1. CONTRAST NEPHROPATHY MARC J. SCHWEIGER Director Cardiac Catheterization Laboratories, Baystate Medical Center

2. CONTRAST NEPHROPATHY Patients with CRF and those on Dialysis Background Limitations of Studies Prevention –What is the Appropriate Hydration Regimen? –N Acetycysteine –Calculating Adjusted Contrast Dose –Non Ionic and Isoosmolar Contrast Recommendations

3. SURVIVAL OF DIALYSIS PATIENTS 29.4 + 4.048.4 + 2.067.2 + 1.5Stent 28.6 + 1.748.2 + 1.565.7+1.4PTCA 37.0 + 1.756.4 + 1.471.5+1.1CABG 48 months24 months 12 months

4. P<0.001 In-Hospital Mortality 1-Year Mortality P<0.001 25.9% 3.4% 6.7% 17.5% 0% 10% 20% 30% -DM/-CRF n=5278 +DM/-CRF n=1681 -DM/+CRF n=371 +DM/+CRF N=300 Mehran, et al. J Am Coll Cardiol 2000; 35: I 878 Post PCI Prognosis in Pts with DM/CRF

5. CONTRAST NEPHROPATHY Patients with CRF and those on Dialysis Background Limitations of Studies Prevention –What is the Appropriate Hydration Regimen? –N-acetylcysteine –Calculating Adjusted Contrast Dose –Non Ionic and Isoosmolar Contrast Recommendations

6. A temporary increase in renal transport work in the thick ascending limb of Henle's loop (  in oxygen consumption) + Constriction of medullary capillaries (  in medullary oxygen delivery) LEAD TO MEDULLARY ANGINA A temporary increase in renal transport work in the thick ascending limb of Henle's loop (  in oxygen consumption) + Constriction of medullary capillaries (  in medullary oxygen delivery) LEAD TO MEDULLARY ANGINA Contrast Media Induce Medullary Hypoxia Solomon, et al. Kidney Int 1998; 230-242

7. Post Intervention: Contrast Nephropathy Contrast nephropathy is the third leading cause of acute renal failure in hospitalized patients (9- 40% incid. in DM with mild to moderate CRI). Defined as increase in creatinine >0.5mgm/dl(or increase of > 25% within 48hrs. Related to preexisting renal dysfunction Diabetes mellitus is additive risk in presence of renal dysfunction Diabetes mellitus without renal dysfunction – some conflicting data but most likely increased risk Tommaso CL, Cathet Cardiovasc Diag 1994; 31:316-321.

8. Parfrey PS, et al. NEJM 1989; 329: 43-149 Rudnick, et al. Kidney Int 1995; 47: 254-261 CIN: Epidemiologic issues 3rd most common cause of hospital acquired renal failure Occurs in 1.5% of patients without diabetes or chronic renal insufficiency Occurs in 7 - 12% of patients with chronic renal insufficiency But, occurs in 33 - 48% of patients with both chronic renal insufficiency and diabetes mellitus

9. Incidence & Prognostic Importance of ARF following PCI Baseline Cr < 2.0 mg/dl, diabetic patients had higher risk of ARF than nondiabetic pts –Cr < 1.1(risk 3.7 % vs 2.0%, p=0.05) –Cr 1.2-1.9(risk 4.5% vs 1.9%, p<0.001) Baseline Cr > 2.0 mg/dl, risk high regardless of diabetes status –Cr. 2.0-2.9 mg/dl, risk 22.4% –Cr > 3 mg/dl, risk 30.6%

10. Prediction of RCN Requiring Dialysis After PCI N=3695 Independent risk factors: CrCl>>Diabetes>>Contrast Volume Mean age = 65, mean contrast volume 250 cc (cath + PCI) McCullough PA, Am J Med 1997;103:386-375.

11. Incidence of Contrast Induced Renal Dysfunction in Diabetic Patients % Serum Creatinine (mg/dl) 28831 2131022 5462 Berns A, Kidney International, 1987

12. Impact of Renal Failure on Mortality No ARF CIN ARF + Dialysis p<0.0000001 McCullough, et al. Am J Med 1997; 103: 375

13. Contrast-Induced Nephropathy (CIN) Definition: Acute decline in renal function (Cr rise> 25-50% or 0.5- 1mg/dl) after administration of contrast in absence of other causes Time course of contrast induced renal insufficiency: Often occurs within 24-48 hours of exposure Typical peak creatinine after 3-5 days Return to baseline within 7-10 days in most cases

14. Risk Factors for CIN Other nephrotoxins Other nephrotoxins Low cardiac output Low cardiac output Class IV CHF Class IV CHF Hypotension Hypotension Volume depletion Volume depletion Multiple myeloma ? Multiple myeloma ? Diabetes mellitus with renal insufficiency Diabetes mellitus with renal insufficiency Renal insufficiency Renal insufficiency Patient-related Risk Factors High volume of contrast media High volume of contrast media High osmolality of contrast media High osmolality of contrast media High viscosity of contrast media ? High viscosity of contrast media ? Intra-arterial injection site Intra-arterial injection site Multiple contrast media injection within 72 hrs Multiple contrast media injection within 72 hrs Procedure-related Risk Factors

15. Post Intervention Contrast Nephropathy Amount of contrast more critical than type If creatinine >2 mg/dl, risk is 2% if 125 cc (mostly non ionic contrast) Risk is higher when contrast repeated <72 hr –one study reported 40% increased risk <72 hrs. (Jevniker et. al, Nephron 1988;48:300-305.) –Ad hoc PCI ill advised in higher risk patients unless absolutely mandatory

16. Post Intervention Contrast Nephropathy Post intervention management –if patient high risk (creatinine >2 mg/dl, esp if diabetic; repeat contrast <72 hrs; large volume of contrast, etc.) check creatinine/BUN next day –if low risk but large volume used, check labs Treatment –hydrate –creatinine back to baseline 2-7 days –dialysis rarely necessary

17. Incidence & Prognostic Importance of Acute Renal Failure Following PCI Mayo Clinic Retrospective Analysis Circulation. 105,2259-2264,2002 N=7586 ARF defined as increase in Cr >0.5 mg/dl Incidence 3.3% Incidence related to baseline serum Cr & presence of diabetes

18. Multivariate Predictors of ARF + Predictors: Baseline Cr., MI w/in proceeding 24h, diabetes, age, history of CHF, peripheral vascular disease, volume (O.R. 1.12 for each 100 cc increase, 95% CI 1.02 – 1.23, p=0.02) Negative Predictors: Successful Procedure, RCA PCI

19. Long Term Prognostic Implications of ARF after PCI (Hospital Survivors) 6890 non ARF patients: mortality at 6 months, 1 year and 5 years 2.3%,3.7%,14.5%. 185 ARF patients: 9.8%, 12.1%,44.6%(p<0.0001) Non ARF patients – risk of MI: 2.7%,3.8%,10.5% ARF patients- risk of MI: 4.3%, 7%,10.5%(p=0.003)

20. ARF – Clinical Outcomes Diminished Procedural Success(72.8% vs 94%, p<0.0001) Increased Q wave MI(3.9% vs. 0.9%, p<0.0001) In hospital mortality 22% vs 1.4%(p<0.0001) Multivariate Predictors of in hospital mortality: Shock, ARF (not baseline Cr)

21. Prognostic Implications of Further Renal Function Deterioration following PCI in patient with pre-existing CRF 439 pts with baseline serum cr. > 1.8 All well hydrated, all received non ionic dye 161 pts(37%) had increase in serum cr > 25% or required dialysis and 278(63%) did not JACC, 2000; 36: 1542-8

22. DM, <25% creatinine increase No DM, <25% creatinine increase DM,  25% creatinine increase No DM,  25% creatinine increase 0 0% 20% 40% 60% 80% 100% 123456789101112 Time (Months) Event-Free Survival 80% 80% 64% 55% CIN After PCI: 1-Year Event-Free Survival Cr. Increase & DM Gruberg, et al. JACC 2000; 36: 1542-8

23. Cumulative 1-Year Mortality Significant increase in mortality noted when Cr. increase  25% (p<0.0001) % Increase in Serum Creatinine CIN After PCI: 33.5% 37% 18% 16.5% 15% n= % S. Creatinine Increase & 1-Year Mortality Gruberg, et al. JACC 2000; 36: 1542-8

24. Consequences of Acute Renal Failure After adjustment for comorbid risk factors, ARF independently increases risk of death 1 Estimated cost of therapy $128,000 per episode 2 (if dialysis initiated) 1 Levy, et al, JAMA, 1996, 275: 1489- 2 Hamel, et al, Annals of Internal Medicine, 1997, 195-202

25. Summary of Risk and Impact of RCN Renal insufficiency is independently associated with all causes of mortality and cardiovascular mortality Baseline renal insufficiency, diabetes, and dehydration predispose patients to contrast-induced renal failure Once contrast-induced renal failure occurs, it is associated with a markedly higher in-hospital and long-term mortality following PCI Diabetes and CRF have additive adverse effects on long-term prognosis after PCI RCN dramatically increases hospital costs by increasing length of stay and need for dialysis

26. Limitations of CIN Studies Small numbers – not megatrials that cardiologists are used to Varying treatments used –Differing hydration regiments Varying definitions –Outcomes vary by definitions Serum Cr- not Creatinine Clearance

27. Frequency of Contrast- Induced Nephropathy N=1826 consecutive patients undergoing PCI McCullough PA, Am J Med 1997;103:386-375. *Validated at 16.5% in 8,628 consecutive series at Washington Hospital Center, Iakovou, et al. ACC 2002 14.5%*

28. Cockroft Gault Formula Creatinine Clearance –Males – (140-age)(body weight in kg) 72(serum Cr.) -Females- (140-age)(body weight in kg)(0.85) - 72(serum Cr.)

29. CONTRAST NEPHROPATHY Patients with CRF and those on Dialysis Background Limitations of Studies Prevention –What is the Appropriate Hydration Regimen? –N-acetylcysteine (Mucomyst) –Calculating Adjusted Contrast Dose –Non Ionic and Isoosmolar Contrast Recommendations

30. Post Intervention Contrast Nephropathy Failed agents for prevention/mitigation of contrast-induced nephropathy –Calcium channel antagonists –adenosine antagonists –dopamine –mannitol –furosemide –endothelin-receptor antagonists

31. Ongoing Studies; Results Pending RCT Ioxaglate vs. Iodixanol Ongoing Studies; Results Pending RCTFenoldopam No benefit Prospective Pre-emptive Dialysis Reduced incidence of CIN vs. high osmolar contrast RCT Low Osmolar Contrast Reduced incidence of CIN after low volume I.V. contrast RCTn-Acetycysteine Not adequately studied Prospective Calcium Channel Blocker Potential benefit RCT Adenosine Antagonist No benefit RCTDopamine RCT Endothelin Antagonist No benefit RCT Atrial Natriuretic Peptide Increased incidence of CIN RCTMannitol RCTFurosemide Reduced incidence of CIN RCTHydration Result Result Trial Design Intervention RCT = Randomized Clinical Trial

32. Dopamine and Aminophylline RCT’s 60 patients with creatinine ¡Ã1.5 (mean 2.0 mg/dl) Coronary angioplasty All hydrated with 0.45%NS at 1 ml/kg/h starting 12h before Randomized to saline, dopamine (2.5 mcg/kg/min), or aminophylline (load + 0.4 mg/kg/h) CIN = SCr. ¡Ã25% over baseline Low osmolar contrast used; mean dose ¡Ö 200 ml Abizaid, et al. Am J Cardiol 1999, 83: 260 % RCIN

33. HYDRATION- Goal: Produce both volume expansion and a large volume of dilute urine Various protocols in the literature Should be suited to the clinical situation

34. Prevention of CIN Solomon, et al. NEJM 1994; 331: 1416-1420 0% 10% 20% 30% 40% 50% 60% Saline Saline + Mannitol Saline + Furosemide Non-DM DM % CIN 78 Pts with CRI (Cr 1.6-4.2 mg/dl) IV Fluids: 1/2 NS @ 1ml/kg/hr for 12 hr before & after contrast Mannitol: 50 g 1 hr before contrast Furosemide: 80 mg IV 30 min before contrast 78 Pts with CRI (Cr 1.6-4.2 mg/dl) IV Fluids: 1/2 NS @ 1ml/kg/hr for 12 hr before & after contrast Mannitol: 50 g 1 hr before contrast Furosemide: 80 mg IV 30 min before contrast 7% 14% 17% 38% 36% 43%

35. Comparison of 2 Hydration Regimen in 1620 pts undergoing PCI Randomly assigned to receive isotonic or half isotonic (with glucose) morning of (elective) or immediately before (emergent) PCI –1mg/kg body weight/hr continued until next AM Increase in serum cr. > 0.5 defined as contrast mediated nephropathy Increase in CMR in half isotonic compared with isotonic(2.0% vs 0.7%, p=0.04) –3 gps benefited most: > 250 cc contrast, women,dm No difference in cardiac or pvd complications Archive Intern Med. 2002 162:329-336

36. Optimal Hydration Regimen Mueller et al Arch Intern Med 2002

37. Optimal Hydration 0.9 NS vs 0.45 NS Mueller et al Arch Intern Med 2002

38. CIN: Effect of N-acetylcysteine Prospective, randomized 83 high risk patients –CrCl < 50 ml/min –Diabetes 33% IV Contrast for CT (75 ml of Low Osmolar CM) n-AC 600 bid x 2 days pre- CIN definition: creatinine increase of 0.5 mg/dl Hydration with 0.45% @ 1 ml/kg/h x 24 h Prospective, randomized 83 high risk patients –CrCl < 50 ml/min –Diabetes 33% IV Contrast for CT (75 ml of Low Osmolar CM) n-AC 600 bid x 2 days pre- CIN definition: creatinine increase of 0.5 mg/dl Hydration with 0.45% @ 1 ml/kg/h x 24 h Tepel, et al. NEJM 2000; 343: 180-184 0% 5% 10% 15% 20% 25% Control (42) AC (41) CIN (%) p= 0.01 21% 2%

39. N-acetylcysteine Meta-analysis –Seem to favor –Little down side –Data not overwhelming Limitations –Sometimes hard to pre treat –Time constrains Rappid Trial

40. N=80 All Cr Clearance 1.36 mg/dl Randomized to IV NAC(150 mg/kg in 500 cc NS over 30min. pre procedure, then 50 mg/kg in 500 cc over 4 hours) or IV hydration(1 cc/kg/hr ) 12 hours pre and post All received Visapaque

41. Rappid Results CIN in 2% of NAC vs 21% of hydration pts (p=0.45) Mean Serum Cr fell in NAC group (p=0.02) and was unchanged in hydration group 3 pts had NAC discontinued after bolus because of flushing, itching, and or rash

42. ADJUSTED CONTRAST DOSE PREDICTS NEPHROPATHY REQUIRING DIALYSIS Michigan Data Base- 16,592 PCI’s Developmental, validation data set MRCD = 5cc X body weight (kg)/serum cr. NRD(0.44 %, 0.35%), mortality(39%, 26%) Unadjusted contrast dose not a univariate predictor AJC 2002; 90: 1068-1073

43. ADJUSTED CONTRAST DOSE 3.3-12.86.2Exceeding MRCD 1.5-9.33.7Cardiogenic Shock 1.8-7.13.6Peripheral Vascular D. 2.2-9.24.5Congestive Heart Failure 1.2-4.52.3Diabetes 2.4-10.45.0Renal Insufficiency 95% CIAdjusted ORXvariate Predictors of NRD

44. ADJUSTED CONTRAST DOSE Progressive increased incidence of nephropathy related dialysis with increasing number of risk factors Among risk factors, contrast dose is potentially modifiable Once MRCD exceeded, there was a progressive exponential increase in NRD –2.4% NRD if MRCD exceeded, 0.18% if not –1-1.5 MRCD- 1% NRD, 1.5-2 – 3.5%, 2-3 – 7%, >3- 8%

45. CONTRAST NEPHROPATHY Patients on Dialysis Background of Problem Newer Data –Prognosis and Incidence – All Comers –Prognosis and Incidence – Pre-existing Renal d. –Calculating Adjusted Contrast Dose –Non Ionic and Isoosmolar Contrast Recommendations

46. Effects of Ionic vs Non Ionic Contrast on Renal Function post angiography- Gomes et al:Radiology 1989

47. Incidence of CIN (Cr. Increase >1mg/dl) in pts with preexisting renal disease: Ionic High Osmolar vs Ionic Low Osmolar Contrast - Rudrick MR et al: Kidney International: 1995 NNon IonicIonic Cr. > 1.5mg/dl2964%7% Cr. > 1.5 mg/dl + doabetes mellitus 21312%21% Cr. < 1.5 mg/dl35900 Cr. < 1.5 mg/dl + Diabetes mellitus 3151% total11833%7%(p<0.002)

48. META ANALYSIS 39 Trials - 5146 patients CIN > 0.5 mg/dl CIN in 7% of all patients CIN in 30% of CRI patients For CRI, NNT=8 (treat 8 to prevent 1 CIN case) Low osmolar group including Ioxaglate (Hexabrix) superior to High osmolar group; Iodixanol (Visipaque) not studied 39 Trials - 5146 patients CIN > 0.5 mg/dl CIN in 7% of all patients CIN in 30% of CRI patients For CRI, NNT=8 (treat 8 to prevent 1 CIN case) Low osmolar group including Ioxaglate (Hexabrix) superior to High osmolar group; Iodixanol (Visipaque) not studied Barrett, et al. Radiology 1993; 188: 171-178 0 0.2 0.4 0.6 0.8 11.2 High Osm Low Osm Relative Risk of CIN 1.0 0.61 High vs. Low Osmolar Contrast Media

49. ISOOSMOLAR VS LOW OSMOLAR CONTRAST 129 high risk patient (diabetes, serum cr.>1.5<3.5 Iodixanol(visapaque)-320 mg iodine/dl, 290 mOsm/kg water vs. Iohexol(omnipaque)- 350 mg iodine/dl, 780 mOsm/kg water All patients well hydrated Average contrast 166 cc NEJM: 2/6/03

50. ISOOSMOLAR vs LOW OSMOLAR CONTRAST Day 0 to day 3 – mean peak increase in creatinine 0.13 vs. 0.55(iodixanol vs iohexol, p=0.001) Increase in serum creatinie > 0.5 mg/dl- 2/64(3%) iodixanol; 17/65(26%) iohexol; p=.002 Increase in serum creatine >1 mg/dl- 0 iodixanol, 10/65(15%) iohexol Mean change in serum cr. from day 0 to 7- 0.07 vs 0.24 mg/dl; p=0.003 Acute Renal Failure – 0% vs. 9%

51. VALOR Trial US Prospective Double Blind Randomized Trial – up to 60 Sites Patients with CRI (Defined as Cr >1.5mg/dL in women and 1.7 mg/dL in men) Creatinine Measured to 72 hours post procedure or until peak occurs 2 Groups: –Iodixanol and N-acetylcysteine –LOCM and N-acetylcysteine

52. CONTRAST NEPHROPATHY Patients with CRF and those on Dialysis Background Limitations of Studies Prevention –What is the Appropriate Hydration Regimen? –N-acetylcysteine –Calculating Adjusted Contrast Dose –Non Ionic Contrast –Isoosmolar Contrast Recommendations

53. PROPOSED GUIDELINES FOR HIGH RISK PATIENTS Aggressive Hydration Determine MRCD( 5cc x weight(kg)/serum Cr. Avoid exceeding( mix contrast, LV gram) Consider staged procedure Non Ionic Contrast Isoosmolar Contrast(? need more data) N-acetylcysteine

54. Summary Contrast-Induced Nephropathy is a common complication of intravenous contrast exposure in higher-risk patients Even with chemical resolution of CIN and a return of serum creatinine towards baseline, the 1-year mortality remains over 25%, making prevention mandatory in higher-risk patients High-risk characteristics include renal insufficiency (Cr > 1.5 mg/dL) and diabetes Pathophysiology of CIN seems to involve contrast-induced renal medullary ischemia Mannitol, furosemide, aminophylline, and “renal dose” dopamine are ineffective in preventing RCN N-acetylcysteine has been shown to prevent CIN though data is somewhat controversial Non ionic isoosmolar agents show promise

55. Summary of Risk and Impact of CIN Renal insufficiency is independently associated with all causes of mortality and cardiovascular mortality Baseline renal insufficiency, diabetes, and dehydration predispose patients to contrast-induced renal failure Once contrast-induced renal failure occurs, it is associated with a markedly higher in-hospital and long-term mortality following PCI Diabetes and CRF have additive adverse effects on long-term prognosis after PCI CIN dramatically increases hospital costs by increasing length of stay and need for dialysis

56. CIN: Incidence & Risk Factors 0.011.002-1.0131.008 Contrast dose 0.011.41-21.325.47Diabetes <0.0010.77-0.890.83 Cr Clearance PCIOR Predictors of ARF +Dialysis 1,826 consecutive pts undergoing PCI: CIN without dialysis occurred 14.5% CIN with dialysis occurred 0.8% McCullough, et al. Am J Med 1997; 103: 375

57. In-Hospital Outcomes 1-Year Outcomes P<0.001 P=NS Gruberg, et al. JACC 2000; 36: 1542-8 Independent predictors of late death: Cr. rise (OR 3.86, p<0.001) and Age (OR 1.05, p=0.03) P<0.001 CIN after PCI in Pts With CRF

58. Fenoldopam for Prevention of Contrast Nephropathy Not currently FDA approved for this indication Peripheral dopamine-1 receptor agonist Proposed mechanism of renal protection: –vasodilatation of efferent and afferent arterioles –maintains or increases glomerular filtration rate –promotes natriuresis and diuresis

59. Renal Function Deterioration with Pre Existing Renal D Independent Predictors: LVEF, Contrast Volume(not creatinine) In hospitalMortality 14.9% vs. 4.9%, 1 year 37.7% vs. 19.4% 31% required dialysis – in hospital mortality 22.6%, 1 year 45.2%(35.4% for those with renal deterioration not requiring dialysis)