Associations of systemic inflammatory regulators with CKD and kidney function: evidence from the bidirectional mendelian randomization study.

Previous observational studies have reported that systemic inflammatory regulators are related to the development of chronic kidney disease (CKD); however, whether these associations are causal remains unclear. The current study aimed to investigate the potential causal relationships between systemic inflammatory regulators and CKD and kidney function. We performed bidirectional two-sample Mendelian randomization (MR) analyses to infer the underlying causal associations between 41 systemic inflammatory regulators and CKD and kidney function. The inverse-variance weighting (IVW) test was used as the primary analysis method. In addition, sensitivity analyses were executed via the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test and the weighted median test. The findings revealed 12 suggestive associations between 11 genetically predicted systemic inflammatory regulators and CKD or kidney function in the forward analyses, including 4 for CKD, 3 for blood urea nitrogen (BUN), 4 for eGFRcrea and 1 for eGFRcys. In the other direction, we identified 6 significant causal associations, including CKD with granulocyte-colony stimulating factor (GCSF) (IVW β = 0.145; 95% CI, 0.042 to 0.248; P = 0.006), CKD with stem cell factor (SCF) (IVW β = 0.228; 95% CI, 0.133 to 0.323; P = 2.40 × 10- 6), eGFRcrea with SCF (IVW β =-2.90; 95% CI, -3.934 to -1.867; P = 3.76 × 10- 8), eGFRcys with GCSF (IVW β =-1.382; 95% CI, -2.404 to -0.361; P = 0.008), eGFRcys with interferon gamma (IFNg) (IVW β =-1.339; 95% CI, -2.313 to -0.366; P = 0.007) and eGFRcys with vascular endothelial growth factor (VEGF) (IVW β =-1.709; 95% CI, -2.720 to -0.699; P = 9.13 × 10- 4). Our findings support causal links between systemic inflammatory regulators and CKD or kidney function both in the forward and reverse MR analyses.

Liu H ，Xiang W ，Wu W ，Zhou G ，Yuan J ... -  《BMC Nephrology》

Causal effects of systemic inflammatory regulators on chronic kidney diseases and renal function: a bidirectional Mendelian randomization study.

While targeted systemic inflammatory modulators show promise in preventing chronic kidney disease (CKD) progression, the causal link between specific inflammatory factors and CKD remains uncertain. Using a genome-wide association study of 41 serum cytokines from 8,293 Finnish individuals, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. In addition, we genetically predicted causal associations between inflammatory factors and 5 phenotypes, including CKD, estimated glomerular filtration rate (eGFR), dialysis, rapid progression of CKD, and rapid decline in eGFR. Inverse variance weighting (IVW) served as the primary MR method, while MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were utilized for sensitivity analysis. Cochrane's Q test for heterogeneity. Leave-one-out method ensured stability of MR results, and Bonferroni correction assessed causal relationship strength. Seventeen cytokines were associated with diverse renal outcomes. Among them, after Bonferroni correction test, higher tumor necrosis factor alpha levels were associated with a rapid decrease in eGFR (OR = 1.064, 95% CI 1.028 - 1.103, P = 0.001), higher interleukin-4 levels were associated with an increase in eGFR (β = 0.003, 95% CI 0.001 - 0.005, P = 0.002), and higher growth regulated oncogene alpha (GROα) levels were associated with an increased risk of CKD (OR=1.035, 95% CI 1.012 - 1.058, P = 0.003). In contrast, genetic susceptibility to CKD was associated with an increase in GROa, and a decrease in eGFR may lead to an increase in stem cell factor. We did not find the presence of horizontal pleiotropy during the analysis. We discovered causally related inflammatory factors that contribute to the initiation and progression of CKD at the genetic prediction level.

Li H ，Li M ，Liu C ，He P ，Dong A ，Dong S ，Zhang M ... -  《Frontiers in Immunology》

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 relationship between basal metabolic rate and kidney function: a bidirectional two-sample mendelian randomization study.

The relationship between basal metabolic rate (BMR) and Chronic kidney disease (CKD) remains unclear and controversial. In this study, we investigated the causal role of BMR in renal injury, and inversely, whether altered renal function causes changes in BMR. In this two-sample mendelian randomization (MR) study, Genetic data were accessed from published genome-wide association studies (GWAS) for BMR ((n = 454,874) and indices of renal function, i.e. estimated glomerular filtration rate (eGFR) based on creatinine (n =1, 004, 040), CKD (n=480, 698), and blood urea nitrogen (BUN) (n =852, 678) in European. The inverse variance weighted (IVW) random-effects MR method serves as the main analysis, accompanied by several sensitivity MR analyses. We also performed a reverse MR to explore the causal effects of the above indices of renal function on the BMR. We found that genetically predicted BMR was negatively related to eGFR, (β= -0.032, P = 4.95*10-12). Similar results were obtained using the MR-Egger (β= -0.040, P = 0.002), weighted median (β= -0.04, P= 5.35×10-11) and weighted mode method (β= -0.05, P=9.92×10-7). Higher BMR had a causal effect on an increased risk of CKD (OR =1.36, 95% CI = 1.11-1.66, P =0.003). In reverse MR, lower eGFR was related to higher BMR (β= -0.64, P = 2.32×10-6, IVW analysis). Bidirectional MR supports no causal association was observed between BMR and BUN. Sensitivity analyses confirmed these findings, indicating the robustness of the results. Genetically predicted high BMR is associated with impaired kidney function. Conversely, genetically predicted decreased eGFR is associated with higher BMR.

Zhou C ，Peng Y ，Zhan L ，Zha Y ... -  《-》

Genetically determined blood lead is associated with reduced renal function amongst individuals with type 2 diabetes mellitus: insight from Mendelian Randomisation.

Some observational studies indicate a link between blood lead and kidney function although results remain controversial. In this study, Mendelian randomisation (MR) analysis was applied to obtain unconfounded estimates of the casual association of genetically determined blood lead with estimated glomerular filtration rate (eGFR) and the risk of chronic kidney disease (CKD). Data from the largest genome-wide association studies (GWAS) on blood lead, eGFR and CKD, from predominantly ethnically European populations, were analysed in total, as well as separately in individuals with or without type 2 diabetes mellitus. Inverse variance weighted (IVW) method, weighted median (WM)-based method, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier (PRESSO) as well as the leave-one-out method were applied. In a general population, lifetime blood lead levels had no significant effect on risk of CKD (IVW: p = 0.652) and eGFR (IVW: p = 0.668). After grouping by type 2 diabetes status (no diabetes vs. diabetes), genetically higher levels of blood lead had a significant negative impact among subjects with type 2 diabetes (IVW = Beta: -0.03416, p = 0.0132) but not in subjects without (IVW: p = 0.823), with low likelihood of heterogeneity for any estimates (IVW p > 0.158). MR-PRESSO did not highlight any outliers. Pleiotropy test, with very negligible intercept and insignificant p-value, indicated a low likelihood of pleiotropy for all estimations. The leave-one-out method demonstrated that links were not driven by a single SNP. Our results show, for the first time, that among subjects with type 2 diabetes, higher blood lead levels are potentially related to less favourable renal function. Further studies are needed to confirm our results. KEY MESSAGES: What is already known about this subject? Chronic kidney disease is associated with unfavourable lifestyle behaviours and conditions such as type 2 diabetes. Observational studies have reported an association between blood lead and reduced estimated glomerular filtration rate, but the relationship between lead exposure and renal function remains controversial. What is the key question? Using Mendelian randomisation with data from 5433 individuals from the UK and Australian populations, does genetically determined blood lead have a potentially causal effect on estimated glomerular filtration rate and the risk of chronic kidney disease? What are the new findings? Blood lead levels have a potentially causal effect on reduced renal function in individuals with type 2 diabetes. In subjects without diabetes, no such causal relationship was identified. How might this impact on clinical practice in the foreseeable future? This highlights the risk of elevated blood lead, for example, due to environmental exposure, amongst those with type 2 diabetes, which may predispose them to impaired renal function.

Mazidi M ，Kirwan R ，Davies IG 《-》