Prevention of Contrast-Induced Nephropathy (CIN) Sepehr Khashaei , MD Assistant professor Department of Internal Medicin

1. Prevention of Contrast-Induced Nephropathy (CIN)SepehrKhashaei, MDAssistant professorDepartment of Internal Medicine

2. What will be covered today? • Definition of CIN • Why is prevention of CIN important? • Some other information/statistics about CIN • Who is at high risk for CIN? • Information and conclusions based on outcomes from clinical trials • Simple measures for prevention • Cost to patients. • References. • Questions and discussion.

3. Please save all your questions and discussions for the end.

4. Definition of CIN • CIN is defined as an increase in baseline serum creatinine level of 25% or an absolute increase of 0.5 mg/dL, 2 to 5 days after radiocontrast administration.

5. Why is prevention of CIN important? • Radiocontrast administration is a common cause of hospital-acquired acute renal failure (10% of cases). • In its severe form, CIN is associated with clinically significant morbidity and mortality, including prolonged hospitalization, requirement for dialysis, and an increased risk for death. • CIN increases the costs of medical care by at least extending the hospital stay. • There is no specific treatment once CIN develops, and management must be as for any cause of ATN, with focus on maintaining fluid and electrolyte balance. The best treatment of CIN is prevention.

6. Some other information/statistics about CIN • Individuals with pre-existing renal insufficiency and diabetes are much more likely to experience contrast-induced nephropathy. • Typically, serum creatinine levels begin to increase at 48-72 hours, peak at 3 to 5 days, and return to baseline within another 3-5 days. • In most cases there is no permanent sequelae.

7. Some data from 2004 • More than a million radiocontrast procedures were performed annually. • Incidence of CIN was 150,000/yr. • 1% of CIN required dialysis and caused prolongation of hospital stay to an average of 17 days. • For episodes that did not require dialysis, there was prolongation of hospital stay by 2 days on an average.

8. Total CT scans with contrast done in 2009 at all UNM facilities where 18,350.

9. Who is at high risk? • Patients with GFR <60 ml/min particularly if diabetic. • UNM radiology department uses a creatinine of >1.0 for a female and >1.3 for a male as definition of a high risk patient.

10. Proposed interventions studied in literature • Saline hydration • Diuretics • Mannitol • Intravenous bicarbonate • Saline plus Mannitol • Saline plus diuretics • Oral hydration • Calcium channel antagonists (i.e. nifedipine) • Theophylline • Endothelin receptor antagonists • Dopamine • Fenoldopam (dopamine-1 receptor) • Antioxidant N-acetylcysteine • Iso-osmolar or low-osmolal contrast agents • Hemodialysis • Hemofiltration • Use of MRI in place of CT • Atrialnatriuretic peptide • Statins • Ascorbic acid

11. Simple measures for prevention • The use of lower doses of contrast. • Avoidance of repetitive contrast studies that are closely spaced (within 48-72 hours). • Avoidance of volume depletion • Avoidance of NSAIDS • Avoidance of nephrotoxic drugs

12. Information and conclusions based on outcomes from clinical trials

13. Patients with near-normal kidney function are at little risk for CIN (about 3%) and few precautions are necessary other than avoidance of volume depletion.

14. The patients at increased risk for contrast-induced nephropathy are diabetics (especially insulin-dependent diabetics) and patients with underlying renal insufficiency (12-50% incidence).

15. The effects of poor hydration and the volume of contrast medium administered are less clear but are possible risk factors.

16. Risk factors may be additive.

17. The risk for CIN does not appear to be influenced by the patient’s age or sex.

18. Absence of risk factors does not preclude the development of CIN.

19. Although theoretically beneficial, there is little evidence in support of vasodilators (such as nifedipine, captopril, prostglandin E, low-dose dopamine, fenoldopam, endothelin receptor antagonists, and theophylline) in reducing risk of CIN.

20. Infuse NS (Grade 1B) at a rate of 1ml/Kg per hour starting at least two and preferably 6-12 hours prior to the procedure, and continuing for 6 to 12 hours after contrast administration. The duration of administration of fluid should be directly proportional to the degree of renal impairment (e.g., should be longer for individuals with more severe renal impairment). Dose should be adjusted depending on patient’s underlying medical condition and their level of hydration. Hydration with NS was superior to 1/2NS at least in one clinical trial.

21. Intravenous hydration is superior to oral hydration. Oral hydration with water alone should not be used.

22. Use, if possible, ultrasonography, MRI without gadolinium contrast, or CT scanning without radiocontrast agents.

23. Based on limited literature, it is difficult to be certain that gadolinium used in MRI scanning is completely free of nephroxicity in high-risk patients. Also, gadolinium-based imaging should not be performed, if at all possible, in patients with GFR <30 ml/min because of risk of nephrogenic systemic fibrosis. In such patients, if a contrast study is necessary, use of low-osmolar or isoosmolar iodinated contrast media, using all the preventive measures that are available, is preferred.

24. Oral acetylcysteineadministed as 1200mg twice daily the day before and the day after the procedure (Grade 2B). Do not use iv acetylcysteine for prevention of CIN (Grade 2B).

25. Do not use mannitol or other diuretics prophylactically (Grade 1B). • However, diuretics may be required to treat volume overload.

26. Do not use high osmolal agents (1400 to 1800 mosmol/KG) (Grade 1A).

27. Use nonionic isoosmolar agents such as iodixanol (Visipaque) or nonionic low-osmolal agents such as iopamidol (Isoview) (Grade 1B) if a contrast study is necessary.

28. Low or iso-osmolar nonionic contrast • Decreased incidence of CIN. • Cost reductions • Increased patient tolerability • Decreased hypersensitivity reactions • The benefit is higher in diabetics with renal insufficiency • Now administered for the majority of radiologic procedures that use iv contrast media. • There appears to be little or no advantage in the prevention of CIN when compared to ionic hyperosmolar agents in patients with normal renal function. • At UNM we use iopamidol (a low-osmolar non-ionic agent) on all adults who have contrast studies regardless of their GFR.

29. Among patients with stage 3 and 4 CKD do not perform prophylactic hemofiltration (see below) or hemodialysis (Grade 1B). • Hemofiltration is expensive, logically cumbersome and associated with significant risks, its effectiveness compared to other less expensive strategies is not well established, and the reported benefits are implausible. Therefore currently prophylactic hemofiltration is not recommended.

30. Among patients with stage 5 CKD, most suggest hemodialysis after contrast exposure if there is already a functioning access (Grade 2C) (although there is lack of sufficient data). Do not place a temporary access for prophylactic hemodialysis in these patients.

31. The effectiveness of sodium bicarbonate treatment to prevent CIN remains uncertain. Earlier reports probably overestimated the magnitude of any benefit, whereas larger, more recent trials have had neutral results. Large multicenter trials are required to clarify whether sodium bicarbonate has value for prevention of CIN before routine use can be recommended.

32. Cost to patients • One bag of NS (1000cc) = $40.00 • 1200mg of acetylcysteine = $5.00 • One day on 4-W = $5,489 (Medicine Subacute) • One day on 4-E = $7,129 (Med/surgSubacute) • One day on 4-S = $6, 863 (Orthopedics) • One day on 5-W = $ 4,049 (General Medicine) • One day on 5-S = $6,152 (NeuroScience) • One day on 6-S = $7,580 (General Surgery) • One day on 7-S = $8,517 (Cardiothoracic) • One day on Medical ICU = $7,747

33. References • Asif, A, Epstein, M. Prevention of Radiocontrast-Induced Nephropathy. AM J Kidney Dis 2004; 44:12-24 • Rudnick, M, Feldman, H. Contrast-Induced Nephropathy: what are the true clinical consequences?. Clin J Am Soc Nephrol 2008; 3:263. • Rudnick, MR, Goldfarb, S, Wexler, L, et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: A randomized trial. Kidney Int 1995; 47:254. • Barrett, BJ. Contrast nephrotoxicity. J Am Soc Nephrol 1994; 5:125 • Shwab, SJ, Hlatky, MA, Pieper, KS, et al. Contrast nephrotoxicity: a randomized controlled trial of a nonionic and an ionic radiographic contrast agent. N Engl J Med 1989; 320:149. • Solomon, R, Werner, C, Mann, D, et al. Effects of saline, mannitol, and furosemide on acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994; 331: 1416.

34. Weisbord, SD, Palevsky, PM. Prevention of contrast-induced nephropathy with volume expansion. Clin J Am Soc Nephrol 2008; 3:273. • Taylor, AJ, Hotchkiss, D, Morse, RW, McCabe, J. PREPARED: Preparation for Angiography in Renal Dysfunction: a randomized trial of inpatient vs outpatient hydration protocols for cardiac catheterization in mild-to-moderate renal dysfunction. Chest 1998; 114:1570. • Kshirsagar, AV, Poole, C, Mottl, A et al. N-acetylcysteine for prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials. J Am Soc Nephrol 2004; 15:761. • Alonso, a, Lau, J, Jaber, BL, Weintraub, A. Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2004; 43:1. • Gonzales, DA, Norsworthy, KJ, Kern, SJ, et al. A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity. BMC Med 2007; 5:32. • Trivedi, H, Daram, S, Szabo, A, et al. High-dose N-acetylcysteine for the prevention of contrast-induced nephropathy. Am J Med 2009; 122:874.

35. Klarenbach, SW, Pannu, N, Tonelli, MA, Manns, BJ. Cost-effectiveness of hemofiltration to prevent contrast nephropathy in patients with chronic kidney disease. Crit Care Med 2006; 34:1044. • Lee, PT, Chou, KJ, Liu, CP, et al. Renal protection for coronary angiography in advanced renal failure patients by prophylactic hemodialysis. A randomized controlled trial. J Am CollCardiol 2007; 50:1015. • Ledneva, E, Karie, S, Launay-Vacher, V, et al. Renal safety of gadollinium-based contrast media in patients with chronic renal insufficiency. Radiology 2009; 250:618. • Kurnik, BR, Allgren, RL Genter, FC, et al. Prospective study of atrialnatriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 1998; 31:674. • Patti, G, Nusca, A, Chello, M, et al. Usefulness of statin pretreatment to prevent contrast-induced nephropathy and to improve long-term outcome in patients undergoing percutaneous coronary intervention. Am J Cardiol 2008; 101:279. • Briguori, C, Airoldi, F, D’Andrea, D, et al. Renal Insufficency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation 2007; 115:1211.

36. 19. Zoungas, S, Ninomiya, T, Huxley R, et al. Systemic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Inern Med. 2009 Nov 3; 151 (9): 631-8 20. Stone GW, McCullough PA, Tumlin JA, et al: Fenoldopammesylate for prevention of contrast-induced nephropathy: a randomized controlled trial. CONTRAST Investigators. JAMA 290:2284-2291,2003. 21. Kuhn, K, Chen, N, Dushyant, VS, et al: The PREDICT study: A randomized double-blind comparison of contrast-induced nephropathy after low- or isoosmolar contrast agent exposure. AJR 191: 151-157, July 2008. 22. Lautin, EM, Freeman, NJ, et al: Radiocontrast-associated renal dysfunction: incidence and risk factors. AJR 157: 49-58, July 1991.

37. Questions and discussion