Binswanger, U.

Briner, J.

Bruder, E.

Burger, H. R.

Gantenbein, H.

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Nephrol Dial Transplant (1995) 10: 287-289case ReportNephrologyDialysisTransplantationRecurrence of Fabry's disease in a renal allograft 14 years aftertransplantationH. Gantenbein1, E. Bruder2, H. R. Burger2, J. Briner2 and U. Binswanger1'Department of Internal Medicine, Section of Nephrology,2 Department of Pathology, University Hospital Zurich,SwitzerlandKey words: Fabry's disease; renal transplantation;recurrence of diseaseIntroductionFabry's disease (a-galactosidase-deficiency), an inbornerror of glycosphingolipid metabolism, results fromthe defective activity of the lysosomal enzyme a-galac-tosidase. The enzymatic defect, transmitted by anX-linked recessive gene, leads to the progressive accu-mulation of neutral glycosphingolipids with terminala-galactosyl moieties in most visceral tissues and bodyfluids. Characteristic clinical manifestations of the dis-ease are onset of pain and paraesthesias in the extrem-ities, vessel ectasia (angiokeratomata) in skin andmucous membranes, and hypohidrosis during child-hood or adolescence. Corneal and lenticular opacitiesare early findings. With increasing age renal failureand a dilated cardiomyopathy can develop. Kidneytransplantation successfully corrects renal insufficiency[1] and was regarded by some authors as a possibleway for correcting not only renal insufficiency, butalso the enzymatic deficiency by replacement of a-galactosidase through the transplanted kidney [2,3].We report a case of Fabry's disease in which the diseaserecurred in the transplanted kidney 14 years aftersuccessful renal transplantation.Case reportOur male patient was born in 1947, and did well until1974 when for the first time impaired renal functionwas described. In 1978 the diagnosis of Fabry's diseasewas made. There were typical opacities in the corneasas well as skin changes (angiokeratomatas). Ceramid-trihexosid concentration was elevated in the urine. Incultured fibroblasts of the skin a diminished activityCorrespondence and offprint requests to: Prof. U. Binswanger,Departement fur Innere Medizin, Abteilung Nephrologie,Ramistrasse 100, CH-8091 Zurich, Switzerland.of a-galactosidase was found. In the same year thekidney function deteriorated and haemodialysis wasrequired.One year later, the patient was successfully trans-planted. A few days after transplantation a rejectionwas postulated and the patient received 3 x 1000 mgsolumedrol i.v. The following course was unevent-ful and renal function was stable until 1993.Immunosuppressive maintenance therapy included10 mg prednisone and 100 mg azathioprine. Aftertransplantation the patient became HBs-Ag and HBe-Ag positive; it was suspected that he became infectedthrough six blood transfusions during the transplanta-tion period. During follow-up chronic aggressive hep-atitis B was diagnosed and the patient developedcirrhosis of the liver. In 1981 he exhibited femur headnecrosis on both sides, probably related to steroidmedication after transplantation. Hip replacement wasperformed in 1981 on the left side, and on the rightside in 1982. The patient was hospitalized in August1985 because of deep-vein thrombosis of the left leg.In 1987 a cholecystectomy was performed because ofacute cholecystitis; in the same year osteonecrosis ofthe lateral femur condylus was diagnosed, eventuallydue to Fabry's disease or steroid therapy.During 1992 infection of the right hip joint withSalmonella enteritidis was observed. Treatment withciprofloxacin was begun and a new artificial joint wasimplanted.In 1993 deterioration of the clinical status of thepatient began. Liver function became worse, the patientgained weight and the kidney function deteriorated.The patient was hospitalized. The diagnosis of activa-tion of hepatitis B and liver cirrhosis was made and ahepatorenal syndrome was suspected. Renal functionbecame worse despite treatment with vasoactive sub-stances and volume substitution. In the end stage ofthe disease, a continuous venovenous haemofiltrationwas begun. The patient died 2 days later from car-diac failure.Autopsy findingsAutopsy was performed 27.5 h after death.Morphological findings were: Excentric hypertrophy11995 European Dialysis and Transplant Association-European Renal Association288of both cardiac ventricles with signs of relative coron-ary insufficiency, micronodular cirrhosis and cholest-asis of the liver, adenoma of Papilla vateri, focuses ofinfarction of the spleen, and atrophy of the adrenalcortex. Deposits of ceramid-trihexosid were demon-strable in walls of blood vessels, myocardial cells,Kupffer cells and also in liver cells. The patient's ownkidney showed massive cortical atrophy and completeloss of glomeruli. Residual tubules were dilated andtubular epithelium appeared vacuolated in paraffinsections (Figure 1). Electron-microscopy revealed mas-sive deposits of ceramid-trihexosid in tubular epithe-lium, tubular lumen, interstitial macrophages, andendothelial cells. Although the kidney transplant wasof normal light-microscopic appearance, ultrastruc-turally deposits of ceramid-trihexosid in endothelialcells (Figure 2) as well as in tubular epithelium(Figure 3) were observed.DiscussionIn this 46-year-old male patient, recurrent Fabry'sdisease was noted in the transplanted kidney 14 yearsafter successful allotransplantation. There was an accu-mulation of ceramid-trihexosid in several organs aswell as in tubular epithelial cells and endothelial cellsof the transplanted kidney.The description of recurrence of Fabry's disease inthe transplanted kidney is rare. We found only fourother cases in the literature [4-7]. In 1981 we reporteda case from our centre in which, 14 years after success-ful transplantation, no signs of de novo Fabry's diseasein the transplanted kidney could be found [8].Four possibilities for recurrence can be thought of:1. Inadequate enzyme replacement for complete meta-bolization of the ceramid-trihexosid produced.2. Increased production of ceramid-trihexosid, whichcannot be totally metabolized in presence of normalenzyme activity. This seems to us the most probablehypothesis. It explains why only small amounts ofH. Gantenbein et al* HiFig. I. Patient's kidney (H&Ex460). Vacuolization of tubularepithelium.Fig. 2. Kidney transplant (EM x 3700, inset x 83 700). Formalinfixed and refixed in glutaraldehyde. Endothelial cell showing extens-ive ceramid-trihexosid deposition. Inset demonstrates lamellar struc-tures with periodicity.ceramid-trihexosid are found (that are seen only byelectron-microscopy) and why the deposits arealways in the vascular endothelium. Friedlanderet al. [4] performed a renal biopsy in a patient 8years after transplantation with normal renal func-tion. Light-microscopy showed no abnormalities,but electron-microscopy revealed occasional smallmyelin figures in the vascular endothelium compat-ible with early accumulation of ceramid-trihexosid.Mosnier et al. [5] also described a case in whichautopsy was performed II years after successfultransplantation. Sphingolipid inclusions were foundin endothelial cells of capillaries by electron-microscopy.Recolonization of the graft vascular system throughhost endothelium. This theory was formulated byMcMahon et al. [6]. They described a male patientwith blood group B, who was transplanted with akidney from a donor with blood group O. Theyshowed, that the donor allograft endothelium wasslowly replaced by cells displaying both cytoplasmicmetabolic inclusions and surface immunologicalmarkers specific to the host phenotype with com-plete recolonization of the graft vascular system byhost endothelium.Presence of a circulating inhibitor of a-galactosid-ase. Faraggiana et al. [7] described a patient whodied of heart failure 6 months after kidney trans-Recurrence of Fabry's disease in a renal allograftFig. 3. Kidney transplant (EM x 900, inset x 83 700). Formalin fixedand refixed in glutaraldehyde. Tubular epithelium snowing ceramid-trihexosid deposition. Inset demonstrates lamellar structure withperiodicity.plantation. They found a small number of typicaldeposits in the transplanted kidney. In this case acirculating a-galactosidase inhibitor was demon-strated, but this was not investigated in our patient.Survival of the allograft in our patient for 14 yearswith well-maintained structure of the kidney at autopsysuggests that the indication for kidney allotransplant-ation is not limited by the possibility of graft failurefrom recurrence of Fabry's disease.For other organ damage it is expected that progres-sion of pre-existing lesions should be slowed down.Cardiac pathology in the patient reported includedmainly dilatation, which is compatible with normalblood pressure without medical treatment observedclinically. The possibility that the amount of ceramid-289trihexosid deposited in myocardial cells contributed toterminal cardiac insufficiency cannot be totallyexcluded.Concerning the course of hepatitis B, high antigentitres up to 280 000 E/ml in the absence of anti-Hbsantigen and positive Hbe antigenaemia in 1991 wereobserved. GOT and GPT levels were elevated slightlyand intermittently during the whole course. This con-stellation is very likely to be related to immunosuppres-sive therapy. An influence of Fabry's disease of theliver on the course of the hepatitis B infection seemsrather remote.In summary, this case illustrates that kidney trans-plantation cannot heal Fabry's disease by enzymetransplantation in all patients. Several explanations forrecurrent disease are discussed which may explain thevariable occurrence of Fabry's deposits in transplantedkidneys. Nevertheless a patient can be successfullytreated for kidney failure during an extended timeperiod. The extent of heart damage might decide thelong-term survival of patients (8, this report). Ethicalconcern to include patients with Fabry disease intransplantation programmes seems not to be justifiedeven in times of transplant organ shortage.References1. Desnick RJ, Bishop DF. Fabry disease: a-galactosidase defi-ciency. In: Scriver R, Beaudet AL, Sly WS, Valle D. Themetabolic basis of inherited disease. McGraw-Hill, New York,1989: 6th edn: 1751-17802. Clarke JTR, Guttman RD, Wolfe LS, Beaudoin JG, MorehouseDD. Enzyme replacement therapy by renal allotransplantationin Fabry's disease. N Engl J Med 1972; 287: 12153. Krivit W, Desnick RJ, Bernloko RW, Wold F. Enzyme trans-plantation in Fabry's disease. N Engl J Med 1972; 287: 12484. Friedlaender MM, Kopolovic J, Rubinger D et al Renal biopsyin Fabry's disease eight years after successful renal transplanta-tion. Clin Nephrol 1987; 27: 206-2115. Mosnier JF, Degott C, Bedrossian J et al. Recurrence of Fabry'sdisease in a renal allograft eleven years after successful renaltransplantation. Transplantation 1991; 51: 759-7626. MacMahon J, Tubbs R, Gephardt G, Steinmuller D. Pseudorecurrence of Fabry's disease in renal allograft (Abstract). LabInvest 1986; 54: 42A7. Farragiana T, Churg J, Grishman E et al Light- and electron-microscopic histochemistry of Fabry's disease. Am J Pathol1981; 103: 247-2628. Bannwart F. Morbus Fabry. Licht- und elektronen mikroskop-ischer Herzbefund 12 Jahre nach erfolgreicherNierentransplantation. Schweiz Med Wocheuschr 1982; 112:1742-1747Received for publication: 9.8.94Accepted: 20.10.94

Recurrence of Fabry's disease in a renal allograft 14 years after transplantation

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