Deceased Donor Kidney Transplantation in Elderly Patients: Is There a Difference in Outcomes?

Deceased Donor Kidney Transplantation in Elderly Patients: Is There a Difference in Outcomes? R.F. Saidi, P.T. Kennealey, N. Elias, T. Kawai, M. Hertl, M. Farrell, N. Goes, C. Hartono, N. Tolkoff-Rubin, A.B. Cosimi, and D.S.C. Ko ABSTRACT Introduction. There is a paucity of data on long-term outcomes of older kidney recipients. Our aim was to compare the early and long-term outcomes of deceased donor kidney transplantation in patients aged ⱖ60 years with outcomes in younger recipients. Materials and Methods. From 1998 to 2005, we performed 271 deceased donor kidney transplants. There were 76 recepients (28.1%) ⬎60 years old. Older candidates were carefully selected based on their physiologic, cardiac, and performance status. Demographic data, including clinical characteristics, early complications, mortality, and patient and graft survival rates, were collected and analyzed. Results. Older patients had comparable perioperative mortality and morbidity, incidence of delayed graft function (DGF), length of stay, and readmissions compared with younger patients. The rates of acute rejection and major infections were also comparable between the 2 study groups. Among older recipients, 25/76 (32.1%) patients received extended criteria donor kidneys compared with only 35/195 (17.9%) of younger patients (P ⬍ .001). Nevertheless, equivalent 1-, 3-, and 5-year allograft survival rates were observed in elderly and young patients; 91.5% versus, 92.5%, 78.5% versus 81.9%, and 75.6% versus 78.5%, respectively. Overall patient survival was also comparable in both groups. Conclusion. Kidney transplantation in appropriately selected elderly recipients provides equivalent outcomes compared with those observed in younger patients. These observations support the notion that older recipients should not lose access to deceased donor kidney transplantation in the effort to achieve a perceived gain in social utility.

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HE PREVALENCE and incidence of end-stage renal disease (ESRD) in the United States have expanded as expected life spans increase. Today, patients ⬎60 years of age account for ⬎53% of the ESRD population requiring renal replacement therapies.1 Hemodialysis (HD) is the most commonly used modality of renal replacement therapy in these patients, but HD is associated with significant morbidity, mortality, and poor quality of life. Kidney transplantation, therefore, is the treatment of choice for all ESRD patients, although the severe donor organ shortage makes this treatment impossible for many suitable candidates. Before the advent of nonselective immunosuppressive regimens, renal transplantation was not advocated as treatment for ESRD in patients ⬎60 because of less favorable graft and patient survival rates. More recently, however, it has been shown that patient survival is prolonged and even increased among older

transplanted patients as well, in comparison with comparable hemodialyzed patients awaiting transplantation.2– 4 Between 1991 and 1997 in the United States, renal transplantation in patients ⬎60 years of age provide a 61% decrease in long-term risk of death resulting in an additional 4-year life expectancy, as compared with those patients remaining on hemodialysis.3 However, few data on long-term follow-up in elderly transplant recipients are available and yet the ever increasing proportions of potential transplant candidates From the Department of Surgery, Transplantation Unit (R.F.S., P.T.K., N.E., T.K., M.H., M.F., A.B.C., D.S.C.K.), and the Renal Unit (N.G., C.H., N.T.-R.), Massachusetts General Hospital, Boston, Massachusetts. Address reprint requests to Dicken S. C. Ko, MD, Massachusetts General Hospital, Blake 655, 55 Fruit Street, Boston, MA 02114. E-mail: [email protected]

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0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.08.127

Transplantation Proceedings, 40, 3413–3417 (2008)

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being added to the United Network for Organ Sharing (UNOS) deceased donor kidney recipient list are older patients. In this retrospective study, we report a single-center, long-term follow-up of kidney transplantation in patients ⬎60 years. The aims of this study were to determine whether long-term patient and graft survival rates in this cohort could support a policy of continued equitable allocation of deceased donor kidneys to appropriately selected ESRD patients ⬎60 years old and to identify which factors played a role in long-term graft and patient survival. METHODS We conducted a retrospective analysis of a prospectively collected database of all deceased donor (DD) kidney transplants performed in adult recipients at Massachusetts General Hospital from January 1, 1998, through December 31, 2005. The only exclusions were pediatric patients (⬍20 years of age), simultaneous kidney–pancreas transplantation, other multi-organ transplants (heart– kidney, liver– kidney), and living donor kidney allograft recipients. A total of 271 DD kidney transplants met the entry criteria of which 163 (60.1%) were from standard criteria donors (SCD), 53 (20.3%) extended criteria donors (ECD), and 53 (19.6%) donation after cardiac death (DCD). There were 76 recipients (28.1%) who were ⬎60 years old. ECDs were defined by the UNOS criteria as all DDs ⬎60 years old as well as DDs 50 –59 years of age with ⱖ2 of the following comorbidities: (1) history of hypertension, (2) cerebrovascular cause of brain death, or (3) terminal serum creatinine (SCr) level ⬎1.5 mg/dL. DCDs included all donors for whom cardiopulmonary measures were discontinued before the patient progressed to cardiac arrest. Donor kidney biopsy was regularly used in the evaluation of preexisting and terminal parenchymal pathology in ECD donors. A biopsy showing ⬎20% glomerulosclerosis or moderate to severe tubular, interstitial, or vascular changes was deemed at our center to be a contraindication to kidney utilization. All ECDs and, whenever possible, DCD kidneys were placed on a pulsatile perfusion apparatus to potentially minimize preservation injury. Although pump parameters were not exclusively used to discard kidneys, a flow rate ⬎80 mL/min and a resistance ⬍0.40 mmHg after a minimum of 6 hours on the perfusion apparatus were considered to be reasonable thresholds for utilization. For purposes of this study, any DD that was not categorized as ECD or DCD criteria was defined as an SCD. Delayed graft function (DGF) was defined as the need for dialysis in the first week posttransplant. Renal allograft loss was defined as death with a functioning graft, allograft nephrectomy, resumption of dialysis, or return to the pretransplant SCr level in recipients who had undergone preemptive transplantation. All transplant candidates were evaluated with comprehensive pretransplant medical, surgical, and psychosocial evaluations with emphasis on the cardiovascular system and any other nonrenal organ failure to determine operative risks. Older candidates were carefully selected based on their physiologic, cardiac, and performance status. They undergo cardiac stress tests and echocardiograms, and are evaluated accordingly with coronary angiograms to rule out lesions that can be addressed. Prior coronary revascularizations are also reevaluated to ensure the appropriateness of their candidacy. Any comorbidities, such as pulmonary, history of cancers, and strokes, are carefully evaluated to ensure that they are acceptable for undergoing renal transplantation. Moreover, their

SAIDI, KENNEALEY, ELIAS ET AL physical activity level, social independence, and functional capacity are all evaluated by our multidisciplinary team to ensure that a posttransplant supportive environment is present. We modify immunosuppression in the older group to minimize calcineurin inhibitor toxicities with slightly lower levels, reduce prednisone to the lowest even with complete withdrawal, and minimize the bone marrow toxicities of the antimetabolites immunosuppressives. All patients who were offered an ECD kidney underwent a standardized informed consent process. Listing patients for an ECD kidney neither mandated nor restricted them to receiving an ECD kidney, as the decision to accept any kidney, whether from an ECD or SCD, is reaffirmed at the time of the offer with informed consent. At the time of transplantation, patients were selected on the basis of blood type compatibility, waiting time, human leukocyte antigen (HLA)-matching, a negative cross-match, and special listing for ECD (when applicable) in accordance with UNOS guidelines. All DD kidney transplant patients received depleting antibody induction using rabbit antithymocyte globulin at a dose of 1.5 mg/kg per day based on actual body weight. The first infusion was begun before allograft reperfusion intraoperatively; subsequent infusions were administered at postoperative days 1 and 2. Depending on initial graft function, 1–2 more doses were administered to enable a delay in initiating tacrolimus (TAC). Maintenance immunosuppression consisted of TAC, mycophenolate mofetil (MMF), and tapering doses of steroids. The administration of TAC was delayed until the patient had exhibited a diuresis and a declining SCr level to ⬍5.0 mg/dL. Target 12-hour TAC trough levels were based on donor quality and recipient immunologic risk but typically ranged from 8 to 12 ng/mL. All patients received surgical site prophylaxis with a firstgeneration cephalosporin for 24 hours, antifungal prophylaxis with clotrimazole for 5 days, and anti-Pneumocystis prophylaxis with sulfamethoxazole/trimethoprim for 6 months. The prophylaxis regimen was tailored if there was a history of allergy to standard protocol drugs. Antiviral prophylaxis consisted of oral valganciclovir for 4 – 6 months if either the donor or the recipient cytomegalovirus (CMV) serologic status was positive. Oral famciclovir was used if both donor and recipient serologies were negative. In the event of donor CMV positivity and recipient CMV negativity, the antiviral prophylaxis continued to 1 year posttransplant and CMV antigenemia assay was used to detect subclinical replication that might dictate length of prophylaxis therarpy. Before valganciclovir become commercially available (June 2001), oral ganciclovir 1000 mg PO TID was used. Univariate analysis was performed by the unpaired t-test for continuous variables, the ␹2 test for categorical variables, and the Fisher exact test when data were sparse. Unadjusted actual patient and graft survival rates were reported. Patient and graft survival curves were also computed using the Kaplan–Meier method and compared using the log-rank test. Categorical data were summarized as proportions and percentages, and continuous data were summarized as means and standard deviations. P ⬍ .05 was considered significant.

RESULTS

Of the 76 patients (28.1%) who were ⬎60 years old, 25 (32.1%) received ECD, 14 DCD, and 37 SCD kidneys. Of 195 younger recipients, only 35 (17.9%) received ECD kidneys (P ⬍ .001).

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Table 1. Donor and Recipient Characteristics*

Donor age Donor BMI Donor HTN Terminal serum Cr CIT (hr) ECD Recipient age (mean) Recipient gender: male

⬍60 Years (n ⫽ 195)

⬎60 Years (n ⫽ 76)

48.2 ⫾ 7.2** 27.4 ⫾ 7.4 14.6% 0.9 ⫾ 0.29 15.9 ⫾ 7.4 15.4% 46 111 (56.9%)

52.1 ⫾ 8.6** 25.5 ⫾ 6.7 27.3% 1.01 ⫾ 0.42 16.5 ⫾ 6.8 32.1%** 68 41 (53.9%)

Abbreviations: BMI, body mass index; CIT, cold ischemic time; Cr, creatinine; ECD, extended criteria donor; HTN, hypertension. *Mean ⫾ standard deviation. **P ⬍ .01.

Donor, recipient, and allograft characteristics are summarized in Table 1. Because there were more older recipients who received ECD allografts, donor age was higher in these patients and more donors had a history of hypertension. However, donor body mass index (BMI) donor terminal SCr levels, and cold ischemia times were comparable. Initial and subsequent graft function, perioperative mortality, and resource utilization were similar in both age groups. Mean SCr at 1 month in recipients ⬎60 years old was 1.5 mg/dL compared with 1.3 mg/dL in younger recipients (P ⬎ .05). Mean Scr at 12 and 24 months in older groups was comparable with younger groups; 1.5 and 1.6 versus 1.4 and 1.5 mg/dL, respectively (P ⬎ .05). The rate of DGF of ECD kidney recipients in the older group was higher (Table 2; 23.4% vs 20.1%, respectively, P ⬍.05). The incidence of acute rejection (14.7% vs 13.6%), length of stay (6.1 vs 5.8 days), and 90-day readmission rate (22.4% vs 20.6%) were comparable between the 2 groups (Table 2). Early and long-term allograft and patient survival were also comparable in both groups. DISCUSSION

According to the US Census Bureau, Americans in the 65– 84 years of age range constituted 10.9% of the population in 2000; by 2050, they are projected to make up 15.7%.5 The demographics of ESRD demonstrate a constant increase in the age of new patients starting renal replacement therapy every year.1 With the aging of the American population, further growth in the population of elderly patients with ESRD is clearly anticipated. Approximately 160,000 patients in the United States ⬎65 years (and ⬎70,000 ⬎75 years) currently receive renal replacement therapy.1 This group of elderly patients, who are either on dialysis or have a functioning kidney transplant, represents ⬎50% of patients in the ESRD program. Of the 94,256 patients on the waiting list as of December 29,2006, 13,472 (14.3%) are ⱖ65 years of age and 42,050 (44.6%) are 50 – 64 years of age.1 Kidney transplantation is the preferred treatment for most patients with ESRD because it is associated with greater longevity and better quality of life compared with HD.2 Some previous studies have shown a significantly

longer life expectancy is extended to older patients (⬎60 years) after DD kidney transplantation compared with similar older patients on the waiting list.3 Thus, despite their limited life expectancy, patients ⬎60 years old seem to derive comparable benefits from renal transplantation, as documented by the excellent graft survival rate reported in our study. Patient and graft survivals after a 5-year follow-up in this transplanted elderly population were comparable with those observed in younger recipients. Similarly, early patient and allograft survival, incidences of DGF and rejection, length of stay, and readmission rates were comparable in both groups. In this study, older recipients had a much higher rate of receiving ECD kidneys (32.1% vs 15.4%), but experienced similar rates of short- and long-term allograft and patient survivals and resource utilization compared with younger recipients. Overall, elderly recipients seem to do equally well with either ECD or SCD kidneys. Review of our experience emphasizes that elderly patients have the potential for additional quality years of life after DD kidney transplantation. The average 70-year-old patient on dialysis in the United States lives another 3 years, as opposed to 13.4 years for a 70-year-old in the general population.1 Transplantation provides better quality of life than dialysis for such patients. Moreover, kidney transplantation is more cost effective than dialysis.2– 4 Our observations confirm those of Rao et al6 from the Scientific Registry of Transplant Recipients (SRTR), which evaluated kidney transplantation in elderly patients ⬎70 years of age. They showed survival in the elderly after DD kidney transplantation was significantly greater than that achieved by candidates who remained on the waiting list. The greatest benefit of transplantation was identified among elderly patients with a primary diagnosis of hypertension or diabetes. Among dialysis patients ages ⱖ70 years, transplantation was associated with a 41% lower risk of death compared with the survival of comparable candidates on the waiting list.7–11 A similar study from Queensland, Australia,11,12 but with a slightly younger patient population (the mean age of recipients, 65.8 years) reported a 76% decrease in mortality risk for transplant recipients compared with those who remained on the waiting list. However, not all studies have found transplantation to Table 2. Comparing Early and Long-Term Outcomes of Kidney Transplantation in Elderly and Young Patients

Perioperative mortality Delayed graft function Time (d) to Cr ⬍3 (mg/dL) Acute rejection Length of stay (d) Readmission 5-Year graft survival 5-Year patient survival

ⱖ60 Years old (n ⫽ 6)

⬍60 years (n ⫽ 95)

P

1.3% 23.4% 5.6 14.7% 6.1 22.4% 75.6% 88.2%

1.02% 20.1% 5.2 13.6% 5.8 20.6% 78.5% 89.7%

NS NS NS NS NS NS NS

Abbreviations: Cr, creatinine; NS, not significant.

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confer a survival benefit for the elderly. In their report from the registry data of Catalonia, Bonal et al13 reported equivalent survival for dialysis and transplantation in patients ages 65–70 years. Data from Finland suggest worse survival outcomes for patients ⬎60 years old after renal transplantation compared with the waiting list cohort remaining on dialysis.14 Our data disagree with these studies, presumably because of our vigorous transplant candidacy selection and also a robust optimization of comorbidities to minimize operative risks, as well as promoting their health and wellness. In our experience, older recipients (ⱖ60 years) composed 28.1% of our DD kidney transplantation population, ECDs accounted for nearly 20.3% of our DD kidney transplant activity, with older recipients having a much higher rate of receiving ECD kidneys but experienced similar rates of short- and long-term allograft and patient survival as those observed in younger recipients. Moore et al15 recently looked at their experience with 114 patients ⬎60 years old after kidney transplantation. They also noticed comparable outcomes when comparing older with younger recipients, despite the fact that more patients in older group received ECD allografts (54% vs 39%).15 In 2000, the US Department of Health and Human Services (DHHS) implemented a “Final Rule” legislation that established a regulatory framework for the structure and operations of the Organ Procurement and Transplantation Network (OPTN). Under the terms of the Final Rule, policies are developed through the OPTN committees and Board of Directors and become binding upon OPTN members when approved by the Secretary of the DHHS. The rule promoted the development of new guidelines for DD kidney allocation in ways that provide the greatest social equity, clinical utility, and human justice. To achieve these noble goals, the transplant community is left to wrestle with how to interpret and define these elements such that the issues are balanced. This formidable task has troubled our community over the last 3 years. Proponents of utility emphasize providing the greatest benefit to the most patients for the longest time, thereby promoting the longevity of a scare nonrenewable resource. This weighting of priorities would be a significant departure from the previous allocation policy, which considers justice and utility in organ allocation more prominenthy. Critics of such an emphasis on social utility argue that organ allocation infringes on the basic premise of individual rights of equal access to health care in this country. Certain groups, including the highly sensitized, retransplants, diabetics, pediatrics and adolescent patients, the elderly, and minorities, might be disproportionately affected depending on the modeling of the future allocation system. In our review, however, we found that transplant recipients ⬎60 years old achieved similar survival rates to those observed in younger patients. Thus, the notion that allocating a DD kidney to an elderly patient will not provide a sufficient increase in life-years from transplant is only correct if the

SAIDI, KENNEALEY, ELIAS ET AL

twilight years of someone’s life are considered to be less valuable, less worthy, and less important than those of younger individuals. Overutilization or weighting of this numeric basis intrinsic to the life-years gained analysis, despite satisfying the demands of social utility, can potentially negate the issue of justice, individual worth, and self-value. Such “values and worth” do have medical benchmarks that we can apply to a formula to determine or execute a sequence of algorithms to derive. Herein lies the difficulty and the opposition to apply justice to a mathematical medical model. Of what weight are we putting justice into the equation? Isn’t each case of social justice potentially debatable? Can’t each be surmised as a generality? “Utility” versus “equity” can be mutually exclusive and divisive principles. The Final Rule is a set of challengeable guidelines that has a presumptious title, which predictably and ultimately cannot convey finality. Our results as well as those from other studies16 –25 suggest that age per se is not a contraindication to renal transplantation. We should consider every patient ⬎60 years as a potential recipient in their evaluation. If they meet the medical and surgical criteria, their candidacy should not be denied. Their survival can be improved by a careful selection and thoroughly assessing cardiac and infectious risk as well as a tailored immunosuppression. In conclusion, older patients with ESRD present a significant challenge and many management issues remain subject to further elucidation and studies. The results of this review focusing on the results of transplantation in the older population suggest that allograft and patient survival characteristics are favorable in appropriately selected recipients. With the prevailing shortage of organs, kidney transplantation should clearly not be used indiscriminately in the elderly, but neither should the elderly be denied access simply on the basis of age. Careful assessment of “biological” rather than “chronological” age should be used on an individual basis rather than establishing age limits. Our experience as well as that of others cited in this discussion hopefully will bring further awareness to the development of a new kidney allocation policies in the United States. Elderly patients simply cannot be denied or have reduced access to DD kidney transplantation. REFERENCES 1. USRDS 2004 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2004 2. Ismail N, Hakim RM, Oreopoulos DG, et al: Renal replacement therapies in the elderly: part I. Hemodialysis and chronic peritoneal dialysis. Am J Kidney Dis 22:759, 1993 3. Cameron JI, Whiteside C, Katz J, et al: Differences in quality of life across renal replacement therapies: a meta-analytic comparison. Am J Kidney Dis 35:629, 2000 4. Oniscu GC, Brown H, Forsythe JL: How old is old for transplantation? Am J Transplant 4:2067, 2004 5. US Census Bureau: U.S. Interim Projections by Age, Sex, Race, and Hispanic Origin. Available: http://www.census.gov. Accessed March 18, 2004

OUTCOMES IN ELDERLY RECIPIENTS 6. Rao PS, Merion RM, Ashby VB, et al: Renal transplantation in elderly patients older than 70 years of age: results from the Scientific Registry of Transplant Recipients. Transplantation 83: 1069, 2007 7. Fauchald P, Albertchtsen D, Leivestad T, et al: Renal replacement therapy in elderly patients. Transplant Int 1:131, 1988 8. Ismail N, Hakim RM, Helderman JH: Renal replacement therapies in the elderly: part II. Renal Transplantation. Am J Kidney Dis 23:1, 1994 9. Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation and recipients of a first cadaveric transplant. N Engl J Med 341:1725, 1999 10. Pirsch JD, Statta RJ, Armbrust MJ et al: Cadaveric renal transplantation with cyclosporine in patients more than 60 years of age. Transplantation 47:259, 1989 11. Ponticelli C: Should renal transplantation be offered to older patients? Nephrol Dial Transplant 15:315, 2000 12. Johnson DW, Herzig K, Purdie D, et al: A comparison of the effects of dialysis and renal transplantation on the survival of older uremic patients. Transplantation 69:794, 2000 13. Bonal J, Cleries M, Vela E: Transplantation versus haemodialysis in elderly patients. Renal Registry Committee. Nephrol Dial Transplant 12:261, 1997 14. Kyllonen L, Ahonen J: Kidney transplantation in the elderly in Finland. Transplant Proc 22:163, 1990 15. Moore PS, Farney AC, Hartmann EL, et al: Experience with deceased donor kidney transplantation in 114 patients over age 60. Surgery 142:514, 2007

3417 16. Benedetti E, Matas AJ, Hakim N, et al: Renal transplantation for patients 60 years of age or older: a single institution experience. Ann Surg 220:445, 1994 17. Tesi RJ, Elkhamamas EA, Davies EA, et al: Renal transplantation in older people. Lancet 343:461, 1994 18. Cantarovich D, Baatrad R, Baranger T, et al: Cadaveric renal transplantation after 60 years of age: a single center experience. Transplant Int 7:33, 1994 19. Morris PJ, Johnson RJ, Fuggle SV, et al: Analysis of factors that affect outcome of primary cadaveric renal transplantation in the UK. Lancet 354:1147, 1999 20. Alexander JW, Bennett LE, Breen TJ: Effect of donor age on outcome of kidney transplantation. Transplantation 57:871, 1994 21. Terasaki PL, Gjertson DW, Cecka JM, et al: Significance of the donor age effect on kidney transplants. Clin Transplant 11:366, 1997 22. Cecka JM, Terasaki PI: Optimal use for older donors kidneys: older recipients. Transplant Proc 27:801, 1995 23. Basar H, Soran A, Shapiro R, et al: Renal transplantation in recipients over the age of 60: the impact of donor age. Transplantation 67:1191, 1999 24. Shimmura H, Tanabe K, Ishikawa N, et al: Influence of donor renal reserve on the long-term results of living kidney transplantation from elderly donors. Transplant Proc 31:2874, 1999 25. Kumar MS, Panigrahi D, Dezii CM, et al: Long-term function and survival of elderly donor kidneys transplanted into young adults. Transplantation 65:282, 1998