Experimental contrast-associated nephropathy and its clinical implications

Abstract

Acute renal failure after contrast media injection has been recognized for at least 35 years but the exact mechanism responsible for the renal injury remains an enigma. The clinical characteristics of contrast-induced nephropathy (CAN) are wellknown although more recently the nonoliguric presentation has occurred at an increased frequency—in 70 to 90% of cases. For nonoliguric presentation of CAN, one can expect an asymptomatic increase in serum creatinine, the mean peak occurring at 4.2 days. If oliguric, the fractional excretion of sodium will be <1% and resistant to either fluid challenge or loop diuretics. Preexisting renal insufficiency, with or without diabetes mellitus, increases the risk of CAN 6- to 10-fold but recovery is expected, with <10% of all patients requiring dialytic support. Despite the growing body of published reports, the lack of a suitable animal model to evaluate various proposed mechanisms of renal injury has compromised our ability to devise a technique for preventing CAN. A popular scheme has been proposed to describe the possible sequence by which ischemia or nephrotoxins, or both, induce acute renal failure. In particular, a vascular mechanism (i.e., ischemia), is an appealing explanation for CAN since acute changes in renal hemodynamics after contrast media injection have been confirmed by several animal experiments. Unlike other vascular beds in which contrast media induce acute vasoconstriction followed by vasodilatation, the initial effect on the renal circulation is acute vasodilatation, followed by progressive vasoconstriction, increasing renal vascular resistance and a concomitant decrease in both renal blood flow and glomerular filtration rate. The intensity of the vasoconstrictive phase is reduced by either simultaneous volume repletion or pretreatment with a high-salt diet. However, these renal hemodynamic changes are short-lived, with complete return to normal within 1 to 2 hours after the procedure. Since clinically significant CAN involves continued deterioration of renal function for 3 to 10 days after the procedure, a more severe experimental renal insult is needed to mimic the clinical state. Examination of patients at risk for CAN (i.e., chronic renal insufficiency, diabetic nephropathy, congestive heart failure and hypertension) reveals that preexisting renal ischemia is a common association. Under these circumstances, renal ischemia will induce stimulation of both endogenous vasoconstrictors (angiotensin II, norepinephrine and vasopressin) and vasodilator substances (prostaglandin I 2 [PGI 2] and prostaglandin E 2 [PGE 2]). A disturbance of this balanced vasoconstrictor/vasodilator action on renal circulation will cause acute deterioration of renal function. Animal experiments suggest that contrast agents act in a manner similar to nonsteroidal antiinflammatory agents by selectively inhibiting the vasodilatation caused by prostaglandins and inducing renal dysfunction. Circulating angiotensin II causes both renal vasoconstriction, principally in the efferent arterioles, and de novo synthesis of vasodilator prostaglandins. In the unstimulated state, circulating angiotensin II induces a balanced state between constriction and dilatation resulting in normal renal vascular resistance. When renin release is stimulated, the associated increase in angiotensin II results in increased vasoconstrictive and vasodilatory actions, with the final effect on renal vascular resistance being either unchanged or modestly increased. However, selective interference with the prostaglandin limb of the stimulation causes a reduction in renal blood flow, and the possibility of a reduction in glomerular filtration rate. From animal studies one of the effects of contrast media is to interfere with PGI 2 production, thus resembling nonsteroidal antiinflammatory drugs with regard to the pathophysiologic process leading to acute renal failure.