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The Value of Renal Biopsy
The Value of Renal Biopsy Liliane Morel-Maroger, M.D.
T
HE VALUE of the renal biopsy has recently been questioned, especially in the American scientific literature, and several groups of established clinicians in the U.S. regard renal biopsy as a hazardous and unnecessary luxury . This has led several renal pathologists to critically reexamine their own activity. From an experience based on the examination of 8000 renal biopsies between January 1964 and August 1981, I have obviously a biased point of view, as it is humiliating to find out that one's permanent activity has mainly been devoted to a useless hobby . I will however try to review briefly the implications of following renal patients with and without a renal biopsy. The use of renal biopsies requires a very close cooperation and understanding between renal clinicians and pathologists. These latter should sometimes remember that the aim of pathology is to communicate in an understandable and easy manner what they have seen through a microscope. The replacement of some simple words in a conclusion by numbers and subgroups may lead to terrible confusion . For instance the recommendations of WHO to assess a renal biopsy may lead to the following type of reports: patient "Mr Smith is II a, i b 34, " and if I were a clinician I would prefer to read "Mr. S . has a focal glomerulonephritis involving 1,4 of the glomeruli, with lesions of moderate severity and little damage of tubes, interstitium and vessels. " There are some circumstances in which renal biopsy should be performed rapidly and the result used for therapeutic purposes, and I will briefly review these in this article. On the other hand, while some biopsies are probably of no practical immediate use to the patient, they add to the general knowledge, and contribute to the advancement of nephrology in general. For the present article I will only review the use of renal biopsies in a population of adult patients. Although needle From the Service de Nephrologie, lnstitut National de la Sante et De La Recherche Medicale. (Dir. ProfG. Richet.) Reprint requests should be addressed 10 Liliane MorelMaroger. M.D. , lNSERM(U 64) , Service de Nephrologie, Hopital Tenon , 4 Rue de la Chine, 75020. Paris, France. © 1982 by Th e National Kidney Foundation , Inc. 0272-63861821040244-05$01 .0010
244
renal biopsies are easily performed, they should not be done by junior residents or fellows unless this is part of their training as future nephrologists. This procedure, safe in the hands of trained physicians , can be a source of accidents and pain when this is not the case, and the quality of the fragments of renal tissue obtained is largely dependent upon the experience of the operator. In addition the renal biopsy should be performed either in the presence of the renal pathologist (I do most of the biopsies myself) or one of the representatives of the laboratory to make sure that the renal tissue is properly treated from the beginning. A sufficient piece of cortex must be available both for light microscopy and immunofluorescence . Ideally two or three glomeruli should also be fixed for electronmicroscopy (EM), although I do not think that it is compulsory to have EM if the aim is to achieve a diagnosis. In 95% of renal biopsies a diagnosis can be achieved with the combination of good reliable light microscopy and immunofluorescence. However any work involving research would considerably benefit from ultrastructural examination. For light microscopy we use Dubosq-Brazil's fixative (Alcoholic Bouin), but Helly, corrosive formalin and Carnoy's also give good results. However, whatever the fixative chosen, thin slides of 2-3 microns, and serial sections are necessary. We always keep a few thick sections (5-10 microns) to look for amyloidosis. Numerous stains are also required: systematically haematoxylin-eosin. PAS, silver stain, Congo red , and a good trichromic stain (Masson's trichrome with light green is convenient). At least 20 sections from one renal biopsy should be examined in detail using high magnification which will show most of the glomerular lesions except minimal anomalies of the glomerular basement membrane. For fluorescence, we remain faithful to fluorescein or rhodamin, as peroxidase seems more difficult to handle properly. Also with fixed tissue further treated by trypsin, the results are less satisfactory at present than those obtained with snap frozen tissue cut in a cryostat, but hopefully in the future , paraffin embedded material may be used both for light microscopy and im-
American Journal of Kidney Diseases, Vol. I, No.4 (January), 1982
245
VALUE OF RENAL BIOPSY
munochemistry. Directly fluorescein or rhodamin labeled antisera are applied after the usual controls have been performed: anti IgG, IgA, IgM, C3 , C 1q , fibrinogen-fibrin, kappa, lambda allow a categorization of most findings in some of the current groups of disease . 1·7 . 13 The indications for renal biopsy should be weighed against the potential dangers of this procedure in all the usual clinical syndromes. It is difficult to accept the idea recently expressed that it is less dangerous to blindly treat a patient with 1 or 2 mg/kg/24 hr of steroids, sometimes in combination with cyclophosphamide, than to do a renal biopsy in an acutely ill patient. If necessary a renal biopsy should be processed and read within 2 days . Finally it is important to distinguish the circumstances in which renal biopsy is necessary to take therapeutic measures, from those in which this is useful in a more prospective way, for instance in therapeutic trials. In adult patients biopsies are necessary for diagnostic purposes in the following syndromes: nephrotic syndrome, acute failure of unknown or doubtful etiology, nephrotic syndrome , rapidly progressive renal failure, and a large number of systemic diseases sometimes in the absence of renal symptomatology. A discussion of these areas follows . NEPHROTIC SYNDROME (NS)
The policy which is adopted by pediatricians is not applicable to adult patients, as the proportion of lipoid nephrosis is smaller, and therefore steroids should be given in cases identified on a morphological basis. The most common lesion in adult NS is membranous glomerulonephritis (GN) and it is still questionable whether steroids affect the natural course of this disease , benign in some series , more severe in others . In addition , the finding of membranous GN in an elderly subject must lead to extensive search for cancer, and it is not exceptional (F. Mignon) that NS reveals an epithelial cancer at a stage where the lesions are still reversible. The other lesions which may be found in adult NS are minimal changes or focal hyalinosis, and in both these lesions the absence of deposits of immunoglobulins and complement along the glomerular basement membrane (GBM) allows an early differential diagnosis with membranous GN , even in the absence of silver stained spikes . Membranoproliferative ON (MPGN) is not a
very common disorder in adults . Dense deposits are very rare, whereas subendothelial deposits are more common. In this latter condition some histologic and fluorescent particularities may give an insight on an associated underlying disease which may not be obvious . For instance extensive deposits of IgA and C3 are often a good marker of a liver disease with MPGN: the association of numerous polymorphs with.extensive granular deposits of C3 may suggest an underlying bacterial disorder whose cure may reverse the course of the ON . Amyloidosis is far from exceptional. In the light of recent work amyloidosis may be the marker of a plasma cell disorder , sometimes in the absence of a circulating Ig spike, indicating the presence of a monoclonal gammopathy , which may be controlled by specific treatment. Also if amyloidosis is of AA type, extensive search for an etiology may be helpful in the future management of the patient. The discovery of amyloidosis usually counterindicates the use of steroids. Finally renal biopsy in nephrotic patients may show unexpected lesions . This has been the case in several patients who had light chain systemic deposition , a group of diseases which is recognized with increased frequency. It is noteworthy that in series of patients from the groups of Hopital Necker and Hopital Tenon reported in 1981 by Ganeval et aI., the disease presentation was due to renal symptoms and the diagnosis of a plasma cell dyscrasia resulted from the histology of the renal lesions. s Although such facts are rare, they clearly demonstrate the kind of information that may be obtained from renal biopsies . ACUTE RENAL FAILURE
If the systematic use of renal biopsies in acute renal failure is useless, there remains approximately one-fifth of the patients in whom acute renal failure occurs in the absence of a well identified triggering event. Renal biopsy is justified in acute renal failure because of the high mortality in this group of patients, as there is the possibility of defining and treating the cause of the lesions in at least 20% of cases. 9 •10 Our policy in the Department of Nephrology of G. Richet has been to perform an early biopsy in acute renal failure when the diagnosis of acute tubular necrosis was not established clinically.n Although this attitude was criticized by several clinicians, the exact figures
246
LILIANE MOREL-MAROGER
gathered in 1981 by Duhoux, et al. provided a good survey of our results. In the intensive care unit of this hospital renal biopsies were performed in 178 patients out of a total 889 patients admitted for acute renal failure. It is likely that some of the diagnoses established or suggested by renal histology would have been made clinically. However, renal biopsy contributed in the management of 74.7% of patients. Even if this optimistic view may be tempered, there remain a number of patients in whom therapeutic attitudes were influenced by the renal histologic findings (44.4%). In addition, the type of glomerular lesions in anuric patients is of critical importance since those with pure endocapillary proliferative GN will recover spontaneously, whereas those with crescentic GN require active, somewhat hazardous therapy; namely immunosuppression, steroids and/or plasma exchange. SYSTEMIC DISEASES
Renal complications are common in systemic lupus erythematosus and in vasculitis, both diseases representing a major cause of renal involvement. In systemic lupus, the early works of Pollak and Pi rani , further confirmed by subsequent groups, have established that the renal damage varies largely from patient to patient, governing both the therapeutic attitude and the prognosis. There is a form of consensus based partly on a WHO working group to recognize five types of lesions: minimal, membranous, me sangial, diffuse proliferative, and membranoproliferative. 12 The notion of active lesions, which could be analyzed on a semiquantitative basis, was introduced long ago by Pirani and it is now well recognized that such lesions are highly susceptible to becoming sclerotic, but are also, as a whole, potentially reversible under treatment. 13 Several attempts to correlate the findings on renal biopsies with serologic measurements such as anti-DNA antibodies, antinuclear factors, complement, and circulating immune complexes have shown that all these parameters may be used statistically. However in a given patient presenting with nephrotic syndrome the immunologic measurements will not give an exact reflection of active renal lesions, for instance the extent of necrosis wire loop deposits, nuclear fragments, and cellular crescents. By contrast in membranous GN which may present with identical clinical and im-
munologic symptomatology, the glomerular lesions are not active and will not, as a rule, respond to therapy. Also, patients with only asymptomatic mild proteinuria or hematuria may have minimal lesions, but they also may have an active mesangial GN with foci of necrosis and segmental crescents, considered by several authors as a clear cut indication for active therapy. Lastly, even in patients who have no renal symptoms, in some instances we have found cellular proliferation within the glomeruli. The use of semiquantitative methods has also been useful in long-term management of patients with lupus GN, when the morphologist has to examine serial biopsies. 13 The clinicians would like to know whether the lesions are still active, whether sclerosis has developed, and will be able to judge the efficacy of therapy on precise data which may achieve a good precision. For several years we have been using classification of lupus GN which is largely based on the recommendations of the WHO. We also separately score active and sclerotic lesions, thus trying to convert impressions into figures. The activity score represents the sum of all active lesions seen on a biopsy, whereas the score for sclerosis takes into account separately tubulointerstitial sclerosis and the proportion of scarred glomeruli. Immunofluorescence gives precious additional information. From a practical point of view the immune deposits which contain IgG, as a rule, are much better identified than they would be by light microscopy. In our view they give the same kind of information as that gained from EM, but at a lower cost. For routine purposes EM in systemic lupus erythematosus is not to be considered as a compulsory tool, whatever its theoretical interest. Renal biopsy also contributes in other systemic diseases. This is obviously very clear in systemic vasculitis, since in polyarteritis nodosa and Wegener's granulomatosis active therapy is now possible. 14 Although some clinicians would choose to treat all patients who have renal symptoms and vasculitis with cytostatic agents combined with steroids and sometimes plasma exchange, this attitude appears slightly old fashioned. We have learned from large series of patients that purely cellular crescents are reversible to a certain extent, and deserve active therapy. On the contrary, when all glomeruli are sclerotic with fibrous crescents, the renal lesions
247
VALUE OF RENAL BIOPSY
per se do not justify weeks of intensive therapy with the risk of gastrointestinal bleeding and infection for a patient who will certainly require maintenance dialysis . Lastly, the immunofluorescence findings differ in Wegner 's granulomatosis, and polyarteritis nodosa , and in SchonleinHenoch nephritis . In this latter condition IgA and fibrin are found regularly in the glomeruli, whereas immunoglobulins are not present in the first two. The understanding of dysproteinemias - as a group of diseases - has advanced from the systematic use of renal biopsies. Several decades ago, two causes of renal damage were accepted as a consequence of mUltiple myeloma: tubular lesions with myeloma casts and amyloidosis. A new entity known as light chain systemic deposition and characterized by a unique combination of light , electron, and fluorescence findings has been identified on renal tissue . In these patients who have nodular glomerulosclerosis, the discovery of a non symptomatic gammopathy may be useful not only for a given patient, but also for the general understanding of renal disease. Finally a renal biopsy may be helpful in a number of systemic diseases where renal disease is not the principal site of involvement. This is the case in mixed cryoglobulinemia with renal failure. The characteristic eosinophilic deposits occluding the capillary loops, first recognized by Meltzer and McCIuskey 15 contain both IgG and IgM present in the cryoprecipitates. These immune deposits in the kidney may clear under immunosuppressive treatment. This is also the case in rapidly progressive renal failure with or without pulmonary symptoms. Although antibodies directed against glomerular basement membranes may be detected in the serum, there is no other means by which the extent of glomerular necrosis and crescents, i.e ., the renal prognosis, can be identified within 24 hr of admission in a given patient. 16 The attitude towards the systemic use of renal biopsies in large controlled studies of serious life threatening diseases should no longer be the subject of discussion, even if only ethical issues are raised. Perhaps one should wonder whether the administration of cyclophosphamide , steroids, and eventually plasma exchange is ethical when this is done semiblindly. Would anyone treat hemoptysis and pulmonary illness without a chest radiogram and proper bacteriology? Unequivocally the an-
swer would be yes only if the patient and the doctor were on a desert island lacking medical facilities. In my opinion nephrology should not find itself in this position , although not all would agree. 17 ASYMPTOMATIC URINARY ANOMALIES
If we consider now the use of renal biopsy in asymptomatic patients with mild proteinuria or hematuria, the attitude should be nuanced. In a department specialized in renal diseases, renal biopsy adds to the general knowledge. For instance without the long-term meticulous work of Robinson 18 the histologic background of isolated proteinuria would still be unknown . Even when no active therapy is expected , patients and their doctors sometimes wish to know whether severe renal symptoms are likely to develop, whether vaccination is safe, and whether a pregnancy is likely to be uneventful or should be avoided. In such cases the data provided by renal biopsy are not replaceable by the other laboratory or clinical investigations. TRANSPLANTATION
The methods to correctly interpret renal lesions in transplantation are far from elucidated. However , the distinction of de novo glomerulonephritis from transplant glomerulonephritis has only been made possible by examination of renal biopsies. Even if the histologic changes are equivocal, hopefully some of the mechanisms leading to deterioration of renal function will be elucidated through identification of renal reactions, identifying either mediators of inflammation or antigens and cells within the transplant. It is indeed possible that the presence and role of subpopulations of lymphocytes and macrophages in rejection can be assessed within the renal tissue obtained at biopsy. CONCLUSION
Whatever the amount of basic knowledge accumulated by the study of experimental renal diseases,16,19-20 a systematic analyis of human biopsies has shown in the last 20 yr that the natural history of nephritis is only now beginning to emerge from obscurity, and that further investigation is still needed before the accurate diagnosis and management of renal diseases can be based strictly on noninvasive techniques .
248
LILIANE MOREL-MAROGER
REFERENCES 1. Berger J, Yaneva H, Hinglais N: Immunofluorescence des glomerulo-nephrites, in Actualites Nephrologiques de I'Hopital Necker. Paris, Flammarion Edit, 1971, P 17 2. Cameron JS: Clinicopathological correlates in glomerulonephritis: Problems and limitations. Clin Nephrol 41:1, 1975 3. Habib R, Kleinknecht C: The primary nephrotic syndrome of childhood: Classification and clinicopathologic study of 406 cases, in Sommers SS (ed): Pathology Annual. New York, Appleton Century Croft, 1971 4. Heptinstall RH: Pathology of the Kidney (ed 2). Boston, Little Brown and Co, 1974, vol 2 5. Morel-Maroger L, Leathem A, Richet G: Glomerular abnormalities in nonsystemic diseases: Relationship between finding by light microscopy and immunofluoresence in 433 renal biopsy specimens. Am J Med 53:70, 1972 6. Morel-Maroger L, Verroust P: Clinicopathological correlations in glomerular diseases, in Jones NF (ed): Recent Advances in Renal Disease, vol 1. Edinburgh, Churchill Livingstone, 1975, p 48 7. Royer P, Habib R, Mathieu, et al: Nephrologie Pediatrique. Paris, Flammarion Edit, 1975 8. Ganeval D, Mignon F, Preud'Homme JL, et al: Depots de charines legeres er d'immunoglobulines monoclonales: Aspects nephrologiques et hypotheses physiopathologiques, in Grunfeld JP (ed): Actualities Nephrologiques de I 'Hopi tal Necker. Paris, Flammarion, 1981, p 179 9. Beaufrils M, Morel-Maroger L, Sraer JD, et al: Acute renal failure of glomerular origin during visceral abcesses. N Engl J Med 295:185, 1976
10. Wilson DM, Turner DR, Cameron JS, et al: Value of renal biopsy in acute intrinsic renal failure. Br Med J 2:459, 1976 11. Duhoux P, Kourilsky 0, Kanfer A, et al: Les insuffisances renales aigues necessitant un traitement etiopathogenique, in Kuss R. Legrain M (eds): Seminaires d 'Uro-nephrologie. Paris, Masson, 1981 12. Appel GB, Silva FG, Pirani CL, et al: Renal involvement in systemic lupus erythematosus: A study of 56 patients emphasizing histologic classification. Medicine 57:371, 1978 13. Morel-Maroger L, Mery J, Droz D, et al: Aspects evolutifs des glomerulonephrites lupiques: Apport des biopsies renales iteratives, in Actualities Nephrologiques de I'Hopital Necker. Paris, Flammarion, 1976, p 71 14. Fauci AS, Katz P, Haynes BF, et al: Cyclophosphamide therapy on severe systemic necrotizing vasculitis. N Engl J Med301:235, 1979 15. Meltzer M, Elias K, McCluskey RT, et al: Cryoglobulinemia: A clinical and laboratory study. Am J Med 40:831, 1966 16. Wilson CB, Dixon FJ: Diagnosis of immunopathologic renal disease. Kidney Int 5:389, 1973 17. Pauker SG, Kassirer JP: The threshold approach to clinical decision making. N Engl J Med 302:1109, 1980 18. Robinson RR: Isolated proteinuria in asymptomatic patients. Kidney Int 18:395, 1980 19. Germuth FJ, Rodriguez E: Immunopathology of the Renal Glomerulus (vol 1). Boston, Little Brown and Co, 1973 20. Peters DK, William DG: Pathogenetic mechanisms in glomerulonephritis, in Jones NF (ed): Recent Advances in Renal Disease. London, Churchill Livingstone, 1975
T
HE VALUE of the renal biopsy has recently been questioned, especially in the American scientific literature, and several groups of established clinicians in the U.S. regard renal biopsy as a hazardous and unnecessary luxury . This has led several renal pathologists to critically reexamine their own activity. From an experience based on the examination of 8000 renal biopsies between January 1964 and August 1981, I have obviously a biased point of view, as it is humiliating to find out that one's permanent activity has mainly been devoted to a useless hobby . I will however try to review briefly the implications of following renal patients with and without a renal biopsy. The use of renal biopsies requires a very close cooperation and understanding between renal clinicians and pathologists. These latter should sometimes remember that the aim of pathology is to communicate in an understandable and easy manner what they have seen through a microscope. The replacement of some simple words in a conclusion by numbers and subgroups may lead to terrible confusion . For instance the recommendations of WHO to assess a renal biopsy may lead to the following type of reports: patient "Mr Smith is II a, i b 34, " and if I were a clinician I would prefer to read "Mr. S . has a focal glomerulonephritis involving 1,4 of the glomeruli, with lesions of moderate severity and little damage of tubes, interstitium and vessels. " There are some circumstances in which renal biopsy should be performed rapidly and the result used for therapeutic purposes, and I will briefly review these in this article. On the other hand, while some biopsies are probably of no practical immediate use to the patient, they add to the general knowledge, and contribute to the advancement of nephrology in general. For the present article I will only review the use of renal biopsies in a population of adult patients. Although needle From the Service de Nephrologie, lnstitut National de la Sante et De La Recherche Medicale. (Dir. ProfG. Richet.) Reprint requests should be addressed 10 Liliane MorelMaroger. M.D. , lNSERM(U 64) , Service de Nephrologie, Hopital Tenon , 4 Rue de la Chine, 75020. Paris, France. © 1982 by Th e National Kidney Foundation , Inc. 0272-63861821040244-05$01 .0010
244
renal biopsies are easily performed, they should not be done by junior residents or fellows unless this is part of their training as future nephrologists. This procedure, safe in the hands of trained physicians , can be a source of accidents and pain when this is not the case, and the quality of the fragments of renal tissue obtained is largely dependent upon the experience of the operator. In addition the renal biopsy should be performed either in the presence of the renal pathologist (I do most of the biopsies myself) or one of the representatives of the laboratory to make sure that the renal tissue is properly treated from the beginning. A sufficient piece of cortex must be available both for light microscopy and immunofluorescence . Ideally two or three glomeruli should also be fixed for electronmicroscopy (EM), although I do not think that it is compulsory to have EM if the aim is to achieve a diagnosis. In 95% of renal biopsies a diagnosis can be achieved with the combination of good reliable light microscopy and immunofluorescence. However any work involving research would considerably benefit from ultrastructural examination. For light microscopy we use Dubosq-Brazil's fixative (Alcoholic Bouin), but Helly, corrosive formalin and Carnoy's also give good results. However, whatever the fixative chosen, thin slides of 2-3 microns, and serial sections are necessary. We always keep a few thick sections (5-10 microns) to look for amyloidosis. Numerous stains are also required: systematically haematoxylin-eosin. PAS, silver stain, Congo red , and a good trichromic stain (Masson's trichrome with light green is convenient). At least 20 sections from one renal biopsy should be examined in detail using high magnification which will show most of the glomerular lesions except minimal anomalies of the glomerular basement membrane. For fluorescence, we remain faithful to fluorescein or rhodamin, as peroxidase seems more difficult to handle properly. Also with fixed tissue further treated by trypsin, the results are less satisfactory at present than those obtained with snap frozen tissue cut in a cryostat, but hopefully in the future , paraffin embedded material may be used both for light microscopy and im-
American Journal of Kidney Diseases, Vol. I, No.4 (January), 1982
245
VALUE OF RENAL BIOPSY
munochemistry. Directly fluorescein or rhodamin labeled antisera are applied after the usual controls have been performed: anti IgG, IgA, IgM, C3 , C 1q , fibrinogen-fibrin, kappa, lambda allow a categorization of most findings in some of the current groups of disease . 1·7 . 13 The indications for renal biopsy should be weighed against the potential dangers of this procedure in all the usual clinical syndromes. It is difficult to accept the idea recently expressed that it is less dangerous to blindly treat a patient with 1 or 2 mg/kg/24 hr of steroids, sometimes in combination with cyclophosphamide, than to do a renal biopsy in an acutely ill patient. If necessary a renal biopsy should be processed and read within 2 days . Finally it is important to distinguish the circumstances in which renal biopsy is necessary to take therapeutic measures, from those in which this is useful in a more prospective way, for instance in therapeutic trials. In adult patients biopsies are necessary for diagnostic purposes in the following syndromes: nephrotic syndrome, acute failure of unknown or doubtful etiology, nephrotic syndrome , rapidly progressive renal failure, and a large number of systemic diseases sometimes in the absence of renal symptomatology. A discussion of these areas follows . NEPHROTIC SYNDROME (NS)
The policy which is adopted by pediatricians is not applicable to adult patients, as the proportion of lipoid nephrosis is smaller, and therefore steroids should be given in cases identified on a morphological basis. The most common lesion in adult NS is membranous glomerulonephritis (GN) and it is still questionable whether steroids affect the natural course of this disease , benign in some series , more severe in others . In addition , the finding of membranous GN in an elderly subject must lead to extensive search for cancer, and it is not exceptional (F. Mignon) that NS reveals an epithelial cancer at a stage where the lesions are still reversible. The other lesions which may be found in adult NS are minimal changes or focal hyalinosis, and in both these lesions the absence of deposits of immunoglobulins and complement along the glomerular basement membrane (GBM) allows an early differential diagnosis with membranous GN , even in the absence of silver stained spikes . Membranoproliferative ON (MPGN) is not a
very common disorder in adults . Dense deposits are very rare, whereas subendothelial deposits are more common. In this latter condition some histologic and fluorescent particularities may give an insight on an associated underlying disease which may not be obvious . For instance extensive deposits of IgA and C3 are often a good marker of a liver disease with MPGN: the association of numerous polymorphs with.extensive granular deposits of C3 may suggest an underlying bacterial disorder whose cure may reverse the course of the ON . Amyloidosis is far from exceptional. In the light of recent work amyloidosis may be the marker of a plasma cell disorder , sometimes in the absence of a circulating Ig spike, indicating the presence of a monoclonal gammopathy , which may be controlled by specific treatment. Also if amyloidosis is of AA type, extensive search for an etiology may be helpful in the future management of the patient. The discovery of amyloidosis usually counterindicates the use of steroids. Finally renal biopsy in nephrotic patients may show unexpected lesions . This has been the case in several patients who had light chain systemic deposition , a group of diseases which is recognized with increased frequency. It is noteworthy that in series of patients from the groups of Hopital Necker and Hopital Tenon reported in 1981 by Ganeval et aI., the disease presentation was due to renal symptoms and the diagnosis of a plasma cell dyscrasia resulted from the histology of the renal lesions. s Although such facts are rare, they clearly demonstrate the kind of information that may be obtained from renal biopsies . ACUTE RENAL FAILURE
If the systematic use of renal biopsies in acute renal failure is useless, there remains approximately one-fifth of the patients in whom acute renal failure occurs in the absence of a well identified triggering event. Renal biopsy is justified in acute renal failure because of the high mortality in this group of patients, as there is the possibility of defining and treating the cause of the lesions in at least 20% of cases. 9 •10 Our policy in the Department of Nephrology of G. Richet has been to perform an early biopsy in acute renal failure when the diagnosis of acute tubular necrosis was not established clinically.n Although this attitude was criticized by several clinicians, the exact figures
246
LILIANE MOREL-MAROGER
gathered in 1981 by Duhoux, et al. provided a good survey of our results. In the intensive care unit of this hospital renal biopsies were performed in 178 patients out of a total 889 patients admitted for acute renal failure. It is likely that some of the diagnoses established or suggested by renal histology would have been made clinically. However, renal biopsy contributed in the management of 74.7% of patients. Even if this optimistic view may be tempered, there remain a number of patients in whom therapeutic attitudes were influenced by the renal histologic findings (44.4%). In addition, the type of glomerular lesions in anuric patients is of critical importance since those with pure endocapillary proliferative GN will recover spontaneously, whereas those with crescentic GN require active, somewhat hazardous therapy; namely immunosuppression, steroids and/or plasma exchange. SYSTEMIC DISEASES
Renal complications are common in systemic lupus erythematosus and in vasculitis, both diseases representing a major cause of renal involvement. In systemic lupus, the early works of Pollak and Pi rani , further confirmed by subsequent groups, have established that the renal damage varies largely from patient to patient, governing both the therapeutic attitude and the prognosis. There is a form of consensus based partly on a WHO working group to recognize five types of lesions: minimal, membranous, me sangial, diffuse proliferative, and membranoproliferative. 12 The notion of active lesions, which could be analyzed on a semiquantitative basis, was introduced long ago by Pirani and it is now well recognized that such lesions are highly susceptible to becoming sclerotic, but are also, as a whole, potentially reversible under treatment. 13 Several attempts to correlate the findings on renal biopsies with serologic measurements such as anti-DNA antibodies, antinuclear factors, complement, and circulating immune complexes have shown that all these parameters may be used statistically. However in a given patient presenting with nephrotic syndrome the immunologic measurements will not give an exact reflection of active renal lesions, for instance the extent of necrosis wire loop deposits, nuclear fragments, and cellular crescents. By contrast in membranous GN which may present with identical clinical and im-
munologic symptomatology, the glomerular lesions are not active and will not, as a rule, respond to therapy. Also, patients with only asymptomatic mild proteinuria or hematuria may have minimal lesions, but they also may have an active mesangial GN with foci of necrosis and segmental crescents, considered by several authors as a clear cut indication for active therapy. Lastly, even in patients who have no renal symptoms, in some instances we have found cellular proliferation within the glomeruli. The use of semiquantitative methods has also been useful in long-term management of patients with lupus GN, when the morphologist has to examine serial biopsies. 13 The clinicians would like to know whether the lesions are still active, whether sclerosis has developed, and will be able to judge the efficacy of therapy on precise data which may achieve a good precision. For several years we have been using classification of lupus GN which is largely based on the recommendations of the WHO. We also separately score active and sclerotic lesions, thus trying to convert impressions into figures. The activity score represents the sum of all active lesions seen on a biopsy, whereas the score for sclerosis takes into account separately tubulointerstitial sclerosis and the proportion of scarred glomeruli. Immunofluorescence gives precious additional information. From a practical point of view the immune deposits which contain IgG, as a rule, are much better identified than they would be by light microscopy. In our view they give the same kind of information as that gained from EM, but at a lower cost. For routine purposes EM in systemic lupus erythematosus is not to be considered as a compulsory tool, whatever its theoretical interest. Renal biopsy also contributes in other systemic diseases. This is obviously very clear in systemic vasculitis, since in polyarteritis nodosa and Wegener's granulomatosis active therapy is now possible. 14 Although some clinicians would choose to treat all patients who have renal symptoms and vasculitis with cytostatic agents combined with steroids and sometimes plasma exchange, this attitude appears slightly old fashioned. We have learned from large series of patients that purely cellular crescents are reversible to a certain extent, and deserve active therapy. On the contrary, when all glomeruli are sclerotic with fibrous crescents, the renal lesions
247
VALUE OF RENAL BIOPSY
per se do not justify weeks of intensive therapy with the risk of gastrointestinal bleeding and infection for a patient who will certainly require maintenance dialysis . Lastly, the immunofluorescence findings differ in Wegner 's granulomatosis, and polyarteritis nodosa , and in SchonleinHenoch nephritis . In this latter condition IgA and fibrin are found regularly in the glomeruli, whereas immunoglobulins are not present in the first two. The understanding of dysproteinemias - as a group of diseases - has advanced from the systematic use of renal biopsies. Several decades ago, two causes of renal damage were accepted as a consequence of mUltiple myeloma: tubular lesions with myeloma casts and amyloidosis. A new entity known as light chain systemic deposition and characterized by a unique combination of light , electron, and fluorescence findings has been identified on renal tissue . In these patients who have nodular glomerulosclerosis, the discovery of a non symptomatic gammopathy may be useful not only for a given patient, but also for the general understanding of renal disease. Finally a renal biopsy may be helpful in a number of systemic diseases where renal disease is not the principal site of involvement. This is the case in mixed cryoglobulinemia with renal failure. The characteristic eosinophilic deposits occluding the capillary loops, first recognized by Meltzer and McCIuskey 15 contain both IgG and IgM present in the cryoprecipitates. These immune deposits in the kidney may clear under immunosuppressive treatment. This is also the case in rapidly progressive renal failure with or without pulmonary symptoms. Although antibodies directed against glomerular basement membranes may be detected in the serum, there is no other means by which the extent of glomerular necrosis and crescents, i.e ., the renal prognosis, can be identified within 24 hr of admission in a given patient. 16 The attitude towards the systemic use of renal biopsies in large controlled studies of serious life threatening diseases should no longer be the subject of discussion, even if only ethical issues are raised. Perhaps one should wonder whether the administration of cyclophosphamide , steroids, and eventually plasma exchange is ethical when this is done semiblindly. Would anyone treat hemoptysis and pulmonary illness without a chest radiogram and proper bacteriology? Unequivocally the an-
swer would be yes only if the patient and the doctor were on a desert island lacking medical facilities. In my opinion nephrology should not find itself in this position , although not all would agree. 17 ASYMPTOMATIC URINARY ANOMALIES
If we consider now the use of renal biopsy in asymptomatic patients with mild proteinuria or hematuria, the attitude should be nuanced. In a department specialized in renal diseases, renal biopsy adds to the general knowledge. For instance without the long-term meticulous work of Robinson 18 the histologic background of isolated proteinuria would still be unknown . Even when no active therapy is expected , patients and their doctors sometimes wish to know whether severe renal symptoms are likely to develop, whether vaccination is safe, and whether a pregnancy is likely to be uneventful or should be avoided. In such cases the data provided by renal biopsy are not replaceable by the other laboratory or clinical investigations. TRANSPLANTATION
The methods to correctly interpret renal lesions in transplantation are far from elucidated. However , the distinction of de novo glomerulonephritis from transplant glomerulonephritis has only been made possible by examination of renal biopsies. Even if the histologic changes are equivocal, hopefully some of the mechanisms leading to deterioration of renal function will be elucidated through identification of renal reactions, identifying either mediators of inflammation or antigens and cells within the transplant. It is indeed possible that the presence and role of subpopulations of lymphocytes and macrophages in rejection can be assessed within the renal tissue obtained at biopsy. CONCLUSION
Whatever the amount of basic knowledge accumulated by the study of experimental renal diseases,16,19-20 a systematic analyis of human biopsies has shown in the last 20 yr that the natural history of nephritis is only now beginning to emerge from obscurity, and that further investigation is still needed before the accurate diagnosis and management of renal diseases can be based strictly on noninvasive techniques .
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