Quantitative high resolution 1H NMR urinalysis studies on the biochemical effects of cadmium in the rat

Quantitative changes in the urinary excretion patterns of low molecular weight compounds were followed for up to 30 days after dosing of adult Sprague-Dawley rats with single intraperitoneal injections of CdCl2 (6-24 mumol/kg), using high resolution 1H NMR multicomponent urinalysis. There was a marked reduction in the rate of urinary excretion of citrate, 2-oxoglutarate, and succinate within 4.5 hr of the administration of 24 mumol/kg Cd2+. This continued for up to 4 days after dosing in male rats and was consistent with a renal tubular acidosis, caused by inhibition of carbonic anhydrase. Histological examination of the kidneys showed no evidence of structural abnormalities at any Cd2+ dose level. Creatinine excretion was not affected by Cd2+ treatment at any dose level but hippurate excretion was significantly reduced. Severe testicular damage was noted within 24 hr of Cd2+ treatment at doses of greater than 9 mumol/kg and the degree of damage appeared to be correlated with the presence of large amounts of creatine (up to 20 mM) in the urine. Analysis of homogenates of healthy testicular material indicated the presence of high concentrations of free creatine. Cadmium-induced creatinuria appears to result from direct release of creatine from the necrotic cells of the seminiferous tubules and, hence, the measurement of creatine excretion rates may provide a useful noninvasive indicator of testicular necrosis. Because NMR is nonselective in terms of metabolite detection, this work has shed new light on the changes in urinary composition arising from Cd toxicity. As such, the technique is potentially very valuable in the search for new metabolic markers of toxicity and organ dysfunction.