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Perspectiva 286 Obesity and kidney disease - C. P. Kovesdy et al of the so-called obesity-related glomerulopathy (ORG) has increased ten-fold between 1986 and 200041. Importantly, ORG often presents along with pathophysiologic processes related to other conditions or advanced age, conspiring to result in more accentuated kidney damage in patients with high blood pressure47 or in the elderly14,39. Obesity is associated with a number of risk factors contributing to the higher incidence and prevalence of nephrolithiasis. Higher body weight is associated with lower urine pH48 and increased urinary oxalate49, uric acid, sodium and phosphate excretion50. Diets richer in protein and sodium may lead to a more acidic urine and decrease in urinary citrate, also contributing to kidney stone risk. The insulin resistance characteristic of obesity may also predispose to nephrolithiasis51 through its impact on tubular Na-H exchanger52 and ammoniagenesis53, and the promotion of an acidic milieu54. Complicating the picture is the fact that some weight loss therapies result in a worsening, rather than an improvement in the risk for kidney stone formation; e.g. gastric surgery can lead to a substantial increase in enteral oxalate absorption and enhanced risk of nephrolithiasis55. The mechanisms behind the increased risk of kidney cancers observed in obese individuals are less well characterized. Insulin resistance, and the consequent chronic hyperinsulinemia and increased production of insulin-like growth factor 1 and numerous complex secondary humoral effects may exert stimulating effects on the growth of various types of tumor cells56. More recently, the endocrine functions of adipose tissue57, its effects on immunity58, and the generation of an inflammatory milieu with complex effects on cancers59,60 have emerged as additional explanations. Obesity in patients with advanced kidney disease: The need for a nuanced approach Considering the above evidence about the overwhelmingly deleterious effects of obesity on various disease processes, it is seemingly counterintuitive that obesity has been consistently associated with lower mortality rates in patients with advanced CKD19,61 and ESRD62,63. Similar “paradoxical” associations have also been described in other populations, such as in patients with congestive heart failure64, chronic obstructive pulmonary disease65, rheumatoid arthritis66, and even in old individuals67. It is possible that the seemingly protective effect of a high BMI is the result of the imperfection of BMI as a measure of obesity, as it does not differentiate the effects of adiposity from those of higher non-adipose tissue. Indeed, studies that separated the effects of a higher waist circumference from those of higher BMI showed a reversal of the inverse association with mortality23,24. Higher muscle mass has also been shown to explain at least some of the positive effects attributed to elevated BMI63,68. However, there is also evidence to suggest that higher adiposity, especially subcutaneous (non-visceral) fat, may also be associated with better outcomes in ESRD patients.62 Such benefits may indeed be present in patients who have very low short term life expectancy, such as most ESRD patients69. Indeed, some studies that examined the association of BMI with time-dependent survival in ESRD have shown a marked contrast between protective short term effects vs. deleterious longer term effects of higher BMI70. There are several putative short term benefits that higher body mass could portend, especially to sicker individuals. These include a benefit from the better nutritional status typically seen in obese individuals, and which provides better protein and energy reserves in the face of acute illness, and a higher muscle mass with enhanced antioxidant capacity63 and lower circulating actin and higher plasma gelsolin levels71, which are associated with better outcomes. Other hypothetically beneficial characteristics of obesity include a more stable hemodynamic status with mitigation of stress responses and heightened sympathetic and renin-angiotensin activity72; increased production of adiponectines73 and soluble tumor necrosis factor alfa receptors74 by adipose tissue neutralizing the adverse effects of tumor necrosis factor alfa; enhanced binding of circulating endotoxins75 by the characteristically higher cholesterol levels seen in obesity; and sequestration of uremic toxins by adipose tissue76. Potential interventions for management of obesity Obesity engenders kidney injury via direct mechanisms through deranged synthesis of various adipose tissue cytokines with nephrotoxic Rev Med Chile 2017; 145: 281-291


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