Postgrad Med J: first published as 10.1136/pgmj.35.409.604 on 1 November 1959. Downloaded from 604

RENAL BIOPSY AND GLOMERULONEPHRITIS By J. H. Ross, M.D., M.R.C.P. Senior Medical Registrar, The Connaught Hospital, and Assistant, The Mledical Unit, The London Hospital

Introduction sufficient to establish a diagnosis in a few condi- Safe methods of percutaneous renal biopsy were tions such as amyloid disease and diabetic first described by Perez Ara (1950) and Iversen , but cortex with at least io and Brun (I95I) who used aspiration techniques. glomeruli is necessary for an accurate assessment Many different methods have since been described; of the renal structure; occasionally, up to 40 the simplest is that of Kark and Muehrcke (1954) glomeruli may be present in a single specimen. who use the Franklin modification of the Vim- The revelation of gross structural changes in Silverman needle. the kidneys of patients who can be recognized Brun and Raaschou (1958) have recently re- clinically as having chronic glomerulonephritis is viewed the majority of publications concerned of little value and does not contribute to manage- with renal biopsy and have concluded that the risk ment or prognosis. In contrast, biopsy specimensProtected by copyright. to the patients is slight. They mentioned three from patients in the early stages of glomerulo- fatalities which have been reported but considered , particularly those who have developed that, in each case, death was probably due to the the insidiously without disease process rather than the investigation. haematuria or renal failure or who showy no Retroperitoneal haematomata have been recorded evidence of disease other than proteinuria, may in patients with hypertension or uraemia but are provide useful information. The value of histo- unusual. Gross haematuria is uncommon (it oc- logical study in such cases is, however, limited by curred in 7.9 per cent. of 51o biopsy attempts by the interpretation of the significance of minor Brun and Raaschou, 1958, and 7 per cent. of ioo non-specific lesions. Insufficient time has passed biopsy attempts by Muehrcke, Kark and Pirani, since the introduction of renal biopsy to allow 1955). Pain in the loin following the procedure is many conclusions to be drawn as to the correlation also unusual. Although the procedure is simple, between such histological features and the sub- it should not be undertaken without careful sequent progress of the patients. instruction. The application of renal biopsy to the study of http://pmj.bmj.com/ The contraindications observed by those ex- glomerulonephritis will be discussed in this article; perienced in renal biopsy have varied considerably. many references to its use in other renal diseases A haemorrhagic diathesis is, of course, an absolute may be found in the review by Bnm and contraindication. Patients with , Raaschou (1958). pyonephrosis, renal tuberculosis or neoplasm, very small kidneys, only one or who are The Nephrotic Syndrome (Type U Nephritis) unable to cooperate, should not be submitted to Variations in and criteria, terminology diagnostic on September 28, 2021 by guest. the procedure. Most authors have considered as with so much of the literature of renal disease, uraemia a contraindication because of the asso- have made it difficult to compare the results of ciated haemorrhagic tendency, but Brun and different workers, especially when full case reports Raaschou (I958) have not found any significant have not been presented. increase in the frequency of haematuria after The term ' nephrotic syndrome' was first in- biopsy in II9 uraemic patients and, in fact; con- troduced by Leiter in I931 to differentiate the sider acute uraemia of unknown aetiology to be an association of massive proteinuria, oedema, hypo- indication for the investigation. proteinaemia and hypercholesterolaemia with Tissue, adequate for histological examination, renal disease such as glomerulonephritis from can be obtained in about 75 per cent. of cases. The ' lipoid ' which was considered to have specimen may be regarded as representative of the the same four features without hypertension, kidney except in focal diseases such as pyelo- nitrogen retention, an excess of red blood cells in nephritis. Very small fragments of tissue may be the urine or histological glomerular lesions. Postgrad Med J: first published as 10.1136/pgmj.35.409.604 on 1 November 1959. Downloaded from November 1959 ROSS: Renal Biopsy and Glomerulonephritis 605 lar lesions at present give the best indication of the subsequent progress which may be expected, but further study may reveal the significance of minor tubular and interstitial features. The finding of ...... generalized basement membrane thickening (Fig. i) or intercapillary hyalinization in the glomeruli probably indicates that recovery is impossible and that progress to renal failure with hypertension, even though it may be delayed for many years, is inevitable; the use of steroids for the treatment of patients with these lesions is usually disappointing. The recognition of small increases in basement membrane thickening is, however, difficult and, in ...;^°.',...l.... addition, Rich (957) has shown, in necropsy specimens, that the lesions may be more pro- nounced in the juxtamedullary zone than in the outer cortex; such considerations may cast doubt on the interpretation of some small specimens. The interpretation of minor focal lesions in the kidneys of these patients is even more difficult. Increase in tuft cells, basement membrane thickening, intercapillary hyalinization and capsu- lar adhesions are found diffusely or locally in occasional glomeruli but are not generalized Protected by copyright. (Bjornoboe et al., 1952; Kark et al., I955; Ross and Ross, 1957; Joekes et al., 1958). Recovery from the disease is still possible and the severity of the FIG. i -Glomerulus with diffuse basement membrane lesions may give some indication of the thickening. This feature was present in all of I5 subsequent progress of the patient; conclusions glomeruli in the specimen from a man aged 52 years beyond these are not yet possible. There has been with the nephrotic syndrome of seven months only one report of serial biopsies duration. Renal failure and hypertension have demonstrating developed. Heidenhain's Azan stain, x 310. that such minor lesions precede generalized base- ment membrane thickening (Joekes et al., 1958) but circumstantial evidence suggests that this may 'Nephrotic syndrome' is not a diagnosis in itself be a frequent structural sequence. It seems un- and should always be qualified by the associated likely that any small structural differences in these disease process or aetiological agent if these can be cases will be recognized by conventional micro- recognized clinically or histologically (Kark et al., scopy which will allow the histologist to foretell http://pmj.bmj.com/ 1958, listed 31 possible causes of the syndrome). recovery, a long benign course or progress to The condition, when no cause has been identified, renal failure. has been variously termed 'type II nephritis,' Some biopsy specimens from these patients 'lipoid nephrosis,' the 'uncomplicated' or 'idio'- show no glomerular lesions at all; again, recovery pathic' nephrotic syndrome or has been given a may occur but cannot be foretold with certainty. histological label according to the school of thought Prolonged follow-up of a large number of patients of the observer. In this article, type II nephritis is necessary before more definite conclusions can on September 28, 2021 by guest. will be the name used whether the fully developed be reached. Electron microscope studies (Far- lesions described by Ellis in 1942 (the mem- quhar et al., I957 a, b and c; Folli et al., 1958; branous or lobular glomerulonephritis of Allen, Brun and Raaschou, I958) have shown that an I95I and 1955) are shown to be present or not. abnormality of the glomerular epithelial cells may Amyloid disease may occasionally be revealed be found in biopsy specimens from patients with unexpectedly by biopsy in patients considered early type II nephritis (the authors used different clinically to have early type II nephritis (Bjornoboe nomenclature) even when conventional micro- et al., I952; Ross and Ross, 1957). This finding scopy has revealed no abnormalities. The charac- suggests a worse prognosis and may prevent teristic 'foot processes' of normal epithelial cells valueless treatment with steroids. (podocytes) disappear and the epithelial cytoplasm Patients with early type Ir nephritis, whose becomes closely applied to the basement mem- clinical features are similar, may be found to have branes of the capillary loops. This change has not strikingly different histological lesions. Glomeru- been noted in acute nephritis but it is still not clear Postgrad Med J: first published as 10.1136/pgmj.35.409.604 on 1 November 1959. Downloaded from 6o6 POSTGRADUATE MEDICAL JOURNAL November 1959 w.b 44 sI4 ......

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FIG. 3.-Case 2. Glomerulus with small areas of base- FIG. 2.-Case i. One of the most severely affected ment membrane thickening and intercapillary glomeruli in the specimen, showing intercapillary hyalinization adherent to Bowman's capsule. hyalinization and capsular adhesion. Periodic- Periodic-acid-Schiff stain, x 330. acid-Schiff stain, X 330. if its recognition can be used to differentiate a appeared after another four months and she has 'particular variety of nephritis or if it has any remained well for a further i i months. special functional significance. Folli et al. (1958) reported reversal of this lesion with recovery of a Case 2 patient from the nephrotic syndrome; they used A woman of 65 years, known to have had benign http://pmj.bmj.com/ the diagnosis 'lipoid nephrosis' for patients with essential hypertension without proteinuria pre- electronmicroscopic podocyte lesions but without viously, developed the nephrotic syndrome with- membranous glomerulonephritis. out impairment of renal function tests. A biopsy The following case notes illustrate some of the specimen, obtained I7 months later, contained 28 points which have been discussed. glomeruli; the majority showed minor lesions, as in Fig. 3. There was slight tubular atrophy and Case i diffuse collagenous increase of the interstitial A woman of 5I years developed the nephrotic tissue. Oedema persisted for many months but on September 28, 2021 by guest. syndrome without hypertension or nitrogen re- had disappeared and there was only very slight tention. A biopsy specimen, obtained two months proteinuria I9 months after biopsy, when she un- after the onset of oedema, contained i8 glomeruli; fortunately died from causes unrelated to her renal one was completely hyalinized but the majority disease. showed only slight hypercellularity with occasional increase in intercapillary material and a few cap- Case 3 sular adhesions (Fig. 2). The tubules were normal A Pakistani seaman, aged 4I years, developed and there was no increase in interstitial tissue. She gross proteinuria and oedema with hypertension -was treated with mercurial diuretics without but without haematuria. Six months after the response but had a large diuresis whilst receiving onset his renal function was normal (blood urea an ion-exchange resin. Four months after the 31 mg./ioo ml., maximum urine urea concentra- biopsy she was free from oedema, proteinuria dis- tion 25.2 g./l., creatinine clearance 98 ml./min.). Postgrad Med J: first published as 10.1136/pgmj.35.409.604 on 1 November 1959. Downloaded from November 1959 ROSS: Renal Biopsy and Glomerulonephritis 607 When a biopsy specimen was obtained two months later there was moderate renal failure (blood urea 6o mg./ioo ml., maximum urine urea concentration 13.2 g./l., creatinine clearance 34 ml./min.). I4 enlarged hypercellular glomeruli had many small areas in the tufts which were ad- herent to Bowman's capsule and contained in- creased intercapillary material and thickened capillary basement membranes. There was diffuse collagenous increase of the interstitial tissue and many convoluted tubules were dilated and lined by ragged vacuolated cells. The lesions of the K Aj.' tubules may have been related to potassium de- pletion present at the time of the biopsy. The glomerular lesions in this case were similar to those in cases i and 2 but were more intense and could be correlated with the more severe clinical features of the disease. When the patient was last seen, io months after the biopsy, renal failure was r far advanced. A Case 4

A renal biopsy specimen was obtained from a Protected by copyright. boy aged nine years who had had the nephrotic syndrome for three and a half years with slight occasional hypertension but without haematuria or impairment of renal function. Immediately prior a FIG. 4.-Case 5. Glomerulus which is normal apart to the biopsy, massive diuresis, accompanied by from capsular adhesion and very slight adjacent diminution in proteinuria, followed a course of hyalinization. Heidenhain's Azan stain. X 370. ACTH. Treatment with prednisone was con- tinued until seven months after the biopsy, when he lost proteinuria and was well in every respect. been considered to be due to benign essential The specimen contained 14 glomeruli, four of hypertension. which were completely hyalinized. The re- A renal biopsy specimen was obtained three mainder were normal apart from occasional cap- years after proteinuria had ceased. There were no sular adhesions and a few small areas containing abnormalities in the eight glomeruli examined increased cells and intercapillary material or slight apart from a few capsular adhesions associated with http://pmj.bmj.com/ basement membrane thickening. The tubules were slight focal increase in intercapillary material normal but there was slight diffuse interstitial (Fig. 4). There were no tubular abnormalities but fibrosis. there was very slight focal interstitial fibrosis. These findings were of particular interest, The abnormalities in the glomeruli of this small demonstrating that recovery can occur in spite of specimen were considered to be the healed remains focal glomerular hyalinization. It is possible that of focal glomerular lesions. It is much more likely the higher recovery rate in children with type II that diffuse basement membrane thickening had nephritis is due to the disease remaining focal. never developed, even after four years of the on September 28, 2021 by guest. Prolonged observation is necessary before re- disease, rather than that it had been pre3ent and covery can be considered complete, as relapses had resolved. havre been reported many months or years after loss of proteinuria (Rennie, 1947; Roscoe, I956). Case 6 A man of 34 years was found to have heavy Case 5 proteinuria when he attended hospital with a com- A woman, aged 49 years, developed the neph- plaint of backache. He had never had oedema, his rotic syndrome which persisted, with intermittent blood pressure was normal and renal function tests gross oedema, for four years and then resolved were unimpaired. A biopsy specimen showed IO completely. She has remained well, without of I7 glomeruli to be completely hyalinized; the proteinuria, for a further five years. Raised blood remainder had diffuse basement membrane pressure, present during and since the disease, has thickening and patchy intercapillary hyalinization Postgrad Med J: first published as 10.1136/pgmj.35.409.604 on 1 November 1959. Downloaded from 6o8 POSTGRADUATE MEDICAL JOURNAL November I959

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FIG. 6.-Glomerulus with intercapillary fibrillar ma- FIG. 5.-Case 6. Glomeruli with basement membrane terial. The specimen, from a man of 47 years, was thickening and intercapillary hyalinization. Focal taken during recovery from acute nephritis whilst tubular atrophy and dilatation. Interstitial fibrosis. proteinuria and impairment of renal function tests Periodic-acid-Schiff stain, X IOO. were still present. Four months later he was well in every respect. The glomeruli were also hyper- cellular with a slight excess of polymorphonuclear leucocytes in the tufts and there was focal perivas- (Fig. 5). There was focal tubular atrophy and cular fibrosis. Periodic-acid-Schiff stain, X dilatation as well as interstitial fibrosis. 230. This illustrates the value of renal biopsy in patients with proteinuria of obscure origin, for the and histological features. The finding ofgeneralized lesions were those of fully developed type II ' irreversible' changes in the glomeruli was con- nephritis and indicated a poor prognosis with sidered to indicate a hopeless prognosis in six http://pmj.bmj.com/ eventual renal failure. cases. The authors were surprised to observe ' chronic' collagenous glomerular lesions in some Acute (Type I) Glomerulonephritis specimens; these may have been due to previous Hutt et al. (1958) have studied renal biopsy renal disease or it is possible that such lesions specimens from I5 patients diagnosed clinically as develop more rapidly than was previously thought having acute glomerulonephritis (three had no possible. proteinuria or haematuria). They found a The demonstration of intense inflammatory and reasonable correlation between the severity of the necrotic lesions in the kidneys of patients with on September 28, 2021 by guest. clinical and of the histological features. The severe acute nephritis is not unexpected. It will glomerular tuft lesions were those which have be of more value if structural changes can be been described previously in post-mortem material recognized which will allow differentiation between but the three atypical cases mentioned above only mild cases who will recover and mild cases who will had minor changes in the cells of Bowman's progress slowly to renal failure. Hutt et al. (1958) capsule. Impairment of renal ability to concen- obtained one specimen six weeks after the onset of trate was correlated with the severity of the oedema and haematuria and about four weeks tubular lesions. after recovery had commenced; only slight pro- Brun et al. (1958) obtained biopsy specimens liferative changes and a patchy increase of periodic- from 9 to 49 days after the onset of symptoms in I3 acid-Schiff staining fibrils were present in the patients with acute glomerulonephritis. Again, glomeruli. The author has observed similar there was a good correlation between the clinical lesions in specimens from two patients recovering Postgrad Med J: first published as 10.1136/pgmj.35.409.604 on 1 November 1959. Downloaded from November 1959 ROSS: Renal Biopsy and Glomerulonephritis 609

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. FIG. 8.-Another part of the specimen shown in Fig. 7. FIG. 7.-Part of specimen from a boy aged I5 years who Glomerulus with capsular adhesion. Red blood had had at least six attacks of haematuria during the cells in capsular space and in adjacent convoluted i8 months preceding biopsy. There is increase of tubules. Increase of interstitial tissue. Haema- interstitial tissue with focal chronic inflammatorv toxylin and eosin, x 410. cell infiltration and two glomeruli show ischaemic changes with shrunken tufts and thickened cap- sules. Haematoxylin and eosin, x IOO. specimens from nine patients with very mild from the acute stage of the disease (Fig. 6); one nephritis associated with acute pharyngitis. Clini- of them has made a complete recoverv, the other cal and immunological studies excluded recent still has slight proteinuria one year after biopsy. group A haemolytic streptococcal infection and Perhaps the finding of collagenous glomeruli or haematuria alone was the predominant feature of http://pmj.bmj.com/ diffuse interstitial fibrosis will be correlated with the disease. The glomerular le3ions were mild ana failure to recover and a slowly progressive course, focal and were contrasted with the more severe when more patients have been studied. proliferative lesions observed in specimens from Farquhar et al. (I957 b and c) have described patients with typical acute nephritis following the electronmicroscopic glomerular lesions in group A haemolytic streptococcal infections. The acute glomerulonephritis. In the early stages the mild disease was presumably acute 'focal neph- ritis' occurring at the height of an unidentified hypercellularity was found to be mainly due to an on September 28, 2021 by guest. increase in the number of the endothelial cells. infection. The cytoplasm of both epithelial and endothelial Ross (1959) has studied five specimens from cells was swollen but the foot processes were nine patients with recurrent focal nephritis. This normal except in severely affected areas. Material unusual disease, which occurs in young patients, is resembling basement membrane substance and characterized by repeated attacks of haematuria believed to originate from endothelial cells ac- without oedema, hypertension or nitrogen reten- cumulated within the tufts; this is probably the tion. Following a number of attacks, which can be material forming the P.A.S. fibrils seen on conven- initiated by a variety of infections, proteinuria may tional microscopy and which may accumulate persist. Renal function remains normal even after sufficiently to form 'hyaline' glomeruli. many years. The glomerular lesions are focal and consist of small areas in the tufts containing in- Focal Glomerulonephritis creased cells and intercapillary material with asso- Bates et al. (I957) described renal biopsy ciated adhesions to Bowman's capsule. Intersti- Postgrad Med J: first published as 10.1136/pgmj.35.409.604 on 1 November 1959. Downloaded from 610 POSTGRADUATE MEDICAL JOURNAL November 1959 tial inflammation also occurs and after BIBLIOGRAPHY repeated ALLEN, A. C. (gs19), 'The Kidney: Medical and Surgical attacks the structural damage may be quite severe Diseases,' Grune and Stratton, New York, Ist ed. (Figs. 7 and 8). Long-term treatment with peni- ALLEN, A. C. (i955), Amer. J. Med., 18, 277. and short courses of steroids have not been BATES, R. C., JENNINGS, R. B., and EARLE, D. P. (1957), cillin Ibid., 23, 50o. found to prevent or shorten the attacks of BJORNEBOE, M., BRUN, C., GORMSEN, H., IVERSEN, P., haematuria. and RAASCHOU, F. (1952), Acta. med. scand., I42, 233. BRUN, C., GORMSEN, H., HILDEN, T., IVERSEN, P., and RAASCHOU, F. (1958), Ibid., x60, Is5. Conclusions BRUN, C., and RAASCHOU, F. (1958), Amer. J. Med., 24, 676. ELLIS, A. (1942), Lancet, i, I, 34, 72. Renal biopsy may occasionally be a considerable FARQUHAR, M. G., VERNIER, R. L., and GOOD, R. A. (I957a), in Amer. J. Path., 33, 791. aid to diagnosis and prognosis individual FARQUHAR, M. G., VERNIER, R. L., and GOOD, R. A. (I957b), patients with glomerulonephritis. Frequently, Sckweiz. med. Wschr., 17, 50. FARQUHAR, M. G., VERNIER, R. L., and GOOD, R. A. however, the lesions revealed are either those that (I957c), J. exp. Med., Io6, 649. might be expected from a study of the clinical FOLLI, G., POLLAK, V. E., REID, R. T. W., PIRANI, C. L., features or are to in- and KARK, R. M. (1958), Ann. intern. Med., 49, 775. insufficiently specific give HUTT, M. S. R., PINNIGER, J. L., and DE WARDENER, H. E. formation of immediate value to the clinician. (I958), Quart. J. Med., 27, 265. Further detailed studies with observa- IVERSEN, P., and BRUN, C. (i951), Amer. J. Med., II, 324. prolonged JOEKES, A. M., HEPTINSTALL, R. H., and PORTER, K. A. tion of the patients and the new techniques of (i958), Quart. J. Med., 27, 495. and KARK, R. M., and MUEHRCKE, R. C. (1954), Lancet, i, Io47. electronmicroscopy, histochemistry antigen- KARK, R. M., MUEHRCKE, R. C., PIRANI, C. L., and antibody reaction localization (Mellors and Ortega, POLLAK, V. E. (1955), J. clin. Invest., 34, 944. should lead to which will in- KARK, R. M., PIRANI, C. L., POLLAK, V. E., MUEHRCKE, 1956) knowledge R. C., and BLAINEY, J. D. (1958), Ann. intern. Med., 49, 751. crease the value of the procedure. LEITER, L. (I931), Medicine (Baltimore), o0, 135. MELLORS, R. C., and ORTEGA, L. G. (r956), Amer. J. Path.,

32, 455. Protected by copyright. Acknowledgments MUEHRCKE, R. C., KARK, R. M., and PIRANI, C. L. (I955), I am to Professor Clifford Wilson and .. Urol., 74, 267. grateful PEREZ ARA, A. (1950), Bol. Liga Cdncer (Habana), 25, 121. Professor Dorothy Russell for permission to quote RENNIE, J. B. (I947), Quart J. Med., I6, 21. cases studied at the London Hospital and to re- RICH, A. R. (1957), Bull. Johns Hopk. hosp., 100, 173. in the Bern- ROSCOE, M. H. (I956), Quart..7. Med., 25, 253. produce microphotographs prepared ROSS, J. H., and ROSS, I. P. (1957), Lancet, ii, 559. hard Baron Institute of Pathology. ROSS, J. H. (1959), publication in preparation.

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Bibliography continuedfrom page 603-A. A. G. Lewis, B.Sc., M.D., M.R.C.P. SMITH, HOMER W. (x956), 'Principles of Renal Physiology,' VANDER, A. J., MALVIN, R. L., WILDE, W. S., and New York, O.U.P. SULLIVAN, L. P. (1958), Amer. J. Med., 25, 497. SMITH, HOMER W. (1958), Bull. N.Y. Acad. Med., 35, 293. WALKER, A. M., BOTT, P. A., OLIVER, J., and MAC- M. Amer. F. (1958), Helvet. med. Acta, 25, 5I6. DOWELL, (I941), J. Physiol., 134, 580. REUBI, DE WARDENER, H. E., and HERXHEIMER, A. W. (1957), RHODIN, J. (1958), Amer. Y. Med., 24, 66i. .7. Physiol., 139, 42. TRUETA, J., BARCLAY, A. E., DANIEL, P. M., FRANKLIN, WINTON, F. R. (1956), in ' Moder Views on the Secretion of the K. J., and PRICHARD, M. M. L. (I947), 'Studies of the Urine,' London, Churchill. Renal Blackwell. WIRZ, H. (x954), in the Ciba Foundation Symposium on the Circulation,' Oxford, Kidney, London, Churchill. ULLRICH, K. J., and JARAUSCH, K. H. (1956), Pflug Archiv. WIRZ, H. (I956), in 'The Neurohypophysis,' Butter- ges. Physiol., 262, 537. worth's Scientific Publications. London,