© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2015: 29: 167–175 DOI: 10.1111/ctr.12481
Clinical Transplantation
Review Article
Clinical issues in renal transplantation in the elderly Hod T, Goldfarb-Rumyantzev AS. Clinical issues in renal transplantation in the elderly.
Tammy Hoda,b and Alexander S. Goldfarb-Rumyantzevb,c a
Abstract: Kidney transplantation is the best renal replacement therapy option and is superior to dialysis in elderly end-stage renal disease (ESRD) patients. Furthermore, the outcome of transplantation in the elderly is comparable to younger patients in terms of allograft survival. The exact nature of this phenomenon is not completely clear. As the elderly population continues to grow, it becomes more important to identify specific issues associated with kidney transplantation. In particular, elderly transplant recipients might have a lower chance of acute rejection as their immune systems seem to be less reactive. This might predispose elderly recipients to greater risk of post-transplant infectious complications or malignancies. Furthermore, due to differences in pharmacokinetics, elderly recipients might require lower doses of immunosuppressive medication. As the main cause of graft failure in the elderly is death with a functioning graft and also considering the scarcity of donor organs, it might make sense to recommend transplanting elderly recipients with extended criteria donor kidneys. This approach would balance shorter patient survival compared to younger recipients. In conclusion, old age should not preclude ESRD patients from kidney transplantation. However, specific differences that have to do with immunosuppression and other aspects of managing elderly transplant recipients should be considered.
Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, bDivision of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School and cTransplant Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA Key words: elderly – end-stage renal disease – outcome – transplantation Corresponding author: Alexander S. Goldfarb-Rumyantzev, MD, PhD, Division of Nephrology, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, FA-832 Boston, MA 02215, USA. Tel.: +617-632-9880; fax: +617-632-9890; e-mail: [email protected] Conflict of interest: None. Accepted for publication 3 November 2014
Advanced age is no longer a barrier to kidney transplantation; to the contrary, the upper age limit to receive a kidney transplant has progressively risen over the years and people aged 60–70 are not considered “old” in a biologic sense. In fact, there are few distinct groups within the aging population. For example, the very old are classed as being (≥75 yr), the elderly are (≥70 yr), and the seniors are (60–69 yr). While the aging population is growing rapidly, there is a simultaneous growth in those requiring renal replacement therapy both in Europe and in the United States (1, 2). For a number of years, dialysis has been the preferred treatment for older uremic patients, based on the convenience and safety of this procedure, while kidney transplantation has been regarded with skepticism owing to the increased risk of complica-
tions. This concept is no longer valid, as several studies have shown superior long-term survival and quality of life following transplantation compared with continuation of dialysis in patients of advanced age (3–6), and even in patients older than 70 yr (7). While age plays an important role in the selection of transplant candidates, older patients are carefully selected with their health status undergoing greater scrutiny compared to younger recipients and the healthiest ones being added to the transplant list. Given these findings and procedures, frailty as a measure of physiologic reserve (or “physiologic age”) (8) would probably be a better potential predictor of kidney transplant outcome than would chronological age. Unfortunately, information regarding the relationship between frailty and renal transplant outcome is
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very limited in the literature, while age on the other hand is factual and does not require additional calculations. This possibly explains the fact that age has been studied widely as a clinical predictor of kidney transplant outcome. Therefore, in this review, we aimed at describing the clinical role of age. That being said, the heterogeneity of the population in a given age group should be noted. Wolfe et al. demonstrated in 1999 that primary deceased donor transplantation led to an increased cumulative survival rate after the first year posttransplantation with an increased projected life span of five yr for patients aged 60–74 yr without diabetes and three yr for the same age group patients with diabetes as compared with patients on the maintenance hemodialysis (4). Furthermore, in another study from 2005, the expected survival rates for kidney transplant wait-listed dialysis patients aged ≥70 yr were 4.5 yr but were 8.2 yr for those who received a kidney transplant (9). Thus, as an increasing number of older patients have become candidates for kidney transplantation, the outcomes of renal transplantation in the aging population remain understudied (Table 1). In this review, we seek to better define the outcomes of renal transplantation in this vulnerable population and specifically those related to acute rejections (ARs), graft survival, patient sur-
vival, immunosuppressive treatment, and advanced donor age. Acute rejection in the elderly
The incidence of AR was studied in elderly recipients in comparison to younger ones (Table 2). Generally, fewer AR episodes develop in elderly recipients than in the younger group (10–13). Mendonca et al. (13) demonstrated a significantly higher incidence of AR in the younger adults aged 50–59 (37.6%) compared with those ≥60 yr of age (22.7%). Similarly, another retrospective analysis (14) revealed a significantly higher incidence of rejection in recipients between ages 18 and 59 (24.2%) compared with recipients older than 60 yr of age (7.0%). However, these reports were published in the mid-2000s, and the incidence of AR has decreased dramatically across the board in the transplant population since then. Of note is the finding that a difference in AR rate was found between subgroups of the aging patients. In a European population of recipients older than 70, AR rates of 35% were found within the first 12 wk of post-transplantation as opposed to 44% in patients aged 60–69 yr and 45% among their younger control group aged 40–54 yr (15).
Table 1. Summary of studies comparing the outcome between ESRD patients with renal transplant vs. those remaining on dialysis References
Study design
Results
Port et al. (1993) (3)
Patient mortality risk was analyzed by treatment modality from ESRD onset (n = 5020), to wait-listing for renal transplant (n = 1569), to receiving a cadaveric first transplant (n = 799) Longitudinal study of mortality in 228 552 ESRD patients, where 46 164 were placed on a waiting list for transplantation, and 23 275 received a first cadaveric transplant
Mortality risk following renal transplantation was initially increased, but there was a long-term survival benefit compared with similar patients on dialysis Mortality ratio for ESRD patients awaiting transplantation was lower compared to all patients on dialysis. Relative risk of death in the first two wk of post-transplant was 2.8 times as high as that for patients on dialysis but much lower at 18 months of post-transplant (RR 0.32, p < 0.001) Transplant recipients had a lower long-term RR of death, and the risk reduction was greatest in recipients with longer waiting times (RR of death 12 months after transplantation for recipients with waiting times of zero, one, two, three yr was 0.49, 0.43, 0.38, 0.34, p = 0.0006) An increased mortality in the first year after transplantation compared to wait-listed patients. Patients starting dialysis between 1990 and 1999 had no significant long-term benefits of transplantation. However, there is a substantial long-term benefit of transplantation among those starting dialysis after the year 2000; HR for death 0.40 (0.19–0.83), p = 0.014
Wolf et al. (1999) (4)
Gill et al. (2005) (9)
Heldal et al. (2010) (7)
Longitudinal study of mortality among 63 783 transplant candidates on dialysis to determine the RR of death and increase in life expectancy among subjects who received a first cadaveric transplant compared to subjects who had equivalent waiting times but remained on dialysis Survival rates of 286 ESRD patients >70 yr who were analyzed and comparisons were made between those who received a transplant (n = 233) and those who did not, and further between two time points
HR, hazard ratio; ESRD, end-stage renal disease.
168
Renal transplant outcome in the elderly Table 2. Reports demonstrating the association between age and acute rejection incidence References
Study design
Results
Tesi et al. (1994) (6)
Outcome analysis of 1222 recipients and comparison between those 65 years) kidney transplant recipients. Transplantation 2008: 86: 1379. 55. PATEL SJ, KNIGHT RJ, SUKI WN et al. Rabbit antithymocyte induction and dosing in deceased donor renal transplant recipients over 60 yr of age. Clin Transplant 2011: 25: E250.
56. RAMALHO AL, CUSTODIO FB, TOKUDA BM et al. Clinical and histopathologic comparative analysis between kidney transplant recipients from expanded-criteria donors and standard-criteria donors. Transplant Proc 2013: 45: 3234. 57. WOLFE RA, MCCULLOUGH KP, LEICHTMAN AB. Predictability of survival models for waiting list and transplant patients: calculating LYFT. Am J Transplant 2009: 9: 1523. 58. WOLFE RA, MCCULLOUGH KP, SCHAUBEL DE et al. Calculating life years from transplant (LYFT): methods for kidney and kidney-pancreas candidates. Am J Transplant 2008: 8: 997. 59. RAO PS, SCHAUBEL DE, GUIDINGER MK et al. A comprehensive risk quantification score for deceased donor kidneys: the kidney donor risk index. Transplantation 2009: 88: 231. 60. VAN WALRAVEN C, AUSTIN PC, KNOLL G. Predicting potential survival benefit of renal transplantation in patients with chronic kidney disease. CMAJ 2010: 182: 666. 61. HANF W, PETRUZZO P, MEAS-YEDID V, BERTHILLER J, MARTIN X, MORELON E et al. Dual kidney transplantation from uncontrolled deceased donors after cardiac arrest: a possible option. Int J Urol 2014: 21: 204. 62. KLAIR T, GREGG A, PHAIR J, KAYLER LK. Outcomes of adult dual kidney transplants by KDRI in the United States. Am J Transplant 2013: 13: 2433. 63. EKSER B, FURIAN L, BROGGIATO A et al. Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients. Am J Transplant 2010: 10: 2000. 64. REMUZZI G, CRAVEDI P, PERNA A et al.; Dual Kidney Transplant Group. Long-term outcome of renal transplantation from older donors. N Engl J Med 2006: 354: 343. 65. OJO AO, HANSON JA, MEIER-KRIESCHE H et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001: 12: 589. 66. KLOP KW, DOLS LF, WEIMAR W, DOOPER IM, IJZERMANS JN, KOK NF. Quality of life of elderly live kidney donors. Transplantation 2013: 96: 644. 67. MERION RM, ASHBY VB, WOLFE RA et al. Deceaseddonor characteristics and the survival benefit of kidney transplantation. JAMA 2005: 294: 2726. 68. FRITSCHE L, HORSTRUP J, BUDDE K et al. Old-for-old kidney allocation allows successful expansion of the donor and recipient pool. Am J Transplant 2003: 3: 1434. 69. COHEN B, SMITS JM, HAASE B, PERSIJN G, VANRENTERGHEM Y, FREI U. Expanding the donor pool to increase renal transplantation. Nephrol Dial Transplant 2005: 20: 34. 70. ARNS W, CITTERIO F, CAMPISTOL JM. ‘Old-for-old’–new strategies for renal transplantation. Nephrol Dial Transplant 2007: 22: 336. 71. OPPENHEIMER F, ALJAMA P, ASENSIO PEINADO C, BUSTAMANTE BUSTAMANTE J, CRESPO ALBIACH JF, GUIRADO PERICH L. The impact of donor age on the results of renal transplantation. Nephrol Dial Transplant 2004: 19(Suppl 3): iii11. 72. IRISH WD, ILSLEY JN, SCHNITZLER MA, FENG S, BRENNAN DC. A risk prediction model for delayed graft function in the current era of deceased donor renal transplantation. Am J Transplant 2010: 10: 2279.
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Clin Transplant 2015: 29: 167–175 DOI: 10.1111/ctr.12481
Clinical Transplantation
Review Article
Clinical issues in renal transplantation in the elderly Hod T, Goldfarb-Rumyantzev AS. Clinical issues in renal transplantation in the elderly.
Tammy Hoda,b and Alexander S. Goldfarb-Rumyantzevb,c a
Abstract: Kidney transplantation is the best renal replacement therapy option and is superior to dialysis in elderly end-stage renal disease (ESRD) patients. Furthermore, the outcome of transplantation in the elderly is comparable to younger patients in terms of allograft survival. The exact nature of this phenomenon is not completely clear. As the elderly population continues to grow, it becomes more important to identify specific issues associated with kidney transplantation. In particular, elderly transplant recipients might have a lower chance of acute rejection as their immune systems seem to be less reactive. This might predispose elderly recipients to greater risk of post-transplant infectious complications or malignancies. Furthermore, due to differences in pharmacokinetics, elderly recipients might require lower doses of immunosuppressive medication. As the main cause of graft failure in the elderly is death with a functioning graft and also considering the scarcity of donor organs, it might make sense to recommend transplanting elderly recipients with extended criteria donor kidneys. This approach would balance shorter patient survival compared to younger recipients. In conclusion, old age should not preclude ESRD patients from kidney transplantation. However, specific differences that have to do with immunosuppression and other aspects of managing elderly transplant recipients should be considered.
Center for Vascular Biology Research, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, bDivision of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School and cTransplant Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA Key words: elderly – end-stage renal disease – outcome – transplantation Corresponding author: Alexander S. Goldfarb-Rumyantzev, MD, PhD, Division of Nephrology, Beth Israel Deaconess Medical Center, 185 Pilgrim Rd, FA-832 Boston, MA 02215, USA. Tel.: +617-632-9880; fax: +617-632-9890; e-mail: [email protected] Conflict of interest: None. Accepted for publication 3 November 2014
Advanced age is no longer a barrier to kidney transplantation; to the contrary, the upper age limit to receive a kidney transplant has progressively risen over the years and people aged 60–70 are not considered “old” in a biologic sense. In fact, there are few distinct groups within the aging population. For example, the very old are classed as being (≥75 yr), the elderly are (≥70 yr), and the seniors are (60–69 yr). While the aging population is growing rapidly, there is a simultaneous growth in those requiring renal replacement therapy both in Europe and in the United States (1, 2). For a number of years, dialysis has been the preferred treatment for older uremic patients, based on the convenience and safety of this procedure, while kidney transplantation has been regarded with skepticism owing to the increased risk of complica-
tions. This concept is no longer valid, as several studies have shown superior long-term survival and quality of life following transplantation compared with continuation of dialysis in patients of advanced age (3–6), and even in patients older than 70 yr (7). While age plays an important role in the selection of transplant candidates, older patients are carefully selected with their health status undergoing greater scrutiny compared to younger recipients and the healthiest ones being added to the transplant list. Given these findings and procedures, frailty as a measure of physiologic reserve (or “physiologic age”) (8) would probably be a better potential predictor of kidney transplant outcome than would chronological age. Unfortunately, information regarding the relationship between frailty and renal transplant outcome is
167
Hod and Goldfarb-Rumyantzev
very limited in the literature, while age on the other hand is factual and does not require additional calculations. This possibly explains the fact that age has been studied widely as a clinical predictor of kidney transplant outcome. Therefore, in this review, we aimed at describing the clinical role of age. That being said, the heterogeneity of the population in a given age group should be noted. Wolfe et al. demonstrated in 1999 that primary deceased donor transplantation led to an increased cumulative survival rate after the first year posttransplantation with an increased projected life span of five yr for patients aged 60–74 yr without diabetes and three yr for the same age group patients with diabetes as compared with patients on the maintenance hemodialysis (4). Furthermore, in another study from 2005, the expected survival rates for kidney transplant wait-listed dialysis patients aged ≥70 yr were 4.5 yr but were 8.2 yr for those who received a kidney transplant (9). Thus, as an increasing number of older patients have become candidates for kidney transplantation, the outcomes of renal transplantation in the aging population remain understudied (Table 1). In this review, we seek to better define the outcomes of renal transplantation in this vulnerable population and specifically those related to acute rejections (ARs), graft survival, patient sur-
vival, immunosuppressive treatment, and advanced donor age. Acute rejection in the elderly
The incidence of AR was studied in elderly recipients in comparison to younger ones (Table 2). Generally, fewer AR episodes develop in elderly recipients than in the younger group (10–13). Mendonca et al. (13) demonstrated a significantly higher incidence of AR in the younger adults aged 50–59 (37.6%) compared with those ≥60 yr of age (22.7%). Similarly, another retrospective analysis (14) revealed a significantly higher incidence of rejection in recipients between ages 18 and 59 (24.2%) compared with recipients older than 60 yr of age (7.0%). However, these reports were published in the mid-2000s, and the incidence of AR has decreased dramatically across the board in the transplant population since then. Of note is the finding that a difference in AR rate was found between subgroups of the aging patients. In a European population of recipients older than 70, AR rates of 35% were found within the first 12 wk of post-transplantation as opposed to 44% in patients aged 60–69 yr and 45% among their younger control group aged 40–54 yr (15).
Table 1. Summary of studies comparing the outcome between ESRD patients with renal transplant vs. those remaining on dialysis References
Study design
Results
Port et al. (1993) (3)
Patient mortality risk was analyzed by treatment modality from ESRD onset (n = 5020), to wait-listing for renal transplant (n = 1569), to receiving a cadaveric first transplant (n = 799) Longitudinal study of mortality in 228 552 ESRD patients, where 46 164 were placed on a waiting list for transplantation, and 23 275 received a first cadaveric transplant
Mortality risk following renal transplantation was initially increased, but there was a long-term survival benefit compared with similar patients on dialysis Mortality ratio for ESRD patients awaiting transplantation was lower compared to all patients on dialysis. Relative risk of death in the first two wk of post-transplant was 2.8 times as high as that for patients on dialysis but much lower at 18 months of post-transplant (RR 0.32, p < 0.001) Transplant recipients had a lower long-term RR of death, and the risk reduction was greatest in recipients with longer waiting times (RR of death 12 months after transplantation for recipients with waiting times of zero, one, two, three yr was 0.49, 0.43, 0.38, 0.34, p = 0.0006) An increased mortality in the first year after transplantation compared to wait-listed patients. Patients starting dialysis between 1990 and 1999 had no significant long-term benefits of transplantation. However, there is a substantial long-term benefit of transplantation among those starting dialysis after the year 2000; HR for death 0.40 (0.19–0.83), p = 0.014
Wolf et al. (1999) (4)
Gill et al. (2005) (9)
Heldal et al. (2010) (7)
Longitudinal study of mortality among 63 783 transplant candidates on dialysis to determine the RR of death and increase in life expectancy among subjects who received a first cadaveric transplant compared to subjects who had equivalent waiting times but remained on dialysis Survival rates of 286 ESRD patients >70 yr who were analyzed and comparisons were made between those who received a transplant (n = 233) and those who did not, and further between two time points
HR, hazard ratio; ESRD, end-stage renal disease.
168
Renal transplant outcome in the elderly Table 2. Reports demonstrating the association between age and acute rejection incidence References
Study design
Results
Tesi et al. (1994) (6)
Outcome analysis of 1222 recipients and comparison between those 65 years) kidney transplant recipients. Transplantation 2008: 86: 1379. 55. PATEL SJ, KNIGHT RJ, SUKI WN et al. Rabbit antithymocyte induction and dosing in deceased donor renal transplant recipients over 60 yr of age. Clin Transplant 2011: 25: E250.
56. RAMALHO AL, CUSTODIO FB, TOKUDA BM et al. Clinical and histopathologic comparative analysis between kidney transplant recipients from expanded-criteria donors and standard-criteria donors. Transplant Proc 2013: 45: 3234. 57. WOLFE RA, MCCULLOUGH KP, LEICHTMAN AB. Predictability of survival models for waiting list and transplant patients: calculating LYFT. Am J Transplant 2009: 9: 1523. 58. WOLFE RA, MCCULLOUGH KP, SCHAUBEL DE et al. Calculating life years from transplant (LYFT): methods for kidney and kidney-pancreas candidates. Am J Transplant 2008: 8: 997. 59. RAO PS, SCHAUBEL DE, GUIDINGER MK et al. A comprehensive risk quantification score for deceased donor kidneys: the kidney donor risk index. Transplantation 2009: 88: 231. 60. VAN WALRAVEN C, AUSTIN PC, KNOLL G. Predicting potential survival benefit of renal transplantation in patients with chronic kidney disease. CMAJ 2010: 182: 666. 61. HANF W, PETRUZZO P, MEAS-YEDID V, BERTHILLER J, MARTIN X, MORELON E et al. Dual kidney transplantation from uncontrolled deceased donors after cardiac arrest: a possible option. Int J Urol 2014: 21: 204. 62. KLAIR T, GREGG A, PHAIR J, KAYLER LK. Outcomes of adult dual kidney transplants by KDRI in the United States. Am J Transplant 2013: 13: 2433. 63. EKSER B, FURIAN L, BROGGIATO A et al. Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients. Am J Transplant 2010: 10: 2000. 64. REMUZZI G, CRAVEDI P, PERNA A et al.; Dual Kidney Transplant Group. Long-term outcome of renal transplantation from older donors. N Engl J Med 2006: 354: 343. 65. OJO AO, HANSON JA, MEIER-KRIESCHE H et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001: 12: 589. 66. KLOP KW, DOLS LF, WEIMAR W, DOOPER IM, IJZERMANS JN, KOK NF. Quality of life of elderly live kidney donors. Transplantation 2013: 96: 644. 67. MERION RM, ASHBY VB, WOLFE RA et al. Deceaseddonor characteristics and the survival benefit of kidney transplantation. JAMA 2005: 294: 2726. 68. FRITSCHE L, HORSTRUP J, BUDDE K et al. Old-for-old kidney allocation allows successful expansion of the donor and recipient pool. Am J Transplant 2003: 3: 1434. 69. COHEN B, SMITS JM, HAASE B, PERSIJN G, VANRENTERGHEM Y, FREI U. Expanding the donor pool to increase renal transplantation. Nephrol Dial Transplant 2005: 20: 34. 70. ARNS W, CITTERIO F, CAMPISTOL JM. ‘Old-for-old’–new strategies for renal transplantation. Nephrol Dial Transplant 2007: 22: 336. 71. OPPENHEIMER F, ALJAMA P, ASENSIO PEINADO C, BUSTAMANTE BUSTAMANTE J, CRESPO ALBIACH JF, GUIRADO PERICH L. The impact of donor age on the results of renal transplantation. Nephrol Dial Transplant 2004: 19(Suppl 3): iii11. 72. IRISH WD, ILSLEY JN, SCHNITZLER MA, FENG S, BRENNAN DC. A risk prediction model for delayed graft function in the current era of deceased donor renal transplantation. Am J Transplant 2010: 10: 2279.
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