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Steroid withdrawal in renal transplant recipients
Steroid Withdrawal in Renal Transplant Recipients C. Ponticelli, A. Tarantino, and G. Montagnino
D
ESPITE the progress of immunosuppression, death still represents a leading cause of failure in renal transplantation, accounting for 46% of graft failures occurring after the 3rd year posttransplantation.1 In most cases death occurs either by cardiovascular disease or by infections.1 Both of these complications may be triggered or favored by the use of corticosteroids, which can also expose patients to a number of other invalidating and even lifethreatening side effects. Thus, many investigators have tried to eliminate the use of corticosteroids either by avoiding these agents during the perioperative period or by withdrawing them some months after transplantation in patients with stable renal function. Although good results have been reported with the latter strategy,2,3 there are two main disadvantages with late steroid withdrawal. First, many steroid-related side effects—such as cataracts, osteopenia, hypertension, cardiovascular disease, early infections, and diabetes—may develop within the first months after transplantation, so that a late withdrawal cannot prevent their development and the related consequences. Second, there is an increased risk of late acute rejection,4 which may be difficult to detect and which may lead to irreversible lesions. As a matter of fact, in an English trial a substantial proportion of patients showed a reduction of graft function after a late withdrawal of corticosteroids,5 and in a Canadian study the progressive tapering of corticosteroids resulted in an increased incidence of chronic rejection and graft failure, which could be appreciated only in the long term.6 Conversely, early withdrawal of corticosteroids may have the advantage of preventing the development of steroidrelated side effects. Although the risk of acute rejection may be higher with a steroid-free immunosuppression, the diagnosis of an early rejection is usually easy, and most early rejections can be fully reversed by appropriate therapy. Various randomized trials have been done in patients treated with cyclosporine (CyA). A meta-analysis of these studies showed that the risk of acute rejection was higher in patients without steroids than in controls receiving steroids; however, the graft survival at 1 year was similar in the two groups.4 Unfortunately, little information is available about the long-term results with steroid-free immunosuppression. In 1990 a multicenter randomized trial was begun in Italy in order to compare the results of monotherapy with CyA alone, double therapy with CyA plus steroids, and triple © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
therapy with CyA plus azathioprine plus steroids. The demographic characteristics of the patients were similar in the three groups. Patients who did not require dialysis or did not experience a rejection at 5 days were randomized to receive one of the three therapies on the 5th day after transplantation. The results at 4 years have already been published elsewhere.7 We continued to follow these patients and have reviewed the results at 9 years’ posttransplant. According to the intention-to-treat analysis, at 9 years the survival rate was 94% in patients assigned to monotherapy, 87% for those given double therapy, and 87% for those given triple therapy. Only 1 of 115 patients assigned to monotherapy died of cardiovascular disease versus 10 of 239 patients assigned to receive steroids (6 cardiac deaths of 117 patients given double therapy and 4 deaths in 122 patients (given triple therapy). The 9-year actuarial graft survival was 74% for monotherapy, 72% for triple therapy, and 66% for double therapy. Despite the fact that patients assigned to monotherapy experienced significantly more acute rejections (146 in 117 patients vs. 99 of 117 for double therapy, P ⬍ .001, and 98 of 122 for triple therapy, P ⬍ .001) only 3 patients in monotherapy lost their allograft because of acute rejection versus 6 in double therapy and 2 in triple therapy. The most important causes of graft failure were chronic allograft nephropathy (13 in monotherapy, 15 in double therapy, 11 in triple therapy) and death (6, 13, and 12, respectively). The mean levels of creatinine clearance were 57, 64, and 62 mL/min, respectively. We also compared the major complications in patients assigned to steroid-free immunosuppression with CyA alone and in those given steroids from the beginning (double plus triple therapy). Patients assigned to monotherapy had cardiovascular complications in 18.3% of cases versus 32.2% in those given steroids (P ⫽ .009), osteoporosis in 14.7% versus 32.2% (P ⫽ .000), cataracts in 14% versus 40.6% (P ⫽ .000), infections in 50.4% versus 60.7% (P ⫽ .09). In contrast, more patients randomized to CyA alone tended to develop gum hypertrophy (33.0% vs 22.6%,
From the Divisione di Nefrologia e Dialisi, IRCCS Ospedale Maggiore di Milano, Milan, Italy. Address reprint requests to Claudio Ponticelli, MD, Divisione di Nefrologia e Dialisi, IRCCS Ospedale Maggiore di Milano, Via della Commenda 15, 20122 Milano, Italy. 0041-1345/01/$–see front matter PII S0041-1345(00)02298-3 987
Transplantation Proceedings, 33, 987–988 (2001)
988
P ⬍ .05). As pointed out above, all these data were analyzed according to the intention-to-treat principle. Many patients initially randomized to monotherapy were also given corticosteroids during the study. According to the protocol, all patients experiencing two rejections had to be given corticosteroids, and other patients received maintenance corticosteroid treatment for various other reasons. At the last follow-up visit, 48% of patients initially randomized to monotherapy were still without corticosteroids. Patients who needed to have corticosteroids reintroduced because of repeated acute rejections or because of progressive graft dysfunction obviously had a worse prognosis than did those who could be maintained with a steroid-free immunosuppression. However, there are no data on the long-term outcome of these particular patients. To evaluate this point better, we retrospectively investigated our own cumulative experience with CyA monotherapy at the Division of Nephrology of Ospedale Maggiore in Milan.8 The median follow-up for 143 kidney transplant recipients (120 from cadaveric donors and 23 from living donors) assigned to receive CyA alone was 85.8 months. At the end of the follow-up, 49 patients were still in monotherapy, whereas 94 patients were put on corticosteroids at a median of 38 days following transplantation in three-fourth cases because of repeat or severe acute rejection. The cumulative patient survival at 11 years was 89%. The cumulative 11-year graft survival was 62%, being significantly lower for those who had to have corticosteroids added (53% vs 82%; P ⫽ .002). However, the graft half-life was 15.89 years in the group switched to corticosteroids. Variables at transplantation that correlated with a better graft survival were younger age, short duration of dialysis, living donation, and CyA administered in a single daily dose. Multivariate analysis of time-dependent variables showed that delayed graft function and the need to add steroids were associated with a poorer graft survival. Patients who underwent therapeutical conversion developed significantly more infections, more cataracts, more cardiovascular complications, and more arterial hypertension than did patients who remained on CyA alone.
PONTICELLI, TARANTINO, AND MONTAGNINO
after transplantation. Cardiovascular disease, ocular complications, bone complications, and infections are less frequent with steroid-free immunosuppression. Despite an increased risk of acute rejection, the long-term graft survival in patients given CyA alone is similar to that obtained with an association of CyA with steroids. The results are particularly good for those patients who do not need to have corticosteroids added. Despite the inferior results observed in patients who had to have corticosteroids introduced, the long-term graft survival is quite good even in this group. These results were obtained with the old formulation of CyA. It is likely that the use of a combination of newer immunosuppressive drugs (Neoral; tacrolimus; mycophenolate mofetil; anti-CD25 monoclonal antibodies; Rapamycine, RAD) may allow us to further reduce the risk of acute rejection and to increase the number of patients who can be maintained indefinitely without steroids.
ACKNOWLEDGMENTS We are grateful to the colleagues who provided an up-date of the Simtre study, namely Dr G. Segoloni (Turin), Dr V. Cambi (Parma), Dr G. Rizzo (Pisa), Dr P. Altieri (Cagliari), Dr P. Patrono (Lecce), Dr M. Castagneto (Roma), Dr M. Salvadori (Firenze), Dr G.B. Sorba (Sassari), Dr V. Andreucci (Napoli), and Dr C. Casciani (Roma).
REFERENCES 1. Gjertson DW: In Terasaki PI, Cecka JM (eds): Clinical Transplants 1998. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1999, p 399 2. Hollander AAMJ, Hene RJ, Hermans J, et al: J Am Soc Nephrol 8:294, 1997 3. Opelz G: Transplantation 58:443, 1994 4. Hricick DE, O’Toole MA, Heerson J: J Am Soc Nephrol 4:1300, 1993 5. Ratcliffe PJ, Dudley CRK, Higgins RM, et al: Lancet 2:643, 1996 6. Sinclair NR: Can Med Assoc J 147:645, 1992
CONCLUSIONS
7. Ponticelli C, Tarantino A, Segoloni GP, et al: J Am Soc Nephrol 8:646, 1997
In summary, according to the intention-to treat, steroid-free immunosuppression with CyA alone can reduce mortality
8. Montagnino G, Tarantino A, Maccario M, et al: Am J Kidney Dis 35:1135, 2000
D
ESPITE the progress of immunosuppression, death still represents a leading cause of failure in renal transplantation, accounting for 46% of graft failures occurring after the 3rd year posttransplantation.1 In most cases death occurs either by cardiovascular disease or by infections.1 Both of these complications may be triggered or favored by the use of corticosteroids, which can also expose patients to a number of other invalidating and even lifethreatening side effects. Thus, many investigators have tried to eliminate the use of corticosteroids either by avoiding these agents during the perioperative period or by withdrawing them some months after transplantation in patients with stable renal function. Although good results have been reported with the latter strategy,2,3 there are two main disadvantages with late steroid withdrawal. First, many steroid-related side effects—such as cataracts, osteopenia, hypertension, cardiovascular disease, early infections, and diabetes—may develop within the first months after transplantation, so that a late withdrawal cannot prevent their development and the related consequences. Second, there is an increased risk of late acute rejection,4 which may be difficult to detect and which may lead to irreversible lesions. As a matter of fact, in an English trial a substantial proportion of patients showed a reduction of graft function after a late withdrawal of corticosteroids,5 and in a Canadian study the progressive tapering of corticosteroids resulted in an increased incidence of chronic rejection and graft failure, which could be appreciated only in the long term.6 Conversely, early withdrawal of corticosteroids may have the advantage of preventing the development of steroidrelated side effects. Although the risk of acute rejection may be higher with a steroid-free immunosuppression, the diagnosis of an early rejection is usually easy, and most early rejections can be fully reversed by appropriate therapy. Various randomized trials have been done in patients treated with cyclosporine (CyA). A meta-analysis of these studies showed that the risk of acute rejection was higher in patients without steroids than in controls receiving steroids; however, the graft survival at 1 year was similar in the two groups.4 Unfortunately, little information is available about the long-term results with steroid-free immunosuppression. In 1990 a multicenter randomized trial was begun in Italy in order to compare the results of monotherapy with CyA alone, double therapy with CyA plus steroids, and triple © 2001 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
therapy with CyA plus azathioprine plus steroids. The demographic characteristics of the patients were similar in the three groups. Patients who did not require dialysis or did not experience a rejection at 5 days were randomized to receive one of the three therapies on the 5th day after transplantation. The results at 4 years have already been published elsewhere.7 We continued to follow these patients and have reviewed the results at 9 years’ posttransplant. According to the intention-to-treat analysis, at 9 years the survival rate was 94% in patients assigned to monotherapy, 87% for those given double therapy, and 87% for those given triple therapy. Only 1 of 115 patients assigned to monotherapy died of cardiovascular disease versus 10 of 239 patients assigned to receive steroids (6 cardiac deaths of 117 patients given double therapy and 4 deaths in 122 patients (given triple therapy). The 9-year actuarial graft survival was 74% for monotherapy, 72% for triple therapy, and 66% for double therapy. Despite the fact that patients assigned to monotherapy experienced significantly more acute rejections (146 in 117 patients vs. 99 of 117 for double therapy, P ⬍ .001, and 98 of 122 for triple therapy, P ⬍ .001) only 3 patients in monotherapy lost their allograft because of acute rejection versus 6 in double therapy and 2 in triple therapy. The most important causes of graft failure were chronic allograft nephropathy (13 in monotherapy, 15 in double therapy, 11 in triple therapy) and death (6, 13, and 12, respectively). The mean levels of creatinine clearance were 57, 64, and 62 mL/min, respectively. We also compared the major complications in patients assigned to steroid-free immunosuppression with CyA alone and in those given steroids from the beginning (double plus triple therapy). Patients assigned to monotherapy had cardiovascular complications in 18.3% of cases versus 32.2% in those given steroids (P ⫽ .009), osteoporosis in 14.7% versus 32.2% (P ⫽ .000), cataracts in 14% versus 40.6% (P ⫽ .000), infections in 50.4% versus 60.7% (P ⫽ .09). In contrast, more patients randomized to CyA alone tended to develop gum hypertrophy (33.0% vs 22.6%,
From the Divisione di Nefrologia e Dialisi, IRCCS Ospedale Maggiore di Milano, Milan, Italy. Address reprint requests to Claudio Ponticelli, MD, Divisione di Nefrologia e Dialisi, IRCCS Ospedale Maggiore di Milano, Via della Commenda 15, 20122 Milano, Italy. 0041-1345/01/$–see front matter PII S0041-1345(00)02298-3 987
Transplantation Proceedings, 33, 987–988 (2001)
988
P ⬍ .05). As pointed out above, all these data were analyzed according to the intention-to-treat principle. Many patients initially randomized to monotherapy were also given corticosteroids during the study. According to the protocol, all patients experiencing two rejections had to be given corticosteroids, and other patients received maintenance corticosteroid treatment for various other reasons. At the last follow-up visit, 48% of patients initially randomized to monotherapy were still without corticosteroids. Patients who needed to have corticosteroids reintroduced because of repeated acute rejections or because of progressive graft dysfunction obviously had a worse prognosis than did those who could be maintained with a steroid-free immunosuppression. However, there are no data on the long-term outcome of these particular patients. To evaluate this point better, we retrospectively investigated our own cumulative experience with CyA monotherapy at the Division of Nephrology of Ospedale Maggiore in Milan.8 The median follow-up for 143 kidney transplant recipients (120 from cadaveric donors and 23 from living donors) assigned to receive CyA alone was 85.8 months. At the end of the follow-up, 49 patients were still in monotherapy, whereas 94 patients were put on corticosteroids at a median of 38 days following transplantation in three-fourth cases because of repeat or severe acute rejection. The cumulative patient survival at 11 years was 89%. The cumulative 11-year graft survival was 62%, being significantly lower for those who had to have corticosteroids added (53% vs 82%; P ⫽ .002). However, the graft half-life was 15.89 years in the group switched to corticosteroids. Variables at transplantation that correlated with a better graft survival were younger age, short duration of dialysis, living donation, and CyA administered in a single daily dose. Multivariate analysis of time-dependent variables showed that delayed graft function and the need to add steroids were associated with a poorer graft survival. Patients who underwent therapeutical conversion developed significantly more infections, more cataracts, more cardiovascular complications, and more arterial hypertension than did patients who remained on CyA alone.
PONTICELLI, TARANTINO, AND MONTAGNINO
after transplantation. Cardiovascular disease, ocular complications, bone complications, and infections are less frequent with steroid-free immunosuppression. Despite an increased risk of acute rejection, the long-term graft survival in patients given CyA alone is similar to that obtained with an association of CyA with steroids. The results are particularly good for those patients who do not need to have corticosteroids added. Despite the inferior results observed in patients who had to have corticosteroids introduced, the long-term graft survival is quite good even in this group. These results were obtained with the old formulation of CyA. It is likely that the use of a combination of newer immunosuppressive drugs (Neoral; tacrolimus; mycophenolate mofetil; anti-CD25 monoclonal antibodies; Rapamycine, RAD) may allow us to further reduce the risk of acute rejection and to increase the number of patients who can be maintained indefinitely without steroids.
ACKNOWLEDGMENTS We are grateful to the colleagues who provided an up-date of the Simtre study, namely Dr G. Segoloni (Turin), Dr V. Cambi (Parma), Dr G. Rizzo (Pisa), Dr P. Altieri (Cagliari), Dr P. Patrono (Lecce), Dr M. Castagneto (Roma), Dr M. Salvadori (Firenze), Dr G.B. Sorba (Sassari), Dr V. Andreucci (Napoli), and Dr C. Casciani (Roma).
REFERENCES 1. Gjertson DW: In Terasaki PI, Cecka JM (eds): Clinical Transplants 1998. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1999, p 399 2. Hollander AAMJ, Hene RJ, Hermans J, et al: J Am Soc Nephrol 8:294, 1997 3. Opelz G: Transplantation 58:443, 1994 4. Hricick DE, O’Toole MA, Heerson J: J Am Soc Nephrol 4:1300, 1993 5. Ratcliffe PJ, Dudley CRK, Higgins RM, et al: Lancet 2:643, 1996 6. Sinclair NR: Can Med Assoc J 147:645, 1992
CONCLUSIONS
7. Ponticelli C, Tarantino A, Segoloni GP, et al: J Am Soc Nephrol 8:646, 1997
In summary, according to the intention-to treat, steroid-free immunosuppression with CyA alone can reduce mortality
8. Montagnino G, Tarantino A, Maccario M, et al: Am J Kidney Dis 35:1135, 2000