Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy

Abstract

We designed a prospective, double-blind controlled trial to determine predictors of loss of renal function in patients with insulin dependent diabetes and established nephropathy. A total of 409 insulin-dependent diabetic patients with established nephropathy enrolled in a trial on the effect of Captopril on the rate of progression of renal disease. Baseline demographic, clinical (history and physical) and laboratory parameters were analyzed as risk factors for time to progression. Dichotomous characteristics were compared by Fisher's exact test and continuous characteristics with the Wilcoxon rank-sum test. Univariate proportional hazards regression analysis was used to estimate relative risk of nephropathy progression, and bivariate proportional hazard regression to identify interactions with the treatment group assignment. Multivariate proportional hazard regression was employed to determine which characteristics were independent risk factors. We found that a number of demographic and clinical characteristics were significantly associated with nephropathy progression even after adjustment for treatment group. However, after multivariate analysis, the risk factors that independently predicted progression were onset of IDDM later in life, parental diagnosis of IDDM, the presence of edema, increased mean arterial pressure, and an abnormal electrocardiogram. Likewise, a number of laboratory characteristics were also predictive of nephropathy progression. A low hematocrit, high blood sugar, and higher protein excretion predicted nephropathy progression as did a higher serum creatinine, particularly in the face of a normal serum albumin. In conclusion, this study identifies a number of clinical and laboratory risk factors that can predict which patients with insulin-dependent diabetes with established nephropathy are more likely to sustain a clinically important decrease in renal function over a median follow-up of three years.

Estrogens and the diabetic kidney

“…The existing data are contradictory: studies report that diabetic females progress either at a faster rate [6][7][8][9][10] or a slower rate [13][14][15][16] than age-matched diabetic men, or that there are no sex differences in the rate of progression. 11,12 This lack of conclusive data on the effects of sex on diabetic renal disease reflects the fact that few studies have addressed this issue and that the studies that did were limited by differences in study populations and methodology and by not specifically addressing factors such as age, hormonal status, duration and type of diabetes, ethnicity, demographic characteristics, blood pressure, blood glucose control, or antihypertensive therapy.…”

“…In a randomized trial of captopril in type 1 DM, no effects of sex on the course of diabetic renal disease was observed after a 3-year follow-up. 11,18 Similarly, no effects of sex on the progression of diabetic renal disease over 2 years were observed in a prospective study examining the effects of smoking 19 or in a Danish cohort of normoalbuminuric patients followed for 11 years. 12 Male sex was found to be associated with a decline in glomerular filtration rate over 5 years in a prospective study of a smaller cohort of patients with established diabetic nephropathy.…”

“…However, in the setting of diabetes mellitus (DM), this sex difference in the incidence and progression of renal disease has not been fully established. Whereas some studies report that male sex is a risk factor for the development and progression of renal disease in diabetes, [6][7][8][9][10] others indicate no sex differences 11,12 or even increased risk in women. [13][14][15][16] The reasons for these contradictory reports are numerous, including different patient populations studied, different study designs, and inadequate analysis.…”

Surrogate End Points for Clinical Trials of Kidney Disease Progression

“…Therefore, substantial GFR decline is an intermediate outcome for the clinical end point of kidney failure, irrespective of the study population or therapeutic intervention, and an accepted surrogate end point for clinical trials. A number of clinical trials have used decline in GFR as a surrogate end point (7)(8)(9)(10) and have highlighted a number of important issues. First, substantial GFR decline can be appreciated only late in the course of CKD (Figure 2).…”

The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases

“…Moreover, pharmacological inhibition of the CB 1 receptor by AM251 ameliorates STZ-induced albuminuria and prevents the downregulation of podocyte proteins implicated in the maintenance of glomerular permselectivity to proteins [33]. Because proteinuria is an independent predictor of renal outcome in patients with type 1 DM [64], a recent study tested the specific role of CB 1 receptors in mediating urinary protein excretion. Using a genetic CB 1 activation mouse model and pharmacological stimulation of CB 1 in rats, Hsu et al [65] showed that CB 1 receptor activation/stimulation increases urinary protein levels and is associated with enhanced glomerular CB 1 and vascular endothelial growth factor (VEGF) expression levels, as well as a subsequent reduction in nephrin gene and protein expression levels, suggesting a CB 1 /VEGFdependent signaling pathway that may lead to podocyte dysfunction and proteinuria.…”