Background: Whether there is a causal relationship between childhood obesity and increased risk of chronic kidney disease (CKD) remains controversial. This study sought to explore how body size in childhood and adulthood independently affects CKD risk in later life using a Mendelian randomization (MR) approach. Methods: Univariate and multivariate MR was used to estimate total and independent effects of body size exposures. Genetic associations with early-life and adult body size were obtained from a genome-wide association study of 453,169 participants in the U.K. Biobank, and genetic associations with CKD were obtained from the CKDGen and FinnGen consortia. Results: A larger genetically predicted early-life body size was associated with an increased risk of CKD (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.14 to 1.41; P= 1.70E-05) and increased blood urea nitrogen (BUN) levels (β=0.010; 95% CI, 0.005 to 0.021; P=0.001). However, the association between the impact of early-life body size on CKD (OR, 1.12; 95% CI, 0.95 to 1.31; P=0.173) and BUN level (β=0.001; 95% CI, –0.010 to 0.012;P= 0.853) did not remain statistically significant after adjustment for adult body size. Larger genetically predicted adult body size was associated with an increased risk of CKD (OR, 1.37; 95% CI, 1.21 to 1.54; P= 4.60E-07), decreased estimated glomerular filtration rate (β=–0.011; 95% CI, –0.017 to –0.006; P=5.79E-05), and increased BUN level (β= 0.010; 95% CI, 0.002 to 0.019; P= 0.018). Conclusion Our research indicates that the significant correlation between early-life body size and CKD risk is likely due to maintaining a large body size into adulthood.

Background: Whether there is a causal relationship between childhood obesity and increased risk of chronic kidney disease (CKD) remains controversial. This study sought to explore how body size in childhood and adulthood independently affects CKD risk in later life using a Mendelian randomization (MR) approach. Methods: Univariate and multivariate MR was used to estimate total and independent effects of body size exposures. Genetic associations with early-life and adult body size were obtained from a genome-wide association study of 453,169 participants in the U.K. Biobank, and genetic associations with CKD were obtained from the CKDGen and FinnGen consortia. Results: A larger genetically predicted early-life body size was associated with an increased risk of CKD (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.14 to 1.41; P= 1.70E-05) and increased blood urea nitrogen (BUN) levels (β=0.010; 95% CI, 0.005 to 0.021; P=0.001). However, the association between the impact of early-life body size on CKD (OR, 1.12; 95% CI, 0.95 to 1.31; P=0.173) and BUN level (β=0.001; 95% CI, –0.010 to 0.012;P= 0.853) did not remain statistically significant after adjustment for adult body size. Larger genetically predicted adult body size was associated with an increased risk of CKD (OR, 1.37; 95% CI, 1.21 to 1.54; P= 4.60E-07), decreased estimated glomerular filtration rate (β=–0.011; 95% CI, –0.017 to –0.006; P=5.79E-05), and increased BUN level (β= 0.010; 95% CI, 0.002 to 0.019; P= 0.018). Conclusion Our research indicates that the significant correlation between early-life body size and CKD risk is likely due to maintaining a large body size into adulthood.

Background: Whether there is a causal relationship between childhood obesity and increased risk of chronic kidney disease (CKD) remains controversial. This study sought to explore how body size in childhood and adulthood independently affects CKD risk in later life using a Mendelian randomization (MR) approach. Methods: Univariate and multivariate MR was used to estimate total and independent effects of body size exposures. Genetic associations with early-life and adult body size were obtained from a genome-wide association study of 453,169 participants in the U.K. Biobank, and genetic associations with CKD were obtained from the CKDGen and FinnGen consortia. Results: A larger genetically predicted early-life body size was associated with an increased risk of CKD (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.14 to 1.41; P= 1.70E-05) and increased blood urea nitrogen (BUN) levels (β=0.010; 95% CI, 0.005 to 0.021; P=0.001). However, the association between the impact of early-life body size on CKD (OR, 1.12; 95% CI, 0.95 to 1.31; P=0.173) and BUN level (β=0.001; 95% CI, –0.010 to 0.012;P= 0.853) did not remain statistically significant after adjustment for adult body size. Larger genetically predicted adult body size was associated with an increased risk of CKD (OR, 1.37; 95% CI, 1.21 to 1.54; P= 4.60E-07), decreased estimated glomerular filtration rate (β=–0.011; 95% CI, –0.017 to –0.006; P=5.79E-05), and increased BUN level (β= 0.010; 95% CI, 0.002 to 0.019; P= 0.018). Conclusion Our research indicates that the significant correlation between early-life body size and CKD risk is likely due to maintaining a large body size into adulthood.

Objective : To investigate the molecular mechanisms underlying the feedback regulation of single immunoglobin interleukin-1 related receptor ( SIGIRR) expression by the nuclear factor kappa-κB ( NF-κB) in human renal tubular epithelial cells ( HKC) ． Methods : The pLNCX2-G418-SIGIRR overexpression vector was constructed by molecular cloning，and the SIGIRR overexpression cells and control cells were constructed by infecting HKC cells after packaging with PT67 cells．Using IL-1 β induction，Western blot verified that overexpression of SIGIRR inhibited NF-κB activation．After using NF-κB blocker and interfering with NF-κB activity ，immunofluorescence assay verified that activated NF-κB regulated SIGIRR expression． Online tools predicted the presence of NF-κB binding sites in the SIGIRR promoter region．The SIGIRR promoter sequence containing the binding site was obtained from within human genomic DNA by molecular cloning，ligated to the luciferase vector pGL3-Luc，constructed pGL3-Luc-SIGIRR , and mutated the binding site．The luciferase reporter gene assay and chromatin immunopre- cipitation technique ( ChIP) were used to jointly verify that activated NF-κB could bind to the SIGIRR promoter region to regulate SIGIRR gene expression. Results : The results showed that the constructed pLNCX2-G418-SIGIRR retroviral vector was verified by enzymatic digestion and sequencing to be identical to the coding sequence of the SIGIRR gene for comparison，the recombinant and control vectors were transferred into HKC cells after viral packaging，and the HKC / SIGIRR experimental and HKC / Co control cell lines were successfully constructed at the mRNA and protein levels of SIGIRR expression differences were statistically significant (P＜0．05，P＜0. 001) ．Overexpression of SIGIRR cell groups reduced IL-1 β-induced NF-κB activation compared to control cells (P＜0. 001) . SIGIRR expression was downregulated after inhibition of NF-κB activation and interference with NF-κB expression. After extracting human genomic DNA ，the SIGIRR target promoter sequence was obtained by molecular cloning method and linked to the vector，and the pGL3-Luc-SIGIRR luciferase vector was successfully constructed and targeted to mutate the vector，which was verified to be identical to the target sequence by digestion and sequencing. The luciferase reporter gene assay and CHIP assay confirmed that NF-κB could bind to SIGIRR promoter region and regulate SIGIRR expression． Conclusion It has been verified that SIGIRR can influence the activation of NF-κB in HKC cells，and activated NF-κB can bind to the promoter region of SIGIRR and regulate the gene expression changes of SIGIRR , forming a feedback system to control the over-activation of NF-κB.