Blood Pressure and Diabetic Nephropathy

Diabetic nephropathy and obesity At the Clinical Update in Diabetic Nephropathy at the American Diabetes Association Scientific Sessions, Karen A. Griffin (Maywood, IL) discussed interrelationships between obesity and the kidney, noting that obesity appears to be related to the increase in end-stage renal disease (ESRD), in part because of its relationship to diabetes and hypertension, but with a 1.2-to 1.6-fold increase in chronic kidney disease (CKD) risk even correcting for these associations. Reviewing CKD staging, in stages 3, 4, and 5, the glomerular filtration rate (GFR) is 30–59, 15–29, and 15 ml/min per 1.73 m BSA, respectively, and Griffin pointed out that the adjustment for body surface is quite important when considering the effect of body size. In a Kaiser Permanente analysis of 1,471 subjects developing ESRD in a 8,347,955 person-year followup, adjusted for age, sex, race, education, cigarette use, diabetes, blood pressure, lipids, and other variables, obesity increased the likelihood of ESRD with BMI 35 associated with a 5-fold increase, BMI 30–34.9 associated with a 3-fold increase, and BMI 25–29.9 associated with a 1.5-fold increase in risk (1). There are a number of different forms of obesityrelated CKD, with the majority of cases associated with microalbuminuria, endothelial dysfunction, and mild-tomoderate decrease in GFR, mainly associated with cardiovascular risk. Coexistent obesity and CKD lead, however, to accelerated progression of the latter (2,3). A form of glomerulopathy occurs with obesity characterized by glomerular enlargement (which is more common in obesity) and focal segmental glomerulosclerosis (4). The pathogenesis may involve hyperfiltration, leading to glomerular capillary injury and sclerosis, in a fashion similar to occurring experimentally with 5/6 nephrectomy (5). From a hemodynamic point of view, there is a high GFR in obesity (6)—a phenomenon demonstrated in comparison of body mass among a variety of different mammalian species. GFR decreases after weight loss in morbid obesity (7,8). Griffin noted that hyperfiltration, which occurs with loss of renal mass, as in renal transplant donors, or with increased metabolic requirement, as in pregnancy, predominantly reflects increased glomerular capillary flow rather than an increase in glomerular pressure. Most patients with hypertension develop benign nephrosclerosis, other than at extremely high blood pressure levels, while those with nonproteinuric CKD and, to an even greater extent, those with diabetic nephropathy and other renal diseases develop renal damage in a fashion related to blood pressure but at much lower blood pressure levels (9); Griffin showed experimental models of this (10), supporting the recommendation that blood pressure goals in persons with diabetes or with renal disease should be lower than those for the overall population with essential hypertension. There are protective renal autoregulatory mechanisms that reduce susceptibility to hypertensive damage (11,12) in the absence of renal disease. Obesity does not in itself result in increased susceptibility to loss of renal autoregulation, but there is an eightfold variation in number of glomeruli per kidney present at birth, with lower number in subjects with lower birth weight (a risk factor for insulin resistance), with the number not changing subsequently (13). Obese individuals who happen to have a low glomerular number may then be at greater risk of extreme increase in glomerular size and hence of developing pressure injury, with increase in glomerular size potentially increasing the susceptibility to injury by increasing glomerular capillary wall stress (14). Griffin concluded by proposing a multihit concept of the pathogenesis of progressive glomerulosclerosis in obesity, based on the combination of decreased nephron number and/or other underlying CKD increasing likelihood of deterioration in the face of the glomerular hyperfiltration and increase in glomerular size developing from the obesity itself (15).