- Email: [email protected]
Long-Term outcome of sirolimus rescue in Kidney–Pancreas transplantation
Long-Term Outcome of Sirolimus Rescue in Kidney–Pancreas Transplantation J. Rogers, E.E. Ashcraft, P.K. Baliga, K.D. Chavin, A. Lin, O. Emovon, F. Afzal, G.M. Baillie, D.J. Taber, S. Alvarez, R.C. Pullatt, and P.R. Rajagopalan ABSTRACT The aim of this study was to evaluate long-term outcome of sirolimus (SRL) rescue in kidney–pancreas transplantation (KPTx). We reviewed 112 KPTx performed at our institution from 12/3/95 to 6/27/02. All patients received antibody (Ab) induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Thirty-five patients (31%) had SRL substituted for MMF for the following indications: (1) acute rejection (AR) of kidney or pancreas despite adequate TAC levels; (2) intolerance of full-dose MMF; (3) rising creatinine; and (4) TAC-induced hyperglycemia. Target SRL and TAC levels were 10 ng/mL and 5 ng/mL, respectively. Mean follow-up was 3 ⫾ 2 years overall and 1.2 ⫾ 0.5 years after SRL rescue. No patients died. One- and 3-year actuarial kidney and pancreas graft survival was 97%, 97%, and 95%, 90%, respectively. Of 10 patients switched to SRL for AR, 1 kidney failed from Ab-resistant AR, 1 kidney developed borderline AR, and the other 8 remain AR-free. Seven other patients developed AR despite therapeutic SRL levels; of these, 6 (86%) had mean TAC levels of ⬍4.5 in the month preceding AR. Mean creatinine overall and for the rising creatinine group remained stable. All patients switched to SRL for TAC-induced hyperglycemia or MMF intolerance demonstrated biochemical or clinical improvement. Sirolimus-related infection or other serious adverse events (SAE) were uncommon. In conclusion, KPTx recipients can be safely switched to SRL with long-term stabilization of renal function, excellent graft and patient survival, and no increase in SAE. A minimum TAC level of 4.5 ng/mL may be necessary to prevent late AR.
T
HE COMBINATION of tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids has become the backbone of maintenance immunosuppression in kidney– pancreas transplantation (KPTx) and has been largely responsible for the decreased incidence of acute rejection over the past decade.1,2 Despite their efficacy, these medications may cause a variety of side effects that can at times necessitate a change in immunosuppressive strategy. Tacrolimus is associated with dose-dependent acute and chronic nephrotoxicity as well as islet toxicity, resulting in hyperglycemia. Both of these toxic manifestations of TAC pose obvious impediments to long-term success of KPTx. The most common side effects of MMF are gastrointestinal (diarrhea and/or gastric distress) and hematologic (neutropenia, thrombocytopenia). Although reduction of TAC and MMF doses may result in improvement or resolution of these undesirable side effects, decreasing immunosuppression may put both kidney and pancreas grafts at undue risk
for acute rejection (AR), with an associated increased risk of graft loss. Sirolimus (SRL), a potent immunosuppressive agent with a different mechanism of action than calcineurin inhibitors such as TAC, acts by inhibiting cytokine-induced signal transduction3 and distinguishes itself from TAC by being neither nephrotoxic nor islet toxic. Although SRL is associated with dyslipidemia, neutropenia, and thrombocytopenia, gastrointestinal side effects are less common than that seen with MMF. We have therefore switched KPTx recipients to SRL-based immunosuppression in cases where the From the Division of Transplant Surgery, Medical University of South Carolina, Charleston, South Carolina. Address reprint requests to Jeffrey Rogers, MD, Assistant Professor of Surgery, Division of Transplant Surgery, Medical University of South Carolina, 96 Jonathan Lucas St., CSB 404, Charleston, SC 29425. E-mail: [email protected]
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.04.044
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1058
Transplantation Proceedings, 36, 1058 –1060 (2004)
SIROLIMUS RESCUE
1059 Table 1. Mean Serum Creatinine Over Time After SRL Rescue
Overall Rising creatinine group
Creatinine at SRL Rescue
Creatinine at 6 Months
Creatinine at 1 Year
P Value
1.8 ⫾ 0.8 mg/dL 2.3 ⫾ 0.8 mg/dL
1.7 ⫾ 0.8 mg/dL 2.5 ⫾ 1.1 mg/dL
2.0 ⫾ 0.9 mg/dL 2.5 ⫾ 1.0 mg/dL
0.5* 0.9*
*Analysis of variance (ANOVA).
combination of TAC, MMF, and steroids became inadequate, undesirable, or poorly tolerated. There are limited data regarding the efficacy of SRL as a primary immunosuppressant in combination with either TAC or cyclosporine (CyA) in pancreas transplantation4 – 6; however, use of SRL as a rescue agent in KPTx has not been well described. The aim of this study was to evaluate the long-term outcome of SRL rescue in KPTx. PATIENTS AND METHODS We retrospectively reviewed 112 KPTx performed at our institution from 12/3/95 to 6/27/02. Systemic-enteric implantation of the pancreas graft was employed in all cases. All patients received antibody induction with either OKT3 or an interleukin-2 receptor– antagonist and maintenance immunosuppression with TAC, MMF, and steroids. The TAC was started within 24 hours of transplantation, with target serum trough levels of 12 to 15 ng/mL for the first month posttransplant, 10 to 12 ng/mL in months 2 to 4, and 8 to 10 ng/mL thereafter. The MMF was started within 24 hours of transplantation at a dose of 2 to 3 g daily. Methylprednisolone 500 mg was administered intraoperatively with taper to oral prednisone 15 mg daily by the 6th postoperative week. When SRL rescue was indicated, SRL was dosed to achieve a target level of 10 ng/mL with a concurrent reduction in TAC dose to achieve a trough level of 5 ng/mL. The diagnosis of rejection was based exclusively on renal or pancreas allograft histopathology.
RESULTS
Thirty-five patients (31%) had SRL substituted for MMF. There were 26 simultaneous kidney–pancreas recipients and 9 pancreas-after-kidney recipients. There were 20 females (57.1%) and 15 males (42.9%), with a mean age of 38 ⫾ 9 years. Indications for SRL rescue were (1) AR of kidney or pancreas graft despite adequate TAC levels as outlined above (n ⫽ 10, 7 kidney, 3 pancreas, 29%); (2) intolerance of full-dose MMF (n ⫽ 12, 34%); (3) rising creatinine (n ⫽ 9, 26%); and (4) TAC-induced hyperglycemia (n ⫽ 4, 11%). Mean time from kidney or pancreas transplant to SRL rescue was 1.9 ⫾ 1.9 years and 1.3 ⫾ 1.5 years, respectively. Mean follow-up was 3 ⫾ 2 years overall, and 1.2 ⫾ 0.5 years after SRL rescue. No patients died. One- and 3-year actuarial kidney and pancreas graft survival rates were 97%, 97%, and 95%, 90%, respectively. Of 7 patients switched to SRL for kidney. AR, 1 kidney was lost to Ab-resistant AR. Of the 6 functioning kidney grafts, 1 developed borderline AR; the other 5 remain AR-free more than 1 year after SRL rescue. All 3 patients switched to SRL for pancreas AR remain AR-free more than 1 year after SRL rescue. Seven other patients not switched to SRL for AR developed AR (3 pancreas, 4 kidney) at a mean of 8 ⫾ 6 months after SRL rescue. Six of these 7 (86%, 3
pancreas, 3 kidney) had mean TAC levels of less than 4.5 ng/mL during the month preceding diagnosis of AR. Overall incidences of kidney and pancreas AR and grade of AR did not differ before and after switch to SRL. Mean serum creatinine overall and for the rising creatinine group remained over time (Table 1). Twelve patients were switched to SRL for gastrointestinal side effects of MMF; 7 had intractable diarrhea with a negative infectious workup, and 5 had upper gastrointestinal symptoms unresponsive to medical therapy. All 12 patients had complete, long-term resolution of gastrointestinal symptoms after SRL rescue. Four patients were switched to SRL for TAC-induced hyperglycemia. None of these patients had biochemical or biopsy evidence of pancreas AR. Mean serum glucose of these patients was 414 ⫾ 24 mg/dL at the time of SRL rescue (range 386 to 442 mg/dL) and was 116 ⫾ 15 mg/dL at 1 month following switch to SRL (range 102 to 136 mg/dL). Four patients (11%) developed serious adverse events (SAE) on SRL (2 bacterial pneumonia, 1 cytomegalovirus colitis, 1 polyoma virus nephropathy). Sirolimus was discontinued indefinitely in 5 (14%) patients (1 severe rash, 2 nonhealing foot infections, 2 trying to get pregnant). Incidence of infectious episodes did not differ before and after switch to SRL. Lipid profile at 6 months was similar to preswitch (pre-SRL: cholesterol 173 ⫾ 43 mg/dL, triglycerides 123 ⫾ 73 mg/dL; 6 months’ post-SRL: cholesterol 181 ⫾ 58 mg/dL, triglycerides 126 ⫾ 50 mg/dL); however, 40% of patients on SRL required lipid-lowering agents. DISCUSSION
Several studies have shown that SRL provides excellent prophylaxis against AR with preservation of renal function when used in conjunction with low-dose CyA in renal transplantation.7,8 A recent prospective, randomized study reported that CyA can be completely eliminated in de novo renal transplant recipients with concentration-controlled dosing of SRL, and that addition of low-dose CyA does not increase immunosuppressive efficacy and is likely to be detrimental to renal function.9 Data regarding use of SRL in KPTx has been relatively scarce, with only a few studies in the published reports. Excellent results have been reported using thymoglobulin induction with TAC and SRL maintenance therapy and steroid withdrawal.4,5 A regimen of thymoglobulin induction in combination with SRL and low-dose CyA maintenance immunosuppression has also been shown to effectively prevent AR, with minimal adverse effects,6 although SRL has not been well described as a rescue agent in KPTx. We have converted KPTx recipients to SRL-based immunosuppression with low-dose TAC in
1060
cases where the combination of TAC, MMF, and steroids became inadequate, undesirable, or poorly tolerated. In the present study, we have shown that KPTx recipients can be safely switched to SRL-based immunosuppression with long-term stabilization of renal function, excellent kidney and pancreas graft survival and patient survival, and no increased risk of AR, infection, or other SAE. However, 6 of 7 patients who developed AR after being switched to SRL had mean TAC levels of less than 4.5 ng/mL during the month preceding diagnosis of AR, suggesting that a minimum TAC level of 4.5 ng/mL may be necessary to prevent late AR with the currently employed target SRL levels. Finally, whereas CyA has been successfully eliminated with SRL based-immunosuppression in renal transplantation, it does not appear that TAC can be completely eliminated using the current immunosuppressive regimen without a significant risk of AR. This may be due to the inherently higher incidence of AR in KPTx compared to kidney transplantation alone.10 It is possible that higher target SRL levels might permit elimination of TAC in KPTx; however, this might come at the expense of an
ROGERS, ASHCRAFT, BALIGA ET AL
increased risk of SRL-related complications. Further study is warranted.
REFERENCES 1. Gruessner AC, Sutherland DER: In Cecka JM, Terasaki PI (eds): Clinical Transplants 1999. Los Angeles, Calif: UCLA Immunogenetics Center; 2000, p 51 2. Stratta RJ: Transpl Immunol 6:69, 1998 3. Citterlo F, Scata P, Violi P, et al: Transplant Proc 35:1292, 2003 4. MacDonald AS, Kiberd B, Salazar A, et al: Am J Transplant 2(suppl 3):141, 2002 5. Kaufman DB, Leventhal JR, Koffron AJ, et al: Transplantation 73:169, 2002 6. Knight RJ, Kerman RH, Scott Z, et al: Transplantation 75:1301, 2003 7. Johnson RW, Kreiss H, Oberbauer R: Transplantation 72: 777, 2001 8. Gonwa TA, Hricik DE, Brinker K, et al: Transplantation 74:1560, 2002 9. Baboolal K: Transplantation 75:1404, 2003 10. Cheung AH, Sutherland DER, Gillingham KJ, et al: Kidney Int 41:924, 1992
T
HE COMBINATION of tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids has become the backbone of maintenance immunosuppression in kidney– pancreas transplantation (KPTx) and has been largely responsible for the decreased incidence of acute rejection over the past decade.1,2 Despite their efficacy, these medications may cause a variety of side effects that can at times necessitate a change in immunosuppressive strategy. Tacrolimus is associated with dose-dependent acute and chronic nephrotoxicity as well as islet toxicity, resulting in hyperglycemia. Both of these toxic manifestations of TAC pose obvious impediments to long-term success of KPTx. The most common side effects of MMF are gastrointestinal (diarrhea and/or gastric distress) and hematologic (neutropenia, thrombocytopenia). Although reduction of TAC and MMF doses may result in improvement or resolution of these undesirable side effects, decreasing immunosuppression may put both kidney and pancreas grafts at undue risk
for acute rejection (AR), with an associated increased risk of graft loss. Sirolimus (SRL), a potent immunosuppressive agent with a different mechanism of action than calcineurin inhibitors such as TAC, acts by inhibiting cytokine-induced signal transduction3 and distinguishes itself from TAC by being neither nephrotoxic nor islet toxic. Although SRL is associated with dyslipidemia, neutropenia, and thrombocytopenia, gastrointestinal side effects are less common than that seen with MMF. We have therefore switched KPTx recipients to SRL-based immunosuppression in cases where the From the Division of Transplant Surgery, Medical University of South Carolina, Charleston, South Carolina. Address reprint requests to Jeffrey Rogers, MD, Assistant Professor of Surgery, Division of Transplant Surgery, Medical University of South Carolina, 96 Jonathan Lucas St., CSB 404, Charleston, SC 29425. E-mail: [email protected]
0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.04.044
© 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1058
Transplantation Proceedings, 36, 1058 –1060 (2004)
SIROLIMUS RESCUE
1059 Table 1. Mean Serum Creatinine Over Time After SRL Rescue
Overall Rising creatinine group
Creatinine at SRL Rescue
Creatinine at 6 Months
Creatinine at 1 Year
P Value
1.8 ⫾ 0.8 mg/dL 2.3 ⫾ 0.8 mg/dL
1.7 ⫾ 0.8 mg/dL 2.5 ⫾ 1.1 mg/dL
2.0 ⫾ 0.9 mg/dL 2.5 ⫾ 1.0 mg/dL
0.5* 0.9*
*Analysis of variance (ANOVA).
combination of TAC, MMF, and steroids became inadequate, undesirable, or poorly tolerated. There are limited data regarding the efficacy of SRL as a primary immunosuppressant in combination with either TAC or cyclosporine (CyA) in pancreas transplantation4 – 6; however, use of SRL as a rescue agent in KPTx has not been well described. The aim of this study was to evaluate the long-term outcome of SRL rescue in KPTx. PATIENTS AND METHODS We retrospectively reviewed 112 KPTx performed at our institution from 12/3/95 to 6/27/02. Systemic-enteric implantation of the pancreas graft was employed in all cases. All patients received antibody induction with either OKT3 or an interleukin-2 receptor– antagonist and maintenance immunosuppression with TAC, MMF, and steroids. The TAC was started within 24 hours of transplantation, with target serum trough levels of 12 to 15 ng/mL for the first month posttransplant, 10 to 12 ng/mL in months 2 to 4, and 8 to 10 ng/mL thereafter. The MMF was started within 24 hours of transplantation at a dose of 2 to 3 g daily. Methylprednisolone 500 mg was administered intraoperatively with taper to oral prednisone 15 mg daily by the 6th postoperative week. When SRL rescue was indicated, SRL was dosed to achieve a target level of 10 ng/mL with a concurrent reduction in TAC dose to achieve a trough level of 5 ng/mL. The diagnosis of rejection was based exclusively on renal or pancreas allograft histopathology.
RESULTS
Thirty-five patients (31%) had SRL substituted for MMF. There were 26 simultaneous kidney–pancreas recipients and 9 pancreas-after-kidney recipients. There were 20 females (57.1%) and 15 males (42.9%), with a mean age of 38 ⫾ 9 years. Indications for SRL rescue were (1) AR of kidney or pancreas graft despite adequate TAC levels as outlined above (n ⫽ 10, 7 kidney, 3 pancreas, 29%); (2) intolerance of full-dose MMF (n ⫽ 12, 34%); (3) rising creatinine (n ⫽ 9, 26%); and (4) TAC-induced hyperglycemia (n ⫽ 4, 11%). Mean time from kidney or pancreas transplant to SRL rescue was 1.9 ⫾ 1.9 years and 1.3 ⫾ 1.5 years, respectively. Mean follow-up was 3 ⫾ 2 years overall, and 1.2 ⫾ 0.5 years after SRL rescue. No patients died. One- and 3-year actuarial kidney and pancreas graft survival rates were 97%, 97%, and 95%, 90%, respectively. Of 7 patients switched to SRL for kidney. AR, 1 kidney was lost to Ab-resistant AR. Of the 6 functioning kidney grafts, 1 developed borderline AR; the other 5 remain AR-free more than 1 year after SRL rescue. All 3 patients switched to SRL for pancreas AR remain AR-free more than 1 year after SRL rescue. Seven other patients not switched to SRL for AR developed AR (3 pancreas, 4 kidney) at a mean of 8 ⫾ 6 months after SRL rescue. Six of these 7 (86%, 3
pancreas, 3 kidney) had mean TAC levels of less than 4.5 ng/mL during the month preceding diagnosis of AR. Overall incidences of kidney and pancreas AR and grade of AR did not differ before and after switch to SRL. Mean serum creatinine overall and for the rising creatinine group remained over time (Table 1). Twelve patients were switched to SRL for gastrointestinal side effects of MMF; 7 had intractable diarrhea with a negative infectious workup, and 5 had upper gastrointestinal symptoms unresponsive to medical therapy. All 12 patients had complete, long-term resolution of gastrointestinal symptoms after SRL rescue. Four patients were switched to SRL for TAC-induced hyperglycemia. None of these patients had biochemical or biopsy evidence of pancreas AR. Mean serum glucose of these patients was 414 ⫾ 24 mg/dL at the time of SRL rescue (range 386 to 442 mg/dL) and was 116 ⫾ 15 mg/dL at 1 month following switch to SRL (range 102 to 136 mg/dL). Four patients (11%) developed serious adverse events (SAE) on SRL (2 bacterial pneumonia, 1 cytomegalovirus colitis, 1 polyoma virus nephropathy). Sirolimus was discontinued indefinitely in 5 (14%) patients (1 severe rash, 2 nonhealing foot infections, 2 trying to get pregnant). Incidence of infectious episodes did not differ before and after switch to SRL. Lipid profile at 6 months was similar to preswitch (pre-SRL: cholesterol 173 ⫾ 43 mg/dL, triglycerides 123 ⫾ 73 mg/dL; 6 months’ post-SRL: cholesterol 181 ⫾ 58 mg/dL, triglycerides 126 ⫾ 50 mg/dL); however, 40% of patients on SRL required lipid-lowering agents. DISCUSSION
Several studies have shown that SRL provides excellent prophylaxis against AR with preservation of renal function when used in conjunction with low-dose CyA in renal transplantation.7,8 A recent prospective, randomized study reported that CyA can be completely eliminated in de novo renal transplant recipients with concentration-controlled dosing of SRL, and that addition of low-dose CyA does not increase immunosuppressive efficacy and is likely to be detrimental to renal function.9 Data regarding use of SRL in KPTx has been relatively scarce, with only a few studies in the published reports. Excellent results have been reported using thymoglobulin induction with TAC and SRL maintenance therapy and steroid withdrawal.4,5 A regimen of thymoglobulin induction in combination with SRL and low-dose CyA maintenance immunosuppression has also been shown to effectively prevent AR, with minimal adverse effects,6 although SRL has not been well described as a rescue agent in KPTx. We have converted KPTx recipients to SRL-based immunosuppression with low-dose TAC in
1060
cases where the combination of TAC, MMF, and steroids became inadequate, undesirable, or poorly tolerated. In the present study, we have shown that KPTx recipients can be safely switched to SRL-based immunosuppression with long-term stabilization of renal function, excellent kidney and pancreas graft survival and patient survival, and no increased risk of AR, infection, or other SAE. However, 6 of 7 patients who developed AR after being switched to SRL had mean TAC levels of less than 4.5 ng/mL during the month preceding diagnosis of AR, suggesting that a minimum TAC level of 4.5 ng/mL may be necessary to prevent late AR with the currently employed target SRL levels. Finally, whereas CyA has been successfully eliminated with SRL based-immunosuppression in renal transplantation, it does not appear that TAC can be completely eliminated using the current immunosuppressive regimen without a significant risk of AR. This may be due to the inherently higher incidence of AR in KPTx compared to kidney transplantation alone.10 It is possible that higher target SRL levels might permit elimination of TAC in KPTx; however, this might come at the expense of an
ROGERS, ASHCRAFT, BALIGA ET AL
increased risk of SRL-related complications. Further study is warranted.
REFERENCES 1. Gruessner AC, Sutherland DER: In Cecka JM, Terasaki PI (eds): Clinical Transplants 1999. Los Angeles, Calif: UCLA Immunogenetics Center; 2000, p 51 2. Stratta RJ: Transpl Immunol 6:69, 1998 3. Citterlo F, Scata P, Violi P, et al: Transplant Proc 35:1292, 2003 4. MacDonald AS, Kiberd B, Salazar A, et al: Am J Transplant 2(suppl 3):141, 2002 5. Kaufman DB, Leventhal JR, Koffron AJ, et al: Transplantation 73:169, 2002 6. Knight RJ, Kerman RH, Scott Z, et al: Transplantation 75:1301, 2003 7. Johnson RW, Kreiss H, Oberbauer R: Transplantation 72: 777, 2001 8. Gonwa TA, Hricik DE, Brinker K, et al: Transplantation 74:1560, 2002 9. Baboolal K: Transplantation 75:1404, 2003 10. Cheung AH, Sutherland DER, Gillingham KJ, et al: Kidney Int 41:924, 1992