Blood metabolites and chronic kidney disease: a Mendelian randomization study.

Human blood metabolites have demonstrated close associations with chronic kidney disease (CKD) in observational studies. Nonetheless, the causal relationship between metabolites and CKD is still unclear. This study aimed to assess the associations between metabolites and CKD risk. We applied a two-sample Mendelian randomization (MR) analysis to evaluate relationships between 1400 blood metabolites and eight phenotypes (outcomes) (CKD, estimated glomerular filtration rate(eGFR), urine albumin to creatinine ratio, rapid progress to CKD, rapid decline of eGFR, membranous nephropathy, immunoglobulin A nephropathy, and diabetic nephropathy). The inverse variance weighted (IVW), MR-Egger, and weighted median were used to investigate the causal relationship. Sensitivity analyses were performed with Cochran's Q, MR-Egger intercept, MR-PRESSO Global test, and leave-one-out analysis. Bonferroni correction was used to test the strength of the causal relationship. Through the MR analysis of 1400 metabolites and eight clinical phenotypes, a total of 48 metabolites were found to be associated with various outcomes. Among them, N-acetylleucine (OR = 0.923, 95%CI: 0.89-0.957, PIVW = 1.450 × 10-5) has a strong causal relationship with lower risk of CKD after the Bonferroni-corrected test, whereas Glycine to alanine ratio has a strong causal relationship with higher risk of CKD (OR = 1.106, 95%CI: 1.063-1.151, PIVW = 5.850 × 10-7). No horizontal pleiotropy and heterogeneity were detected. Our study offers groundbreaking insights into the integration of metabolomics and genomics to reveal the pathogenesis of and therapeutic strategies for CKD. It underscores 48 metabolites as potential causal candidates, meriting further investigation.

Hou Y ，Xiao Z ，Zhu Y ，Li Y ，Liu Q ，Wang Z ... -  《BMC Medical Genomics》

Causal effects of plasma metabolites on chronic kidney diseases and renal function: a bidirectional Mendelian randomization study.

Despite the potential demonstrated by targeted plasma metabolite modulators in halting the progression of chronic kidney disease (CKD), a lingering uncertainty persists concerning the causal relationship between distinct plasma metabolites and the onset and progression of CKD. A genome-wide association study was conducted on 1,091 metabolites and 309 metabolite ratios derived from a cohort of 8,299 unrelated individuals of European descent. Employing a bidirectional two-sample Mendelian randomization (MR) analysis in conjunction with colocalization analysis, we systematically investigated the associations between these metabolites and three phenotypes: CKD, creatinine-estimated glomerular filtration rate (creatinine-eGFR), and urine albumin creatinine ratio (UACR). In the MR analysis, the primary analytical approach employed was inverse variance weighting (IVW), and sensitivity analysis was executed utilizing the MR-Egger method and MR-pleiotropy residual sum and outlier (MR-PRESSO). Heterogeneity was carefully evaluated through Cochrane's Q test. To ensure the robustness of our MR results, the leave-one-out method was implemented, and the strength of causal relationships was subjected to scrutiny via Bonferroni correction. Our thorough MR analysis involving 1,400 plasma metabolites and three clinical phenotypes yielded a discerning identification of 21 plasma metabolites significantly associated with diverse outcomes. Specifically, in the forward MR analysis, 6 plasma metabolites were determined to be causally associated with CKD, 16 with creatinine-eGFR, and 7 with UACR. Substantiated by robust evidence from colocalization analysis, 6 plasma metabolites shared causal variants with CKD, 16 with creatinine-eGFR, and 7 with UACR. In the reverse analysis, a diminished creatinine-eGFR was linked to elevated levels of nine plasma metabolites. Notably, no discernible associations were observed between other plasma metabolites and CKD, creatinine-eGFR, and UACR. Importantly, our analysis detected no evidence of horizontal pleiotropy. This study elucidates specific plasma metabolites causally associated with CKD and renal functions, providing potential targets for intervention. These findings contribute to an enriched understanding of the genetic underpinnings of CKD and renal functions, paving the way for precision medicine applications and therapeutic strategies aimed at impeding disease progression.

Zhao X ，Gao J ，Kou K ，Wang X ，Gao X ，Wang Y ，Zhou H ，Li F ... -  《Frontiers in Endocrinology》

Causal Effects of Specific Gut Microbiota on Chronic Kidney Diseases and Renal Function-A Two-Sample Mendelian Randomization Study.

Li N ，Wang Y ，Wei P ，Min Y ，Yu M ，Zhou G ，Yuan G ，Sun J ，Dai H ，Zhou E ，He W ，Sheng M ，Gao K ，Zheng M ，Sun W ，Zhou D ，Zhang L ... -  《Nutrients》

Causality of Genetically Determined Metabolites on Chronic Kidney Disease: A Two-Sample Mendelian Randomization Study In Silico.

Zhang Z ，Cao B ，Wu Q 《-》

Causal effects of human serum metabolites on occurrence and progress indicators of chronic kidney disease: a two-sample Mendelian randomization study.

Yin Y ，Shan C ，Han Q ，Chen C ，Wang Z ，Huang Z ，Chen H ，Sun L ，Fei S ，Tao J ，Han Z ，Tan R ，Gu M ，Ju X ... -  《Frontiers in Nutrition》