Manifestation of renal disease in obesity: pathophysiology of obesity-related dysfunction of the kidney

John A D’Elia, Bijan Roshan, Manish Maski, Larry A WeinrauchJoslin Diabetes Center, Renal Unit, Beth Israel Deaconess Medical Center, Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Boston and Cambridge, MassachusettsAbstract: Albuminuria in individuals whose body mass index exceeds 40 kg/m2 is associated with the presence of large glomeruli, thickened basement membrane and epithelial cellular (podocyte) distortion. Obstructive sleep apnea magnifies glomerular injury as well, probably through a vasoconstrictive mechanism. Insulin resistance from excess fatty acids is exacerbated by decreased secretion of high molecular weight adiponectin from adipose cells in the obese state. Adiponectin potentiates insulin in its post-receptor signaling resulting in glucose oxidation in mitochondria. Recent studies of podocyte physiology have concentrated on the structural and functional requirements that prevent glomerular albumin leakage. The architecture of the podocyte involves nephrin and podocin, proteins that cooperate to keep slit pores between foot processes competent to retain albumin. Insulin and adiponectin are necessary for high-energy phosphate generation. When fatty acids bind to albumin, the toxicity to proximal renal tubules is magnified. Albumin and fatty acids are elevated in urine of individuals with obesity related nephrotic syndrome. Fatty acid accumulation and resistin inhibit insulin and adiponectin. Study of cytokines produced by adipose tissue (adiponectin and leptin) and macrophages (resistin) has led to a better understanding of the relationship between weight and hypertension. Leptin, is presumably secreted after food intake to inhibit the midbrain/ hypothalamic appetite centers. Resistance to leptin results in excess signaling to hypothalamic sympathetics leading to hypertension. Demonstration of the existence of a cerebral receptor mutation provide evidence for a role in hypertension of a central nervous reflex arc in humans. Further understanding of obesityrelated renal dysfunction has been accomplished recently using experimental models. Rapid weight loss following bariatric surgery may reverse renal pathology of obesity with restoration of normal blood pressure.Keywords: glomerulomegaly, podocyte hypertrophy, obesity, albuminuria, adiponectin, insulin, leptin