The Effect of Cadmium on GFR Is Clarified by Normalization of Excretion Rates to Creatinine Clearance

Erroneous conclusions may result from normalization of urine cadmium and N-acetyl-beta-D-glucosaminidase concentrations ([Cd](u) and [NAG](u)) to the urine creatinine concentration ([cr](u)). In theory, the sources of these errors are nullified by normalization of excretion rates (E-Cd and E-NAG) to creatinine clearance (C-cr). We hypothesized that this alternate approach would clarify the contribution of Cd-induced tubular injury to nephron loss. We studied 931 Thai subjects with a wide range of environmental Cd exposure. For x = Cd or NAG, E-x/E-cr and E-x/C-cr were calculated as [x](u)/[cr](u) and [x](u)[cr](p)/[cr](u), respectively. Glomerular filtration rate (GFR) was estimated according to the Chronic Kidney Disease (CKD) Epidemiology Collaboration (eGFR), and CKD was defined as eGFR < 60 mL/min/1.73m(2). In multivariable logistic regression analyses, prevalence odds ratios (PORs) for CKD were higher for log(E-Cd/C-cr) and log(E-NAG/C-cr) than for log(E-Cd/E-cr) and log(E-NAG/E-cr). Doubling of E-Cd/C-cr and E-NAG/C-cr increased POR by 132% and 168%; doubling of E-Cd/E-cr and E-NAG/E-cr increased POR by 64% and 54%. As log(E-Cd/C-cr) rose, associations of eGFR with log(E-Cd/C-cr) and log(E-NAG/C-cr) became stronger, while associations of eGFR with log(E-Cd/E-cr) and log(E-NAG/E-cr) became insignificant. In univariate regressions of eGFR on each of these logarithmic variables, R-2 was consistently higher with normalization to C-cr. Our tabular and graphic analyses uniformly indicate that normalization to C-cr clarified relationships of E-Cd and E-NAG to eGFR.