Tissue expression of tubular injury markers is associated with renal function decline in diabetic nephropathy

Equations to estimate glomerular filtration rate (GFR) are routinely used to assess kidney function. Current equations have limited precision and systematically underestimate measured GFR at higher values. To develop a new estimating equation for GFR: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Cross-sectional analysis with separate pooled data sets for equation development and validation and a representative sample of the U.S. population for prevalence estimates. Research studies and clinical populations ("studies") with measured GFR and NHANES (National Health and Nutrition Examination Survey), 1999 to 2006. 8254 participants in 10 studies (equation development data set) and 3896 participants in 16 studies (validation data set). Prevalence estimates were based on 16,032 participants in NHANES. GFR, measured as the clearance of exogenous filtration markers (iothalamate in the development data set; iothalamate and other markers in the validation data set), and linear regression to estimate the logarithm of measured GFR from standardized creatinine levels, sex, race, and age. In the validation data set, the CKD-EPI equation performed better than the Modification of Diet in Renal Disease Study equation, especially at higher GFR (P < 0.001 for all subsequent comparisons), with less bias (median difference between measured and estimated GFR, 2.5 vs. 5.5 mL/min per 1.73 m(2)), improved precision (interquartile range [IQR] of the differences, 16.6 vs. 18.3 mL/min per 1.73 m(2)), and greater accuracy (percentage of estimated GFR within 30% of measured GFR, 84.1% vs. 80.6%). In NHANES, the median estimated GFR was 94.5 mL/min per 1.73 m(2) (IQR, 79.7 to 108.1) vs. 85.0 (IQR, 72.9 to 98.5) mL/min per 1.73 m(2), and the prevalence of chronic kidney disease was 11.5% (95% CI, 10.6% to 12.4%) versus 13.1% (CI, 12.1% to 14.0%). The sample contained a limited number of elderly people and racial and ethnic minorities with measured GFR. The CKD-EPI creatinine equation is more accurate than the Modification of Diet in Renal Disease Study equation and could replace it for routine clinical use. National Institute of Diabetes and Digestive and Kidney Diseases.

Although pathologic classifications exist for several renal diseases, including IgA nephropathy, focal segmental glomerulosclerosis, and lupus nephritis, a uniform classification for diabetic nephropathy is lacking. Our aim, commissioned by the Research Committee of the Renal Pathology Society, was to develop a consensus classification combining type1 and type 2 diabetic nephropathies. Such a classification should discriminate lesions by various degrees of severity that would be easy to use internationally in clinical practice. We divide diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy are classified as follows: Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy. A good interobserver reproducibility for the four classes of DN was shown (intraclass correlation coefficient = 0.84) in a test of this classification.

It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.