Key words : Elderly recipient, Extended criteria donor, Renal transplant

Introduction

The prevalence of end-stage kidney disease (ESKD) in the elderly keeps on increasing.¹ Current guidelines recommend kidney transplant (KT) as the best mode of renal replacement therapy for most patients, irrespective of their age.² Advanced age is no longer considered as an absolute contraindication for KT, and the age cutoff used to define the “elderly recipient” has progressively increased.³ According to data, the age of the recipient does not preclude the advantages of KT, such as better survival and quality of life.^4,5

The widening disparity between the number of patients on wait lists and the availability of suitable donor organs has been a major limiting factor for the more widespread adoption of KT in patients with ESKD. The utilization of kidneys from nonstandard donors (NSD) has emerged as a solution for this problem. With regard to KT, extended criteria donors (ECDs) and donors after circulatory death (DCD) are categorized as NSDs. An ECD is defined as a brain dead organ donor (DBD) who is ?60 years of age or a donor aged 51 to 59 years with at least 2 of the following risk factors: hypertension, cerebrovascular cause of death, or terminal creatinine >1.5 mg/dL.⁶

Patients who receive KTs from ECDs or DCDs have better outcomes than those who remain on dialysis. However, when compared with KT from a living donor (LD) or a KT from an SCD, recipients of these marginal allografts have increased risks of complications such as delayed graft function (DGF) and acute rejection.5

Current national organ allocation policies tend to age match donor-recipient pairs, so elderly patients listed for deceased donor KTs are more likely to receive organ offers from ECDs or elderly DCDs.7 Recipients with advanced age are more likely to have comorbidities, and their physiology may not tolerate the added toll of a serious posttransplant complication. Thus, the decision to transplant an elderly recipient with an NSD kidney may not be straightforward. In this retrospective study, we examined the outcomes of such NSD KTs performed at the Royal Liverpool University Hospital in recipients aged ?70 years.

Materials and Methods

Electronic medical records of patients who received a KT at the Royal Liverpool University Hospital from April 1, 2015, through May 31, 2021, were retros-pectively reviewed to identify recipients who were aged ?70 years at the time of transplant. The standard induction immunosuppression regimen was 2 doses of intravenous basiliximab. Sensitized recipients, the presence of 2 mismatches at the HLA DR locus, and those who were transplanted with a DCD organ were preferentially given a single dose of subcutaneous alemtuzumab 30 mg at the induction. Maintenance immunosuppression was with tacrolimus and mycophenolate mofetil. After discharge from the hospital, patients were followed up at transplant or nephrology clinics as outpatients.

Outcomes after KT of those who received a kidney from an NSD donor (group 1) were compared against those who received a kidney from an SCD or LD (group 2). Living donors included related (parents to offspring and sibling to sibling) and nonrelated (spouse to spouse) donors. Delayed graft function was defined as the need for dialysis within the first week of transplant.

Statistical analyses
We analyzed data using SPSS statistical software. We used the Fisher exact test to determine the rela-tionship between 2 variables and the independent sample t test to compare means across the groups. We used Kaplan-Meier survival curves to calculate and compare recipient and graft survival rates. P < .05 was statistically significant.

Results

Recipient and transplant characteristics
During the study period, 670 KTs were conducted at our center, and 67 recipients (10%) were aged ?70 years at the time of transplant. Among those recipients ?70 years of age, most received organs from DCDs (32/67, 47.8%), followed by DBDs (27/67, 40.3%) and LDs (8/67, 11.9%: 2 parent to offspring donations, 4 sibling to sibling donations, and 2 spouse to spouse donations). Group 1 included 54 recipients (80.6%) who had KTs from DCDs (n = 32) or extended criteria DBDs (n = 22), and group 2 included 13 recipients who had KTs from SCDs (n = 5) or LDs (n = 8).

The 2 groups had similar demographic characteristics, such as male-female distribution, mean age, and comorbid conditions. There were no significant differences in the degree of HLA mismatch or the agent used for induction immuno-suppression. The mean cold ischemia time (CIT) was significantly longer for recipients in group 1 (860.3 vs 548.08 min; P = .001). These findings are summarized in Table 1.

Patient and graft survival
The median follow-up duration was 31 months (range, 1-73 months). At the end of follow-up, 19/54 recipients (35.18%) in group 1 and 1/13 recipients (7.69%) in group 2 had died. The commonest cause of death among patients in group 1 was infections (n = 8) followed by cardiovascular causes (n = 7) and malignancies (n = 4). The single patient death recorded in group 2 was due to myocardial infarction. The recipient survival rate was significantly less in group 1 (log rank = 0.037). Table 2 shows overall recipient survival rates at 1, 3, and 5 years posttransplant. Figure 1 depicts the Kaplan-Meier survival curves for recipients in each group.

Death-censored graft survival rates in groups 1 and 2 at the end of follow-up were 88.88% (48/54) and 100% (13/13), respectively. There was no significant difference in graft survival between the groups (log rank = 0.218).

Graft function
There was no statistically significant difference in the mean serum creatinine level across the 2 groups at 3 months, 6 months, and 1 year. However, at 2 years (P = .014) and 3 years (P = .048), a significantly higher mean serum creatinine value was noted in group 1.

Posttransplant complications
The incidence of DGF was significantly greater in group 1 versus group 2 (13/54 vs 0/13; P = .044). Twelve recipients in group 1 were treated for acute rejection, whereas 0 recipients in group 2 had this complication (P = .057). There was no statistically significant difference in the incidence of viral or bacterial infections between the 2 groups (Table 3).

Discussion

The burden of ESKD in the elderly population continues to increase.1 Kidney transplant has been recommended as the optimum mode of renal replacement therapy for selected patients with advanced age. At present, no upper age cutoff has been recommended to exclude a patient with ESKD as a potential KT candidate.² Thus, the number of elderly recipients who are listed for KT has increased, and there is a reciprocal rise in the number of transplants performed in this age group.^8,9 Previous studies have reported encouraging outcomes in KT recipients over 70 years of age, and currently “fit” octogenarians are offered KT.^10,11

To bridge the ever-widening gap between the supply and demand for transplantable organs, the utilization of kidneys from NSDs has increased.⁵ The present national organ allocation policies prefe-rentially offer kidneys retrieved from such NSDs to elderly recipients.^3,7 The rationale behind this practice is to achieve a better match between the life expectancy of the recipient and the donor organ, as kidneys from NSDs have a comparatively lower average length of function.⁷ Another proposed advantage of such allocation is the reduction of waiting time for elderly recipients; elderly recipients are at a higher risk of death if they remain on wait lists for prolonged durations.^3,12

Previous studies have reported conflicting outcomes after NSD KTs in elderly recipients. Rao and colleagues noted a 25% reduction in the mortality risk in recipients ?70 years of age when they were transplanted with ECD kidneys.¹⁰ In another study, Savoye and colleagues reported that ESKD patients aged 60 years or more had better survival after receiving transplants from ECDs compared with remaining on the waiting list.¹³ In contrast, Bonal and colleagues noted that ESKD patients from 65 to 70 years of age had no mortality benefit after transplant.⁹ Another study from Peters-Sengers and colleagues reported that recipients aged ?65 years who received a kidney from an elderly donor had a 5-year mortality rate comparable to those who remained on dialysis.⁷

Our findings suggested that recipients aged 70 years or above who were transplanted with LD or SCD kidneys do better in terms of survival than recipients in the same age group who have received an NSD kidney. The overall graft survival was not significantly different across the 2 groups, but graft function at 2 and 3 years posttransplant was inferior in those transplanted with an NSD kidney. When recipient- and transplant-related factors were compared between the 2 groups, apart from the difference in the source of the donor organs, recipients in group 1 (NSD recipients) had significantly longer CIT and greater incidence of DGF. We believe that these disparities may have contributed to the inferior recipient and graft outcomes seen in group 1. Thus, interventions aimed at limiting the CIT and DGF may improvethe outcomes of NSD transplants in elderly recipients.

The value of limiting CIT has been recognized before by the Eurotransplant Senior Program, which allocates kidneys retrieved from deceased donors aged ?65 to recipients aged ?65 on a regional basis. This strategy limits the CIT compared with offering such marginal organs on a national level.¹⁴

Donor-related risk factors for DGF, such as advanced age, presence of hypertension, and DCD status, are more common in NSD kidneys.¹⁶ Delayed graft function has been recognized as a predictor of adverse graft and recipient outcomes after KT.^15,16 Recent studies have indicated that machine perfusion of deceased donor kidneys significantly reduces the risk of DGF compared with traditional static cold storage.17 Thus, machine perfusion of marginal allografts before implantation may lead to better outcomes in elderly recipients who receive such organs.

Gill and colleagues reported that older recipients with high cardiovascular risk have significantly reduced risk of perioperative mortality when they are preferentially transplanted with kidneys procured from LDs.¹⁶ Thus, for elderly recipients with a high cardiovascular risk, LD transplants should be encouraged. Donor nephrectomy can be performed safely in carefully selected elderly LDs, and a LD transplant between an age-matched donor-recipient pair will be an acceptable option.^18,19 When there are no suitable LDs, consideration should be given to allocating better quality DBD organs to elderly patients with risk factors.

Conclusions

Our experience with transplanting recipients aged 70 years or more with NSD kidneys indicated that these recipients have a higher risk of mortality compared with those of similar age who received an SCD or a LD transplant. There are several limiting factors in our study. It was a retrospective, single-center study with a small sample size, and the comparison group included those who received kidneys from standard criteria DBD donors as well as LDs. However, we believe that our findings highlight that there is a need for a national study with larger patient numbers to examine the post-KT outcomes of elderly recipients who receive NSD kidneys. Furthermore, strategies should be considered that may improve the outcomes of such transplants in the elderly, such as limiting the CIT and machine perfusion of donor organs.

References:

1. Pyart R, Evans KM, Steenkamp R, et al. The 21st UK Renal Registry Annual Report: a summary of analyses of adult data in 2017. Nephron. 2020;144(2):59-66. doi:10.1159/000504851
   CrossRef PubMed:https://pubmed.ncbi.nlm.nih.gov/31825944/
2. Kasiske BL, Cangro CB, Hariharan S, et al. The evaluation of renal transplantation candidates: clinical practice guidelines. Am J Transplant. 2001;1 Suppl 2:3-95.
   CrossRef - PubMed
   
3. Shah T, Bunnapradist S, Hutchinson I, et al. The evolving notion of “senior” kidney transplant recipients. Clin Transplant. 2008;22(6):794-802. doi:10.1111/j.1399-0012.2008.00881.x
   CrossRef - PubMed
   
4. De Rosa P, Muscogiuri G, Sarno G. Expanded criteria donors in kidney transplantation: the role of older donors in a setting of older recipients. ISRN Transplantation. 2013;2013:301025. doi:10.5402/2013/301025
   CrossRef - PubMed
   
5. Filiopoulos V, Boletis JN. Renal transplantation with expanded criteria donors: which is the optimal immunosuppression? World J Transplant. 2016;6(1):103-114. doi:10.5500/wjt.v6.i1.103
   CrossRef - PubMed
   
6. Metzger RA, Delmonico FL, Feng S, Port FK, Wynn JJ, Merion RM. Expanded criteria donors for kidney transplantation. Am J Transplant. 2003;3 Suppl 4:114-125. doi:10.1034/j.1600-6143.3.s4.11.x
   CrossRef - PubMed
   
7. Peters-Sengers H, Berger SP, Heemskerk MB, et al. Stretching the limits of renal transplantation in elderly recipients of grafts from elderly deceased donors. J Am Soc Nephrol. 2017;28(2):621-631. doi:10.1681/ASN.2015080879
   CrossRef - PubMed
   
8. Pippias M, Stel VS, Kramer A, et al. Access to kidney transplantation in European adults aged 75-84 years and related outcomes: an analysis of the European Renal Association-European Dialysis and Transplant Association Registry. Transpl Int. 2018;31(5):540-553. doi:10.1111/tri.13125
   CrossRef - PubMed
   
9. Bonal J, Cleries M, Vela E. Transplantation versus haemodialysis in elderly patients. Renal Registry Committee. Nephrol Dial Transplant. 1997;12(2):261-264. doi:10.1093/ndt/12.2.261
   CrossRef - PubMed
   
10. Rao PS, Merion RM, Ashby VB, Port FK, Wolfe RA, Kayler LK. Renal transplantation in elderly patients older than 70 years of age: results from the Scientific Registry of Transplant Recipients. Transplantation. 2007;83(8):1069-1074. doi:10.1097/01.tp.0000259621.56861.31
    CrossRef - PubMed
    
11. Herrero JC, Gutierrez E, Martinez A, et al. Results of kidney transplantation in recipients over 70 years of age: experience at a single center. Transplant Proc. 2003;35(5):1675-1676. doi:10.1016/s0041-1345(03)00618-3
    CrossRef - PubMed
    
12. Frei U, Noeldeke J, Machold-Fabrizii V, et al. Prospective age-matching in elderly kidney transplant recipients--a 5-year analysis of the Eurotransplant Senior Program. Am J Transplant. 2008;8(1):50-57. doi:10.1111/j.1600-6143.2007.02014.x
    CrossRef - PubMed
    
13. Savoye E, Tamarelle D, Chalem Y, Rebibou JM, Tuppin P. Survival benefits of kidney transplantation with expanded criteria deceased donors in patients aged 60 years and over. Transplantation. 2007;84(12):1618-1624. doi:10.1097/01.tp.0000295988.28127.dd
    CrossRef - PubMed
    
14. Hod T, Goldfarb-Rumyantzev AS. Clinical issues in renal transplantation in the elderly. Clin Transplant. 2015;29(2):167-175. doi:10.1111/ctr.12481
    CrossRef - PubMed
    
15. Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. 2004;364(9447):1814-1827. doi:10.1016/S0140-6736(04)17406-0
    CrossRef - PubMed
    
16. Gill JS, Schaeffner E, Chadban S, et al. Quantification of the early risk of death in elderly kidney transplant recipients. Am J Transplant. 2013;13(2):427-432. doi:10.1111/j.1600-6143.2012.04323.x
    CrossRef - PubMed
    
17. Tingle SJ, Figueiredo RS, Moir JA, Goodfellow M, Talbot D, Wilson CH. Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation. Cochrane Database Syst Rev. 2019;3:CD011671. doi:10.1002/14651858.CD011671.pub2
    CrossRef - PubMed
    
18. Haberal M, Gulay H, Koc M, Guven S, Karamehmetoglu M, Hamaloglu E. Kidney transplantation from aged donors. Transplant Proc. 1991;23(5):2624-2625.
    CrossRef - PubMed
    
19. Haberal M, Sert S, Altunkan S, Gulay H, Hamaloglu E, Bulut O. Kidney transplantation from elderly living donors. Int J Artif Organs. 1991;14(6):335-337.
    CrossRef - PubMed