preprint · medRxiv
Nephrotic syndrome is a common childhood kidney condition categorised by whether patients respond to steroid therapy or resist it. Predicting treatment outcomes at early presentation remains difficult. Using genome-wide data from nearly two thousand children with nephrotic syndrome alongside healthy controls, researchers assessed human leukocyte antigen alleles and polygenic risk scores. The findings demonstrate that steroid-sensitive cases associate strongly with specific immune-related genes, including variations in HLA class II loci and the CLEC16A gene. One specific HLA haplotype conferred a four-fold increase in the likelihood of having steroid-sensitive disease. Combining this HLA haplotype, the polygenic risk score, and the patient age of disease onset generated a predictive model capable of separating steroid-sensitive from steroid-resistant cases with up to seventy-one percent accuracy, confirming distinct immune mechanisms between the forms.
Children diagnosed with nephrotic syndrome currently face uncertainty regarding whether standard steroid treatments will work. By demonstrating that genetic profiling and age of onset can predict therapeutic response, this research helps define biological differences between subtypes. This knowledge provides a pathway toward earlier identification of non-responsive patients, potentially sparing them ineffective treatments.
The research points toward diagnostic tools and clinical decision-support algorithms for paediatric nephrologists. These could be integrated into genetic testing platforms or hospital diagnostics to guide early therapy selection. The technology is at an applied research stage, having been validated across two patient cohorts, but it will require clinical trial evaluation and further regulatory development before adoption in healthcare settings.
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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 currently no reliable predictors of therapy response at initial clinical presentation. Methods We conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched controls. 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 ∼4 times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at onset of the disease was the best predictor of steroid responsiveness with an AUC 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 and provide a foundation for more accurate diagnoses and tailored and individualized treatment. Translational statement To identify biomarkers of pattern of steroid responsiveness in childhood-onset nephrotic syndrome, we carried out a case-control study that included over 4,000 samples, including 994 patients with NS in the discovery phase and an additional 1,003 cases from two independent replication cohorts. We identified significant risk of steroid-sensitive NS (SSNS) at HLA class II genes and CLEC16A (a gene important in the regulation of T and B lymphocytes). The HLA haplotype DRB1*07:01∼DQA1*02:01∼DQB1*02:02 was associated with four-fold increased odds of SSNS. A model incorporating HLA haplotype, polygenic risk score, and age at onset of the disease was the best predictor of steroid responsiveness providing useful delineation of steroid sensitivity from steroid resistance. In conclusion, age at onset of disease, HLA class II variants and polygenic risk scores are useful biomarkers of corticosteroid response in childhood NS and may serve as useful clinical decision support tools to guide treatment. Abstract Figure Graphical Abstract
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DOI: 10.1101/2025.08.01.25332825
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