THE FIRST K. PRATHAP MEMORIAL LECTURE · delivering tlie First K. Prathap Meriiorial Lectul-e. The late Professor Prathap had a great interest in the study of renal disease, and had

Malaysian J Path01 1986; 8: 17-39

THE FIRST K. PRATHAP MEMORIAL LECTURE

THE CONTRIBUTION OF PATHOLOGY IN RENAL DISEASE

R A J A S I N N I A H . M A , MBBCh. BAO. MD. PhD, FRCPI , FRCPA. FRCPath

Professor o f Parliolopy. Ueparn11c.nt o f Parlrolo~j~.Faclr l ty 01' Aledicine. Nariotral Clril*ersir,~' 01. Sitrgapore. Sir~gapore 05 1 1

INTRODUCTION HISTORICAL PERSPECTIVE Mr. Chairman and Learned Metiibers of tlie

Malaysian Socicty of Pathologists. i wish to thank you for bestowing on me tlie honour o f delivering tlie First K. Prathap Meriiorial Lectul-e. The late Professor Prathap had a great interest in the study of renal disease, and had contributed to its l i teratu~e. Therefore i t is fitting that I have chosen as the t l ie~ne of my lecture "The Contribution of Pathology in Renal Disease".

Nephrologj~ has gained much prominence and importance. not because it is a major cause of death but the advent of dialysis and transplantation have prolonged the lives of end- stage renal disease patients. Diseases of the genitourinary tract rank 12th among the causes of deaths in Japan and many Western countries'' 2' 3' and the 0th maior cause of deaths by broad groups of causes in Singapore per 100,000 pol)i~ld tion.' Dial-vsis treatment is in its fifth decade 01' clinical application, and the number of living patients undergoing such treatment is nearlv 0.5 r n i l l i ~ n . ~ The true incidence 01' dialysis treatable end-stage renal failure has been estirnatcd at 5 0 to l 0 0 patients per rnillion population each year.7 Thougli dialysis and transplantation treatment have made re~narkable progress in medicine, the

~ ~

cost is prohibitive, and only a few countries will be able to afford i t . The United States of America is spending over USS3 billion. Few countries have these resources, and the pro- blems arc most acute in the "Third World Countries". Tlie only solution out of this quandary is I'or us to obtain a better understanding of the renal diseases with identification of aetiological agents which should lead to niore cost-effective therapy and prevention.

Glomerulonephritis is the most common kidney disease leading to dialysis and transplantation treatment, followed by pyelonephritis and tubulo-interstitial nephritis, congenital renal cystic disease and niultisystem diseases. The patl~ological study of these lesions lies at the heart of the solution.

Since ancient times ina i has believed in impurities in tlie body as tlie cause ut' disease. The historical Greeks and Hottzans based their diagnosis on six criteria: patient's behavious, the excreta, other effluvia 1'1.o1n the body, swellings, character and location of the pain, and qualities o f the pulse. The Arabic con- tributjon to medicine through the Arabist pracritioners (8th tu 12th Century) was in the development o f el'l'icient llosp~tals and pharmacy as a science. Their ernpliasis on examining the urine l'or its colour, consistency, sediment, smell and taste Iwlped to determine what was wrong with a patient, to predict his prognosis and to guide treatment. These concepts were taken to Europe by the returning Crusaders, and became part o(' the medical teaching in the Un~vcrsities to be es tab l i s l~ed .~

Cbntribution o f Morbid Anatomy The systematic study ol' organ parhology

wa_s pioneered by Curl Rokira~uky ( 1804 78) and Rudolf Virchow ( 182 1 - 1002) i l l Austria and Germany. They strove to integrate clinical medicine, morbid anatonly and physiology, with classif'ication of the anatoniical changes produced by disease. These rcvolutiona~y approaches radically altered tlie direct~on ul' medicine toward the concept that diseasc was produced by disturbances i" the s t r u c t u ~ c and f'unction of the body cells.

Tlie masterful reports I'rom Guy's Hospilal, London, by Richard Rrighl (1789 1855) on the clinical and pathological nature 01' Jiscases of the. kidneys (Fig. l ) led to the beginning ol' our present knowledge uf renal diseases. The condition named "Rrighr 'S Disease " was based on observations after dcatli with symptoms during life, with close correlation wllicli exists both between f'unctional and organic disease as determined by tlie examination of autopsy materials (Fig. 2 ) . Froin this tirnc on rnany methods were devised to predict the renal pathology and prognosis f'rorn clinical para- meters, without the opportunity of seeing the

Address for reprint requests: Professor R. Sinniah. Department of Pathology, Faculty of Medicine, National University o f Singapore, Singapore 0511 .

Malaysian J Pathol August 1986

R E P O R T S

M E D I C A L C A S E S ,

S E L E C T E D

WITH A VIEW' OF ILLUSTIIA'TING

T H E S Y M P T O M S A N D C U R E O F D I S E 1 i s E s

DY A R E F E R E K C E T O

M O R B I D A N A T O M Y .

FIG. I

BY RICHAHD BRIGHT, 31.1). F.1i.S. Xc.

1 . E C T U R E R ON T H E P R A C T I C E O F . I IEL)I ( ' ISE .

A S D O S E OF TIIF. PIIYSICI:\SS TO

GIIY'J I IUSI ' ITAL.

L O N D O N :

I ' l l l N l ' E l ) DT RICIIAI tL) TAII.OlL. REL) L l O S COL'IIT, l'l.!LI:T S'I'1:I:C'I'.

The p r o f o ~ ~ n d l y influcntial "Reports of Medical Cases" by Richard Bright ( 1 877). whicll correlated clinical syl)dl.onles to morbid anatomy.

PLATE 11.

KIDNEY IN DROPSY.

Flc. l . External appearance of one of the kidneys of S A L L A W A Y (page 19.67. 75. &C.). ['art of the tunic is removed. to shuw more plainly the tuberculated aod motley appearance of the surface. The secretion of this kidney was albumino~is, and general dropsical etfusion was a promi- nent symptom.

F I ~ . . 9. A longitudinal section of the same kidney, showing its internal texture p a t l y altered : the general colour yellow.-the lighter parts r r r r more opake than the rest, while the coloured broken lines, proceeding in n direction perpcndicular to the external surfuce, corresponded nearly r i th the more vasculdr parts of the structure.

Frc. S. A portiw of a loogitudioal section of one of the same kiclneyr. which had been injected r i th fine red size bp the arterin, showing a l a r ~ e portion of the kidney nearly impermeable.

F1c.4. A portionof oneof the kidneys of C*D>IORE (page 14, 111 . 119, 115) in a state of degeneration after long sufiering from chronic t1i.l- ease. The state of the urtne r a g not particularly ascertnined, and no mn- terial dropsical effusion had taken place.

Fig. l

Fig. 2

. I l.

*,

Fig. 3 Fig. L

FIG. 2 : Richard Bright described and illustrated the morphological changes in the kidneys, and correlated them t o the clinical symptoms, leading t o nephritis being referred as Bright's disease.

Malaysian J Path01 August 1986

tissues during life, but none were satisfactory. The first attempt at a clinicopathological

correlation was made by Volhard and Fahr (1914), who subdivided glomerulonephritis into diffuse and focal lesions, with acute, chronic and end stage." In 1942 Ellis" attempted to improve this classification basing the criteria on the time of onset of clinical disease. It did not prove helpful to use clinical symptoms to diagnose pathological lesions.

In 1950 Perez reported percutaneous renal biopsy was a safe and relatively simple clinical procedure, which was confirmed by lversen and run.'* The examination of renal biopsies during life led to the present understanding of renal disease. Contribution of Immunopathology

Immunology as a science developed in association with the study of infectious diseases. The pioneering works of Pasteur, Koch, Beh- ring, Kitasato and Ehrlich in the latter part of the 19th century laid the principles of immunological response to injury and infections. The use of immunological and electron microsco- pica1 techniques have been utilized extensively in the study of human renal biopsy specimens, and in experimental animals. Studies on serum sickness in man and experimental animals implicated immune reactions in the development of associated glomerulonephritis.

From the observations of extensive expe- rience from human and experimental glomeru-

lonephritis, there appeared to be four major mechanisms of glomerular injury. M any human glomerulonephritides were due to the localization of circulating immune complexes, involving the formation of small, soluble antigen-antibody complexes in the presence of an excess of antigen.'39 l 4 . The localization of the complexes may be determined by its size; small complexes passing through the glomerular basement membrane and deposit in the subepithe- lium; larger size immune complexes through the subendothelium-mesangial system." It has been demonstrated that the glomerular capillary wall contains negatively charged molecules, which may influence the deposition of charged immune complexes, in the subendothelial and subepithelial regions.I6 . With immunofluorescent microscopy, it is now accepted that granular deposits of irnmunoglobulins along the GBM indicate immune complex glomerulonephritis (Fig. 3) e.g. in acute poststreptococcal glomerulonephritis, and other types of glomerulonephritis i.e. systemic lupus erythematosus with renal involvement.19 ? 20 Immune complex glomerulonephritis accounted for most of the human glomerulo- nephritis5. Antibodies may be produced against GBM, as in the experimental Masugi type nephritis2' or anti-GBM antibody nephritis, with continuous linear deposits of 1gG and C3 along the glomerular basement membrane (Fig. 4). Goodpasture's syndrome

FIG. 3 : Im~~itlnoiluo~~escence pattern of gran~~las deposits in the glomcsul~~s, which denotes an immune complex type glornerulonephritis, with 1pG deposits along the glomerular basement membra&. (Immunofluorescence microscopy X 350)

20

FIG. S : Light ~nicroscopy of early stage 1, membranous nephropathy which is indistin- guishable from minor change lesion. The capillary loops are thin and there are no spikes. (PAS-silver stain X 640)

lonephritis types 1 and 3 was based on the In diabetes mellitus thickening of the glomeru- additional presence of subepithelial dense lar basement membrane is a very early sign,"' deposits in the latter.37 - 38 Electron microscopy with concomittant increase in mesangial matrix. also shows the very striking change in the presence of electron dense deposits in the lamina densa of the capillary basement membrane in dense deposit glomemlonephritis, metnbranoproliferative glomerulonephritis type 2 with intramembranous deposits.39 140 41

Ultrastructural studies of lupus nephritis have shown a good correlation between the sites of the deposits and the pattern of glomerulonephritis, and the severity of clinical manifestation. In the groups of patients with

Amyloid may also be identified by electron microscopy, with fine non-branching fibrils, &

7-10 nm in diameter, arranged in criss-crossing bundles.46 The nephropathy in various dyspro- teinemias also show characteristic fibrils or tubules which may be formed in the subendo- * thelium or epithelium.47 " 49 Many of the hereditary nephropathies show characteristic ultrastructural changes. In Alport's syndrome there is segmental thickening and splitting of the glomerular basement membrane

subendothelial deposits, the renal involvement and small dense particles between the parallel was the most severe, while pure mesangial layers." 52 In benign recurrent haematuria, deposits do not lead to severe glomerulone- thin basement membrane diseuse, there may phritis. The electron microscopical examination of ~?lembranous lupus nephritis and idiopathic membranous nephropathy will show additional mesangial deposits in the former (Fig. g), which feature is important in distinguishing these lesions.29 9 4 2 *43 744 The presence of heavy intraendothelial cytoplasmic inclusions of tubuloreticular structures seen in over 95% of lupus nephritis may be an aid in its diagnosis, where dense deposits are seen at various sites in the glomerulus.

Electron microscopy has also contributed to the better understanding, and diagnosis of metabolic diseases with renal involvement.

be segmental thinning of the basement me&- brane, with the lamina densa reduced to less than half its normal thickness (Fig. 9), to measure as little as 60-80 m. This lesion can be diagnosed only by electron microscopy. Characteristic ultrastructural changes are also seen in the Nail-Patella sjwdrome, Fabry's disease and Familial Lecithiti-cl~ol~sterol Acyl Transferase Defi~iency.'~ ' ' THE W.H.O. CLASSIFICATIONS OF RENAL DISEASES 4

The study of percutaneous or open renal biopsies over the last three decades has contri-

9

RENAL DISEASE

3 C A C W

e, e, C I I

m 2 .- --S a P ELL' 0 C)

'i; E .i e, S + - 3 2 g.E

e,

- 5 5 g:; a:*;; m m W &, 2 .g .- e, m ";S .- a .e ' = W - $ 5 22

;h0 W *U2 5 C 0 ,a:d 0, a x he, W X as5 g Szc l U m m o g 0 U 2 " e .t; .,. h 0 .- E S 'S E G W E g 0 .z .C, L. 2 m - -

0-D U b: a 3 2 GG.Z?e.

Mula~tsian J I'athol I

RENAL DISEASE

-.. . \- - . . .-- --!!"?----g

'ICY -

Epi

FIG. 9 Electron micrograph of segment ,Lu,,,~rulus shows marked thinning of the glomerular basement membrane (BM) in a patient with "Benign recurrent haematuria". Epi = epithelia1 cell; M M = mesang~al matrix. (Electron microscopy X 6,300).

RENAL DISEASE

buted to the great progress in nephrology. With accumulation of knowledge, we begin to classify diseases and lesions as it is the logical road to scientific analysis. Several recent efforts were made by international groups t o provide a systematic classification." 56 " With the large numbers of papers published from many centres from around the World, it was imperative that international agreement was reached on the criteria for diagnosis, a standardized nomenclature, and a uniform system of classification. Renal diseases can present in a limited number of clinical syndromes, and it has been shown that almost any type of glomerular pathology can be found in any of the syndromes, and vice versa." The renal biopsy provides a more exact diagnosis if correlated with clinical and laboratory data.

The classification should reflect the present state of knowledge, and by using the interna- tionally agreed criteria for diagnosis, the

studies by nephrologists, pathologists and epidemiologists in one country can be com- pared with another. To achieve these objectives, the World Health Organization in 1974 established a Collaborating Center for the Histologcal Classification of Renal Diseases at the Department of Pathology, Mount Sinai School of Medicine in New York, under the leadership of Dr. J. Churg. The center worked with pathologists and nephrologists from 14 countries to produce the First Volume, Renal Disease: Classification and Atlas o f Glornerular Diseases. s9

The Book consists of two sections:- the first gives a complete listing of glomerular lesions and their definitions. The main clinical and morphological features including light, electron and immunofluorescence microscopy are described. The second section describes in detail and illustrates the various glomerular lesions. This standardized classification is being used extensively, and a shortened version of

Table 1 W.H.O. CLASSIFICATION OF GLOMERULAR DISEASES

1. Primary Glomerular Diseases (Glomerulonephritis and Related Conditions) A. Minor Glomerular Abnormalities B. Focal/Segmental Lesions (with only minor abnormalities in other glomeruli) C. Diffuse Glomerulonephritis

a. Membranous Glomerulonephritis (Membranous Nephropathy) b. Prolit'erative Glomerulonephritis

Mesangial Proliferative Glomerulonephritis Endocapillary Proliferative Glomerulonephritis Mesangiocapillary Glomerulonephritis (Membranoproliferative Glomerulonep-

hritis Types 1 and 3) Dense Deposit Glomerulonephritis (Dense Deposit Disease)

(Membranoproliferative Glomerulonephritis Type 2) Crescentic (Extracapillary) Glomerulonephritis

c. Sclerosing Glomerulonephritis D. Unclassified Glomerulonephritis

2. Glomerulonephritis of Systemic Diseases

3. Glomerular Lesions in Vascular Diseases

4. Glomerular Lesions in Metabolic Diseases

5. Hereditary Nephropathies

f 6. Miscellaneous Glomerular Diseases

7. End Stage Kidney 0

8. Glomerular Lesions Following Transplantation

Malaysia~ J Pathol Auptsr 1986

Table 2 W.H.O. MORPHOLOGICAL CLASSIFICATION O F LUPUS NEPHRII'IS (MODIFIED)

1. Normal Glomeruli a ) Nil (by all techniques) b ) Nornlal by light microscopy, but deposits by electron or i1nrnunotluorcsct'11cc micro-

scopy

11. Pure Mesangial Alterations (Mesangiopathy) a ) Mesarigial widening and/or mild liypercellulari~y (+ j b) Moderate hypercellularity (++)

Ill . Focal Segmental Glomerulonephritis (associated with mild o r llioderate nlesang~al alterations) a) "Active" necrotizing lesior~s b) "Acrive" and sclerosi~ig lesions c) Sclerosing lesions

IV. Diffuse Glomerulonephritis (severe mcsangial, endocapillasy ul- ~ilcsangio-capiIl21-y psolil'e- ration and/or extensive subendothelial deposits) a ) Without seg~~lental lesions b) With "active" necrotizing lesions c ) With "active" and sclerosing lesions d ) With sclerosing lesions

V. Diffuse Membranous Glomerulonephritis a) Pure membranous glomerulonephritis b) Associated with lesions of Category 11 (a or b) c ) Associated with lesions of Category 111 (a -- c) d) Associated with lesions of Category IV (a - d)

VI. Advanced Sclerosing Glomerulonephritis

the classification is shown in Table 1. The W.H.O. Morphologic Classification of Lopus Nephritis (see modified Table 2) is now being used almost universally to grade the severity of the lesions, and prognosis.

The second volume, Classification and Atlas o f Tubulo-Interstitial ~iseases" again represents a collaborative effort of pathologists and nephrologists from many countries of the World. A great variety of aetiological agents and several pathogenetic mechanisms lead to tubulo-interstitial damage with similar histological changes. Therefore, this classification takes into account aetiological, pathogenetic and clinical features. The format of the book is similar t o volume I.

The third volume, now in publication, will deal with Vascular Diseases o f the Kidney and Development and Hereditary Diseases. The fourth volume, now in preparation will deal with Infectious and Tropical Diseases of the Kidney.

These four volumes should, hopefully,

classify all the known renal diseases, excluding tumours, and enable pathologists, nephrologists and epidemiologists to diagnose the various diseases seen in their countries using the same criteria, and therefore compare their data. This should lead us to a better understanding of renal diseases, and hopefully towards better treatment and prevention.

IDENTIFICATION O F MAJOR RENAL LE- SIONS IN SOME CLINICAL SYNDROMES

Nephrotic Syndrome

It is the knowledge gained from the study of renal biopsies which has helped us t o better understand this disease(s). Though the aetiological agent(s) may not be known in the majority of cases, it is now well established that Minimal change (lipoid nephrosis) is more common in children than in adults. The majority respond well to steroid therapy with complete remission of the proteinuria. When they d o not respond, renal biopsy often reveals focal segmental sclerosis and hyalinosis. The information gained

RENAL DISEASE

I'rom studies 1.rorn many centres, and especially is now recognized to be the most commotl thc Reports I'rom the International Study of primary glomcrulonephritis in many parts of Kidncy Discases in Children liavc revolutionized the world." The lirst cases in Southeast Asia t l ~ e treatment of cliilrlliood rioplirotic syn- were reported from Singapore in 1974."*6x, d lle5h. 5 8 . h l . 6 2 . 6.3. h4 a Mcnihratrorrs ncphro- The diagnosis of' this discasc is made by immu- ,7nrl11, is :I colnnloli cause ot ' ncphrotic syn- nupatliology, with thc I'inding of the cliaracte- drolnc ill ad~rlts. a r~d I I S I I ; I I I L . du 1101 I.CSI)C)II~ to ristic mcsangial deposition of IgA (Fig. IO),

8 cor[icostcroicl t l i e r a l ) y : ' ~ ~ i Singapore 10'1; of' which Inay be associated with IgG and/or IgM patients with IRA ~ l e p h r o p o t l ~ ~ ~ prcsent with in approximately 50T of the cases. Thc activa- ncpl~rotic s v n d r o ~ ~ i c . ~ " lion of' cotnplcmcnt C3 is via thc alternativc

pathway.69 and properdin may be utilized. Haematuria This anrl the predominance of IgA hclps to

l-l lc nlaiul- causes ul . l laenla~ul~ia . c i t l l e r gross distin~uish this from mesangial lupus nephritis or microscopical. havc includcd tumours of u'ith IgA!IgG

t l l c kidney, r c n a ~ pelvis, Llre ter , prostate and Epidemiological studies done in Singapore

urc t l l r a : rcllal and vesicle stones, infections, S ~ O " ' C C ~ IgA tiephropathy t o occur in > 5057 of a r l a l y c s i c I l c , , ~ r o p a t l l v papillary necrosis. young. male army rccruits with asyn1ntomatic vascu la l - lnal l .ormat~ons, inl.cctions and coawla- microwcopical Il ;~c~iiaturia-p~.c, tcinuria.~' '" and

abnormalities and polycystic kidney IgA dcposits in 4V ol' a "normal" autopsy discasc. t l l c advcnt o l . renal biopsy studies, p o ~ u l a t i o n . ' ~ The discase most commonly scvcra l g l u n l c r u l a r lesions ol. nlajor importancc prescnls as haematuria, which usually follows

as causcs ot' haematuria liavc bccn discovered. an uppcr respiratory inl'ection. Other clinical

T/,irl basemcnr l,7c,mbranc disease and A(porr S manifestations arc ncphrotic syndrome, acutc s~~ndronic havc ulrcady hccn described. nephritis, hypertension or acute renal failure:

~l~~ glolncrulonephritis of lna,ol- with a large proportion being asymptomatic

importancc as a cause I,aen1aturia is lgA and dctectcd on routine medical examination. l \ fc . t~hropa~~~l~, (Hcrwr li l-st desc ribed A bio13sy studies have show11 that i l l P ; ~ ~ . ~ ~ I~)(,s..(,~,(>z. 60 to protcinuria > I gmlday, glomerular sclerosis, Fcographical ilnportallcc i n we artcrial lhypcrtension, severe intra- and extra-

s~loLlld tliscLlss t l , c problcnl ill detail. capillary proliferation and periphcral extcnsion

l n i c i a l l y i t was acccptcd as an entity, but of ' IgA deposits as dctermined by immunolluo- *

8 FIG. 10 : The cha~.actcristic distribution of' IgA deposits along tlic ccntrilobulrr stalks ol'

the glomerular ~nesangiuni in IgA nephropathy ol' Berger. (Immunolluorescence microscopy X 350).

P

29

FIG. 1 l : IgA neph~upathy with extensive peripheral extensions of thc deposits along the subendothelium of the glomerular basement membrane. (Inimunot1uorescence microscopy X 350).

rescence (Fig. 11) and electron microscopy, denote a poor The IgA deposits cause mesangiolysis and also stimulate the cells to proliferative and ultimately lead to glomerular sclerosis.75

IgA nephropathy has immunopathological features similar t o the glomerulonephritis in the Henoch Schonlein s y n d r o ~ n e , ~ ~ 77 78 and is considered by many to be a forme fruste of Berger's disease with systemic manifestations. The aetiology of the disease(s) is as yet ill understood. Figure 1267 shows the possible mechanisms for the IgA mesangial deposits, which also can be seen in cases of liver cirr- h ~ s i s . ~ ~ +80 cancers, especially lnucin secreting a d e n ~ c a r c i n o m a s , ~ ~ , and ankylosing spondy- l i t i ~ . ' ~ Both human and experimental studiesa3

indicate the mesangial IgA deposits are probably derived from mucosally-presented antigen(s). There is increased production of IgA and its polymers by both mucosal and peripheral blood lymphocytes. Mediators other than IgA alone are involved in the glomerular injury. The role of the phagocytic reticuloendothelial system in the catabolism of IgA associated- immune complexes has also t o be studied. Though the enigma of IgA nephropathy has not been solved, it is likely that with increasing knowledge of pathogenesis and mediation, this widespread disease will ultimately lend itself t o more effective treatment and hopefully its prevention.

Acute Glomerulonephritis The clinical features of Bright's disease or

acute nephritis have been well documented t o occur either sporadically or in epidemics especially after streptococcal infections. It T

has been known that the ma,iority of patients recover, with a proportion going into chronic renal failure or dying in the acute J Though the disease has been recognised since Richard Bright's descriptions in 1827,9 it is the study of sequential biopsies that have given us an insight into its b e l ~ a v i o u r . ~ ~ . "n the acute phase, there is diffirsc) endocapillary proliferation with exudative lesions uf polymorphonuclear infiltrates. There are subcpithelial granular deposits of immune complexes with IgC and C3, with subepithelial l iun~ps seen on electron microscopy. These changes dis- appear or resolve within 2 to 3 months. In some cases, the mesangial hypercellularity may persist for years, with these niesangial changes corresponding t o the chronic latent phase of the disease. In the patients with rapid progression and poor prognosis, the underlying pathology is usually the development of super- imposed extracapillary proliferation with cres- cents f o r i i ~ a t i o n . ~ ~

IgA nephropathv is now also known to present as acute nephritis in approximately a

1 of cases.69

RENAL DISEASE

NASOPHAWNX

"lr-d a n t i m 6) kcreascd IpA-

spccitic wppnsvr T cells activity

Removed by Mesangium Latent Renal Symptomatic No symptoms, no renal ckvnag~ disease Renal Oiuaso

(Non-Nephritogenic) v RENAL FAILURE

FIG. 12 : Possible mechanisms for IgA mesangial deposition. (Courtesy of R. Sinniah, Am J Nephrol 1985; 5: 79).

Renal Lesions in Systemic ("Collagen") Diseases nofluorescent and electron microscopy.29, 441

Renal biopsy has contributed greatly to the 5 9 9 The sites of immune complex deposits understanding of the multisystem, "collagen" give a good index of the severity of di- diseases. It has been shown that SLE patients sease; most severe with subendothelial and with no clinical or laboratory evidence of renal intramembranous deposits. Disease activity involvement will show a glomer~lonephriti~ can be determined by .the finding of fibrinoid or tubulo-interstitial nephritis by either light changes, karryorrhexis and interstitial inflam- microscopy or more commonly by immu-

Malaysian J Pathol August 1986

mation. In Sclerodemza, the vascular damage quently the intrarenal capillaries and can be determined by biopsy even in the arterioles are occluded by microthrombi. absence of hypertension. Wegener's syndrome After a few days there is renal cortical and Goodpasture's syndrome can be diagnosed necrosis. - accurately only by biopsy. These conditions may lead t o rapidly progressive glomerulonephritis, and a renal biopsy may show a diffuse crescentic glomerulonephritis (Fig. 1 3), with linear fluorescence along the glomerular basement membrane of IgG and C3 in Good- pasture's syndrome (Fig. 14). This finding of anti-GBM antibodies may be indicative for instituting immunosuppressive treatment and p la~maphares is .~~

(ii) Acute rejection may occur at any time during the life of the graft, but are un- common after one year. There is a wide spectrum of changes with combinations P of predominantly cellular rejection and antibody-mediated vascular damage. In early stages the rejection is often of the cellular type and is amenable t o immunosuppressive therapy. The biopsy shows the interstitium and intertubular ca illaries R t o contain mononuclear cells, lymp ocytes and lymphoblasts (Fig. 15). The glomeruli, Biopsy In Renal Transplantation

Dialysis and renal transplantation were instituted widely in the second half of the 20th Century. Failures in transplantation were identified to be rejection only when renal biopsies and nephrectomies were examined under the microscope. The stages and the pathological features of transplant rejection have been well documented by

arterioles and arteries are usually normal, and there are no significant immunoglohulin orcomplement deposits. With predominant1.v humoral (vascular) rejection there is interstitial oedema and focal haemorrhages. There is only slight to moderate mononuclear cell infiltration. T h e vessels show severe vasculitis and contain fibrin thrombi,

(i) Hyperacute rejection which occurs some 10 to 20 minutes after blood flow is re- established in the kidney. The glomerular and intertubular capillaries show platelet aggregates, followed by polymorphonuclear neutrophils along the capillary wall, with fibrin in the lumen soon after, and subse-

and there are foci of fibrinoid necrosis in the walls of small arteries and arterioles (Fig. 16). With immunofluorescence microscopy, IgG, IgM, C l , C3 and fibrinogen are commonly present in the wall of arteries and arterioles and glomeruli. If uncontrolled it leads to cortical necrosis.

:r m: -- *, * ;#,- - !Y<:-:-T4<y - c - - y -. W.* W*-+ a , -. - . -

C i. L .

l', . i . I I

FIG. 13 : Crescentic (extracapillary) glomemlonephritis with circumferential involvcnient in a patient with rapidly progressive glomemlonephritis (PAS silver stain X 350).

RENAL DISEASE

FIG, 14 : llnniunofluorescence microscopy of renal biopsy from the case in Fig. 13 showing 1gG and C3 linear deposits along the glomerular basement membrane. Patient was diagnosed Goodpasture's syndrome. (Immunofluorescence microscopy X 300).

FIG. 15 : Acute rejection of human renal allograft showing predominantly cellular rejection with massive mononuclear cell infiltration. Lymphocytes-lymphoblasts are

b found within peritubular capillaries and interstitium, and some of the tubules show necrosis. (PAS silver stain X 250).


FIG. 16 : Acute rejection of human renal allograft predominantly humoral vascular type. There is a vasculitis with fibrinoid necrosis, and infiltration of the small artery by polymorphonuclear neutrophils. There is lymphocytic cellular infiltrate of the surrounding interstitium. (H & E X 250).

High dosage steroids are needed, and in dense deposit disease, type 2 mesangioca- * resistant cases, the outlook is poor. pillary g lomeru l~nephr i t i s ,~~~ membranous

(iii) Chronic rejection nephr~pathy,~' focal segmental glomemloscle- This may occur after one or more episodes rosis, 96 and r Henoch Schonlein purpura. 97

of acute rejection that are partially respon- Recurrence of other metabolic diseases havs

sive to high-dose steroids. The biopsy been reported.

shows arterial narrowing and glomerulopathy, with tubular atrophy and interstitial fibrosis. Tubulo-Interstitial Diseases

Therefore the renal biopsy can establish the accurate diagnosis in the recipient as to the condition of the allograft. In the early post- transplant period, the biopsy can diagnose whether hyperacute rejection or acute tubular necrosis is the cause of the renal disorder. It is now also well recognized that a number of renal disease processes are likely to recur in transplanted kidney. The recurrence has been reported in anti-GBM-mediated glomemlone- p h r i t i ~ , ~ ~ Berger's IgA nephropathy,

Diseases affecting the tubulo-interstitium may mimic many of the clinical syndromes due to lesions in the glomerulus. Tubulo-interstitial nephropathies represent a heterogeneous group of disorders with diverse aetiologies. This group of disorders includes pyelonephritis and drug- induced kidney disease. These various conditions may mimic the clinical syndromes of acute nephritis, acute renal failure, massive proteinuria leading to nephrotic syndrome, gross haematuria and chronic renal failure. Biopsy will 4 show a variety of tubular changes, interstitial

RENAL DISEASE

oedema, and cellular infiltrates of lymphocytes, eosinophils, plasma cells, histiocytes and less commonly polymorphonuclear neutrophils, in acute tubulo-interstitial nephritis, which will help to distinguish from the above clinical syndromes due to glomerular diseases.

Renal pathology including gross and microscopical examination, im~nunofluorescence microscopy and in some cases electron microscopy, when taken into account with the clinical, r;ldiological, aetiological and pathogenetic mechanisms have helped in a better understanding 01' tlic pathogenesis and treatment of many ol' thesc tubulo-interstitial disorders. The pathological features of tubulo-interstitial discases, aetiologies and pathogenetic mechanisms have been well documented in several books60, 9 8 t 99 and time does not allow us to go into the ddtails in this area of renal pathology.

Vascular, Congenital and Hereditary Renal Diseases

Thcse areas of kidney disease are too vast for any meaningful discussion in the time allotted for this lecture, except to comment that the renal pathologist has, and continues to contribute to a better understanding of these discases.

THE FUTURE ROLE O F RENAL PATHO- LOGY

In this brief lecture, I have outlined the contribution 01' pathology in the better understanding 01' renal diseases. Biopsy is now widely used for diagnosis, management, classification and investigation of kidney diseases. At present i t is thc only method of making a precise ~norphological diagnosis, on which the treatment and prognosis are based. Much information gained fro111 the correlation between structure and function in health and disease has led to a better understanding of the various diseascs that affect the kidney, and which present in a limited number of clinical syndromes.

The classification and exa ln i~~a t ion of the kidney along conventional lines by observing the changes in the glomerulus, tubules, inter- s t i t iu~n and blood vessels is artificial as the various structural elements of the kidney are closely inter-related anatomically and func- tionally. These inter-relationships are now being better understood, largely due to the ~norphological studies correlated with physio- logical and clinical diseases, and biochenlical functions of the kidney.

Molecular biology has made impressive strides in the last decade, and attempts are

being made to define the molecular basis of disease. We may be on the threshold of stud- ying the cell components and products of cells which may enable us t o better understand the modes of renal injury and the pathogenetic mechanisms involved. These new investigative approaches should prove invaluable in the understanding, better care of the patient with renal disease, and finally its prevention. It appears new and exciting horizons are opening for our young renal pathologists, and our discipline will continue t o be a major contribu- tor to renal medicine.

ACKNOWLEDGEMENTS

This work was supported by grants from the National University of' Singapore, The Singapore Turf Club. and I I I C P.B. Davar Memorial Fund. 1 wish to thank the Technicians and Secretarial staff of thc University Depart- ment of Pathology.

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Documents

THE FIRST K. PRATHAP MEMORIAL LECTURE · delivering tlie First K. Prathap Meriiorial Lectul-e. The late Professor Prathap had a great interest in the study of renal disease, and had