Long-Term Outcome of Renal Transplantation in Patients With Familial Mediterranean Fever Amyloidosis: A Single-Center Experience A.S. Abedi, J.M. Nakhjavani, and J. Etemadi ABSTRACT Introduction. Familial Mediterranean fever (FMF) is an autosomal-recessive disorder, affecting multiple organs. The AA type of amyloidosis is most common and serious complication cause nephropathy and end-stage renal disease (ESRD). Renal transplantation (RTX) remains treatment of choice for ESRD. We aimed to investigate long-term results of RTX in patients with FMF amyloidosis. Patients and Methods. We compared the outcomes of 18 patients (12 men and 6 women) with FMF amyloidosis among 601 (2.9%) transplants with 200 control patients. Demographic data and gene analysis were evaluated. Results. In our study the 1-year graft and patient survivals were 94.44% and 100%, respectively. At 5 years after RTX, they were 94.73% and 88.88%, respectively, in the FMF group without difference from controls. Mean creatinine level at 1 and 5 years were 1.43 0.54 and 1.73 0.89, respectively. The results of MEFV mutation analyses were: M694V/M694V homozygote in 1 patient, M694V/EQ148 in 3, M694V/V726A in 2, 680M-I/E148Q in 3, M694V/M680I in 5, R202Q/M680I in 2, and M694V/R202Q in 2. Recurrence was noticed in 1 patient with M694V/M680I. One patient died because of graft loss and cardiac complications with M694V/M680I gene analysis. Colchicine was reduced in 4 patients owing to side effects. Conclusion. Long-term outcomes of transplantation in patients with amyloidosis secondary to FMF is similar to that in the general transplant population and maintenance colchicine, even after decreasing its dose, effectively prevents recurrence of amyloidosis in the allograft.
F
AMILIAL MEDITERRANEAN FEVER (FMF) is an autosomal-recessive disorder1 caused by a mutation in the MEFV gene. It is characterized by sporadic, paroxysmal attacks of fever and serosal inflammation of the peritoneum, pleura, and synovium.2 It may affect large joints. The most severe and important complication of FMF is development of AA amyloidosis, which causes nephrotic syndrome and nephropathy. This leads to end-stage renal disease (ESRD), which has been reported at 0.3% in the United States, 1.6% in European countries,3 4.2% in Turkey, and 6% in Israel.1 Different durations are also reported (2e13years). FMF is common in some Mediterranean ethnic groups, including Jewish, Arabic, Egyptian, Israeli, and Turkish and Armenian populations. Renal transplantation (RTX) is the treatment of choice in ESRD owing to FMF, although recurrence of amyloid A deposition in the allograft can occur in 20% of cases4,5; however, graft survival has been
reported as acceptable.6,7 Because of conflicting data about the outcome of RTX in these patients, the aim of this study was to evaluate the short- and long-term outcomes of RTX in patients with FMF amyloidosis in our center. PATIENTS AND METHOD We compared the results of RTX in 18 patients with FMF amyloidosis among 60 1(2.9%) transplants with 200 age- and gender-matched, non-FMF RTX patients as controls. In 2 groups,
From the Transplantation Ward, Imam Reza Hospital, Chronic Renal Disease Research Center of Tabriz University of Medical Science, Tabriz, Iran. Address correspondence to Sima Abedi Azar, Associate Professor of Tabriz University of Medical Science, Tabriz University of Medical Science. E-mail: [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.09.021
ª 2013 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
3502
Transplantation Proceedings, 45, 3502e3504 (2013)
16; one died at month 46 17 17 17 17; 15.4 in one with 17; 20.3 in one with acute rejection acute rejection 18
Mean glomerular filtration rate (mL/min) No. of patients
57.43 6.59
55.11 7.65
53.71 3.67
0 0 0 17 (1 lost the graft) 17 17 210.09 44.18 198.99 55.31 310.15 40.22 17 17 16; 4100 mg in one with disease recurrence 49.22 5.10 47.18 4.16 44.13 2.17 1 18 190.42 18.09 18
36 24 Months after RTX
12 6
We included 18 patients (12 men and 6 women) with FMF amyloidosis with a mean age of 40.52 7.1 years among 601 (2.9%) transplants with 200 controls (120 men and 80 women) with a mean age of 41.93 10.93 years (P < .2). Mean transplantation duration was 76.42 11.66 in FMF and 72 12.14 in controls. Mean blood urea and creatinine in FMF group was 44.05 9.34 and 1.43 0.54 mg/dL 1 year after RTX without being different from controls (44.26 10.4). Blood urea and 1.39 0.30 creatinine (P < .9). However, there was a significant difference between FMF groups in blood urea (49.73 24.63) and creatinine (1.73 0.89) with controls (52.66 26.58 and 1.49; P < .005) 5 years after RTX. The 1-year graft and patient survivals were 94.44% and 100%, respectively, in the FMF group and 94.73% and 88.88% at 5 years after RTX in the FMF group without a difference from controls. The mean creatinine levels at 1 and 5 years were 1.43 0.54 and 1.73 0.89 mg/dL respectively in patients. The results of MEFV mutation analyses were M694V/ M694V homozygote in 1 patient, M694V/EQ148 in 3, M694V/V726A in 2, 680M-I/E148Q in 3, M694V/M680I in 5, R202Q/M680I in 2, and M694V/R202Q in 2. Recurrence was noticed in 1 patient with M694V/M680I with clinically severe FMF attack and nephrotic range proteinuria, and 1 patient died because of graft loss and cardiac complications with M694V/M680I gene analysis. Colchicine was reduced in 4 patients owing to side effects. Some of
3
RESULTS
1
immunosuppression and duration of transplantation were similar. All patients has MEFV mutation analysis and renal biopsy before RTX. Blood urea, creatinine, urinalysis, and cyclosporine levels were measured monthly and 24-hour proteinuria every 3 months. Demographic data, transplantation duration, blood pressure, cytomegalovirus infection, hepatitis C virus infection, and acute rejection episodes were recorded for all patients. Gene analysis was done in all FMF patients, and all of them were received colchicine 1.5 to 2 g/d. All patients in both groups were followed for 5 years.
Table 2. Paraclinical Parameters of FMF Patients Who Underwent Renal Transplantation
13 2 1 2 2/18 (11.1%) 1 in month 1, other in month 6
60
18 40.52 7.11 Male, 12; female, 6 Unrelated living donor 100% Hemodialysis 9.89 5.81 76.42 11.66
1 18 150.64 37.17 18
Clinical Data Findings
Number of patients Mean age (y) Gender Donor source Dialysis treatment Mean dialysis duration (mo) Mean transplantation duration (mo) Panel-reactive antibody 0 2/30 (6%) 3/30 (10%) 1/30 (3%) Acute rejection episodes
Acute rejection episodes 0 Number of patients 18 Mean 24-hour proteinuria (mg/L) 170.76 23.11 No. of patients 18
Table 1. Demographic and Clinical Parameters of FMF Patients Who Underwent Renal Transplantation
41.13 3.15
3503
0 16 292.83 54.16 16
LONG-TERM OUTCOMES IN FMF
3504
demographic, conical, and paraclinical features are summarized in Tables 1 and 2. All patients were given triple immunosuppressive treatment with cyclosporine, mycophenolate mofetil, and steroids, and received colchicine. Posttransplant complications included acute rejection episodes in 2 of 18 FMF patients (11.1%) and 10% in controls. Cytomegalovirus infection occurred in 10.5% of FMFs and 11% of controls. DISCUSSION
FMF as an autosomal-recessive disease characterized with recurrent episodes of fever and serositis affects kidneys, by development of type AA amyloidosis causes proteinuria and nephropathy and leads to ESRD after 2 to 13 years.8 RTX remains treatment of choice for ESRD owing to FMF amyloidosis compared with hemodialysis or peritoneal dialysis, because of the higher morbidity and mortality rates of these patients on dialysis.2,9 FMF accounted for 2% to 4% of all RTX in a study by Sherif et al2 and 2.9% in our study. This is comparable with previous studies and may be because of the genetic and geographic similarities of the participants. In this study, the 1-year graft and patient survivals were 94.44% and 100%, respectively, in the FMF group, which was not different from controls or other studies.4 In addition, the 5-year graft and patient survivals (94.73% and 88.88%) were comparable in the 2 groups, and was similar to previous studies.10 Recurrence of renal amyloidosis was noted only in 1 patient (of 18) in our study and it was similar to other studies. Recurrence has been noted in transplanted kidneys, but the data are conflicting, because it was not proved in some studies and was hypothesized to be related to the prophylactic effect of immunosuppressive therapy and colchicine, which prevents FMF at doses of 1.5 mg/d.2,10e12 In our study, maintenance colchicine treatment was reduced in 4 patients because of side effects, and these 4 remain recurrence free through follow-up recurrence. An acute rejection episode developed in 1 patient and improved after antirejection treatment. This is similar to other studies. FMF is not a predisposing factor for acute rejection episodes.13 The result of MEFV mutation analysis were M694V/ M694V homozygote in 1, M694V/EQ148 in 3, M694V/ V726A in 2, 680M-I/E148Q in 3, M694V/M680I in 5, R202Q/M680I in 2, and M694V/R202Q in 2, with more
ABEDI, NAKHJAVANI, AND ETEMADI
frequency in M694V/M680I. This emphasizes in frequency of M694Vgen in homozygous or heterozygous form with some differences with other studied, which M694V/ M694V is the most common in other studies.10 However, the episode of acute rejection and disease recurrence occurred in a patient with a M694V/M694V mutation. In conclusion, the long-term outcomes of transplantation in patients with amyloidosis secondary to FMF is similar to that in the general transplant population and maintenance colchicine, even at a low dose, seems to effectively prevent recurrence of amyloidosis in the allograft. REFERENCES 1. Severa MS, Turkmena A, Sahina S, et al. Renal transplantation in amyloidosis secondary to familial Mediterranean fever. Transplant Proc. 2001;33:3392e3393. 2. Sherif AM, Refaie AF, Sobh MA, et al. Long-term outcome of live donor kidney transplantation for renal amyloidosis. Am J Kidney Dis. 2003;42:370e375. 3. Keven K, Sengul S, Kutlay S, et al. Long-term outcome of renal transplantation in patients with familial Mediterranean fever amyloidosis: a single-center experience. Transplant Proc. 2004;36: 2632e2634. 4. Moser C, Pohl G, Haslinger I, et al. Successful treatment of familial Mediterranean fever with Anakinra and outcome after renal transplantation. Nephrol Dial Transplant. 2009;24: 676e678. 5. Moroni G, Banfi G, Montoli A, et al. Chronic dialysis in patients with systemic amyloidosis: the experience in northern Italy. Clin Nephrol. 1992;38:81. 6. Bollee G, Guery B, Joly D, et al. Presentation and outcome of patients with systemic amyloidosis undergoing dialysis. Clin J Am Soc Nephrol. 2008;3:375. 7. El-Shanti HI. Familial Mediterranean fever and renal disease. Saudi J Kidney Dis Transpl. 2003;14:378e385. 8. Martinez-Vea A, Garcia C, Carreras N, et al. End-stage renal disease in systemic amyloidosis: clinical course and outcome on dialysis. Am J Nephrol. 1990;10:283e289. 9. Sobh M, Refaie A, Moustafa F, et al. Study of live donor kidney transplantation outcome in recipients with renal amyloidosis. Nephrol Dial Transplant. 1994;9:704. 10. Ben-Zvi I, Danilesko I, Yahalom G, et al. Risk factors for amyloidosis and impact of kidney transplantation on the course of familial Mediterranean fever. Isr Med Assoc J. 2012;14: 221e224. 11. Pasternack A, Ahonen J, Kuhlback B. Renal transplantation in 45 patients with amyloidosis. Transplantation. 1986;42:598. 12. Celik A, Saglam F, Dolek D, et al. Outcome of kidney transplantation for renal amyloidosis: a single-center experience. Transplant Proc. 2006;38:435e439. 13. Erdem E, Karatas A, Kaya C, et al. Renal transplantation in patients with familial Mediterranean fever. Clin Rheumatol. 2012;31:1183e1186.
F
AMILIAL MEDITERRANEAN FEVER (FMF) is an autosomal-recessive disorder1 caused by a mutation in the MEFV gene. It is characterized by sporadic, paroxysmal attacks of fever and serosal inflammation of the peritoneum, pleura, and synovium.2 It may affect large joints. The most severe and important complication of FMF is development of AA amyloidosis, which causes nephrotic syndrome and nephropathy. This leads to end-stage renal disease (ESRD), which has been reported at 0.3% in the United States, 1.6% in European countries,3 4.2% in Turkey, and 6% in Israel.1 Different durations are also reported (2e13years). FMF is common in some Mediterranean ethnic groups, including Jewish, Arabic, Egyptian, Israeli, and Turkish and Armenian populations. Renal transplantation (RTX) is the treatment of choice in ESRD owing to FMF, although recurrence of amyloid A deposition in the allograft can occur in 20% of cases4,5; however, graft survival has been
reported as acceptable.6,7 Because of conflicting data about the outcome of RTX in these patients, the aim of this study was to evaluate the short- and long-term outcomes of RTX in patients with FMF amyloidosis in our center. PATIENTS AND METHOD We compared the results of RTX in 18 patients with FMF amyloidosis among 60 1(2.9%) transplants with 200 age- and gender-matched, non-FMF RTX patients as controls. In 2 groups,
From the Transplantation Ward, Imam Reza Hospital, Chronic Renal Disease Research Center of Tabriz University of Medical Science, Tabriz, Iran. Address correspondence to Sima Abedi Azar, Associate Professor of Tabriz University of Medical Science, Tabriz University of Medical Science. E-mail: [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.09.021
ª 2013 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
3502
Transplantation Proceedings, 45, 3502e3504 (2013)
16; one died at month 46 17 17 17 17; 15.4 in one with 17; 20.3 in one with acute rejection acute rejection 18
Mean glomerular filtration rate (mL/min) No. of patients
57.43 6.59
55.11 7.65
53.71 3.67
0 0 0 17 (1 lost the graft) 17 17 210.09 44.18 198.99 55.31 310.15 40.22 17 17 16; 4100 mg in one with disease recurrence 49.22 5.10 47.18 4.16 44.13 2.17 1 18 190.42 18.09 18
36 24 Months after RTX
12 6
We included 18 patients (12 men and 6 women) with FMF amyloidosis with a mean age of 40.52 7.1 years among 601 (2.9%) transplants with 200 controls (120 men and 80 women) with a mean age of 41.93 10.93 years (P < .2). Mean transplantation duration was 76.42 11.66 in FMF and 72 12.14 in controls. Mean blood urea and creatinine in FMF group was 44.05 9.34 and 1.43 0.54 mg/dL 1 year after RTX without being different from controls (44.26 10.4). Blood urea and 1.39 0.30 creatinine (P < .9). However, there was a significant difference between FMF groups in blood urea (49.73 24.63) and creatinine (1.73 0.89) with controls (52.66 26.58 and 1.49; P < .005) 5 years after RTX. The 1-year graft and patient survivals were 94.44% and 100%, respectively, in the FMF group and 94.73% and 88.88% at 5 years after RTX in the FMF group without a difference from controls. The mean creatinine levels at 1 and 5 years were 1.43 0.54 and 1.73 0.89 mg/dL respectively in patients. The results of MEFV mutation analyses were M694V/ M694V homozygote in 1 patient, M694V/EQ148 in 3, M694V/V726A in 2, 680M-I/E148Q in 3, M694V/M680I in 5, R202Q/M680I in 2, and M694V/R202Q in 2. Recurrence was noticed in 1 patient with M694V/M680I with clinically severe FMF attack and nephrotic range proteinuria, and 1 patient died because of graft loss and cardiac complications with M694V/M680I gene analysis. Colchicine was reduced in 4 patients owing to side effects. Some of
3
RESULTS
1
immunosuppression and duration of transplantation were similar. All patients has MEFV mutation analysis and renal biopsy before RTX. Blood urea, creatinine, urinalysis, and cyclosporine levels were measured monthly and 24-hour proteinuria every 3 months. Demographic data, transplantation duration, blood pressure, cytomegalovirus infection, hepatitis C virus infection, and acute rejection episodes were recorded for all patients. Gene analysis was done in all FMF patients, and all of them were received colchicine 1.5 to 2 g/d. All patients in both groups were followed for 5 years.
Table 2. Paraclinical Parameters of FMF Patients Who Underwent Renal Transplantation
13 2 1 2 2/18 (11.1%) 1 in month 1, other in month 6
60
18 40.52 7.11 Male, 12; female, 6 Unrelated living donor 100% Hemodialysis 9.89 5.81 76.42 11.66
1 18 150.64 37.17 18
Clinical Data Findings
Number of patients Mean age (y) Gender Donor source Dialysis treatment Mean dialysis duration (mo) Mean transplantation duration (mo) Panel-reactive antibody 0 2/30 (6%) 3/30 (10%) 1/30 (3%) Acute rejection episodes
Acute rejection episodes 0 Number of patients 18 Mean 24-hour proteinuria (mg/L) 170.76 23.11 No. of patients 18
Table 1. Demographic and Clinical Parameters of FMF Patients Who Underwent Renal Transplantation
41.13 3.15
3503
0 16 292.83 54.16 16
LONG-TERM OUTCOMES IN FMF
3504
demographic, conical, and paraclinical features are summarized in Tables 1 and 2. All patients were given triple immunosuppressive treatment with cyclosporine, mycophenolate mofetil, and steroids, and received colchicine. Posttransplant complications included acute rejection episodes in 2 of 18 FMF patients (11.1%) and 10% in controls. Cytomegalovirus infection occurred in 10.5% of FMFs and 11% of controls. DISCUSSION
FMF as an autosomal-recessive disease characterized with recurrent episodes of fever and serositis affects kidneys, by development of type AA amyloidosis causes proteinuria and nephropathy and leads to ESRD after 2 to 13 years.8 RTX remains treatment of choice for ESRD owing to FMF amyloidosis compared with hemodialysis or peritoneal dialysis, because of the higher morbidity and mortality rates of these patients on dialysis.2,9 FMF accounted for 2% to 4% of all RTX in a study by Sherif et al2 and 2.9% in our study. This is comparable with previous studies and may be because of the genetic and geographic similarities of the participants. In this study, the 1-year graft and patient survivals were 94.44% and 100%, respectively, in the FMF group, which was not different from controls or other studies.4 In addition, the 5-year graft and patient survivals (94.73% and 88.88%) were comparable in the 2 groups, and was similar to previous studies.10 Recurrence of renal amyloidosis was noted only in 1 patient (of 18) in our study and it was similar to other studies. Recurrence has been noted in transplanted kidneys, but the data are conflicting, because it was not proved in some studies and was hypothesized to be related to the prophylactic effect of immunosuppressive therapy and colchicine, which prevents FMF at doses of 1.5 mg/d.2,10e12 In our study, maintenance colchicine treatment was reduced in 4 patients because of side effects, and these 4 remain recurrence free through follow-up recurrence. An acute rejection episode developed in 1 patient and improved after antirejection treatment. This is similar to other studies. FMF is not a predisposing factor for acute rejection episodes.13 The result of MEFV mutation analysis were M694V/ M694V homozygote in 1, M694V/EQ148 in 3, M694V/ V726A in 2, 680M-I/E148Q in 3, M694V/M680I in 5, R202Q/M680I in 2, and M694V/R202Q in 2, with more
ABEDI, NAKHJAVANI, AND ETEMADI
frequency in M694V/M680I. This emphasizes in frequency of M694Vgen in homozygous or heterozygous form with some differences with other studied, which M694V/ M694V is the most common in other studies.10 However, the episode of acute rejection and disease recurrence occurred in a patient with a M694V/M694V mutation. In conclusion, the long-term outcomes of transplantation in patients with amyloidosis secondary to FMF is similar to that in the general transplant population and maintenance colchicine, even at a low dose, seems to effectively prevent recurrence of amyloidosis in the allograft. REFERENCES 1. Severa MS, Turkmena A, Sahina S, et al. Renal transplantation in amyloidosis secondary to familial Mediterranean fever. Transplant Proc. 2001;33:3392e3393. 2. Sherif AM, Refaie AF, Sobh MA, et al. Long-term outcome of live donor kidney transplantation for renal amyloidosis. Am J Kidney Dis. 2003;42:370e375. 3. Keven K, Sengul S, Kutlay S, et al. Long-term outcome of renal transplantation in patients with familial Mediterranean fever amyloidosis: a single-center experience. Transplant Proc. 2004;36: 2632e2634. 4. Moser C, Pohl G, Haslinger I, et al. Successful treatment of familial Mediterranean fever with Anakinra and outcome after renal transplantation. Nephrol Dial Transplant. 2009;24: 676e678. 5. Moroni G, Banfi G, Montoli A, et al. Chronic dialysis in patients with systemic amyloidosis: the experience in northern Italy. Clin Nephrol. 1992;38:81. 6. Bollee G, Guery B, Joly D, et al. Presentation and outcome of patients with systemic amyloidosis undergoing dialysis. Clin J Am Soc Nephrol. 2008;3:375. 7. El-Shanti HI. Familial Mediterranean fever and renal disease. Saudi J Kidney Dis Transpl. 2003;14:378e385. 8. Martinez-Vea A, Garcia C, Carreras N, et al. End-stage renal disease in systemic amyloidosis: clinical course and outcome on dialysis. Am J Nephrol. 1990;10:283e289. 9. Sobh M, Refaie A, Moustafa F, et al. Study of live donor kidney transplantation outcome in recipients with renal amyloidosis. Nephrol Dial Transplant. 1994;9:704. 10. Ben-Zvi I, Danilesko I, Yahalom G, et al. Risk factors for amyloidosis and impact of kidney transplantation on the course of familial Mediterranean fever. Isr Med Assoc J. 2012;14: 221e224. 11. Pasternack A, Ahonen J, Kuhlback B. Renal transplantation in 45 patients with amyloidosis. Transplantation. 1986;42:598. 12. Celik A, Saglam F, Dolek D, et al. Outcome of kidney transplantation for renal amyloidosis: a single-center experience. Transplant Proc. 2006;38:435e439. 13. Erdem E, Karatas A, Kaya C, et al. Renal transplantation in patients with familial Mediterranean fever. Clin Rheumatol. 2012;31:1183e1186.
