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. 2024 Mar 1;19(3):345-354.
doi: 10.2215/CJN.0000000000000370. Epub 2023 Nov 29.

Time-Varying Determinants of Graft Failure in Pediatric Kidney Transplantation in Europe

Ferran Coens  1 , Noël Knops  2   3 , Ineke Tieken  4 , Serge Vogelaar  4 , Andreas Bender  5   6 , Jon Jin Kim  7 , Kai Krupka  8   9 , Lars Pape  9   10 , Ann Raes  1 , Burkhard Tönshoff  8   9 , Agnieszka Prytula  1 ; CERTAIN Registry
Collaborators, Affiliations

Time-Varying Determinants of Graft Failure in Pediatric Kidney Transplantation in Europe

Ferran Coens et al. Clin J Am Soc Nephrol. .

Abstract

Background: Little is known about the time-varying determinants of kidney graft failure in children.

Methods: We performed a retrospective study of primary pediatric kidney transplant recipients (younger than 18 years) from the Eurotransplant registry (1990-2020). Piece-wise exponential additive mixed models were applied to analyze time-varying recipient, donor, and transplant risk factors. Primary outcome was death-censored graft failure.

Results: We report on 4528 kidney transplantations, of which 68% with deceased and 32% with living donor. One thousand six hundred and thirty-eight recipients experienced graft failure, and 168 died with a functioning graft. Between 2011 and 2020, the 5-year graft failure risk was 10% for deceased donor and 4% for living donor kidney transplant recipients. Risk of graft failure decreased five-fold from 1990 to 2020. The association between living donor transplantation and the lower risk of graft failure was strongest in the first month post-transplant (adjusted hazard ratio, 0.58; 95% confidence interval, 0.46 to 0.73) and remained statistically significant until 12 years post-transplant. Risk factors for graft failure in the first 2 years were deceased donor younger than 12 years or older than 46 years, potentially recurrent kidney disease, and panel-reactive antibody >0%. Other determinants of graft failure included dialysis before transplantation (until 5 years post-transplant), human leukocyte antigen mismatch 2-4 (0-15 years post-transplant), human leukocyte antigen mismatch 5-6 (2-12 years post-transplant), and hemodialysis (8-14 years post-transplant). Recipients older than 11 years at transplantation had a higher risk of graft failure 1-8 years post-transplant compared with other age groups, whereas young recipients had a lower risk throughout follow-up. Analysis of the combined effect of post-transplant time and recipient age showed a higher rate of graft failure during the first 5 years post-transplant in adolescents compared with young transplant recipients. In contrast to deceased donor younger than 12 years, deceased donor older than 46 years was consistently associated with a higher graft failure risk.

Conclusions: We report a long-term inverse association between living donor kidney transplantation and the risk of graft failure. The determinants of graft failure varied with time. There was a significant cumulative effect of adolescence and time post-transplant. The ideal donor age window was dependent on time post-transplant.

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Conflict of interest statement

J.J. Kim acknowledges funding from a MRC NIHR fellowship (MR/V037900/1). N. Knops reports research funding from Sandoz. L. Pape reports consultancy for Alexion, Alnylam, Chiesi, Neovii, and Novartis; research funding from Chiesi, Germany; and honoraria from Alexion and Chiesi. A. Prytula reports research funding from Astellas and Novo Nordisk. I. Tieken reports other interests or relationships with Eurotransplant. B. Toenshoff reports consulting fees from Bristol-Myers Squibb, Chiesi, CSL Behring Biotherapies for Life, and Vifor; research grants from Astellas, Chiesi, and Novartis; and participation in advisory boards of Bristol-Myers Squibb, Chiesi, and Vifor. S. Vogelaar reports employment with Eurotransplant International. Cooperative European Paediatric Renal TransplAnt INitiative (CERTAIN) registry acknowledges financial contribution from the Dietmar Hopp Stiftung, the European Society for Pediatric Nephrology (ESPN), the German Society for Pediatric Nephrology (GPN), and by grants from the pharmaceutical companies Astellas and Novartis. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Death-censored graft survival after primary kidney transplantation with 95% confidence intervals (CI), stratified by transplant period and donor type. Shades represent 95% CI. DD, deceased donor; LD, living donor.
Figure 2
Figure 2
Baseline hazard, time-fixed effect of transplant year, and hazard ratios for graft failure by time post-transplant for HLA mismatch 5–6, PRA, potentially recurrent kidney disease, cystic kidney disease, hemodialysis, and living donor source. Baseline hazard (A), time-fixed effect of transplant year (B), and hazard ratios for graft failure by time post-transplant for HLA mismatch 5–6 (C), PRA (D and E), potentially recurrent kidney disease (F), cystic kidney disease (G), hemodialysis (H), and living donor source (I). Solid lines represent HR; shades represent 95% CI. All models were adjusted for potential time-varying effects of recipient and donor sex, donor source, PRA, kidney disease, donor/recipient age, and time-fixed effects of transplant year and transplant country and included all primary kidney transplants unless otherwise noted. (C) Analysis restricted to all deceased donor transplants and additionally adjusted for potential time-varying effect of HLA mismatch. (H) Analysis restricted to all non-preemptive deceased donor transplants between 2001 and 2020 and additionally adjusted for potential time-varying effect of HLA mismatch, dialysis vintage, and modality. CAKUT, congenital anomalies of the kidney and urinary tract; HLA, human leukocyte antigen; HR, hazard ratio; PRA, panel-reactive antibody.
Figure 3
Figure 3
Hazard ratios for graft failure by time post-transplant for recipient age at transplantation, dialysis vintage, deceased donor age, and living donor age. Hazard ratios for graft failure by time post-transplant for recipient age at transplantation (A), dialysis vintage (B), deceased donor age (C), and living donor age (D). All models were adjusted for potential time-varying effects of recipient and donor sex, donor source, PRA, kidney disease, donor/recipient age, and time-fixed effects of transplant year and transplant country and included all primary kidney transplants unless otherwise noted. (B) Analysis restricted to all deceased donor transplants between 2001 and 2020 and additionally adjusted for potential time-varying effect of HLA mismatch and dialysis vintage. (C) Analysis restricted to all deceased donor transplants and additionally adjusted for potential time-varying effect of HLA mismatch. (D) Analysis restricted to all living donor transplants.
Figure 4
Figure 4
Baseline hazard ratio for graft failure for a 5-, 10-, and 15-year-old recipient at transplantation between 1 and 15 years post-transplant. Baseline hazard ratio for graft failure for a 5- (A and D), 10- (B and D), and 15-year-old (C and D) recipient at transplantation between 1 and 15 years post-transplant. Facets illustrate the combined effect of time post-transplant (baseline hazard) and the time-varying effect of recipient age. Solid lines represent HR; shades represent 95% CI. The model was adjusted for potential time-varying effects of recipient and donor sex, donor source, PRA, kidney disease, donor/recipient age, and time-fixed effects of transplant year and transplant country and included all primary kidney transplants.
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