Binet, I.

Bock, A.

Fischer, A.

Oertli, D.

Thiel, G.

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Nephrol Dial Transplant (1996) 11: 2077-2079Case ReportNephrologyDialysisTransplantationFatal outcome of renal transplantation in a patient with theWiskott-Aldrich syndromeA. Fischer1,1. Binet1, D. Oertli2, A. Bock1 and G. Thiel1'Division of Nephrology, Department of Internal Medicine, and 2Department of Surgery, Kantonsspital, University of Basel,Basel, SwitzerlandKey words: B-cell lymphoma; renal transplantation;Wiskott-Aldrich syndromeIntroductionTwo cases of successful cadaveric renal transplantationin patients with the Wiskott-Aldrich syndrome havepreviously been reported in the literature [1,2]. Thefirst patient [1] had an almost uneventful outcome,while the second one [2] had to be treated with high-dose methylprednisolone for biopsy-proven cellularrejection. The optimal immunosuppressive regimen inpatients with Wiskott-Aldrich syndrome remainsunknown. We report here the case of aWiskott-Aldrich patient who underwent living-relatedrenal transplantation. This patient however developeda number of infectious and non-infectious complica-tions which led to his death 3 months aftertransplantation.Case reportThe patient, a 41-year-old man with a strong familyhistory of an X-linked transmitted syndrome (17 affec-ted men and 10 female carriers in the last threegenerations), presented in early childhood with severethrombocytopenia, allergic eczema, and recurrentinfections (bronchitis, herpetic keratitis). Since 1982he had developed progressive renal insufficiency withmicrohaematuria and proteinuria, which was presumedto be due to I gA nephropathy (no biopsy wasobtained, but a brother of the patient who died at theage of 32 suffered from the Wiskott-Aldrich syndromeand developed end-stage renal failure due to biopsy-proven I gA nephropathy). Haemodialysis treatmentwas started in April 1991. In preparation for renaltransplantation the patient underwent splenectomy inCorrespondence and offprint requests to: Prof. Gilbert Thiel, Divisionof Nephrology, Department of Internal Medicine, Kantonsspital,Petersgraben 4, CH^031 Basel, Switzerland.January 1994, which resulted in normalization of theplatelet count.In August 1994 he received a one-haplotype-matchedliving-related kidney graft (the donor was his fatherborn in 1925). CMV constellation was donor positive/recipient positive. Epstein-Barr virus serology wasI gG positive and I gM negative for both recipient anddonor. Because of the underlying immunosuppression,our usual induction protocol (quadruple therapyincluding antithymocyte globulin (ATG), azathioprine(Aza), prednisone (Pred), and CsA was modified byomitting ATG. CsA (dose adjusted to maintain atrough whole-blood level of 200-250 ng/ml), Aza(2 mg/kg), and methylprednisolone (1 g, 0.5 g, 0.25 gintravenously respectively on day 0, 1, 2) tapered to0.5 mg/kg Pred by day 3 were administered as usual.The onset of renal function was prompt. On day 5creatinine increased and three methylprednisolonepulses were administered. Transplant biopsy failed toconfirm rejection and functional CsA toxicity wassuspected. Creatinine decreased (151 umol/1 onday 14). On day 22 creatinine increased to 229 umol/1and a second renal biopsy showed a moderate infiltr-ative and proliferative transplant vasculopathy withareas of arteriolar necrosis. ATG (0.2 ml/kg per day)was administered for 7 days with a good effect onrenal function.On day 30 the patient developed CMV disease andwas treated with ganciclovir. Because of severe leukop-enia filgrastim was administered over 5 days. On day 39a catheter sepsis with coagulase-negative staphylococciwas diagnosed and treated with vancomycin. Onday 46, several herpes zoster vesicles appeared on theplantar edge of the left foot. On day 52 the patientdeveloped fever and paroxysmal excruciating pain radi-ating to the left lower limb with a SI dermatometopography. Acyclovir was administered and clona-zepam was necessary to control pain, which was inter-preted as zoster neuralgia. From days 76 to 78 thepatient was given three methylprednisolone pulses forbiopsy-proven interstitial rejection (creatinine237 umol/1.).High fever appeared associated with rising liverO 1996 European Renal Association-European Dialysis and Transplant Association2078enzymes (ASAT up to 858 U/l, ALAT up to 369 U/l).Ganciclovir and imipenem were given but withoutimprovement of the patient's condition. A liver biopsyon day 88 revealed a malignant high-grade B-cell non-Hodgkin lymphoma (large-cell immunoblastic accord-ing to International Working Formulation) with mas-sive periportal infiltration. A thoracoabdominal CTscan and bone marrow aspiration failed to demonstrateany other foci of the lymphoma. CsA was stopped onday 88 and a first cycle of chemotherapy consisting ofadriamycin and cyclophosphamide was administered.On the same day, Pneumocystis carinii pneumonia wasdiagnosed and treatment with co-trimoxazole was insti-tuted. Haemodialysis was then started because of pro-gressive oliguria. On day 91 the patient developedmassive epistaxis and melena requiring transfusionalsupport; platelets had decreased to 38000/mm3. Twodays later a subdural haematoma was diagnosed byCT scan.Over the following days the patient's conditionrapidly deteriorated. He became unresponsive,developed severe hypotension, and died on day 98.Autopsy was not performed because of family refusal.Post-mortem liver biopsy showed persistent lymphoma.Post-mortem transplant biopsy showed mild sclerotictransplant vasculopathy.DiscussionThe Wiskott-Aldrich syndrome is a rare X-linkedsyndrome associating B- and T-cell immunodeficiency,thrombocytopenia, and eczema. As recently described[3,4] there is a defective expression of the CD43molecule on T cells, which may compromise the antigenspecific activation of T cells by impairing interactionwith ICAM-1. This same mechanism may underlie thepropensity for infections and the increased incidenceof B-cell lymphoma for which this syndrome is known[5]. The ideal treatment for patients with theWiskott-Aldrich syndrome is HLA-identical bone-marrow transplantation from a sibling donor, whichcures the underlying immunodeficiency, although suchdonors are available for only a few Wiskott-Aldrichpatients [6,7]. An alternative therapeutic approach issplenectomy, which has been shown to improve bothsurvival and quality of life [7].One variant of the syndrome is associated with I gAnephropathy, potentially leading to end-stage renalfailure [8-10]. Renal transplantation is not usuallyrecommended in this condition because of the under-lying immunodeficiency and the increased risk oflymphoma. The patient reported by Webb et al. [1]was given a reduced immunosuppressive regimen(triple therapy with Aza in a reduced dose, CsA, andPred). There was no rejection episode and a primaryCMV seroconversion illness resolved rapidly aftertreatment with anti-CMV hyperimmune globulins. Avery similar immunosuppressive regimen was initiallyused by Meisels et al. [2]; Aza had to be discontinuedon day 12 because of thrombocytopenia. Their patient,A. Fischer et al.however, had to be treated twice with high-dosemethylprednisolone, the first time for clinically sus-pected rejection, the second time for biopsy-provencellular rejection. This shows that despite the under-lying defect in cellular immunity their patient was ableto develop an immune response to allograft antigens.Our patient underwent a one-haplotype-matchedliving-related renal transplantation. He received twocourses of high dose methylprednisolone, and wasadditionally treated with ATG because of vascularrejection. The following course proceeded to thedreaded 'worst-case scenario': several infectious com-plications followed each other in rapid succession anda fatal high grade B-cell lymphoma of the liverdeveloped.Such a dramatic outcome raises ethical as well asmedical considerations. Our observation suggests thatrenal transplantation remains a high-risk procedure inpatients with the Wiskott-Aldrich syndrome. Thesepatients are able to mount a severe rejection reactionagainst the transplanted kidney and their increasedpropensity to develop lymphoma limits drastically thetherapeutic possibilities if such a rejection occurs.Retrospectively it is evident that we superseded thislimitation. We probably should have reduced theamount of Aza in our induction protocol, and certainlyshould not have used ATG at all. The patient was aperfectly well-informed man working in a leadingparamedical position. Every step in his treatment wasthoroughly discussed and our error was to accept hiswillingness to undergo a risky treatment. Is it at allethical to transplant a patient with the Wiskott-Aldrichsyndrome? The answer to this question depends prob-ably most on the subjective quality of life duringchronic dialysis treatment. If renal transplantation isattempted, Aza dose is to be reduced and antilympho-cyte globulins are to be strictly avoided, even if thismeans rapidly losing the graft.References1. Webb MC, Andrews PA, Koffman CG, Cameron JS. Renaltransplantation in Wiskott-Aldrich syndrome. Transplantation1993; 56: 747-7482. Meisels IS, Strom TB, Roy-Chaudhury P et al. Renal allograftrejection in a patient with the Wiskott-Aldrich syndrome.Transplantation 1995; 59: 1214-12153. Park JK, Rosenstein YJ, Remold-O'Donnel E, Bierer BE, RosenFS, Burakoff SJ. Enhancement of T-cell activation by the CD43 molecule whose expression is defective in Wiskott-Aldrichsyndrome. Nature 1991; 350: 706-7094. Rosenstein YJ, Park JK, Hahn WC, Rosen FS, Bierer BE,Burakoff SJ. CD 43, a molecule defective in Wiskott-Aldrichsyndrome binds ICAM-1. Nature 1991; 354: 233-2355. Cotelingam JD, Witebsky FG, Hsu SM, Blaese RM, Jaffe ES.Malignant lymphoma in patients with the Wiskott-Aldrichsyndrome. Cancer Invest 1985; 3: 515-5226. Rimm IJ, Rappeport JM. Bone marrow transplantation for theWiskott-Aldrich syndrome. Long-term follow-up.Transplantation 1990; 50: 617-6207. Mullen CA, Anderson KD, Blaese M. Splenectomy and/or bonemarrow transplantation in the management of theWiskott-Aldrich syndrome: long-term follow-up of 62 cases.Blood 1993; 82: 2961-2966Fatal outcome of renal transplantation in Wiskott-Aldrich syndrome8. Guttenberger J, Trygstad CW, Stiehm ER el at. Familial throm-bocytopenia, elevated serum I gA levels and renal disease. Areport of kindred. Am J Med 1970; 49: 729-7419. Standen GR, Lillicrap DP, Mathews N, Bloom AL. Inheritedthrombocytopenia, elevated serum I gA and renal disease.Identification of a variant of the Wiskott-Aldrich syndrome. QJ Med 1986; 59: 401^0810. Spittler LE, Wray BB, Morgenmanns S, Miller JJ, O'Reilly RJ,Lagios M. Nephropathy in the Wiskott-Aldnch syndrome.Pediatrics 1980; 66: 391-3982079Received for publication' 1.12.95Accepted in revised form. 8.12 95Editor's notePlease see also The Interesting(pp. 2093-2095 in this issue).Case by Hitzig and Triniger

Fatal outcome of renal transplantation in a patient with the Wiskott-Aldrich syndrome

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