Nephrotoxicity in High-Risk Patients Study of IsoOsmolar and Low-Osmolar Non-Ionic Contrast Media Study - NEPHRIC


The goal of the trial was to compare the nephrotoxic effects of the iso-osmolar, nonionic contrast agent, iodixanol, vs the low-osmolar, nonionic contrast agent, iohexol in high-risk patients.

Study Design

Study Design:

Patients Enrolled: 129
Mean Follow Up: 7 days
Mean Patient Age: mean 71 years
Female: 27

Patient Populations:

Age >18 years, referred for coronary or aortofemoral angiography, diabetes (type 1 or 2) being treated with insulin or oral antidiabetic drugs, and either a stable serum creatinine concentration (1.5-3.5 mg/dL for men and 1.3-3.5 mg/dL for women) within 3 months before enrollment or a calculated creatinine clearance <=60 ml/min.


Pregnancy, lactation, IV administration of an iodinated contrast medium in prior 7 days, treatment with metformin or nonsteroidal anti-inflammatory drugs in prior 48 hours, use of nephrotoxic drugs in prior 7 days, history of serious reactions to iodinated contrast agents, newly discovered unstable diabetes, severe concomitant disease, renal transplantation, or end-stage renal disease necessitating dialysis.

Primary Endpoints:

Peak increase from baseline in the creatinine concentration during the 3 days after angiography

Secondary Endpoints:

Number of patients with a peak increase of >=0.5 mg/dL and the number with a peak increase of >=1.0 mg/dL during days 0 through 3; change in the serum creatinine concentration from day 0 to day 7

Drug/Procedures Used:

Patients were randomized to the nonionic, iso-osmolar, dimeric contrast medium, iodixanol (320 mg of iodine per mL; 290 mOsm per kg of water) (n=64) or the nonionic, low-osmolar, monomeric contrast medium iohexol (350 mg of iodine per mL; 780 mOsm per kg of water) (n=65). Serum creatinine was measured at baseline and days 2, 3, and 7.

Concomitant Medications:

Recommended (but not required): 500 ml of water orally, 500 ml of saline IV, or both before angiography and 1 liter of 0.9% saline or similar fluids IV from the start of the procedure.

Principal Findings:

The peak increase in serum creatinine concentration through day 3 was reduced among patients administered iodixanol vs iohexol (0.13 mg/dL vs 0.55 mg/dL, p=0.001). In the iohexol but not the iodixanol arm, a higher baseline serum creatinine concentration was associated with a higher peak Cr increase between day 0 and day 3 (p<0.001 for interaction). The mean change in the serum creatinine concentration between day 0 and day 7 was less in the iodixanol arm (0.07 mg/dL) vs the iohexol arm (0.24 mg/dL, p=0.003). The incidence of nephropathy using a cutpoint of an increase in the serum creatinine concentration of >=0.5 mg/dL was 3% in the iodixanol arm (2/64) and 26% in the iohexol arm (17/65, p=0.002). Using a cutpoint of >=1.0 mg/dL, the rate was 0% vs 15%, respectively.


Among high-risk patients with diabetes and serum creatinine of 1.5-3.5 mg/dL who underwent coronary or aortofemoral angiography, use of the iso-osmolar contrast agent iodixanol was associated with a lower peak increase in serum creatinine concentration through day 3. Contrast-induced nephropathy is a serious side effect of the use of iodinated contrast agents for angiography, especially in patients at higher risk for renal failure such as diabetics. Several randomized trials have shown that in high-risk patients, use of low-osmolar contrast agents reduces the risk of nephropathy compared with use of high-osmolar contrast agent. However, this is the first randomized trial to compare the use of a low-osmolar contrast agent with an iso-osmolar contrast agent in high-risk diabetic patients. Early trials in low-risk patients (non-diabetics with normal renal function at baseline) did not show a difference in contrast-induced nephropathy with iodixanol compared with low-osmolar contrast agents. In should be noted that in non-diabetics with normal renal function at baseline, the overall risk for development of contrast-induced nephropathy is much lower than in diabetics with impaired baseline renal function, which may explain some of the lack of benefit with iodixanol seen in the lower-risk population.


N Engl J Med 2003;348:491-499.

Keywords: Contrast Media, Iodine, Iohexol, Insulin, Triiodobenzoic Acids, Renal Insufficiency, Hypoglycemic Agents, Creatinine, Diabetes Mellitus

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