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Introduction: Observational studies suggest that obesity is a risk factor of chronic kidney disease (CKD). It is unclear whether this reflects a direct causal effect of obesity or an effect mediated by obesity-related metabolic changes. Hypotheses: We hypothesised that 1) obesity is a causal risk factor of CKD defined as eGFR 2 and 2) this causal effect is mediated through changes in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterols, triglycerides, glucose, blood pressure and C-reactive protein (CRP) levels. Methods: To assess causality and investigate mediation, we used a combination of observational, two-step Mendelian randomization, and mediation analyses on individual-level data from two cohorts of the Danish general population (N=117,213). Results: Observationally, higher BMI was associated with a lower eGFR (change in eGFR; -0.81, confidence interval [CI]: -0.89- -0.73)) and a higher risk of CKD (odds ratio [OR]:1.19; 95% CI: 1.16-1.22) per 5kg/m 2 higher BMI (p for trend for both -40 ). Mendelian randomization analyses supported a causal effect of higher BMI on lower eGFR (change in eGFR -17.3 mL/min/1.73m 2 (95%CI: -19.3- -15.3), and risk of CKD (risk ratio [RR]6.99 (95%CI: 1.63-30.1) per 5kg/m 2 higher BMI. Measured BMI and the BMI allele score used in Mendelian randomization analyses were associated with changes in levels of LDL and HDL cholesterols, triglycerides, glucose, blood pressure, and CRP. Observational and Mendelian randomization analyses showed evidence to support a causal effect of changes in levels of systolic and diastolic blood pressure, LDL cholesterol and CRP with lower eGFR and higher risk of CKD. Of the excess risk of CKD coming from high BMI, elevated systolic and diastolic blood pressure mediated 18%(95%CI:14-22) and 9% (7-11), respectively. 9% (95%CI: 8-12) was mediated by elevated LDL cholesterol and 29% (95%CI: 23-35) by elevated CRP. Conclusion: Triangulating evidence from observational and Mendelian randomization analyses provided evidence to support a causal role of obesity on the risk of CKD and that this causal effect may be partly mediated by elevated systolic and diastolic blood pressure, CRP and LDL cholesterol levels.

We thank Dr Scharnagl and colleagues and Dr Jones and colleagues for their positive comments on our recent article1 on remnant cholesterol and low-density lipoprotein (LDL) cholesterol as causal risk factors for ischemic heart disease with and without low-grade inflammation. We agree that because of the complexity of the lipoprotein metabolism with many subclasses of lipoproteins and their different lipid contents, our calculation of nonfasting remnant cholesterol as nonfasting total cholesterol minus LDL cholesterol minus high-density lipoprotein cholesterol is a simple way of estimating remnant cholesterol levels. Thus, our calculation of remnant cholesterol cannot answer the question of whether some subclasses of remnants or some lipid fractions of remnants are more atherogenic than others; however, it is exactly the simplicity of our calculation that makes it clinically useful. Clinicians anywhere can use our method to …

Background— Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are causally associated with ischemic heart disease (IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is currently unknown. Methods and Results— We studied 60 608 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study, of whom 10 668 had IHD diagnosed between 1977 and 2011. We genotyped for variants affecting levels of nonfasting remnant cholesterol, LDL cholesterol, C-reactive protein by CRP alleles, and C-reactive protein by IL6R alleles. Using a multidirectional mendelian randomization design, we investigated possible causal associations between the lipoproteins and C-reactive protein and between the lipoproteins and IHD. A 1-mmol/L(39 mg/dL) higher level of nonfasting remnant cholesterol was associated observationally with a 37% (95% confidence interval, 35–39) higher C-reactive protein level and causally with a 28% (95% confidence interval, 10–48) higher level. For LDL cholesterol, a 1-mmol/L (39-mg/dL) higher level was associated observationally with a 7% (95% confidence interval, 6–7) higher C-reactive protein level, but we found no causal association. Likewise, higher levels of C-reactive protein did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol. Finally, the causal risk ratio for IHD for a 1-mmol/L (39-mg/dL) higher level was 3.3 (95% confidence interval, 2.1–5.2) for nonfasting remnant cholesterol and 1.8 (95% confidence interval, 1.5–2.2) for LDL cholesterol. The causal associations for remnant cholesterol were present even in those without diabetes mellitus and obesity. Conclusions— Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation.