Document Type

Article

Publication Date

6-2026

Identifier

DOI: 10.1016/j.kint.2026.01.026; PMCID: PMC13065301

Abstract

INTRODUCTION: Nephrotic syndrome (NS), a common glomerular disease in children, is classified based on response to corticosteroid therapy as either steroid-sensitive nephrotic syndrome (SSNS), or steroid-resistant nephrotic syndrome (SRNS). However, there are no current reliable predictors of therapy response at initial clinical presentation.

METHODS: To evaluate predictors, we conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 children (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched control individuals.

RESULTS: A significant association with HLA loci defined by variants in HLA-DQB1, HLA-DRB1, and HLA-DQA1 were found for SSNS (but not SRNS), along with a second immune-related SSNS locus: CLEC16A. A PRS that discriminates between SSNS and SRNS was validated in two independent cohorts. The HLA haplotype HLA- DRB1∗07:01∼DQA1∗02:01∼DQB1∗02:02 was associated with about four times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at disease onset was the best predictor of steroid responsiveness with an area under the curve of 0.68-0.70 and an overall classification accuracy of SSNS versus SRNS of 67-71%.

CONCLUSIONS: Our findings confirm that SSNS, unlike SRNS, is an immune-mediated HLA-associated disorder. The PRS for therapy response and HLA haplotype can serve as biomarkers, provide a foundation for more accurate diagnoses and tailored individualized treatment.

Journal Title

Kidney international

Volume

109

Issue

6

First Page

1256

Last Page

1268

MeSH Keywords

Humans; Nephrotic Syndrome; Child; Female; Male; Genome-Wide Association Study; Child, Preschool; HLA-DQ alpha-Chains; HLA-DRB1 Chains; Multifactorial Inheritance; Adolescent; Treatment Outcome; HLA-DQ beta-Chains; Case-Control Studies; Haplotypes; Risk Assessment; Adrenal Cortex Hormones; Risk Factors; Genetic Predisposition to Disease; Biomarkers; Infant; Drug Resistance; Genetic Risk Score

PubMed ID

41748071

Keywords

HLA haplotype; nephrotic syndrome; polygenic risk score; therapy response

Comments

Grants and funding

This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

Publisher's Link: https://www.kidney-international.org/article/S0085-2538(26)00134-1/fulltext

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