Interleukins (ILs), key cytokine family of inflammatory response, are closely associated with kidney function. However, the causal effect of various ILs on kidney function needs further investigation. Here we show two-sample summary-level Mendelian randomization (MR) analysis that examined the causality between serum IL levels and kidney function. Genetic variants with strong association with serum IL levels were obtained from a previous genome-wide association study meta-analysis. Summary-level data for estimated glomerular filtration rate (eGFR) were obtained from CKDGen database. As a main MR analysis, multiplicative random-effects inverse-variance weighted method was performed. Pleiotropy-robust MR analysis, including MR-Egger with bootstrapped error and weighted median methods, were also implemented. We tested the causal estimates from nine ILs on eGFR traits. Among the results, higher genetically predicted serum IL-1 receptor antagonist level was significantly associated with higher eGFR values in the meta-analysis of CKDGen and the UK Biobank data. In addition, the result was consistent towards eGFR decline phenotype of the outcome database. Otherwise, nonsignificant association was identified between other genetically predicted ILs and eGFR outcome. These findings support the clinical importance of IL-1 receptor antagonist-associated pathway in relation to kidney function in the general individuals, particularly highlighting the importance of IL-1 receptor antagonist.

Background Interleukins (ILs), key cytokine family of inflammatory response, are closely associated with kidney function. However, the causal effect of various ILs on kidney function needs further investigation. Methods We performed two-sample summary-level mendelian randomization (MR) analysis. Genetic variants with strong association with serum IL levels were obtained from a previous genome-wide association study meta-analysis. Summary-level data for eGFR were obtained from CKDGen database. A replication analysis was performed in the independent UK Biobank data. As a main MR analysis, multiplicative random-effect inverse-variance weighed method was performed. Pleiotropy-robust MR analysis, including MR-Egger with bootstrapped error and weighed-median methods, were also implemented. Results We tested the causal estimates from nine ILs on eGFR traits. Among the results, higher genetically predicted serum IL-1ra level was significantly associated with higher eGFR values, both in the CKDGen and the UK Biobank data. In addition, the result was consistent towards eGFR decline phenotype of the outcome database. Otherwise, nonsignificant association was identified between other genetically predicted ILs and eGFR outcome. Conclusions These findings support the clinical importance of IL-1 associated pathway in relation to kidney function in the general individuals, particularly highlighting the importance of IL-1ra.

Background and Aims Interleukins (ILs), key cytokine family of inflammatory response, are closely associated with kidney function. However, the causal effect of various ILs on kidney function needs further investigation. Method We performed two-sample summary-level mendelian randomization (MR) analysis (Fig. 1). Genetic variants with strong association with serum IL levels were obtained from a previous genome-wide association study meta-analysis. Summary-level data for eGFR were obtained from CKDGen database. A replication analysis was performed in the independent UK Biobank data. As a main MR analysis, multiplicative random-effect inverse-variance weighed method was performed. Pleiotropy-robust MR analysis, including MR-Egger with bootstrapped error and weighed-median methods, were also implemented. Results We tested the causal estimates from nine ILs on eGFR traits. Among ILs, we found that genetically predicted serum IL-1ra level showed consistently significant association (P <0.05) with eGFR, also supported by significant (P <0.05) pleiotropy-robust MR results. Using 20 SNPs (18 of pQTL and 2 of eQTL SNPs), genetically predicted higher serum IL-1ra level was significantly associated (<0.05) with higher eGFR in multiplicative random effect IVW analysis (Fig. 2). In addition, the result was consistent towards eGFR decline phenotype of the outcome database. Otherwise, nonsignificant association was identified between other genetically predicted ILs and eGFR outcome (Fig. 3). Conclusion These findings support the clinical importance of IL-1 associated pathway in relation to kidney function in the general individuals, particularly highlighting the importance of IL-1ra.

Background and Aims We report the baseline and genetic characteristics of the nationwide genetic cohort for Korean hereditary cystic kidney disease prior to detailed molecular analysis. Method We performed a 3-year prospective, multicenter cohort study at 9 hospitals from May 2019 to May 2022. Patients with more than 3 renal cysts were enrolled and classified into 3 categories: typical and atypical autosomal dominant polycystic kidney disease (ADPKD), and pediatric PKD. Clinical and genetic characteristics were compared among categories. Genetic analysis was performed by using gene panel comprised of 89 ciliopathy-related genes. Results A total of 798 patients were enrolled. Mean age was 42.7 ± 17.3 years, and 47.8% were male. Patients were categorized into typical ADPKD (560, 70.2%), atypical ADPKD (165, 20.7%), and pediatric PKD (73, 9.1%). Typical ADPKD by Mayo imaging classification (MIC) I was as follows: 1A 55 (9.9%), 1B 149 (26.9%), 1C 198 (35.8%), 1D 90 (16.3%), and 1E 61 (11.0%) (n = 553). Atypical ADPKD by MIC II included bilateral cystic with bilateral atrophic (31, 37.3%), lopsided (27, 32.5%), unilateral (9, 10.8%), segmental (8, 9.6%), bilateral cystic with unilateral atrophic (7, 8.4%), and asymmetric (1, 1.2%). The mean age was lower in the typical ADPKD group compared to atypical group (45.3 ± 13.3 vs. 48.9 ± 15.8, p = 0.003). Height-adjusted total kidney volume was greater in the typical group than atypical group (947.4 ± 762.5 mL/m vs. 528.2 ± 587.6 mL/m, p<0.001). Pathogenic variants were found in 57.3% of the patients by ciliopathy-related gene panel. Typical ADPKD group demonstrated higher discovery rate (62.3%) compared to atypical ADPKD group (41.8%) or pediatric PKD group (53.4%). Conclusion This is the first nationwide cohort for genetic characterization of Korean hereditary cystic kidney disease patients. We report the baseline characteristics and genetic findings of the cohort prior to detailed molecular analysis.

Background: Glomerular diseases encompass a group of kidney diseases that may share common gene expression pathways. We aimed to analyze glomerular-specific gene expression profiles across various glomerular diseases. Methods: We performed spatial transcriptomic profiling using formalin-fixed paraffin-embedded kidney biopsy specimens of controls and patients with five types of glomerular diseases using the GeoMx Digital Spatial Profiler. We identified common differentially expressed genes (DEGs) across glomerular diseases and performed Gene Ontology (GO) annotation by using the ToppGene suite. Results: A total of 35 DEGs were consistently downregulated in glomeruli across the disease compared to the control, while none of the DEGs were consistently upregulated. Twelve of 35 downregulated DEGs, including the two hub genes FOS and JUN, were annotated with molecular function GO terms related to DNA-binding transcription factor activity. Other notable DEGs consistently downregulated and annotated in the pathway analysis included NR4A3, KLF9, EGR1, and ATF3. The annotated biological process GO terms included response to lipid-related (17/35 DEGs), response to steroid hormone (12/35 DEGs), or cell cycle regulation (10/35 DEGs). Conclusions: Identifying common DEGs by spatial transcriptomic analysis provides insights into the underlying molecular mechanisms of glomerular diseases and may lead to novel assessment or therapeutic strategies.