- Email: [email protected]
Rapid conversion to sirolimus for chronic progressive deterioration of the renal function in kidney allograft recipients
IMMUNOSUPPRESSION
Rapid Conversion to Sirolimus for Chronic Progressive Deterioration of the Renal Function in Kidney Allograft Recipients F. Citterlo, M.C. Scata`, P. Violi, J. Romagnoli, U. Pozzetto, G. Nanni, and M. Castagneto ABSTRACT The aim of this study was to evaluate the safety of conversion to sirolimus (SRL) immunosuppression among 19 renal transplant recipients (KTX) with progressive chronic renal allograft dysfunction (CRAD). Conversion to SRL was performed with concomitant sharp withdrawal of the calcineurin inhibitor (CI). SRL was added at a starting dose of 3 mg, then adjusted to obtain SRL target trough blood levels of 8 to 10 ng/mL. CI were stopped the evening before starting SRL. All patients enrolled in the study have now completed 6 months of follow-up: all are alive without acute rejection or major infection following rapid conversion to SRL. No significant change in the 6 months postconversion hematologic and hepatic profile was observed compared with the preconversion values, while significant dyslipidemia was induced. After conversion to SRL, significant amelioration of the renal function was found in 36% of patients, stabilization in 21%, and continuous deterioration in 43%. Patients whose renal function improved were found to have been converted at a significantly lower creatinine: (pre 2.6 ⫾ 0.9 vs post 1.9 ⫾ 0.2; P ⫽ .038) with respect to those patients who had continuous renal deterioration. In KTX with CRAD, sharp withdrawal of CI with concomitant conversion to SRL is safe, avoiding major infections, acute rejections, and significant side effects. Short-term amelioration of the renal function is best obtained when early conversion is performed. Long-term follow-up will be necessary to confirm these preliminary data.
C
HRONIC RENAL allograft dysfunction (CRAD) is the major cause of renal graft loss in the maintenance phase after transplantation. Immune and nonimmune factors have been implicated in the development of CRAD. No strategy using current immunosuppressive agents addresses the issue of CRAD.1 While cyclosporine and tacrolimus are the mainstays of posttransplant immunosuppression, both drugs block the calcineurin pathway (calcineurin inhibitors, CI). The most disturbing side effect 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00375-0 1292
of CI is functional renal toxicity, leading to increased blood pressure and reduced glomerular filtration rate. Structural
From the Department of Surgery, Division of Organ Transplantation, Catholic University, Rome, Italy. Address reprint requests to Franco Citterio, Department of Surgery, Division of Organ Transplantation, Catholic University, C.N.R., Centro per la Fisiopatologia dello Shock Largo A. Gemelli 8, 00168 Rome, Italy. E-mail: [email protected] © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 1292-1294 (2003)
RAPID CONVERSION TO SIROLIMUS
1293
Table 1. Safety Data 6 Months Postconversion to Sirolimus
Weight (kg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Hemoglobin (g/dL) Platelets (cells ⫻ 1000/mL) White blood cells (cells ⫻ 1000/mL) Cholesterol (mg/dL) Triglycerides (mg/dL) Glucose (mg/dL) SGOT (UI/L) SGPT (UI/L) Bilirubin (mg/dL)
Preconversion
Postconversion
Paired t Test
64 ⫾ 10 141 ⫾ 21 84 ⫾ 6 11.3 ⫾ 2.4 200 ⫾ 62 7.2 ⫾ 2.4 215 ⫾ 51 156 ⫾ 61 83 ⫾ 14 27 ⫾ 32 34 ⫾ 55 0.75 ⫾ 0.5
69 ⫾ 16 144 ⫾ 13 87 ⫾ 6 10.4 ⫾ 1.9 180 ⫾ 79 6.8 ⫾ 1.6 242 ⫾ 73 230 ⫾ 133 81 ⫾ 12 43 ⫾ 60 29 ⫾ 39 0.51 ⫾ 0.17
.4766 .7041 .0890 .3405 .1051 .4959 .0438 .0213 .3998 .2903 .5356 .2016
nephrotoxic damage may also arise from the chronic use of CI and contribute to the development of CRAD. Sirolimus (SRL) has been proposed as an immunosuppressive agent to allow withdrawal of CI and improve renal function.2 SRL a powerful immunosuppressant, has a mechanism of action different from CI, namely blockade at a later phase of the immune process by inhibiting the cytokine-induced signal transduction. This mechanism has not yet been associated with nephrotoxicity. In humans, SRL has recently been shown to allow early cyclosporine elimination in de novo renal transplant recipients, improving renal function.3 In animal models, SRL inhibits the myointimal proliferation postangioplasty4 and post-allogenic vascular allografts.5 These characteristics of SRL action may be relevant to control the intimal hyperplasia present in CRAD, indicating a possible benefit of converting transplant recipients with declining renal function to SRL. The present study was designed to explore the safety of a sharp conversion to SRL immunosuppression for KTX patients with progressive allograft dysfunction. PATIENTS AND METHODS Nineteen long-term kidney transplant recipients (KTX) were switched to SRL (Rapamune, Wyeth) immunosuppression at 6 to 308 months post-TX. The indication for conversion was a progressive declining renal function. The criteria to switch patients included a progression of serum creatinine in the 2 to 4.5 mg/dL range, or proteinuria ⬎ 500 mg/24 hour despite a putatively “optimal” level of cyclosporine or tacrolimus exposure. In addition a renal biopsy showing fibrosis, tubular atrophy and intimal hyperplasia was considered strong evidence for the conversion. All patients provided informed consent. Conversion to SRL as the sole immunosuppressant was planned in 14 patients. These patients underwent abrupt cessation of cyclosporine or tacrolimus the evening before and SRL addition the following morning at the dose of 3 mg orally. The remaining five patients underwent conversion to SRL that was not initially followed by discontinuation of tacrolimus, although the tacrolimus was drastically reduced to trough blood levels of less than 5 ng/mL for 3 months before being discontinued. In both groups steroid therapy was unchanged. The SRL doses were adjusted to obtain trough blood levels in the range of 8 to 10 ng/mL. SRL trough blood levels were monitored 7 days after conversion, every week for
the first month, every 2 weeks for the second and third months, then monthly thereafter. The following parameters were monitored: vital signs, complete blood cells counts, calculated creatinine clearance, serum creatinine, 24-hour proteinuria, blood glucose, liver enzymes, lipid profile, body weight, concomitant drugs. All patients have completed 6 months of follow-up. The statistical analysis used Student’s t test for paired data, assessing the differences in the mean values of measured parameters.
RESULTS
Nineteen KTX with progressively declining renal function, at 104 ⫾ 73 months posttransplantation, were converted to SRL therapy. Five KTX were women and 14 were men. Eight KTX, had received a kidney from a living related donor, and 11, from a cadaveric donor. Baseline immunosuppression included cyclosporine in 13 patients, tacrolimus in five patients, and azathioprine in one patient. Median serum creatinine at the time of conversion was 2.85 mg/dL. Pre- and 6 months postconversion hematological, lipid, liver, and metabolic profiles of these KTX are reported in Table 1. There were significant changes only in the lipid profile, with elevation of the cholesterol and triglycerides after conversion to SRL (P ⬍ .0438 and ⬍.0213, respectively). Within the first 6 months of observation after conversion to SRL, no acute rejection episode, tumor, or major infection requiring hospitalization occurred. Two patients discontinued SRL within 1 month: one because of severe eyelid edema and the other, to untreatable pruritus. Mean SRL maintenance doses at 6 months were 3.7 ⫾ 1.7 mg/day, leading to are 8.25 ⫾ 3.2 ng/mL (mean ⫾ SD) trough blood levels. After conversion to SRL, significant amelioration of the renal function was displayed by 36% of points, stabilization in 21%, and continuous deterioration in 43%. Patients who improved their renal function were found to have been converted at a creatinine value significantly lower (serum creatinine mg/dL: pre 2.6 ⫾ 0.9 vs post 1.9 ⫾ 0.2; P ⫽ .038) than the patients who showed continuous renal deterioration (serum creatinine mg/dL: pre 3.3 ⫾ 0.7 vs post 5.4 ⫾ 1.4; P ⫽ .0102).
LITTERIO, SCATA`, VIOLI ET AL
1294
DISCUSSION
Prolongation of allograft survival is a major objective of new immunosuppressive agents. In renal transplantation death with a functioning allograft and CRAD are the main obstacles to long-term graft survival. These two complications are both related to vascular diseases. In this perspective, inhibition of myointimal proliferation obtained with SRL treatment in animal and human studies6 may be useful. SRL may reduce the progression of atherosclerosis in renal tissue, avoiding the local hypoxia that leads to fibrosis. In fact, current immunosuppression led to approximately two thirds of kidney allografts with histological evidence of interstitial fibrosis and scarring at 2 years after transplantation.7 To test the hypothesis that SRL may at least in part control the progressive deterioration of the renal function, we designed a study to convert KTX with evidences of progressive CRAD to SRL immunosuppression. The first problem was how to switch KTX receiving CI therapy to SRL. The approach that was first described to convert KTX to SRL was not very convincing.8 In this exploratory study, SRL was added at fixed doses of 5 mg/d. The study was not concentration controlled CI were either slowly tapered over 2 to 8 weeks or stopped completely at the time of the switch. The incidence of infectious complications among the 17 KTX was high: five pneumonia, one PTLD, one CMV, and eight apthous ulcers. The authors concluded that SRL conversion provides adequate immunosuppression and that the drug levels should be monitored. Our approach in the present study was different. We
started from the consideration that long-term KTX with CRAD are fragile patients with a low risk of acute rejection and a high risk of over immunosuppression. For these reasons we elected to stop the CI immediately at the time of the switch, and start with low SRL doses, monitoring the drug levels after the first week. This approach was successful. Neither infectious complication requiring hospitalization nor acute rejection episodes were observed. The strategy benefited 36% of KTX, but the observation period is too short to affirm that the amelioration is a stable effect of SRL conversion and not only the consequence of withdrawal of the CI. In conclusion, our study shows that conversion to SRL with a concomitant sharp withdrawal of CI may be done safely in long-term renal allograft recipients with progressively declining renal function. REFERENCES 1. Monaco AP, Burke JF, Ferguson RM, et al: Am J Kidney Dis 33:150, 1999 2. Johnson RW, Kreiss H, Oberbauer R: Transplantation 72: 777, 2001 3. Gonwa TA, Hricik DE, Brinker K, et al: Transplantation 74:1560, 2002 4. Burke SE, Lubbers NL, Chen YW: J Cardiovasc Pharmacol 33:829, 1999 5. Ikonen TS, Gummert JF, Hayase M, et al: Transplantation 70:969, 2000 6. Morice MC, Serruys PW, Sousa JE, et al: N Engl J Med 346:1773, 2002 7. Solez K, Vincenti F, Filo RS: Transplantation 66:1736, 1998 8. Dominguez J, Mahalati K, Kibert B, et al: Transplantation 70:1244, 2000
Rapid Conversion to Sirolimus for Chronic Progressive Deterioration of the Renal Function in Kidney Allograft Recipients F. Citterlo, M.C. Scata`, P. Violi, J. Romagnoli, U. Pozzetto, G. Nanni, and M. Castagneto ABSTRACT The aim of this study was to evaluate the safety of conversion to sirolimus (SRL) immunosuppression among 19 renal transplant recipients (KTX) with progressive chronic renal allograft dysfunction (CRAD). Conversion to SRL was performed with concomitant sharp withdrawal of the calcineurin inhibitor (CI). SRL was added at a starting dose of 3 mg, then adjusted to obtain SRL target trough blood levels of 8 to 10 ng/mL. CI were stopped the evening before starting SRL. All patients enrolled in the study have now completed 6 months of follow-up: all are alive without acute rejection or major infection following rapid conversion to SRL. No significant change in the 6 months postconversion hematologic and hepatic profile was observed compared with the preconversion values, while significant dyslipidemia was induced. After conversion to SRL, significant amelioration of the renal function was found in 36% of patients, stabilization in 21%, and continuous deterioration in 43%. Patients whose renal function improved were found to have been converted at a significantly lower creatinine: (pre 2.6 ⫾ 0.9 vs post 1.9 ⫾ 0.2; P ⫽ .038) with respect to those patients who had continuous renal deterioration. In KTX with CRAD, sharp withdrawal of CI with concomitant conversion to SRL is safe, avoiding major infections, acute rejections, and significant side effects. Short-term amelioration of the renal function is best obtained when early conversion is performed. Long-term follow-up will be necessary to confirm these preliminary data.
C
HRONIC RENAL allograft dysfunction (CRAD) is the major cause of renal graft loss in the maintenance phase after transplantation. Immune and nonimmune factors have been implicated in the development of CRAD. No strategy using current immunosuppressive agents addresses the issue of CRAD.1 While cyclosporine and tacrolimus are the mainstays of posttransplant immunosuppression, both drugs block the calcineurin pathway (calcineurin inhibitors, CI). The most disturbing side effect 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00375-0 1292
of CI is functional renal toxicity, leading to increased blood pressure and reduced glomerular filtration rate. Structural
From the Department of Surgery, Division of Organ Transplantation, Catholic University, Rome, Italy. Address reprint requests to Franco Citterio, Department of Surgery, Division of Organ Transplantation, Catholic University, C.N.R., Centro per la Fisiopatologia dello Shock Largo A. Gemelli 8, 00168 Rome, Italy. E-mail: [email protected] © 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 1292-1294 (2003)
RAPID CONVERSION TO SIROLIMUS
1293
Table 1. Safety Data 6 Months Postconversion to Sirolimus
Weight (kg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Hemoglobin (g/dL) Platelets (cells ⫻ 1000/mL) White blood cells (cells ⫻ 1000/mL) Cholesterol (mg/dL) Triglycerides (mg/dL) Glucose (mg/dL) SGOT (UI/L) SGPT (UI/L) Bilirubin (mg/dL)
Preconversion
Postconversion
Paired t Test
64 ⫾ 10 141 ⫾ 21 84 ⫾ 6 11.3 ⫾ 2.4 200 ⫾ 62 7.2 ⫾ 2.4 215 ⫾ 51 156 ⫾ 61 83 ⫾ 14 27 ⫾ 32 34 ⫾ 55 0.75 ⫾ 0.5
69 ⫾ 16 144 ⫾ 13 87 ⫾ 6 10.4 ⫾ 1.9 180 ⫾ 79 6.8 ⫾ 1.6 242 ⫾ 73 230 ⫾ 133 81 ⫾ 12 43 ⫾ 60 29 ⫾ 39 0.51 ⫾ 0.17
.4766 .7041 .0890 .3405 .1051 .4959 .0438 .0213 .3998 .2903 .5356 .2016
nephrotoxic damage may also arise from the chronic use of CI and contribute to the development of CRAD. Sirolimus (SRL) has been proposed as an immunosuppressive agent to allow withdrawal of CI and improve renal function.2 SRL a powerful immunosuppressant, has a mechanism of action different from CI, namely blockade at a later phase of the immune process by inhibiting the cytokine-induced signal transduction. This mechanism has not yet been associated with nephrotoxicity. In humans, SRL has recently been shown to allow early cyclosporine elimination in de novo renal transplant recipients, improving renal function.3 In animal models, SRL inhibits the myointimal proliferation postangioplasty4 and post-allogenic vascular allografts.5 These characteristics of SRL action may be relevant to control the intimal hyperplasia present in CRAD, indicating a possible benefit of converting transplant recipients with declining renal function to SRL. The present study was designed to explore the safety of a sharp conversion to SRL immunosuppression for KTX patients with progressive allograft dysfunction. PATIENTS AND METHODS Nineteen long-term kidney transplant recipients (KTX) were switched to SRL (Rapamune, Wyeth) immunosuppression at 6 to 308 months post-TX. The indication for conversion was a progressive declining renal function. The criteria to switch patients included a progression of serum creatinine in the 2 to 4.5 mg/dL range, or proteinuria ⬎ 500 mg/24 hour despite a putatively “optimal” level of cyclosporine or tacrolimus exposure. In addition a renal biopsy showing fibrosis, tubular atrophy and intimal hyperplasia was considered strong evidence for the conversion. All patients provided informed consent. Conversion to SRL as the sole immunosuppressant was planned in 14 patients. These patients underwent abrupt cessation of cyclosporine or tacrolimus the evening before and SRL addition the following morning at the dose of 3 mg orally. The remaining five patients underwent conversion to SRL that was not initially followed by discontinuation of tacrolimus, although the tacrolimus was drastically reduced to trough blood levels of less than 5 ng/mL for 3 months before being discontinued. In both groups steroid therapy was unchanged. The SRL doses were adjusted to obtain trough blood levels in the range of 8 to 10 ng/mL. SRL trough blood levels were monitored 7 days after conversion, every week for
the first month, every 2 weeks for the second and third months, then monthly thereafter. The following parameters were monitored: vital signs, complete blood cells counts, calculated creatinine clearance, serum creatinine, 24-hour proteinuria, blood glucose, liver enzymes, lipid profile, body weight, concomitant drugs. All patients have completed 6 months of follow-up. The statistical analysis used Student’s t test for paired data, assessing the differences in the mean values of measured parameters.
RESULTS
Nineteen KTX with progressively declining renal function, at 104 ⫾ 73 months posttransplantation, were converted to SRL therapy. Five KTX were women and 14 were men. Eight KTX, had received a kidney from a living related donor, and 11, from a cadaveric donor. Baseline immunosuppression included cyclosporine in 13 patients, tacrolimus in five patients, and azathioprine in one patient. Median serum creatinine at the time of conversion was 2.85 mg/dL. Pre- and 6 months postconversion hematological, lipid, liver, and metabolic profiles of these KTX are reported in Table 1. There were significant changes only in the lipid profile, with elevation of the cholesterol and triglycerides after conversion to SRL (P ⬍ .0438 and ⬍.0213, respectively). Within the first 6 months of observation after conversion to SRL, no acute rejection episode, tumor, or major infection requiring hospitalization occurred. Two patients discontinued SRL within 1 month: one because of severe eyelid edema and the other, to untreatable pruritus. Mean SRL maintenance doses at 6 months were 3.7 ⫾ 1.7 mg/day, leading to are 8.25 ⫾ 3.2 ng/mL (mean ⫾ SD) trough blood levels. After conversion to SRL, significant amelioration of the renal function was displayed by 36% of points, stabilization in 21%, and continuous deterioration in 43%. Patients who improved their renal function were found to have been converted at a creatinine value significantly lower (serum creatinine mg/dL: pre 2.6 ⫾ 0.9 vs post 1.9 ⫾ 0.2; P ⫽ .038) than the patients who showed continuous renal deterioration (serum creatinine mg/dL: pre 3.3 ⫾ 0.7 vs post 5.4 ⫾ 1.4; P ⫽ .0102).
LITTERIO, SCATA`, VIOLI ET AL
1294
DISCUSSION
Prolongation of allograft survival is a major objective of new immunosuppressive agents. In renal transplantation death with a functioning allograft and CRAD are the main obstacles to long-term graft survival. These two complications are both related to vascular diseases. In this perspective, inhibition of myointimal proliferation obtained with SRL treatment in animal and human studies6 may be useful. SRL may reduce the progression of atherosclerosis in renal tissue, avoiding the local hypoxia that leads to fibrosis. In fact, current immunosuppression led to approximately two thirds of kidney allografts with histological evidence of interstitial fibrosis and scarring at 2 years after transplantation.7 To test the hypothesis that SRL may at least in part control the progressive deterioration of the renal function, we designed a study to convert KTX with evidences of progressive CRAD to SRL immunosuppression. The first problem was how to switch KTX receiving CI therapy to SRL. The approach that was first described to convert KTX to SRL was not very convincing.8 In this exploratory study, SRL was added at fixed doses of 5 mg/d. The study was not concentration controlled CI were either slowly tapered over 2 to 8 weeks or stopped completely at the time of the switch. The incidence of infectious complications among the 17 KTX was high: five pneumonia, one PTLD, one CMV, and eight apthous ulcers. The authors concluded that SRL conversion provides adequate immunosuppression and that the drug levels should be monitored. Our approach in the present study was different. We
started from the consideration that long-term KTX with CRAD are fragile patients with a low risk of acute rejection and a high risk of over immunosuppression. For these reasons we elected to stop the CI immediately at the time of the switch, and start with low SRL doses, monitoring the drug levels after the first week. This approach was successful. Neither infectious complication requiring hospitalization nor acute rejection episodes were observed. The strategy benefited 36% of KTX, but the observation period is too short to affirm that the amelioration is a stable effect of SRL conversion and not only the consequence of withdrawal of the CI. In conclusion, our study shows that conversion to SRL with a concomitant sharp withdrawal of CI may be done safely in long-term renal allograft recipients with progressively declining renal function. REFERENCES 1. Monaco AP, Burke JF, Ferguson RM, et al: Am J Kidney Dis 33:150, 1999 2. Johnson RW, Kreiss H, Oberbauer R: Transplantation 72: 777, 2001 3. Gonwa TA, Hricik DE, Brinker K, et al: Transplantation 74:1560, 2002 4. Burke SE, Lubbers NL, Chen YW: J Cardiovasc Pharmacol 33:829, 1999 5. Ikonen TS, Gummert JF, Hayase M, et al: Transplantation 70:969, 2000 6. Morice MC, Serruys PW, Sousa JE, et al: N Engl J Med 346:1773, 2002 7. Solez K, Vincenti F, Filo RS: Transplantation 66:1736, 1998 8. Dominguez J, Mahalati K, Kibert B, et al: Transplantation 70:1244, 2000