Study Details Causal Effect of Obesity on Diabetic Nephropathy

Zhi-Hong Liu, MD, PhD

New research is shedding light on the causal relationship between BMI and diabetic nephropathy and the contrast in increased risk seen among women with type 2 diabetes compared with their male counterparts.

An analysis of data from more than 150,000 patients from a database in Japan, results of the study demonstrate a single standard deviation increase in BMI was associated with a 3.7-fold increase in odds of diabetic nephropathy, but sex-stratified analyses suggested this effect was more apparent in women, with women experiencing 14-fold increase odds of diabetic nephropathy compared to a 3.5-fold increase in men.

“Our research highlights how obesity contributes to the incidence and progression of diabetic nephropathy in people with type 2 diabetes, especially for women,” said Zhi-Hong Liu, MD, of Jinling Hospital and Nanjing University School of Medicine in Nanjing, China, in a statement from the Endocrine Society. “Managing your blood pressure and blood sugar may not be enough to slow the progression to end-stage renal disease, and our study shows how important it is for people with diabetes to also manage their weight."

Investigators designed the current study based on the results of a previous genome-wide association study (GWAS) of diabetic nephropathy in type 2 diabetes diagnosed by renal biopsy, with the intent of using Mendelian randomization methods to estimate the causal effect of BMI on nephropathy and other kidney-specific outcomes in patients with type 2 diabetes. From the previous GWAS, investigators identified 85 loci associated with BMI from a cohort of 158,284 Japanese individuals, including 3972 with type 2 diabetes, from the BioBank Japan database. Of these 85 genetic variants identified in the original study, 56 were chosen as instrumental variables for the analyses in the current study.

The outcome of interest for the study was the causal effect of BMI on diabetic nephropathy, eGFR, and proteinuria in type 2 diabetes according to a two-sample Mendelian randomization sample. Investigators used a generalized summary Mendelian randomization analysis as the primary method and six other robust methods to test assumptions.

For the purpose of analysis, diabetic nephropathy was defined as having a previous history of type 2 diabetes, persistent albuminuria or decreased renal function, biopsy-proven kidney disease as a direct result of diabetes mellitus, and being without diseases concomitant with nondiabetic kidney diseases.

Upon analysis, results indicated a single standard deviation increase in BMI was causally associated with greater risk for diabetic nephropathy (OR, 3.76 [95% CI, 1.88-7.53]; P <.001) and lower eGFR levels (OR, 0.71 [95% CI, 0.59-0.86]; P <.001), but there was no causal association observed between BMI and proteinuria (P=.02). In sex-stratified analyses, results suggested the causal effect of BMI on risk of diabetic nephropathy was greater among women (OR, 14.81 [95% CI, 2.67-28.05]; P=.002) than among their male counterparts (OR, 3.48 [95% CI, 1.18-10.27]; P=.02).

Investigators pointed out results of sensitivity analyses failed to provide evidence for violation of the Mendelian randomization assumptions. Investigators also noted multiple limitations to consider when interpreting the results of their study, including being specific to individuals in Asia and conducting analyses under the assumption the association between BMI and diabetic nephropathy was linear.

“People with diabetes and obesity should have their kidneys checked more often as they are at high risk, and while chronic kidney disease has no cure, early detection and obesity treatment could slow the progression to end-stage kidney disease,” Liu said.

This study, “Body Mass Index and Risk of Diabetic Nephropathy: A Mendelian Randomization Study,” was published in the Journal of Clinical Endocrinology and Metabolism.