© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 1372–1382 DOI: 10.1111/ctr.12463
Clinical Transplantation
Influence of recipient age on deceased donor kidney transplant outcomes in the expanded criteria donor era Al-Shraideh Y, Farooq U, Farney AC, Palanisamy A, Rogers J, Orlando G, Buckley MR, Reeves-Daniel A, Doares W, Kaczmorski S, Gautreaux MD, Iskandar SS, Hairston G, Brim E, Mangus M, Stratta RJ. Influence of recipient age on deceased donor kidney transplant outcomes in the expanded criteria donor era. Abstract: Methods: We performed a retrospective single-center review of 884 deceased donor (DD) kidney transplants (KTs) in patients (pts) aged ≥40 yr. Results: One hundred and four (11.8%) pts were ≥70 (mean 74), 286 (32.3%) were 60–69 (mean 64), and 494 (55.9%) were 40–59 (mean 51) yr of age; the proportion receiving expanded criteria donor (ECD) kidneys were 66%, 49%, and 30%, respectively (p < 0.001). Mean waiting time (15 months) was shorter for pts ≥70 yr compared to the other two groups combined (23 months, p = 0.002). With mean follow-up ranging from 54 to 70 months, actual pt (81% vs. 72%, p = 0.002) and graft (66% vs. 58.5%, p = 0.03) survival rates were higher in the younger compared to the two older groups, whereas death-censored graft survival was similar (76% vs. 73%, p = NS). The incidence of death with a functioning graft correlated with older recipient age group, increasing from 13% to 18% to 23% (p = 0.01). The incidence of delayed graft function was similar (31.8% overall), and renal function, morbidity, and resource utilization were similar among groups. Conclusions: By directing ECD kidneys to selected older pts, waiting times are reduced and censored survival outcomes are similar to middleaged patients, suggesting that matching strategies for graft and patient lifespan are warranted.
Yousef Al-Shraideha, Umar Farooqa, Alan C. Farneya, Amudha Palanisamyb, Jeffrey Rogersa, Giuseppe Orlandoa, Michael R. Buckleya, Amber Reeves-Danielb, William Doaresc, Scott Kaczmorskic, Michael D. Gautreauxa, Samy S. Iskandard, Gloria Hairstona, Elizabeth Brima, Margaret Mangusa and Robert J. Strattaa a
Department of General Surgery, Wake Forest School of Medicine, bDepartment of Internal Medicine, Wake Forest School of Medicine, c Department of Pharmacy, Wake Forest School of Medicine and dDepartment of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA Key words: age matching – death with a functioning graft – deceased donors – delayed graft function – expanded criteria donor – kidney transplant – recipient age Corresponding author: Robert J. Stratta, MD, Department of General Surgery, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. Tel.: 001 336 716 0548; fax: 001 336 713 5055; e-mail: [email protected] Conflict of interest: None. Accepted for publication 8 September 2014
In the recent past, advanced chronological age was a contraindication for both organ donation and transplantation. According to the 2014, United States Renal Data System (USRDS) report providing data through 2012, in the decade from 2002 to 2012, the number of patients on the kidney waiting list aged 65 and older (the so-called elderly) tripled, their proportion on the waiting list nearly doubled, and the number who actually received kidney transplants (KT) doubled (1, 2). In addition, both
1372
their mortality on the waiting list and their willingness to accept a kidney from an expanded criteria donor (ECD) were 1.5 times higher than the remainder of younger patients on the waiting list (1, 2). The elderly represent the largest proportionate increase in the waiting list over the past decade (1–4). Data from the USRDS report showed that within three yr of listing, older patients are more likely than their younger counterparts to receive a
Kidney transplantation and elderly deceased donor (DD) KT, less likely to receive a living donor KT, and more likely to die before receiving any KT (1, 2). A recent study demonstrated that 46% of KT candidates ≥60 yr of age placed on the waiting list will actually die before receiving a DD KT (5). Moreover, changes in kidney allocation policy are intended to promote better matching of graft and patient longevity, and in this model, age is one of the four factors being used in a formula to estimate post-transplant recipient survival (6). These changes have occurred because of the convergence of demographic inevitability and medical advances. The aging donor and recipient populations have led to new challenges in KT (3–15). Controversy exists regarding the optimal approach to the elderly donor and recipient, particularly because each have been associated with reduced six-month allograft function and decreased longterm graft survival (16–19). A number of strategies have been proposed including matching by age, medical risks, serology, histocompatibility, size, nephron mass, and expected longevity (20–25). The purpose of this study was to review, retrospectively, our single-center experience in DD KT in the ECD era with respect to recipient age in patients receiving contemporary immunosuppression with an emphasis on patients aged 40 yr and older.
Methods Study design
We conducted a retrospective chart review of all DD KTs performed at our center from 10/1/01 to 1/1/12 (minimum two yr follow-up). Specific exclusions included adult recipients less than age 40 yr, pediatric recipients (younger than age 19 yr), simultaneous kidney–pancreas transplant recipients, and living donor KT recipients. During this 10.5-yr study period, a total of 884 DD KTs met the entry criteria and were categorized by recipient age into the elderly (≥age 70), older (60–69 yr), and middle (40–59 yr) age groups. Standardized donor and recipient selection and management algorithms were followed during the period of study. Definitions
ECDs were defined by the standard United Network for Organ Sharing (UNOS) criteria (16). For purposes of this study, any DD not meeting ECD criteria was defined as a standard criteria donor (SCD). Delayed graft function (DGF) was defined
as the need for dialysis for any reason in the firstweek post-transplant. Renal allograft loss was defined as death with a functioning graft (DWFG,) transplant nephrectomy, return to dialysis, retransplantation, or return to the pre-transplant serum creatinine (SCr) level in preemptively transplanted patients. Donor selection
No specific donor upper age limit was excluded from consideration, although the oldest donor in this series was 78 yr. In general, ECDs with other risk factors (positive hepatitis B or C serology, high-risk social/sexual behavior, central nervous system malignancy) were excluded from consideration. A history of diabetes was not a contraindication to using an ECD kidney, unless the donor had documented proteinuria or a decline in renal function. The Cockcroft–Gault formula was employed to estimate donor creatinine clearance, using both actual and ideal body weight to calculate a range of potential donor kidney function and to determine single or dual KT into a single recipient (26–30). If the estimated creatinine clearance was >70 mL/min, then a single KT was performed, preferably into a recipient with a body mass index (BMI) < 25 kg/m2. If the estimated creatinine clearance was 2.0 mg/dL, then the kidney(s) from an ECD were not used. Donor kidney biopsy was also used to assist in the evaluation of pre-existing and terminal renal parenchymal injury. In general, if the biopsy showed moderate to severe vascular changes (atherosclerosis, intimal thickening or hyalinization, or microvascular thrombosis), moderate to severe tubular changes (necrosis, edema, or atrophy), or moderate to severe interstitial changes (infiltrates or fibrosis), then the kidney was not accepted for transplantation. In addition, >50% glomerulosclerosis was an absolute contraindication, and 35–50% glomerulosclerosis a relative contraindication, for kidney utilization (26–28). Whenever possible, ECD kidneys were placed on a pulsatile perfusion pump to minimize preservation injury, maintain functional reserve, and provide another means of assessment. Within our organ procurement organization, kidneys are placed routinely on the perfusion pump if the donor is above 40 yr of age, hemodynamically unstable, oliguric (urine output 1.2 mg/dL, has a history of hypertension or diabetes, or at the accepting center’s discretion. Although pump parameters were not exclusively used to discard kidneys, a flow rate above 80 mL/ min and a resistance below 0.35 mm Hg/mL/min after a minimum of 6 h on the perfusion apparatus were considered as thresholds for utilization. Recipient evaluation and selection
At our center, no specific upper age limit was an absolute contraindication to KT, although the oldest recipient in this series was 84 yr. All patients underwent a comprehensive pre-transplant medical, psychosocial, and financial evaluation, with emphasis placed on the cardiovascular system to determine operative risks and physiological age (26, 27). Non-contrast abdominal/pelvic computerized tomographic imaging (to assess iliac artery calcifications) and cardiac stress testing were performed in all patients age 40 yr and older. The presence of a positive cardiac stress test mandated subsequent cardiology consultation and heart catheterization regardless of age as did the presence of significant pulmonary hypertension or valvular disease. In general, our philosophy was to consider patients below age 70 yr “a candidate for KT until proven otherwise,” whereas patients above age 70 yr were considered to be “not a candidate for KT until proven otherwise.” In other words, elderly patients needed to be reasonably well compensated and functional and not have multiple other comorbidities. All patients age 70 yr and older underwent carotid and iliac artery duplex ultrasonographic imaging, cardiology consultation, and heart catheterization, whereas this testing was more selective in patients 40 yr) and smaller size BMI < 25 kg/m2) matching and identifying low immunological risk patients such as primary transplant, good human leukocyte antigen (HLA) matching, low panel reactive antibody (PRA) level, and informed consent (26, 27). In addition, age matching between donor and recipient was a consideration as we tried to avoid age mismatching >15 yr. Immunosuppression
Nearly all DD KT patients received depleting antibody induction with either rabbit antithymocyte globulin or alemtuzumab 30 mg intravenous as a single intra-operative dose (29). Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil (MMF), and rapid tapering doses of steroids or early steroid withdrawal based on immunological risk stratification. In patients ≥60 yr of age, only half doses of MMF (500 mg bid or 360 mg bid of mycophenolate) were administered (29). Early steroid withdrawal was performed in low-risk patients, whereas steroids were continued in high immunological risk patients such as patients receiving retransplants, patients with a current PRA level >20%, and patients experiencing DGF. Post-transplant management
All patients received surgical site prophylaxis with a first-generation cephalosporin for 24 h, antifungal prophylaxis with nystatin or fluconazole for 1–2 months, and anti-Pneumocystis prophylaxis with sulfamethoxazole–trimethoprim (dapsone if allergic to sulfa) for at least 12 months. Antiviral prophylaxis consisted of oral valganciclovir for 3–6 months, depending on donor and recipient cytomegalovirus (CMV) serologic status. Specifics regarding drug dosing and duration have been published previously (26–29). Most patients
Kidney transplantation and elderly received aspirin prophylaxis. Treatment of hypertension, hyperlipidemia, anemia, diabetes, and other medical conditions was initiated as indicated, aiming to maintain the blood pressure
Clin Transplant 2014: 28: 1372–1382 DOI: 10.1111/ctr.12463
Clinical Transplantation
Influence of recipient age on deceased donor kidney transplant outcomes in the expanded criteria donor era Al-Shraideh Y, Farooq U, Farney AC, Palanisamy A, Rogers J, Orlando G, Buckley MR, Reeves-Daniel A, Doares W, Kaczmorski S, Gautreaux MD, Iskandar SS, Hairston G, Brim E, Mangus M, Stratta RJ. Influence of recipient age on deceased donor kidney transplant outcomes in the expanded criteria donor era. Abstract: Methods: We performed a retrospective single-center review of 884 deceased donor (DD) kidney transplants (KTs) in patients (pts) aged ≥40 yr. Results: One hundred and four (11.8%) pts were ≥70 (mean 74), 286 (32.3%) were 60–69 (mean 64), and 494 (55.9%) were 40–59 (mean 51) yr of age; the proportion receiving expanded criteria donor (ECD) kidneys were 66%, 49%, and 30%, respectively (p < 0.001). Mean waiting time (15 months) was shorter for pts ≥70 yr compared to the other two groups combined (23 months, p = 0.002). With mean follow-up ranging from 54 to 70 months, actual pt (81% vs. 72%, p = 0.002) and graft (66% vs. 58.5%, p = 0.03) survival rates were higher in the younger compared to the two older groups, whereas death-censored graft survival was similar (76% vs. 73%, p = NS). The incidence of death with a functioning graft correlated with older recipient age group, increasing from 13% to 18% to 23% (p = 0.01). The incidence of delayed graft function was similar (31.8% overall), and renal function, morbidity, and resource utilization were similar among groups. Conclusions: By directing ECD kidneys to selected older pts, waiting times are reduced and censored survival outcomes are similar to middleaged patients, suggesting that matching strategies for graft and patient lifespan are warranted.
Yousef Al-Shraideha, Umar Farooqa, Alan C. Farneya, Amudha Palanisamyb, Jeffrey Rogersa, Giuseppe Orlandoa, Michael R. Buckleya, Amber Reeves-Danielb, William Doaresc, Scott Kaczmorskic, Michael D. Gautreauxa, Samy S. Iskandard, Gloria Hairstona, Elizabeth Brima, Margaret Mangusa and Robert J. Strattaa a
Department of General Surgery, Wake Forest School of Medicine, bDepartment of Internal Medicine, Wake Forest School of Medicine, c Department of Pharmacy, Wake Forest School of Medicine and dDepartment of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA Key words: age matching – death with a functioning graft – deceased donors – delayed graft function – expanded criteria donor – kidney transplant – recipient age Corresponding author: Robert J. Stratta, MD, Department of General Surgery, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA. Tel.: 001 336 716 0548; fax: 001 336 713 5055; e-mail: [email protected] Conflict of interest: None. Accepted for publication 8 September 2014
In the recent past, advanced chronological age was a contraindication for both organ donation and transplantation. According to the 2014, United States Renal Data System (USRDS) report providing data through 2012, in the decade from 2002 to 2012, the number of patients on the kidney waiting list aged 65 and older (the so-called elderly) tripled, their proportion on the waiting list nearly doubled, and the number who actually received kidney transplants (KT) doubled (1, 2). In addition, both
1372
their mortality on the waiting list and their willingness to accept a kidney from an expanded criteria donor (ECD) were 1.5 times higher than the remainder of younger patients on the waiting list (1, 2). The elderly represent the largest proportionate increase in the waiting list over the past decade (1–4). Data from the USRDS report showed that within three yr of listing, older patients are more likely than their younger counterparts to receive a
Kidney transplantation and elderly deceased donor (DD) KT, less likely to receive a living donor KT, and more likely to die before receiving any KT (1, 2). A recent study demonstrated that 46% of KT candidates ≥60 yr of age placed on the waiting list will actually die before receiving a DD KT (5). Moreover, changes in kidney allocation policy are intended to promote better matching of graft and patient longevity, and in this model, age is one of the four factors being used in a formula to estimate post-transplant recipient survival (6). These changes have occurred because of the convergence of demographic inevitability and medical advances. The aging donor and recipient populations have led to new challenges in KT (3–15). Controversy exists regarding the optimal approach to the elderly donor and recipient, particularly because each have been associated with reduced six-month allograft function and decreased longterm graft survival (16–19). A number of strategies have been proposed including matching by age, medical risks, serology, histocompatibility, size, nephron mass, and expected longevity (20–25). The purpose of this study was to review, retrospectively, our single-center experience in DD KT in the ECD era with respect to recipient age in patients receiving contemporary immunosuppression with an emphasis on patients aged 40 yr and older.
Methods Study design
We conducted a retrospective chart review of all DD KTs performed at our center from 10/1/01 to 1/1/12 (minimum two yr follow-up). Specific exclusions included adult recipients less than age 40 yr, pediatric recipients (younger than age 19 yr), simultaneous kidney–pancreas transplant recipients, and living donor KT recipients. During this 10.5-yr study period, a total of 884 DD KTs met the entry criteria and were categorized by recipient age into the elderly (≥age 70), older (60–69 yr), and middle (40–59 yr) age groups. Standardized donor and recipient selection and management algorithms were followed during the period of study. Definitions
ECDs were defined by the standard United Network for Organ Sharing (UNOS) criteria (16). For purposes of this study, any DD not meeting ECD criteria was defined as a standard criteria donor (SCD). Delayed graft function (DGF) was defined
as the need for dialysis for any reason in the firstweek post-transplant. Renal allograft loss was defined as death with a functioning graft (DWFG,) transplant nephrectomy, return to dialysis, retransplantation, or return to the pre-transplant serum creatinine (SCr) level in preemptively transplanted patients. Donor selection
No specific donor upper age limit was excluded from consideration, although the oldest donor in this series was 78 yr. In general, ECDs with other risk factors (positive hepatitis B or C serology, high-risk social/sexual behavior, central nervous system malignancy) were excluded from consideration. A history of diabetes was not a contraindication to using an ECD kidney, unless the donor had documented proteinuria or a decline in renal function. The Cockcroft–Gault formula was employed to estimate donor creatinine clearance, using both actual and ideal body weight to calculate a range of potential donor kidney function and to determine single or dual KT into a single recipient (26–30). If the estimated creatinine clearance was >70 mL/min, then a single KT was performed, preferably into a recipient with a body mass index (BMI) < 25 kg/m2. If the estimated creatinine clearance was 2.0 mg/dL, then the kidney(s) from an ECD were not used. Donor kidney biopsy was also used to assist in the evaluation of pre-existing and terminal renal parenchymal injury. In general, if the biopsy showed moderate to severe vascular changes (atherosclerosis, intimal thickening or hyalinization, or microvascular thrombosis), moderate to severe tubular changes (necrosis, edema, or atrophy), or moderate to severe interstitial changes (infiltrates or fibrosis), then the kidney was not accepted for transplantation. In addition, >50% glomerulosclerosis was an absolute contraindication, and 35–50% glomerulosclerosis a relative contraindication, for kidney utilization (26–28). Whenever possible, ECD kidneys were placed on a pulsatile perfusion pump to minimize preservation injury, maintain functional reserve, and provide another means of assessment. Within our organ procurement organization, kidneys are placed routinely on the perfusion pump if the donor is above 40 yr of age, hemodynamically unstable, oliguric (urine output 1.2 mg/dL, has a history of hypertension or diabetes, or at the accepting center’s discretion. Although pump parameters were not exclusively used to discard kidneys, a flow rate above 80 mL/ min and a resistance below 0.35 mm Hg/mL/min after a minimum of 6 h on the perfusion apparatus were considered as thresholds for utilization. Recipient evaluation and selection
At our center, no specific upper age limit was an absolute contraindication to KT, although the oldest recipient in this series was 84 yr. All patients underwent a comprehensive pre-transplant medical, psychosocial, and financial evaluation, with emphasis placed on the cardiovascular system to determine operative risks and physiological age (26, 27). Non-contrast abdominal/pelvic computerized tomographic imaging (to assess iliac artery calcifications) and cardiac stress testing were performed in all patients age 40 yr and older. The presence of a positive cardiac stress test mandated subsequent cardiology consultation and heart catheterization regardless of age as did the presence of significant pulmonary hypertension or valvular disease. In general, our philosophy was to consider patients below age 70 yr “a candidate for KT until proven otherwise,” whereas patients above age 70 yr were considered to be “not a candidate for KT until proven otherwise.” In other words, elderly patients needed to be reasonably well compensated and functional and not have multiple other comorbidities. All patients age 70 yr and older underwent carotid and iliac artery duplex ultrasonographic imaging, cardiology consultation, and heart catheterization, whereas this testing was more selective in patients 40 yr) and smaller size BMI < 25 kg/m2) matching and identifying low immunological risk patients such as primary transplant, good human leukocyte antigen (HLA) matching, low panel reactive antibody (PRA) level, and informed consent (26, 27). In addition, age matching between donor and recipient was a consideration as we tried to avoid age mismatching >15 yr. Immunosuppression
Nearly all DD KT patients received depleting antibody induction with either rabbit antithymocyte globulin or alemtuzumab 30 mg intravenous as a single intra-operative dose (29). Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil (MMF), and rapid tapering doses of steroids or early steroid withdrawal based on immunological risk stratification. In patients ≥60 yr of age, only half doses of MMF (500 mg bid or 360 mg bid of mycophenolate) were administered (29). Early steroid withdrawal was performed in low-risk patients, whereas steroids were continued in high immunological risk patients such as patients receiving retransplants, patients with a current PRA level >20%, and patients experiencing DGF. Post-transplant management
All patients received surgical site prophylaxis with a first-generation cephalosporin for 24 h, antifungal prophylaxis with nystatin or fluconazole for 1–2 months, and anti-Pneumocystis prophylaxis with sulfamethoxazole–trimethoprim (dapsone if allergic to sulfa) for at least 12 months. Antiviral prophylaxis consisted of oral valganciclovir for 3–6 months, depending on donor and recipient cytomegalovirus (CMV) serologic status. Specifics regarding drug dosing and duration have been published previously (26–29). Most patients
Kidney transplantation and elderly received aspirin prophylaxis. Treatment of hypertension, hyperlipidemia, anemia, diabetes, and other medical conditions was initiated as indicated, aiming to maintain the blood pressure
