Abstract
Performing third or fourth kidney transplantation (3KT and 4KT) in older patients is rare due to surgical and immunologic challenges. We aimed to analyze and compare the outcomes of younger (18–64 years) and older (≥65 years) recipients of 3KT and 4KT. Between 1990 and 2016, we identified 5,816 recipients of 3KTs (153 were older) and 886 recipients of 4KTs (18 were older). The incidences of delayed graft function (24.3%vs.24.8%, p=0.89), primary non-function (3.2%vs.1.3%, p=0.21), 1-year acute rejection (18.6%vs.14.8%, p=0.24), and 5-year death censored graft failure (DCGF) (24.8%vs.17.9%, p=0.06) were not different between younger and older recipients of 3KT. However, 5-year mortality was higher in older recipients (14.0%vs.33.8%, p<0.001) which remained significant after adjustment (aHR=3.21, 95%CI:2.59–3.99). Similar patterns were noted in the 4KT cohort. When compared with waitlisted patients, 3KT and 4KT are associated with a lower risk of mortality; aHR=0.37, 95%CI:0.33–0.41 and aHR=0.31, 95%CI:0.24–0.41, respectively. This survival benefit did not differ by recipient age (younger versus older, P for interaction=3KT:0.49 and 4KT:0.58). In the largest cohort described to date, we report that there is a survival benefit of 3KT and 4KT even among older patients. Although a highly selected cohort, our results support improving access to 3KT and 4KT.
Introduction
In patients with two previous kidney transplantations (KTs), performing a surgical procedure on previously operated iliac fossae can be technically challenging. This combined with the immunologic barriers due to sensitization from previous grafts results in higher rates of post-operative complications following a third or fourth KT (3KT or 4KT). (1–11) However, survival benefit to 3KT has been demonstrated, and single centers have reported positive experiences with 4KT, although the cohorts have been ≤15 recipients. (1–6, 8–16) Recently a registry analysis reported that graft and patient survival of 4KTs were comparable to 3KTs, and the number of these transplants has increased over the past three decades. (17)
However, the mean or median recipient age in the above-cited studies was 32–48 years and none have specifically looked at older adults (≥65 years of age). In older patients with two or more preceding graft failures, there are other factors that can contribute to operative challenges and inferior outcomes, such as, a higher risk of cardiovascular morbidity and mortality, increased frailty, and vascular challenges due to the cumulative atherosclerotic burden of age, renal failure, and immunosuppressive medications. (1, 3, 7, 10, 18–20) Analyzing outcomes in older patients is needed to inform practice and policy as KT rates have doubled in the past three decades and patient longevity is increasing. (21) Thus, many who were transplanted at a young age, may end up with second or third graft failure at age ≥65 years. (22) To address this knowledge gap, we aimed to analyze and compare the characteristics and outcomes in older and younger patients following 3KT and 4KT. In addition, we wanted to analyze the survival benefit of 3KT and 4KT in younger and older patients.
Methods
Data source
This study used data from the United States Renal Data System (USRDS) that contains information on patients with end-stage renal disease in the US. The institutional review board at the Johns Hopkins University School of Medicine determined this study to be exempt under the Code of Federal Regulations.
Patient population
We included all adult (age ≥18 years) kidney-only recipients who received a 3KT or a 4KT during the period between January 1, 1990, and December 31, 2016. To ascertain those who received 3KT or 4KT, we identified those with a sequence number of the transplant using the variable name “INCCOUNT” in the USRDS dataset. We divided the cohort by age into younger patients who were 18–64 years at the time of transplant versus older patients who were ≥65 years. Some recipients received both a 3KT and 4KT during this time and were included in the analysis as separate entries. In the older cohort, no patient received KT five or higher, thus this analysis was not pursued.
Outcomes
Outcomes of interest were delayed graft function (DGF), primary non-function (PNF), acute rejection, death-censored graft failure (DCGF), all-cause graft failure (ACGF), and patient mortality. Acute rejection was defined as rejection episodes within the first year of 3KT or 4KT. Graft loss was defined as an irreversible graft failure signified by return to long-term dialysis or listing for another KT. ACGF was defined as death or graft loss.
Survival benefit of 3KT and 4KT
We also wanted to ascertain the survival benefit of 3KT and 4KT compared with waitlisted patients. To do this, we used the Transplant Waiting List file that contains data of patients on kidney waiting list per listing event to identify those who were waitlisted for 3KT and 4KT. Patients who were waitlisted prior to 1990 and those were <18 years of age at waitlisting were excluded from this analysis.
Statistical analysis
We used a logistic model to compare the risks of DGF, PNF, and 1-year acute rejection between older and younger recipients. Kaplan-Meier estimator was used to estimate the 1-, 3-, and 5-year DCGF, ACGF, and mortality. Log-rank test and regression analysis was used to compare these outcomes between older and younger recipients of 3KT or 4KT. In the latter analysis, we adjusted for diabetes, preemptive transplant, transplant era (1990–2009 versus 2010–2016), induction agent (T-cell depleting versus others), and donor type (living versus deceased). To compare the survival benefit of a 3KT and a 4KT, we treated transplantation as a time-dependent variable and conducted a Cox proportional hazard regression analysis for the hazard of mortality amongst patients who were transplanted versus those who were on the waitlist during this time period. We adjusted for recipient age, sex, race, and BMI, and we also conducted an interaction term analyses to examine whether the mortality advantage was modified by the age at listing (18–64 versus ≥65 years). Also, we conducted a sensitivity analysis to analyze the impact of panel reactive antibody (PRA) and type of donor (living versus deceased) for the outcome of DCGF, and whether this varied by the age of the recipient as well. Lastly, we conducted an era analysis in older patients only to ascertain changes in outcomes over time. All analyses were performed using Stata 16.0/MP for Linux (College Station, Texas) and R version 3.6.2.
Results
Characteristics of the 3KT cohort
Between 1990–2016, we identified 5,816 recipients of a 3KT. Of these, only 2.6% were ≥65 years of age at transplant. Overall, there were fewer female recipients (42.5%), non-White recipients (29.4%), expanded criteria donors (ECD) (8.3%) and living donor transplants (26.7%), and the median recipient BMI was 24.2 kg/m2 (IQR:21.5–28.0) (Table 1). Only 11.1% received preemptive transplants and the median time on dialysis was 3.0 years (IQR:0.9–6.9). Most of the patients had a PRA ≥10 (76.0%) and 51.6% received T-cell depleting agents. The 5-year survival of the preceding grafts was low (first KT:32.2% and second KT:49.7%) and the rates of PNF (first KT:10.9% and second KT:8.0%) and acute rejection (first KT:38.9% and second KT:31.3%) were high (Supplementary Table 1).
Table 1:
Characteristics of patients who received a third kidney transplant between January 1, 1990 and December 31, 2016 stratified by age at transplantation (older: ≥65 years versus younger: 18–64 years)
| Total cohort (n=5,816) |
Younger (n=5,663) |
Older (n=153) |
|
|---|---|---|---|
| Recipient characteristics | |||
| Age (y), median (IQR) | 41.0 (33.0, 50.0) | 41.0 (33.0, 49.0) | 68.0 (66.0, 70.0) |
| Female | 42.5% | 42.6% | 40.5% |
| BMI (kg/m2), median (IQR) | 24.2 (21.5, 28.0) | 24.2 (21.5, 28.0) | 25.0 (22.7, 28.9) |
| Diabetes | 12.0% | 11.8% | 19.6% |
| Race/ethnicity | |||
| White | 70.6% | 70.7% | 68.7% |
| Black | 15.7% | 15.5% | 22.4% |
| Hispanic/Latino | 10.8% | 10.9% | 6.1% |
| Other/multi-racial | 2.9% | 2.9% | 2.7% |
| Attended college | 55.4% | 55.1% | 61.8% |
| Years on dialysis before the third transplant, median (IQR) | 3.0 (0.9, 6.9) | 3.0 (0.9, 7.0) | 1.7 (0.7, 4.7) |
| Survival of the preceding graft in years, median (IQR) | |||
| Second | 5.0 (1.4, 9.6) | 4.9 (1.4, 9.5) | 6.5 (1.5, 11.9) |
| First | 2.6 (0.4, 6.4) | 2.6 (0.4, 6.4) | 3.7 (0.6, 7.9) |
| Characteristics of the third KT | |||
| Transplant year | |||
| 1990–1999 | 32.7% | 33.1% | 14.4% |
| 2000–2009 | 41.3% | 41.5% | 35.3% |
| 2010–2016 | 26.0% | 25.4% | 50.3% |
| Preemptive transplant | 11.1% | 11.1% | 14.4% |
| Peak PRA | |||
| 0–9 | 24.0% | 23.8% | 29.9% |
| 10–79 | 30.7% | 30.8% | 26.5% |
| 80–100 | 45.3% | 45.4% | 43.5% |
| HLA mismatch | |||
| 0–1 | 2.9% | 2.9% | 1.3% |
| 2–4 | 49.5% | 49.8% | 41.1% |
| 5–6 | 47.6% | 47.3% | 57.6% |
| ABO incompatibility | 0.8% | 0.8% | 0.0% |
| Induction agent | |||
| T-cell depleting | 51.6% | 51.6% | 52.3% |
| Interleukin-2 receptor antagonist | 10.2% | 10.0% | 17.6% |
| None | 34.6% | 34.8% | 26.1% |
| Other/Multiple | 3.6% | 3.6% | 3.9% |
| Cold ischemia time (hr), median (IQR) | 17.0 (7.4, 24.0) | 17.0 (7.2, 24.0) | 18.0 (10.5, 24.0) |
| Donor characteristics | |||
| Age (y), median (IQR) | 37.0 (24.0, 48.0) | 36.0 (24.0, 48.0) | 42.0 (27.0, 51.0) |
| Female | 44.9% | 44.8% | 46.4% |
| Living donor | 26.7% | 26.9% | 21.6% |
| Expanded criteria donor* | 8.3% | 8.1% | 16.1% |
| Donation after circulatory death* | 6.6% | 6.5% | 10.0% |
among deceased donor only
When comparing characteristics of the younger and older cohort there were some notable differences. In older patients, about half of the 3KTs were performed from 2010–2016 (50.3%). When compared with younger recipients, older recipients spent less time on dialysis after second graft failure (younger: 3.0 years, IQR:0.9–7.0 vs. older: 1.7 years, IQR:0.7–4.7), there were more patients with diabetes (11.8% vs. 19.6%) and the survival of both the preceding grafts was better. There were fewer living donors (26.9% vs 21.6%) and more ECD transplants (8.1% vs. 16.1%) in the older cohort. Also, there were more Black recipients (15.5% vs. 22.4%), fewer Hispanic recipients (10.9% vs. 6.1%), and more college-educated patients (55.1% vs. 61.8%) in the older cohort. It is worth reporting that the median cold ischemia time (CIT) was only slightly higher in the older cohort (17.0 hours, IQR:7.2–24.0 vs. 18.0 hours, IQR:10.5–24.0) (Table 1).
Outcomes following 3KT
In the total cohort, 24.4% experienced DGF, 3.1% had PNF and 18.5% experienced acute rejection within 1-year. Outcomes between younger and older recipients of 3KT were not different: DGF: 24.3% vs. 24.8%, p=0.89; PNF: 3.2% vs. 1.3%, p=0.21; and 1-year acute rejection: 18.6% vs. 14.8%, p=0.24. In the total cohort, the 1-, 3-, and 5-year DCGF was 10.6%, 17.9% and 24.6%, ACGF was 13.4%, 22.8% and 31.9%, and mortality was 4.6%, 8.8% and 14.5%, respectively. When compared with younger recipients, older recipients did not have higher DCGF (1-year: 10.6% vs. 9.4%; 3-year: 18.0% vs. 13.8%, 5-year: 24.8% vs. 17.9%, p=0.06). However, older recipients of 3KT had higher ACGF (1-year: 13.3% vs. 15.0%; 3-year: 22.7% vs. 26.8%; 5-year: 31.7% vs. 39.8%, p<0.001) and mortality (1-year: 4.4% vs. 11.1%; 3-year: 8.4% vs. 20.9%; 5-year: 14.1% vs. 33.8%, p<0.001) (Figure 1). Similarly, the risk of DCGF in older recipients was not different when compared with younger recipients (aHR=0.87, 95% confidence interval (CI):0.61–1.23). However, the risk was greater for the outcomes of ACGF and mortality (aHR=1.72, 95%CI:1.39–2.12 and aHR=3.21, 95%CI:2.59–3.99, respectively) in older recipients.
Figure 1:
Cumulative incidence of (a) death-censored graft failure, (b) all-cause graft failure and (c) mortality in younger (18–64 years) and older adults (≥65 years) who received third kidney transplantation between January 1, 1990, and December 31, 2016.
Characteristics of the 4KT cohort
Between 1990–2016, we identified 886 recipients of a 4KT. Of these, only 2.0% were ≥65 years of age at transplant (Table 2). Similar to the 3KT cohort, there were fewer female recipients (42.6%), non-White recipients (22.9%), ECDs (8.3%) and living donor transplants (26.0%), and the median recipient BMI was 24.1 kg/m2 (IQR:21.3–27.8). Only 10.5% received preemptive transplants, the median time on dialysis was 3.0 years (IQR:0.8–8.4) and the majority of patients had a PRA ≥10 (82.4%) and 48.6% received T-cell depleting agents. Of note, however, the median survival of the first graft in the 4KT cohort was quite low (1.2 years, IQR:0.2–4.0). In fact, the 5-year survival of the preceding grafts, especially the first KT, was low (first KT:19.4%, second KT: 29.0% and third KT: 45.3%) and the rates of PNF (first KT:13.9%, second KT: 10.1% and third KT: 9.7%) and acute rejection (first KT:40.9%, second KT: 34.8% and third KT: 31.0%) were higher than expected (Supplementary Table 2). Older recipients represented a small and selective cohort and most of the 4KTs were performed from 2010–2016 (44.4%). Notably, the median CIT was lower in the older cohort (18.1 hours, IQR:9.0–24.4 vs. 15.3 hours, IQR:10.5–21.5) (Table 2).
Table 2:
Characteristics of patients who received a fourth kidney transplant between January 1, 1990 and December 31, 2016 stratified by age at transplantation (older: ≥65 years versus younger: 18–64 years)
| Total cohort (n=886) |
Younger (n=868) |
Older (n=18) |
|
|---|---|---|---|
| Recipient characteristics | |||
| Age (y), median (IQR) | 41.0 (33.0, 49.0) | 41.0 (33.0, 48.0) | 67.0 (65.0, 71.0) |
| Female | 42.6% | 42.5% | 44.4% |
| BMI (kg/m2), median (IQR) | 24.1 (21.3, 27.8) | 24.1 (21.3, 27.8) | 24.7 (20.4, 27.0) |
| Diabetes | 10.6% | 10.7% | 5.6% |
| Race/ethnicity | |||
| White | 77.1% | 76.9% | 88.2% |
| Black | 12.4% | 12.5% | 5.9% |
| Hispanic/Latino | 8.6% | 8.6% | 5.9% |
| Other/multi-racial | 1.9% | 1.9% | 0.0% |
| Attended college | 57.9% | 57.4% | 80.0% |
| Years on dialysis before the fourth transplant, median (IQR) | 3.0 (0.8, 8.4) | 3.1 (0.8, 8.6) | 1.5 (0.5, 3.4) |
| Survival of the preceding graft in years, median (IQR) | |||
| Third | 4.3 (1.0, 8.3) | 4.3 (0.9, 8.3) | 6.7 (3.9, 10.0) |
| Second | 2.2 (0.3, 5.6) | 2.1 (0.3, 5.6) | 4.9 (0.5, 9.6) |
| First | 1.2 (0.2, 4.0) | 1.2 (0.3, 4.0) | 0.5 (0.1, 2.4) |
| Characteristics of the third KT | |||
| Transplant year | |||
| 1990–1999 | 34.9% | 35.3% | 16.7% |
| 2000–2009 | 40.3% | 40.3% | 38.9% |
| 2010–2016 | 24.8% | 24.4% | 44.4% |
| Preemptive transplant | 10.5% | 10.4% | 16.7% |
| Peak PRA | |||
| 0–9 | 17.6% | 17.1% | 41.2% |
| 10–79 | 30.6% | 30.7% | 23.5% |
| 80–100 | 51.8% | 52.1% | 35.3% |
| HLA mismatch | |||
| 0–1 | 4.4% | 4.3% | 5.6% |
| 2–4 | 58.0% | 58.5% | 33.3% |
| 5–6 | 37.7% | 37.2% | 61.1% |
| ABO incompatibility | 1.2% | 1.2% | 5.6% |
| Induction agent | |||
| T-cell depleting | 48.6% | 48.5% | 55.6% |
| Interleukin-2 receptor antagonist | 9.9% | 10.0% | 5.6% |
| None | 36.0% | 35.9% | 38.9% |
| Other/Multiple | 5.4% | 5.5% | 0.0% |
| Cold ischemia time (hr), median (IQR) | 18.0 (9.0, 24.3) | 18.1 (9.0, 24.4) | 15.3 (10.5, 21.5) |
| Donor characteristics | |||
| Age (y), median (IQR) | 37.0 (23.0, 48.0) | 37.0 (23.0, 48.0) | 43.0 (22.0, 56.0) |
| Female | 45.9% | 45.9% | 50.0% |
| Living donor | 26.0% | 25.8% | 33.3% |
| Expanded criteria donor* | 8.3% | 8.4% | 0.0% |
| Donation after circulatory death* | 5.8% | 5.6% | 16.7% |
among deceased donor only
Outcomes following 4KT
In the total cohort, 26.9% experienced DGF, 4.4% had PNF and 20.0% experienced acute rejection within 1-year. Outcomes between younger and older recipients were not different: DGF: 27.1% vs. 16.7%, p=0.33; PNF: 4.5% vs. 0%, p=NA; and 1-year acute rejection: 19.9% vs. 22.2%, p=0.81. In the total cohort, the 1-, 3-, and 5-year DCGF was 13.1%, 21.3% and 29.4%, ACGF was 15.6%, 26.1% and 35.9%, and mortality was 4.8%, 10.3% and 15.6%, respectively. When compared with younger recipients, DCGF and ACGF appear to be higher in older recipients but due to small numbers in the older 4KT cohort, it failed to reach significance. The 1-, 3-, and 5-year DCGF was 13.2% vs. 5.9%, 21.2% vs. 26.1%, and 29.2% vs. 45.2% (p=0.50) and ACGF was 15.7% vs. 11.1%, 25.8% vs. 38.9% and 35.4% vs. 60.4% (p=0.06), respectively. The 1-,3- and 5-year mortality was however worse in the older 4KT cohort: 4.8% vs. 5.6%, 10.1% vs. 16.7% and 15.2% vs. 36.5% in the younger and older cohorts (p=0.01), respectively (Figure 2). The risk of DCGF in older recipients was not different when compared with younger recipients (aHR=1.56, 95%CI:0.73–3.21). However, the risk of ACGF (aHR=2.01, 95%CI:1.13–3.59) and mortality (aHR=2.66, 95%CI:1.36–5.18) was higher among older recipients.
Figure 2:
Cumulative incidence of (a) death-censored graft failure, (b) all-cause graft failure and (c) mortality in younger (18–64 years) and older adults (≥65 years) who received fourth kidney transplantation between January 1, 1990 and December 31, 2016.
Survival benefit of 3KT and 4KT
We identified 10,430 adult patients who were listed for a 3KT between 1990–2016 and 5,323 of these were transplanted during the study period. The incidence rate of death for recipients of 3KT was 3.1 per 100 patient-years and 7.2 per 100 patient-years among patients who were waitlisted for a 3KT. The aHR of mortality for those transplanted was lower than for those who were waitlisted (aHR=0.37;95%CI: 0.33–0.41). This survival benefit did not differ by age (18–64 versus ≥65 years, P for interaction=0.49).
Similarly, we identified 1,559 adult patients who were listed for 4KT between 1990–2016 and 774 of these were transplanted during the study period. The incidence rate of death for recipients of 4KT was 2.9 per 100 patient-years and 7.7 per 100 patient-years among patients who were waitlisted for a 4KT. The aHR of mortality for those transplanted was lower than for those who were waitlisted in this cohort as well (aHR=0.31 (95%CI: 0.24–0.41). This survival benefit did not differ by age either (18–64 versus ≥65 years, P for interaction=0.58) (Table 3).
Table 3:
The mortality rates and hazard of mortality amongst adult patients receiving a third or fourth kidney transplantation (KT) versus those waitlisted from 1990–2016
| Incidence rate of death per 100 patient-years | Adjusted hazard ratio (95% confidence interval) | ||
|---|---|---|---|
| Listed (n=10,430) |
Transplanted (n=5,323) |
||
| Third KT | 7.2 | 3.1 | 0.37 (0.33–0.41) |
| Listed (n=1,559) |
Transplanted (n=774) |
||
| Fourth KT | 7.7 | 2.9 | 0.31 (0.24–0.41) |
Sensitivity analysis
A living donor KT was associated with decreased hazard for both 3KT (aHR=0.68, 95%CI:0.61–0.75) and 4KT (aHR=0.61, 95%CI: 0.48–0.78) and this interaction did not differ by age (3KT:P for interaction=0.12; 4KT:P for interaction=0.51). Also, high PRA was associated with the risk of DCGF (Table 4).
Table 4:
The adjusted hazard for death-censored graft failure by type of donor and PRA in third and fourth kidney transplant recipients
| Third kidney transplant recipients (n=5,816) | P-value for interaction (18–64 versus ≥65 years) | Fourth kidney transplant recipients (n=886) | P-value for interaction (18–64 versus ≥65 years) | |
|---|---|---|---|---|
| Donor type | ||||
| Deceased | Reference | Reference | ||
| Living | 0.68 (0.61–0.75) | 0.12 | 0.61 (0.48–0.78) | 0.51 |
| PRA | ||||
| 0–9 | Reference | Reference | ||
| 10–79 | 1.17 (1.05–1.31) | 0.74 | 1.14 (0.84–1.54)a | - |
| 80–100 | 1.15 (1.03–1.28) | 0.63 | 1.00 (0.75–1.33)a | - |
The model including the interaction term of PRA and age was not fitted.
Era analysis
In the older cohort of 3KTs, the outcome of mortality but not DCGF has improved significantly in the last decade. In the older cohort of 4KTs, neither the outcome of mortality nor DCGF have improved significantly over time; however, the numbers were too small to arrive at a meaningful conclusion (Supplementary Table 3).
Discussion
We have identified the largest cohort of patients with 3KT (5,816) and 4KT (886) and report that overall outcomes are good in these highly selected group of patients. Although mortality was greater among older recipients of 3KT and 4KT, we report that graft outcomes, i.e., rates of DGF, PNF, 1-year acute rejection and DCGF between older and younger patients were not statistically different. Most importantly, we found that patients with 3KT and 4KT had a 63% and 69% lower hazard of mortality when compared with patients who were waitlisted for a 3KT and a 4KT respectively; this survival benefit did not differ by age at transplant. This indicates that there is a survival benefit to 3KT and 4KT in older adults. To our knowledge, this is the first study to compare outcomes in older and younger recipients of 3KT and 4KT.
In younger cohorts of 3KT, previous research found comparable outcomes in single-center studies. (1–6, 8–16) Depending on the type of donor and immunological compatibility, DGF rates range from 0–52%, and 5-year patient and graft survival rates range from 74–100% and 50–76%, respectively. (1–6, 8–11, 14, 15, 23) Redfield and colleagues reported that in 2,492 3KTs from 1995–2009, where mean recipient age was 39 years, 5-year graft survival in deceased donor recipients was 69.9% and in living donor recipients was 79.2%. (12) More recently, Petrun and colleagues reported similar survival in 2,823 3KTs from 1987 and 2018. (17) The discrepancies in the number of 3KTs in the cohort are due to the different databases used to identify these cohorts. Regardless, we now add to this literature by reporting outcomes of 5,816 3KTs. More importantly, we report that graft outcomes in older and younger third transplant recipients were not statistically different, and that 3KT is associated with a significant survival benefit.
When specifically looking at 4KT outcomes, in single-center studies where the cohort comprised of no more than 15 patients, DGF rates were as high as 63% and graft and patient survival rates were variable. (1, 4, 6, 7, 13–16) Petrun and colleagues did identify 232 4KTs between 1987 and 2018. (17) In our cohort of close to 900 4KTs, 5-year DCGF was 29.4%, ACGF was 35.9% and mortality patient survival was 15.6%. Although our cohort of older 4KTs was only 18 patients, we report acceptable graft outcomes.
We, however, caution against the broader application of our findings given that a very selected group of patients with graft failure are considered for 3KT or 4KT. First, there appear to be some prejudicial preferences as the PNF and acute rejection rates of preceding transplants are higher and graft survival appears to be much lower than the national performance measures. (24) This may indicate an unexpected event, failure in the systems and processes of care that may have led to higher willingness from the transplant center to pursue 3KT or 4KT. (25) It may also be due to patient-level factors, such as, education, race and other socio-economic factors that are known to impact access to transplantation. We also report that donor quality appears to be better. For example, in our cohort of 3KTs, only 12% received transplants from ECDs and in the 4KT cohort, none received ECDs. In our previous work in older adults, 32% and 18% of older adults with first KT and second KT received ECDs, respectively. (26, 27) Thus, not only are a highly selected group of older adults receiving 3KT and 4KT, but even donor selection seems preferential.
A few other findings merit discussion. First, there is a survival benefit of second KT when compared with waitlisted patients in younger and older cohorts. (28, 29) We now report a survival benefit to 3KT and 4KT and that this relationship did not differ based on the age of the recipient. Second, we report that poor survival of the previous grafts does not necessarily portend worse outcomes of the subsequent grafts. We agree with others that immune-mediated considerations are likely more relevant than surgical challenges in 3KT and 4KT. (1, 3, 4, 23) Also, despite the well-known surgical challenges, CIT between younger and older were not different. Third, as is well known with first and second KT, even in cohorts of 3KT and 4KT, living donor kidney transplantation is associated with superior outcomes. Last, we noted that most recipients of 3KT and 4KT are male, Caucasians, non-diabetics, and college educated. Thus, similar to the first and second KT cohorts, there are disparities in access to 3KT and 4KT, however, this remains to be further explored.
This study is limited by the variables that are available for analysis by USRDS; specifically, more granular ascertainment of comorbidities and early surgical complications is not possible. However, these surgical complications may contribute to early graft loss, and we do report the outcome of PNF. Several center- and physician-level factors could not be accounted for, and these cohorts likely represent a highly selected group who are predisposed to have good outcomes and seem to be receiving superior quality of donors. Thus, we acknowledge that our findings are not universally applicable. Last, causes of death and graft loss were missing in the majority and we could not explore this further to inform clinical knowledge and practice. Regardless, we report the characteristics and outcomes of the largest a cohort of older patients with 3KT and 4KT and report favorable outcomes, and a significant survival benefit.
In conclusion, we report that there is a significant survival benefit to 3KT and 4KT even among older patients. Although a highly selected cohort, outcomes following KT ≥3 are acceptable and comparable to the younger cohort of patients. Our results support improving access to 3KT and 4KT in older adults and that advanced age should not be a contraindication to a 3KT or 4KT. However, effort should be directed towards guiding the selection and management of patients with two or more graft failure and addressing some glaring disparities in access to 3KT and 4KT.
Supplementary Material
Acknowledgments
The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government.
This study was supported by NIH R01DK120518 (McAdams-DeMarco) and K24AI144954 (Segev). Mara McAdams-DeMarco was also supported by R01AG055781 from the National Institute on Aging and R01DK114074 from NIDDK. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, writing, review, or approval of the manuscript.
Abbreviations
- 3KT
third kidney transplantation
- 4KT
fourth kidney transplantation
- ACGF
all-cause graft failure
- CIT
cold ischemia time
- DCGF
death censored graft failure
- DGF
delayed graft function
- PNF
primary non-function
Footnotes
Disclosure
The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Dr. Segev receives speaking honoraria from Sanofi and Novartis. Dr. Shaifali Sandal has received an education grant from Amgen Canada. The other authors have no conflicts of interest to disclose.
Supporting Information
Additional supporting information may be found online in the Supporting Information section at the end of the article.
Data Availability Statement
This study entails analysis of publicly available data in the USRDS data set.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
This study entails analysis of publicly available data in the USRDS data set.