Role of obesity in chronic kidney disease progression

Abstract

Obesity is a global health epidemic linked to numerous chronic disease conditions and consequences, including type 2 diabetes mellitus (T2DM), cardiovascular disease, chronic kidney disease (CKD) and premature mortality. CKD, which can progress to end stage renal disease (ESRD) and/or dialysis with limited treatment options beyond slowing its advancement, is increasingly being recognized as a result or consequence of obesity. This review examines the pathophysiological mechanisms connecting obesity to the development and progression of CKD, via a condition known as obesity related kidney disease (ORKD). Importantly, ORKD has a distinct set of pathophysiological lesions from diabetic nephropathy, as free fatty acid and triglyceride deposition in ORKD dominates over hyperglycemia-induced renal injury in the context of diabetes. Since T2DM is commonly associated with obesity, it is important to recognize ORKD as a distinct entity which likely needs a distinct approach towards its management. Although CKD is the end result of many pathophysiological processes including obesity, the process by which it develops in each condition is vastly different. By synthesizing current preclinical and clinical evidence, we highlight the role of obesity as a modifiable risk factor for CKD and explore obesity-targeted interventions that reduce hyperfiltration among potential strategies to reduce CKD incidence and delay progression to ESRD.

Keywords: CKD progression; Chronic Kidney Disease (CKD); Disease mechanisms; Hyperfiltration; Obesity Related Kidney Disease (ORKD).

Fig. 1

The schematic illustrates the underlying mechanisms in obesity that contribute to obesity related kidney disease (ORKD). Hyperfiltration is a prominent feature of ORKD. While the contributing proportion of each of the factors to ORKD may not be known, eventually the combination leads to proteinuria, tubular atrophy and interstitial fibrosis and decreases in GFR, which result in CKD progression. Abbreviation ROS = Reactive Oxygen Species, GFR = Glomerular Filtration Rate, NHE3 = Sodium Hydrogen Exchanger Isoform 3, CKD = Chronic Kidney Disease, HTN = Hypertension.

Fig. 2

Immunohistochemistry sections highlighting intra-renal fat absorption and accumulation. PAS stain (left panels, black arrows) demonstrates WD-fed mice develop vacuoles in the brush border membranes of tubules and fat droplets are visible (Right panels, black arrows) on Oil Red O stain only in the WD-fed mouse. (CD = Common Diet; WD = Western Diet).

Fig. 3

Peri-renal fat depots in obese mouse (WD-fed) and lean mouse (CD-fed). As is evident, the obese mouse has increased amounts of peri-renal and other fat depots compared to the lean mouse. Increased peri-renal adiposity serves as a pathway to development and progression of ORCKD. Blue arrowheads = Peri-renal fat, Green arrowheads = kidneys, Red arrowheads = Epididymal fat.