ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 11, No. 4Copyright © 1981, Institute for Clinical Science, Inc.

Acquired Lesions in Transplanted Kidneys

JAMES E. WENZL, M.D.* and HENRY F. KROUS, M.D.

Departm ents o f Pediatrics and Pathology, The Oklahoma Children s Memorial Hospital,

University o f Oklahoma Health Sciences Center, Oklahoma City, OK 73190

ABSTRACT

A retrospective study of acquired renal lesions in 42 renal transplants in children revealed a variety of histologic lesions. Although acute and chronic rejection changes were the most frequent, a number of metabolic, infectious, vascular, and other lesions were encountered. Renal biopsy allows rapid diagnosis of these lesions, permitting rational planning for therapy.

Introduction

The treatment of end-stage renal dis­ease by means of renal transplantation is now widely accepted. When successful, such therapy restores quality of life and health to patients who would otherwise be d ependen t upon hem odialysis or peritoneal dialysis. However, successful engraftment is fraught with many techni­cal, immunologic, metabolic, and infecti­ous hazards, and the complication rate of such a procedure remains high. Whereas great effort is made to insure that a renal allograft is healthy at the time of its trans­fer into the rec ip ien t, a variety of pathologic changes may soon appear within the allograft. Percutaneous renal biopsy of the engrafted organ affords the clinician and pathologist the opportunity to identify rapidly those changes and plan for therapy on a rational basis. Our experi-

Address reprint requests to James E. WenzI, M.D., D epartm en t o f Pediatrics, P.O. Box 26901, Ok­lahoma City, OK 73190.

ence with percutaneous renal biopsy is reviewed in the diagnosis of acquired renal lesions which have emerged in 42 renal allografts in children engrafted at the Oklahoma Children’s Memorial Hos­pital. It is emphasized that the authors are not reporting an inclusive review of all renal allograft lesions but are reviewing our clinicopathological experience.

Rejection

A c u t e R e j e c t i o n

Despite continuous immunosuppres­sive therapy, most patients with renal al­lografts undergo one or several episodes of acute rejection. These tend to be more intense during the first few weeks after transplantation but may occur anytime, especially if the patien t’s medicaticJn compliance is poor. Biopsy of the kidney will show varying degrees of two princi­pal findings, depending upon whether the rejection is predom inantly cellular or humoral in origin. In predominantly cel­

3160091-7370/81/0700-0316 $00.90 © Institute for Clinical Science, Inc.

ACQ UIRED LESIO N S IN TRA N SPLA N TED KIDNEYS 317

lu lar rejection, there is w idesp read in ter­stitial edem a and infiltration of the cortex by lym phoid cells (figure 1). P eritubu lar cap illaries show en d o th e lia l and b ase­m en t m em brane dam age, and renal tu b u ­lar injury is no t uncom m on. I f the acute rejection is prim arily hum oral, the lym ­phocytic reaction is less p rom inen t and the m ajor site of injury is in the small blood vessels, includ ing capillaries, ven­ules, and arterio les. T h ese vessels b e ­com e obstructed by p la te le t aggregates, follow ed by the appearance of fibrin and n eu troph ilic po lym orphonuclear leuko­cytes. C ellu lar and hum oral changes may coexist, and both may be com pletely or p a t ia l ly re v e rs e d by v ig o ro u s a n t i ­rejection therapy.

C h r o n i c R e j e c t i o n

C hronic rejection is the second most com m on acquired lesion encoun te red in renal allografts following transplantation. T he m ajor changes of chronic rejection are two-fold: arterial narrow ing o f the renal vessels and glom erular capillary th icken­

ing; these may be diffuse or segm ental. T he latter change is often focal w ith some glom eruli being spared. Arterial narrow ­ing is m ost com m on in the larger (inter­lobular and arcuate) arteries, b u t vessels of any size may be affected, includ ing the m ain renal artery (figure 2). T he genesis o f the a rte ria l n arrow ing is re la ted to p la te le t and fibrin deposition on arterial w alls, w ith gradual coverage by en d o ­thelium and incorporation into the intim a. Is c h e m ic tu b u la r a tro p h y a n d in te r ­stitial fibrosis are late b u t invariable find­ings. In contrast w ith the lesions of acute rejection, chronic rejection changes are not reversib le w ith im m unosuppressive or o ther therapy and herald a gradual loss o f graft function.

Metabolic Disorders

C y s t i n o s i s

N ephropathic, or childhood cystinosis, is characterized by progressive cystine crystal deposition in the cornea, conjunc­tiv a , b o n e m arrow , ly m p h o cy te s , r e ­

F ig u r e 1. A cute rejec­t io n c h a r a c te r iz e d b y ly m p h o c y tic in filtration , focus o f tubular n ecrosis and in terstitia l edem a. H & E , orig inal m agnifica­tion; x 250.

}A

318 W EN ZL AND KROUS

F ig u r e 2. Chronic re­jection characterized by severe intimal fibrosis of an arcuate artery; there is also in te rs titia l fibrosis and tubular atrophy. H & E, original magnification; x 250.

ticu loendothelial system, liver, and kid­neys. D eath from end-stage renal disease usually occurs in the first decade of life o w in g to p ro g re s s iv e im p a irm e n t o f g lom erular and tubu lar function. Since the basic defect appears to be a gene ti­cally de term ined in tracellu lar accum ula­tion of cystine, a transp lan ted kidney from a donor w ithout the defect should not suc­cum b to progressive in tracellu lar cystine crysta l accu m u la tio n . R enal b iopsy of these ch ild ren following transplantation shows m ild cystine crystal deposition in in terstitia l cells, presum ably of host ori­gin, and occasional crystals in m esangial cells (figure 3). Those crystal depositions do not appear to shorten graft survival, and renal function studies have not revealed recurrence of the Fanconi syndrom e, the c h a ra c te r is t ic p re s e n t in g fe a tu re o f cystinosis.4

O x a l o s is

E ith e r o f tw o form s o f p rim ary hyperoxalu ria m ay lead to progressive deposition of oxalate in kidneys and other

body tissues, leading to renal failure at variab le ages. To date , no com ple te ly satisfactory therapy has b een found to p reven t recurren t oxalate deposition in kidneys transplan ted into these children. Previously a report was p resen ted by us of a ch ild w ho su cc u m b e d to re c u rre n t oxalosis in h e r tran sp lan ted k idney 23 m onths after transplantation .2 Serial b iop­sies revealed progressive oxalate deposi­tion and consequen t tubu lar destruction and in terstitia l fibrosis (figure 4). D espite aggressive m edical attem pts to p reven t recu rren t deposition, she d ied of urem ia.

Infection

C y t o m e g a l o v i r u s

C ytom egalovirus infection rem ains a com m on even t in transplan ted patients. Pulm onary, renal, hepatic , and bone m ar­row involvem ent is common, as is fever. C ytom egalovirus in fec tion in six post­transp lan t ch ildren has b een diagnosed by us by serologic or histologic means. Graft dysfunction has b een an invariable

ACQUIRED LESIO N S IN TRA N SPLA N TED KIDNEYS 3 1 9

%

F ig u r e 3. C ystin e crystals w ith in the renal in terstitium are ea sily se en w ith th e aid o f p o larized light. H & E , original m agnification, x 250.

F ig u r e 4. Oxalate crystals seen under polarized light are most prom inent within tubules. H & E, original magnification; x 100.

early clinical finding and, histologically, the affected kidney may show only vary­ing degrees of in terstitia l edem a and n ec­rotizing in terstitia l changes w ith typical inclusions in tu b u lar cells (figure 5). Al­though renal biopsy is not always defin i­tive,3 early histologic identification per­

mits expectant therapy w ithout resorting to increased im m unosuppression w hich may w orsen the severity of the infection. Such therapy has perm itted survival of each child , and in only one was there perm anen t reduction of renal function as a consequence of infection.

F ig u r e 5. In the center of the field, the nuclear and cy top lasm ic in c lu ­sions ty p ica l o f cy to­megalovirus infection are noted in an enlarged cell. H & E, original magnifica­tion; x 100.

r

320 W E N ZL AND KROUS

F ig u r e 6. T h e glom er­u lus m anifests segm en ta l m e sa n g ia l s c le r o s is and cap illa ry c o lla p se w h ile o th e r r e g io n s are r e la ­t iv e ly norm al. H & E , orig­inal m agnification; x 400.

Recurrence of Glomerular Disease

F o c a l S e g m e n t a l G l o m e r u l o s c l e r o s i s

Focal segm ental glom erulosclerosis in ch ildren is classically associated w ith a steroid resistan t nephrotic syndrom e w ith m icrohem aturia. T he typical juxtam edul- lary focal segm ental g lom erular lesion usually contains p rom inen t deposits of

im m unoglobulin and com plem ent com­ponents and often progresses to end-stage renal disease. T hree ch ildren w ith this en ­tity have b een transplan ted , two of whom have d e v e lo p e d re c u rre n t h eavy p ro ­teinuria and a nephrotic syndrome within the first m onth follow ing transplantation. Both ch ild ren sub seq u en tly received a second allograft, and biopsy of th ree of the allografts revealed recurrence of typical focal s e g m e n ta l g lo m e ru lo sc le ro s is

F ig u r e 7. T h e infarcted portion o f the k id n ey on th e left is sharply dem ar­ca ted from v ia b le t issu e on the right. H & E, origi­nal m agnification; x 40.

ACQ UIRED LESIONS IN TRA N SPLA N TED KIDNEYS 321

(figure 6). T he th ird child has show n no ev idence of graft dysfunction 28 m onths post-transplant.

Arterial Lesions

R e n a l I n f a r c t i o n

A 16-year-old boy received an HLA-4 antigen m atch k idney from his brother. F o llow ing engraftm en t, th e re was im ­m ediate estab lishm ent of excellen t renal function. H ow ever, a m oderate decrease in graft func tion asso c ia ted w ith graft te n d e rn e ss su d d en ly d ev e lo p e d th ree m onths later. Renal b iopsy revealed nor­mal renal tissue w ith a focal area of necro­sis at one end of the specim en (figure 7). Subsequen t graft arteriography revealed a large renal infarct secondary to occlusion of an in terlobar artery. A lthough such in ­farcts have b een reported to be related to delayed re jection ,1 there was no evidence or rejection in this boy at the tim e of d is­covery o f the infarct. H is renal function has rem ained stable for the past 14 months w ith no further infarction episodes.

R e n a l A r t e r y S t e n o s i s

A 16-year-old girl w ith end-stage kid­ney disease and a nephro tic syndrom e re­ceived an HLA-2 an tigen m atch cadaveric renal allograft. H er initial graft function was ex cellen t; how ever, th ree m onths a f te r t r a n s p la n ta tio n , sh e d e v e lo p e d h y p e r te n s io n . P ro g re s s iv e ly se v e re hypertension over the next th ree m onths caused congestive heart failure and death. At postm ortem exam ination, the extra- renal donor artery adjacent to the arterial anastom osis show ed concentric intim al fibrosis and severe stenosis (figure 8). Re­jection changes w ere o f m ild severity; there w ere no o ther arterial lesions. Al­though renal artery stenosis has b een re­p o r te d to re s u lt from in tim a l in ju ry , m echanical obstruction, vascular obstruc­tio n or v a s c u la r le ak from th e a n a s ­tom osis,1 these factors could not be im pli­cated in this case.

F ig u r e 8. The extrarenal artery of the allograft demonstrates concentric intimal fibrosis with nar­rowing of the lumen. There is segmental disruption of the internal elastic lamina. Note the absence of vasculitis. V erhoeff van G ieson (VVG), original magnification; x 100.

Summary

P erc u ta n eo u s ren a l b iopsy o f tran s­p lan ted allografts is a valuable tool for rapid histologic assessm ent o f causes of graft dysfunction. A variety o f new ly ac­qu ired lesions may be elucidated at m in­imal risk to the pa tien t or his graft. Such elucidation perm its rational p lann ing for therapy of these patients.

R eferences

1. C h a t t e r je e , S. N.: Manual of Renal Transplan­tation. New York, Springer-Verlag, 1979, pp. 1 4 0 -1 4 2 .

2. H a l v e r s t a d t , D . B. an d W e n z l ,J . E.: Primary hyperoxaluria and renal transplantation. J. Urol. I l l : 3 9 8 -4 0 2 , 1974.

3. H am ed , I. A ., W e n z l , J. E ., L e o n a r d , J. C ., A l t s h u l e r , G . P ., an d P e d e r s o n , J. A.: P ulm onary cytom egalov iru s in fection: D e te c ­tion by G allium 67 im aging in th e transplant p atient. Arch. Intern. M ed. 139:286-288, 1979.

4. M a le k z a d e h , M. H ., P e n n is i, A. J., U i t t e n - b o g o a r t , C. H ., K o r s c h , B. M ., F in e , R. N., and M ain , M. E.: Current issues in pediatric renal transplantation. Ped. Clin. North Amer. 23 :8 5 7 -8 7 3 , 1976.