Cohort Study and Bias Analysis of the Obesity Paradox Across Stages of Chronic Kidney Disease

Abstract

Objective: In advanced chronic kidney disease (CKD), patients with obesity often have better outcomes than patients without obesity, often called the 'obesity paradox'. Yet, in CKD, the prevalence of inflammation increases as CKD progresses. Although a potential confounder, inflammation may be left unaccounted in obesity-mortality studies. We examined the associations of body mass index (BMI) with all-cause and cause-specific mortality across CKD stages, with consideration for uncontrolled confounding due to unmeasured inflammation.

Methods: We investigated 2,703,512 patients with BMI data between 2004 and 2006. We used Cox models to examine the associations of BMI with all-cause, cardiovascular, and cancer mortality, (ref: BMI 25-<30 kg/m²), adjusted for clinical characteristics and stratified by CKD stages. To address uncontrolled confounding, we performed bias analysis using a weighted probabilistic model of inflammation given the observed data applied to weighted Cox models.

Results: The cohort included 5% females and 14% African Americans. In adjusted analyses, the associations of the BMI with all-cause and cardiovascular mortality showed a reverse J-shape, where a higher BMI (>40 kg/m²) was associated with a higher risk. Conversely, a lower mortality risk was observed with a BMI 30-<35 kg/m² across all CKD stages and for BMI >40 kg/m² in CKD stage 4/5. Cancer mortality analyses showed an inverse relationship. Bias analysis for uncontrolled confounding suggested that independent of inflammation, the obesity paradox was present.

Conclusion: We observed the presence of the obesity paradox in this study. This association was consistent in advanced CKD and in our bias analysis, suggesting that inflammation may not fully explain the observed BMI-mortality associations including in patients with CKD.

Keywords: bias analysis; body mass index; chronic kidney disease; inflammation; mortality; obesity paradox.

Figure 1.

Association of the body mass index with (A) all-cause, (B) cardiovascular, and (C) cancer mortality across strata of CKD stages after case-mix + laboratory adjustment. Covariate adjustment included the following: age, gender, race, ethnicity, ever smoking status, ever alcoholism status, Charlson comorbidity index, chronic obstructive pulmonary disease, cancer, diabetes, ischemic heart disease (including myocardial infarction), congestive heart failure, peripheral vascular disease, cerebrovascular disease, atrial fibrillation, prescription for renin-angiotensin-aldosterone system inhibitors (RAASi), statins, beta blockers, and alpha blockers, and systolic and diastolic blood pressures. CKD, chronic kidney disease.