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

International Journal of Nephrology and Renovascular Disease Dovepress open access to scientific and medical research re v ie w International Journal of Nephrology and Renovascular Disease downloaded from https://www.dovepress.com/ by 106.158.8.56 on 04-Aug-2020 For personal use only. Open Access Full Text Article Manifestation of renal disease in obesity: pathophysiology of obesity-related dysfunction of the kidney This article was published in the following Dove Press journal: International Journal of Nephrology and Renovascular Disease 5 November 2009 Number of times this article has been viewed John A D’Elia Bijan Roshan Manish Maski Larry A Weinrauch Joslin Diabetes Center, Renal Unit, Beth Israel Deaconess Medical Center, Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Boston and Cambridge, Massachusetts Correspondence: Larry A Weinrauch 521 Mount Auburn Street Watertown, Massachusetts 02472, USA Tel +617 923 0800 Email submit your manuscript | www.dovepress.com Dovepress Powered by TCPDF (www.tcpdf.org) Abstract: 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 An association of body mass index (BMI) with risk of kidney disease was summarized from the Boston University Framingham study as a single unit increase of BMI accounting for a 20% increase of kidney disease over 20 years of follow up.1 A recent study from Copenhagen involving 20,000 women and 17,000 men aged 30–80 years found that for each 10% increase in BMI, the systolic blood pressure was 2.0–6.0 mm Hg higher along with an increase in diastolic pressure of 1–3 mm Hg.2 Visceral adipose was quantified by CT scan in a study from Laval University, Quebec.3 A significant correlation between mass of visceral adipose and level of blood pressure was noted. Kidney donors who were obese, or who became obese during an 11 year follow up International Journal of Nephrology and Renovascular Disease 2009:2 39–49 © 2009 D’Elia et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. 39 Dovepress International Journal of Nephrology and Renovascular Disease downloaded from https://www.dovepress.com/ by 106.158.8.56 on 04-Aug-2020 For personal use only. D’Elia et al at the University of California, San Francisco were found to have higher blood pressure than nonobese kidney donors even though proteinuria and nitrogen waste products in the plasma were not different4 When obesity is accompanied by persistent proteinuria of greater than 1 gm/day, findings at light microscopy include focal, segmental and global sclerosis. As lesions progress, individuals may become dependent upon renal replacement therapy. Since obese individuals do relatively well from earlier stages of chronic kidney disease through the stage of hemodialysis, this group is an important component of individuals awaiting kidney transplantation. Investigators from the Department of Nephrology, University of Vienna have concluded from a review of 50,000 patients in the Austrian Dialysis Transplantation Registry that cardiovascular mortality was significantly decreased for BMI 30–35 kg/m2 compared to less than 30 kg/m2.5 Individuals with obesity-related renal failure that is not complicated by accelerated hypertension or profound insulin resistance do well on hemodialysis because of residual function in their large kidneys, in contrast to smaller people with diminutive kidneys. Many patients have been overweight since adolescence. Although elevations of blood glucose and blood pressure may not have occurred until many years later, official statistics may label the cause as hypertensive nephrosclerosis or diabetic nephropathy. It is reasonable to assume that if obesity promotes pathologic renal changes or accelerates damage from other entities that loss of excess body weight would ameliorate such changes, as well as having a beneficial effect on glucose metabolism and blood pressure. Proteinuria in obesity is associated with changes in structure of the epithelial cell of the glomerulus (podocyte): changes in pathophysiology of the glomerulus are better understood than those of the proximal tubule Anatomical studies of the renal glomerulus correlate with the physiology of obesity Investigators from the Autonomous University of Barcelona described a distinct obesity-related change in the renal glomerulus.6 Extremely obese individuals (BMI  40 kg/m2) undergoing renal biopsy during bariatric surgery were compared with a group of age-matched patients studied at the time of elective nephrectomy. Twenty-four hour protein 40 Powered by TCPDF (www.tcpdf.org) submit your manuscript | www.dovepress.com Dovepress excretion was statistically different: 100–340 in the bariatric group vs 100–120 mg/day (p = 0.01) in the non-obese group. Fasting blood sugar levels also were different 88–117 vs 85–99 mg/dl (...truncated)