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-β-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.