Iso-Osmolar Radio Contrast Iodixanol in Patients with Chronic Kidney Disease

George M. Tadros, MD, Jamil A. Malik, MD, Connie L. Manske, MD, Bertram L. Kasiske, MD, Stacy E. Dickinson, MD, 1Charles A. Herzog, MD, Robert F. Wilson, MD, Gladwin Das, MD, Carmelo J. Panetta, MD
George M. Tadros, MD, Jamil A. Malik, MD, Connie L. Manske, MD, Bertram L. Kasiske, MD, Stacy E. Dickinson, MD, 1Charles A. Herzog, MD, Robert F. Wilson, MD, Gladwin Das, MD, Carmelo J. Panetta, MD
Intravascular administration of iodinated radio contrast agents is a common cause of hospital-acquired acute renal failure. Although the clinical presentation of contrast-induced nephropathy (CIN) has been well described, the incidence of CIN with new iso-osmolar radio contrast agents has not been thoroughly evaluated. Decreasing levels of renal function act as a major adverse prognostic factor after contrast exposure, with or without percutaneous coronary intervention.1–4 Various strategies for the prevention of CIN have been investigated,5 some with detrimental results,6 and others were neutral to kidney function.6,7 Potential beneficial interventions include intravenous hydration with normal saline,8 N-acetylcysteine,9–11 the iso-osmolar contrast agent iodixanol,12,13 hemofiltration14 and limiting the volume of contrast.15 Despite the increasing prevalence of coronary artery disease in patients with chronic kidney disease (CKD), there is often great reluctance to utilize coronary angiography, due to concerns that radio contrast exposure will worsen kidney function.15 Furthermore, the concern for CIN forces most of those with CKD to have staged percutaneous coronary or other intravascular intervention after angiography, increasing cost and delays in management.16 This concern becomes heightened if the patient is on the verge of requiring dialysis or being evaluated for kidney transplantation. The aim of this retrospective study is to investigate the correlation between volume of contrast, and the change in serum creatinine, the occurrence of CIN and the need for dialysis in patients with moderate-to-severe CKD using the iso-osmolar radiocontrast iodixanol. Methods Patients. All consecutive angiographic cases with CKD defined as estimated creatinine clearance (CCR) 17 Patients who were currently on dialysis prior to angiography or received a kidney transplant within 7 days after the procedure were excluded from the study. Baseline characteristics recorded included age, sex, weight and presence of diabetes type 2, cardiac risk factors, and presenting blood pressure. Hypotension was defined as a systolic blood pressure 15 This group was comprised of 42 diabetic patients with severe CKD (CCR Angiography protocol. Angiography was performed on digital imaging systems. The amount of contrast infused was accurately estimated with an automated power injection device (Acist medical systems, Inc., Eden Prairie, Minnesota). All patients had serum creatinine checked at least once within 7 days after the procedure, and their peak serum creatinine was recorded for analysis. The absolute change in serum creatinine and calculated CCR were calculated. We defined CIN as an absolute rise in serum creatinine > 0.5 mg/dL and/or a rise > 25% from baseline. Medical records and the dialysis unit records were searched for any occurrence of nephropathy requiring dialysis in the 7 days post-angiography. Maximum radiographic contrast dose was calculated for all patients as 5 mL x body weight (in Kg) divided by serum creatinine (mg/dL), as previously described.18 This contrast limit was converted to a dichotomous variable by dividing the actual amount of contrast received by the calculated maximum radiographic contrast dose to determine the “contrast ratio.”19 The occurrence of any in-hospital major adverse cardiovascular event (MACE) defined as any death, cardiac arrest, myocardial infarction, new onset heart failure, stroke, and need for urgent coronary revascularization was searched for in the hospital records. Statistical analysis. Univariate analysis was performed to compare diabetic patients with severe CKD to historical controls. The two-sample t-test was applied to the continuous variables, and either the Chi-square or Fisher’s Exact test was carried out for the categorical factors. Multivariate analysis, which included logistic and multiple regression, was utilized to identify independent risk factors of CIN and for absolute change in creatinine after adjusting for baseline characteristics. Since the distribution of the volume of contrast was skewed to larger values, we used the Spearman non-parametric correlation to measure the association between the amount of contrast and change in creatinine. All data analyses were performed using JMP statistical software (version 3.2.6, SAS Institute, Inc., Cary, North Carolina), R software (version 1.7.1, 2003). A p-value 60 mL/min. Serum creatinine measured 3.0 ± 2.2 days after angiography, with 87 of 117 patients having their peak rise in creatinine measured within the first 4 days. The mean serum creatinine did not significantly change after the procedure (Table 2). Four patients underwent dialysis after the procedure. The reasons for worsening renal function according to the renal consultation were rejection of kidney transplant, sepsis, and prior diagnosis of progressive kidney failure, respectively. In two patients, dialysis was considered a possibility before angiography was performed. The last case underwent emergent coronary bypass surgery after angiography with an intra-aortic balloon placement required due to shock. Twenty-two patients (18.8%) fulfilled the criteria for CIN, yet the mean volume of contrast was not significantly different compared to those without CIN (Figure 1). A non-significant negative correlation was found between the change in serum creatinine and the volume of contrast in the 117 cases (Figure 2). Four patients had an absolute increase in their serum Cr > 2 mg/dl, with one of them requiring dialysis. All four of them had received N-acetylcysteine and intravenous hydration. In-hospital follow-up revealed occurrence of MACE in 19/117 patients (16%), with emergent revascularization and new-onset heart failure comprising the majority. The main predictors of occurrence of MACE were development of CIN (16/19 patients) and peri-procedural hypotension (12/19). There was no significant correlation between the amount of contrast and the occurrence of MACE (r2 = 0.030, p = 0.77). A total of 7 cases had emergent coronary artery bypass surgery, defined as surgery within 7 days of angiography. Those without emergent coronary artery bypass surgery were still not found to have a significant correlation between contrast volume and change in creatinine (n = 110, r2 = 0.00001, p = 0.973). Data available on 97 patients revealed no significant difference in change in creatinine in those who received N-acetylcysteine (n = 72) versus not (n = 24). A total of 95 patients received a mean of 1.2 ± 0.5 L of intravenous peri-procedural hydration in the form of either normal saline or half-normal saline. There was no significant difference in the total amount of intravenous hydration between patients who developed CIN versus not (1.1 ± 0.6 versus 1.2 ± 0.4, p = 0.9). Also, there was no difference in the use of diuretics (62% versus 59%) or ACE inhibitors/ARB (35% versus 39%) between those who developed CIN versus not. Fifteen patients received a volume of contrast exceeding their maximum radiographic contrast dose with a ratio > 1. There was no significant correlation between the volume of contrast and change in serum creatinine (r2 = 0.0009, p = 0.9). A subgroup had creatinine checked on days 1 through 3, with a non-significant negative correlation (n = 40, r2 = 0.020, p = 0.367) between volume of iodixanol and change in creatinine. PCI was performed in 53 cases (45.3%), age 63.1 ± 12.6 years with a pre-procedure CCR of 33.6 ± 11.7 mL/min. The mean contrast volume was 85 ± 67.3 mL, yet only 9 of these 53 (17%) had CIN. There was no correlation between contrast volume and change in creatinine (r2 = 0.02, p = 0.45). Twenty-two of the 53 patients (41.5%) had ad hoc PCI, (PCI performed immediately after diagnostic angiography). The ad hoc PCI subgroup trended to have a higher volume of contrast (161 ± 82.2 mL), yet the incidence of CIN was not significantly higher (18% versus 17%, p = 1.0). There was no correlation in either the ad hoc subgroup or staged subgroup of volume of contrast and change in creatinine (Figure 3). A subgroup of diabetic patients with severe CKD (CCR 1 CIN is directly related to increases in hospitalization length of stay, cost, and long-term morbidity.2–4 For those patients who require dialysis, a 36% in-hospital mortality rate and an 80% 2-year mortality rate can be expected.1 Risk factors for worsening renal function after angiography include baseline renal dysfunction (estimated CCR 2,3 Prior reports of higher incidence of dialysis in severe CKD patients receiving > 30 mL of contrast has precluded clinicians from referring those patients to angiography and percutaneous coronary intervention.15 An important finding of our study is the absence of any correlation between the volume of contrast received and the change in serum creatinine. A subgroup of patients that received more than 5 mL/kg in contrast (exceeding the recommended maximum amount18) had no significant correlation with change in creatinine and volume of contrast. A subgroup of diabetics with severe CKD had a significantly lower incidence of CIN with the use of the iso-osmolar contrast iodixanol compared to a similar historical control that used the low-osmolar agent iohexol. Analysis in this high-risk group confirmed the absence of a correlation between volume of contrast and change in creatinine in patients who received iso-osmolar contrast, a benefit that was not apparent with iohexol. Although not significant, we observed a greater increase in creatinine with larger volumes in those with diabetes versus those without diabetes and severe CKD. This finding supports continuous caution when using any kind of radiocontrast agents in diabetics with severe CKD, especially when multi-vessel PCI is attempted and larger amounts of dye would be used until further studies are available. In addition, N-acetylcysteine had a non-significant trend toward benefit in this subgroup, probably due to their higher relative risk. Clinical observations over the past two decades have demonstrated a reduction in the incidence of CIN with the introduction of low- and iso-osmolar contrast media. It is currently believed that disturbances in renal hemodynamics and direct tubular epithelial cell toxicity by contrast media are the primary factors responsible for CIN.20 Contrast-induced renal vasoconstriction, which increases with increasing osmolality of the contrast agent, is the basis for the hypothesis that renal ischemia is a major factor in the pathogenesis of CIN.21 Several experimental animal studies provided conflicting data regarding the role of osmolality in the pathogenesis of contrast media nephropathy.20 Contrary to the animal studies, initial clinical studies reported diminished nephrotoxicity following administration of iso-osmolar contrast media. In 1999, Chalmers and Jackson12 reported the results of a single-center, randomized study of iodixanol versus iohexol in 124 patients with CKD undergoing angiography. Their results suggested that iohexol caused CIN, defined as a > 25% increase in baseline creatinine, in twice as many patients as iodixanol (3.7% versus 10%; p = 0.05). In 2003, the multi-center study NEPHRIC13 randomized diabetic patients with CKD to either iodixanol or iohexol during angiography. The incidence of CIN (defined as an increase of > 0.5 mg/dl in serum creatinine) was 3% in the iodixanol group and 26% in the iohexol group. The results of these trials suggested that iso-osmolar agents are significantly less nephrotoxic than low-osmolar agents.16 Given the clinical observations that CIN in high-risk patients is less frequent with low-osmolar compared with high-osmolar contrast agents16,20 and that iso-osmolar contrast agents may be even less nephrotoxic, it is reasonable to conclude that osmolality does play a role in the pathogenesis of contrast-induced renal injury.20 The incidence of CIN in our study is higher than reported in published trials on iodixanol,11–13 though lower compared to other contrast agents.22 Several explanations for the increased incidence include a larger percentage of patients with diabetes with worse baseline creatinine clearance compared to the report by Chalmers and Jackson (p = 0.0144), and a more inclusive definition of CIN, defined as an increase in serum creatinine greater than 0.5 mg/dL, or 25% of baseline. The striking finding in our study is the lack of correlation between volume of contrast and change in creatinine, which was present in the report by Chalmers and Jackson.12 One possible etiology is the use of N-acetylcysteine in the current study, although we were not powered enough to detect any significant difference in serum creatinine in those who received N-acetylcysteine versus those who did not. A recent meta-analysis also suggested the same finding of lack of benefit of N-acetylcysteine in patients receiving iodixanol compared to an apparent benefit for patients receiving low-osmolar radio contrast agents.23 The VALOR study is an ongoing, multi-center, prospective, randomized, double-blind trial comparing the renal effects of the iso-osmolar contrast agent iodixanol to the low-osmolar contrast agent ioversol in subjects with elevated serum creatinine undergoing coronary angiography or interventions.16 The results of our current study allow us to generate several hypotheses for questions that are currently challenging clinicians caring for patients with CKD and coronary artery disease.1 Coronary angiography for patients with severe CKD should not be deferred due to concerns about dialysis.2 Ad hoc percutaneous interventions after angiography may not pose an increased risk for CIN compared to staged procedures.3 Those with diabetes and severe CKD may benefit from N-acetylcysteine, in addition to the use of iso-osmolar contrast and adequate hydration. Study limitations. First, our study is not a randomized trial and we used a group of historical patients as a control group, although the results of this study are hypothesis-generating and could be used as a basis for several future studies on strategies for the prevention of CIN. Second, given the retrospective analysis, it is difficult to decide whether the benefit of reducing CIN was attributed to the type of contrast, the use of N-acetylcysteine, or the use of intravenous hydration. Third, the subgroup with diabetes and severe CKD is smaller than the historical control group, impacting the significance of the findings. Fourth, using our inclusion criteria of having post-procedural creatinine checked within 7 days may have caused us to miss some earlier cases of CIN, and may have impacted the apparent difference in the incidence of CIN between the study diabetic group and the historical group. However, 88/117 (75%) of the patients had their creatinine checked within 4 days, and a subgroup (n = 40) with creatinine available on days 1 through 3 post-angiography had a non-significant negative correlation between the volume of iodixanol and the change in creatinine. Conclusions We conclude from our study that larger volumes of the iso-osmolar contrast iodixanol for angiographic procedures are safer than previously reported in patients with CKD, especially those without diabetes. Caution must still be used when larger than studied volumes of contrast (e.g. > 100 mL) will be used until further studies are performed. Future trials are needed to further elucidate whether ad hoc percutaneous angiographic interventions are equally safe in those with chronic kidney disease, and whether a combined role exists for N-acetylcysteine with an iso-osmolar contrast agent.
1. McCullough PA, Wolyn R, Rocher LL, et al. Acute renal failure after coronary intervention: Incidence, risk factors, and relationship to mortality. Am J Med 1997;103:368–375. 2. Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002;105:2259–2264. 3. Gruberg L, Mintz GS, Mehran R, et al. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol 2000;36:1542–1548. 4. Mangano CM, Diamondstone LS, Ramsay JG, et al. Renal dysfunction after myocardial revascularization: Risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med 1998;128:194–203. 5. Lepor NE. A review of pharmacologic interventions to prevent contrast-induced nephropathy. Rev Cardiovasc Med 2003;4 Suppl 5:S34–42. 6. Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994;331:1416–1420. 7. Stone GW, McCullough PA, Tumlin JA, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: A randomized controlled trial. Jama 2003;290:2284–2291. 8. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: Randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 2002;162:329–336. 9. Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180–184. 10. Birck R, Krzossok S, Markowetz F, et al. Acetylcysteine for prevention of contrast nephropathy: Meta-analysis. Lancet 2003;362:598–603. 11. Baker CS, Wragg A, Kumar S, et al. A rapid protocol for the prevention of contrast-induced renal dysfunction: The RAPPID study. J Am Coll Cardiol 2003;41:2114–2118. 12. Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol 1999;72:701–703. 13. Aspelin P, Aubry P, Fransson SG, et al. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 2003;348:491–499. 14. Marenzi G, Marana I, Lauri G, et al. The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. N Engl J Med 2003;349:1333–1340. 15. Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast nephropathy in azotemic diabetic patients undergoing coronary angiography. Am J Med 1990;89:615–620. 16. Erdogan A, Davidson CJ. Recent clinical trials of iodixanol. Rev Cardiovasc Med 2003;4(Suppl 5):S43–50. 17. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–641. 18. Cigarroa RG, Lange RA, Williams RH, Hillis LD. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. Am J Med 1989;86:649–652. 19. Freeman RV, O'Donnell M, Share D, et al. Nephropathy requiring dialysis after percutaneous coronary intervention and the critical role of an adjusted contrast dose. Am J Cardiol 2002;90:1068–1073. 20. Rudnick MR, Goldfarb S. Pathogenesis of contrast-induced nephropathy: Experimental and clinical observations with an emphasis on the role of osmolality. Rev Cardiovasc Med 2003;4(Suppl 5):S28–33. 21. Heyman SN, Brezis M, Epstein FH, et al. Early renal medullary hypoxic injury from radiocontrast and indomethacin. Kidney Int 1991;40:632–642. 22. McCullough PA, Sandberg KR. Epidemiology of contrast-induced nephropathy. Rev Cardiovasc Med 2003;4(Suppl 5):S3–59. 23. C.J. Wolf RE, A. El-Bialy. Acetylcysteine Prevents Contrast-Induced Nephropathy In Patients Undergoing Coronary Angiography Using Low-Osmolar Contrast Media But Not In Patients Submitted to Iso-Osmolar Contrast Media — A Meta-Analysis. Circulation Supplement. American Heart Association 2004.