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Usefulness of mycophenolate mofetil in patients with chronic renal insufficiency after liver transplantation
Usefulness of Mycophenolate Mofetil in Patients With Chronic Renal Insufficiency After Liver Transplantation J.M. Moreno, E. Rubio, F. Pons, B. Velayos, E. Navarrete, A. Herreros de Tejada, J. Lo´pez-Monclu´s, V. Sa´nchez-Turrio´n, and V. Cuervas-Mons
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EPHROTOXICITY is a common side effect after liver transplantation (LT). Chronic renal insufficiency (CRI) appears in 50% to 79% of patients during long-term follow-up.1–3 The incidence of end-stage renal disease (ESRD) ranges between 2% and 9.5%.1,4 The use of calcineurin inhibitors (CNI) is the main cause of CRI after LT. Although acute renal failure related to CNI responds to dosage adjustment, the management of patients with CRI is difficult because cyclosporine or tacrolimus dose reduction generally does not improve renal function and withdrawal can be associated with graft rejection.5,6 In contrast to CNI, the newer immunosuppressive agents, mycophenolate mofetil (MMF) and sirolimus, are not nephrotoxic. Therefore, trials have been designed to withdraw CNI with the use of these new immunosuppressive agents in patients with chronic renal insufficiency.7–9 MMF is an inhibitor of inosine monophosphate dehydrogenase, which inhibits proliferation of T and B lymphocytes.10 The aim of our study was to evaluate the evolution
of the renal function in patients with chronic renal dysfunction after liver transplantation with the use of mycophenolate mofetil, associated with a slow tapering and withdrawal of CNI. PATIENTS AND METHODS Beginning in February 1997, MMF (1 g/bid) was introduced into the immunosuppressive regimen of 16 adult patients under CNI therapy with CRI after a first liver transplantation; 14 men (87.5 %) and two women (12.5 %), with a mean age of 50 years (SD, 8; range, 37 to 63 years), and a mean follow-up after LT of 64.4 From the Liver Transplantation Unit, Departments of Medicine (J.M.M., F.P., B.V., E.N., A.H., J.L., V.C.) and Surgery (E.R., V.S.), Puerta de Hierro University Hospital, Universidad Auto´noma de Madrid, Madrid, Spain. Address reprint requests to Dr Jose´ Maria Moreno Planas, Unidad de Trasplante Hepa´tico, Hospital Puerto de Hierro, C/San Martin de Porres 4, 28035 Madrid, Spain.
Fig 1. Evolution of the mean serum creatinine level during the follow-up. © 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 715–717 (2003)
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00061-7 715
716
USEFULNESS OF MYCOPHENOLATE MOFETIL
Fig 2. Evolution of creatinine clearance during the follow-up. months (SD, 35.7; range, 15 to 126). The immunosuppression protocol was cyclosporine in 14 patients and tacrolimus in the other two. Slow tapering of CNI with a monthly biochemical and clinical evaluation was carried out. The evolution of serum creatinine, urea nitrogen, uric acid, cholesterol, glucose, AST, ALT, GGT, bilirrubin, and alkaline phosphatase levels, platelets, white and red blood cell counts, hemoglobin and the mean blood pressure were analyzed. The SPSS 10.0 program was used for statistical analysis.
RESULTS
The 16 patients were followed for a mean of 16 months (median, 12; range, 3 to 37) after beginning the treatment with MMF. One patient was retransplanted due to recurrence of hepatitis C but died as a consequence of postoperative complications. The others were alive at the end of follow-up. Complete withdrawal of CNI was achieved in 11 of 16 patients (68.8%); in one patient CNI could not be withdrawn due to graft rejection, which resolved after the reintroduction of cyclosporine. In the other four patients CNI doses continue to be reduced. CNI were withdrawn in four of 16 patients (20%) during the first 6 months after beginning the treatment with MMF. CNI were withdrawn in five of nine patients (55.6%) followed up for 12 months and in five of six patients (83.3 %) followed up for 18 months. A statistically significant decrease occurred in the mean value of the serum creatinine from 1.9 mg/dL to 1.68 mg/dL (n ⫽ 15; SD, 0.24; P ⫽ .001) at 6 months, from 1.93 to 1.78 mg/dL (n ⫽ 9; SD, 0.28; P ⫽ .05) at 12 months, and from 2.07 to 1.72 mg/dL (n ⫽ 6; SD, 0.22; P ⫽ .01) at 18 months from the beginning of treatment with MMF (Fig 1). A
decrease was also seen in the mean value of urea from 84.43 mg/dL (SD, 42) to 68.93 mg/dL (SD, 29; P ⫽ .07) at 6 months, from 91 to 65.89 mg/dL (SD, 24; P ⫽ .01) at 12 months and from 105.6 to 64.6 mg/dL (SD, 29; P ⫽ .03) at 18 months from the beginning of treatment. There was a nonsignificant decrease in the mean values of uric acid and white blood cells and an increase in the mean creatinine clearance (Fig 2). There were no changes in the mean values of liver function tests, cholesterol, glucose, platelets, hemoglobin, and mean blood pressure during the follow-up. MMF was well tolerated: the side effects were asthenia (n ⫽ 6), dyspepsia (n ⫽ 3), leukopenia (n ⫽ 2), diarrhea (n ⫽ 2), oropharyngeal herpes simplex (n ⫽ 2) and anemia (n ⫽ 1). Only one patient had graft rejection, which recovered with the reintroduction of cyclosporine. One patient required a reduction of the MMF dose because of leukopenia. DISCUSSION
Renal dysfunction is a major complication of long-term immunosuppressive therapy with calcineurin inhibitors. Previous reports support the use of MMF in the management of these patients.7,8,11,12 We observed a significant decrease in the mean values of serum creatinine 6, 12, and 18 months after beginning therapy with MMF. These results are similar to those published in the previous series.7,8,11,12 The mean serum urea level also decreased during followup, and there was a nonsignificant increase in the mean value of creatinine clearance. Schlitt reported a significant decrease in systolic and
MORENO, RUBIO, PONS ET AL
diastolic blood pressure and in serum uric acid.11 In our study there was a trend towards a decrease in serum uric acid levels. Although the mean blood pressure was not reduced, there was a trend towards a decrease in the number of antihypertensive drugs required by the patients. We found no changes in cholesterol or glucose concentrations. No significant variation was found when liver function test results at baseline were compared with those at the latest follow-up. Complete withdrawal of CNI was achieved in 69% of our patients; similar to Herrero7 and Schlitt11 who reported 64% and 72%, respectively. Only one patient showed graft rejection. This is lower than that found in the other series,7,11 in which rejection rates ranged between 18% and 21%. There was only one patient who required dose reduction for serious MMF side effects (leukopenia). Asthenia and mild gastrointestinal complaints were the most common adverse events. Other reports show similar results.11 In summary, treatment with MMF in patients with liver transplantation and chronic renal dysfunction allows the withdrawal of CNI in more than half of the patients at 12 months and in more than 80% at 18 months of follow-up. This approach is effective, since renal function improves significatively, and it is also well tolerated and safe because
717
only one of the patients had graft rejection and no major adverse events occurred. REFERENCES 1. Fisher NC, Nightingale PG, Gunson BK, et al: Transplantation 66:59, 1998 2. Sheiner PA, Magliocca JF, Bodian CA, et al: Transplantation 69:781, 2000 3. Moreno JM, Cuervas-Mons V, Rubio E, et al: Gastroenterol Hepatol 25(Suppl 1):63, 2002 4. Gonwa TA, Mai ML, Melton LB, et al: Transplantation 72:1934, 2001 5. Sandborn WJ, Hay JH, Porayko MK, et al: Hepatology 19:925, 1994 6. Chan CY, Dasgupta K, Baker AL: Hepatology 24:1085, 1996 7. Herrero JI, Quiroga J, Sangro B, et al: Liver Transplant Surg 5:414, 1999 8. Papatheodoridis GV, O’Beirne J, Mistry P, et al: Transplantation 68:155, 1999 9. SlapakGI, Neff GW, Montalbano M, et al: 2nd International Congress on Immunosuppression. Dec 2001. Abstract P-233. 10. Allison AC, Eugui EM, Sollinger HW: Transplant Rev 7:129, 1993 11. Schlitt HJ, Barkmann A, Boker KH, et al: Lancet 357:587, 2001 12. Barkmann A, Nashan B, Schmidt HH, et al: Transplantation 69:1886, 2000
N
EPHROTOXICITY is a common side effect after liver transplantation (LT). Chronic renal insufficiency (CRI) appears in 50% to 79% of patients during long-term follow-up.1–3 The incidence of end-stage renal disease (ESRD) ranges between 2% and 9.5%.1,4 The use of calcineurin inhibitors (CNI) is the main cause of CRI after LT. Although acute renal failure related to CNI responds to dosage adjustment, the management of patients with CRI is difficult because cyclosporine or tacrolimus dose reduction generally does not improve renal function and withdrawal can be associated with graft rejection.5,6 In contrast to CNI, the newer immunosuppressive agents, mycophenolate mofetil (MMF) and sirolimus, are not nephrotoxic. Therefore, trials have been designed to withdraw CNI with the use of these new immunosuppressive agents in patients with chronic renal insufficiency.7–9 MMF is an inhibitor of inosine monophosphate dehydrogenase, which inhibits proliferation of T and B lymphocytes.10 The aim of our study was to evaluate the evolution
of the renal function in patients with chronic renal dysfunction after liver transplantation with the use of mycophenolate mofetil, associated with a slow tapering and withdrawal of CNI. PATIENTS AND METHODS Beginning in February 1997, MMF (1 g/bid) was introduced into the immunosuppressive regimen of 16 adult patients under CNI therapy with CRI after a first liver transplantation; 14 men (87.5 %) and two women (12.5 %), with a mean age of 50 years (SD, 8; range, 37 to 63 years), and a mean follow-up after LT of 64.4 From the Liver Transplantation Unit, Departments of Medicine (J.M.M., F.P., B.V., E.N., A.H., J.L., V.C.) and Surgery (E.R., V.S.), Puerta de Hierro University Hospital, Universidad Auto´noma de Madrid, Madrid, Spain. Address reprint requests to Dr Jose´ Maria Moreno Planas, Unidad de Trasplante Hepa´tico, Hospital Puerto de Hierro, C/San Martin de Porres 4, 28035 Madrid, Spain.
Fig 1. Evolution of the mean serum creatinine level during the follow-up. © 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 715–717 (2003)
0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00061-7 715
716
USEFULNESS OF MYCOPHENOLATE MOFETIL
Fig 2. Evolution of creatinine clearance during the follow-up. months (SD, 35.7; range, 15 to 126). The immunosuppression protocol was cyclosporine in 14 patients and tacrolimus in the other two. Slow tapering of CNI with a monthly biochemical and clinical evaluation was carried out. The evolution of serum creatinine, urea nitrogen, uric acid, cholesterol, glucose, AST, ALT, GGT, bilirrubin, and alkaline phosphatase levels, platelets, white and red blood cell counts, hemoglobin and the mean blood pressure were analyzed. The SPSS 10.0 program was used for statistical analysis.
RESULTS
The 16 patients were followed for a mean of 16 months (median, 12; range, 3 to 37) after beginning the treatment with MMF. One patient was retransplanted due to recurrence of hepatitis C but died as a consequence of postoperative complications. The others were alive at the end of follow-up. Complete withdrawal of CNI was achieved in 11 of 16 patients (68.8%); in one patient CNI could not be withdrawn due to graft rejection, which resolved after the reintroduction of cyclosporine. In the other four patients CNI doses continue to be reduced. CNI were withdrawn in four of 16 patients (20%) during the first 6 months after beginning the treatment with MMF. CNI were withdrawn in five of nine patients (55.6%) followed up for 12 months and in five of six patients (83.3 %) followed up for 18 months. A statistically significant decrease occurred in the mean value of the serum creatinine from 1.9 mg/dL to 1.68 mg/dL (n ⫽ 15; SD, 0.24; P ⫽ .001) at 6 months, from 1.93 to 1.78 mg/dL (n ⫽ 9; SD, 0.28; P ⫽ .05) at 12 months, and from 2.07 to 1.72 mg/dL (n ⫽ 6; SD, 0.22; P ⫽ .01) at 18 months from the beginning of treatment with MMF (Fig 1). A
decrease was also seen in the mean value of urea from 84.43 mg/dL (SD, 42) to 68.93 mg/dL (SD, 29; P ⫽ .07) at 6 months, from 91 to 65.89 mg/dL (SD, 24; P ⫽ .01) at 12 months and from 105.6 to 64.6 mg/dL (SD, 29; P ⫽ .03) at 18 months from the beginning of treatment. There was a nonsignificant decrease in the mean values of uric acid and white blood cells and an increase in the mean creatinine clearance (Fig 2). There were no changes in the mean values of liver function tests, cholesterol, glucose, platelets, hemoglobin, and mean blood pressure during the follow-up. MMF was well tolerated: the side effects were asthenia (n ⫽ 6), dyspepsia (n ⫽ 3), leukopenia (n ⫽ 2), diarrhea (n ⫽ 2), oropharyngeal herpes simplex (n ⫽ 2) and anemia (n ⫽ 1). Only one patient had graft rejection, which recovered with the reintroduction of cyclosporine. One patient required a reduction of the MMF dose because of leukopenia. DISCUSSION
Renal dysfunction is a major complication of long-term immunosuppressive therapy with calcineurin inhibitors. Previous reports support the use of MMF in the management of these patients.7,8,11,12 We observed a significant decrease in the mean values of serum creatinine 6, 12, and 18 months after beginning therapy with MMF. These results are similar to those published in the previous series.7,8,11,12 The mean serum urea level also decreased during followup, and there was a nonsignificant increase in the mean value of creatinine clearance. Schlitt reported a significant decrease in systolic and
MORENO, RUBIO, PONS ET AL
diastolic blood pressure and in serum uric acid.11 In our study there was a trend towards a decrease in serum uric acid levels. Although the mean blood pressure was not reduced, there was a trend towards a decrease in the number of antihypertensive drugs required by the patients. We found no changes in cholesterol or glucose concentrations. No significant variation was found when liver function test results at baseline were compared with those at the latest follow-up. Complete withdrawal of CNI was achieved in 69% of our patients; similar to Herrero7 and Schlitt11 who reported 64% and 72%, respectively. Only one patient showed graft rejection. This is lower than that found in the other series,7,11 in which rejection rates ranged between 18% and 21%. There was only one patient who required dose reduction for serious MMF side effects (leukopenia). Asthenia and mild gastrointestinal complaints were the most common adverse events. Other reports show similar results.11 In summary, treatment with MMF in patients with liver transplantation and chronic renal dysfunction allows the withdrawal of CNI in more than half of the patients at 12 months and in more than 80% at 18 months of follow-up. This approach is effective, since renal function improves significatively, and it is also well tolerated and safe because
717
only one of the patients had graft rejection and no major adverse events occurred. REFERENCES 1. Fisher NC, Nightingale PG, Gunson BK, et al: Transplantation 66:59, 1998 2. Sheiner PA, Magliocca JF, Bodian CA, et al: Transplantation 69:781, 2000 3. Moreno JM, Cuervas-Mons V, Rubio E, et al: Gastroenterol Hepatol 25(Suppl 1):63, 2002 4. Gonwa TA, Mai ML, Melton LB, et al: Transplantation 72:1934, 2001 5. Sandborn WJ, Hay JH, Porayko MK, et al: Hepatology 19:925, 1994 6. Chan CY, Dasgupta K, Baker AL: Hepatology 24:1085, 1996 7. Herrero JI, Quiroga J, Sangro B, et al: Liver Transplant Surg 5:414, 1999 8. Papatheodoridis GV, O’Beirne J, Mistry P, et al: Transplantation 68:155, 1999 9. SlapakGI, Neff GW, Montalbano M, et al: 2nd International Congress on Immunosuppression. Dec 2001. Abstract P-233. 10. Allison AC, Eugui EM, Sollinger HW: Transplant Rev 7:129, 1993 11. Schlitt HJ, Barkmann A, Boker KH, et al: Lancet 357:587, 2001 12. Barkmann A, Nashan B, Schmidt HH, et al: Transplantation 69:1886, 2000