Turn Down for What? Patient Outcomes Associated with Declining Increased Infectious Risk Kidneys

Abstract

Transplant candidates who accept a kidney labeled increased risk for disease transmission (IRD) accept a low risk of window period infection, yet those who decline must wait for another offer that might harbor other risks or never even come. To characterize survival benefit of accepting IRD kidneys, we used 2010–2014 SRTR data to identify 104,998 adult transplant candidates who were offered IRD kidneys that were eventually accepted by someone; the median (IQR) KDPI of these kidneys was 30 (16–49). We followed patients from the offer decision until death or end-of-study. After 5 years, only 31.0% of candidates who declined IRDs later received non-IRD DDKTs; the median KDPI of these non-IRD kidneys was 52, compared to 21 of the IRDs they had declined. After a brief risk period in the first 30 days following IRD acceptance [aHR accept vs decline: _1.222.06_3.49, p=0.008] (absolute mortality 0.8% vs. 0.4%), those who accepted IRDs were at 33% lower risk of death 1–6 months post-decision [aHR _0.500.67_0.90, p=0.006], and at 48% lower risk of death beyond 6 months post-decision [aHR _0.460.52_0.58, p<0.001]. Accepting an IRD kidney was associated with substantial long-term survival benefit; providers should consider this benefit when counseling patients on IRD offer acceptance.

INTRODUCTION

The percent of donors labeled increased risk for disease transmission (IRD) has increased from 10% in 2010 to 19.5% in 2015 (1). By definition, organs recovered from IRD donors maintain a low, but non-zero (2–4) risk of disease transmission ranging from <1 in 1000 for hepatitis C to <1 in 10,000 for HIV (5, 6), yet they are more likely to be recovered from younger and healthier donors (1). While IRD kidneys can engender administrative burden through consent documentation (7), medico-legal worries, patient concerns (8, 9), and recipient tracking and retesting, the pool of donors labeled IRD continues to grow as the national drug overdose epidemic persists and infiltrates deceased donor transplantation (10). Understanding the risks and benefits associated with acceptance of IRD kidneys is necessary as these organs continue to be offered to (and declined by) candidates on the deceased donor kidney transplant (DDKT) waitlist.

Unfortunately, the risks associated with IRD kidney transplantation remain controversial. Studies have shown similar (11–13) and higher (14) risk of mortality and reduced (11) and similar (12, 14) risk of graft failure associated with IRD versus standard criteria donor (SCD) kidney transplants. However, candidates on the waitlist do not have the opportunity to choose between simultaneous offers of an IRD kidney and a similar non-IRD kidney. Rather, candidates must decide whether to accept an IRD kidney now or wait for a non-IRD kidney in the future. Through simulation data, our group identified patient subgroups that might benefit from IRD kidney transplants (15); however, we were unable to identify candidates who were offered IRD kidneys or to determine the consequences of declining an IRD kidney using observational data. Furthermore, donors labeled IRD are more likely to be younger, have anoxia as cause of death, and less likely to be classified as extended criteria donors (1), and it is important to understand these donor factors in the context of survival benefit.

To better understand IRD acceptance practices and the impact of these clinical decisions, we used national registry data to study patients who declined an IRD kidney, the natural history of the decision to accept or decline these kidneys, and the survival benefit associated with accepting an IRD kidney.

METHODS

Data source

This study used data from the Scientific Registry of Transplant Recipients (SRTR). The SRTR data system includes data on all donors, wait-listed candidates, and transplant recipients in the U.S., submitted by the members of the Organ Procurement and Transplantation Network (OPTN), and has been described elsewhere (16). The Health Resources and Services Administration (HRSA), U.S. Department of Health and Human Services provides oversight to the activities of the OPTN and SRTR contractors.

Definition of PHS Increased Infectious Risk Donor

From 1994 to February 2014, the Public Health Service (PHS) guidelines mandated that donors who satisfied the following criteria be labeled by the recovering OPO as increased infectious risk or at increased risk for disease transmission (IRD): men who have had sex with men within the preceding 5 years; persons who reported nonmedical injection drug use within the preceding 5 years; persons who have had sex in exchange for money or drugs within the preceding 5 years; persons who have received human-derived clotting factor concentrates; persons who have had sex with any person satisfying the previous criteria or any person with known or suspected HIV infection; persons who have been exposed to HIV-infected blood; inmates of correctional facilities; persons whose medical or physical history reveal evidence of HIV-infection or high-risk behavior; persons who cannot be tested for HIV infection because of refusal or inadequate blood samples; persons with repeatedly reactive screening assays for HIV antibody; and children less than 18 months of age born to mothers with or at risk of HIV infection. In February 2014, the PHS guidelines were updated to include: persons with a history of certain behaviors within the preceding 12 months rather than the preceding five years; women who have had sex with men who have had sex with men in the previous 12 months; persons who were in any form of correctional facility for more than 72 hours in the preceding 12 months; persons who have been on hemodialysis within the preceding 12 months; persons who have been newly diagnosed with or treated for certain sexually transmitted diseases in the previous 12 months; and children who have been breastfed by a mother with known or suspected HIV infection. The 2014 guidelines also exclude some criteria previously required. The 2014 guidelines and changes made with respect to each criterion have been described in more detail elsewhere (1, 3).

Study population

We identified 104,998 adult kidney transplant candidates who were offered an IRD kidney that was eventually used for transplantation (for any patient) between 12/25/2009-1/6/2015. Of the 104,998 candidates, 6,521 accepted the IRD offer and were transplanted; 101,972 declined the IRD kidney, of whom 3,495 later accepted a different IRD kidney during the study period (and are included in both columns of Table 1). Candidates who were offered the IRD kidney in error (i.e. after death or removal from the waitlist, n=424) were excluded. Candidates who accepted an IRD kidney but were not transplanted (n=65) were excluded. We used χ-squared tests and Wilcoxon rank-sum tests to compare demographics (age, sex, race, and insurance type), clinical characteristics (diagnosis, ABO, peak Panel Reactive Antibody status (cPRA), and time on dialysis), and center wait time between candidates who accepted versus declined the IRD kidney. Candidate characteristics at their first IRD offer were used for these comparisons.

Table 1.

Characteristics of candidates on whose behalf IRD kidneys were accepted or declined between 12/25/2009 and 1/6/2015.

	Declined IRD kidney offer (n=101,972)	Accepted IRD kidney offer (n=6,521)	p-value
Age at offer (Med (IQR))	55 (44–63)	55 (45–63)	0.2
Female (%)	35.9	36.2
Race/Ethnicity (%)			<0.001
White	39.3	42.3
Black	31.8	35.3
Latino/Hispanic	19.5	15.0
Other	9.5	7.4
Primary Diagnosis (%)			<0.001
Glomerulonephritis	18.6	20.0
Diabetes	33.6	28.4
Hypertension	23.5	24.0
Other	24.2	27.6
Blood type (%)			<0.001
A	30.0	35.7
AB	3.2	4.7
B	11.1	12.3
O	55.7	47.3
Peak cPRA (%)			<0.001
0%	59.3	58.0
0–80%	31.1	27.4
≥80%	9.6	14.6
Years on dialysis (Med (IQR))	2.0 (0.4–3.8)	3.2 (0.5–5.4)	<0.001
Insurance Type (%)			<0.001
Public	55.4	58.8
Private	44.4	41.0
Other	0.2	0.2
Center time-to-transplant (%)			<0.001
<1 year	3.0	6.4
1–2 years	22.5	29.6
2–3 years	27.9	34.0
>3 years	46.6	30.1

Subsequent outcomes following IRD kidney decline

To understand the consequences of declining an IRD kidney offer, we followed 101,972 candidates who ever declined an IRD offer from the date of initial IRD decline until eventual non-IRD DDKT, IRD DDKT, living donor kidney transplant (LDKT), death, removal from the waitlist, or administrative censoring on 12/31/2016. Among candidates who later received non-IRD kidneys, we compared the KDPI of the accepted non-IRD kidney with the KDPI of the highest-quality IRD kidney they had previously declined using the Wilcoxon matched-pairs signed-ranks test. We reported five-year cumulative incidence of each potential outcome.

Survival benefit of IRD kidney acceptance

To characterize survival benefit associated with accepting an IRD kidney, we identified 5,702 candidates who accepted and were transplanted with an IRD kidney offer and estimated their mortality risk as compared to candidates who previously declined the same IRD kidney offer. To account for differences between offered IRD kidneys, we matched candidates who accepted the IRD kidney with all candidates who had previously declined the exact same IRD kidney. Candidates who accepted the IRD offer were matched with a median (interquartile range (IQR)) of 11 (4–51) candidates who had previously declined the same IRD kidney. Candidates who accepted the IRD kidney at the initial offer (n=819) (i.e. they were the first to receive the offer) were excluded as there were no candidates who declined the kidney with whom they could be compared. A total of 100,959 candidates who declined the IRD offers were identified as matched controls.

Candidates were followed from the date of transplant (for those who accepted) or the date of the IRD offer decline (for those who declined) until date of death or administrative censoring on 12/31/2016, irrespective of subsequent transplants. We used Cox regression with adjustment for candidate demographic and clinical factors to compare patient mortality between those who had accepted versus declined the IRD kidney. Candidates who declined an IRD kidney offer but later accepted a different IRD kidney were considered to have had a time-varying exposure, with time-at-risk between the decline and the acceptance contributing to the decline risk set, and subsequent time-at-risk contributing to the accept risk set. In other words, these candidates were censored at the date of IRD kidney transplant and entered into the IRD acceptance risk group to be followed forward from the date of IRD transplant. Candidates who declined multiple IRD kidneys were included as independent matched controls for each IRD declined. We applied weights to the matched controls to ensure equality in the sum of the weights for candidates who accepted or declined each IRD kidney. To account for different demographic and clinical characteristics of candidates who accepted or declined the IRD kidney offers, we adjusted the final model for candidate blood type, time on dialysis, age at time of offer, race, sex, cPRA, and diagnosis (categorized as glomerulonephritis, diabetes, hypertension, and other). Finally, to determine whether the survival benefit of IRD acceptance varied by center wait time, we tested the interaction between accepting an IRD and the median time-to-transplantation of the candidate’s center in the model.

Time-varying hazard of IRD kidney acceptance

Candidates who accepted the IRD kidney faced a perioperative risk period following transplantation, and those who declined the IRD kidney did not face this perioperative period. As such, the proportional hazards assumption fails, and we must estimate the time-varying nature of the hazard following acceptance of an IRD kidney. We estimated hazard of IRD acceptance within the first 30 days post-acceptance to capture perioperative risk, between 1–6 months post-acceptance, and beyond 6 months post-acceptance; these time bins were determined empirically.

Quality and discard of IRD kidneys

To understand whether high quality IRD kidneys were being discarded (defined as recovered but not transplanted), we identified 7,670 IRD and 51,832 non-IRD kidneys that were used for kidney transplant and 1,580 IRD and 11,815 non-IRD kidneys that were discarded between 12/25/2009 and 1/6/2015. Donors with unknown PHS-guidelines IRD designation (n=47) were excluded. Using the Kidney Donor Profile Index (KDPI), we compared the quality of IRD and non-IRD kidneys that were used and the quality of those that were discarded using Wilcoxon rank sum tests. We estimated the relative rate of discard of IRD versus non-IRD kidneys using modified Poisson regression. To determine whether discard of IRD kidneys varied by KDPI, we tested the interaction between the relative rate of discard and categories of KDPI of the recovered kidney; KDPI categories <30, 30–50, 51–70, and 71–100 were determined empirically.

Sensitivity analysis

To determine whether the use of candidates who declined multiple IRD offers as independently matched controls introduced a bias in our final model, we performed a sensitivity analysis in which, for each candidate who accepted an IRD kidney, we selected a single matched control from those who declined the same kidney. Sampling was done without replacement such that no candidate was a control for more than one IRD recipient.

RESULTS

Study population

Compared to candidates who declined IRD kidneys, candidates who accepted IRD kidneys were more likely to be white (42.3% vs 39.3%, p<0.001), have glomerulonephritis (20.0% vs 18.6%, p<0.001), and be highly sensitized (cPRA≥80: 14.6% vs 9.6%, p<0.001) (Table 1). Candidates who accepted IRDs had spent more time on dialysis prior to the IRD offer (med (IQR) 3.2 years (0.5–5.4) vs 2.0 years (0.4–3.8), p<0.001) and were more likely to be listed at centers with shorter median wait time (30.1% of IRD acceptors vs 46.6% of IRD decliners at centers with >3 year wait time, p<0.001). The percent of candidates who accepted an IRD offer increased slightly over the study period such that 3.5%, 6.6%, 6.9%, 5.8%, and 7.8% of candidates accepted IRD offers with each year of the study, respectively.

Consequences of declining an IRD kidney

Five years after the decision to decline an IRD kidney, 31.0% of candidates had received a non-IRD DDKT, 6.1% had received an IRD DDKT, 8.0% had received an LDKT, 20.0% had died, 19.5% were removed from the waitlist for other reasons, and 15.5% were still on the waitlist (Figure 1). We identified 29,134 candidates who declined an IRD and later received a non-IRD DDKT. These candidates declined IRDs with a median (IQR) KDPI of 21 (10–38) and accepted non-IRDs with a median KDPI of 52 (30–72) (Figure 2). This represents a median (IQR) difference of 25 (0.4 to 48) KDPI percentage points between what they had accepted and had previously declined (p<0.001). We identified 5,672 candidates who declined an IRD and later received an IRD DDKT. These candidates declined a similar distribution of IRD kidneys with KDPI 21 (11–39), and later accepted IRD kidneys with median KDPI of 33 (18–52).

Figure 1. Subsequent outcomes among candidates (n=101,972) who declined an IRD kidney between 12/25/2009-1/6/2015.

Candidates followed from data of IRD decline. Five-year cumulative incidence reported for each potential outcome.

*Reasons for removal from the waitlist included transferred to another center, transplant at another center, candidate condition improved, candidate removed in error, transplanted in another country, unable to contact candidate, refused transplant, and other.

Figure 2.

Among candidates who declined an IRD kidney and later received a non-IRD DDKT: KDPI of the highest quality IRD that they had declined and KDPI of the non-IRD kidney that they eventually accepted.

Survival benefit of IRD kidney acceptance

Those who accepted IRD kidneys experienced a perioperative risk period within 30-days post-acceptance, with a 2-fold higher risk of death compared to those who declined the IRD offer (aHR _1.222.06_3.49, p<0.01) (Table 2). This elevated hazard translated to a crude mortality of 0.8% among those who accepted the IRD offer and 0.4% mortality among those who declined the IRD offer (Figure 3). Following this perioperative period, those who accepted IRD kidneys were at a 33% reduced risk of death 1 – 6 months post-decision (aHR, _0.500.67_0.90, p<0.01) and at an 48% reduced risk of death after 6 months post-decision (aHR _0.460.52_0.58, p<0.001) compared to those who declined the IRD (Table 2). Five years post-decision, crude mortality was 14.0% among those who accepted the IRD offer and 22.5% among those who declined (Figure 3, p<0.001). The interaction between center median time to transplantation and the survival benefit of accepting an IRD was not statistically significant (p=0.8), indicating that the survival benefit incurred by accepting an IRD transplant did not vary by center-level differences in time-to-transplantation.

Table 2.

Time-varying hazard ratio of mortality associated with accepting versus declining an IRD kidney offer.

Time post-decision	aHR of Acceptance vs Decline	p-value
Within 30 days	1.222.063.49	<0.01
1–6 months	0.500.670.90	<0.01
After 6 months	0.460.520.58	<0.001

Candidates matched on IRD kidney. Model adjusted for candidate age, sex, race/ethnicity, primary indication for transplant, time on dialysis, calculated panel reactive antibody status, and blood type.

Figure 3. Patient mortality among those who accepted versus declined the IRD kidney offer.

Candidates matched on IRD kidney offer. Within the first 30 days post-acceptance, mortality was 0.8% and 0.4% for those who accepted versus declined the IRD offer, respectively. Five years post-acceptance, mortality was 14.0% and 22.5% among those who accepted versus declined the IRD offer, respectively.

Quality and discard of IRD kidneys

Over the study period, IRD and non-IRD kidneys accepted for transplantation had a median (IQR) KDPI of 30 (16–49) and 44 (21–67), respectively (Figure 4a). IRD and non-IRD kidneys that were discarded had median KDPI of 64 (43–83) and 84 (66–93), respectively (Figure 4b). Among discarded kidneys, 34% of IRDs compared to 12% of non-IRDs had KDPI below 50. IRD kidneys were more likely to be discarded than non-IRD kidneys in each KDPI strata, however, the relative rate of discard varied across strata (p-value interaction term<0.001). IRD kidneys with KDPI<30 were 1.53-times more likely to be discarded (Relative rate (RR): _1.301.53_1.81), with KDPI 30–50 were 2.17-times more likely (RR: _1.932.17_2.44, p<0.001), with KDPI 51–70 were 1.59-times more likely (RR: _1.451.59_1.75), and with KDPI>70 were 1.13-times more likely to be discarded (RR: _1.061.13_1.20) than non-IRD kidneys with the same KDPI (p-values<0.001).

Figure 4. Distribution of KDPI among IRD and non-IRD kidneys that were (a) used for transplant or (b) discarded over the study period.

(a) IRD and Non-IRD kidneys that were used for transplantation

(b) IRD and Non-IRD kidneys that were discarded

Sensitivity analysis

In an analysis that matched without replacement, our inferences with respect to the survival benefit of accepting an IRD kidney were consistent with the main model (aHR within 30 days: _1.462.64-_4.78, p=0.001; aHR from 1–6 months: _0.510.69_0.94, p=0.02; and aHR beyond 6 months: _0.470.53_0.60, p<0.001).

DISCUSSION

In this national study, we found that acceptance of an IRD kidney was associated with long-term survival benefit when compared to declining the IRD offer. Candidates who accepted IRD kidney offers experienced a 48% reduced risk of death that continued beyond six-months after the decision to accept the IRD kidney. Among candidates who declined IRD kidneys, only 31% of candidates received non-IRD kidney transplants within five years of the IRD-decline, and they accepted non-IRD kidneys with significantly higher KDPI than the IRD kidney they had declined. Finally, we found that IRD kidneys were more likely to be discarded than non-IRD kidneys across KDPI, however IRD kidneys with KDPI 30–50 faced the highest relative rate of discard at 2.17-times the rate of comparable non-IRD kidneys.

By definition, IRD kidneys are associated with an increased risk of infection, around 1 in 1000 risk of HCV and 1 in 10,000 risk of HIV (5, 6). The estimated risk of infection also varies by the criterion for which the donor was labeled IRD, with injection drug users posing the highest HCV risk at 32.4 per 10,000, men who have sex with men at 3.5 per 10,000, and hemophiliac donors at 0.027 per 10,000 (5). One study of IRD recipients has shown higher mortality in IRD as compared to SCD recipients (14), however, this analysis was based on data from 1996 to 2007 and the clinical characteristics of donors labeled IRD has changed significantly over time, even more so since the PHS guidelines change in 2014 (1). More recent studies of outcomes following IRD transplants have shown similar patient mortality and graft loss between IRD and non-IRD recipients (11, 12). More importantly, however, is the fact that candidates on the waitlist are not faced with the decision to accept an IRD or non-IRD kidney of similar quality at the same time, in which case the decision might be clear. Candidates are more often faced with the decision to accept an IRD kidney or to decline it and wait for a non-IRD kidney without knowing how long they will have to wait. Our study suggests that IRD kidneys provide a significant and substantial survival benefit to candidates who accepted them for transplant compared to those who declined them and waited for a non-IRD kidney. While we were unable to determine viral transmission in candidates who accepted IRD kidneys, the risks of disease transmission, while non-zero (17), are low, with separate studies of 368 (14), 89 (11), and 50 IRD recipients (12) each having reported zero viral transmissions after 3.9 years, 4.3 years, and 11.3 months of follow-up time, respectively.

The benefit of accepting marginal kidneys can vary on a case-by-case basis or depend on the candidate’s expected time to another kidney offer (18); however, our analysis showed that benefit of IRD kidneys remained significant after adjustment for recipient characteristics and that it did not depend on center wait time. The benefit of IRD kidneys despite candidate factors is likely related to the high quality of each offer. While other studies aim to demonstrate benefit of kidneys known to be associated with worse outcomes, IRD kidneys in our study had a median KDPI of 30, and were more likely to be recovered from younger, healthier donors (1, 12). Additionally, we were able to more accurately estimate survival benefit by identifying the population of candidates who were offered IRD kidneys. Previous analyses of survival benefit were limited to using candidates who remained on the waitlist as the comparison group (18, 19), whereas patients who received the marginal kidney offer and turned it down are likely different from candidates who might not have received the offer at all.

We also found that 34% of the pool of discarded IRD kidneys have KDPI below 50, and that IRD kidneys face a 1.13–2.17-times higher rate of discard than comparable IRD kidneys depending on KDPI. These findings are consistent with other studies that have shown elevated rates of discard within this phenotype of recovered deceased-donor kidneys (20, 21). However, we have also shown that IRD kidneys within the low-to-middle range of KDPI (30–50) faced greater scrutiny when considered for transplant and were 2.2-times more likely to be discarded than comparable non-IRD kidneys, while IRD kidneys with higher KDPI (70–100) were only 1.13-times more likely to be discarded than comparable non-IRD kidneys. This analysis indicates that despite the high quality of IRD kidneys, they continue to be regarded with disparate scrutiny for transplantation (22), and it further supports the current discourse on improving utilization of these organs (20, 23–25).

It is important to note that our survival benefit analysis included only IRD kidneys that were eventually transplanted. However, given the lengthy kidney transplant waitlist, continued poor outcomes of candidates who remain waitlisted, and the increase in available IRD kidneys driven by the national drug overdose epidemic (10), it is reasonable to believe that this analysis underestimates the benefits provided by IRD kidneys for candidates on the waitlist (26) and that increased utilization of these kidneys could improve waitlist outcomes.

Our study has several limitations that merit discussion. While our prior simulation of survival benefit did show that benefit varied with specific risk category of the donor (15), our ability to determine such differences in the current study is limited by the granularity of our data. However, the rates of disease transmission following IRD transplant are low (5, 6), and thus the unmeasured rates of disease transmission are unlikely to change the main inferences of our survival benefit analysis. Our use of candidates who declined an IRD offer as the matched controls for the transplanted candidate might be confounded by indication if there are unmeasured differences in the health of patients who accepted or declined IRD kidney offers. However, our use of candidates who declined the same IRD kidney allowed for the closest approximation of the counterfactual in this estimation of survival benefit.

We have found that accepting an IRD kidney was associated with long-term survival benefit, and we have quantified the potential consequences of declining an IRD kidney that patients and providers need to discuss when an IRD kidney becomes available. Kidney transplant candidates might be best served with open discussion about the potential benefits of IRD kidneys during listing and offer acceptance decision-making processes.

ABBREVIATIONS

aHR

adjusted hazard ratio

aOR

adjusted odds ratio

BMI

body mass index

CDC

Centers for Disease Control and Prevention

DDKT

deceased donor kidney transplant

cPRA

calculated panel reactive antibody

IRD

increased risk for disease transmission

IQR

interquartile range

KDPI

kidney donor profile index

OPTN

Organ Procurement and Transplantation Network

PHS

Public Health Service

SCD

standard criteria donor

SRTR

Scientific Registry of Transplant Recipients