A bidirectional Mendelian randomization study supports causal effects of kidney function on blood pressure

Yu, Zhi; Coresh, Josef; Qi, Guanghao; Boerwinkle, Eric; Snieder, Harold; Teumer, Alexander; Pattaro, Cristian; Köttgen, Anna; Chatterjee, Nilanjan; Tin, Adrienne

doi:10.1016/j.kint.2020.04.044

Cited by 86 publications

(89 citation statements)

References 62 publications

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“…47 Some of the previously conducted MR studies showed that higher values of genetically predicted BP lead to increased risk of albuminuria 21 and hypertensive renal disease 48 but did not demonstrate a causal effect of BP on kidney function parameters. 36 This may suggest that the detected signal of causality from BP to kidney health index is driven primarily by either of these phenotypes (given that they were used to define the composite renal outcome). Most importantly however, BP does not fully account for the causal effect of both obesity measures on the kidney health index.…”

Section: Discussionmentioning

confidence: 99%

Obesity as a cause of kidney disease – insights from Mendelian randomisation studies

Eales

Jiang

et al. 2020

Preprint

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Objective: To examine if modifiable anthropometric indices of obesity exert putatively causal effects on different measures of kidney health and disease. Design: Conventional observational and Mendelian randomisation study. Setting: UK Biobank and international genome-wide association studies. Participants: Approximately 300,000 participants of white-British ancestry from UK Biobank and up to 480,000 participants of predominantly European ancestry from genome-wide association studies. Main outcome measures: Estimated glomerular filtration, blood urea nitrogen, kidney health index, chronic kidney disease, hypertensive renal disease, renal failure, acute renal failure, other disorders of kidney and ureters, IgA nephropathy and diabetic nephropathy. Results: The Mendelian randomisation analysis indicated that increasing values of genetically predicted body mass index (BMI) and waist circumference were causally linked to changes in renal function indices including reduced estimated glomerular filtration and increased blood urea nitrogen in UK Biobank individuals. These associations were replicated using data from CKDGen Consortium individuals. One standard deviation increase in genetically-predicted BMI and waist circumference decreased the relative odds of kidney health index by 14% and 18% (OR=0·86 ; 95%CI: 0·82-0·92 ; P=9·18×10-6 for BMI and OR=0·82 ; 95%CI: 0·75-0·90 ; P=2·12×10-5 for waist circumference, respectively). Approximately 13-16% of the causal effect of obesity indices on kidney health was mediated by blood pressure. Obesity increased the risk of both acute and chronic kidney disease of several aetiologies including hypertensive renal disease and diabetic nephropathy. Conclusions: These findings indicate that obesity is causally linked to indices of renal health and the risk of different kidney diseases. This evidence substantiates the value of weight loss as a strategy of preventing and/or counteracting a decline in kidney health as well as decreasing the risk of renal disease.

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Section: Discussionmentioning

confidence: 99%

Obesity as a cause of kidney disease – insights from Mendelian randomisation studies

Eales

Jiang

et al. 2020

Preprint

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“…After linkage disequilibrium analysis, removing the potential confounders and fully considering the potential effect between creatinine metabolism and renal function, 35 SNP are included. The specific process has been described in the study of Yu et al 22 The 17 SNP are not found in the outcome summary data (ADPN). For the 17 SNP that could not be extracted from the outcome summary data (ADPN), the proxy SNP ( R 2 > 0.9) could be further determined, and nine SNP without the proxy SNP will not be included in the analysis.…”

Section: Methodsmentioning

confidence: 99%

Adiponectin affects estimated glomerular filtration rate: A two‐sample bidirectional Mendelian randomization study

et al. 2021

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Background The causal relationship between adiponectin (ADPN) and estimated glomerular filtration rate (eGFR) is unclear. This study adopts a two‐sample bidirectional Mendelian randomization (MR) study to explore the causal relationship between ADPN and eGFR. Methods Using eight single nucleotide polymorphisms (SNP) of ADPN and 26 SNP of eGFR as instrumental variables, the study performs a two‐sample bidirectional MR study using MR inverse‐variance weighted (IVW), MR‐Egger and weighted median approach to evaluate the causal relationship between ADPN and eGFR. Using the genetic risk score (GRS) of ADPN and eGFR as instrumental variables, the study performs a second MR analysis to assess the association between ADPN and eGFR. Results In ADPN to eGFR MR analysis, the IVW, weighted median and GRS analysis all showed that ADPN had a causal effect on eGFR after removing potential confounders of the ADPN‐eGFR relation (IVW: β = .016, P = .002; weighted median: β = .012, P = .022; GRS: β = .016, P = 1.48E‐05). As both ADPN and eGFR were natural log‐transformed in the corresponding GWAS, eGFR increased by 0.15% for any 10% increase in ADPN. In eGFR to ADPN MR analysis, eGFR had no causal effect on ADPN after removing potential confounders of the eGFR‐ADPN relation (All P values > 0.05). The heterogeneity test and sensitivity analysis indicated some heterogeneity, but no directional pleiotropy. Conclusion Adiponectin has a causal effect on eGFR, while eGFR has no causal effect on ADPN. ADPN may be a clinical target for improving eGFR and treating chronic kidney disease caused by decreased eGFR.

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“…Risk factors associated with CKD progression include, cardiovascular disease, age, proteinuria, acute kidney injury, hypertension, diabetes, smoking, African, African-Caribbean or Asian family origin, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) and untreated urinary outflow tract obstruction [ 26 ]. Hypertension was considered to be on the causal pathway as it is also an outcome of worse kidney function [ 27 ]. Previous literature shows that low SES, high BMI, persistent asthma, cancer, COPD and rheumatoid arthritis are risk factors for CKD [ 28 – 33 ].…”

Section: Methodsmentioning

confidence: 99%

The association between chronic kidney disease and tuberculosis; a comparative cohort study in England

et al. 2020

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Background People with end-stage kidney disease have an increased risk of active tuberculosis (TB). Previous systematic reviews have demonstrated that patients with chronic kidney disease (CKD) have increased risk of severe community-acquired infections. We investigated the association between CKD (prior to renal replacement therapy) and incidence of TB in UK General Practice. Methods Using the UK Clinical Practice Research Datalink, 242,349 patients with CKD (stages 3-5) (estimated glomerular filtration rate < 60 mL/min/1.73 m2 for ≥3 months) between April 2004 and March 2014 were identified and individually matched (by age, gender, general practice and calendar time) to a control from the general population without known CKD. The association between CKD (overall and by stage) and incident TB was investigated using a Poisson regression analysis adjusted for age, gender, ethnicity, socio-economic status, chronic obstructive pulmonary disease (COPD) and diabetes. Results The incidence of TB was higher amongst patients with CKD compared to those without CKD: 14.63 and 9.89 cases per 100,000 person-years. After adjusting for age, gender, ethnicity, socio-economic status, diabetes and COPD, the association between CKD and TB remained (adjusted rate ratio [RR] 1.42, 95% confidence interval [CI] 1.01–1.85). The association may be stronger amongst those from non-white ethnic minorities (adjusted RR 2.83, 95%CI 1.32–6.03, p-value for interaction with ethnicity = 0.061). Amongst those with CKD stages 3–5, there was no evidence of a trend with CKD severity. Conclusions CKD is associated with an increased risk of TB diagnosis in a UK General Practice cohort. This group of patients should be considered for testing and treating for latent TB.

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A bidirectional Mendelian randomization study supports causal effects of kidney function on blood pressure

Cited by 86 publications

References 62 publications

Obesity as a cause of kidney disease – insights from Mendelian randomisation studies

Obesity as a cause of kidney disease – insights from Mendelian randomisation studies

Adiponectin affects estimated glomerular filtration rate: A two‐sample bidirectional Mendelian randomization study

The association between chronic kidney disease and tuberculosis; a comparative cohort study in England

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