Preventing Renal Functional Abnormalities Predisposing to Chronic Kidney Disease in Abdominal Obesity: A Randomized, Parallel-Group, Pilot Study of Calorie REstriction in Subjects With Abdominal Obesity and Type 2 Diabetes at Increased Renal and Cardiovascular Risk

Background:

Obesity is the major risk factor for type 2 diabetes, which in turn is associated with nephropathy in about one third of patients. Obesity is also an independent risk factor for chronic renal disease, regardless of the association with diabetes. Furthermore, chronic renal disease is the strongest risk factor for cardiovascular morbidity and mortality in people with diabetes and without. However, the mechanisms responsible for the adverse nephrologic effects of obesity and type 2 diabetes are not clear, but likely involve insulin resistance, low-grade systemic inflammation, hyperlipidemia, and increased synthesis of vasoactive and fibrogenic substances, including angiotensin II, insulin, leptin and transforming growth factor β1. These substances may individually or interactively affect glomerular hyperfiltration, renal venous pressure, mesangial cell hypertrophy and matrix production, ultimately leading to renal scarring, impaired glomerular filtration rate, micro- and macro- albuminuria and end-stage renal disease (ESDR). Of interest, the risk for glomerular hyperfiltration and hyperperfusion is enhanced especially in subjects with abdominal obesity. Both conditions predispose to microalbuminuria, an early marker of renal disease and increased cardiovascular risk.

A growing body of evidence is now showing that calorie restriction (CR) improves many of the metabolic abnormalities associated with obesity and type 2 diabetes. In particular, it was recently demonstrated that long-term CR results in profound and sustained beneficial effects on the major atherosclerosis risk factors, serum Total cholesterol, Low density lipoprotein (LDL)-C, High density lipoprotein (HDL)-C, triglycerides, and blood pressure. CR also provides a powerful protective effect against obesity, insulin resistance, inflammation, as reflected in extremely low C reactive protein (CRP) levels and tumor necrosis factor (TNF)-alpha, and cardiovascular aging itself (i.e. left ventricular stiffness). We also found that long-term CR reduces serum concentrations of proinflammatory cytokines, triiodothyronine and growth factors such as platelet-derived growth factor (PDGF), and transforming growth factor (TGF)-beta-1, also factors actively involved in the progression of chronic kidney diseases. Taken together, these preliminary evidences suggest that CR might prevent renal function deterioration in diabetic, obese patients. However, this hypothesis has not been tested so far.

Objectives:

• The major goal of this pilot, explorative study is to provide a comprehensive evaluation of the effects of CR on the pathophysiological mechanisms that may affect the onset and the progression of chronic kidney disease in subjects with abdominal obesity and type 2 diabetes.
• Evaluate whether CR reduces the glomerular filtration rate (GFR) in subjects with abdominal obesity and type 2 diabetes, but still no evidence of renal disease [serum creatinine <1.2 mg/dL and albuminuria <20 μg/min (median of the 3 consecutive measurements in overnight urine collections)], and to assess whether CR reduces also kidney perfusion and/or filtration fraction, and whether these hemodynamic changes correlate with a concomitant reduction in urinary albumin excretion rate.
• Investigate the relationships between the changes in renal hemodynamics and/or albuminuria and the concomitant changes in abdominal circumference, body weight, body mass index, blood pressure, insulin sensitivity (as assessed by euglycemic-hyperinsulinemic clamp), serum lipids, adipokines levels (namely adiponectin, leptin), angiotensin II, and markers of chronic inflammation.
• Assess whether CR may reduce risk factors for cardiovascular disease (CVD) in diabetic, obese patients (insulin resistance, visceral obesity, hypertension).