Is Chronic Kidney Disease Due to Cadmium Exposure Inevitable and Can It Be Reversed?

Abstract

Cadmium (Cd) is a metal with no nutritional value or physiological role. However, it is found in the body of most people because it is a contaminant of nearly all food types and is readily absorbed. The body burden of Cd is determined principally by its intestinal absorption rate as there is no mechanism for its elimination. Most acquired Cd accumulates within the kidney tubular cells, where its levels increase through to the age of 50 years but decline thereafter due to its release into the urine as the injured tubular cells die. This is associated with progressive kidney disease, which is signified by a sustained decline in the estimated glomerular filtration rate (eGFR) and albuminuria. Generally, reductions in eGFR after Cd exposure are irreversible, and are likely to decline further towards kidney failure if exposure persists. There is no evidence that the elimination of current environmental exposure can reverse these effects and no theoretical reason to believe that such a reversal is possible. This review aims to provide an update on urinary and blood Cd levels that were found to be associated with GFR loss and albuminuria in the general populations. A special emphasis is placed on the mechanisms underlying albumin excretion in Cd-exposed persons, and for an accurate measure of the doses-response relationships between Cd exposure and eGFR, its excretion rate must be normalised to creatinine clearance. The difficult challenge of establishing realistic Cd exposure guidelines such that human health is protected, is discussed.

Keywords: GFR; albuminuria; cadmium; chronic kidney disease; health risk; protein reabsorption; β2-microglobulin.

Figure 1

Tubular reabsorption of β₂-microglobulin (β₂M) and albumin. β₂M is reabsorbed by receptor-mediated endocytosis (RME) and is catabolised (C) in lysosomes. Only a small fraction of albumin is reabsorbed via RME. Most albumin is returned to the circulation via transcytosis. Cd intoxication increases the excretion of both β₂M and albumin. As a carrier of Cd, the reabsorption of albumin may provide a delivery route for Cd to PTCs.

Figure 2

Proposed pathogenesis of reduced proximal tubular reabsorption of albumin and β2-microglobulin after exposure to cadmium. In S1, all β₂M is reabsorbed through receptor-mediated endocytosis (RME) and is catabolised (C) in lysosomes. Albumin is reabsorbed through RME in S1 and transcytosis in S1, S2 and S3. A small fraction of reabsorbed albumin is subjected to lysosomal catabolism, while most is returned to the blood stream via transcytosis. Cd impairs RME function, which reduces the reabsorption of both albumin and β₂M.

Figure 3

Determination of the NOAEL equivalent of kidney cadmium burden. Pairs of E_Cd/C_cr and eGFR data were fitted to (a) an inverse exponential model; (b) a natural logarithmic model; (c) an exponential model; and (d) Hill model. Bootstrap curves for model averaging (e). BMDL/BMDU values of E_Cd/C_cr producing a 5% reduction in eGFR (f). Data are from Satarug et al., 2022 [24].

Figure 4

The paradox relationships between the eGFR and urinary excretion rate of cadmium. In women and men with low Cd burdens (a,b), eGFR showed a positive association with Cd exposure. Conversely, eGFR showed an inverse association with Cd exposure in women and men (c,d) who had a high Cd burden. Data are from Satarug et al., 2023 [114].