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Excellent Results With Calcineurin Inhibitor–Free Initial Immunosuppression in Old Recipients of Old Kidneys
New Regimens
INDUCTION THERAPY Excellent Results With Calcineurin Inhibitor–free Initial Immunosuppression in Old Recipients of Old Kidneys C. Bösmüller, R. Öllinger, W. Mark, G. Brandacher, S. Schneeberger, F. Cakar, H. Bonatti, and R. Margreiter ABSTRACT The ever increasing demand for donor organs has forced transplant surgeons to liberalize selection criteria. To avoid initial nephrotoxicity to kidneys from donors over 65 years of age, immunosuppression was begun with an IL-2 receptor antibody, mycophenolate mofetil, and steroids in a total of 38 recipients over 65 years. Calcineurin inhibitors (CI) were added after sufficient graft function was reached. After a mean cold ischemia time of 14:01 hours and a delayed function rate of 31%, patient survival, graft survival, and serum creatinine were 97.4%, 94.7%, and 1.5 mg/dL at 1 and 92.1%, 92.1%, and 1.7 mg/dL at 2 years, respectively. Thus, excellent results can be achieved in old recipients of old donor kidneys with CI-free initial immunosuppression.
T
HE EUROTRANSPLANT old-for-old-program was established for the better use of elderly donor kidneys to meet the ever increasing demand for donor organs.1–5 The protocol foresees the transplantation of kidneys from donors more than 65 years of age to recipients over 65. To keep cold ischemia as short as possible kidneys from local donors were preferentially allocated to local recipients. In these patients immunosuppression was started without a calcineurin inhibitor (CI), which was added after stabilization of graft function.5 PATIENTS AND METHODS Between June 1999 and November 2003 a total of 38 recipients aged 67.9 (65 to 80) years of kidneys from donors aged 69.3 (65 to 83) years were given an initial CI-free immunosuppression, consisting of basiliximab 2 ⫻ 20 mg at day 0 ⫹ 4 (n ⫽ 30)/daclizumab 1 mg/kg body weight 5 times in 2-week intervals (n ⫽ 8) ⫹ mycophenolate mofetil ⫹ steroids. Cyclosporine (n ⫽ 28, trough level 180 to 200 ng/mL) was started at day 8 (4 to 42), or tacrolimus (n ⫽ 10, trough level 8 to 10 ng/mL) at day 4 (1 to 6). Kidneys were poorly matched for HLA: MM-AB 2.6 (0 to 4), MM-DR 1.3 (0 to 2). Mean cold ischemia was 14:01 (05:04 to 22:50) hours. The demographic data are depicted in Table 1. All patients were carefully evaluated before transplantation © 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 37, 881– 883 (2005)
with regard to their cardiovascular risk with echocardiography together with exercise stress test/myocardial szintigraphy or coronarangiography when clinically indicated. All patients were heparinized posttransplant and/or given acetylsalicylic acid. In patients with a malignancy following transplantation, immunosuppression was reduced and converted to rapamycine (Table 2). Apart from one intracerebral B-cell lymphoma, which was irradiated, all other tumors were treated surgically. Values were given as means plus range; survival was calculated according to Kaplan-Meier.
RESULTS
Delayed graft function was seen in 12 patients, but all of them recovered. Ten acute rejection episodes were treated with pulsed steroids and were reversed in all cases. The posttransplant complications are depicted in Table 2. Apart from one listeria meningitis, all infections were successfully treated. One graft was lost at month 6 due to chronic rejection. One patient each died of heart failure at month 11, neurological disorder at From the Department of General and Transplant Surgery, Innsbruck Medical University, Innsbruck, Austria. Address reprint requests to Dr Robert Öllinger, Anichstr 35, A-6020 Innsbruck, Austria. E-mail: [email protected] 0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.12.028 881
BÖSMU¨LLER, ÖLLINGER, MARK ET AL
882
Table 2. Results
Table 1. Demographic Data Gender (M/F) First transplant Second transplant Age (y) HLA-antibody Pretransplant dialysis (mo) Donor age (y) MM-AB MM-DR Cold ischemia time (h) Anastomosis time (min) Primary disease Chronic glomerulonephritis Polycystic disease Chronic pyelonephritis Nephrosclerosis Diabetic nephropathy Wegener’s Disease Balkan nephropathy Tumor Light chain gammopathy Unknown Comorbidities Hypertension Coronary heart disease Osteoporosis Malignancy
19/19 37 1 67.9 (65–73) 1 31.6 (8–65) 69.3 (65–83) 2.6 (1–4) 1.3 (0–2) 14:01 (05:04–22:50) 30.9 13 6 5 4 4 2 1 1 1 1 30 (mean demand of 2.1 antihypertensive drugs) 11 (PTCA: 5, ACB: 1) 5 3 (⬎5 years recurrence free)
month 17, and cancer at month 27; all of them with a functioning graft. In the patient who died of cardiac failure, coronary heart disease was known before transplantation. Patient/graft survival was calculated to be 97.4%/94.7% at 1 year and 92.1% each at 2 years. Mean serum creatinine levels at months 6/12/24 were 1.5/1.5/1.7 mg/dL, respectively.
DISCUSSION AND CONCLUSION
Despite the fact that the outcome of transplanting elderly donor kidneys to elderly recipients was reported to be less successful as compared to kidneys from younger donors, Eurotransplant designed the so-called “old-for-old” program.6 To improve results we decided to carefully evaluate the coronary risk of potential recipients, to keep cold ischemia as short as possible, and to avoid any further damage to the graft by potentially nephrotoxic drugs.7,8 Following these rules we did not observe any major cardiac events or death perioperatively. As the acute rejection rate of 10/38 (26.3%, all reversible) does not significantly differ from other patient populations, the initial CI-free immunosuppression followed by later introduction of CI seems to be sufficient. The higher incidence of malignancies can be explained by the age of these patients. After a reduction of the immu-
Delayed graft function Acute rejection Complications Infections bacterial Urinary tract Sepsis Pancreatitis Gastritis Enteritis Pneumonia Pleuritis Bronchitis Sinusitis Erysipela Phlebitis Meningitis Parotitis Eyelid phlegmone Viral Herpes labialis CMV Herpes zoster Herpes analis Influenza Cardiac Heart failure Mitral valve regurgitation Angina Surgical Lymphocele Ileus Ureter necrosis Hematoma Bones Traumatic finger amputation Traumatic fracture Symphysis Nose Femur Tumors Pancreas Prostate Skin (squamaous cell) CNS B-cell lymphoma
12/38 (31.6%) 10 (all reversible)
19 4 2 2 2 1 1 1 1 1 1 1 1 1 14 4 1 1 1 2 (1 lethal, month 11) 2 1 2 2 2 2 1 1 1 1 2 1 1 1
(months 12, 26) (month 7) (month 12) (month 19)
nosuppression and/or conversion to rapamycine together with specific treatment, actually four of the five patients are currently in complete remission. From this experience it is concluded that excellent results can be achieved in old recipients of old donor kidneys with CI-free initial immunosuppression.
REFERENCES 1. Raine AEG, Margreiter R, Brunner FP, et al: Report on management of renal failure in Europe, XXII. Nephrol Dial Transpl 1991(suppl 2):7, 1992
CACINEURIN INHIBITOR–FREE INITIAL IMMUNOSUPPRESSION 2. Fritsche L, Horstrup J, Budde K, et al: Old-for-old kidney allocation allows successful expansion of the donor and recipient pool. Am J Transpl 3:1434, 2003 3. Giessing M, Budde K, Fritsche L, et al: Old-for-old cadaveric renal transplantation: surgical findings, perioperative complications and outcome. Eur Urol 44:701, 2003 4. Schlieper G, Ivens K, Voiculescu A, et al: Eurotransplant SeniorProgram “old for old”: results from 10 patients. Clin Transpl 15:100, 2001 5. Emparan C, Laukötter M, Wolters H, et al: Calcineurin-free protocols with Basilixmab induction allow patients included in “old
883 to old” programs achieve standard kidney transplant function. Transpl Proc 35:1326, 2003 6. Jassal SV, Opelz G, Cole E: Transplantation in the elderly: a review. Geriatr Nephrol Urol 7:157, 1997 7. De Lemos JA, Hillis LD: Diagnosis and management of coronary artery disease in patients with end-stage renal desease on hemodialysis. J Am Soc Nephrol 7:2044, 1996 8. ACC/AHA Task Force Report Special Report: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. J Cardiothor Vasc Anesth 10:540, 1996
INDUCTION THERAPY Excellent Results With Calcineurin Inhibitor–free Initial Immunosuppression in Old Recipients of Old Kidneys C. Bösmüller, R. Öllinger, W. Mark, G. Brandacher, S. Schneeberger, F. Cakar, H. Bonatti, and R. Margreiter ABSTRACT The ever increasing demand for donor organs has forced transplant surgeons to liberalize selection criteria. To avoid initial nephrotoxicity to kidneys from donors over 65 years of age, immunosuppression was begun with an IL-2 receptor antibody, mycophenolate mofetil, and steroids in a total of 38 recipients over 65 years. Calcineurin inhibitors (CI) were added after sufficient graft function was reached. After a mean cold ischemia time of 14:01 hours and a delayed function rate of 31%, patient survival, graft survival, and serum creatinine were 97.4%, 94.7%, and 1.5 mg/dL at 1 and 92.1%, 92.1%, and 1.7 mg/dL at 2 years, respectively. Thus, excellent results can be achieved in old recipients of old donor kidneys with CI-free initial immunosuppression.
T
HE EUROTRANSPLANT old-for-old-program was established for the better use of elderly donor kidneys to meet the ever increasing demand for donor organs.1–5 The protocol foresees the transplantation of kidneys from donors more than 65 years of age to recipients over 65. To keep cold ischemia as short as possible kidneys from local donors were preferentially allocated to local recipients. In these patients immunosuppression was started without a calcineurin inhibitor (CI), which was added after stabilization of graft function.5 PATIENTS AND METHODS Between June 1999 and November 2003 a total of 38 recipients aged 67.9 (65 to 80) years of kidneys from donors aged 69.3 (65 to 83) years were given an initial CI-free immunosuppression, consisting of basiliximab 2 ⫻ 20 mg at day 0 ⫹ 4 (n ⫽ 30)/daclizumab 1 mg/kg body weight 5 times in 2-week intervals (n ⫽ 8) ⫹ mycophenolate mofetil ⫹ steroids. Cyclosporine (n ⫽ 28, trough level 180 to 200 ng/mL) was started at day 8 (4 to 42), or tacrolimus (n ⫽ 10, trough level 8 to 10 ng/mL) at day 4 (1 to 6). Kidneys were poorly matched for HLA: MM-AB 2.6 (0 to 4), MM-DR 1.3 (0 to 2). Mean cold ischemia was 14:01 (05:04 to 22:50) hours. The demographic data are depicted in Table 1. All patients were carefully evaluated before transplantation © 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 37, 881– 883 (2005)
with regard to their cardiovascular risk with echocardiography together with exercise stress test/myocardial szintigraphy or coronarangiography when clinically indicated. All patients were heparinized posttransplant and/or given acetylsalicylic acid. In patients with a malignancy following transplantation, immunosuppression was reduced and converted to rapamycine (Table 2). Apart from one intracerebral B-cell lymphoma, which was irradiated, all other tumors were treated surgically. Values were given as means plus range; survival was calculated according to Kaplan-Meier.
RESULTS
Delayed graft function was seen in 12 patients, but all of them recovered. Ten acute rejection episodes were treated with pulsed steroids and were reversed in all cases. The posttransplant complications are depicted in Table 2. Apart from one listeria meningitis, all infections were successfully treated. One graft was lost at month 6 due to chronic rejection. One patient each died of heart failure at month 11, neurological disorder at From the Department of General and Transplant Surgery, Innsbruck Medical University, Innsbruck, Austria. Address reprint requests to Dr Robert Öllinger, Anichstr 35, A-6020 Innsbruck, Austria. E-mail: [email protected] 0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.12.028 881
BÖSMU¨LLER, ÖLLINGER, MARK ET AL
882
Table 2. Results
Table 1. Demographic Data Gender (M/F) First transplant Second transplant Age (y) HLA-antibody Pretransplant dialysis (mo) Donor age (y) MM-AB MM-DR Cold ischemia time (h) Anastomosis time (min) Primary disease Chronic glomerulonephritis Polycystic disease Chronic pyelonephritis Nephrosclerosis Diabetic nephropathy Wegener’s Disease Balkan nephropathy Tumor Light chain gammopathy Unknown Comorbidities Hypertension Coronary heart disease Osteoporosis Malignancy
19/19 37 1 67.9 (65–73) 1 31.6 (8–65) 69.3 (65–83) 2.6 (1–4) 1.3 (0–2) 14:01 (05:04–22:50) 30.9 13 6 5 4 4 2 1 1 1 1 30 (mean demand of 2.1 antihypertensive drugs) 11 (PTCA: 5, ACB: 1) 5 3 (⬎5 years recurrence free)
month 17, and cancer at month 27; all of them with a functioning graft. In the patient who died of cardiac failure, coronary heart disease was known before transplantation. Patient/graft survival was calculated to be 97.4%/94.7% at 1 year and 92.1% each at 2 years. Mean serum creatinine levels at months 6/12/24 were 1.5/1.5/1.7 mg/dL, respectively.
DISCUSSION AND CONCLUSION
Despite the fact that the outcome of transplanting elderly donor kidneys to elderly recipients was reported to be less successful as compared to kidneys from younger donors, Eurotransplant designed the so-called “old-for-old” program.6 To improve results we decided to carefully evaluate the coronary risk of potential recipients, to keep cold ischemia as short as possible, and to avoid any further damage to the graft by potentially nephrotoxic drugs.7,8 Following these rules we did not observe any major cardiac events or death perioperatively. As the acute rejection rate of 10/38 (26.3%, all reversible) does not significantly differ from other patient populations, the initial CI-free immunosuppression followed by later introduction of CI seems to be sufficient. The higher incidence of malignancies can be explained by the age of these patients. After a reduction of the immu-
Delayed graft function Acute rejection Complications Infections bacterial Urinary tract Sepsis Pancreatitis Gastritis Enteritis Pneumonia Pleuritis Bronchitis Sinusitis Erysipela Phlebitis Meningitis Parotitis Eyelid phlegmone Viral Herpes labialis CMV Herpes zoster Herpes analis Influenza Cardiac Heart failure Mitral valve regurgitation Angina Surgical Lymphocele Ileus Ureter necrosis Hematoma Bones Traumatic finger amputation Traumatic fracture Symphysis Nose Femur Tumors Pancreas Prostate Skin (squamaous cell) CNS B-cell lymphoma
12/38 (31.6%) 10 (all reversible)
19 4 2 2 2 1 1 1 1 1 1 1 1 1 14 4 1 1 1 2 (1 lethal, month 11) 2 1 2 2 2 2 1 1 1 1 2 1 1 1
(months 12, 26) (month 7) (month 12) (month 19)
nosuppression and/or conversion to rapamycine together with specific treatment, actually four of the five patients are currently in complete remission. From this experience it is concluded that excellent results can be achieved in old recipients of old donor kidneys with CI-free initial immunosuppression.
REFERENCES 1. Raine AEG, Margreiter R, Brunner FP, et al: Report on management of renal failure in Europe, XXII. Nephrol Dial Transpl 1991(suppl 2):7, 1992
CACINEURIN INHIBITOR–FREE INITIAL IMMUNOSUPPRESSION 2. Fritsche L, Horstrup J, Budde K, et al: Old-for-old kidney allocation allows successful expansion of the donor and recipient pool. Am J Transpl 3:1434, 2003 3. Giessing M, Budde K, Fritsche L, et al: Old-for-old cadaveric renal transplantation: surgical findings, perioperative complications and outcome. Eur Urol 44:701, 2003 4. Schlieper G, Ivens K, Voiculescu A, et al: Eurotransplant SeniorProgram “old for old”: results from 10 patients. Clin Transpl 15:100, 2001 5. Emparan C, Laukötter M, Wolters H, et al: Calcineurin-free protocols with Basilixmab induction allow patients included in “old
883 to old” programs achieve standard kidney transplant function. Transpl Proc 35:1326, 2003 6. Jassal SV, Opelz G, Cole E: Transplantation in the elderly: a review. Geriatr Nephrol Urol 7:157, 1997 7. De Lemos JA, Hillis LD: Diagnosis and management of coronary artery disease in patients with end-stage renal desease on hemodialysis. J Am Soc Nephrol 7:2044, 1996 8. ACC/AHA Task Force Report Special Report: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. J Cardiothor Vasc Anesth 10:540, 1996