Contrast Nephropathy and Its Management

Preexisting Renal Impairment

Patients at highest risk for developing CIN are those with preexisting renal impairment, particularly when reduction in renal function is associated with diabetes mellitus. Renal impairment is defined as serum Cr greater than 1.5 mg/dL (130 µmol/L) or a calculated or estimated creatinine clearance (CrCl) less than 60 mL/min/1.73 m ² . To a large extent the degree of renal insufficiency present before administration of contrast material determines the severity of CIN. CrCl of 30 mL/min or less markedly increases the incidence and severity of CIN. The importance of diabetes mellitus without renal impairment as a risk factor for CIN remains to be clarified, but some studies have identified diabetes mellitus as an independent risk factor for this complication. Caution is warranted in diabetic patients because endothelial dysfunction may exist, predisposing the patient to CIN through alterations in the production of vasoactive mediators in the kidney, particularly the vasodilator nitric oxide.

Type of Contrast Medium

The type of CM is an important factor in determining the development and severity of CIN. In a meta-analysis of comparative trials, Barrett and Carlisle showed that the incidence of CIN in at-risk patients was significantly higher with high-osmolar contrast agents (>1500 mOsm/kg) than with low-osmolar agents (<915 mOsm/kg). Thus high-osmolar CM should be avoided in patients at increased risk of CIN. The question remains whether there is a difference in nephrotoxic potential between low-osmolar and iso-osmolar (290 mOsm/kg) agents. A total of nine low-osmolar contrast agents—eight nonionic monomers (iohexol, iomeprol, iopamidol, iopentol, ioxilan, iopromide, ioversol, iobitridol) and one ionic dimer (ioxaglate)—as well as one iso-osmolar nonionic dimer (iodixanol) are approved for intravascular use. In 2003 Aspelin and coworkers, in a study of 129 diabetic patients with preexisting renal impairment undergoing angiography (the NEPHRIC study), reported a 3% incidence of CIN with iodixanol and 26% with the low-osmolar nonionic monomer iohexol. In that study the two groups differed significantly with regard to the frequency of interventional procedures and the duration of diabetes but were otherwise comparable. Similarly in patients with baseline renal impairment, one third of whom had diabetes, Chalmers and colleagues observed less reduction in renal function with iodixanol than with iohexol. However, a low incidence of CIN with iodixanol was not observed in other studies. Stone and associates reported a 33.3% incidence of CIN with iodixanol and 25.3% with other types of low-osmolar agents, but the difference was not statistically significant. In two additional studies the incidence of CIN with iodixanol was 12% and 21%.

Several new comparative studies have been carried out since the NEPHRIC study, with mixed results. Two recent reports were in concordance with the findings of the NEPHRIC study, but none of the others confirmed a lower incidence of CIN with iodixanol than with low-osmolar agents. Jo and coworkers reported a higher incidence of CIN after administration of ioxaglate (25%) in comparison to iodixanol (8.2%) in patients with renal impairment undergoing coronary angiography. In a meta-analysis of 2727 patients from 16 double-blind randomized controlled studies, McCullough and colleagues reported that the incidence of CIN after intraarterial administration was 1.4% with iodixanol and 3.5% with low-osmolar CM. Analysis of a subgroup of patients with diabetes mellitus and chronic kidney disease showed that the incidence of CIN was 3.5% with iodixanol and 15.5% with low-osmolar media. The report concluded that renal failure appears to be significantly reduced by the use of iodixanol in patients undergoing angiography. However, the study had certain limitations: the dose of CM was significantly higher in the low-osmolar group (iodine 58.9 g/examination) than in the iodixanol group (iodine 55.4 g/examination, P = .003), and no data on the state of hydration were available. In a retrospective analysis of 52,526 patients who received coronary angiography and intervention, the incidence of renal failure within 12 months was significantly higher with iodixanol (1.8%) in comparison to ioxaglate (1%). In a study of 285 patients undergoing cardiac angiography receiving either iopamidol or iodixanol-320, Jingwei and associates found no significant difference in the incidence of CIN between the tested agents: 19.4% with iopamidol and 11.7% with iodixanol.

Barrett et al. reported a 2.6% rate of CIN with iodixanol and 0% with iopamidol in a randomized multicenter trial (IMPACT) of patients with renal impairment (glomerular filtration rate [GFR] ≤ 60 mL/min) undergoing MDCT who received intravenous (IV) equi-iodine doses (40 g) of either iopamidol-370 or iodixanol-320 administered at 4 mL/sec. Results of the IMPACT study were similar to those of previous smaller studies by Carraro and coworkers and Kolehmainen and Soiva in patients with chronic kidney disease. Carraro's group conducted a prospective randomized double-blind comparison of iodixanol and iopromide (nonionic monomer) in 64 patients with moderate to severe renal insufficiency undergoing excretory urography. Renal function was assessed before and 1, 6, 24, and 48 hours and 7 days after the contrast-enhanced examination. One nondiabetic patient in the iodixanol group developed CIN (serum Cr increasing from 2.5 to 5.4 mg/dL in 24 hours, returning to baseline by the 48-hour evaluation), and no cases of CIN were observed in the iopromide group. Using the same study design, Kolehmainen and Soiva compared iodixanol to the nonionic monomer iobitridol in 50 patients with severe kidney disease undergoing cranial or body CT procedures. Both groups received similar volumes of contrast (113.3 mL of iobitridol, 112.7 mL of iodixanol) and had similar baseline renal function (CrCl 28.7 mL/min in the iobitridol group, 27.5 mL/min in the iodixanol group). The incidence of CIN in both groups was 17%.

Dose and Route of Administration

The nephrotoxic effect of CM is dose dependent: the higher the dose, the greater the risk of CIN. In one study it was observed that 100 mL was the cutoff dose below which there was no CIN requiring dialysis. Multiple injections of CM within 72 hours in patients with renal impairment are also likely to increase the risk of CIN. The clearance of CM from the body is prolonged in patients with reduced renal function, and it is feasible that repeat injections within 72 hours could result in a cumulative renal insult.

Route of administration is also important. Contrast media are less nephrotoxic when administered IV than when given intraarterially in the renal arteries or the aorta proximal to the origin of the renal blood vessels. The acute intrarenal concentration of CM is much higher after intraarterial injection than after IV administration.

Other Risk Factors

Other risk factors for CIN may include old age, dehydration, congestive cardiac failure, multiple myeloma, concurrent use of nephrotoxic drugs, hypertension, hyperuricemia, and proteinuria. Dehydration or congestive cardiac failure can lead to a reduction in renal perfusion, enhancing the ischemic insult of CM. Although multiple myeloma has been considered a risk factor for CIN, if dehydration is avoided, administration of low-osmolar CM rarely leads to CIN in patients with myeloma.

Concurrent use of nephrotoxic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs) and aminoglycosides is likely to exaggerate the nephrotoxic effects of CM. NSAID use, particularly in large doses or for prolonged periods, can lead to marked renal medullary ischemia, which theoretically can aggravate the ischemic and hypoxic insult induced by CM in the kidney. Nephropathy is more common in patients with hypertension, hyperuricemia, or proteinuria than in patients without these factors, making them more vulnerable to the renal effects of CM.