Opioids Induce Renal Abnormalities in Tumor-Bearing Mice

Abstract

The etiology of renal dysfunction in cancer patients is likely to be multifactorial. A large proportion of these patients receive opioid analgesics, but whether opioids contribute to renal dysfunction remains uncertain. In a murine cancer model, we examined the effects of chronic opioid administration on renal function and pathology, and the molecular mechanisms involved.C3H/HeJ mice implanted with 2472 tumor cells were treated with either morphine or hydromorphone in clinically relevant doses, or PBS (controls). Renal function was assessed by blood and urine chemistry as well as by measuring mean arterial pressure (MAP) and kidney perfusion. Pathological changes in the kidneys were examined by routine histology. Molecular changes were examined by assessing eNOS, iNOS, HO-1 and COX-2 expression in whole-kidney lysates by Western immunoblotting, and cellular colocalization of these enzymes was determined using immunofluorescence microscopy.Three weeks of opioid treatment resulted in increased kidney weight, elevated BUN and proteinuria, and decreased MAP. This was accompanied by histological abnormalities including glomerular enlargement, hypercellularity, peritubular congestion, vasodilatation and tubular casts. The vasoregulatory molecules iNOS, eNOS, HO-1 and COX-2 were upregulated in the kidneys. The NOS inhibitor L-NAME prevented the morphine-induced increase in perfusion and kidney weight.The chronic use of clinically relevant doses of opioidsleads to structural kidney abnormalities, upregulates NOS, COX-2 and HO-1, and results in renal dysfunction in a murine model of cancer.