Increase, Cytotoxicity (renal tubular cell) leads to Occurrence, Kidney toxicity

Renal tubular cells are very important functional units of the nephrons (Priante et al., 2019). The tubular cells are essential for the proper removal of waste material from the blood, as well as retaining essential nutrients, water, and salt levels for homeostatic blood content (Priante et al., 2019). The S3 segment of the proximal tubule in particular is highly susceptible to damage by environmental toxicants (Lentini et al., 2017). Apoptosis is the preferred method of cell death for renal tubule cells, as injured cells need to be removed without inducing an inflammatory response (Priante et al., 2019). By forming apoptotic bodies that can be recycled via phagocytes or epithelial cells, the kidney avoids the induction of an inflammatory response which causes the injury of surrounding, healthy cells. However, when apoptotic bodies are not phagocytosed quickly enough, their membranes can become damaged. This causes the apoptotic bodies to enter secondary necrosis, lysing and releasing their contents to the extracellular space. The immune cells will instigate an inflammatory response as a result, causing the injury to nearby tubular cells through the release of granule contents of by the immune cells (Priante et al., 2019). Remarkably, thanks to compensatory functional, molecular, and structural changes in the kidney, the remaining healthy nephrons are able to function adequately until more than 75% of them die (Orr and Bridges, 2017). After the loss of more than 75% of the nephrons however the remaining nephrons are no longer able to effectively remove environmental toxicants or waste from the filtrate, resulting in failed renal function (Orr and Bridges, 2017).

Dose Concordance

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Temporal concordance

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Incidence concordance

One article showed that rats treated once with 5 mg/kg uranyl acetate showed significantly increased proximal tubular cytotoxicity and significant increase in serum creatinine 3 days after the treatment (Sano et al., 2000).

Other Evidence

“Chronic exposure: After ingestion or inhalation, cadmium is transported to the liver and to the kidney by metallothionein, which binds cadmium. Signs of cell apoptosis and cytokine pathway activation are common in this syndrome. A typical, chronic tubular-interstitial nephropathy is produced by the accumulation of this metal in the medulla and S1 segment of the proximal tubule.” (Lentini et al., 2017)

 “Acute exposure: The ionized free form induces cellular toxicity reducing phosphate and glucose transport and inhibiting mitochondrial respiration, with membrane rupture of the proximal tubular cells of the nephron (17).

 “Organic mercury gives skin manifestations and neurological disturbances such as hearing loss, paraesthesia and ataxia. Mercury-related kidney damage can due to tubular dysfunction with elevated urinary excretion of albumin, transferrin, retinol binding protein, and β-galactosidase and a nephrotic syndrome with membranous nephropathy pattern (21).” (Lentini et al., 2017)

Orr and Bridges (2017) found that exposure to heavy metals **** “Indeed, it has also been suggested that exposure to heavy metals can negatively alter the function of the remaining functional nephrons [11,12]. These adverse effects could conceivably lead to additional and/or more rapid cell death and glomerulosclerosis, which would further reduce the functional renal mass of the patient.” (Orr & Bridges, 2017)

“In the rat, an acute perfusion of Cd2+ caused hypercalciuria, hyperphosphaturia and hypokaliuria without modification of glomerular filtration rate (GFR) [1]. By contrast, a single, 20-fold lower dose of Pb2+, Hg2+ induced glomerular and tubular damage characterized by a reduced GFR, glycosuria, proteinuria and a rapid obstruction of the tubular system [13], illustrating that the pattern of nephrotoxicity differs between heavy metals. Therefore, Pb2+ and Hg2+ are more dangerous than Cd2+ because they induce an irreversible renal insufficiency even during acute intoxication.” (Barbier et al., 2005)

There are no currently known inconsistencies or uncertainties for this relationship.

There is a defined response-response relationship for renal tubule cytotoxicity leading to kidney failure. The loss of 75% of the nephrons to damage is the threshold for kidney failure (Orr and Bridges, 2017). This is due to the ability of the kidneys to make changes in the structure and function of the remaining nephrons at a molecular level to compensate for the lost nephrons (Orr and Bridges, 2017). The kidneys are able to retain adequate functioning until only 25% of the original nephrons remain, at which point the compensatory changes cannot maintain kidney functioning and kidney failure is final (Orr and Bridges, 2017).

There are no known feedforward/feedback loops that influence this relationship.