Outcomes in Recipients of Deceased-Donor AKI Kidneys

Some kidneys from deceased donors have been affected by acute kidney injury (AKI) related to the circumstances of death or to complications of treatment. Approximately one-third of kidneys from decreased donors with AKI are discarded, a rate that is higher than that in donors without AKI.

There are few data available on the risk of immunological complications associated with transplanting AKI kidneys. Tissue inflammation in AKI is related to multiple pathways. Peter P. Reese, MD, PhD, hypothesized that recipients of AKI kidneys would experience increased rates of acute rejection, both cellular and antibody, and formation of de novo donor-specific antibody (DSA).

To test the hypothesis, the researchers conducted a multicenter, prospective cohort study that included testing deceased-donor urine for injury biomarkers and detailed chart review of recipient outcomes, including biopsies. Detailed immunological data in the Deceased Donor Study were utilized to assess whether donor kidney injury and inflammation were associated with allograft failure and rejection. Results were reported in the American Journal of Kidney Diseases [2023;81(2):222-231].

AKI was identified using conventional serological definitions that rely on changes in serum creatinine concentration in addition to characterizing injury using urinary biomarkers including interleukin-18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). Using a subset of centers that had clinical protocols for routine posttransplant assessment of DSA, the researchers developed a study protocol to “harmonize adjudication of a composite outcome that included de novo DSA within 1 year after transplant.”

The primary outcome of interest was a composite of graft failure not due to death or biopsy-proven acute rejection (BPAR) in the first year following transplant. A secondary outcome was a composite of graft failure, rejection, or de novo DSA within the first year. Analyses utilized multivariable Fine-Gray models with death as a competing risk. The researchers measured concentrations of IL-18, KIM-1, and NGAL in deceased donor urine, and donor critical AKI was assessed using Acute Kidney Injury Network (AKIN) criteria.

The primary cohort included 1137 deceased-donor kidney transplant recipients at 13 centers. Mean recipient age was 53.7 years, 61% were male, 14% had received a previous kidney transplant, and 15% had estimated panel reactive antibody (PRA) >80%. Eighty-two percent of the cohort received rabbit antihymocyte globulin induction therapy, 15% received basiliximab, and 3% received alemtuzumab.

Compared with recipients who did not experience the primary composite outcome of rejection or allograft failure, those who did were more likely to be Black (57% vs 45%; P=.003), to have prior transplants (19% vs 13%; P=.04), and to have calculated PRA titers >80% (21% vs 14%; P=.05) for the association with all four levels of PRA. They were less likely to be discharged from the transplant hospital on tacrolimus (89% vs 97%; P<.001) or mycophenolate (93% vs 97%; P=.02). Thirty-seven percent of recipients experienced delayed graft function (DGF); those who experienced the primary outcome were more likely to have DGF than those without the primary outcome (54% vs 35%; P<.001).

Mean terminal serum creatinine was 1.21 for the deceased kidney donors, and 19% were DCD (donation after cardiovascular determination of death). Using AKIN stages of CKD, 73% of the kidneys were from donors with no AKI, 16% from donors with stage 1 AKI, 6% from donors with stage 2 AKI, and 5% from donors with stage 3 AKI.

During the first year following transplantation, 14% of kidney transplant recipients (n=159) experienced the primary outcome of graft failure or BPAR (107 met the primary outcome due to BPAR). Seventy-seven of the BPAR episodes were acute cellular rejection only, eight were antibody-mediated rejection only, 12 were both acute cellular rejection and antibody-mediated rejection, and 10 could not be definitively classified.

In multivariable analyses, there were no significant associations between urinary injury biomarkers and the primary  outcome. In fully adjusted models comparing highest- versus lowest-tertile biomarker concentrations, the subdistribution hazard ratios were 0.76 (95% CI, 0.45-1.28) for IL-18, 1.20 (95% CI, 0.69-2.07) for KIM-1, and 1.14 (95% CI, 0.71-1.84) for NGAL.

The subcohort with DSA screening included 422 recipients at five centers. Of those, 13% (n=54) had pretransplant DSA. By year 1, 20% (n=85) experienced the composite outcome of graft failure, acute rejection, and/or de novo DSA. Thirty-eight experienced the rejection outcome, 35 the de novo DSA outcome, and 12 the graft failure outcome. Twelve recipients died by year 1.

There was no significant association between urinary biomarkers and the secondary composite outcome. In fully adjusted models comparing the highest-tertile versus the lowest-tertile biomarker concentrations, the subdistribution HRs were 0.81 (95%CI, 0.42-1.56) for IL-18, 0.9 (95% CI, 0.43-1.87) for KIM-1, and 0.66 (95% CI, 0.34-1.29) for NGAL.

The association of urinary NGAL with rejection or allograft failure was modified by DCD status. There were no significant associations between donor urinary biomarkers and the outcome of BPAR, graft failure, or death. There was no association between donor AKI defined with the AKIN scale with the primary or secondary outcomes or with the outcomes of the exploratory analyses.

Limitations to the study cited by the authors included the possibility that an association between AKI and subclinical rejection was undetected due to limited power or because surveillance biopsies were not part of center protocols, and the possibility that centers accepted only AKI kidneys with otherwise favorable characteristics.

In conclusion, the researchers said, “In the multicenter study with close follow-up of recipients, donor injury biomarkers were associated with neither the primary outcome of graft failure and rejection nor a secondary outcome that included de novo DSA. These results should be confirmed in other cohorts. For transplant centers trying to develop greater experience with transplanting donor AKI kidneys, these findings provide initial evidence that accepting deceased-donor kidneys with AKI will not substantially increase risks of acute rejection under a regimen of robust immunosuppression.”

Takeaway Points

1. To test the hypothesis that recipients of AKI kidneys would experience increased rates of acute rejection, both cellular and antibody, and formation of de novo donor-specific antibody (DSA), researchers conducted a multicenter, prospective cohort study that included testing deceased-donor urine for injury biomarkers.
2. There were no significant associations between donor urinary injury biomarkers and the primary outcome of a composite of biopsy-proven acute rejection (BPAR) and graft failure.
3. There was also no association between the donor urinary injury biomarkers and the secondary outcome of a composite of BPAR, graft failure, and/or de novo donor-specific antibody.