressure to normal levels We are thus faced with a high blood pressure of an exclusively neurogenic and renul origin (insospastic) although it is necessarıls humoral in its peripheral mechanism alter in extensive sympathectomy In relation to the previous dis cussion it is interesting to note that the depressor nen es is such (carotidal and cardio zortic) may become hypotonic under the influence of renal ischemir renal ischemi thus activates hypertensive reflexes (BOL CRAFRT, I LAUT & HEIMAS 1937 D ·74 THE VERVE SUPPLY TO THC LIDES To sum up the function of the juxtaglomerular apparatus, on The modified muscle cells have an endocrine appearince and ar the suprarenal like cells found in the hilum of the kidney They m viscular hormone for the glomerular tuft, in hypersecrction of this followed by the flooding of the general circulation by it, followed E striction and hypertension The secretion of this hormone may be re various ways some characteristics of the blood flowing through the be adequate stimul the nerves of the artcriolır wall muy influenc fied cells reacting to stimulı arısing in the kidncy itself (short reflex macular urca, for instance) or outside the kidney (long reflexes fo splanchic nerves) The endocrine substance would act on the mic cells and other contractile cells present in their vicinity A prolo construction will bring the degeneration of the glomerular tuft and the glomerular vessel as such It should be emphasized that in a nor oning kidney the role of the macula densa is very important adapt culation through the nephron to the composition of urine (this either by a nervous or by an endocrine mechanism) As we said previously the hypertension may also be the result of of other vasosensitive zones but in the long run when nephrector relieve the high blood pressure any more the disease is probal localized to the brain stem and mechanically incurable ·BIBLIOGRAPHY B This list is by no means exhaustive, the reader will find here the publications quoted in the text, and some other ones which may help him if he cannot find the literature se mention 1 ANINOTO, K, T, Jap Path Soc 28 321-324, 1928 2 APTZ, K, l'irchow - Arch f path inat, 311 285 431, 1943 3 APPELT, H Zische ſ miki anat lorsch, 45 179-197, 1939 4 Azot LAY, I, ramp! rend soc de brol , 46 336 338, 1891 Azour AY, 1,, Compt rend Soc de brol , 47 590-591, 1895 6 BARGUAY W, Zischr Zellforsck u miks Inet, 26 761-788, 1937 7 BAVAY, 1, Descloppement et Inatomie du Systeme nen cux du Poumon cher Ilfomnc et les Vertebres superieurs Thèse de Gerece, Ivo 204 pp. Impriinerie du Journal de Genese, 1940 8 BALM414, 1, Compt rend Soc de phys et d'histoire naturelle de Gencir, 58 74 78, 1975 BENER, H. 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·80
THE NERVE SUPPI Y 10 THE KIDVES
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195 VAN CAUPENHOUT, E , Acta Anal , 4 73-78, 1947
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197 VAN CAMPENHOUT, L & WITSCHI, C, J Clin Endocrinol 8 273-274, 1948
198 VAN CAMPENHOUT, E, Re Canad de brol, 8 374-429, 1949
199 VAN GEURTRUYDEN, J, Arch de biol 57 145-181, 1946
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202 VAN GELDEREN, C, Heliet Chir Acta, 16 423-437, 1349
203
204
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208 YOUNG
209 YOUNG
210 YOUNG
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