Effect of Acetazolamide and Furosemide on Obesity-induced Glomerular Hyperfiltration

BACKGROUND Almost half of the causes of death in the industrial world are due to cardio-vascular (CV) disease. Two of the main risk factors for CV disease have become much more prevalent during the last decades, reaching epidemic dimensions in the 21st century: hypertension and obesity. In 2003-2004, 66% of the adult USA population had a body mass index(BMI)over 25, while 32% had a BMI over 30 .Hypertension is more prevalent in obese than in lean subjects .The cause and effect relationship between these two conditions is supported by the fact that weight loss is associated with a decrease in blood pressure .

Salt retention by the kidney is one of the important mechanisms involved in the pathogenesis of hypertension in obesity. Studies in animal models and in humans showed that increased salt reabsorption occurs in the tubules in obesity. Another renal functional abnormality occurring in obesity is glomerular hyperfiltration, characterized by increased renal plasma flow (RPF) and increased glomerular filtration rate(GFR) up to twice the normal level . The structural basis to these functional abnormalities is renal hypertrophy and glomerular enlargement.

These functional and structural abnormalities have deleterious consequences:

1. Increased urinary albumin excretion. Microalbuminuria, an important risk factor for CV disease, has a high prevalence in obese subjects .
2. Increased risk for the development of focal segmental glomerulosclerosis, the so-called obesity related glomerulopathy. The incidence of this disease has multiplied 10 times within 15 yrs in the USA .
3. Increased rate of progression of chronic renal insufficiency in kidney disease not primarily caused by obesity. Following initial glomerular damage from any cause, the number of remnant functioning glomeruli decreases. The consequent compensatory increase in single nephron filtration rate of these remnant glomeruli leads to further glomerular damage in kidney disease not related to obesity . In the obese with chronic renal damage, the obesity related hyperfiltration amplifies the compensatory augmentation in single nephron GFR of remnant nephrons, thus worsening glomerular damage, irrespective of the cause of the primary insult.

The clinical relevance of these abnormalities is reflected in the sharp increase in the risk of developing end stage renal disease in the obese. This relative risk, independently of confounders as diabetes mellitus, hypertension and dyslipidemia, is 3 to 5 depending on the severity of obesity .