Background: Kidney transplant survival beneﬁts are not observed for around 8 months after transplantation because of a higher complications rate in early post-transplant periods. This study compares survival of patients awaiting transplantation with survival of transplant recipients and non-listed dialysis patients in Ireland. Methods: In this retrospective analysis, the relative-risk (RR) of death was assessed with time-dependent, non-proportional hazards analysis, with adjustment for age, cause of end-stage kidney disease (ESKD), time from ﬁrst treatment for ESKD to placement on the waiting list and year of initial placement on the list. Results: A total of 3597 patients were included. Annual death rates per 100 patient-years at risk for all patients on dialysis, waiting-list patients and transplant recipients were 16.5, 2.4 and 1.2, respectively. Death rate was highest among diabetics. The relative risk of death for all patients on dialysis was ﬁve times higher than the waiting-list patients [RR, 4.90; 95% conﬁdence interval (CI), 3.70–6.52; P< 0.001]. Time to survival equilibration was 1 year. Thereafter, the 5-year mortality risk was estimated to be 47% lower than that of the patients on the waiting list (RR, 0.53; 95% CI, 0.37–0.77; P¼ 0.001). Conclusions: Transplant recipients had a higher risk of death initially, but a better long-term survival. Time to death risk equilibration was longer compared with other studies. This could be explained by better survival rates in our waiting-list cohort. Key words: dialysis, kidney transplantation, mortality, survival analysis, waiting list Unfortunately, patients with high cardiovascular risk might not Introduction see a survival benefit for a period of up to 6–12 months after Kidney transplantation remains the best available treatment having a successful kidney transplant [1, 4]. It has been shown for end-stage kidney disease (ESKD). When successful, trans- before that patients who are on the waiting list for transplanta- plantation reduces mortality and improves the quality of life tion have a better survival compared with non-listed dialysis for most patients when compared with dialysis [1–3]. However, patients [1, 4]. The most likely explanation for this observation the degree of pre-existing cardiovascular risk in kidney trans- is that the KTR group comprises patients who were carefully plant recipients (KTR) is a major determinant of post- selected from the dialysis population, and they likely represent transplantation survival. Starting from Day 1, survival benefits the healthiest individuals compared with those who were not are seen in patients with low and intermediate risk . listed for transplantation. In fact, it has been shown, in previous Received: June 2, 2017. Editorial decision: August 3, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact firstname.lastname@example.org Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/389/4557548 by Ed 'DeepDyve' Gillespie user on 20 June 2018 390 | M.A. Kaballo et al. studies, that dialysis patients who were on the deceased-donor classified into subgroups of diabetes mellitus, glomerulonephri- kidney transplantation waiting list were usually healthier and tis or others. The loss of an allograft and the removal from the younger than non-listed dialysis patients [5–7]. transplant waiting list did not exclude affected patients from Waiting times for transplantation are on the rise and, subse- the analyses. Analyses were conducted according to the inten- quently, the burden of comorbid disease in patients awaiting tion to treat analysis. All data were analysed using STATA transplantation is increasing. The main reason behind this is Version 10.0 (College Station, TX, USA). P< 0.05 was considered the shortage of heart-beating organs. The rate of growth of the to be statistically significant. chronic kidney disease/ESKD population has continued to increase while the transplant organs availability rate has not Results grown at the same pace. During the last decade, the number of adults waiting for a kidney transplant almost doubled in the During the study period, 10 years, a total of 3597 patients were USA . Every year, waiting times are getting longer. Around commenced on dialysis. Subsequently, 1157 patients were 10 000 patients, approximately, wait for at least 11 years to placed on the transplant waiting list, 990 received a deceased- receive a kidney transplant . To keep up with the pace of the donor kidney and 1450 were not eligible for transplantation. rapidly expanding pool of patients waiting for a kidney trans- Mean age (standard deviation) was 46 (615) years. Mean follow- plant, optimization of the use of available allografts is required. up was 2.5 years. Baseline characteristics of the study popula- This increases pressure on many transplant centres to develop tion are shown in Table 1. robust selection criteria to determine those patients who will The group of patients on dialysis but not on the transplant benefit most from receiving a transplant. Previous studies by waiting list had an annual death rate that was seven times Wolfe et al.  and Gill et al.  have shown survival benefits of higher than the group of patients on the waiting list. The annual kidney transplantation in various groups of patients. In this death rate for patients on the waiting list was twice as high as study, we wanted to assess if it was possible to demonstrate that for KTR (Table 2). The unadjusted annual death rate per 100 this effect in a single transplant centre experience. Therefore, patient-years at risk was 1.2 for KTRs, 2.4 for patients on the comparing the survival of KTR with the survival of patients waiting list and 16.5 for all patients on dialysis (Table 2). awaiting transplantation and non-listed dialysis patients in Compared with dialysis patients on the transplant waiting Ireland was the main aim of this study. list, the relative risk of death was five times higher for patients on dialysis not on the transplant waiting list [RR, 4.90; 95% con- fidence interval (CI), 3.70–6.52; P < 0.001]. Materials and methods Figure 1 shows the adjusted relative risk of death among KTR, as compared with patients on the waiting list. Relative risk Study population and data source was adjusted for age, sex and diabetes as the cause of ESKD and We carried out an analysis of the National Renal Transplant other causes of ESKD. The relative risk of death was signifi- Registry and the Beaumont Hospital Renal Database (Clinical cantly lower in transplant recipients among each subgroup Vision 3.4a Version 18.104.22.168, Clinical Computing, Cincinnati, OH, except for the age 60–70 years subgroup. However, the relative USA) from 1 January 2004 to 31 December 2013, to determine the risk in the latter subgroup was not statistically significant. mortality of KTR, dialysis patients on the transplant waiting list A comparison was made between KTRs and patients on the and non-listed dialysis patients. This registry is maintained pro- waiting list who had not yet received a deceased-donor kidney spectively by dedicated full-time staff. A total of 1538 adult transplant, but who had equal lengths of follow-up since place- renal transplants were performed during this study period. The ment on the waiting list; patients with unsuccessful transplan- National Kidney Transplant Centre at Beaumont Hospital has tation were included in this comparison. During the first performed all adult renal transplants in Ireland since 1987 (pre- 4 weeks after transplantation, the adjusted relative risk of death vious transplant surgery in Ireland was performed at the among the KTRs was 1.7 times higher than the risk among Charitable Infirmary, Jervis Street, since 1964). Elderly patients patients on the transplant waiting list. This risk continued to with an age of #2;70 years comprised <0.5% of KTRs and hence increase during the first 12 weeks and peaked at 1.9 times as they were excluded from this study. We also excluded patients high by the end of Week 12. Although this risk of death started who received a pre-emptive kidney transplant and recipients of to fall thereafter, it remained elevated until 1 year post-trans- a living-donor transplant. plantation. After this time, the risk was lower among the KTRs (Figure 2). The 5-year mortality risk was estimated to be 47% lower than that of patients on the waiting list (RR, 0.53; 95% CI, Analytical methods 0.37–0.77; P ¼ 0.001). Analysis of survival was from the time of initial inclusion in the transplant waiting list to the time of death. We censored data Discussion when the patient received the first transplant from a living donor or on 31 December 2013. Some patients switched between Our analysis showed that transplantation improved survival in the dialysis and the transplantation groups during follow-up KTRs. In the subgroups analysis, according to age, sex and cause and hence time-dependent, non-proportional hazards analysis of ESKD, the mortality rate for all patients on dialysis was five was used to account for this switching. We calculated the num- times higher than that of patients who were on the transplant ber of days between inclusion in the transplant waiting list and waiting list. These findings prove the fact that there is substan- the time at which the death rates equalized in the two groups; tial selection of healthier patients for placement on the waiting we calculated cumulative survival probabilities as well. Both list for transplantation. calculations were adjusted for the time spent on the waiting The annual relative risk of death in our cohort was 1.2 per list. The analyses were adjusted for age, sex, year of placement 100 patient-years for deceased-donor transplant recipients. on the waiting list, time from first dialysis for ESKD to inclusion This risk is lower compared with findings reported in previous in the waiting list and the cause of ESKD. The latter was studies [1, 3]. Wolfe et al. reported a relative risk of 3.8 in their Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/389/4557548 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Survival of kidney transplant recipients | 391 Table 1. Characteristics of the study population All patients on dialysis Patients on the waiting list Deceased-donor transplant recipients Characteristic n ¼ 1450 n ¼ 1157 n ¼ 990 P-value Age number (%) 19 years 58 (4) 97 (8) 62 (6) <0.001 20–39 years 317 (22) 372 (32) 334 (34) 40–59 years 615 (42) 517 (45) 436 (44) 60–70 years 460 (32) 171 (15) 158 (16) Sex Male 923 (64) 751 (65) 624 (63) 0.646 Female 527 (36) 406 (35) 366 (37) Cause of ESKD Diabetes mellitus 141 (10) 66 (6) 57 (6) <0.001 Glomerulonephritis 214 (15) 230 (20) 214 (22) Others 1095 (75) 861 (74) 719 (72) Table 2. Annual death rates per 100 patient-years Patients on the Recipients of Patients on dialy- transplant wait- deceased-donor sis not on pool ing list (rate per transplants (rate per 100 100 patient- (rate per 100 Variable patient-years) years) patient-years) All patients 16.5 2.4 1.2 Age (years) 0–19 12.9 0.8 0.0 20–39 3.1 2.1 0.3 40–59 14.2 2.3 0.9 60–70 23.2 3.9 4.7 Sex Male 16.5 2.5 1.1 Female 16.6 2.1 1.5 Cause of ESKD Fig. 1. Relative risk of death for transplant recipients compared with on-pool Diabetes 19.0 5.5 3.8 dialysis patients. Subgroups were classiﬁed according to age, sex and diabetes Other 16.1 2.1 1.1 as the cause of ESKD and other causes of ESKD. The relative risk was adjusted for age, sex and diabetes as the cause of ESKD and other causes of ESKD. cohort . Gill et al. stratified this relative risk of death according to waiting times for transplantation . They showed a risk of likely explanation for this difference is that our waiting list, i.e. patients in Ireland, are healthier compared with their counter- 4.0 per 100 patient-years for deceased-donor transplant recipi- ents who waited for up to 36 months before transplantation. parts in USA, because of the stringent criteria used for inclusion into the kidney transplant pool in Ireland. This long-term Waiting times beyond 36 months increased the risk to 5.4 . Another important finding demonstrated by our study was improvement in survival was significant for all patients’ sub- groups, when compared with the survival rate among corre- that the relative risk of death among KTR, who received their first transplant, relative to that among patients on the transplant sponding dialysis patients on the transplant waiting list. The excess early mortality after transplantation remains an impor- waiting list varies significantly with time. Mortality was higher in the transplantation group immediately after transplantation. tant consideration that should be addressed adequately when counselling potential transplant recipients. This finding was demonstrated in previous studies [1, 4]. The leading cause of death during the early post-transplantation Both Wolfe et al. and Gill et al. showed that elderly transplant recipients’ survival benefits from transplantation when com- period is cardiovascular disease . Previous studies have shown the importance of optimizing the management of cardiovascular pared with dialysis patients on the transplant waiting list [1, 4]. We found that transplant recipients with ages 60–70 years had a risk factors in wait-listed patients by coordination between neph- rologists and transplant teams . Unfortunately, so far no stud- higher risk of death by 1.2 times than those on the transplant waiting list. However, this finding was not statistically signifi- ies have shown a strategy or an intervention to reduce cardiovascular mortality during the early post-transplant period cant. Gill et al. showed that the time to equal survival was 521 days and 470 days for elderly recipients of a deceased-donor . Other important causes of high mortality in the early post- transplantation period are complications of surgery and effects of kidney transplant, with high cardiovascular risk and low cardio- vascular risk, respectively . Schaeffner et al. demonstrated immunosuppression medications at high doses. Subsequently, the risk of death decreased and the survival benefit began to be that only 7% of patients who are #2;65 years of age are transplanted after 3 years of initiating dialysis . Schold et al. observed (time to equal survival) 365 days after transplantation. In comparison with our findings, Wolfe et al.demonstrated a showed that the 5-year probability of deceased-donor trans- plantation in patients aged #2;65 years is nearly equal to the shorter time to equal survival, i.e. 244 days . We think the most Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/389/4557548 by Ed 'DeepDyve' Gillespie user on 20 June 2018 392 | M.A. Kaballo et al. 2.00 1.75 1.50 1.25 1.00 0.75 0.50 0.25 Time since transplantation Fig. 2. Adjusted relative risk of death for transplant recipients compared with on-pool dialysis patients during the ﬁrst 5 years post-transplant. The reference group was the 1157 patients on dialysis who were on the transplant waiting list (RR, 1.0). Values were adjusted for age, sex cause of ESKD, year of placement on the waiting list and time from ﬁrst treatment for ESKD to placement on the waiting list. probability of death on the waiting list . This reflects the interval between placement on the transplant waiting list and importance of longer follow-up periods, where the survival ben- transplantation; this helped to minimize the potential effects of efit in the elderly becomes more apparent in subsequent years outcomes improvement over time. following transplantation. In contrast to this, the survival of eld- This study has some limitations. Firstly, we did not study erly dialysis patients on the waiting list reduces significantly the use of transplants from living donors, although it has a year after year. Therefore, a short follow-up period might be better outcome than deceased-donor transplantation [18, 19]. misleading when comparing the elderly patients’ survival, and Secondly, although our multivariate analyses were adjusted for might show a better survival in the waiting-list cohort than in differences in a variety of factors that impact transplant out- transplant recipients. Additionally, Gill et al. demonstrated that, come, there are undoubtedly unaccounted differences between in low cardiovascular risk patients, living-donor kidney trans- standard and Extended Criteria Donor recipients in this study plantation was associated with an immediate survival advant- that may confound our findings. Thirdly, despite including a age compared with dialysis . reasonable number of transplant recipients in Ireland, the Our study has a number of strengths. Generally, in this results may be difficult to apply to individual patients. Fourthly, study, we employed similar methods to those used by Wolfe et in the last two decades, both short- and long-term survival have al.. An important strength is that we used an intention to been improving for patients on dialysis and transplant recipi- treat analysis and hence mortality post-transplantation assess- ents , and this could affect our results. Finally, limitations of ment was independent of allograft function. This type of analy- observational studies and secondary analyses of registry data sis also allows comparison of KTRs with patients on the cannot be overlooked when appraising this study. transplant waiting list who had equal lengths of time on the In conclusion, this study, based on Irish data, shows that waiting list. This approach and methodology have previously dialysis patients who were on the transplantation waiting list been used in other studies [1, 14–16]. The estimation of time to had a better survival when compared with dialysis patients equal risk and equal survival in this study was determined in who were not listed. First-time KTRs, who received a deceased- KTRs compared with similar risk patients who remained on the donor kidney transplant, had a higher risk of death initially waiting list, and differs from that in the study done by Merion when compared with dialysis patients who remained on the et al. . In their study, the outcomes after Extended Criteria transplant waiting list, but their long-term survival was better. Donor transplantation were compared with continued waiting Time to equal survival was longer compared with other studies; on the transplant waiting list and transplantation from a stand- this could be explained by better survival rates in our waiting ard criteria deceased donor. As a result, the times to equal risk list cohort. However, this excess early mortality after transplan- and equal survival among Extended Criteria Donor recipients tation remains an important consideration that should be are longer than those among KTRs in this study. We adjusted addressed adequately when counselling potential transplant for the year of placement on the transplant waiting list and the recipients about transplantation. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/389/4557548 by Ed 'DeepDyve' Gillespie user on 20 June 2018 1 month 3 months 1 yea 2 years 3 years 4 years 5 years Relative risk of death Survival of kidney transplant recipients | 393 10. Gill JS, Rose C, Pereira BJ et al. The importance of transitions Acknowledgements between dialysis and transplantation in the care of end- The authors thank Cathal Collier for the great effort he put stage kidney disease patients. Kidney Int 2007; 71: 442–447 into the National Renal Transplant Registry and the Beaumont 11. Lentine KL, Hurst FP, Jindal RM et al. Cardiovascular risk Hospital Renal Database, which made this study possible. No assessment among potential kidney transplant candidates: support or funding was used for this submission. approaches and controversies. Am J Kidney Dis 2010; 55: 152–167 12. Schaeffner ES, Rose C, Gill JS. Access to kidney transplan- Conflict of interest statement tation among the elderly in the United States: a glass None declared. half full, not half empty. Clin J Am Soc Nephrol 2010; 5: 2109–2114 13. Schold J, Srinivas TR, Sehgal AR et al. Half of kidney trans- References plant candidates who are older than 60 years now placed on 1. Wolfe R, Ashby V, Milford E et al. Comparison of mortality in the waiting list will die before receiving a deceased-donor all patients on dialysis, patients on dialysis awaiting trans- transplant. Clin J Am Soc Nephrol 2009; 4: 1239–1245 plantation, and recipients of a ﬁrst deceased-donor trans- 14. Mauger EA, Wolfe RA, Port FK. Transient effects in the Cox plant. N Engl J Med 1999; 341: 1725–1730 proportional hazards regression model. Stat Med 1995; 14: 2. Laupacis A, Keown P, Pus N et al.Astudyofthe qualityoflifeand 1553–1565 cost-utility of renal transplantation. Kidney Int 1996; 50: 235–242 15. Port FK, Wolfe RA, Mauger EA et al. Comparison of survival 3. Gill JS, Tonelli M, Johnson N et al. The impact of waiting time probabilities for dialysis patients vs cadaveric renal trans- and comorbid conditions on the survival beneﬁt of kidney plant recipients. J Am Med Assoc 1993; 270: 1339–1343 transplantation. Kidney Int 2005; 68: 2345–2351 16. Ojo AO, Port FK, Wolfe RA et al. Comparative mortality risks of 4. Gill JS, Schaeffner E, Chadban, S et al. Quantiﬁcation of the chronic dialysis and cadaveric transplantation in black end- early risk of death in elderly kidney transplant recipients. stage kidney disease patients. Am J Kidney Dis 1994; 24: 59–64 Am J Transplant 2013; 13: 427–432 17. Merion RM, Ashby VB, Wolfe RA et al. Deceased-donor char- 5. Gaylin DS, Held PJ, Port FK et al. The impact of comorbid and acteristics and the survival beneﬁt of kidney transplanta- sociodemographic factors on access to renal transplanta- tion. J Am Med Assoc 2005; 294: 2726–2733 tion. J Am Med Assoc 1993; 269: 603–608 18. Ojo AO, Port FK, Mauger EA et al. Relative impact of donor 6. Held PJ, Pauly MV, Bovbjerg RR et al. Access to kidney trans- type on renal allograft survival in black and white recipients. plantation: has the United States eliminated income and Am J Kidney Dis 1995; 25: 623–628 racial differences? Arch Intern Med 1988; 148: 2594–2600 19. Terasaki PI, Cecka JM, Gjertson DW et al. High survival rates 7. Kasiske BL, London W, Ellison MD. Race and socioeconomic of kidney transplants from spousal and living unrelated factors inﬂuencing early placement on the kidney trans- donors. N Engl J Med 1995; 333: 333–336 20. United States Renal Data System. 2014 USRDS Annual Data plant waiting list. J Am Soc Nephrol 1998; 9: 2142–2147 Report: Epidemiology of Kidney Disease in the United States. 8. Matas AJ, Smith JM, Skeans MA et al. OPTN/SRTR 2013 annual Bethesda, MD: National Institutes of Health, National data report: kidney. Am J Transplant 2015; 15: 1–34 9. Gill JS, Pereira BJ. Death in the ﬁrst year after kidney trans- Institute of Diabetes and Digestive and Kidney Diseases, 2014, https://www.usrds.org/2014/view/Default.aspx (22 November plantation: Implications for patients on the transplant wait- 2016, date last accessed) ing list. Transplantation 2003; 75: 113–117 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/389/4557548 by Ed 'DeepDyve' Gillespie user on 20 June 2018
Clinical Kidney Journal – Oxford University Press
Published: Oct 18, 2017
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