A consideration of the histopathologic basis for the nephrotic syndrome

A Consideration of the.Histopathologic Basis for the Nephrotic Syndrome B y D~,vu) P.

EAItLE~ ROBERT B. |ENNtNC,,S ANl) M.~"tA BEnN~:

E W C O N C E P T S Jn medicine :have been a s confusing and controversial as have been fires e of )'nephrosisy .'rod fl-~e '~nephroti c syndrome." The confusion and file controversies are still 3vit h us. But serial renal biopsies, imW0ved technics for histol0gic examination, including electron microscopy( and, above a!l,careful Correlation of histologic findings witht!~e ~natura ! !fistory'.~ and biologic aspects of file disease states associated with the nephrotic Syndrome are beginning to p u t some Orderin tlae cilaos, First,• however, w e will m a k e a few: general remarks about the classification of renal disease. l n o t l r :considerations of tlle nephr0tie Syndrome we x~dli att e m p t to review the historica!de~,,elopment of t h e concepts, define the syndrome, and, o n the basis of current information incltl(ting some Of our own observations, we will suggesi w h a t seems to uS to be a reasonable synthesis of fact and fancy. Our remarks will not be rigorously restricted t o renal biopsy findings.

F

CLakSSIFICATION OF RENAL DISEASF.

Diseases of: t!m kidney still defy satisfactory pathologic o r Clinical Classification. Obviously an etiologic classification would b e most Useful. Unfortunately, known etiologies are all too few. T}le Same agent o r disease may produce a variety of different Pathologic changes in the kidney :and, conversely, a particular renal histologic lesion may be the result o f a variety of unrelated insults. T h e clinician favors a few easily observed clinical abnormalities in his attempts to approadl tlm problem logically. Thus,: the clinician - is very likely tO be satisfied with a diagnosis of nephrosis o r perh.aps chroni c g!omerulonephritis " i n a n y patient w i r e tinS the nephroti c syndrome, even though a considerable n u m b e r of diffexent diseases c o u l d b e resp0nsible. Thepaflaologist Cannot escape t h e necessity to Color his diagnosis, e0rrectly orline0rrectly, by :certain facts he f i n d s i n the clinical protocols of the patients he autopsies. Patches/of interstitial fibrosis w i t h some round Celt intlItration are likely t o b e a t t r i b u t e d to pyelonephriti s in children or young adults but are usually thougl~t to be fl~e result of vascular nephroscierosis in the elderly, unless perchance theclinieailhist0ry recorded a n episode of urinary tract infection a l most •"mytime in the past: Front:the Departmmut:~ of Medicine•and Pathology, Northwestern University Medical Schooi a n d the DelJartmeTzts o[ Medi¢-ine of •t h e V. A. Research Hospitat, the Passaeant Mcvnorial HospitaLand the/Chicago ~Veslezd Memor~al Hospital; Chicago. Supported in part by grants [or the U. S. Public Itealth Sercice (H-1815 and H.1890), the Otho S. A. Sprague Foundation a n d the Hart[oral Foundation. Dr. Bernik ts a Trainee Of a U. ,S. Public Health SerLqce Cardio~agc~dar Research Training Grant (HTS-5344). 148

T t l l i, 1 ] [ ] N T O P A T i

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Then, too, .some renal diseases have rather characteristic renal lesions lo which we c a n pin labels, such as renal arnyloidosis and diabetic glomeruloscler-osis .(Kimmelstiet-X,Vilson disease). -Even though we don't k n o w the .precise etiology or exact pathogenesis it seems quite logical to l.ise these labels. In contrasl; several ctisease states, such as periarteritis.nodosa.and systemic lupus erytl)ematosus, which can b e diagnosed quite definitely on clinical grounds, may involve the kidneys in a variety (?f different, ways. Thus,. in these and similar circumstances the temptation is great to make renal diagnoses.sue1| ns lupus nephropathy even though t h e ltistologic evidence iS.llOt conclusive. P e r h a p s one .of the greatest advantages that has a c c r u e d to the recently developed technic of pe,'eutaneous renal 1)iopsy!-a has been the growing necessity., of cooperation b e t w e e n patlmlogist and e!inieal inves{igato f Even brief contact, if serious, can go a long way in developing a common language...But, as things stand now, we believe thai n o maiversat system of classification for bilateral parenehymal renal disease is reasmml)]e. Until S~mh a t | m e as an-aeeeptabte classification system can b e achieved it will remain extremely important for a]l workers (especially, authors) in the field of renal disease to define aeeurately whal they mean t)y the labels they attacr]~ {o disease.states. "l'l-1E N F.t~ !-11~O't'1 (5 S"t'.N" l)lt(.)i.X 11:"

]'lie nephrotic syndronm is lisually dei'ined as tlie combination of heavvproteinuria, decreased serum altnun[n, edema and hyperlipemia, it has been d e a r since the time of R i c h m d Bright 4 t h a t s o m e patients with renal disease tire edematous and have lipenclic serum and mm'ked prote.inuria. Bright found large white kidneys at p o s t m o r t e m examination of patients with this clinical picture. N1any investigators ]lave confirmed Bright's observations, l lowever, it soon hecame a p p a r e n t that some patients xvit]i the n e p h r o t i e syndrome might have n o r m a l , slightly contracted, or even very granular contracted kidneys. . at postmortem examination. These gross findings sometimes may be Correlated fairly well ~.git}i the clinical course. T h e l a r g e white kidneys are usually found in patients dying while markedly e d e m a t o u s ; grossly, nonnat kidneys mayi:be noted i n patients who die while, in remission;, while c o n t r a c t e d kidneys are found in patients dying in r e n a l failure usually some m o n t h s after the disappearance of e d e m a . OnfortunateIy, liowever, the clinieal C o u r s e may be as variable as elm gross pathologic findings:-Tim syndrome, often lasts for So m a n y years that objective correlations with end Stage.material o b t a i n e d at .autopsy are impossibl e . T h e difficulties of elinie0Pathologie correlation are increased by the fact that the nepllrotie s)mdrome is .not exMbited by reD, m a n y . p a t i e n t s w i t h renal disease. O u r renal clinic in a larg e university in the center of a metropolitan a r e a h a s . h a d the opportuni~, to study carefully 0nly 4~) patients with this symptom Complex during the past four years. It is, therefore, difficult for a n y one investigator:to follow:as m a n y p a t i e n t s : a s h e w(mld.lil
.

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syndrome o n l y r a r e l y could be correlated with concurrent histologic studies. Many internists, frustrated in their attempts on clinical grounds to distinguish between nephr0sis and Chronic glomerulonephritis, came to believe that ne;phrosis w a s m e r e l y One pllase of chronic glomerfdonephritis. Pediatricians, however, who d i d ' s e e spontaneoUS complete remissions in nephrosis in childhood, genera!fy fel~ that nephrosis and 6hronie glomerulonephritis were different ,liteases. Fortunately, ,lie d e v e l o p m e n t o f t h e perCutaneous renal biopsy technic has made:possible study of renal histopatlmloKy early in tim ~course of renal disease, ill additi0n, ~elec.tr0i~ ~nicroscopy and ne~wer Cutting and staining technics have given ,_is additional powerful tools for studying glomerular lesions. Driginally, ,nephr0sis was thought tO be d u e t o diseas~ of the tu|mles. • However, L6hlein,r"~Schlayer,;':Addis m and BelU * related t h e p r o t e i n u r i a of nephrosis to glonierular lesions. With t h e a d v e n t 0 f the g l o m e r u l a r filtrationtUbi~lereabsorption theories of renal function, leakage or loss of protein through dmnaged glomeruli became generally accepted as the basic pathogenic mechanism. All:availal)le physiologic, pathologi c and experimental evidence, indirect as i t is, confirms this point of view. T h e many hyalinc droplets in the tubule eells appear to represent reabsorption of excess amotmts of protein lost iilto the flltratc 6f diseased glomerulL Reabsorption and storage of lipids in the tubules undoubtedly is responsible for the "'large white kidney" so h'equmxtty ~:;sociated with tim nephrotic syndrome. Despite current.evidence, in f a v o r o f the gh, n~ert,lar origin of the nephr,,tic s y n d r o m e , the possibility that impaired al~ilit,, o f the t[d)ulcs to reabsorb protein might Flay a r01e in some instances o f the nephrotic synch'ome has not been entirely ruled out. At best, however, this pathogenesis could be applied o n b , to those patients who have n o demonstrable glomerular capillary basemen, m e m b r a n e lc~ions. On the basis of present evidence we feel that this is an unlikely pathogenesis. T h e nephrotic sy,ndrome may occur whenever albumin is lost in the urine in amounts suf~cient to rest, It in Such a decrease in serum alhtmain that edema eilsiies, Generally, btit not always, t h e deere.ased serum albumi|~ is associated with lwperlipem!a and !~ypereholesterolemia, Renal loss Of albumin is the ~ -

5

G

m a y ' b e influenced by extrarenal metabolic, hormonal or nutritional factors. H e n c e , attempts have been m a d e t o establish quantitative criteria for the nephrotic Syndrome. Berman and Sehreiner, ,v-"for instance, " base their definition of the nephr0tic s y n d r o m e on 24 hour urinary protein excretion. T h e y classify m-~-patient ~ h 0 excretes more than 3.5 Gin. p r o t e i n p e r day as nephrotie. A1d!0ugb most patients w i t h the c o m p l e t e nephrotic syndrome d o e x c r e t e m o r e than 3.5 Gin. protein per day, s o m e w i t h o u t any other d e m e n t of the nep|irotic s-¢ndromc may" have transient proteinuria o f this magmitude for days Or w e e k s . l~aldwin and McCI{lskey~a define the nephrotie s y n d r o m e its "~em~I loss of alb u m i n resulting in diminished serum eoncentratkm, vi~riably associated w i t h hyperlipoidemia and edema." T h e y "consider tlio serum albumin coneentrathm reduced w l m n it is less than 3 Gin. per 1 0 0 ml." Here again one may set* ~flqculties x~qth arbitrary quantitative limits of lhis sort. Not infrt'quently we

T t I I,; I | I S T O I ' A T ! t O L O G t C EIASIS I*'Oll TI*Lt~ R I ' I P I I I i O T I ( ' I

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].5.I

have obsexved patients with slight to m o d e r a t e p m t e i n u r i a (less than 3.5 Gin. per 24 hours) who had serum albumin concentrations less than 3 Gin. per 100 ml. due to nutritional factors, to i!~f!aminator3" disease or to liver disease, and in whom the diagnosis of the nephrotic s y n d r o m e would be questionable. Wilson and I-leymann zl have gone so far us to suggest t h a t t h e majority : o f patients with acute glomer~donephritis have u transient nephrotic syndrome on the basis of decreased concentration of albumin and increased concentration of cholesterol in the serum. One might point out, however, that the edema of acute gtomerulonephritis is associated with hyperv~!emia, ~:''27 w h i l e that ef the full Mown nephrotie s y n d r o m e is associated with hypovolemia. ~'*-~ F o r our present purposes, which a r e to define the types of renal lesions associated with the ncphrotie syndrome, we r e q u i r e that o u r patients have unequivocal evidence which included heavy proteinuria, serum albumin less than 3 Gin. pe r 100 ml. and edema not due to ~letnte glomerulonephrit!s or t o congestive heart failure. \Ve recognize that rigid criteria will eliminate from consideration patients with slight to moderate proteim,ria which very well could be due to t h e same types of diseases or glomerular lesions responsible 1Lot the full-blown nephrotic syndrome. ANALYSIS OF It ts'rot,oetc: [;'INDtN(;S ty TIIt.: NI::I'I~llOT~(: SYND)IOMI;: Even before the t)erlh>rmanee of renal biopsy, a m n n b e r of workers had noted the association of the nephrotic s y n d r o m e with certain systemic diseases . ar~C]~ amyloids~ch ~,s systemic lupus tx;.thcmatosus, diabetes l~el~lt . . . . us . . . .*. .... osis, ~,~:~ and with several infections such as syphilis e*'e*~ and malariaY 7 It also has been deseril:~ed as being caused b y renal vein throml~osis, ='~.:::* d r u g toxicity (especially to Tridione :*') and mercurial dim'eties :~ ), bee stings :~ and poison oak or poison ivy r e a c t i o n s . :~:~.:~* Finally, the development of the nephrotie sw~drome has been noted d,~ring the course of chronic proliferative (poststreptocoeeal) N u m e r o u s authors are l~eginning, to report renal lnop. y findings, in patients: with the nephrotie syndrome. ~ - a , ~ - , t - * , ' ~. * . ~' Almost all series contain a se;~ttering of tt~e conditions described above. ]h~wever, the majority of instances are not associated with a n y recognizable etiology or systemic disease. Further, tl{e types of patients i n c l u d e d i n any small series is subject to the bias of patient material available or the r e s e a r c h i n t e r e s t s of the investigator. T h e hisloI~athologic criteria used . b y different authors have seldom b ~ n described and their terminologies rarely defined. Nevertheless, i t has b e c o m e a p p a r e n t that Mmost e v e r y series included a fair nutnlmr of patients, especialIy a m o n g children, whose gtomeruli a p p e a r normal by Tight microscopy. Vernier and his colleagues, 4a hn-. instance, found ¢mly ncmnal glomeruli in the :first biopsies in I4 of 21 childrm~ with the uncomplicated or "pure" nephrotie syndrome. By electro n miFr0s¢0py "smudging . in the glomerular epnthehal eell,~ w a s demonstrated, as so ably described b y F'arquhar4'~.4 ~ a n d ~thers. 4'','~ ,,,1 The remaii,ilJg l)alients in this group w e r e said to have minimal or m o d e r a t e proliferative glomerulon(,l)hritis, Sev(~,n ehihtre.n with a combination of the nephrotie s y n d r o m e and "'nephritic" signs, such ~ls he,maluria, hyl~n'lensio|| m~d some impairment l'~|"renal function, w~'r~e found o n biopsy to have "'Inlmlar" glomt~,r|n-

I 5 . .O, .

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lonephritis either alone or in combination with "membranous" glonmrulonephritis. A m o n g adults, P011ak, Kark and their c~glleagues ~ found six o~ N3 nephrotic patients t o h a v e normal glomeruli by light microscopy. B a l d w i n and McCluskey ~a. .state: I~ a f e v ¢ i o f Our patients~ in wliom }~iopsy. was p e r f o r m e d early in theirdisease, there were VirtuaI!y no glomerular abnormalities appare n t o n ligllt microscopy: 0 In contrast, H e r m a n and Sd~reiner ~z have described gl0merular abnormalities in renal biopsies h'om all l)Lzt 6 h e of 45 patients with th e?nep!ir0tic~syndrbm e. A l l t h e s e and also 0 f l i e r investigators h a v e u s e d descriptive diagnoses such as membranous, m~)u ar and s u b a c ~ t e glomerulonephritis to ide!atify t h e gl0meruIar lesions sc~en in ren~it biopsies from tta ei r nephr0t ic patients. AI)ULTS W I T I I " r i t e N ~:PIIII(:YI'IC SYNDI{O~\ [ 1,3 The remainder of tiffs essay wil] b e-devoted to an analysi s of our own ol)servations i n 3 5 adu!ts with the nephrotie*syndrome, w i t l i references to observations from the literatm-e. Each p a t m n t had at one time or another unequivocal e~idenee of the nephrotie syndrome , and from each at least one a d e q u a t e biopsy w a s obtained , Proteinuria r a n g e d £ r o m 4 t o 40 Gin. per dav and all had senim a l b u m i n c0neentrations less t]mn *3 Gin; p e r 100 ml. Hyperctmlestcrolemia was present in:all hut/two patients: ]n t h e t w 0 excePtiOnS sertim Cholesterol rallies were i n t h e high nonnal* range,' Our Observations are far fr~ml complete a n d , therefore, w e Sometimes will go beyond. ~lvailable ,~ftets-:, in making :our intcrpretations..However; w e will m a k e every effort to separate fact anti fancy. O u r patients are Classified into Several main groups in taMe I. O u r classification like of o t h e r workers in this field, is based on descriptive histopathology and is not intended to Convey any etiologic or patliogenetic implications. Sum S mattes of several laboratory Observations, and of the response of tlie patie,~ts to steroid therapy are presented i n t a b l e s 2 and 3, OBSI~VATION$

QN 35

No Glomer~Har LeMons NJ Light A.Iicrosco;~tl By light microscopy t h e glomerular basement m e m b r a n e s a p p e a r e d thin a n d normal in all g l o m e r u l i s~udied i n n i n e 3atients with the ne hrofie s a drome. Endothelial Cells Were p r e s e n t in normal numbers, a s were g l o m e r u l a r er~ithe!ial ceils (fig: l ) . Presumably the epRhel!al cell foot processes in t h e gl0meruli of:all these patients would h a v e a p p e a r e d diffUsely ~ u d g e d by electron rnicr0Scopy, a s described b y Farquhar~S .~ and ofhers2~,~~°,~x Olomeruli from four. o f nine patients~ in this .group .were s t u d i e d by ~eleetr0n microscopy. T a b l e 1 .--Hisiologlc D i t z g n o s i s o]~ Ret~al Biopsy 11~ 35 A d u l t s w i t h

the Nephrotic S y n d r o m e t t l s tol~ltic JJiagr~osis

" N o r n m | glomeradi ''° ~lembranous Proliferative Miseellancol~s Total

*6|omendi normal b y light microscopy,

]t4o. o f Patients

l*r~g~si+~ Disease

9

7 14 5

I 4 8 ,5

4 5

~3

18

II

Dead

1

T I t I~ I J I S T O I > A ' T H O I , O f ; I C B A S I S lvO]:f T I , t E N E P l I I ~ O T I C SYNDIIOIM|{

153

Fig. ! : - - ( J a ' 0 This glomeruhis is from at bhJl~Sy obtahmd in :l-31 year okl white male 22 weeks after lie first became nephrottie. Tim ed0mi~_ and the l:m)tehmri~ disai)peared after several weeks of Ireatment with Steroids. However, 6 Weeks befi~ro the biopsy lhe tmpln-otie syiMrome recurred. At the thi'm t,f biop:;)' the ~urina Q" exerot~ot, of l)rotei~ was 6--I0 Gin. per daV..Serum :a|bm.nin Was 1,0 Gin. per 100 ml. and ~erum el~otesleroI 97.5mg. T~er i 0 0 "m| lie was agair~ treated"with S}(~roids for 33 Weeks. "l'he edema and tl'-~e*proteimu-ia" disappeared and have not reem'rc:d durin~ three vein's of follow-~q). All 2,'3 gl0mcndi, obtained w e r e imrmal.and .similar to the one illu:;trated. Note tlmt the. capilhu-y loops are. wide|v patent~ that the baseme~t lne_,n[mm,~ are thi,~, and that t h e ghmmrulus has a ~mrmal degree of" eellular~ty. The <\vt~p!asn~ of t}m lgroximM tu|.)nhtr dells show m;~II(, hvalilte dr0plel.s. (He|lv's [ixation. 21, section, hematox;,,lin alld eosin stabl, X 8]-t). T i m .glomcru!i in o n e biopsy , o b t a i n e d from a p a t i e n t some. months :after: a steroid i n d u c e d remission, w e r e e n t i r e l y n o r m a l (fig. • ° ) . Ea0h :glmn0rulus s t u d i e d in the r e m a i n i n g p a ~ 0 n t s d e m o n s t r a t e d u n i f o r m l y s m u d g e d f o 0 t pro7 cesses (fig. 3 ) : T h e s m u d g i n g ",',,as not v i s i b l e i n thh] sections: ( o u r m a t o r i a l i s r o u t i n e l y cut at 2 and 0.5 p. s t u d i e d b y light m i c r o s c o p y ) . H o w e v e r ; It h e [epith e|ial dells o f t e n a p p e a r e d s w o l l e n a ~ d m o r e bas0phiiic t h i n ( normal. E v i d e n c e is a c c u m u / a t i n g that the epithelial ce|l Clmnges a r c s e c o n d a r y a n d r e p r e s e n t reaction o f d i e cell to al)sorption o f excess a m o u n t s Of p r 0 t e i n wl~ich: k:aked l h r o u g h capillary basemel)t membranes." - Curiously, however, it is Our impres= s[o n from a s t u d y o f 0 u r o w n material .and o f t h e ]itorattn'O.thal Ih0 eapi]klQ, b a s e m e n t m e m b r a n e a p p e a r s normal i n . t h e s e patients, e v e n a i : h i g ! m s t . m a g n i Iic'ati0n p o s s i b l e With the e l e c t r o n microsCope. \Ve. h a v e nOt'ob;~erved tli0 :defects or "|~om." ,s'" in the b a s e m e n t m e m b r a n e s describe(l b y Spire. r'a T h e d a m a g e must l m at truly m o l e c l d a r level. T h e cvto)lasma I . Of m a n y epithelial c e l l s of proximal e o | | v o h , t e d tl.,buIes a r e filled with h y a l i n e ¢trol)lets a n d lipM vnelmh:s. H y a l i n e casts, m a y be seen in

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Fig. 2 . ~ ( N e u ) This is an electron mierogralg~ from a biopsy obtained 7 5 weeks :after the first a p p e a r a n c e of the neplirotle s~,udr0me in a I 7 year~ old white female. Steroid l l , e r a p v . w a s b e g t m s h 0 r t l y ~lfter the ol~set. Her. itrJnc b e c a m e iiegat!ve 15 we6kS before, this bi6psv. was Obtained. Lxmmnatmlt "" by " : . .- light microscopy showed e]ox,en l m n n a | glomen~h.. ' . . ! he. . . u|trastnictHre . . . .glomer~dlts" studied " of a" .single; hv elecIron " ,as normal A ~ortior~ of this ~Iomerulits is i]lus~-ated in this tigurt all cell (ep). i s in the center b e t w e e ,ns of three glomerular Ceapillaries h e foot processes ( f p ) of. the el c e l l covetthe b a s e m e n t membrnl~e (|~m) Of tl~e c,apillar/es. Note that the b a ~ m e n t m e m b r a n e is ?of normal t h i e k n e ~ . A 01in layer of. b n d o t h e | i a l c d ! (e n) is present on "

'

figllre 3-. (Osmic and fixation, RCA E M U 3C electr~n mieros~'opc, X 4 0 , 0 0 0 ) . occasit~" " - l~a!. t n b u i c s . T h e r e n a l interstititm-, in s e v e r e l y n e p h r o t i c p a t i e n t s m a y b e e d e r n a t o u s , : - a n d c~ceasional|y s m a l l i n c k l e n t a l loci o f h~lerstltial fibrosis m a y b e present~ R e n a l b l o o d vessels a r e g e n e r a l l y n orlnal: G'linieal|y, t h e n i n e P a t i e n t s in this g r o u p w e r e q u i t e 1re|term. T h e y r a n g e d hm ag~r f r o m I 3 t o 34 y e a r s . N o n e h a d h)q~ertension o r {~,vidtrne¢., o f r e n a l ftmc-tional ilnl~airlnetlt. M | t r r o s t ' o p i e |t~.'ltlattlria w a s nt~t~;ditl six p a t k ' n t s f r o m l i m e

'1"f t1,~ ]-I I S ' I ' O P A T | I O i . ( ~ I(~ ] ~ A S I S [:f)il T I l E N E P ] ! R O T I ( ; SY N|)I~O~,I !~

]~

Fig. 3 . - - : ( C u l ) T h i s ' m i c r o g r a p h s!Jows.lhe s m u d g i n g of. tile fOOt processes of tile epithelial ceils t y p i c a l of p a t i e n t s w i t h - t h e nephrollc s y n d r o m e whose glomeruli appeared normal b y light microscopy. This partiet~lar s p e c i m e n ~,~ls Sclect~xI .for presentation becatuse it shows this lesion m o s t clearly. Entirely similar filtdings w e r e exhibited 1Ly the. g l o m e n d i of the four a d u l t r~ephroties xvith no lesiou t,).r ~ligl~t m~croscol~r w h i c h ~ c h,~ e s t u d i ~ b('. electron n~icroscopy. This b i o p ~ , w a s s~d;n)itted Io our l a b o r a t o r y for e l e c t r o a microscopy b y Dr. ~J:ick Mctcoff of N'lidHel l~eese lt~spital. I t was ot;tairJed from arl 9. re(ruth, old patiellt w i t h cm{genit~d 1~oplarosis. T h e |tm~en of the g|o!nerulttr capillary (Cap) contains ;m ervlhrocvtt~ ( r b c ) . q'hc" capillar)' wall shows ;~ clear laver . of. 6t~d~tht:lial . . ceil cytoplasm ( e , ) ' , ~t thin discrete bas~,l~el~t me~nbr~me ( b i n ) , a1~d a relativuly thick l~wer t~f epith~li::l~ cell cytt>p]:~sm (el>). This | a t t e r ]~vcr covers the cr~llrt~ s~trfiiet; o f l/~e t';~l>itlar3- :~tl shows ~t~ discr~'l~ foot proctrsse:~ s~;et,:as are ilh~str~tlt, d i~ fig. 2. All porlio,~s of this glou~eruh~s sht~w~,d similar fi~di~g.*;, (t)sn~ic acid fl:~dhm. t~(:A E M U 3¢',~ eletqr~m

]..56

E A I t L E ~ J E N N I~N " f:.S A N D B E I t N I K

.hap~ the.rueS t ~eonsistentabliormality w a s " a •,deerea./md*eeerum antiStreptolysin wit|i:, a decreilsed, gamma? gl0bulinconCenti;~-,ti0n-in the 7serum, ~;he ASO titer i /creased,eo 100 units or more in-fiye-patiei~l[s fit the t i m e of ree0very from: the nephr0tie. syildrolne. Somewhat. t o Our. s u r p r i s ¢ serum, complement a~;-~ was moderately, decreased hiTonly four :of the nine patients:, b e i n g i!ormal in four imd aetm;lly ilmreased i n o n e patient { tabte2}. However; the first serum complement meastnaement i~ 0he pdtient 5cVaSZ:madenear the time 0f recovery during ster9i/d therapyL in those patients who had decreased s e r u m Complement, the levels retfirned to n 0 r m a l w h e n : the n e p l ! r 0 t i c s y n d r o m e was con trolled. N0ne 0!,the p~tients had positive tests for lt!pus e~,thematosus cells. All patients iii t!)iS g r o u p w e r e t r e a t e d w i t h steroid hormones, ACTH, or both .(table ,3). Excellent responses w e r e obtained in eight. Of tJae nine patients. Contin(md therapy in tw0 patients,: howeve r, still is required to maintain norreal protein~free tirine. Th e nephrotic syndr0m e had bee n p)esentbefore biopsy and beh)re beginning, of therapy for 0nly days or. weeks ;n five of t h e eight patimjts~and between two and three InonthS i n three. F0r. reasons .tmknown,: o,!~ patient (GaselV,.reff: 4 7 ) f a i l e d to respond to vig0rou.~; Steroid therapy h~stituted eig!~t days after the oi{set of t h e nephrotie syndrome[ Six :months 1ater her ~n@lrotie, s y n d r o m e w a s unaltered. At this time another r~nal biopsy revea|ed that all glomeruli Were Still n o r m a l by light torero, copy. Steroid therapy was di.tm0ntinued. Some mvmths later evidence of renal insut~eiency developed. A t this time renal b i o p s y revealed advanced membranot~s glomerulonephritis and rather marked interstitial fibr0sis. She died With granular contracted kidneys almost three years after onset, avVe do not know *whether this eombinali0n of events was hm~oenstanee.0r wlmthor: it :

N

*

J

Table 2 . ~ S e r u m . Compleraen¢ and Streptococcal. AT t~bodws ( A S O , A S K , A l l ) in the Nephrotie S y n d r o m e •S e r u ~ Co m l ~ t em en t Decr~ed • NorTnal " "Increased

Group

Streptococcal Antiboclte~-D ec ffe~ed T~Orma~ Iner~ed

r

3

1

8

0

0

~,lembranotis 3 2 Proliferative 10 4 Miscellaneous 2 3 °6|orneruli normal by light microscopy.

2 0 0

7 7 1.

0 5 I

0 1 3

" N o r m a l glotneruli "'~

4

Table 3 . - - E f f e c t o] Steroid T h e r a p y in Adtllts w i t h lhe Nephrolie S y n d r o m e Oro.l~.

~ a . Of P a t iv n t ,$

"Normal glomer. |i"a 9 Membranous 7 Proliferative 4 Miscellaneous 2 *G|bmenili normal by ligl!t m,icroscopy.

Excellent

~i 1 0 0

Efft~vt o f T h e r n p y G~-~| Slight

2 1 1 0

0 3 1 0

l'~on4.

I 2 o

T H E I-tlSTOI~ATItOLO(;](.: BAS15 FOt~ "l't-li5 Nt".,I'I-IItOTI(7 S'I'N1)I~;O~I t~

] ~7'

r e p r e s e n t e d an a c c e l e r a t e d b u t c o m m o n trarlsition in t h e n a t u r a l h i s t o r y o f a disease. Interestingly, the disease in eight of our nine patients w i t h normal glomeruli b y light microscopy had been p r e s e n t for tess than three m o n t h s p r i o r to biopsy. In c o n t r a s t , t h e n e p h r o t i e s y n d r o m e had been presen t prior to b i o p s y for f o u r to 20 m o n t h s in six out of seven patients with +neml)ranous lesions. Similarly, t h e n e p h r 0 t i e s y n d r o m e I-,ad been p r e s e n t for on b, weeks 0r+.a few m o n t h s prior to biopsy in 18 o f 2 1 c]~ildrei~ r e p o r t e d b), Vernier a n d e e l leagues 4:~ as h a v i n g n o r m a l glomeruli, b u t for mm'e than a y e a r in six of Seven patients d e s c r i b e d aS having lobt~lar g|omerulo]~eFd~ritis.

Membranous Gtomerulomwh.riHs T h i c k e n i n g of the gloinerular cal~illarv l~usernent m e m b r a n e s was tlm major Criterion for the histupathologie diagnosis of men'dn'anous gtomertdonephritis. "vVe excluded from this p r i m a r y diagnosis tlmse instances w h e r e thickened b a s e m e n t m e m b r a n e s a p p e a r e d to be s e e o l l d a r v to a l / d localized in m'(-.as of severe proliferation, necrosis or thrombosis as part of a n o t h e r disease process. This differentiation was sometimes r a t h e r difficult, especially w h e n the ]O.'-;ions were focally distrilnlted, since m o d e r a t e to severe m e m b r a n o u s c h a n g e s app a r e n t l y m a y lead to m o d e r a t e endothelial cell proliferation, g l o m e r u l a r fibrosis a n d e v e n t u a l l y hyalinization. Electron microscopy reveals that several different processes m a y be responsible for thickening of the capillary b a s e m e n t m e m branes. F a r q u h a r r''-' notes that the "tllickening occurs by a d d i t i o n of r e l a t i v e l y h o m o g e n e o u s material r e s e m b l i n g normal b a s e m e n t m e n a b r a n e in d e n s i t y a n d texture. She believes t h a t this .is the usual m e m b r a n o u s g l o m e r u l o n e p h r j t i s of childhood. At times she also has noted "dense fibrinoid b e t w e e n the e n d o t h e ]ium a n d b a s e m e n t m e m b r a n e or p e r m e a t i n g the m e m b r a n e in focal areas." In adults, h o w e v e r , F a r q u h a r , '5'' F'iaschi, ~z a n d M o v a t a n d M c G r e g o r ~° h a v e o b s e r v e d that t h i c k e n i n g t~sually is the result of addition or deposition of h e t e r o g e n e o u s material on the epithelial side of t h e b a s e m e n t m e m b r a n e . In some areas this m a t e r i a l a p p e a r s dense a n d m a y represent protein or fibrinaid deposits+ In t~ther areas the n e w material uppears lighter a n d contains vesicles or fibrillar material. M u c h w o r k r e m a i n s to b e done on t h e n l t r a s t r u e t u r a l c h a n g e s Of the membrm~ons group. T h e p r i m a r y g h n n e r u l a r lesion in seven of ore" a d u h nepbr<~lic patients app e a r e d to be t h i e k e n i n g of the capillary b a s e m e n t m e m b r a n e ( figsl 4 . 6 a n d 7 ) . This process w a s diffuse, involving att capillaries in five of the seven patients. In the r e m a i n i n g two p a t i e n t s most of the glomeruli w e r e severely+ involved b u t several w e r e entirely normal. \ V h e t h e r the diffuse a n d focal lesions repres e n t the s a m e disease is not known. For purposes of convenience, however, w e will consider b o t h ~,pes in this section. T h e only g l o m e r u l a r lesion b y light m i c r o s c o p y in t h r e e p a t i e n t s was t h i c k e n i n g of the b a s e m e n t m e m b r a n e , f l o w ever, mild to m o d e r a t e endothelial h y p e r e e l l u l a r i t y was n o t e d in the o t h e r p a t i e n t s (figs. 5 and 8 ) . In general, the renal disease in the four p a t i e n t s witll h y p e r e e l l u l a r i t y a p p e a r e d tO b e r a t h e r severe a n d progressive. Several biopsies in three p a t i e n t s r e v e a l e d some g l o m e r u l a r scarring a n d hyalinization. F i b r i n o i d was r a r e l y observed. In these und one o t h e r patient, interstitial fibrosis w a s

J-,~b

l?,~XllLtfl~-J [:~NNIN(IS ~,kND l~lrillN 1K

4.---,(N!ee) Tl~is g!omerutus i S from a ~biopsy o b t a i n e d 12 weeks a f t e r t h e onset of the nephrotie syndrome in a 2 6 y e n r old white m a l e dental Student. t | e was ~ra6tieall)~" edemas-free at~ the rime of b~op.~:¢. ~tis urine eontai~ed 4 plus prote[~ n~d ~arO erythr0eytes. Se~:ttn¥.a l b u m i n x~.~ls3.8" Gin2 ~per: i 00 ml, and s~rum ch0|esteml 406 rag. per. ,i00 ml, All 5 glomeruli,inthe. . . bi0psv were similar, to tlae o n e ilhustrated. Note tt~at, the b a s e m e n t membranes are tl{icker,~than l~.onna! (compare to the basemel~t membranes,offig, t )-and that tile glo1~erutns .is not bvpercellulair. (:onnective t i s s u e a n d periodic aei~l-Setiiff stains confirmed t/mr tim m e m b r a n e s were thic'ker~d. T}m hemat0xylin and e0sin stain 2above is not.sufflcient to establish mild (:lti'~:&eni~ig |Jeeause-all. three .el&mentS of 0~e g l o m e r u l a r e a p i l | a r - ¢ w a l l st~;in eosiuotihilieallv. ThielCening~0[ the cytoplasm of t h e endothelial o r ~ i t h e i i a l ceil laver em~ therefore. be mistaker~ for basement i n e m b n m e O~iek, " This is especially trim when ~t|ie kidneys are fixed m Hefty s flxativea t h e evt 0 f .some of the "pr(~-:imal t~)|mlar cells ;~t d~e lower l e f t m~d r i g h t h a n d con~ers of d~eifigure show mtmer~ms snm]| cytoplasmic vacu~es (fatty Change). Many ]~valh'~e droi~letsare ~resent in the cytoplasm . of.some oilier proximal tubtdesTin t~le leer|on. ~,Tl~e gl0mer~tm< arie,,iole. a t the top hiIus, of.then-,fer0graph is .normal. Tl3e p a t i e n t was treated With high dolSes of steroids laegitming 3 }reeks after biop.~y. His p r o t e i n u r i a gradually disappeared. ' - syndrome. :~ •S t e r o i d s were d~seontinued 1 :/z )'eros ,tfter onset of the nephrotte !t'o teinuria 1,as not xeeurred. (l'][dly's fiXaNOn, hematoxylin and eosin stain, ' 2t~. section, x: 6 0 s ) . F i g .

,

-

,

"

.

..

:t,-

,

.

~

,

m o d e r a t e t o s e v e r e (fig. 7 ) . D e p o s i t s , a p p a r e n t l y of p r o t e i n m a t e r i a l , w e r e n o t e d b y ! i ~ ! t J n i c r o s c o p y b e t w e e n t h e epit!ieliaI c e i l s a n d t h e b a s e m e n t m e m b r a n e in s e v e r a l p a t i e n t s . E l e c t r o n m i c r o s 6 o p y in the one p a t i e n t of this group Studied b y this t e c | m i c r e v e a l e d j r r e g u | a r d e p o s i t i o n of p r o t e i n a c e o u s m a t e r i a l b e t w e e n t]ie foot p r o c e s s e s o f t|m c p i t t m l i a l c e i l s . T h i s m a t e r i a l was slightly more dense than basement membrane. T h e patientts in this g r o u p r a n g e d in a g e from :24 to 6:] years. O n e p a t i e n t

T ! t1~; 111ST()1:)AT},i()I,O(; I(j ,t:)AS 15 i1;'O1i T I I E N F,I?)I 1110TI(~' ,SY N l)lIO~%Ila;

] 59

Fig. 5.--(I)tmQ' This glmnerulus is represel~lat!ve of 9. obtained from.a 28 year ~ld White fen~ale biopsied 1 6 Weeks after she fi~t b e c a m e nephr01ic. \Ve did'~o{ Proteinuria decreased {i,:30 rag. per. 100 ml.'.an d edmna disapp~r~ared R,i(!mut ti'eatment. H0wever~ three ~weeks before t h e biops 5 proteimtria and edema* recurred. A t the time of biopsy her uri{io c(,m{M)ied 4 plus protein (4-6 Gin. I)er d a y } / a n d 3 - 4 er~throcytes f~¢r' high pox~u," fietd:,Note that tlie Isasemcrtt m~..~l~bra,~(~s 0 f t h e capillary loops of}his glomeruhis are very thick imd that l.alt capillary t0i'5psare i~g volved about equalIv, Each glomerulus-i~( lhe bi0psv Showed Similar'fiudings except tor regions of }{'vali~;~izntioni n three. 1,~ additi0,i, s o m e of the 10b~dar Staif;{:,.iof .,his glomer~alus are. slightt{" hvpereelluiar and lhiekened w}0a material sh0wi~~g the simm optical and stai~i{~g <:ha~'acteristics as basement membrane. T h i s glomerulus itlus i trates severe diffuse meml)ra)mus glomen)lor a)~d" shoul~tl)e compared t o 0 i e milder-exainple of this disease, illustrated ,~ a 4. FatD: . a n d " h y a l i n e (h:oplet ehang(.~ are exhibiled by tim Cytoplasm of some of tlm proximal tubular ceils. l)etq)ite steroid tlmtvqpy, protci,mria and edema persisted fo~' 14-weeks after. the .!~i6p.~Lv at Which time:she ~vts lost to follow-up. (Helly's ~xation,:-Heidenhain's c~mneetive tissue stain, 21, seeti0n, :<, 510). h a d no Immaturia, four hnd occasional mild mierosc0pic h e m a t u r i a , wl~ile two h a d p e r s i s t e n t ' a n d . significant microscopic hematuria~ _Hypertension w a s n o t p r e s e n t in a n y of the patients -,vhel~ first. biopsied or treated. T w o , h 0 w e v e r , h a d mild rdtrogen r e t e n t i o n ( b l o o d urea u i t m g e n 23 and",3,5 m g l p e r ~iC~3 .mlT) w h e n first studied. Again: d e c r e a s e d S e r u m ASO titcrs w e r e charaetc:rlstm (50 o r less Units in all p a t i e n t s ) . Serum c o m p l e m e n t was i n a r k e d l y reduced, in two, slightly r e d u c e d in one, normal {n t w o and, i n c r e a s e d in tWO. S e r u m g a m m a globulin levels w e r e d e c r e a s e d or in the low normal r a n g e in aH patients, Tests for lupus erythematosns cells were consistently negative in all ]patients in this group.

~(J0~

E A I t L E i ~ENNINCS~ AND..BERNIk"

Fig, 6.~(Dum) Thisls a highe r power view o f O~e capillary loops at 5 o'clock in tlgtare 5. The 10werarrov¢ shows a call witl-Dflnely vacuolated attached to the basement membrane. This is au endothelial tted with lipid, a not uncommon finding in p~ tile nel)hrotle s)~ndrome. It is currently considered:to be diagnostic of th~ state. The upper arrow shows a capillar,f loop with a prominent layer. Note O,at the basement membrane .... o f this !ooi~ several other loops in the photomic4ograph are quite irregular. Perhaps this to O~q deposits that many authors have noted o n the epithelial membrane with the electron microscope. ( × 1830). The n~TJhrotie syndrome or evidence of renal diseas,, Itad been present for 3 to 82 weeks prior to i~stitution of t r e a ~ e n t and 1t to 122 weeks prior to biopsy i n t h e patients in tile membranous group. Tro~ltment with Steroids wa.~ instituted in a l l patients in tiffs group. Raflmr high prolonged doses in o n e patient with thickening of the basement membranes blit no hypereellularity resulted in a .slow but complete remtssmn of the nephrotie syndrome n n d protein,rin. T h e patient's urine w a s normal one year after eessatmn of treatment. Ghne.other patient with a similar lesion Jest his nephrotic syndrome and has shown a sz~nfficant but sh3w and incomplete improvement in protemttr|a on prolonged flmrapy with hlgla d o ~ s of ste toids. Oeteetal)le bttt slight, transient and elin|eally inconsequential iml~rovemen~ were noted in •two patients. TherE~py i n d u e d no significant changes in the la.,mmning pntmnts, but in two, therapy wns given at low d o s e s for relatively sho~ periods of time. Despite t h e n q ~ tmpn|m~ent o f renal Iimetion }ms been progrc~sive iJ~ all b , t the flr.~t two pattent~ mcmttoned ~d~ove. Two have died in t~remta, We have n o d|reet evidence., bul ~trongly ~,lspect that the endothelial proltferatlon and tnt~rstithd d m t t g ~ ob~c~ved in ~ome of these patients were set.-

THE: H I S ~ P A T I , I O L ~ I C

BASIS -,FOil T'I--~ :'.Nl~l°~OTl~. SYNDI~OI~J~I~

I~

some instances of membra_rlous gi0merulonephritiS may be expressions o f antigen~antibody reactions. Inter~tingly;:l~owever~ renal Vein thrombosis js ~daaracterized by thickened glomertilar capillary basement membranes.~s,~a W e flare observed this in one such patient who is discussed with the miscellaneous group below. This patien t also had deposits on the outside of the glomerular capillary basement membranes. Proli[eratioe Glomerulonephrit~s

Diffuse endothelial cell proliferation is the characteristic histopathologic lesion of poststreptocoeeal glomerulonephritis.at, -~n-:*~.-~sWhen this disease fails ¢o heal, fl~e proliferated cells are located in thickened iobular stalk_~ of all glomeruli. I~,~s It is this lesion that is responsible for the |obulated appearance of the glomeruli in chronic glomerulonephrltis. "I~ae disease in many patients with diffuse lobular nephritis and the nephrotie syndrome undoubtedly began as poststreptocoecaI acute glomerulonephritis. However, eehronie proliferative glomerular lesions may be assocwated witti features such its fibrinoid deposition and other evidene~ ofinflammatory reactions and/or membranous changes, systemic diseases such as lupus erythematosus. ~° Apparently several, types of acute glomerular injury may In followed by proliferation. Again, for the sake of convenience, all our patients with proliferative lesions will be considered together. Glomerular lesions w e r e Consldered to be primarily the result of proliferation of endothelial cells (flgs. 9 and 1 0 ) i n 14 of our .35 patients with the nephrotic synck-ome. In nine of these patient: the lesions were diffuse similar to poststreptocx~eeal chronic diffuse proliferative Indeed, in six of these nine patients we have excellent evidence that their disease was initiated by acute nephritis following a strePtococcal infection. O n e o f the remaining t h r e e patients with diffuse prohfcrative glomerular lemons had senlm Type 12 streptococcal (neph~togenic strain) antibodies. Two patients wRh far a d v a n ~ d renal d "lsease showed diffuse glomcrt|h|r proliferation phts some thickened capillary basement membranes. The proliferative lesions were fccall,y. distributed in the remaining three patients, Evidence of preceding streptococcal :infections was not obtained in any of file last five patients. One, however, had Type 12 antibodies. Aft patients in this group had significant microscopic hematuria at time of biopsy wl~teh persisted throughout the follow-up period, Hypertension was

L62

, E A I I L E . ~ : ,! I ~ N N I N G S

"AND

:Jl:it~ 1~.~ l K

8

7

9 [ T O I l 1 -a

a l t e r , t h e ::o~

31~.-~m~

I0 rag. per ~

effc~t-Oa~=the differ-

Som~ b~n~ na ~ a n o t h e r

'rttE IIISTOPA~IOL~IC

BASIS FOB THE oNEPIIROTIG $¥NDRO.~IE

163

the.iJauents in tliis: gmup;.Five already:have diedin :tiremia~

glOmeru Iar capillary basement membranes.. Considerab]6 -pro tein-deposits:.were

J.{~

F.,A/ILE.. JENNIN(;-S .-ANI).'.BEHNIK

~nfth patient,

He,dEed ~in uremia Several years after tlae onset of )ea!ed 'lesions througl~out both kidneys . . . .

THE

I t l S T O P A T H O L O O , I C . B A S I S :~FOI~ ; T ~

:NEPH/~OTIC: SYNDROM[E

1 (6b

Fig; l ! r ..-~7(Ric~ lets :are~ shown in of :proximal t u b u l a r .ce]|s i n t h Th~s Js t] tient l g u r e 9,. T h e , stain ..with. a z-o e a" r~m' .m e. ,- . (Hell d ..r opM. .t.S- . . .a r e : p e r i o ~. ,p'OSlfive :'" ' '. : ' "~:, " .. 'y s fLxation, periodic aeid-Schiff reaction w i t h hematoxx, lin c0unterstain; 2ix section, .X 5 4 0 ) , Fig. 12..-(Bau)::Tlds proxiomal tubllle is from a biopsy obtained 73 w e e k s a f t e r the"onset o f , p r o t e l n u r / a a n d 2 6 w e e ~ a f t e r t h e e a s e t o f t h e nephroti c . s y n d r o m e in a 17 y e a r o l d w h i t e m a l e high school student. T] ~aad c l i n i c a l a c u t e glomero|oneph~t/Sl a t the Onset w i t h azotemia a n d ;maturia. H e was e d e m a t o u s at th H i s urinary protein excretion w a s 7 - 9 Gin; per day. Many cell c a s t s : w e r e :noted. T h e serum albumin w a s 2.3 Gin. p e r ;r~ 418 I00 ml, . . . . . . . was I 3 4 / 9 6 r a m . H g . T h e gl0menlii s h o w e d lobular A c u t e irdlammatop/ Changes eonsisfin " rphonuclear tion a n d fibrinoid d e p o s i t i o n w e r e T h i s proxix shows mulHple small Vaeuole~ w M c h fat sta :o he neutral fat left the l u m e n of flae t~abule. A portion of real h a n g e is at ~ e )f ~ e pie fixation, ,sin s ~ i n , tJon; X )' Fig. 1 3 . - - ( J o b ) T h i s fig~are i l l u s t ~ t e s some of the s ~ a l l e d ,qipid lakes" in t h e inter~titium of the juxtaeortleal m e d u l l a from a biopsy o b t a i n e d 89 w e e k s " u r "ta a n d t h e a R e r t h e onset of p r o t- e m nephrott * e s y n d r o m e in a 24 y e a r old w h i t e m a l e . The.s o~2ur w h e n cells of a limb of Henle's ~me filled wifll Hpid; is impossible b e c a u s e the a r c h i t e c f u ~ cells is so distortc~l b y the fat. S 0 m c authors describe as "re.am" cells hi t h e interstitium. A t may ~ t e this fln£ e of t h e of hhe nei~qrotie state, T h e paUcnt w a s at the ~ m e Of b i o p ~ , ary protein excretion was 4 - 1 6 Gin. p e r ~ y , ~ e serum a l b u m i n ~ s 1.3 Gin. p e r .

.

.

.

~66

EARLE~ J E N N I N G ' S A N D B E l q N I E

e patzent wzth renal vein:thrombosis

R~NAL *.vt!STOPA'r/-IOLOGICFINDI~GS CI~IABACTI~-~t~ISTIC O F NEPEtnOTIC S Y N D R O ~

"r~--~E

N o matter what g!omerular lesion was responsible for the nephrotie syndrome, t h e cytoplasm of many Cells of the proximal convoluted tubules of all patients was loaded with hyaline droplets (fig. 11). Other proximal tubule cells often showed fatty change (figs. 4 and I2). Less frequently the cytoplasm of glomertda r endothelial cells ( or possibly mononuelear cells stuck in capillary loops) was noted r o b e loaded with tiny vacuoles of fi~t (fig. 6). Large needleshaped spaces were noted in protein-precipitated material in the lumens of the tubules of almost all patients who were nephrotic when biopsied (fig. 12). These are presumably aeicular crystals of lipid or ]ipoprotein -which dissolved away when the specimen was embedded. Fm ~1 y, "lipid lakes were noted in the luxtat~rtical medulla in severa| patients (fig. 13). GF.NERAL CO~.i~IEN'I"~ ~ m t the nephrotie :~yndrome m a y be associated with a variety of renal lesions and diseases has bectm~e very obvious. Classifications like that of Ellis, nr w h o divided patients into Type I and T y p e 11 glomerulonephritis, are no longer useful. Ills Type I nephritis obviously is equivalent t() poststreptocoeeal acute glomeru|onephrltis, • * ' ' bttt his "lype " 11 nq~hrttls ' ' " inclndes a vatriety of lesions a n d diseases which tlstlallv have close clinical sttnil~lritles antl whicll happen to be assoelnted at times ~'ith t h e nephrotie syndrome. T h e abtlily to study renal histology .JEtthe early, stages of disease has gone a long ,x~W to distinguish more accurately the lestons which are ttssoclated with vl|rtotts clinical renal syndromes. W e fully expect that further careful correlation of histologie find-wiflz clinical, immunologic, baett, rlologtc and other studies eventtmlly will to mot~ aceur~te diagnosis. I|EFERENCES 1, ^lwalI. 3.: A~plratI~m lJlt;.luyof the: ~. lvt~.r,.m, !P. m,d Bran, (L: Aspllrattm~ ktd,wy, Ineludlng ~el~)rt of a t~.,, blopwy of the kidney, Am. J. Med. of .~my|oJdost~ ~t~gm)m.*d tbrm~h n_~11;324, 1951, l)lrellm~ b l q ~ y of Lhe klt:ln~V h) I944 .'t. Kttrk, R, M., Mtmhreke, 1t, (3., J)Jrm~I, mtd tnve~tli~ated at mz .ot~psy In C, L,, nnd l~llack, V, E.~ The eliul10,~, Aeta reed. ~candlmw.'J43-4,~),

× ]50).

]t~tE I t l S T O I ? A ' I $ ~ [ O L O G I C B A S I S l'~OR T I L E N E

cal v a h m :of: renal biopsy, A n n . Int. Mi~d, 43:807, 1955: 4. BrighL R,: :Rdp0rt s of ~!edica! Ga~cs Selected with a : V i e w 6 f lllustratihg tli0 S~npfoi~!s :and Ciir~ o f l)is[~ases by' a, ]~eference tO: MoVbid~A:l;iitomy, London, Longnlan, ~:"-Bee.% Orrl!% Brown and Greene, 1827[ 5, "~31hard, F . and. F~hr, T.'. ~l)ie Brigt~tsehe Nierenkrankheit, Berlin, Sprh~ger-Verlag, 1914. 6. Munk, F.: Pathologic und K]inik,der Nephrosen, Nephritiden trod Schr6mpfniercn, Berlin, Uri)an ~md Schwarzenberg, 1918. 7. L6hlein, M.: Uber die e n ~ u n d l i e h e n Ver~in~erungen der gI0mer~,li , der menschlichen Nieren m i d ihre B~deutung fur die Nephritis. Arb. Pafl~. Inst. Leipzig, i907. 8. L6hlein, M.: Zur Pathogen~-se der NierenkrankJaeiten, Nepl~ritis und Nephrose mit besonderen Beriichsichtigung der Nephropathia gravidm~um, Deuts¢qne reed. Wdmschr. 44:1187, 1918. 9. Scfla~er, O.: U b ~ die Nephrose, Med. Ktinik 14:53, 1918. I0. Addis, T. and Oliver, J.: q'he Renal Lesion in Bright's Disease, New York, Paul B. :H¢mber, Inc., 1931. 1 1, Bell, E. T.: A clinical and pathological study of subacute and chronic glomerulonephritts including lipotd nephrosin. Am, J. t~dh. 14:591, t938. 12, Berman, L. B , and Schreiner, G, E.: Clinical ~ l d hisiologie sp~:trum Of the nephrotic 8yndrolne. Am. J. Med. 24:~9, 1958. 13. Baldwin, l), S. and McCluskey, R. T.: Naitlral history of the nephrotic syndrome in glomerulone#wttis. PosttCWad, Metl, ~:~O3, 1959, 14. V¢ll~on, S, G. attd lteymann, ~V ,: Acute gl~nt~,~rukmephdtis wtfl~ the nephrotie ~yll¢|rOl|le. I~odtatrics 23:874, 1059. IS. l)avtes, C. E.: Heart hdlure in acute nephrti|s. Quart. J. M(~L 20;163. 1951, 16, Ell'him, L, %V., l:arlu.~r, S. J . Berger, A. 1i.. Ruder, IL, Smith, ~,V, ~V,, mid AII~,~, IL E.: Non,cardiac c'irvlth|h ~ t~)ltgt~Mttnl ~|mulat|ug ~m~ert|ve |tc~a in|lure, Tr. A. Am. l'l~¢~t¢lm~s a7.'7~, 1954, 17. D,,fi!zto, V,, Chr|ttet~vn, R, C,, liegalt, T, J,, Bavr, L, V,, Merlin, Y,, and

HI~OTIC S$NI)IiO~•IE

~8. Eaer,

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tlie in ::

a contr~iindication~ to

"nepltri~s: a e l ! h i , I : .patt~010~e shtdy based :on renalbiopstes[ Medi~ c-ine 36:1;: i957) 21. Kimmelstie "" " !;~ P,:'and :?~,Vtlson; . . . . . . . G:: : ~ t e r Capil|a~], lesions fil~ t!a~ -g!0menili): 0f the kidne31.LAm. J. Patli. !2:83,: 1936[ 22. Farq~har , M . G . , H0pper~ j.,::jr:, arid Moon; H . D.~ D i a b e t i c glomerulo; sclerosis: elec~0n and l i g h t miero~ s - ~ p i e studies. Am. J. Path: 35:723)i 1959. 23. Muehrcke, R. C.; Pirani, C , L . ; Pollak, V. E., and ,Kark,. R. M.: ' Primary renal amyloid0sks with the: nephrotie syndrome s t u d i e d by sedal b i o p s i e s of the kidney: Guy:s Hospl l~ep; 1041 312, 1955. 24. H e m l a n n , G. and Ma~, ~V: L..~:Clini~a! syphiliUe nepluroI~athies. Am; J . Sypli. and Neurol. 19:3, 19~:. ~5. Baker, B. M.: T h e retaken of sypl~ilis to nc~lu-it~. B u l l . Johns. ll0pkinS Hosp. 65:196, 1 9 3 9 ; 20. Thomas, E L%V.and Schur, M.= ~Clinica! nephropathies in early)syphilis. A.Mi A . Arcqa, Int. M e d . ~:679, ~ 1946. .~t. Kcitel, H, G., Goodman, H . C . Havel, R. J., Gordon, I1. S., a n d Baxierf J: IL: Nephrotic syndrome in congenital quartan malaria. J.A:M.A:161:SflO, 1956. 28. Pollak, V. Ei, Kark; R. M , , Pirani, C, I,,, Shafter, }l, E,, and Mtmhrcke, R. C.: Renal vein thromt~sis and .the mT~hrotie syI~dt~Ine, htn. J, Med. 21: 490, 1950, ~"~L l)erow, ]t, A., Sddc~inger, M. J , and Sa V Itz, II, A,: Chroniv progressive occlusion of inferior vena e a v a a n d renal and portid veins, with clinical

16~

pictures of neph.rotte: syndrome: report . of : case, with ''review of litera~ire, A.M.A. Arch. Int. Med. 63:620, 1939, 30, Ba~ett, H. L., Shnons, D, J., and "~Vel~, R. E., Jr.:• N) e pb-rottc syndrome occurring during Trid¢one therapy. Am. J. Med. 4:700, 1948. 31. J~kes, A; M,. Heptlnstall, R. H., and Porter, K. A.: T h e nephrotte syndrome. A study o f renal biopsies in 20 adult patients, Q u a r t J. Med. 27 (N.S.):495, I958. 32. Rytand, D, A.: Onset o f nephrotie syndrome during a reaction to bee sting. Stanford M. Bull. 1 3 : ~ , 1955. 33. Shaffer, B., Burgeon, :C. F., and GosIrma, J. H,: ~Acute glomerulonephritfs follow|rig administmHon of rhus toxin, J.A.M.A, 146:1570, 1951. 34. Rytand, D. A.: Fatal anuria, the nephrot~e syndrome and glomeraflar nepit. ~tLs a s sequels of the dermatitis of ~ l s o n oak, Am. J. Med. 5:548, I ~ 8 . 35. Bloom, ~V. L, and S~gal, D.: The nc~phrotic phase: :tLs frequcncy~ of occurrence and its differential diagnostic value in determining the nature of the renal I ~ i o n in 19.0 patients who died of renal failure. Ann, Int. M~J. 95:15, 1 ~ 6 . 30, L~ng~pe, ~¢. T,: ~ m ~ t h o g e n e s ~ of glomer~alar nephrftfs. ~ Bull. • Jt~ms Hrrp'ldns ltosp. 45:335. 1929. 37. Ellis, A.) Natural history of Bright's disease. L~mcet 7~.1,. 34¢72. 1942, 38. ~ l e , D, P. and J~mings, H. B~: Stttdte~ of r,o s ~ t o c o c c a l nephrRls and other glomeruhr dlseaases. Ann. Int, Med, 51:851, 1059. 39. BlCtudme, M., :Brun, C., Gormsen. M,, $verson, P,, and ll~sdhou, F.: The nephrotl¢ syndrome, I . . Htsttflogtu dmnge,~ |llusla'ated by means of biopsy of tim ~ d n e y , :A~a mt~. scanc~nav, 149:9~3, 1OSg (Suppl. 9~36): 40, Iver~et, P., Bl~rnet)(~:, M., and Kntrup, N; B.: :Biopsy ,tUdt~ of the liver and kidney, Advances Int, Med. OrlOl, I054. 41, l ) a ~ l h , A, E ) m i d ltowe, J. S,~ Kidney blot~y, A revtew of m~e lm))dred snc~oful~l)e¢~llo .{)ioplies, A.M.A. Ard~. lnt; Meal. gO:71~, I055, 4~. Polhk, V, E,, F.nrk, 11, M., l~ranl, C,

~.LA,1RLE, JE,N N I N G S

AND BE1RNIK

L., S~tbdll, J . F , a n d Muehreke, R. C.: ~ sigaiRcanoo and ~potential Vahm of renal biopsy in Bright's disease, J. Chroniv ~ D ~ 5:~, 1 ~ 9 . 43. Vernier, R.. L;, Farqutiar,: M. G., Brttnson, J. G., and G00~ R. A.: Chronic reval disease in children, J. Dis. Chib dren 98:306, 1958. 44. Kark, It, M., ~apA, C .L,, PoLtak, V, E., Mu~.rcke, -R. C . , ' and Blahley, J.. D.: The n~l~-'otie s2~mdromv .in adults: a common ~ o r d e r ~ t h many causes, AJm. /at. Med. 49:751, 1958. 45. FIaschi, E.) A.ndres, G,, Gioeamdli, F., mad Naeearato, R . : Renal hls[opatho l o g y j n Cue pare-nephritiC nephrotSe syndax~me. Seientia /vged, ItM, 7:639,

1959. 46, Galan, E, and Maso, C.: Nec~Jle biopsy in children x~tl~ nephrosis. A study of glomc~adar d a m a g e and effect of adrenal steroids. Pediatrics 20:610, 1957. 47, Earle)D. P. and Jenntngs, R. B.: Early manifes~tions of n e p h r i ~ . M. Clin. Nortl~ Amen,lea 44:59, 191~L 48. Farquhar, M. G,, Vernier, t L L . . and Good, R. A.: An electron microscopic study of the glomexadus in nephrosis, glomertthncpb,rRis and [upu~s erythemato~als. J. E ~ e r . M ~ . t06:649, 1957. 49. Farquhar, ~M; G., Vernier, lq~ L., and Good, B . A . : Studies o n familial nophrosL~ IL Glomertdar changes observed wi~h the electron microscope. Am. J, Path~ ~ : 7 9 1 , I957. 50. Murat, 1-I. Z. and Mcgregor, D. D.: The fine struc~oar~ of ~)e glom~dtts tn membr~azous glomemalonephritis ( lipoid neph_ros|s)' in aduI~. J. Cltn. i)afl~. 32:109, 1959. 51. Folli, O., Poilak, V. g., Reid, B. T., Ptrani) C, L , and Kark, H. M.: Elee¢rc~n mt studies of r~versibte glomen)lar lesions ~ the adult nephretie ~ n d r o m e . Ann, ~ t . Med: 49: 775, 1958. 52. Farqahar, M. G,: Electron nt!crosco_pte studies on the r¢mal glomemlus in tim nc~phrotte syndrome. In Edema. J. | L Mayer, F~Ror. Philadelphia and London, V¢, B, Saunder$ ~ . , 1950. p, 407, 53. ;Spire,. D,: The structural basis of pro-

:11ti'] HtSTOPA"I"HOLOGIC

]3ASI8

FOR

. B. O . i I C , S Y N D R O N - I E~' , T H E ,. N E. P H

teLnuria in man. Am. J. Path. 35:47, 1959. 54. Earle, D, P., L ~ b , E : N;,:Seegal; Di, 57.' glomerul0nephNtls.: l ; C1 n.~ Invest; 19:569,1 9 4 0 . 5 6 . Randall, I~ . ; e n d Bytand, D, A.: ' ,.O. . .-. .I.n. . u r i"n e '

58~

215, 1~5= 56. Lange, K• "s~ Graig, F., Oberman,. :J., • Slohody, L : , Ogur, G. ~and L~astrb~

Dat>id Pi EarN, M.D. wester~i ttobert B. lennings, M:D., No~hwesteni U~ Maria Bernik, M.D,,

Nortltwestern

169