- Email: [email protected]
Kidney Transplantation Improves Survival and Is Indicated in Fabry’s Disease
Kidney Transplantation Improves Survival and Is Indicated in Fabry’s Disease D. Inderbitzin, I. Avital, F. Largiadèr, B. Vogt, and D. Candinas ABSTRACT Background. Fabry’s disease (FD) is an inborn error of glycosphingolipid catabolism with progressive systemic deposition of globotriaosylceramide thereby leading to renal and cardiac failure. Current therapy involves symptomatic medical management, dialysis, enzyme replacement therapy, kidney transplantation (KTx), and more recently gene therapy. Case fatalities occur in the fourth decade of life resulting from uremia unless dialysis or KTx is undertaken. Study Design. This is a retrospective study aimed at determining the effect of KTx on the long-term outcome of patients with FD. Results. Between 1964 and 1998, ten patients with FD received KTx at our institutions. Actuarial patient and graft survivals were 100% and 90% at 5 years; 76% and 66% at 10 years. One kidney graft was lost due to rejection. Patient survival data compared favorably at 5 years with survival of FD patients on hemodialysis alone (41%, P ⬍ .05). Five patients are alive at the time of this study, and five patients died with median survival time after KTx of 128 months (range: 74 –160 months). Conclusions. This study demonstrates an excellent outcome in patients with FD in the first decade after KTx. In the absence of a severe contraindication, we advocate KTx to improve the overall prognosis of patients with renal failure due to FD. Based on the data, enzyme replacement therapy after KTx seems indicated, as FD progresses posttransplant, leading to case fatalities in the second decade after KTx.
F
ABRY’S DISEASE (FD), first described in 1898 by Johann Fabry1 as “Purpura papulosa haemorrhagica Hebrae” and by William Anderson2 as “Angio-Keratoma” is a rare inborn error of glycosphingolipid catabolism3 that results from the defective activity of the lysosomal enzyme ␣-galactosidase A.4 This enzyme cleaves the ␣-galactosyl moiety from globotriaosylceramide. The absence or malfunction of this enzyme, which is transmitted by an X-linked recessive gene (Xq22.1), leads in homozygous men to lysosomal accumulation of glycosphingolipids (globotriaosylceramide and galabiosylceramide) in endothelial cells, smooth muscle cells, leucocytes and fibrocytes in most visceral tissues, as well as in the nervous system, the kidneys, and the heart. With increasing age, however, the progressive glycosphingolipid deposition in the kidney and heart is the cause of most case fatalities.3,5 Current therapy involves symptomatic medical management, hemodialysis, substrate depletion, fetal liver transplantation,6 enzyme replacement,7,8 kidney transplantation (KTx),9 and recently gene therapy.10
Death most often results from uremia unless chronic dialysis or KTx is undertaken. The reported mean age at death of untreated FD patients is 41 years,11 and the 5-year survival on hemodialysis is 41%.12 Early reports regarding KTx for the treatment of endstage renal disease in patients with FD showed a high incidence of septic complications and a survival rate of only 26% at 5 years. It was speculated that either compromised fibroblast function and impaired collagen metabolism or
From the Departments of Visceral and Transplantation Surgery (D.I., D.C.) and Nephrology (B.V.), University Hospital Bern, Bern, Switzerland; the Memorial Sloan Kettering Cancer Center (I.A.), New York, NY; and the Department of Surgery, Division of Visceral Surgery (F.L.), University of Zurich Hospital, Zurich, Switzerland. Address reprint requests to D. Inderbitzin, Department of Visceral and Transplantation Surgery, University Hospital Bern, CH 3010 Bern, Switzerland. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.11.021
Transplantation Proceedings, 37, 4211– 4214 (2005)
4211
4212
INDERBITZIN, AVITAL, LARGIADÈR ET AL Table 1. Demographics
Patient #
Diagnosis Age (years)
Dialysis Initiation Age (years)
Dialysis Duration (months)
KTx Age (years)
KTx Year
1 2 3 4 5 6 7 8 9 10
45 32 43 43 8 15 7 15 36 19
no 32 42 43 25 16 34 44 37 no
0 12 19 49 40 12 12 10 36 0
45 33 44 48 28 17 35 45 40 28
1968 1979 1980 1981 1990 1991 1993 1993 1995 1998
Mean (range)
26 (7–45)
34 (16–44)
19 (10–49)
36 (17–48)
deficient leukocyte function is responsible for the high rate of infectious complications.13 The conclusion drawn from early transplantation series and the consequent recommendation from the National Institute of Health in 1975 was to withhold KTx from patients with FD.14 However, one decade later, careful examination of the immunological state in FD patients did not reveal any specific impairment.15 Furthermore, patient and graft survivals continuously improved after KTx, while posttransplant morbidity decreased.16,17 Therefore, due to the rarity of this disease, the aim of this study was to retrospectively determine the effect of KTx on the long-term outcomes of FD patients.
METHODS This is a retrospective analysis of our experience with KTx for patients with end-stage renal disease due to FD. Data are presented as mean values (range). A cohort of 10 patients has been followed since 1968 with a mean follow-up of 123 (72–160) months. All patients were hemizygous men who received cadaveric kidney allografts. Recurrence of FD after KTx was assessed histologically by renal biopsy or at autopsy when appropriate. Survival analysis was performed according to the Kaplan-Meier method. Patient’s survival after KTx, on dialysis alone, and in historic controls was compared statistically (Jandel Scientific 1.0). P values ⬍ .05 were considered significant. Five patients of our series are currently alive and regularly followed clinically.
RESULTS
Ten patients with end-stage renal failure due to FD received a KTx at our institutions (Table 1). The mean age at diagnosis was 26 (7– 45) years. The mean age at initiation of dialysis was 34 years (16 – 44), and dialysis was maintained for 19 months (10 – 49) before KTx was performed at 36 years of age (17– 48). Systemic clinical signs of FD are summarized in Table 2. Angiokeratomata (9 of 10) and Fabry’s cardiopathy (6 of 10) were the most common findings. Among 10 patients, classical FD symptoms of acroparesthesia, hypohidrosis, and pain were seen in five; fever during FD-crisis in three; and lenticular opacities in two. Five patients (#6 –#10) are presently alive with a functioning graft at 72, 111, 122, 130, and 153 months after (Table 3). Patient #7 suffers from persistent FD-related acroparesthesia. Therefore at 100 months after KTx the patient received enzyme replacement therapy. Patient #9 is suffering from FD-related cardiopathy at 111 months posttransplant. Two patients (#1, #3) died from cardiac complications of FD with functioning grafts at 74 and 153 months after transplant. Patient #2 died due to hepatitis at 160 months after KTx with well-preserved renal function. However, autopsy revealed recurrent FD in the kidney allograft.
Table 2. Systemic Clinical Signs of Fabry’s Disease Patient #
Angiokeratoma
Cardiopathy
Paresthesia
Hypohidrosis
Pain
Fever
Lenticular Opacities
1 2 3 4 5 6 7 8 9 10
⫺ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ 9/10
⫹ ⫹ n.a. ⫹ ⫹ ⫺ ⫹ ⫹ n.a. n.a. 6/10
⫺ n.a. n.a. n.a. ⫹ ⫹ ⫹ n.a. n.a. n.a. 5/10
⫺ n.a. n.a. n.a. ⫹ ⫹ ⫹ ⫹ n.a. ⫹ 5/10
⫺ n.a. n.a. n.a. ⫹ ⫹ ⫹ n.a. ⫹ ⫹ 5/10
⫺ n.a. n.a. n.a. n.a. ⫹ n.a. ⫹ n.a. ⫹ 3/10
⫺ n.a. ⫹ n.a. ⫹ ⫺ ⫹ n.a. n.a. ⫺ 2/10
KIDNEY TRANSPLANT SURVIVAL AND FABRY’S DISEASE
4213
Table 3. Clinical Course After Kidney Transplantation Recurrence of FD in Kidney Allograft? Patient #
1 2 3 4 5 6 7 8 9 10
Comment on Clinical Course
Clinically
Autopsy Biopsy
Died with functioning graft of FD related cardiopathy at 153 months Died with functioning graft of hepatitis at 160 months Died with functioning graft of coronary heart disease at 74 months Lost graft due to rejection at 18 months and died of unknown cause at 138 months Died with functioning graft of FD related bleeding from cerebral aneurysm at 114 months Alive with functioning graft at 153 months Alive with functioning graft at 130 months, initiation of enzyme replacement therapy 100 months after KTx Alive with functioning graft at 122 months Alive with functioning graft at 111 months, FD related cardiopathy Alive with functioning graft at 72 months
no no no n.a.
no yes n.a. n.a.
no
no
no no
n.a. n.a.
no no no
n.a. n.a. n.a.
FD, Fabry’s Disease.
Patient #4, with known FD-related cardiopathy, lost the graft due to rejection at 18 months after KTx, but survived another 120 months. Patient #5 died with a functioning kidney graft of FD-related bleeding from a cerebral aneurysm at 114 months posttransplant. The kidney graft did not show signs of FD recurrence. Actuarial patient survival according to Kaplan-Meier at 5 years was 100% and 76% at 10 years after transplantation (Fig 1). Actuarial graft survival was 90% at 5 years and 66% at 10 years (Fig 2). Only one graft was lost due to rejection. Four patients in our series died with well-preserved renal function at a mean of 128 months (74 –160) after KTx. In the second decade after transplantation, patient survival rapidly declined in our series. At present no patient has survived longer than 14 years after transplantation. We did not observe sepsis, thrombosis, or other early graft failures. DISCUSSION
The age at diagnosis of FD declined significantly over the 35-year time span of this study. While FD was detected in
Fig 1. Actuarial patient survival (Kaplan-Meier estimates) after kidney transplantation. Patient survival was 100% at 5 years and 76% at 10 years posttransplant. Five patients are currently alive and censored. Three patients died in the second decade after KTx.
the third and fourth decade of life in four patients diagnosed in the 1970s, the availability of plasma and blood ␣-galactosidase testing, as well as the recognition of the importance of a systematic family screening for FD after the diagnosis of a first index patient, reduced the mean age at diagnosis to 17 years (7–36) in the 1980s and 1990s (Student t test: P ⬍ .05).5,18 In fact, our series included two brother pairs (#5 and #7 and #6 and #10) diagnosed in early childhood and adolescence. Early diagnosis is certainly crucial to meet current recommendations for the management of patients with FD.5,19,20 In the first decade after KTx, the graft and patient survival rates were comparable to the outcomes observed after KTx performed for other indications. In a casematched study, Ojo et al17 determined Kaplan-Meier estimates of patient and graft survivals after KTx in 96 FD patients to be 83% and 76% at 5 years and 67% and 56% at 10 years. These results are consistent with our experience: patient and graft survival of 100% and 90% at 5 years and 76% and 66% at 10 years. A crucial finding in our series was the decline of the survival curve in the second decade after KTx. Unfortunately, ceramide deposition cannot be pre-
Fig 2. Actuarial graft survival (Kaplan-Meier estimates, loss of graft function was censored). Actuarial graft survival was 90% at 5 years and 66% at 10 years posttransplant.
4214
vented by KTx.21–23 and, in fact, recurrence of FD in the graft was found at autopsy in patient #2. Interestingly, excellent graft function was not impaired by the renal ceramide deposits for 14 years.21,23 However, the attempt to correct the underlying metabolic disorder by transplanting a kidney with normal ␣-galactosidase activity fails, as shown by Spence et al.24 Neither significant elevation of plasma ␣-galactosidase activity in FD patients after KTx nor a decrease in the plasma levels of trihexosyl ceramide were detected in their study. We assume that the disease itself progresses systemically after KTx and that cardiac ceramide deposition22,25 ultimately determines the fate of FD patients in the second decade after KTx. As cardiac function improved during enzyme replacement therapy in patients with FD,26 we therefore propose to routinely continue enzyme replacement therapy after KTx. Failure to mount an adequate immune response as a consequence of the assumed leukocyte dysfunction associated with FD was not observed to be a relevant clinical problem. We speculate that the lethal septic complications described in 1981 by Maizel et al13 might be explained by the early immunosuppression protocols. However, these infectious complications are not reported in the literature after the introduction of modern calcineurin-based immunosuppressive agents. In conclusion, we advocate KTx for patients presenting with end-stage renal failure due to FD to improve the overall prognosis. We propose that systemic enzyme replacement therapy with recombinant human ␣-galactosidase A after KTx should be continued to improve long-term survival in the second decade after transplantation. Additional clinical studies are needed to determine whether this approach prevents cardiac and systemic globotriaosylceramide deposition and thereby preserves cardiovascular function.
REFERENCES 1. Fabry J: Ein Beitrag zur Kenntnis der Purpura haemorrhagica nodularis (Purpura papulosa haemorrhagica Hebrae). Arch Dermatol Syph 43:187, 1898 2. Anderson W: A case of angeio-keratoma. Brit J Derm 10:113, 1898 3. Desnick RJ: The metabolic and molecular bases of inherited disease: Alpha-galactosidase A deficiency: Fabry Disease: 2001, p 3733 Alpha-Galactosidase. New York: McGraw-Hill; 2001, p 3733 4. Friedman GS, Wik D, Silva L, et al: Allograft loss in renal transplant recipients with Fabry’s disease and activated protein C resistance. Transplantation 69:2099, 2000 5. Cho ME, Kopp JB: Fabry disease in the era of enzyme replacement therapy: a renal perspective. Pediatr Nephrol 19:583, 2004
INDERBITZIN, AVITAL, LARGIADÈR ET AL 6. Touraine JL, Malik MC, Traeger J, et al: Attempt at enzyme replacement by fetal liver transplantation in Fabry’s disease [letter]. Lancet 1:1094, 1979 7. Brady RO, Tallman JF, Johnson WG, et al: Replacement therapy for inherited enzyme deficiency. Use of purified ceramidetrihexosidase in Fabry’s disease. N Engl J Med 289:9, 1973 8. Schiffmann R, Kopp JB, Austin HA 3rd, et al: Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA 285:2743, 2001 9. Buhler FR, Thiel G, Dubach UC, et al: Kidney transplantation in Fabry’s disease. Br Med J 3:28, 1973 10. Ziegler RJ, Yew NS, Li C, et al: Correction of enzymatic and lysosomal storage defects in Fabry mice by adenovirus-mediated gene transfer. Hum Gene Ther 10:1667, 1999 11. Colombi A, Kostyal A, Bracher R, et al: Angiokeratoma corporis diffusum-Fabry’s disease. Helv Med Acta 34:67, 1967 12. Tsakiris D, Simpson HK, Jones EH, et al: Report on management of renale failure in Europe, XXVI, 1995. Rare diseases in renal replacement therapy in the ERA-EDTA Registry. Nephrol Dial Transplant 11(suppl 7):4, 1996 13. Maizel SE, Simmons RL, Kjellstrand C, et al: Ten-year experience in renal transplantation for Fabry’s disease. Transplant Proc 13:57, 1981 14. Renal transplantation in congenital and metabolic diseases. A report from the ASC/NIH renal transplant registry. JAMA 232:148, 1975 15. Donati D, Sabbadini MG, Capsoni F, et al: Immune function and renal transplantation in Fabry’s disease. Proc Eur Dial Transplant Assoc Eur Ren Assoc 21:686, 1985 16. Ramos EL: Recurrent diseases in the renal allograft. J Am Soc Nephrol 2:109, 1991 17. Ojo A, Meier-Kriesche HU, Friedman G, et al: Excellent outcome of renal transplantation in patients with Fabry’s disease. Transplantation 69:2337, 2000 18. Sheth KJ, Good TA, Murphy JV: Heterozygote detection in Fabry disease utilizing multiple enzyme activities. Am J Med Genet 10:141, 1981 19. Desnick RJ, Brady R, Barranger J, et al: Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 138:338, 2003 20. Siamopoulos KC: Fabry disease: kidney involvement and enzyme replacement therapy. Kidney Int 65:744, 2004 21. Gantenbein H, Bruder E, Burger HR, et al: Recurrence of Fabry’s disease in a renal allograft 14 years after transplantation. Nephrol Dial Transplant 10:287, 1995 22. Kramer W, Thormann J, Mueller K, et al: Progressive cardiac involvement by Fabry’s disease despite successful renal allotransplantation. Int J Cardiol 7:72, 1985 23. Mosnier JF, Degott C, Bedrossian J, et al: Recurrence of Fabry’s disease in a renal allograft eleven years after successful renal transplantation. Transplantation 51:759, 1991 24. Spence MW, MacKinnon KE, Burgess JK, et al: Failure to correct the metabolic defect by renal allotransplantion in Fabry’s disease. Ann Intern Med 84:13, 1976 25. Bannwart F: Fabry’s disease. Light and electron microscopic cardiac findings 12 years after successful kidney transplantation. Schweiz Med Wochenschr 112:1742, 1982 26. Weidemann F, Breunig F, Beer M, et al: Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study. Circulation 108:1299, 2003
F
ABRY’S DISEASE (FD), first described in 1898 by Johann Fabry1 as “Purpura papulosa haemorrhagica Hebrae” and by William Anderson2 as “Angio-Keratoma” is a rare inborn error of glycosphingolipid catabolism3 that results from the defective activity of the lysosomal enzyme ␣-galactosidase A.4 This enzyme cleaves the ␣-galactosyl moiety from globotriaosylceramide. The absence or malfunction of this enzyme, which is transmitted by an X-linked recessive gene (Xq22.1), leads in homozygous men to lysosomal accumulation of glycosphingolipids (globotriaosylceramide and galabiosylceramide) in endothelial cells, smooth muscle cells, leucocytes and fibrocytes in most visceral tissues, as well as in the nervous system, the kidneys, and the heart. With increasing age, however, the progressive glycosphingolipid deposition in the kidney and heart is the cause of most case fatalities.3,5 Current therapy involves symptomatic medical management, hemodialysis, substrate depletion, fetal liver transplantation,6 enzyme replacement,7,8 kidney transplantation (KTx),9 and recently gene therapy.10
Death most often results from uremia unless chronic dialysis or KTx is undertaken. The reported mean age at death of untreated FD patients is 41 years,11 and the 5-year survival on hemodialysis is 41%.12 Early reports regarding KTx for the treatment of endstage renal disease in patients with FD showed a high incidence of septic complications and a survival rate of only 26% at 5 years. It was speculated that either compromised fibroblast function and impaired collagen metabolism or
From the Departments of Visceral and Transplantation Surgery (D.I., D.C.) and Nephrology (B.V.), University Hospital Bern, Bern, Switzerland; the Memorial Sloan Kettering Cancer Center (I.A.), New York, NY; and the Department of Surgery, Division of Visceral Surgery (F.L.), University of Zurich Hospital, Zurich, Switzerland. Address reprint requests to D. Inderbitzin, Department of Visceral and Transplantation Surgery, University Hospital Bern, CH 3010 Bern, Switzerland. E-mail: [email protected]
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.11.021
Transplantation Proceedings, 37, 4211– 4214 (2005)
4211
4212
INDERBITZIN, AVITAL, LARGIADÈR ET AL Table 1. Demographics
Patient #
Diagnosis Age (years)
Dialysis Initiation Age (years)
Dialysis Duration (months)
KTx Age (years)
KTx Year
1 2 3 4 5 6 7 8 9 10
45 32 43 43 8 15 7 15 36 19
no 32 42 43 25 16 34 44 37 no
0 12 19 49 40 12 12 10 36 0
45 33 44 48 28 17 35 45 40 28
1968 1979 1980 1981 1990 1991 1993 1993 1995 1998
Mean (range)
26 (7–45)
34 (16–44)
19 (10–49)
36 (17–48)
deficient leukocyte function is responsible for the high rate of infectious complications.13 The conclusion drawn from early transplantation series and the consequent recommendation from the National Institute of Health in 1975 was to withhold KTx from patients with FD.14 However, one decade later, careful examination of the immunological state in FD patients did not reveal any specific impairment.15 Furthermore, patient and graft survivals continuously improved after KTx, while posttransplant morbidity decreased.16,17 Therefore, due to the rarity of this disease, the aim of this study was to retrospectively determine the effect of KTx on the long-term outcomes of FD patients.
METHODS This is a retrospective analysis of our experience with KTx for patients with end-stage renal disease due to FD. Data are presented as mean values (range). A cohort of 10 patients has been followed since 1968 with a mean follow-up of 123 (72–160) months. All patients were hemizygous men who received cadaveric kidney allografts. Recurrence of FD after KTx was assessed histologically by renal biopsy or at autopsy when appropriate. Survival analysis was performed according to the Kaplan-Meier method. Patient’s survival after KTx, on dialysis alone, and in historic controls was compared statistically (Jandel Scientific 1.0). P values ⬍ .05 were considered significant. Five patients of our series are currently alive and regularly followed clinically.
RESULTS
Ten patients with end-stage renal failure due to FD received a KTx at our institutions (Table 1). The mean age at diagnosis was 26 (7– 45) years. The mean age at initiation of dialysis was 34 years (16 – 44), and dialysis was maintained for 19 months (10 – 49) before KTx was performed at 36 years of age (17– 48). Systemic clinical signs of FD are summarized in Table 2. Angiokeratomata (9 of 10) and Fabry’s cardiopathy (6 of 10) were the most common findings. Among 10 patients, classical FD symptoms of acroparesthesia, hypohidrosis, and pain were seen in five; fever during FD-crisis in three; and lenticular opacities in two. Five patients (#6 –#10) are presently alive with a functioning graft at 72, 111, 122, 130, and 153 months after (Table 3). Patient #7 suffers from persistent FD-related acroparesthesia. Therefore at 100 months after KTx the patient received enzyme replacement therapy. Patient #9 is suffering from FD-related cardiopathy at 111 months posttransplant. Two patients (#1, #3) died from cardiac complications of FD with functioning grafts at 74 and 153 months after transplant. Patient #2 died due to hepatitis at 160 months after KTx with well-preserved renal function. However, autopsy revealed recurrent FD in the kidney allograft.
Table 2. Systemic Clinical Signs of Fabry’s Disease Patient #
Angiokeratoma
Cardiopathy
Paresthesia
Hypohidrosis
Pain
Fever
Lenticular Opacities
1 2 3 4 5 6 7 8 9 10
⫺ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ 9/10
⫹ ⫹ n.a. ⫹ ⫹ ⫺ ⫹ ⫹ n.a. n.a. 6/10
⫺ n.a. n.a. n.a. ⫹ ⫹ ⫹ n.a. n.a. n.a. 5/10
⫺ n.a. n.a. n.a. ⫹ ⫹ ⫹ ⫹ n.a. ⫹ 5/10
⫺ n.a. n.a. n.a. ⫹ ⫹ ⫹ n.a. ⫹ ⫹ 5/10
⫺ n.a. n.a. n.a. n.a. ⫹ n.a. ⫹ n.a. ⫹ 3/10
⫺ n.a. ⫹ n.a. ⫹ ⫺ ⫹ n.a. n.a. ⫺ 2/10
KIDNEY TRANSPLANT SURVIVAL AND FABRY’S DISEASE
4213
Table 3. Clinical Course After Kidney Transplantation Recurrence of FD in Kidney Allograft? Patient #
1 2 3 4 5 6 7 8 9 10
Comment on Clinical Course
Clinically
Autopsy Biopsy
Died with functioning graft of FD related cardiopathy at 153 months Died with functioning graft of hepatitis at 160 months Died with functioning graft of coronary heart disease at 74 months Lost graft due to rejection at 18 months and died of unknown cause at 138 months Died with functioning graft of FD related bleeding from cerebral aneurysm at 114 months Alive with functioning graft at 153 months Alive with functioning graft at 130 months, initiation of enzyme replacement therapy 100 months after KTx Alive with functioning graft at 122 months Alive with functioning graft at 111 months, FD related cardiopathy Alive with functioning graft at 72 months
no no no n.a.
no yes n.a. n.a.
no
no
no no
n.a. n.a.
no no no
n.a. n.a. n.a.
FD, Fabry’s Disease.
Patient #4, with known FD-related cardiopathy, lost the graft due to rejection at 18 months after KTx, but survived another 120 months. Patient #5 died with a functioning kidney graft of FD-related bleeding from a cerebral aneurysm at 114 months posttransplant. The kidney graft did not show signs of FD recurrence. Actuarial patient survival according to Kaplan-Meier at 5 years was 100% and 76% at 10 years after transplantation (Fig 1). Actuarial graft survival was 90% at 5 years and 66% at 10 years (Fig 2). Only one graft was lost due to rejection. Four patients in our series died with well-preserved renal function at a mean of 128 months (74 –160) after KTx. In the second decade after transplantation, patient survival rapidly declined in our series. At present no patient has survived longer than 14 years after transplantation. We did not observe sepsis, thrombosis, or other early graft failures. DISCUSSION
The age at diagnosis of FD declined significantly over the 35-year time span of this study. While FD was detected in
Fig 1. Actuarial patient survival (Kaplan-Meier estimates) after kidney transplantation. Patient survival was 100% at 5 years and 76% at 10 years posttransplant. Five patients are currently alive and censored. Three patients died in the second decade after KTx.
the third and fourth decade of life in four patients diagnosed in the 1970s, the availability of plasma and blood ␣-galactosidase testing, as well as the recognition of the importance of a systematic family screening for FD after the diagnosis of a first index patient, reduced the mean age at diagnosis to 17 years (7–36) in the 1980s and 1990s (Student t test: P ⬍ .05).5,18 In fact, our series included two brother pairs (#5 and #7 and #6 and #10) diagnosed in early childhood and adolescence. Early diagnosis is certainly crucial to meet current recommendations for the management of patients with FD.5,19,20 In the first decade after KTx, the graft and patient survival rates were comparable to the outcomes observed after KTx performed for other indications. In a casematched study, Ojo et al17 determined Kaplan-Meier estimates of patient and graft survivals after KTx in 96 FD patients to be 83% and 76% at 5 years and 67% and 56% at 10 years. These results are consistent with our experience: patient and graft survival of 100% and 90% at 5 years and 76% and 66% at 10 years. A crucial finding in our series was the decline of the survival curve in the second decade after KTx. Unfortunately, ceramide deposition cannot be pre-
Fig 2. Actuarial graft survival (Kaplan-Meier estimates, loss of graft function was censored). Actuarial graft survival was 90% at 5 years and 66% at 10 years posttransplant.
4214
vented by KTx.21–23 and, in fact, recurrence of FD in the graft was found at autopsy in patient #2. Interestingly, excellent graft function was not impaired by the renal ceramide deposits for 14 years.21,23 However, the attempt to correct the underlying metabolic disorder by transplanting a kidney with normal ␣-galactosidase activity fails, as shown by Spence et al.24 Neither significant elevation of plasma ␣-galactosidase activity in FD patients after KTx nor a decrease in the plasma levels of trihexosyl ceramide were detected in their study. We assume that the disease itself progresses systemically after KTx and that cardiac ceramide deposition22,25 ultimately determines the fate of FD patients in the second decade after KTx. As cardiac function improved during enzyme replacement therapy in patients with FD,26 we therefore propose to routinely continue enzyme replacement therapy after KTx. Failure to mount an adequate immune response as a consequence of the assumed leukocyte dysfunction associated with FD was not observed to be a relevant clinical problem. We speculate that the lethal septic complications described in 1981 by Maizel et al13 might be explained by the early immunosuppression protocols. However, these infectious complications are not reported in the literature after the introduction of modern calcineurin-based immunosuppressive agents. In conclusion, we advocate KTx for patients presenting with end-stage renal failure due to FD to improve the overall prognosis. We propose that systemic enzyme replacement therapy with recombinant human ␣-galactosidase A after KTx should be continued to improve long-term survival in the second decade after transplantation. Additional clinical studies are needed to determine whether this approach prevents cardiac and systemic globotriaosylceramide deposition and thereby preserves cardiovascular function.
REFERENCES 1. Fabry J: Ein Beitrag zur Kenntnis der Purpura haemorrhagica nodularis (Purpura papulosa haemorrhagica Hebrae). Arch Dermatol Syph 43:187, 1898 2. Anderson W: A case of angeio-keratoma. Brit J Derm 10:113, 1898 3. Desnick RJ: The metabolic and molecular bases of inherited disease: Alpha-galactosidase A deficiency: Fabry Disease: 2001, p 3733 Alpha-Galactosidase. New York: McGraw-Hill; 2001, p 3733 4. Friedman GS, Wik D, Silva L, et al: Allograft loss in renal transplant recipients with Fabry’s disease and activated protein C resistance. Transplantation 69:2099, 2000 5. Cho ME, Kopp JB: Fabry disease in the era of enzyme replacement therapy: a renal perspective. Pediatr Nephrol 19:583, 2004
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