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Outcome of renal transplantation under cyclosporine immunosuppression in patients with lupus nephritis
Outcome of Renal Transplantation Under Cyclosporine Immunosuppression in Patients With Lupus Nephritis J. Cobankiat, A. Vathsala, Y.M. Lu, and K.T. Woo
R
ENAL disease occurs in up to 90% of all patients with systemic lupus erythematosus (SLE) and has a profound impact on their prognosis. Despite the advent of high-dose corticosteroid therapy and improvements in immunosuppressive drug regimens, end-stage renal disease (ESRD) continues to be a major cause of morbidity and mortality in this patient population. In Singapore, ESRD secondary to lupus nephritis (LNx) comprises 6.6% of the total dialysis population. Since 1990, the option of renal transplantation (RTx) has been offered to ESRD patients with LNx without other major end organ complications. Thus, increasing numbers of SLE patients are recipients of cadaveric and living-related RTx, and at present they make up 3.3% of all RTx in Singapore. We report on the outcome of 14 patients with ESRD due to LNx who underwent RTx in Singapore General Hospital between January 1991 to April 1999. MATERIALS AND METHODS The study population included 14 patients, all of whom met four or more of the criteria for the classification of SLE as defined by the American Rheumatism Association, serially or simultaneously, sometime before the onset of ESRD. Clinical activity of SLE was judged to be present when one or more of the following were evident and could not be explained by causes other than SLE: arthritis, serositis, cerebritis, vasculitis, oral ulcers, Raynaud’s phenomenon, hemolytic anemia, leucopenia and thrombocytopenia, positive serology for SLE in the presence of low complement titres. Serologic tests for lupus activity (ANF, DSDNA, C3, C4, and CH50) were studied as often as clinically necessary before and after RTx. When none of these features was detected, the disease was considered inactive. Information on recipient age, gender, length of time on dialysis and duration of ESRD prior to RTx, occurrence of rejection episodes, and maintenance immunosuppressive regimens were obtained by retrospective chart review. All patients were followed up until death, graft loss necessitating reinstitution of dialysis, or until April 1999. Actuarial survival curves were calculated using Kaplan Meier estimates from a life-table analysis. Graft survival was determined using either death or graft failure as endpoint, whereas patient survival was determined using death as end-point.
RESULTS
The study population was predominantly women (86%) and Chinese (78%), with a mean age at the time of RTx of 32 ⫾ 5.4 years. The duration of clinical LNx before ESRD was
91.4 ⫾ 45.3 months. Twelve of 14 were on hemodialysis and the remainder was on peritoneal dialysis for a mean interval of 47.3 ⫾ 34.6 months prior to RTx. No patient had clinically active SLE at the time of RTx. The population had inactive LNx for 36.9 ⫾ 32.2 months prior to RTx. Mean maintenance prednisone dose was 4.1 ⫾ 3.2 mg/day at the time of RTx. Seven transplants (50%) were from cadaveric donors, five (35.7%) were from living related donors, and two (14.3%) were from spousal donors. All patients had primary allografts and received cyclosporine (CyA) and prednisone-based immunosuppression. Ten patients received azathioprine (AZA); in addition, two patients received mycophenolate mofetil and two patients received AZA and induction with antilymphocyte serum (ALS). After RTx, five patients (36%) had an episode of early rejection, three of whom responded to a course of methylprednisolone (MP), while two were successfully treated with MP or ALS followed by OKT3. Two graft losses occurred due to late rejection following immunosuppression withdrawal from noncompliance and candidemia, respectively. The single patient death was due to acute myocardial infarction in a 34-year-old male on the 4th posttransplant day. Other significant complications included cytomegalovirus (CMV) pneumonia with Guillain Barre syndrome at 39 days, miliary tuberculosis at 5 months, and tonsillar squamous cell carcinoma at 37.4 months. Average transplant follow-up was 35.85 ⫾ 25.5 months. No recurrence of LNx in the renal allografts was seen, and none of the patients had extrarenal manifestations of SLE post-RTx. DISCUSSION
The present report describes the outcome post-RTx for 14 patients with ESRD due to SLE from a single institution. Actuarial graft and patient survivals were 85.7% and 93%, respectively, after 5 years in patients with LNx, not significantly different from the 85.5% and 92.3% graft and patient survival rates for cadaveric RTx and the 93.1% and 96.4% From the Department of Renal Medicine, Singapore General Hospital, Singapore. Address reprint requests to Dr J. Cobankiat, Department of Renal Medicine, Singapore General Hospital, Outram Road, Singapore 169608.
0041-1345/00/$–see front matter PII S0041-1345(00)01355-5
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1826
Transplantation Proceedings, 32, 1826–1827 (2000)
RENAL TRANSPLANT IN PATIENTS WITH LUPUS
graft and patient survival rates for live-donor RTx, all transplanted under CyA-based immunosuppression from the same institution. Several studies have reported similar graft and patient survivals between LNx and non-LNx patients post RTx.1–9 Bumgardener et al demonstrated similar graft survival rates between SLE patients and matched pair controls.4 Grimbert et al, reporting the results of a multicentre study involving 60 RTx, likewise reported a 5-year graft survival of 69%, a figure not significantly different from their matched non-lupus control group.5 On the other hand, Cattran and Aprile reported significantly lower graft survival at 6 months among LNx patients (63% versus 84% in non-lupus patients).3 Zara and colleagues suggested that a more potent immunosuppressive regimen as with CyA may have contributed to comparable outcomes between LNx and non-LNx RTx patients. Thus, in their series, SLE RTx treated with CyA did as well as their matched controls; however, those who received AZA did significantly worse.8 However, Cheigh et al have reported comparable graft survivals between LNx and non-LNx, AZA-treated RTx.6 The present study also confirms the extremely low rate of recurrence of clinical disease activity as well as LNx in renal allografts post RTx. Thus mean serum creatinine of RTx patients with functioning allografts was 104 mol/L. Many other authors have likewise described a low rate of SLE recurrence in patients following RTx. While some studies have suggested an inverse correlation between duration of dialysis pre-RTx and recurrence, the present study was unable to address this issue due to the small numbers.6,9 Despite comparable graft and patient survivals between LNx and non-LNx RTx, our study suggests higher morbidity post-RTx in LNx patients. The incidence of CMV infection (7% in LNx versus 0.37% and 0.09% in CAD and LRD, non-LNx RTx, respectively), tuberculosis (7% in LNx versus 3.3% and 0.46% in CAD and LRD, non-LNx, respectively), and malignancy (7% in LNx versus 2.7% and 0.18%
1827
in non-LNx, respectively) were noted to be numerically higher in the LNx patients as compared to the total RTx population. The infectious complications were generally noted early post-RTx (⬍6 months) and could have been related to immunosuppression prior to RTx. Furthermore, the single patient death in our study population due to acute myocardial infarction occurred postoperatively, emphasizing the role of premature atherosclerosis in this high-risk patient population. Though our numbers were small and the incidence of complications was not significantly different from that of the total RTx population, the nature of these events suggest the need for vigilance for complications of excessive immunosuppression or steroid use post-RTx in this unique group of patients. In summary, the present study indicates that renal transplantation in patients with ESRD secondary to LNx is an excellent therapeutic modality with satisfactory patient and graft survival outcome, comparable to that of the non-RTx population. Nevertheless, complications due to long-term immunosuppression may increase morbidity due to infections in this patient population. REFERENCES 1. CS/NIH Renal Transplant Registry: JAMA 232:148, 1975 2. Mojcik CF, Klippel JH: Am J Med 101:100, 1996 3. Cattran DC, Aprile M: Ann Intern Med 114:991, 1991 4. Bumgardner GL, Mauer SM, Payne W, et al: Transplantation 46:703, 1988 5. Grimbert P, Frappier J, Bedrossian J, et al: Transplantation 66:1000, 1998 6. Cheigh JS, Kim H, Stanzel KH, et al: Am J Kid Dis 16:189, 1990 7. Nossent HC, Swaak TJ, Berden JHM: Ann Intern Med 114:183, 1991 8. Zara CP, Lipkowitz GS, Perri N, et al: Transplant Proc 21:1648, 1989 9. Roth D, Milgram M, Isquenazi V, et al: Am J Nephrol 7:367, 1987
R
ENAL disease occurs in up to 90% of all patients with systemic lupus erythematosus (SLE) and has a profound impact on their prognosis. Despite the advent of high-dose corticosteroid therapy and improvements in immunosuppressive drug regimens, end-stage renal disease (ESRD) continues to be a major cause of morbidity and mortality in this patient population. In Singapore, ESRD secondary to lupus nephritis (LNx) comprises 6.6% of the total dialysis population. Since 1990, the option of renal transplantation (RTx) has been offered to ESRD patients with LNx without other major end organ complications. Thus, increasing numbers of SLE patients are recipients of cadaveric and living-related RTx, and at present they make up 3.3% of all RTx in Singapore. We report on the outcome of 14 patients with ESRD due to LNx who underwent RTx in Singapore General Hospital between January 1991 to April 1999. MATERIALS AND METHODS The study population included 14 patients, all of whom met four or more of the criteria for the classification of SLE as defined by the American Rheumatism Association, serially or simultaneously, sometime before the onset of ESRD. Clinical activity of SLE was judged to be present when one or more of the following were evident and could not be explained by causes other than SLE: arthritis, serositis, cerebritis, vasculitis, oral ulcers, Raynaud’s phenomenon, hemolytic anemia, leucopenia and thrombocytopenia, positive serology for SLE in the presence of low complement titres. Serologic tests for lupus activity (ANF, DSDNA, C3, C4, and CH50) were studied as often as clinically necessary before and after RTx. When none of these features was detected, the disease was considered inactive. Information on recipient age, gender, length of time on dialysis and duration of ESRD prior to RTx, occurrence of rejection episodes, and maintenance immunosuppressive regimens were obtained by retrospective chart review. All patients were followed up until death, graft loss necessitating reinstitution of dialysis, or until April 1999. Actuarial survival curves were calculated using Kaplan Meier estimates from a life-table analysis. Graft survival was determined using either death or graft failure as endpoint, whereas patient survival was determined using death as end-point.
RESULTS
The study population was predominantly women (86%) and Chinese (78%), with a mean age at the time of RTx of 32 ⫾ 5.4 years. The duration of clinical LNx before ESRD was
91.4 ⫾ 45.3 months. Twelve of 14 were on hemodialysis and the remainder was on peritoneal dialysis for a mean interval of 47.3 ⫾ 34.6 months prior to RTx. No patient had clinically active SLE at the time of RTx. The population had inactive LNx for 36.9 ⫾ 32.2 months prior to RTx. Mean maintenance prednisone dose was 4.1 ⫾ 3.2 mg/day at the time of RTx. Seven transplants (50%) were from cadaveric donors, five (35.7%) were from living related donors, and two (14.3%) were from spousal donors. All patients had primary allografts and received cyclosporine (CyA) and prednisone-based immunosuppression. Ten patients received azathioprine (AZA); in addition, two patients received mycophenolate mofetil and two patients received AZA and induction with antilymphocyte serum (ALS). After RTx, five patients (36%) had an episode of early rejection, three of whom responded to a course of methylprednisolone (MP), while two were successfully treated with MP or ALS followed by OKT3. Two graft losses occurred due to late rejection following immunosuppression withdrawal from noncompliance and candidemia, respectively. The single patient death was due to acute myocardial infarction in a 34-year-old male on the 4th posttransplant day. Other significant complications included cytomegalovirus (CMV) pneumonia with Guillain Barre syndrome at 39 days, miliary tuberculosis at 5 months, and tonsillar squamous cell carcinoma at 37.4 months. Average transplant follow-up was 35.85 ⫾ 25.5 months. No recurrence of LNx in the renal allografts was seen, and none of the patients had extrarenal manifestations of SLE post-RTx. DISCUSSION
The present report describes the outcome post-RTx for 14 patients with ESRD due to SLE from a single institution. Actuarial graft and patient survivals were 85.7% and 93%, respectively, after 5 years in patients with LNx, not significantly different from the 85.5% and 92.3% graft and patient survival rates for cadaveric RTx and the 93.1% and 96.4% From the Department of Renal Medicine, Singapore General Hospital, Singapore. Address reprint requests to Dr J. Cobankiat, Department of Renal Medicine, Singapore General Hospital, Outram Road, Singapore 169608.
0041-1345/00/$–see front matter PII S0041-1345(00)01355-5
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1826
Transplantation Proceedings, 32, 1826–1827 (2000)
RENAL TRANSPLANT IN PATIENTS WITH LUPUS
graft and patient survival rates for live-donor RTx, all transplanted under CyA-based immunosuppression from the same institution. Several studies have reported similar graft and patient survivals between LNx and non-LNx patients post RTx.1–9 Bumgardener et al demonstrated similar graft survival rates between SLE patients and matched pair controls.4 Grimbert et al, reporting the results of a multicentre study involving 60 RTx, likewise reported a 5-year graft survival of 69%, a figure not significantly different from their matched non-lupus control group.5 On the other hand, Cattran and Aprile reported significantly lower graft survival at 6 months among LNx patients (63% versus 84% in non-lupus patients).3 Zara and colleagues suggested that a more potent immunosuppressive regimen as with CyA may have contributed to comparable outcomes between LNx and non-LNx RTx patients. Thus, in their series, SLE RTx treated with CyA did as well as their matched controls; however, those who received AZA did significantly worse.8 However, Cheigh et al have reported comparable graft survivals between LNx and non-LNx, AZA-treated RTx.6 The present study also confirms the extremely low rate of recurrence of clinical disease activity as well as LNx in renal allografts post RTx. Thus mean serum creatinine of RTx patients with functioning allografts was 104 mol/L. Many other authors have likewise described a low rate of SLE recurrence in patients following RTx. While some studies have suggested an inverse correlation between duration of dialysis pre-RTx and recurrence, the present study was unable to address this issue due to the small numbers.6,9 Despite comparable graft and patient survivals between LNx and non-LNx RTx, our study suggests higher morbidity post-RTx in LNx patients. The incidence of CMV infection (7% in LNx versus 0.37% and 0.09% in CAD and LRD, non-LNx RTx, respectively), tuberculosis (7% in LNx versus 3.3% and 0.46% in CAD and LRD, non-LNx, respectively), and malignancy (7% in LNx versus 2.7% and 0.18%
1827
in non-LNx, respectively) were noted to be numerically higher in the LNx patients as compared to the total RTx population. The infectious complications were generally noted early post-RTx (⬍6 months) and could have been related to immunosuppression prior to RTx. Furthermore, the single patient death in our study population due to acute myocardial infarction occurred postoperatively, emphasizing the role of premature atherosclerosis in this high-risk patient population. Though our numbers were small and the incidence of complications was not significantly different from that of the total RTx population, the nature of these events suggest the need for vigilance for complications of excessive immunosuppression or steroid use post-RTx in this unique group of patients. In summary, the present study indicates that renal transplantation in patients with ESRD secondary to LNx is an excellent therapeutic modality with satisfactory patient and graft survival outcome, comparable to that of the non-RTx population. Nevertheless, complications due to long-term immunosuppression may increase morbidity due to infections in this patient population. REFERENCES 1. CS/NIH Renal Transplant Registry: JAMA 232:148, 1975 2. Mojcik CF, Klippel JH: Am J Med 101:100, 1996 3. Cattran DC, Aprile M: Ann Intern Med 114:991, 1991 4. Bumgardner GL, Mauer SM, Payne W, et al: Transplantation 46:703, 1988 5. Grimbert P, Frappier J, Bedrossian J, et al: Transplantation 66:1000, 1998 6. Cheigh JS, Kim H, Stanzel KH, et al: Am J Kid Dis 16:189, 1990 7. Nossent HC, Swaak TJ, Berden JHM: Ann Intern Med 114:183, 1991 8. Zara CP, Lipkowitz GS, Perri N, et al: Transplant Proc 21:1648, 1989 9. Roth D, Milgram M, Isquenazi V, et al: Am J Nephrol 7:367, 1987