ALLEN

BROWNE

CALNE

FELDMAN

GALLE

HAMBURGER

HEDLEY-WHYTE

HILL

KRIEG

MERRILL

MOVAT

NEUSTEIN

OGILVIE

PFEIFFER

PORTER

RIFKIND

SHIBAGAKI

STARZL

TERASAKI

WOODRUFF

ZUKOSKI

English

Crossref

LIGHT AND ELECTRON MICROSCOPIC STUDY OF BIOPSIES FROM THIRTY-THREE HUMAN RENAL ALLOGRAFTS AND AN ISOGRAFT 13/4-21/2 YEARS AFTER TRANSPLANTATION*

Porter, KA

Rendall, JM

Stolinski, C

Terasaki, PI

Marchioro, TL

Starzl, TE

D-Scholarship@Pitt

t J  CLE\%-',- .\?tanon in ;- LIGHT AND ELECTRON hIICROSCOPIC STUDY _i OF BIOPSIES FROM THIRTY-THREE HUMAN ;h 13 nuall-- i _ --. .=z- RENAL ALLOGRAFTS AND AN ISOGRAFT - . .. '."-'1 i i o m o t m  -, . .i. jcsqu'au :  1!-2i YEARS AFTER TRANSPLANTATION* ;, j K. A. Porter, J. M. Rendall, C. Stolinski, P. I. Terasaki. , *! iC!E S: J. G,% , h T. L. Marchioro and T. E. Starzl 43 -4 ,,lar.t3r1on rn 'q  Denver, Col :I -5 -- - Fey, Spring,: -5 7 .vr In the period between November 1962 and March 1964 a t  the  University -=1 .,. hew En% .-,' of Colorado Medical Center, 64 patients received renal allografts and two ...- - received renal isografts from living donors. The identical twins and 34 of the an renal allo-~?- , i.c?d. Sci. In "7 ,)[her patients are still alive (Starzl et al., 1966). ?* . - Of those that  died, 27 did so in the first year and three in the second nu .ep: after renal transpiantation. The pathological changes found in the renal ,r, ~liografts from 29 of these dead patients have already been published (Porter a. -.. 1 ~ c l  , 1.365; Starzl et a!., 1966). _- The present report is a preliminary account of the light and electron micro- - -:()pic changes found in biopsies obtained about two years after transplanta- -Zp. .lOn from 33 of the 34 surviving renal allografts and from one of the  two 2 *.o,orafts. The histopathological findings in each transplant are correlated %$:ti; the relationship of donor to recipient, with the degree of compatibility of - 4 tionor and recipient as shown by lymphocyte typing, with the number of -$ ~llnlcal rejection episodes experienced by the patient, and with renal function. -- - - r b MATERIALS AND METHODS Patients. Each case is denoted by a number prefixed by the letters LD, for ' h p  a!lograft recipients and I D T ,  for the identical twin. This same code has ?-en used previously (Starzl, 1964; Starzl e't al. ,  1965; Starzl et al., 1966) and yT ~L~rther details of any of the patients can be obtained by referring to these - 7)~hl~catlons.  - In all but  two of the patients, splenectomy and bilateral nephrectomy x 4 ,  'ere performed a t  or before the time of transplantation. The  exceptions were 3 - 1-DZ who retained his right kidney and IDT2 in whom splenectomy was un- : .* --- zecessary. The  thymus was removed from 12 of the patients, four before, and ~1:ht between 250-520 days after transplantation. .*- . . .-.. , i i 3 +  ,:* ?I!o- & -6.. " e q  .inti- .$. $)PA, "4 ,:dent ,.%. 1 His .g;: * ... nined ::+, - .^  =- .-. , and  .2. :sxic -2 n ' 3 9  :-- ['om- .: <:ytes I" -:ajar T . . ;!ities :;. . \vas - :affin .+ . .-i '.?tI!>r? i : 3  ..- .- -  . - -  -:-q - .  .ci -. -. - ~ ~ Annals New York Academy of Sciences TABLE 3 ASFOCI.:TION OF LYMPHOCYTE C O M P A T I E i i i T Y  EETLVEEN DONOR AKD RECIPIEST,  AS SHOLVE BY SEROTYPING. \VITH ABSENCE OF APPRECIABLE HISTOLOGICAL DXLIAGE TO T H E  R E S A L  ALLOGRAFT' - . -Number of Allografts that were by Lymphocyte %-ping Histopathology Total Incompatible i n  So ic::: Compatible one o r  more  --.~ groups Slight :. mi?.::: -- No significant chanse o r  slight a 2 10 G ~ o x ~ : -  interstitizl f ibrosis  and/or m e m t  minimal cellular infiltration --- One o r  more major lesions -. - *chi2 = 5.91. P = O.CO8. + Cf:. 'Ti-.. bioprie- gloxc:, bascc;? nsnc'e Number ~f Allografts that were  by changt : Lymphocyte Typing - in the c Histopathology Compatible, o r  in- Incompatible i n  To'a' : vieiv, compatible i n  one group six o r  i n  group Other than two major groups group six Minor to  rnoderate changes Obliterative vascular lesions + glomerular capillary base- ment membrane thickening + cellular infiltration *chi2 = 5.86. P =  0.008. 632 Annals New York Academy of Sciences 8 r.- ; The-e I,- ischemia. A combination of severe vascular lesions and a renln content ap- , proximately threeand one-half times the normal value for kidney tissue has been piexei reported in a renal allograft removed 11 months after transplantation (Shiba- r e v e r ~ ~ o  gaki et al., 1965). I similar - In the past, slight thickening of the glomerular capillary basement mem- phagoc' branes has been recorded as an incidental finding in several renal allografts I 'IFL (Porter et al., 1963; Merrill et al., 1963; Calne et al., 1963). In  one such trans- lesio"s I -  plant which was examined electron microscopically, the basement membrane - .AltPi was found to be focally thickened and there was some fusion of the epithelial - glomeru!f foot processes (SYoodruff et al., 1962). More severe lesions were described b y  , wl-ere t b -  Krieg et al. (1960) in a kidney transplanted only ten days previously. Glorner- ' disease A' ular basement membrane thickening has also been encountered in 36 percent glomerL ' of canine renal allografts in animals which survived beyond 70 days because of forn?atic treatment with immunosuppressive drugs. This change was most pronounced eru!one in a dog whose renal allograft continued to function for one and one-half years ?the crAL' '-:phri:,: ,. - after all treatment had been withdrawn (Porter et al . ,  1964; Zukoski & Ende. 1965). However, in 1964, Hamburger et al. (1964) described three patients ~ h o  '1965'' ' showed proteinuria, renal insufficiency, sudden hypertension or haematur~a , ---1965) 11- three months to one year after successful transplantation of a renal allograft - when o:r. ; -;.used in E One patient died ten months later; another spontaneously recovered over a period of six months; and the third was greatly improved after treatment wlth ' *'$"lonepi-- prednisone. Electron microscopic examination of n biopsy from the second of 1 -:'a?'' "" these renal allografts showed "proliferatior. c: endocapillary cells ~ i t h  sub- , 'I he ; --~-l~l?"-.~:, endothelial and intercellular hyaline deposits." Two further cases, both of - A D  VlOCC i t -  whom subsequently recovered, are mentioned in 2 more recent publication b\ the same authors (Hamburger et  al., 1965). , - *age is a Three aspects of the glomerular lesions in the long-surviving renal trans- \ 7.The 30.- "&ter c: a1 plants described in the present paper are worthy of special emphasis. The most i 2.- I -=z. striking of these is the very high incidence of this complication. The second T h e ,  .%;has oftc. is that these conspicuous glomerular abnormalities were rarely accompanied i .%1962, H - by severe proteinuria and never produced a nephrotic syndrome. The third 1s \ :=+- that, although, under light microscopy, the lesions closely resembled those of -&cally f diffuse membranous glomerulonephritis, ultrastructurally, the deposits on the capillary basement membranes were almost entirely subendothelial, unlike the predominantly subepithelial accumulations in membranous glomerulonephn- tis (Movat et al., 1961). Glomerular deposits between the endothelial cells and rejcc the capillary basement membranes also occur in lupus nephritis (Browne et a /  . , 1963), acute glomerulonephritis (Movat et al., 1962). lipoid nephrosis of chll- dren (Movat et al., 1961) and experimental nephrotoxic serum nephritis (Feld- man et al., 1963). 4 I The nature and origin of the deposits in the renal allografts is unknon ! Immunofluorescent studies indicate that they contain immunoglobulins and 1 ' the third component of complement (PIC-globulin), and that the immuno- 1111 1 globulins can be eluted by pretreatment wlth acid buffers (Calder et a1 , 19661 ? i ? 4 "j i a -1 . - .;n r,,,; m - :its : ns- . . .me :isi. 9 y : t'r- . ?!>C + 9f .;en l.2 Is :ide. :vho 1.1 r:a ., :a 2. r 9 . . w!in :d 2j .<Z& . ' ?  of il 0.g .*2!1s- ?'.oat . ~ o n d  .L:ljcJ' -::ci is .I.+ of :, '!l the -; .t. !he 3n'hr;,-..c I.: asd,: , . e! z:..-: : c hil--ig- 1: .=2. I:* - - .  :1u>'is. ' .- ; 2nd . . :::uno- 196t.i!. , . - - -z. - -  .i . . . , ::a *.-. -.::2$ \. . Porter et al.: Biopsies of Human Renal G r a f t s  633 , These data suggest tha t  the accumulated material may be composed of com- ,!ekes of graft antigen with host antibody. The  prognosis depends upon the  re~ersibilrty or not of these glomerular lesions. Subendothelial deposits of , ,~,dar material are removed in human acute glomerulonephritis, perhaps by 3hagocytosis by endothelial and mesangial cells (Neustein & Davis, 1963). The expenence of Hamburger et al. (1964 & 1965) suggests that  the  glomemlar esions in renal allografts can resolve similarly. Although the renal isograft in the present series showed no evidence of 210rnerulonephntis, this complication has been reported in five renal isografts *here the recipient twins originally suffered from the chronic form of this _Isease. At biopsy or necropsy, three of the  isografts showed a combination of :!omemlar capillary basement membrane thickening and capsular crescent iyrmation (Pfeiffer & Merrill, 1963). However, recrudescence of a n  old glom- ,rulonephritis is unlikely to explain the glomerular lesions in allografts because . l e  original renal condition in several of the recipients was chronic pyelone- ~ i r l t i s  or bilateral polycystic disease (Hamburger et al., 1964; Porter et al., -466). Esperimentally, steroids can produce glomerular lesions (Ogilvie et al., .?55) but not all our patients had been treated with these drugs. Moreover, \hen other series are taken into consideration, even azathioprine has not been -4 in every case showing glomerular lesions. None of the  dogs with glomer- .lonephritic changes in their renal allografts had received steroids (Porter et - 1964). The high incidence of obliterative changes in the interlobular arteries of ?ng surviving renal allografts and the association of these lesions with pre- os.is rejection episodes, suggests that  some degree of permanent arterial dam- :? is a frequent legacy of a clinically recognisable acute allograft reaction. ; possible genesis of the vascular lesions has been discussed elsewhere (Por- r e t a l . ,  1963). The presence of large lymphoid cells with many free cytoplasmic ribosomes - I -  often been noted previously in human renal allografts (Galle & LIontera, * h l .  Hamburger et al., 1965; Starzl et al., 1965). These cells are characteris- .~.?il) found in the acute stage of the rejection of renal allografts in untreated ~nlrzals (Porter et al.,  1964). In the long-surviving renal allografts In treated xtrents, they are probably indicative of a low-grade immunological attack by i..e h a t  which continues between the acute exacerbations recognised clinically I -  rejection. The correlation between the  degree of compatibility of donor and recipient, chon n by the retrospective serotyping of their lymphocytes, and the  histo-  tholog logical findings in the renal allograft was surprisingly good. Of the group f ten patlents whose renal allografts were either normal or only showed mini- ai hlstolog~cal damage, eight were compatible on the basis of lymphocyte . \ ? lnx  Con\sersely, only two of the group of 12 patients whose renal allo- - . f t ~  showed severe pathological changes were considered compatible by oror\ t p  t v n i n o  the othnr ton inrnrnn?tihle in one or more of the n n t i -  634 Annals New York  Academy of Sc' iences . -- . sera groupings being used. These results are iurther evidence tha t  the cyto- cent?rc.:: toxicity tests used in this study are recognising histocompatibility antigens. intn;)?~i!;' Generalized cytomegalic inclusion disease is a common complication in aI;c;rat: patients with renal allografts (Hill et al., 1964; Rifkind, 1965; Hedley- 1~ t h c u z -  White & Craighead, 1965). However, although the lesions are found in many in re.!;? tissues, the occurrence in one of our cases of abundant nuclear and intracyto- plasmic inclusions in the transplant is unusual. . . SUMMARY 1;-e - -  a l l~ \ \  1 ~ r  Thirty-three human renal allografts were biopsied 1: to  2: years after T r u c t .  transplantation. As a control, similar material was obtained a t  a comparaSle time from one renal isograft and from the remaining kidney of one of the donors. ALL: \ I n  23 (69.7Ci) of the renal allografts some of the interlobular arteries wEre C - narrowed by int,: sl thickening. In several kidneys these changes were slight. . BRC"'- Under light rr .croscopy, glomerular lesions. resembling membranolis glom- i erulonephritis, were present in 17 (51.5Cc) of the allografts. Ultrastructurally. c4~fi-1 there were subendothelial deposits of an  amorphous material on the capillarr !,- C4L\F,  basement membranes. The location of this deposit differed from the predomi 1 - nantly subepithelial situation of the accumulations found in membranous B - glomerulonephritis of adults. Subendothelial deposits of a similar material FELIIY' 1 T were also present in the afferent and efferent arterioles of 16 (48.5'3) of the allografts. GAI.I.E A mononuclear cell infiltration was present In 95 ('75.8G) of the allografts ' F U p  to 60 percent of the cells possessed pj-rozixophilic cvtoplasm and, ultra n ~ : , ~ s r  structurally, were either large lymphoid cell; with many free cgtoplasmic ribosomes, or plasma cells. HA\iEL There was hyperplasia of the juxta-glomerillar apparatus in practically all + - the transplants and in the  donor kidney. - HEI'LE Apart from hyperplasia of the juxta-glomerular apparatus and glomerular I G - hypertrophy, ten (30.3%"0)f the allografts were either normal or shoaed \ : minimal damage; another ten (30.3%) showed a combination of interlobular artery narrowing, glomerular lesions and cellular infiltration. Severe lesions in the allografts were associated with two or more bouts of %;, r - clinical rejection. There was also a close relationship between general histo- 1 7 n pathological damage and decreased renal function. When the morphoiogical findings were correlated with the results of lym- phocyte typing of donor and recipient, a significant association was found be- tween lymphocyte compatibility and minor or no histological changes in the graft and lymphocyte incompatibility and major changes in the graft. The obliterative arterial lesions are thought to  be an  irreversible legacy cf damage incurred in past rejection episodes. The glomerular lesions are not the result of either the recipient's original renal disease or of therapy. They mar be due to deposition of antigen-antibody compleres: evidence for another f 3 i' 5 cyto--2 F ~t &gens. ,-= ' c ~ o n  In...$ !ed!ey-& !I many* tracyto+: .& 3 3 :* "a& rs afte-$ p.~rable & of the-% os were :2 s slight.-% ~5 glom- 3 ~turnlly,,; aplllarv-* ,redomi- - Sranous * -  qlaterial r of the ogrsits. :I, u!cra-a~- opla,mic-- :caIiy a i l  = 1meruIar showed ariobular i>Ollts of ral hisco- .. , of Iym- ound be-. es in the  A -- legacy of *e not che ty  may - ,lno:her -< , - Porter et al.: Biopsies of Human Renal Grafts center suggests that  these may sometimes resolve. The  presence of large pyron- ::,,philic lymphoid cells may be indicative of a continuing host response to the .-.!lograft. Hyperplasia of the justa-glomerular apparatus in allografts is usual- ;? thought to be a compensatory phenomenon, but  sometimes it may be partly :n response to ischemia. ACKNOWLEDGikIENTS \Ve are indebted to the  Anatomy department of St. Mary's Hospital for REFERENCES >.LLES, A. C. 1964. The Kidney. Medical and Surgical Diseases. 2nd ed. J. & A. Churchill, London, England. ::?O\vSE, J. T.,  M. P. HUTT, J. F. REGER & S. W. SSIITH. 1963. Localization of "fibri- noid" deposit in lupus nephritis: an  electron microscopic demonstration of glomer- ular endothelial cell phagocytosis. Arthritis & Rheum. 6: 599. -.ALDER. M. W.. T .  L. XlARCHIORO. T. E. STARZL & K. A. PORTER. 1966. (TO be published.) ILSE,  R. Y., L. W. LOUGHBRIDCE, J. B. MACGILLIVRAY, 3. F. ZILVX 8; A. J .  LEVI. 1963. Renal transplantation in man. A report of five cases, using cadaveric donors. Brit. Med. J. 2: 645. -ZiDSlAK, J. D., D. HAMMER & F. J. D I S O S .  1963. Experimental glomerulonephritis. 111. Pathogenesis of glomerular ultrastructural lesions in nephrotoric serum nephritis. Lab. Invest. 12: 748. :LLE,P. R: X I .  DE SIONTERA. 1962. Examen au microscope 6lectronique des ce!lu!es infiltrant le tisju interstitiel d'un homotransplant rknal humain. Rev. F r x c .  Etud. Clin. Biol. 7: 40. -::.>!BURGER. J., J. CROSSIER 8; 5.  DORSIOST. 1964. Observations in patients wirh a well tolerated homotransplanted kidney: possibility of a new secondary disease. Ann. N.  Y. hcad. Sci. 120: 558. :.>:BURGER. J.. J. CROSNIER & J. DORSIOXT. 1965. Experience with 45 renal homo- transplantations in man. Lancet 1: 985. -.?gi.E'i-WHYTE, E. T .  & J. E. CRAIGHEAD. 1965. Generalized cytomegalic inclusion disease after renal homotransplantation. Report of a case with isolation of virus. New Eng. J .  &led. 272: 473. R.  H., D. T. ROWLANDS & D. RIFICISD. 1964. Infectious pulmonary disease in patient= receiving immunosuppressive therapy for organ transplantation. Sew Enp. J. hled. 271: 1021. - ' !'.(;.A. F.. R. P .  BOLASDE, iV. D. HOLDES,  C. A. HUBAY & L. PERSKY. 1960. l l em-  branous plomerulonephritis occurring in a human renal homograft. Am. J. Clin. Path. 34: 155. >Y',.ER. A. F..'r, I.. 5IARCHIOR0,K. A. PORTER, J .  S. ROBERTSOX 8; T. E. STXRZL. 1967- (To he pub!ished.) ','l'yiiT, H. 2.. J. iV. S T E I S E R  & H. J. SLXTER. 1961. The fine structure of the glomeru!us in Bright's disease: a clinico-pathological study. I n  Ciba Foundation Symposium on Renal Biopsy. G. E. W. Wolsrenholme & &I. P. Cameron, Eds. : 10.3. Churchill. London, England. '.'']VAT, H. 2.. J. W.  STEIXER & D. HCHN. 1962. The fine structure of the glomerulus in acute glomerulonephritis. Lab. Invest. 11: 11'7. ': 'iIKILL,J. P.,J. E. AIURRAY, F. J .  TAKACS, E. B. HAGER, R.  E. \VILSOS & G.  d .  D.-\SI- hlI\!. 1963. Successful transplantation of a kidney from a human cadaver. .JXSI;\ 185: 347. Annals New York Academy of Sciences NEUSTEIN, H. B. & W. DAVIS. 1965. Acute glomerulonephritis. A light and electron- microscopy study of 8 serial biopsies. Am. J. Clin. Path. 44: 613. X cc: OGILVIE. R. F., 51. S. SABOUR & N. W .  HORSE. 1965. Light and electron microscopy of prednisolone-induced nephropathy in rabbits. Diabetes 14: 595. PFEIFFER. E. F. & J. P. h1ERRILL. 1962. Die Autoagression in der Pathogenese der diffusen Glomerulonephritis. Deutsche Med. Wschr. 87: 934. PORTER, K. A,. W. B. THOMSON, K. OWEN, J. R. KENYOX, J. F. MOWBRAY & W. S. >, PEART. 1963. Obliterative vascular changes in four human kidney homotrans- ' plants. Brit. hled. J. 2: 639. P0RTER.K.A.. R. Y. CALNE & C. F.+ZLKOSKI. 1964. Vascular and other changes in 200 .. canine renal homotransplants treated with immunosuppressive drugs. Lab. Invest. 13: 809. PORTER, K. A., K. H. JOSEPH, J. M. RENDALL, C. STOLINSKI, R. J. HOEHN & R. r'. CALNE. 1964. The role of lymphocytes in the rejection of canine renal homo- transplants. Lab. Invest. 13: 1080. PORTER, K. A., T. L. MARCHIORO & T. E. STARZL. 1965. Pathological changes in 37 ' The il.' human renal homotransplants treated with immunosuppressive drugs. Brit. .I. -biopsies r .  Urol. 37: 250. .- .. : r  and 1aL.o:: PORTER, K. A., J. B. DOSSETOR, T. L. MARCHIORO. FV. S. PEART, J. M. RENDALL & T. E .." STARZL. 1966. Human renal transplants. I. Glomerular changes. Lab. Invest. (To - '0gr2~h?.  '. be published). ---.the prest-. RIFKIND. D. 1965. Cytomegalovims infection after renal transplantation. Arch. Int. Med. 116: 554. ,' . STARZL, T. E., T. L. MARCHIORO, P. I. TERASAKI. X. A. PORTER, T. D. FARIS, T. J .  -tients bk HERRMAS, D. L.VREDEVOE, XI. P.  HUTT, O.A. OGDES 8: W. R. \I'ADDELL. 1965. -were  cli:. Chronic survival after human renal honotrzmplantation. Lymphocyte-antigen ; . . matching, pathology and influence of thymectomy. Ann. Surg. 162: 743. . . 'Trc;; ,.'. . 

LIGHT AND ELECTRON MICROSCOPIC STUDY OF BIOPSIES FROM THIRTY‐THREE HUMAN RENAL ALLOGRAFTS AND AN ISOGRAFT 1<sup>3</sup>/<inf>4</inf>–2<sup>1</sup>/<inf>2</inf> YEARS AFTER TRANSPLANTATION

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LIGHT AND ELECTRON MICROSCOPIC STUDY OF BIOPSIES FROM THIRTY‐THREE HUMAN RENAL ALLOGRAFTS AND AN ISOGRAFT 1<sup>3</sup>/<inf>4</inf>–2<sup>1</sup>/<inf>2</inf> YEARS AFTER TRANSPLANTATION

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