The Development of Renal Pathology

The Development of Renal Pathology Robert H. Heptinstall, MD

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N HIS LETTER to the contributors of this special edition, the guest editor suggested that we focus on the years 1950 to 1990-the lifetime of the National Kidney Foundation-and that we draw heavily on our own experiences and reflections. The first is easy but, except to the very brash, the second presents problems because it would be all too easy to turn the article into a brochure of self-aggrandizement. Yet , in spite of these reservations, the suggestions have considerable merit and with due diffidence I shall adopt them. RENAL PATHOLOGY BEFORE 1950

To begin, it is of interest to look back and see what was known about renal pathology before 1950. Although published in 1914, Volhard and Fahr ' s monograph "Die Brightsche Nierenkrankheit" 1still provided the cornerstone for our understanding of the pathology of glomerulonephritis, "nephrosis," and hypertensive vascular disease. Considerable information on other aspects of renal pathology was available in Fahr's chapter in the 1925 edition of Henke and Lubarsch's, Handbuch der Speziellen Anatomie und Histologie, 2 and the contributions of this remarkable pathologist (Fig 1) still constantly amaze me. In the United States, Bell's textbook, Renal Diseases,3 first published in 1946, provided serious students of renal pathology with a wealth of information based on the author's personal experience, and McManus's book4 based on the application of the periodic acid-Schiff staining technique had just appeared. Most of the publishe~ pathology was of a descriptive type and based on autopsy studies. For the main part it represented advanced disease, and with few exceptions little information was available on the early stages and on the evolutionary sequences. For this reason , glomerulonephritis in particular was poorly understood and the plethora From the Department of Pathology, The f ohns Hopkins University, School of Medicine, Baltimore , MD. Address reprillf requests to Robert H. Heptinsrall, MD , Prof essor of Pathology, The f ohns Hopkins University, School of Medicine, Baltimore, MD 21205. © 1990 by the National Kidney Foundation, Inc. 0272-6386/90/1606-0010$3.00/0 568

of classifications was a manifestation of this, 1.3.5.6 Important descriptions were also available on a variety of topics such as diabetes mellitus, collagen vascular disease, polyarteritis, amyloid, stone formation, developmental defects, and many others. While most pathologists relied on gross and light microscopic observations, some, like Oliver (Fig 2) , took a different approach and used nephron dissection , In this way, the entire nephron could be reconstructed, the exact site oflesions located, and the heterogeneity of changes in chronic states demonstrated,7 With this unique approac~ , Oliver did much to stimulate ideas on functional behavior in chronic renal failure , and to determine the site of the lesion in "acute tubular necrosis. " 8 It is a little known fact that he and Wilson 9 in 1920 provided the first convincing demonstration of the production of experimental glomerulonephritis by the injection of anti-kidney antibody, Important experimental studies, particularly on pathogenetic mechanisms of glomerulonephritis and vasculitis were begun in the pre-1950 era. These explored the possibility of immunologic processes being involved, and included both the serum sickness model'°·11 and the effects of nephrotoxic antibody.9.12.13 The full impact of these had to await the introduction of immunohistologic methods, about which more will be said later, Notable among experimental studies on the kidney by pathologists were those of Harry Goldblatt on the genesis of hypertension. His work stresses the importance of careful observation in man, because the experiments were prompted by his noticing that hypertensive patients commonly showed narrowing of the renal vasculature at autopsy. Thus, by the middle of the 20th century a great number of anatomical details had been accumulated and some crucial experiments performed , But in spite ofthis there was incredible confusion . This was brought home to me very forcibly in 1951, when on completion of training in pathology I was asked by George Pickering to look at a number of kidneys he had collected over the years, These had been removed surgically for what was considered to be unilateral chronic pyelonephritis in the expectation that the patients' high blood

American Journal of Kidney Diseases, Vol XVI, No 6 (December), 1990: pp 568-573

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THE DEVELOPMENT OF RENAL PATHOLOGY

Fig 1. Theodor Fahr. (Courtesy of Dr. H.E. MacMahon; reprinted with permission from J Hist Med Allied Sci 21:125-146,1966.)

pressures would be lowered. Knowing nothing about pyelonephritis, nor for that matter of any aspect of kidney pathology, I undertook some intensive reading. Apart from a few original articles, there was little written on pyelonephritis to succor the needy. The situation with glomerulonephritis was even worse, with a confusing profusion of different classifications and problems with terminology. The notation subacute was used for two conditions with vastly different clinical pictures , distinctions were drawn between subacute and subchronic , and the membranous form was equated with lipoid nephrosis. Nephrosis was a term used in many different senses and included toxic, lipoid, lower nephron , and even genuine varieties; happily there was no bogus form. Pity the young pathologist entering this arena! There were of course good reasons for this state of affairs . Particularly in glomerulonephritis there were no clinical-pathologic correlations available on the evolution ofthe disease, and the widely held belief that the more chronic forms were inevitably preceded by an acute phase exerted a stultifying effect on progress. Ideas on pathogenesis-apart

Fig 2. chalk.)

Jean R. Oliver. (Courtesy of Dr earl Gotts-

from the thought that an immunologic reaction might be involved-were infantile, and crucial experimental studies, which later made such great contributions to our understanding , had not yet been performed . A knowledge of pathogenesis in establishing pathologic diagnostic criteria cannot be overemphasized and the simplest example of this lies in chronic pyelonephritis . In 1950, and for several years later, controversy raged over the way in which the kidney became infected, and it was not until vesicoureteral reflux became accepted as the mechanism by which bacteria reached the kidney that pathologic diagnostic criteria could be defined with any accuracy. RENAL PATHOLOGY AFTER 1950

The 1950s saw at least three major developments of far-reaching consequence, and it was fortunate that all happened within a few years of each other so that the effects were complementary. The first was the introduction in 1951 of the needle

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biopsy of the kidney as a safe routine procedure by Iversen and Brun. 14 The availability of renal tissue from living patients allowed an opportunity to see the early stages of disease and to follow evolution of the lesions by sequential biopsies. The renal biopsy also provided fresh material so that the other two developments, electron microscopy and immunohistology, could be used. More will be said of these later. The use of the renal biopsy rapidly gained acceptance and by 1961 the various physicians taking part in a Ciba symposium were able to record that over 5,000 biopsies had been performed with little untoward effect. 15 These early years of the biopsy were exciting times and it was indeed fortunate that there was such excellent collaboration between the clinician and pathologist. The original contributions were restricted to the use of the light microscope, but even with this limited approach much progress was made. Renal disease was seen at an early stage and sequential biopsies on a variety of conditions such as poststreptococcal glomerulonephritis and lupus nephritis were performed. 16 18 The nephrotic syndrome could now be broken down into its constituent entities, 19,20 and although before this time such causes as diabetes mellitus and amyloid were recognized, it now became possible to identify the panoply of conditions responsible. Importantly, it became possible to separate lipoid nephrosis (minimal change disease) from membranous glomerulonephritis using silver impregnation techniques. The entity of focal and segmental glomerular sclerosis was identified somewhat later,21 but in retrospect it should be noted that Fahr2 was quite familiar with the lesion, and even today there is no good explanation for the observation previously made by Rich (Fig 3), another of the pioneer renal pathologists, that the affected glomeruli were selectively situated in the juxtamedullary cortex. 22 It also became possible to study poorly understood syndromes whose pathology was largely unknown, and the recognition of focal glomerulonephritis as one of the underlying lesions of recurrent hematuria, Schonlein-Henoch syndrome, etc, provides an example of this. 23,24 I well remember the hostile reception given to the presentation 10ekes and I made to the Renal Association on focal forms of glomerulonephritis, purely because it conflicted with contemporary thinking.

ROBERT H, HEPTINSTALL

Fig 3. Arnold R. Rich demonstrating an autopsy to Louis Hamman, perhaps a case of Hamman-Rich syndrome. (Courtesy of Alan Mason Chesney Medical Archives, Johns Hopkins University School of Medicine.)

These early years of the biopsy were fascinating times and the Renal Association, which met monthly at the Ciba Foundation in London, provided a testing forum for presentation of new data. Not only were your views verbally assailed, but your physical well-being put in danger, for on one occasion I was quite literally thrown off the podium. Admittedly, I had long exceeded my time and the chairman of the session, R.A. McCance from Cambridge, was not one to be trifled with. Even greater progress was made following the introduction of electron microscopy. Although the first commercial production of the electron microscope took place in 1939, it took until the 1950s for significant application of this instrument. The early studies were concerned mainly with describing anatomic features in laboratory animals, but soon there were accounts of human disease using tissue obtained by needle biopsy. 2527 Early observations, to mention only a few, included effacement of the foot processes in minimal change disease, the demonstration of deposits in different sites in glomerulonephritis and systemic lupus erythematosus (SLE), and thickening of the lamina densa in diabetes. With this technique the age-old controversy over the existence of an intercapillary

THE DEVELOPMENT OF RENAL PATHOLOGY

space (mesangium) with its own population of cells was resolved, and its illustration in the report of Latta et al 28 must be one of the most reproduced pictures in the whole of renal pathology. Vast numbers of reports followed over the years and the quality of the pictures improved following the substitution of epoxy resins for methacrylate as the embedding medium. Unique and unsuspected features were revealed, such as splitting or layering of the glomerular basement membrane in Alport' s syndrome 29 ,3o and "fingerprints" in the deposits of SLE. 31 New diseases such as dense deposit disease (type 2 membranoproliferative glomerulonephritis) were discovered ,32 and a less tangible but most important contribution was the way in which it improved our interpretation of light microscopy as a result of better understanding of the structure of the capillary wall and the existence of the mesangium. The scanning electron microscope has not had such an impact on pathology, although it can dramatically demonstrate in panorama what is seen only casually with the transmission electron microscope. Immunohistologic techniques have also had a big impact both on diagnostic pathology and on the elucidation of pathogenetic mechanisms in man and in experimentally induced models. Early application of the fluorescent antibody method to human material was made by various workers in the mid and late 1950s. 33,34 These studies revealed the presence of -y-globulin in the glomeruli of various conditions, notably membranous glomerulonephritis and SLE, and were shortly followed by the demonstration of complement fixation in glomeruli from membranous glomerulonephritis. 35 These and many subsequent observations on renal biopsy material , coupled with the immense amount of experimental work prompted by the pioneer studies of Dixon and Germuth, have firmly established the concept of immunologic injury in the pathogenesis of glomerulonephritis and allied disorders. Of great importance was the identification of antiglomerular basement membrane antibody disease and its separation from the better established immune complex disease. 36 As with electron microscopy, new conditions were uncovered by immunohistology; IgA nephritis 37 and xlight chain disease 38 are good examples, while the demonstration by this technique of a missing antigenes) in Alport's syndrome 39 has prompted tre-

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mendous efforts in identifying and locating the socalled Goodpasture antigen. The scope of immunohistology was expanded with the development of monoclonal antibodies and the introduction of the immunoperoxidase method. Since this topic is the subject of a report by Dixon and Wilson in this issue, nothing more will be said of it. While much of the progress in renal pathology has been in glomerulonephritis, considerable advances are apparent in other areas. Tubulointerstitial nephritis, of which little was known prior to 1950, is now a focus of great activity, particularly since monoclonal antibodies against subsets of lymphocytes and various experimental models are available as investigative tools. As mentioned earlier, one of its constituents, chronic pyelonephritis, is now a well-understood condition, and while the major contribution was made by the late John Hodson, a radiologist, we can console ourselves with the thought that a radiologist is really a gross pathologist working under a handicap. Considerable progress has been made in understanding lupus nephritis, amyloidosis, thrombotic microangiopathy (hemolytic uremic syndrome), toxemia of pregnancy, developmental defects, nonimmunologic glomerular injury, transplantation rejection , the pathology of acute renal failure, and a host of other conditions. It is gratifying that attention has at long last been directed to autosomal dominant polycystic disease, a potent cause of chronic renal failure. Progress in clinical medicine has paradoxically created many problems for the pathologist. Whereas prior to 1950 chronic renal disease culminated in the death of the patient, life can nowadays be sustained by chronic dialysis or transplantation. The emergence of the acquired form of renal cystic disease is one of the consequences of chronic dialysis, and although much is known of the biology and pathology of transplant rejection, questions still remain. Adverse reactions to the increasing armamentarium of drugs administered by physicians bring their own problems and in particular contribute significantly to the pool of acute renal failure. Overindulgence in analgesics has been responsible for veritable outbreaks of papillary necrosis , and abuse of addictive drugs such as heroin produces its own pathology. The present acquired immunodeficiency syndrome (AIDS) epi-

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demic is not without renal manifestations, and while we have some knowledge of the pathology of so-called human immunodeficiency virus-associated nephropathy, ideas of its pathogenesis remain embryonic. RENAL PATHOLOGY TODAY

While much has been learned and many issues resolved, we still have old business to finish and new problems to face. At least we now have practicable nomenclature and classifications of most forms of renal disease so that pathologist and clinician can communicate with each other, even

though we may not completely understand the cause of the particular condition and how it developed. In a general sense we know the likely outcome of most renal diseases, although in the individual case this may be difficult. As a result of many experimental studies, a vast amount is known about renal injury, both immunologic and nonimmunologic, but the application of much of this information to human disease is still awaited. Many techniques are now available and those of the molecular biologist are beginning to be applied. We can only hope that the second 40 years of the National Kidney Foundation will see as much progress as the first.

REFERENCES 1. Volhard F, Fahr T: Die Brightsche Nierenkrankheit. Berlin, Germany, Springer, 1914 2. Fahr T: Pathologische Anatomie des Morbus Brightii, in Henke F, Lubarsch 0 (eds): Handbuch der Speziellen Pathologischen Anatomie und Histologie, vol 6, part 1. Berlin, Germany, Springer, 1925, pp 156472 3. Bell ET: Renal Diseases. London, England, Kimpton, 1946 4. McManus JFA: Medical Diseases of the Kidney. Philadelphia, PA. Lea & Febiger, 1950 5. Longcope WT: Some observations on the course and outcome of hemorrhagic nephritis. Trans Am Clin Climat Assoc 53 :153-171 , 1937 6 . Ellis A: Natural history of Bright's disease: Clinical, histological and experimental observations. Lancet 1:1-7, 1942 7. Oliver J: Architecture of the Kidney in Chronic Bright's Disease. New York, NY, Hoeber, 1939 8. Oliver J, MacDowell M, Tracy A: The pathogenesis of acute renal failure associated with traumatic and toxic injury: Renal ischemia, nephrotoxic damage and the ischemuric episode. J Clin Invest 30:1307-1438 , 1951 9. Wilson Gw, Oliver J: Experiments on the production of specific antisera for infections of unknown cause. III. Nephrotoxins: Their specificity as demonstrated by the method of selective absorption . J Exp Med 32: 183-198, 1920 10. Rich AR, Gregory JE: The experimental demonstration that periarteritis nodosa is a manifestation of hypersensitivity. Bull Hopkins Hosp 72:65-81 , 1943 II. Hawn Cv, Janeway CA: Histological and serological sequences in experimental hypersensitivity. J Exp Med 85: 571590, 1947 12. Masugi M: Uber das Wesen der spezifischen Veriinderungen der Niere und der Leber durch das Nephrotoxin bzw. das Hepatotoxin: Zugleich ein Beitrag zur Pathogenese der Glomerulonephritis und der eklamptischen Lebererkrankung. Beitr Pathol Anat 91 :82- 112 , 1933 13. Cavelti B<\, Cavelti ES : Studies on the pathogenesis of glomerulonephritis. II. Production of glomerulonephritis in rats by means of autoantibodies to kidney. III. Clinical and pathologic aspects of the experimental glomerulonephritis produced in rats by means of autoantibodies to kidney. Arch Pathol 40: 158-162, 163-172, 1945

14. Iversen P, Brun C: Aspiration biopsy of the kidney. Am J Med 1:324-330, 195 I 15. Wolstenhome GE\v, Cameron MP (eds): Ciba Symposium on Renal Biopsy. Boston, MA , Little Brown, 1961, p 371 16. Muehrcke RC, Kark RM, Pirani CL, et al: Lupus nephritis: A clinical and pathologic study based on renal biopsies. Medicine 36:1-145, 1957 17. Hutt MSR, Pinniger JL, de Wardener HE: The relationship between the clinical and the histological features of acute glomerular nephritis: Based on a study of renal biopsy material. Q J Med 27:265-291, 1958 18. Jennings RB, Earle DP: Post-streptococcal glomerulonephritis: Histopathologic and clinical studies of the acute, subsiding acute and early chronic latent phases. J Clin Invest 40:1525-1557,1961 19. Kark RM, Pirani CL, Pollak VE , et al: The nephrotic syndrome in adults: A common disorder with many causes. Ann Intern Med 49:751-774, 1958 20. Habib R, Michielsen P, de Montera E, et al: Clinical microscopic and electron microscopic data in the nephrotic syndrome of unknown origin, in Wolstenholme GEW, Cameron MP (eds): Ciba Foundation Symposium on Renal Biopsy. Boston, MA, Little Brown, 1961, pp 70-92 21. Churg J, Habib R, White RHR: Pathology of the nephrotic syndrome in children: A report for the international study of kidney disease in children. Lancet I : 1299-1302, 1970 22. Rich AR: A hitherto undescribed vulnerability of the juxtamedullary glomeruli in lipoid nephrosis. Bull Hopkins Hosp 100: 173-186, 1957 23 . Heptinstall RH, Joekes AM: Focal glomerulonephritis: A study based on renal biopsies. Q J Med 28:329-346, 1959 24. Ross JH: Recurrent focal nephritis. Q J Med 26:391406, 1960 25. Farquhar MG, Vernier RL, Good RA: The application of electron microscopy in pathology: Study of renal biopsy tissues. Schweiz Med Wochenschr 87 :501-510, 1957 26. Folli G, Pollak VE , Reid RTW, et aI: Electronmicroscopic studies of reversible glomerular lesions in the adult nephrotic syndrome. Ann Intern Med 49:775-795 , 1958 27. Bergstrand A, Bucht H: The glomerular lesions of diabetes mellitus and their electron-microscope appearances. J Pathol Bacteriol 77:231-242, 1959

THE DEVELOPMENT OF RENAL PATHOLOGY 28. Latta H, Maunsbach AB, Madden SC: The centrolobular region of the renal glomerulus studied by electron microscopy. J Ultrastruct Res 4:455-472, 1960 29. Hinglais N , Griinfeld J-p, Bois E: Characteristic ultrastructural lesion of the glomerular basement membrane in progressive hereditary nephritis (AJport's syndrome). Lab Invest 27:473-487, 1972 30. Spear GS , Slusser RJ : AJport's syndrome: Emphasizing electron microscopic studies on the glomerulus. Am J Pathol 69:213-220, 1972 31. Grishman E, Porush JC , Rosen SM, et al: Lupus nephritis with organized deposits in the kidney. Lab Invest 16:717725, 1967 32 . Berger J, Galle P: DepOts denses au sein des membranes basales du rein: Etude en microscopies optique et electronique. Presse Med 71:2351-2354, 1963 33 . Mellors RC, Ortega LG, Holman HR: Role of gamma globulins in pathogenesis of renal lesions in systemic lupus erythematosus and chronic membranous glomerulonephritis, with an observation on the lupus erythematosus cell reaction . J Exp Med 106:191-201 , 1957

573 34. Seegal BC: L'Utilita' della tecnica degli anticorpi fluorescenti nello studio delle nefriti sperimentali. Sue possibili applicazioni per la comprensione della patogenesi di alcune nepropatie umane. Rass Fisiopatol Clin Ter 31:1063-1078, 1959 35. Burkholder P: Complement fixation in diseased tissues: I. Fixation of guinea pig complement in sections of kidney from humans with membranous glomerulonephritis and rats injected with anti-rat kidney serum. J Exp Med 114:605-615 , 1961 36. Lerner RA, Glassock RJ, Dixon FJ: The role of antiglomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med 126:989-1004, 1967 37. Berger J, Hinglais N, Les depOts intercapillaires d' IgAIgG. J Urol Nephrol (Paris) 74:694-695, 1968 38. Randall RE, Williamson WC Jr, Mullinax F, et al: Manifestations of systemic light chain deposition . Am J Med 60:293-299, 1976 39. McCoy RC, Johnson HK, Stone WJ, et al: Absence of nephritogenic GBM antigen(s) in some patients with hereditary nephritis. Kidney Int 21 :642-652, 1982