#1450 Polygenic risk score of native IgA nephropathy predicts risk of post-transplant disease recurrence
Authors: Zanoni Francesca , Naesens Maarten , Leal Rita , Amoroso Antonio , Caliskan Yasar , Keating Brendan , Gharavi Ali , Castellano Giuseppe , Batal Ibrahim , Kiryluk Krzysztof 
Published: May 2024

Abstract

Background and Aims
IgA nephropathy (IgAN) is a polygenic immune-mediated progressive glomerular disease. Recent GWAS reported that high genome-wide polygenic risk score (IgAN GPS), including 1 249 077 variants mapping to systemic immune pathways, was associated with risk of end stage kidney disease (ESKD). Post transplant (KTx) IgAN recurrence occurs in 30% of cases and it is a major cause of graft loss. Pathogenesis and predictors of IgAN recurrence are still not well defined. Herein, we studied the role of native IgAN GPS and clinical factors in predicting post-KTx IgAN recurrence and graft failure in a large cohort of KTx recipients.

Method
Four thousand one hundred eighty six KTx recipients from 6 sites were genome wide genotyped and imputed against multi-ancestry reference panels, retrieving &gt;10 million variants. In each recipient, native IgAN GPS was computed and standard-normalized (i.e. expressed in units of standard deviations from the mean distribution in matched controls). Native kidney disease diagnosis, clinical parameters, and post-KTx outcome data were retrieved retrospectively from clinical charts. The IgAN GPS was tested as predictor of native IgAN in the entire KTx cohort in a logistic regression model adjusted for sex, age, recruitment site, and first 5 PCs. IgAN GPS was tested as predictor of age at transplantation (proxy for age at ESKD) among KTx recipients with native IgAN in a linear regression model adjusted for sex, recruitment site, and first 5 PCs.
In recipients with native IgAN, recipient and donor parameters were individually tested as predictors for time to IgAN recurrence and time to graft failure in Cox proportional hazards models adjusted for recruitment site and first 5 PCs. Predictors with P-value &lt; .1 were included in the multivariable models. Recipient IgAN GPS was added to the clinical models and tested for prediction of time-to IgAN recurrence, and, among KTx recipients with IgAN recurrence, of time-to subsequent graft failure.

Results
Three hundred sixty nine KTx recipients were affected by native IgAN, 271 were of male sex, median age at transplantation was 45 years, and 149 received a living donor KTx. Over a median follow-up time of 46 months, 96 IgAN recurrence events occurred, and, among KTx recipients with recurrent IgAN, 27 subsequent graft failure events occurred after 100 months post KTx. IgAN GPS significantly predicted native IgAN cases among all KTx recipients (OR [95% CI]: 1.95 [1.76,2.16], p = 5.60E-07, AUROC 0.73), and lower age at transplantation among recipients with native IgAN (beta [s.e.]: −1.11[0.55], p = 0.04). Clinical model for IgAN recurrence included age, sex, year of transplant, HLA mismatch, recruitment site, and first 5 PCs; clinical model for graft failure included age, sex, year of transplant, HLA mismatch, type of donation, donor age, sex, rejection events, recruitment site, and first 5 PCs. At the multivariable analysis, IgAN GPS, lower age at transplantation, lower HLA mismatch, and higher year of transplant were independently associated with time to IgAN recurrence (Fig. 1a). Among KTx recipients with recurrent IgAN, higher IgAN GPS predicted time-to graft failure independently from clinical factors (Fig. 1b), but not in non-recurrent cases.

Conclusion
In the KTx setting, IgAN GPS was an independent predictor of IgAN recurrence, suggesting shared genetic susceptibility between native and recurrent IgAN. In addition, associations of IgAN GPS with lower age at transplantation, and with graft failure among recurrent IgAN cases, suggest that IgAN GPS may be predictive of a more aggressive native as well as recurrent disease. Associations with lower HLA mismatch advocate donor-recipient genetic similarities as potential additional predictors of IgAN recurrence. These data, which need external validation, may provide potential new insights into the pathobiology and prediction of recurrent IgAN.