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Understanding obesity and chronic kidney disease.

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    ABSTRACT: Background/Aims: Adult and childhood obesity is an independent risk factor in development of chronic kidney disease (CKD) and its progression to end-stage kidney disease. Pathologic consequences of obesity include non-esterified fatty acid-induced oxidative stress and consequent injury. Since the serine36-phosphorylated p66shc is a newly recognized mediator of oxidative stress and kidney injury, we studied its role in oleic acid (OA)-induced production of reactive oxygen species (ROS), mitochondrial depolarization and injury in cultured renal proximal tubule cells. Methods: Renal proximal tubule cells were used and treated with OA: ROS production, mitochondrial depolarization as well as injury were determined. Transcriptional effects of OA on the p66shc gene were determined in a reporter luciferase assay. The role of p66shc in adverse effects of OA was determined using knockdown, p66shc serine36 phosphorylation and cytochrome c binding-deficient cells. Results: We found that OA increased ROS production via the mitochondria - and to a less extent via the NADPH oxidase - resulting in ROS-dependent mitochondrial depolarization and consequent injury. Interestingly, OA also stimulated the promoter of p66shc. Hence, knockdown of p66shc, impairment its Ser36 phosphorylation (mutation of Ser36 residue to alanine) or cytochrome c binding (W134F mutation) significantly attenuated OA-dependent lipotoxicity. Conclusion: These results offer a novel mechanism by which obesity may lead to renal tubular injury and consequently development of CKD. Manipulation of this pathway may offer therapeutic means to ameliorate obesity-dependent renal lipotoxicity.
    American Journal of Nephrology 08/2013; 38(3):226-232. DOI:10.1159/000354357 · 2.65 Impact Factor
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    ABSTRACT: Obesity is often an absolute contraindication to kidney transplant, but an internal analysis of our center's recipients suggests that not all obese populations exhibit poor outcomes. We used national data to compare outcomes in select groups of morbidly obese and normal-weight recipients after kidney transplant. This study was a retrospective analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing database. The study sample consisted of 30,132 morbidly obese (body mass index [BMI] 35-40 kg/m(2)) and normal-weight (BMI 18.5-24.9 kg/m(2)) patients who underwent primary kidney-only transplantation between 2001 and 2006. Crude 3-year graft and patient survival rates of morbidly obese and normal-weight subgroups were evaluated. Logistic regression modeling compared 3-year graft failure and patient mortality in morbidly obese and normal-weight subgroups with opposite characteristics. Kaplan-Meier survival curves were created for 3-year graft and patient survival. Cox proportional hazard regression modeling was used to determine hazards for patient and graft mortality. No differences in crude graft and patient survival rates were seen between normal weight and morbidly obese recipients who were African American, diabetic, and 50 to 80 years of age. Morbidly obese recipients who were nondialysis dependent, nondiabetic, had good functional status, and received living-donor transplants had significantly lower 3-year graft failure and patient mortality risk compared with normal-weight recipients who were dialysis dependent, diabetic, had poor functional status, and received a deceased-donor transplant, respectively (P < .01). Morbidly obese recipients have significantly lower graft and patient survival curves compared with normal-weight recipients; however, multivariate regression analysis reveals that morbid obesity is not an independent predictor of graft failure or patient mortality. Morbid obesity is not independently associated with graft failure or patient mortality; therefore, it should not be used as a contraindication to kidney transplantation.
    Journal of Renal Nutrition 09/2013; DOI:10.1053/j.jrn.2013.07.001 · 2.55 Impact Factor
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    ABSTRACT: Objectives Obesity is often associated with higher hospital costs because of longer length of stay (LOS) but this has not been well studied in the kidney transplant population. Therefore, we used national data to compare LOS in select groups of morbidly obese and normal weight recipients after kidney transplant. Design This study was a retrospective analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing database. Subjects The study sample consisted of 42,787 morbidly obese (body mass index 35-40 kg/m2) and normal weight (body mass index 18.5-24.9 kg/m2) who underwent primary kidney-only transplantation between 2000 and 2008. Main Outcome Measures Morbidly obese and normal-weight subgroups were crudely evaluated for prolonged LOS (>7 days). Logistic regression modeling compared LOS in morbidly obese and normal-weight subgroups with varying characteristics and determined predictors of prolonged LOS. Results All morbidly obese subgroups had significantly higher crude rates of prolonged LOS (P < .05). However, no significant differences in prolonged LOS were seen between any of the morbidly obese or normal-weight subgroups in multivariate analysis. Morbid obesity was an independent predictor of prolonged LOS (P < .001) but not a stronger predictor than that of being African American, having coronary artery disease, diabetes mellitus, or peripheral vascular disease, being 50 to 80 years of age, having a previous transplant or poor functional status. Receiving a deceased-donor transplant and being dialysis dependent >4 years were significantly better predictors of prolonged LOS compared with morbid obesity (P < .05). Conclusions Some morbidly obese populations have LOS rates that are not significantly different than many commonly transplanted normal weight populations, and the impact morbid obesity has on LOS is not different than many other factors often seen in kidney transplant recipients; therefore, morbid obesity alone should not be a financial consideration in kidney transplant.
    Journal of Renal Nutrition 11/2014; DOI:10.1053/j.jrn.2014.05.007 · 2.55 Impact Factor