Improving Access to Kidney Transplant: Could Kidneys with AKI Help Narrow the Gap?

It is well-established that compared with being on dialysis and on the waiting list for a kidney, receiving a kidney transplant offers longer survival and improved health-related quality of life across multiple domains. Post-transplant 1-year allograft and patient survival have persistently exceeded 90% for over a decade, and the 5-year relative risk of mortality is 75% of kidney recipients) receive a deceased donor kidney, approximately 10% of procured kidneys continue to be discarded, and an exceeding count are added to the waitlist, further widening the organ deficit.2 Over a tenth of individuals waiting for a kidney have been on the waitlist for more than 5 years and remain at an elevated risk of mortality.3 There are ongoing broad-scale efforts to improve organ utilization. In the United States, various strategies have been implemented by the Organ Procurement Transplantation Network and United Network for Organ Sharing including a standardized kidney allocation system (KAS), donor criteria expansion (e.g. hepatitis C positive donors), and, more recently, a distance-based KAS.4 However, kidney discard rates remain high, and there is concern that they have been worsening.3 A key component of the KAS implemented nearly a decade ago to improve kidney utilization is the Kidney Donor Profile Index (KDPI). Used to estimate the longevity of a deceased donor kidney from the time of transplant as compared with all recovered kidneys in the preceding year, the KDPI ranges from 0% to 100% and is estimated using ten variables: age, height, weight, race, ethnicity, hypertension, diabetes mellitus, hepatitis C status, cause of death, and donor serum creatine (SCr).2 Over 2/3 of discarded kidneys are discarded because of high KDPI2 and the proportion of candidates willing to accept a kidney with a high KDPI has been declining since its implementation.3 The inclusion of a static SCr value in the KDPI has particularly been challenged since its implementation.5 The use of SCr as a single cross-sectional value closest to death without considering the donor's baseline kidney function can contribute to inadvertent discard of kidneys with reversible AKI. A recent US registry-based study has in fact revealed that the majority of donor kidneys with elevated terminal SCr have stage 2 or 3 AKI,6 whereas another study including 59,000 patients in this Organ Procurement Transplantation Network/United Network for Organ Sharing database has shown no difference in adjusted risk of death-censored graft loss for kidneys with terminal SCr >2 mg/dl versus ≤2 mg/dl across KDPI ranges.5 These findings are noteworthy as there has been an increase in the discard of kidneys with terminal SCr >1.5 mg/dl from around 30% pre-2014 to approximately 40%, an incidence that is twice as high as those with terminal SCr 1/3 of procured kidneys with stage 2 AKI are discarded and the absolute number of discarded kidneys with AKI has significantly increased.6 This represents major loss as kidneys with stage 2 and 3 AKI comprise approximately 1/5 of donor kidneys. Irrespective of the potential influence of KDPI on decisions to discard donor kidneys with AKI, transplantation of kidneys with AKI in general has been an area of contention for multiple reasons: (1) AKI has been associated with high risk of short-term and long-term mortality and future decline of kidney function in multiple large database studies.7,8 And the more severe the AKI, the worse the outcomes. However, these data have come from health record studies of hospitalized, acutely ill patients where AKI is often a consequence of a systemic illness which is the primary driver of the poor outcomes. (2) Donor AKI (both based on SCr and biomarker change) has been associated with delayed graft function (DGF). DGF is a common complication of deceased donor kidney transplant which has been associated with higher odds of mortality and allograft failure.9 (3) In transplant recipients, there is the added concern that donor AKI could trigger recipient innate immune response increasing the risk of acute allograft rejection. Therefore, there is a great concern that transplanting AKI kidneys could put patients at higher risk of poor outcomes. The study by Scurt et al. in this issue of Kidney360 aims to address these concerns in a meta-analysis of 44 single-center, multicenter, and registry-based cohort studies including >200,000 recipients of donor kidneys with and without AKI.12 The authors examined the association of variously defined donor AKI with short-term outcomes such as DGF and primary nonfunction, as well as longer-term kidney function and mortality at various time points after transplantation (at discharge, 3 months, and at 1, 3, 5, and 8–10 years after deceased donor kidney transplant). Patients transplanted AKI kidneys had a 50% higher risk of DGF and lower kidney function at the time of discharge, with increasing risk of DGF by AKI stage. Hospital length of stay was also higher for recipients of AKI kidneys albeit with significant heterogeneity. Recipients of AKI kidneys had an 11% higher relative risk of allograft failure at 1 year (relative risk, 1.11; 95% confidence interval, 1.02 to 1.21), although there was no difference in graft survival in stratified analysis by AKI definition. There was no difference in risk of mortality at 1 year between those who received AKI kidneys versus no AKI kidneys. The authors further show no difference in primary nonfunction, and regardless of the severity of AKI at the time of transplant and the definition of AKI used, an equivalent risk of mortality and kidney function decline. As expected, longer-term graft and patient survival are similar, as the longer patients survive after the intervention (transplant), organ and patient survival become dependent on recipient rather than donor factors. Scurt et al. further assessed risk of acute rejection among nearly 60,000 kidney transplant recepients and found no increased risk of rejection. The findings of the lack of association with acute rejection are supported by recent evidence from a multicenter cohort study (Deceased Donor Study) by Reese et al. showing lack of association between elevated kidney injury biomarkers, such as IL-18, kidney injury molecule-1, and neutrophil gelatinase lipocalin and acute rejection.10 One of the limitations of the study is the variability of the definition of AKI used by the studies. Some used various arbitrary SCr cutoffs, whereas others used dynamic criteria. There was moderate-to-high risk of bias in several of the used studies, and recipient risk factors were not considered. Heterogeneity is a concern particularly in this type of study where studies that use different AKI definitions are being evaluated. As expected, the authors found those that used a static creatinine cutoff to define AKI had moderate-to-high heterogeneity while those that used a dynamic creatinine change to define AKI had low heterogeneity. This was particularly evident for acute rejection and hospital length of stay. The authors have tried to address their limitations by reporting on heterogeneity and presenting analyses stratified by stages of AKI, definitions of AKI and data source, and assessing for publication bias, with overall consistent findings. There is no question that there is room for improvement in deceased donor kidney utilization. Scurt et al. add to the growing body of evidence6,10,11 that over the long term, recipients of AKI kidneys appear to do just as well as those without AKI, regardless of the severity of AKI, despite a higher risk of DGF and lower kidney function at discharge (Figure 1). Careful consideration of recipient and donor risk for progression including the kidney's extent of fibrosis will likely improve prognostic ability. We argue that modifying the KDPI to account for baseline creatinine and promoting acceptability of donor kidneys with AKI could significantly narrow the access gap and improve survival and quality of life for patients on dialysis.Figure 1: Risk versus overall benefit of considering donor kidneys with AKI. Donor kidneys with AKI are associated with high risk of immediate complications, in particular, DGF, but have comparable long-term outcomes to donor kidneys with no AKI that warrant promoting their acceptability to close the current gap between kidney demand and supply. DGF, delayed graft function; LOS, length of stay; PNF, primary nonfunction.