Hypertension in People Exposed to Environmental Cadmium: Roles for 20-Hydroxyeicosatetraenoic Acid in the Kidney

Chronic kidney disease (CKD) has now reached epidemic proportions in many parts of the world primarily due to the high incidence of diabetes and hypertension. By 2040, CKD is predicted to be the fifth leading cause of years of life lost. Developing strategies to prevent CKD and to reduce its progression to kidney failure is thus of great public health significance. Hypertension is known to be both a cause and a consequence of kidney damage and an eminently modifiable risk factor. An increased risk for hypertension, especially among women, has been linked to chronic exposure to the ubiquitous food contaminant cadmium (Cd). The mechanism is unclear but is likely to involve its action on the proximal tubular cells (PTCs) of the kidney, where Cd accumulates. Here it leads to chronic tubular injury and a sustained drop in the estimated glomerular filtration rate (eGFR), a common sequela of ischemic acute tubular necrosis, acute and chronic tubulointerstitial inflammation, all of which hinders glomerular filtration. The present review discusses exposure levels of Cd that have been associated with an increased risk of hypertension, albuminuria, and eGFR ≤ 60 mL/min/1.73 m2 (low eGFR) in environmentally exposed people. It highlights the potential role for 20-hydroxyeicosatetraenoic acid (20-HETE), the second messenger produced in kidneys, as the contributing factor to gender differentiated effects of Cd-induced hypertension. Use of GFR loss and albumin excretion in toxicological risk calculation, and derivation of Cd exposure limits, instead of β2-microglobulin (β2M) excretion at a rate of 300 µg/g creatinine, are recommended.