Chronology of renal scarring in males with Alport syndrome.

We investigated the onset of renal scarring in 62 males (aged 4-26 years) with Alport syndrome by measuring cortical interstitial volume fraction [Vv (interstitium/cortex)] and percentage global glomerular sclerosis in kidney biopsies. Male pediatric (n = 9) and adult (n = 7) donor kidneys served as controls. Creatinine clearance at the time of biopsy was available for 43 Alport patients. A statistically insignificant correlation between age and Vv (interstitium/cortex) was observed in normal subjects (r = +0.47, slope = 0.0009, P = 0.07). In the Alport patients, age was significantly correlated with Vv (interstitium/cortex (r = +0.49, slope = 0.01, P = 0.001) and global glomerular sclerosis (r = +0.41, P = 0.01), and inversely correlated with creatinine clearance (r = -0.33, P = 0.04). Creatinine clearance was inversely correlated with Vv (interstitium/cortex) (r = -0.78, P = 0.001) and global glomerular sclerosis (r = -0.74, P = 0.001). The correlation with creatinine clearance was especially strong for Vv (interstitium/cortex) values above the normal range, i.e., > 0.2 (r = -0.82, P = 0.001), and was absent for Vv (interstitium/cortex) < 0.2 (r = -0.119, P = 0.55). Creatinine clearance values less than 80 ml/min per 1.73 m2 occurred more frequently in patients with Vv (interstitium/cortex) values > 0.2 (P < 0.0001) and in patients with > 10% globally sclerosed glomeruli (P < 0.001). Patients < or = or > 10 years of age differed in Vv (interstitium/cortex) [0.13 +/- 0.09 (mean +/- SD) vs. 0.24 +/- 0.026, P < 0.001], the frequency of Vv (interstitium/cortex) > 0.2 (3/32 vs. 15/31, P < 0.0001), the frequency of > 10% globally sclerosed glomeruli (3/33 vs. 11/30, P < 0.05), mean creatinine clearance (113 +/- 7 vs. 84 +/- 10 ml/min per 1.73 m2, P = 0.057), and the frequency of creatinine clearance < 80 ml/min per 1.73 m2 (1/20 vs. 11/23, P < 0.01). Thus, reduced creatinine clearance in males with Alport syndrome is associated with Vv (interstitium/cortex) > 0.2 and > 10% globally sclerosed glomeruli. These are frequently detectable in the 2nd decade. We hypothesize that most Alport males will require intervention during the 1st decade for optimal preservation of kidney function.