Contrast-induced nephropathy

Contrast-induced nephropathy
Classification and external resources
ICD-10	N99.0
ICD-9	586

Contrast-induced nephropathy is defined as either a greater than 25% increase of serum creatinine or an absolute increase in serum creatinine of 0.5 mg/dL ^[1] after a radiographic examination using a contrast agent.

A new definition of contrast nephropathy in patients undergoing percutaneous coronary intervention was recently proposed by Harjai, et al. This tripartite definition classifies contrast nephropathy as grade 0 (serum creatinine increase <25% above baseline and <0.5 mg/dL above baseline), grade 1 (serum creatinine increase >/=25% above baseline and <0.5 mg/dL above baseline), or grade 2 (serum creatinine increase >/=0.5 mg/dL above baseline). This classification is prognostic of long-term outcomes of patients after percutaneous coronary intervention. Patients with grade 2 nephropathy had the worst outcome while those with grade 0 nephropathy had the best outcome on long-term follow-up. ^[2]

Risk factors

To minimize the risk for contrast-induced nephropathy, various actions can be taken if the patient has predisposing conditions. These have been reviewed in a meta-analysis.^[3] A separate meta-analysis addresses interventions in for emergent patients with baseline renal insufficiency.^[4]

Three factors have been associated with an increased risk of contrast-induced nephropathy: preexisting renal insufficiency (such as Creatinine clearance < 60 mL/min [1.00 mL/s] - online calculator), preexisting diabetes, and reduced intravascular volume.^[5][6]

A clinical prediction rule is available to estimate probability of nephropathy (increase ≥25% and/or ≥0.5 mg/dl in serum creatinine at 48 h)^[7]:

Risk Factors:

• Systolic blood pressure <80 mm Hg - 5 points
• Intraarterial balloon pump - 5 points
• Congestive heart failure (Class III-IV or history of pulmonary edema) - 5 points
• Age >75 y - 4 points
• Hematocrit level <39% for men and <35% for women - 3 points
• Diabetes - 3 points
• Contrast media volume - 1 point for each 100 mL
• Renal insufficiency:
  • Serum creatinine level >1.5 g/dL - 4 points

or

• Estimated Glomerular filtration rate (online calculator)

• 2 for 40–60 mL/min/1.73 m2
• 4 for 20–40 mL/min/1.73 m2
• 6 for < 20 mL/min/1.73 m2

Scoring:
5 or less points

• Risk of CIN - 7.5
• Risk of Dialysis - 0.04%

6–10 points

• Risk of CIN - 14.0
• Risk of Dialysis - 0.12%

11–16 points

• Risk of CIN - 26.1*
• Risk of Dialysis - 1.09%

>16 points

• Risk of CIN - 57.3
• Risk of Dialysis - 12.8%

Choice of contrast agent

The osmolality of the contrast agent was previously believed to be of paramount importance in contrast-induced nephropathy. Today it has become increasingly clear that other physicochemical properties play a greater role, such as viscosity. Attention should be paid to use contrast agents of low viscosity. Moreover, sufficient fluids should be supplied to limit fluid viscosity of urine. Modern iodinated contrast agents are non-ionic, the older ionic types caused more adverse effects and are not used much anymore.

A former study suggested that iso-osmolar, nonionic contrast media may be superior to others. randomized controlled trial.^[8] However, several subsequent studies failed to confirm this. A large scale study strongly suggested that an iso-osmolar contrast media more often cause clinically relevant kidney failure than a low-osmolar contrast agent. ^[9]

Hydration with or without bicarbonate

Administration of sodium bicarbonate 3 mL/kg per hour for 1 hour before , followed by 1 mL/kg per hour for 6 hours after contrast was found superior to plain saline on one randomized controlled trial of patients with a creatinine of at least 1.1 mg/dL (97.2 µmol/L) .^[10] To make the solution, the study used 154 mL of 1000 mEq/L sodium bicarbonate to 846 mL of 5% dextrose. This is approximately three 50 ml ampules of bicarbonate in 850 ml of water with 5% dextrose. This was subsequently corroborated by a multi-center randomized controlled trial, which also demonstrated that IV hydration with sodium bicarbonate was superior to 0.9% normal saline^[11]. However, additional confirmatory trials with sodium bicarbonate are needed because the largest trial to date showed no benefit of sodium bicarbonate over normal saline .^[12]. The renoprotective effects of bicarbonate are thought to be due to urinary alkalinization, which creates an environment less amenable to the formation of harmful free radicals.^[13].

Alternatively, one randomized controlled trial of patients with a creatinine over 1.6 mg per deciliter (140 µmol per liter) or creatinine clearance below 60 ml per minute used 1 ml/kg of 0.45 percent saline per per hour for 6–12 hours before and after the contrast.^[14]

Methylxanthines

Adenosine antagonists such as the methylxanthines theophylline and aminophylline, may help^[4] although studies have conflicting results.^[15] The best studied dose is 200 mg of theophylline given IV 30 minutes before contrast administration.^[16][17]

N-acetylcysteine

N-acetylcysteine (NAC) 600 mg orally twice a day, on the day before and of the procedure if creatinine clearance is estimated to be less than 60 mL/min [1.00 mL/s]) may reduce nephropathy.^[18]. A randomized controlled trial found higher doses of NAC (1200 mg IV bolus and 1200 mg orally twice daily for 2 days) benefited (relative risk reduction of 74%) patients receiving coronary angioplasty with higher volumes of contrast^[19].

Since publication of the meta-analyses, two small and underpowered negative studies, one of IV NAC^[20] and one of 600 mg give four times around coronary angiography^[21], found statistically insignificant trends towards benefit.

Some authors believe the benefit is not overwhelming.^[22] The strongest results were from an unblinded randomized controlled trial that used NAC intravenously.^[23] A systematic review by Clinical Evidence concluded that NAC is "likely to be beneficial" but did not recommend a specific dose.^[24] One study found that the apparent benefits of NAC may be due to its interference with the creatinine laboratory test itself.^[25] This is supported by a lack of correlation between creatinine levels and cystatin C levels.

In one study 15% of patients receiving NAC intravenously had allergic reactions.^{[23][verification needed]}

Prophylactic hemodialysis

Patients with chronic renal insufficiency and a creatinine over 309.4 µmol/L (3.5 mg.dl) who have elective coronary catheterization, a randomized controlled trial found benefit from prophylactic hemodialysis^[26]

Other interventions

Other pharmacological agents, such as furosemide, mannitol, dopamine, and atrial natriuretic peptide have been tried, but have either not had beneficial effects, or had detrimental effects.^[14][27] Of course, limiting the total contrast volume also aids greatly in reducing the incidence of contrast nephropathy.^{[citation needed]}

Clinical Research

While there are currently no FDA-approved therapies for Contrast Induced Nephropathy, CorMedix, Inc. is currently in the latter part of Stage II clinical trials with approved Phase III Special Protocol Assessment for CRMD001 (unique formulation Deferiprone) to prevent Contrast-Induced Acute Kidney Injury (AKI) and to slow progression of Chronic Kidney Disease (CKD). Dosing trials began in June of 2010 in the sixty patient trial.^[28][29]

References

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2. ^ Harjai KJ, et al. A comparison of contemporary definitions of contrast nephropathy in patients undergoing percutaneous coronary intervention and a proposal for a novel nephropathy grading system. Am J Cardiol 2008;101(6):812-9.
3. ^ Pannu N, Wiebe N, Tonelli M (2006). "Prophylaxis strategies for contrast-induced nephropathy". JAMA 295 (23): 2765–79. doi:10.1001/jama.295.23.2765. PMID 16788132. 
4. ^ ^{a b} Sinert R, Doty CI (2007). "Evidence-based emergency medicine review. Prevention of contrast-induced nephropathy in the emergency department". Annals of emergency medicine 50 (3): 335–45, 345.e1–2. doi:10.1016/j.annemergmed.2007.01.023. PMID 17512638. 
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13. ^ Mueller C, Buerkle G, Buettner H, Petersen J, Perruchoud A, Eriksson U, Marsch S, Roskamm H (2002). "Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty". Arch Intern Med 162 (3): 329–36. doi:10.1001/archinte.162.3.329. PMID 11822926. 
14. ^ ^{a b} Solomon R, Werner C, Mann D, D'Elia J, Silva P (1994). "Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents". N. Engl. J. Med. 331 (21): 1416–20. doi:10.1056/NEJM199411243312104. PMID 7969280. http://content.nejm.org/cgi/content/full/331/21/1416. 
15. ^ Bagshaw SM, Ghali WA (2005). "Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis". Arch. Intern. Med. 165 (10): 1087–93. doi:10.1001/archinte.165.10.1087. PMID 15911721. 
16. ^ Huber W, Schipek C, Ilgmann K, et al. (2003). "Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency". Am. J. Cardiol. 91 (10): 1157–62. doi:10.1016/S0002-9149(03)00259-5. PMID 12745095. 
17. ^ Huber W, Ilgmann K, Page M, et al. (2002). "Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: controlled, randomized, double-blinded study". Radiology 223 (3): 772–9. doi:10.1148/radiol.2233010609. PMID 12034949. 
18. ^ Kay J, Chow W, Chan T, Lo S, Kwok O, Yip A, Fan K, Lee C, Lam W (2003). "Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial". JAMA 289 (5): 553–8. doi:10.1001/jama.289.5.553. PMID 12578487. 
19. ^ Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S, Fabbiocchi F, Montorsi P, Veglia F, Bartorelli A (2006). "N-acetylcysteine and contrast-induced nephropathy in primary angioplasty". N Engl J Med 354 (26): 2773–82. doi:10.1056/NEJMoa054209. PMID 16807414. 
20. ^ Haase M, Haase-Fielitz A, Bagshaw SM, et al. (2007). "Phase II, randomized, controlled trial of high-dose N-acetylcysteine in high-risk cardiac surgery patients". Crit. Care Med. 35 (5): 1324–31. doi:10.1097/01.CCM.0000261887.69976.12. PMID 17414730. 
21. ^ Seyon RA, Jensen LA, Ferguson IA, Williams RG (2007). "Efficacy of N-acetylcysteine and hydration versus placebo and hydration in decreasing contrast-induced renal dysfunction in patients undergoing coronary angiography with or without concomitant percutaneous coronary intervention". Heart & lung : the journal of critical care 36 (3): 195–204. doi:10.1016/j.hrtlng.2006.08.004. PMID 17509426. 
22. ^ Gleeson TG, Bulugahapitiya S (2004). "Contrast-induced nephropathy". AJR Am J Roentgenol 183 (6): 1673–89. PMID 15547209. 
23. ^ ^{a b} Baker CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ (2003). "A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study". J. Am. Coll. Cardiol. 41 (12): 2114–8. doi:10.1016/S0735-1097(03)00487-X. PMID 12821233. 
24. ^ Kellum J, Leblanc M, Venkataraman R (2006). "Renal failure (acute)". Clinical evidence (15): 1191–212. PMID 16973048. http://clinicalevidence.bmj.com/ceweb/conditions/knd/2001/2001.jsp. 
25. ^ Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK (2004). "The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable". J Am Soc Nephrol 15 (2): 407–10. doi:10.1097/01.ASN.0000106780.14856.55. PMID 14747387. 
26. ^ Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW (1999). "Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators". Stroke 30 (6): 1223–9. doi:10.1161/01.STR.30.6.1223. PMID 10356104. 
27. ^ Abizaid AS, Clark CE, Mintz GS, Dosa S, Popma JJ, Pichard AD, Satler LF, Harvey M, Kent KM, Leon MB (1999). "Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency". Am J Cardiol 83 (2): 260–3, A5. doi:10.1016/S0002-9149(98)00833-9. PMID 10073832. 
28. ^ [1], CorMedix June 25, 2010 Press Release, "CorMedix Doses First Patient in Phase II Clinical Trial of CRMD-001"
29. ^ [2], ClinicalTrials.gov, "Deferiprone for the Prevention of Contrast-Induced Acute Kidney Injury"