New approaches for detecting thresholds of human nephrotoxicity using cadmium as an example

Damage to the kidneys is one of the primary toxic actions of metals. Nephrotoxic substances not only cause renal disease directly, but they can also destroy renal reserve capacity, potentially placing those people with additional risk factors, such as diabetes, hypertension, cardiovascular disease, and genetic predispositions, at greater risk. To detect nephrotoxicity in people at a stage where intervention can be effective, sensitive methods are needed. One of the major advantages of using sensitive biomarkers of renal damage is that people who may be particularly susceptible to renal damage can be identified early, at a reversible stage of damage, and the progression to end-stage renal disease may be halted or delayed. Various categories of tests can be used to detect effects of nephrotoxic substances on the kidney. Through the use of biomarkers of damage to various parts of the nephron, U.S. and European studies have both shown a similar pattern of damage among men occupationally exposed to cadmium. These studies indicate various thresholds of renal effects, which researchers suggest represent a cascade of progressively severe damage to the kidney. Research into new biomarkers of damage caused by exposure to nephrotoxic substances centers around mechanisms of cell death, including necrosis and apoptosis; mechanisms of cell growth, regeneration, and proliferation, including factors that control cell cycle, influence gene expression, and modulate nucleic acid synthesis; and genetic factors that increase susceptibility to renal disease. Examples of types of candidate biomarkers include cytokines, lipid mediators, growth factors, transcription factors and protooncogenes, extracellular matrix components (collagen, glycoproteins, and proteoglycans), and cell adhesion molecules. Research into new categories of biomarkers may provide additional insights into the mechanisms of damage caused by nephrotoxins