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Renal recovery after conversion to mycophenolate mofetil (MMF) and sirolimus (sir) as calcineurininhibitor-free immunosuppression in late cardiac transplant recipients
The Journal of Heart and Lung Transplantation Volume 23, Number 2S
79 RENAL RECOVERY AFTER CONVERSION TO MYCOPHENOLATE MOFETIL (MMF) AND SIROLIMUS (Sir) AS CALCINEURININHIBITOR-FREE IMMUNOSUPPRESSION IN LATE CARDIAC TRANSPLANT RECIPIENTS J. Groetzner,1 I. Kaczmarek,1 P. Landwehr,1 M. Mueller,1 L. Buehse,1 M. Vogeser,2 P. Ueberfuhr,1 S. Daebritz,1 B. Meiser,1 B. Reichart,1 1Cardiac Surgery, LMU University Hospital Grosshadern, Munich, Germany; 2Clinical Chemistry, LMU Grosshadern, Munich, Germany Background: Calcineurin-inhibitor-(CNI)-induced renal failure is a common complication after cardiac transplantation (HTx). In this prospective study the impact of immunosuppressive conversion to a CNI-free immunosuppressive regimen (MMF⫹Sir) on efficacy, safety and renal function was evaluated. Methods: Since 2001, 30 HTx-patients (25men, 6woman; 0.2 to 14.2years after HTx) with CNI-based immunosuppression and a serum creatinine ⬎1.9mg/dl were included in the study (group1). Creatinine and cystatin levels were monitored to detect renal function. Conversion was started with 6mg sirolimus, continued with 2mg until target trough levels [8 –14ng/ml] were achieved. MMF was continued trough level adjusted [1.5– 4ug/ml]. Subsequently, CNIs were tapered down and stopped. Clinical follow up included endomyocardial biopsies, echocardiography and laboratory studies. Additionally, all HTx-patients treated at our center between 1996 and 2001 due to chronic renal failure and matching the inclusion criteria were retrospectively analysed and acted as control (group2). Results: Patients demographics and one year survival was comparable: 93% (group1) vs. 90% (group2). No acute rejection episode was detected in either group. Renal function improved significantly after conversion (creatinine: 3.18 ⫾ 0.71mg/dl vs 2.22 ⫾ 0.79mg/dl (p ⫽ 0.001); cystatin pre vs post conversion: 2.95 ⫾ 1.06 mg/l vs 2.02 ⫾ 1.1mg/l, p ⫽ 0.01) and in three patients hemodialysis therapy was stopped completely. In group2 renal impairment was deteriorating (creatinine: 2.44 ⫾ 0.8mg/dl vs 3.28 ⫾ 1mg/dl; p ⫽ 0.01). Although no patient was on hemodialysis prior study entry, it had to be initiated in 10 patients after 1year. Although mild adverse events of CNI-free immunosuppression were common (76%), no patient had to be withdrawn from the study. Conclusions: Conversion from CNI-based immunosuppression to MMF and Sir in HTx-patients with chronic renal failure improves renal function and is efficacious and safe. 80 EARLY EXPERIENCE WITH SIROLIMUS BASED, CALCINEURIN INHIBITOR FREE, IMMUNOSUPPRESSION FOR LUNG TRANSPLANT RECIPIENTS Y. Shargall,1 M. de Perrot,1 T.K. Waddell,1 L.S. Singer,1 D. Hadjiliadis,1 M. Hutcheon,1 S. Chernenko,1 A. Pierre,1 F. D’Ovidio,1 S. Kheshavjee,1 1Toronto Lung Transplant Program, Toronto General Hospital, Toronto, ON, Canada Background: Calcineurin inhibitors (CI) are associated with significant side effects. Sirolimus (SRL) is a new immunosuppressant with novel mechanisms of action, usually used in combination with lower doses of CI, thus providing a renal sparing effect. We report our experience with SRL-based, CI-free, immunosuppression for patients undergoing lung transplantation. Methods: Between 10/00 and 8/03, SRL was used (combined with MMF/Azathioprine and prednisone) as a substitute for CI in 21 lung transplant recipients. We followed renal and lung function, as well as complications potentially related to SRL. Results: Median age was 53 years (24 – 68). 5 patients (4 requiring dialysis) received early SRL based treatment starting 10 to 35 days
Abstracts
S69
after transplant due to acute renal failure. All 5 experienced renal recovery, without bronchial anastomotic complications.16 received late SRL treatment for CI related renal toxicity (n ⫽ 13) or neurological side effects (n ⫽ 3), initiated at a median of 54 months post-transplant (3–170). 2 rejection episodes and 5 complications potentially related to SRL (pneumonia and diarrhea 2 each, leukopenia 1) occurred after a median treatment of 7 months (0.5–36). Treatment was discontinued in 2 patients due to side effects, and 5 died while on SRL. 14 patients treated with SRL for more than 3 months had high creatinine(Cr) levels at the initiation of treatment. 12 experienced improvement in their Cr level (288 ⫾ 46 umol/l pre-treatment vs 168 ⫾ 12 umol/l and 124 ⫾ 20 umol/l after 1 and 3 months of treatment, respectively. p ⫽ 0.002) while 2 eventually progressed to dialysis. Pulmonary function test remained stable after at least 3 months of treatment. No new malignancies were identified. Conclusion: In this early experience, SRL appeared to be a safe and useful alternative to CI in lung transplant recipients. CI induced renal impairment was reversible in most patients, while their lung function remained stable. SRL should be considered as an alternative to CI in selected patients. 81 RAD ALTERS THE IMMUNE RESPONSE IN BRONCHOALVEOLAR LAVAGE(BAL) AND ENDOBRONCHIAL BIOPSY(EBB) POST LUNG TRANSPLANTATION(LTX) G. Snell,1 B. Levvey,1 L. Zheng,2 M. Bailey,2 B. Orsida,2 T. Kotsimbos,1 T. McWillams,1 H. Whitford,1 E.H. Walters,1 T. Willams,1 1Allergy, Immunology & Respiratory Medicine, The Alfred, Melbourne, Australia; 2Monash University, Melbourne, Australia Despite controlling acute rejection, current immunosuppressive regimens in LTX remain ineffective in preventing chronic rejection (Bronchiolitis Obliterans Syndrome-BOS). Aim: To determine if RAD, compared to AZA, alters the cellular and cytokine milleau of the lung allograft over time. Method: 22 stable LTX recipients were randomized to RAD(13) or AZA(9) plus standard cyclosporine/ prednisolone (an ongoing substudy of a larger double-blind clinical trial). BAL& EBB were performed at study entry (T0) & 3– 6 month intervals (T1, T2) to determine extensive cellular & cytokine profiles. Analysis(SAS) involved ANOVA-RM with post-hoc t test or chi squared test. Results: There were no group differences for age, gender, pretransplant diagnosis or time post transplant, & no significant differences at T0 for all cellular/cytokine markers. EBB neutrophils rose progressively in AZA group, while progressively falling in RAD group resulting in a significant difference at T2 (p ⫽ 0.02). BAL & EBB CD4 measures significantly declined in RAD group by T2 (p ⬍ 0.05), a similar trend was seen in AZA group(NS). While BAL TGF & IL8 increased over time, there were no significant differences between groups. BOS Op & BOS incidence was similar in both groups. Conclusion: RAD has contributed to significant & potentially important differences in BAL & EBB cellular profiles over time. Correlation with acute rejection & subsequent BOS development will be of great interest. BAL Neut % BAL CD4 % EBB Neut/mm2 EBB CD4/mm2
T0 AZA
T0 RAD
T1 AZA
T1 RAD
T2 AZA
T2 RAD
8.4 (4.0, 17.6) 33 ⫾ 5 333 ⫾ 63 146 (80, 276)
6.6 (3.3, 13.2) 37 ⫾ 4* 389 ⫾ 57 180 (103, 317)*
6.4 (3.1, 13.4) 39 ⫾ 5 361 ⫾ 67 119 (64, 222)
3.8 (2.0, 7.3) 35 ⫾ 4 359 ⫾ 55 86 (49, 150)
7.7 (3.6, 16.6) 27 ⫾ 5 465 ⫾ 63* 92 (50, 171)
3.9 (2.1, 7.5) 24 ⫾ 5* 264 ⫾ 53* 72 (42, 123)*
Results expressed as mean ⫾ SEM or geometric mean & 95% CI; *p ⬍ 0.05.
Research supported by funding grant from Novartis Pharmaceuticals & Margaret Pratt Foundation
79 RENAL RECOVERY AFTER CONVERSION TO MYCOPHENOLATE MOFETIL (MMF) AND SIROLIMUS (Sir) AS CALCINEURININHIBITOR-FREE IMMUNOSUPPRESSION IN LATE CARDIAC TRANSPLANT RECIPIENTS J. Groetzner,1 I. Kaczmarek,1 P. Landwehr,1 M. Mueller,1 L. Buehse,1 M. Vogeser,2 P. Ueberfuhr,1 S. Daebritz,1 B. Meiser,1 B. Reichart,1 1Cardiac Surgery, LMU University Hospital Grosshadern, Munich, Germany; 2Clinical Chemistry, LMU Grosshadern, Munich, Germany Background: Calcineurin-inhibitor-(CNI)-induced renal failure is a common complication after cardiac transplantation (HTx). In this prospective study the impact of immunosuppressive conversion to a CNI-free immunosuppressive regimen (MMF⫹Sir) on efficacy, safety and renal function was evaluated. Methods: Since 2001, 30 HTx-patients (25men, 6woman; 0.2 to 14.2years after HTx) with CNI-based immunosuppression and a serum creatinine ⬎1.9mg/dl were included in the study (group1). Creatinine and cystatin levels were monitored to detect renal function. Conversion was started with 6mg sirolimus, continued with 2mg until target trough levels [8 –14ng/ml] were achieved. MMF was continued trough level adjusted [1.5– 4ug/ml]. Subsequently, CNIs were tapered down and stopped. Clinical follow up included endomyocardial biopsies, echocardiography and laboratory studies. Additionally, all HTx-patients treated at our center between 1996 and 2001 due to chronic renal failure and matching the inclusion criteria were retrospectively analysed and acted as control (group2). Results: Patients demographics and one year survival was comparable: 93% (group1) vs. 90% (group2). No acute rejection episode was detected in either group. Renal function improved significantly after conversion (creatinine: 3.18 ⫾ 0.71mg/dl vs 2.22 ⫾ 0.79mg/dl (p ⫽ 0.001); cystatin pre vs post conversion: 2.95 ⫾ 1.06 mg/l vs 2.02 ⫾ 1.1mg/l, p ⫽ 0.01) and in three patients hemodialysis therapy was stopped completely. In group2 renal impairment was deteriorating (creatinine: 2.44 ⫾ 0.8mg/dl vs 3.28 ⫾ 1mg/dl; p ⫽ 0.01). Although no patient was on hemodialysis prior study entry, it had to be initiated in 10 patients after 1year. Although mild adverse events of CNI-free immunosuppression were common (76%), no patient had to be withdrawn from the study. Conclusions: Conversion from CNI-based immunosuppression to MMF and Sir in HTx-patients with chronic renal failure improves renal function and is efficacious and safe. 80 EARLY EXPERIENCE WITH SIROLIMUS BASED, CALCINEURIN INHIBITOR FREE, IMMUNOSUPPRESSION FOR LUNG TRANSPLANT RECIPIENTS Y. Shargall,1 M. de Perrot,1 T.K. Waddell,1 L.S. Singer,1 D. Hadjiliadis,1 M. Hutcheon,1 S. Chernenko,1 A. Pierre,1 F. D’Ovidio,1 S. Kheshavjee,1 1Toronto Lung Transplant Program, Toronto General Hospital, Toronto, ON, Canada Background: Calcineurin inhibitors (CI) are associated with significant side effects. Sirolimus (SRL) is a new immunosuppressant with novel mechanisms of action, usually used in combination with lower doses of CI, thus providing a renal sparing effect. We report our experience with SRL-based, CI-free, immunosuppression for patients undergoing lung transplantation. Methods: Between 10/00 and 8/03, SRL was used (combined with MMF/Azathioprine and prednisone) as a substitute for CI in 21 lung transplant recipients. We followed renal and lung function, as well as complications potentially related to SRL. Results: Median age was 53 years (24 – 68). 5 patients (4 requiring dialysis) received early SRL based treatment starting 10 to 35 days
Abstracts
S69
after transplant due to acute renal failure. All 5 experienced renal recovery, without bronchial anastomotic complications.16 received late SRL treatment for CI related renal toxicity (n ⫽ 13) or neurological side effects (n ⫽ 3), initiated at a median of 54 months post-transplant (3–170). 2 rejection episodes and 5 complications potentially related to SRL (pneumonia and diarrhea 2 each, leukopenia 1) occurred after a median treatment of 7 months (0.5–36). Treatment was discontinued in 2 patients due to side effects, and 5 died while on SRL. 14 patients treated with SRL for more than 3 months had high creatinine(Cr) levels at the initiation of treatment. 12 experienced improvement in their Cr level (288 ⫾ 46 umol/l pre-treatment vs 168 ⫾ 12 umol/l and 124 ⫾ 20 umol/l after 1 and 3 months of treatment, respectively. p ⫽ 0.002) while 2 eventually progressed to dialysis. Pulmonary function test remained stable after at least 3 months of treatment. No new malignancies were identified. Conclusion: In this early experience, SRL appeared to be a safe and useful alternative to CI in lung transplant recipients. CI induced renal impairment was reversible in most patients, while their lung function remained stable. SRL should be considered as an alternative to CI in selected patients. 81 RAD ALTERS THE IMMUNE RESPONSE IN BRONCHOALVEOLAR LAVAGE(BAL) AND ENDOBRONCHIAL BIOPSY(EBB) POST LUNG TRANSPLANTATION(LTX) G. Snell,1 B. Levvey,1 L. Zheng,2 M. Bailey,2 B. Orsida,2 T. Kotsimbos,1 T. McWillams,1 H. Whitford,1 E.H. Walters,1 T. Willams,1 1Allergy, Immunology & Respiratory Medicine, The Alfred, Melbourne, Australia; 2Monash University, Melbourne, Australia Despite controlling acute rejection, current immunosuppressive regimens in LTX remain ineffective in preventing chronic rejection (Bronchiolitis Obliterans Syndrome-BOS). Aim: To determine if RAD, compared to AZA, alters the cellular and cytokine milleau of the lung allograft over time. Method: 22 stable LTX recipients were randomized to RAD(13) or AZA(9) plus standard cyclosporine/ prednisolone (an ongoing substudy of a larger double-blind clinical trial). BAL& EBB were performed at study entry (T0) & 3– 6 month intervals (T1, T2) to determine extensive cellular & cytokine profiles. Analysis(SAS) involved ANOVA-RM with post-hoc t test or chi squared test. Results: There were no group differences for age, gender, pretransplant diagnosis or time post transplant, & no significant differences at T0 for all cellular/cytokine markers. EBB neutrophils rose progressively in AZA group, while progressively falling in RAD group resulting in a significant difference at T2 (p ⫽ 0.02). BAL & EBB CD4 measures significantly declined in RAD group by T2 (p ⬍ 0.05), a similar trend was seen in AZA group(NS). While BAL TGF & IL8 increased over time, there were no significant differences between groups. BOS Op & BOS incidence was similar in both groups. Conclusion: RAD has contributed to significant & potentially important differences in BAL & EBB cellular profiles over time. Correlation with acute rejection & subsequent BOS development will be of great interest. BAL Neut % BAL CD4 % EBB Neut/mm2 EBB CD4/mm2
T0 AZA
T0 RAD
T1 AZA
T1 RAD
T2 AZA
T2 RAD
8.4 (4.0, 17.6) 33 ⫾ 5 333 ⫾ 63 146 (80, 276)
6.6 (3.3, 13.2) 37 ⫾ 4* 389 ⫾ 57 180 (103, 317)*
6.4 (3.1, 13.4) 39 ⫾ 5 361 ⫾ 67 119 (64, 222)
3.8 (2.0, 7.3) 35 ⫾ 4 359 ⫾ 55 86 (49, 150)
7.7 (3.6, 16.6) 27 ⫾ 5 465 ⫾ 63* 92 (50, 171)
3.9 (2.1, 7.5) 24 ⫾ 5* 264 ⫾ 53* 72 (42, 123)*
Results expressed as mean ⫾ SEM or geometric mean & 95% CI; *p ⬍ 0.05.
Research supported by funding grant from Novartis Pharmaceuticals & Margaret Pratt Foundation