The present review aims to provide an update on health risks associated with the low-to-moderate levels of environmental cadmium (Cd) and lead (Pb) to which most populations are exposed. Epidemiological studies examining the adverse effects of coexposure to Cd and Pb have shown that Pb may enhance the nephrotoxicity of Cd and vice versa. Herein, the existing tolerable intake levels of Cd and Pb are discussed together with the conventional urinary Cd threshold limit of 5.24 μg/g creatinine. Dietary sources of Cd and Pb and the intake levels reported for average consumers in the U.S., Spain, Korea, Germany and China are summarized. The utility of urine, whole blood, plasma/serum, and erythrocytes to quantify exposure levels of Cd and Pb are discussed. Epidemiological studies that linked one of these measurements to risks of chronic kidney disease (CKD) and mortality from common ailments are reviewed. A Cd intake level of 23.2 μg/day, which is less than half the safe intake stated by the guidelines, may increase the risk of CKD by 73%, and urinary Cd levels one-tenth of the threshold limit, defined by excessive ß₂-microglobulin excretion, were associated with increased risk of CKD, mortality from heart disease, cancer of any site and Alzheimer’s disease. These findings indicate that the current tolerable intake of Cd and the conventional urinary Cd threshold limit do not provide adequate health protection. Any excessive Cd excretion is probably indicative of tubular injury. In light of the evolving realization of the interaction between Cd and Pb, actions to minimize environmental exposure to these toxic metals are imperative.

In theory, the identification of the source of excreted cadmium (Cd) might elucidate the pathogenesis of Cd-induced chronic kidney disease (CKD). With that possibility in mind, we studied Thai subjects with low, moderate, and high Cd exposure. We measured urine concentrations of Cd, ([Cd]_u); N-acetyl-β-d-glucosaminidase, a marker of cellular damage ([NAG]_u); and β₂-microglobulin, an indicator of reabsorptive dysfunction ([β₂MG]_u). To relate excretion rates of these substances to existing nephron mass, we normalized the rates to creatinine clearance, an approximation of the glomerular filtration rate (GFR) (E_Cd/C_cr, E_NAG/C_cr, and E_β2MG/C_cr). To link the loss of intact nephrons to Cd-induced tubular injury, we examined linear and quadratic regressions of estimated GFR (eGFR) on E_Cd/C_cr, eGFR on E_NAG/C_cr, and E_NAG/C_cr on E_Cd/C_cr. Estimated GFR varied inversely with both ratios, and E_NAG/C_cr varied directly with E_Cd/C_cr. Linear and quadratic regressions of E_β2MG/C_cr on E_Cd/C_cr and E_NAG/C_cr were significant in moderate and high Cd-exposure groups. The association of E_NAG/C_cr with E_Cd/C_cr implies that both ratios depicted cellular damage per surviving nephron. Consequently, we infer that excreted Cd emanated from injured tubular cells, and we attribute the reduction of eGFR to the injury. We suggest that E_Cd/C_cr, E_NAG/C_cr, and eGFR were associated with one another because each parameter was determined by the tubular burden of Cd.

The purpose of this NephEd contribution is to introduce a generic method for analyzing plasma concentrations ([x]p). The method is applicable to substances that are filtered by glomeruli, reabsorbed or secreted by tubules, and excreted in urine. The equality from which the method follows states that the filtration rate of substance x is the sum of excretion and net reabsorption rates of x (Fx = Ex + TRx). If x is completely ultrafilterable, Fx = GFR[x]p, and [x]p = Ex/GFR + TRx/GFR. If creatinine clearance (Ccr) is substituted for GFR, Ex/Ccr simplifies to [x]u[cr]p/[cr]u, which can be calculated from measurements in simultaneous aliquots of serum and urine. TRx/Ccr is then deduced as [x]p - Ex/Ccr. The ratios Ex/Ccr and TRx/Ccr - the determinants of [x]p - quantify the amounts of x excreted and reabsorbed per volume of filtrate. If [x]p is abnormal, the generic method identifies which of the determinants is creating the abnormality. If [x]p is normal despite disruptive circumstances, e.g., a reduced GFR, the method elucidates the preservation of normalcy. Herein, we develop these concepts and illustrate their practical utility. .

Urinary cadmium excretion (E_Cd) rises with renal tissue content of the metal. Whereas glomerulopathies are sometimes associated with massive albuminuria, tubular accumulation of Cd typically causes modest albuminuria. Since β₂-microglobulinuria (E_β2M) is an established marker of proximal tubular dysfunction, we hypothesized that a comparison of albuminuria (E_alb) to E_β2M in Cd-exposed subjects would provide evidence of similar mishandling of both proteins. To depict excretion rates per functional nephron, E_Cd, E_alb, and E_β2M were normalized to creatinine clearance (C_cr), a surrogate for the glomerular filtration rate (GFR). Estimation of GFR itself (eGFR) was accomplished with CKD-EPI formulas (2009). Linear and logistic regression analyses were performed to relate E_alb/C_cr, E_β2M/C_cr, and eGFR to several independent variables. Simple linear regressions of eGFR, E_alb/C_cr, and E_β2M/C_cr on E_Cd/C_cr were examined before and after adjustment of dependent variables for age. All regressions were performed after log-transformation of ratios and standardization of all variables. Increments in E_alb/C_cr and E_β2M/C_cr and decrements in eGFR were quantified through four quartiles of E_Cd/C_cr. As age or E_Cd/C_cr rose, E_alb/C_cr and E_β2M/C_cr also rose, and eGFR fell. In linear regressions, slopes relating E_alb/C_cr and E_β2M/C_cr to E_Cd/C_cr were similar. After adjustment of dependent variables for age, coefficients of determination (R²) for all regressions rose by a multiple, and slopes approached unity. E_alb/C_cr and E_β2M/C_cr were similarly associated with each other. Mean E_alb/C_cr and E_β2M/C_cr rose and mean eGFR fell in stepwise fashion through quartiles of E_Cd/C_cr. Whereas E_β2M/C_cr did not vary with blood pressure, E_alb/C_cr rose in association with hypertension in two of the four quartiles. Our data indicate that Cd in renal tissue affected tubular reabsorption of albumin and β₂M similarly in a large cohort of exposed subjects. The results suggest that Cd reduced receptor-mediated endocytosis and subsequent lysosomal degradation of each protein by a shared mechanism.

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/1.73m². 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, R² 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.

Parathyroid hormone (PTH) promotes calcium reabsorption in the cortical distal nephron (CDN). The phosphate concentration ([P]f) rises in that segment in chronic kidney disease (CKD); in theory, high [P]f could reduce availability of calcium for reabsorption and necessitate a compensatory rise in [PTH]. With assumptions, [P]f is proportional to phosphate excreted/volume of filtrate (EP/GFR). We therefore hypothesized that [PTH] would correlate with EP/GFR in CKD, and ΔPTH] would correlate with ΔEP/GFR after sevelamer therapy. We conducted a 4-week, placebo-controlled trial of sevelamer carbonate in patients with CKD. [PTH]1-84 and parameters of phosphate homeostasis were measured before and after treatment. GFR was assumed to equal creatinine clearance (Ccr). Pertinent linear regressions were performed. Phosphate excretion fell in the sevelamer group only. Decrements in [PTH] with sevelamer differed from increments with placebo. With either treatment, [PTH] correlated with EP/Ccr and ΔPTH] correlated with ΔEP/Ccr. Changes in [PTH] were minimal in some sevelamer recipients despite reductions in EP/Ccr; calcium excreted/volume of filtrate was low in these subjects. Phosphate influx affected [PTH] in CKD by determining [P]f in the CDN. In some patients, low calcium influx may have blunted the effect of sevelamer on [PTH].