TY - JOUR
T1 - Deceased-Donor Acute Kidney Injury and Acute Rejection in Kidney Transplant Recipients
T2 - A Multicenter Cohort
AU - Reese, Peter P.
AU - Doshi, Mona D.
AU - Hall, Isaac E.
AU - Besharatian, Behdad
AU - Bromberg, Jonathan S.
AU - Thiessen-Philbrook, Heather
AU - Jia, Yaqi
AU - Kamoun, Malek
AU - Mansour, Sherry G.
AU - Akalin, Enver
AU - Harhay, Meera N.
AU - Mohan, Sumit
AU - Muthukumar, Thangamani
AU - Schröppel, Bernd
AU - Singh, Pooja
AU - Weng, Francis L.
AU - Parikh, Chirag R.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH)/National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01DK93770 and K24DK090203 to Dr Parikh; George M. O’Brien Kidney Center at Yale Grant P30DK079310 to Dr Parikh; and a grant to Dr Hall by the NIH/ National Center for Advancing Translational Sciences (NCATS) under award numbers UL1TR002538 and KL2TR002539 . This work was supported in part by Health Resources and Services Administration contract HHSH250-2019-00001C . The funders did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication.
Funding Information:
The authors declare that they have no relevant financial interests. The following lists nonrelevant financial interests for authors who hold them. Dr Bromberg acknowledges clinical research support from Novartis, CareDx, and Natera. Dr Weng acknowledges support as coinvestigator from Merck, Novartis, Angion Biomedica, CareDx, Medeor Therapeutics, CSL Behring, and Natera. Dr Harhay acknowledges a consultancy agreement with Nephria Bio. Dr Reese has received grant support from Merck, AbbVie, and Gilead related to transplanting organs from HCV-infected donors and has also consulted for VALHealth on the identification of patients with CKD. Dr Parikh is a member of the advisory board of, and owns equity in, RenalytixAI, and also serves as a consultant for Genfit and Novartis. Dr Mohan has received grant support from the Kidney Transplant Collaborative and Angion Biomedica. Dr Schröppel acknowledges consultancy agreements with Novartis, Astellas, Amgen, Vifor Pharma, and AstraZeneka. Dr Akalin is a member of the advisory board for CareDx, Immucor, Exosome, and Takeda; has received grants support from CareDx and Immucor; and is a principal investigator on clinical trials with Astellas, Angion, and Ampylix. All authors report receipt of NIH support.
Publisher Copyright:
© 2022 The Authors
PY - 2023/2
Y1 - 2023/2
N2 - Rationale & Objective: Donor acute kidney injury (AKI) activates innate immunity, enhances HLA expression in the kidney allograft, and provokes recipient alloimmune responses. We hypothesized that injury and inflammation that manifested in deceased-donor urine biomarkers would be associated with higher rates of biopsy-proven acute rejection (BPAR) and allograft failure after transplantation. Study Design: Prospective cohort. Setting & Participants: 862 deceased donors for 1,137 kidney recipients at 13 centers. Exposures: We measured concentrations of interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) in deceased donor urine. We also used the Acute Kidney Injury Network (AKIN) criteria to assess donor clinical AKI. Outcomes: The primary outcome was a composite of BPAR and graft failure (not from death). A secondary outcome was the composite of BPAR, graft failure, and/or de novo donor-specific antibody (DSA). Outcomes were ascertained in the first posttransplant year. Analytical Approach: Multivariable Fine-Gray models with death as a competing risk. Results: Mean recipient age was 54 ± 13 (SD) years, and 82% received antithymocyte globulin. We found no significant associations between donor urinary IL-18, KIM-1, and NGAL and the primary outcome (subdistribution hazard ratio [HR] for highest vs lowest tertile of 0.76 [95% CI, 0.45-1.28], 1.20 [95% CI, 0.69-2.07], and 1.14 [95% CI, 0.71-1.84], respectively). In secondary analyses, we detected no significant associations between clinically defined AKI and the primary outcome or between donor biomarkers and the composite outcome of BPAR, graft failure, and/or de novo DSA. Limitations: BPAR was ascertained through for-cause biopsies, not surveillance biopsies. Conclusions: In a large cohort of kidney recipients who almost all received induction with thymoglobulin, donor injury biomarkers were associated with neither graft failure and rejection nor a secondary outcome that included de novo DSA. These findings provide some reassurance that centers can successfully manage immunological complications using deceased-donor kidneys with AKI.
AB - Rationale & Objective: Donor acute kidney injury (AKI) activates innate immunity, enhances HLA expression in the kidney allograft, and provokes recipient alloimmune responses. We hypothesized that injury and inflammation that manifested in deceased-donor urine biomarkers would be associated with higher rates of biopsy-proven acute rejection (BPAR) and allograft failure after transplantation. Study Design: Prospective cohort. Setting & Participants: 862 deceased donors for 1,137 kidney recipients at 13 centers. Exposures: We measured concentrations of interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) in deceased donor urine. We also used the Acute Kidney Injury Network (AKIN) criteria to assess donor clinical AKI. Outcomes: The primary outcome was a composite of BPAR and graft failure (not from death). A secondary outcome was the composite of BPAR, graft failure, and/or de novo donor-specific antibody (DSA). Outcomes were ascertained in the first posttransplant year. Analytical Approach: Multivariable Fine-Gray models with death as a competing risk. Results: Mean recipient age was 54 ± 13 (SD) years, and 82% received antithymocyte globulin. We found no significant associations between donor urinary IL-18, KIM-1, and NGAL and the primary outcome (subdistribution hazard ratio [HR] for highest vs lowest tertile of 0.76 [95% CI, 0.45-1.28], 1.20 [95% CI, 0.69-2.07], and 1.14 [95% CI, 0.71-1.84], respectively). In secondary analyses, we detected no significant associations between clinically defined AKI and the primary outcome or between donor biomarkers and the composite outcome of BPAR, graft failure, and/or de novo DSA. Limitations: BPAR was ascertained through for-cause biopsies, not surveillance biopsies. Conclusions: In a large cohort of kidney recipients who almost all received induction with thymoglobulin, donor injury biomarkers were associated with neither graft failure and rejection nor a secondary outcome that included de novo DSA. These findings provide some reassurance that centers can successfully manage immunological complications using deceased-donor kidneys with AKI.
KW - Kidney transplantation
KW - acute kidney injury (AKI)
KW - biomarkers
KW - biopsy-proven acute rejection (BPAR)
KW - de novo DSA
KW - deceased organ donation
KW - donor-specific antibody (DSA)
KW - graft failure
KW - inflammation
KW - injury hypothesis
KW - organ acceptance
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U2 - 10.1053/j.ajkd.2022.08.011
DO - 10.1053/j.ajkd.2022.08.011
M3 - Article
C2 - 36191727
AN - SCOPUS:85144506125
SN - 0272-6386
VL - 81
SP - 222-231.e1
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 2
ER -