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Contrast Induced Nephropathy (CIN)
23 April 2014
BCS Editorial
By: Adnan Nadir
Untitled Document
What is CIN and why does it occur?
How common is CIN?
What are the risk factors?
What is the natural course and prognosis after CIN?
What is the management of CIN?
How can CIN be prevented?
Available contrast agents and their use:
Fluid managment:
N. Acetylcystiene (NAC):
Statins:
Other interventions:
Summary:
References:
Contrast induced nephropathy (CIN) refers to a form of acute kidney injury (AKI) that occurs after parenteral administration of radio-contrast agent in the absence of other identifiable causes. CIN is generally defined as an increase in serum creatinine concentration of 44 mol/L (0.5 mg/dl) or 25% above baseline within 48 hours after contrast administration.(1, 2) Animal data suggest that CIN is due to an acute tubular dysfunction, however mechanisms underlying such acute tubular dysfunction in the context of CIN are rather poorly understood.(2, 3) Acute tubular dysfunction seen in settings of CIN is generally less severe and tends to recover more quickly when compared with other forms of acute tubular necrosis (ATN). Postulated mechanisms of this form of acute tubular dysfunction seen in context of CIN include renal vasoconstriction, oxygen-free radical induced tubular injury and a direct toxic effect of the contrast agent. All iodinated contrast agents are highly water soluble, freely filtered by the glomerulus and retained in patients with chronic kidney disease within the tubular cells and the peritubular space. Once filtered by the glomerulus they cause direct oxidative cellular damage, sloughing of renal tubular cells and brush border material and thus result in acute tubular dysfunction. (3)
It is not straightforward to estimate the frequency of CIN for a number of reasons. Firstly, the definition of CIN in the published studies is variable. Secondly, the reported frequency depends upon the presence or absence of risk factors in any given population. Thirdly, it is challenging to reliably exclude other causes of AKI unrelated to CIN. Finally, a reduction in renal function is not uncommon in hospitalized patients who do not receive a contrast agent. With the above in mind it is not surprising to note that the reported risk of CIN ranges from 2-30%.(2, 4-8)
Following risk factors have been described in the literature(1, 7, 8) :
- Chronic kidney disease
- Diabetic Mellitus
- Congestive Cardiac Failure
- High total volume and hyperosmolar ionic contrast agent
- Age >75
- Persistent Hypotension
- Use of an intra-aortic balloon pump
A risk score for the prediction of CIN following PCI has been devised by Mehran et al. This scoring system incorporates many of the above mentioned risk factors. A score of <6, 6-10, 11-16 and >16 indicates a 7.5%, 14%, 26% and 57% risk of developing CIN after PCI respectively.(8)
CIN usually manifests itself within the first 24 to 48 hours after the contrast study. Most patients are non-oliguric and the only apparent abnormality is a mild increase in the serum creatinine. The decline in the estimated GFR after parenteral use of a contrast agent is usually mild. In most cases the serum creatinine starts to improve within 3-7 days and baseline renal function is restored. Renal replacement therapy is rarely required for AKI after contrast administration. For example in one study of 1800 consecutive patients who underwent PCI the incidence of severe AKI requiring dialysis was <1%.(6) Data to support more long term effects of CIN are hard to capture. However, it is increasingly appreciated that residual renal dysfunction may persist even among patients in whom the creatinine returns to baseline. Rudnick et al suggested that CIN is a marker for increased mortality.(9)
The diagnosis is based upon the clinical presentation and the exclusion of other causes of AKI. The differential diagnosis includes ischemic ATN, acute interstitial nephritis, and renal atheroembolism. Ultrasound has no specific role and renal biopsy is not helpful in CIN.
The mantra that “prevention is better than cure” holds true in the case of CIN. There is no specific treatment once contrast-induced AKI develops, and management is largely supportive with the focus on maintaining fluid and electrolyte balance. The indications for renal replacement therapy are the same as in other forms of AKI.
Contrast agents can be ionic or non-ionic and have variable osmolality.(2) First generation contrast agents were ionic monomers and had a higher osmolality (1500 to 1800 mosmol/kg). Newer contrast agents are non-ionic and have lower osmolality. The potential to cause CIN varies with different agents. In general non-ionic agents are better than ionic and low and iso-osmolal agents are superior to hyperosmolal agents.
In the UK two types of nonioinic contrast agents are in widespread use. Iohexol (Omnipaque) is a “low osmolal” agent with osmolality of 600 to 850 mosmol/kg and hence still has a higher viscosity than that of plasma. Iodixanol (Visipaque) is an iso-osmolal agent with approximate osmolality of 290 mosmol/kg which is similar to that of plasma. In a cohort of 129 patients at high risk of developing CIN undergoing coronary angiography, Iodixanol (Visipaque) was shown to be superior to Iohexol (Omnipaque) with less patients developing CIN.(4) A subsequent meta-analysis of 16 randomised trials concluded that the iso-osmolal nonionic contrast agent, iodixanol (Visipaque), appears to reduce the risk of contrast nephropathy in high-risk patients, such as diabetic patients with patients with renal insufficiency, compared with the low-osmolal nonionic agent iohexol (Omnipaque), but not when compared with other low-osmolal nonionic agents.(10) Based on this data the AHA/ACC recommend the use of either an iso-osmolal contrast agent [e.g, iodixanol (Visipaque)] or a low-molecular weight contrast agent other than iohexol (Omnipaque) in patients with CKD(11)
Where there is no contraindication to volume expansion pre-hydration remains critical. It has been shown that oral rehydration, particularly without salt loading, may not be as effective as intravenous fluid administration in reducing the risk of CIN.(12) On the other hand the optimal intravenous hydration regimen for prevention of CIN remains unclear.
Published data suggest that volume expansion with isotonic saline is superior to hypotonic saline.(13) Many studies have explored the role of alkalinisation and some have shown that volume expansion with isotonic sodium bicarbonate may be superior to that achieved with isotonic saline while other studies have found no significant difference. A meta-analysis published in 2010 found that the use of sodium bicarbonate reduced the risk for CIN.(5, 14, 15) Examples of intravenous volume expansion regimens include:
- Normal Saline: 1ml/kg/hr for 12 hours pre and post procedure.
- Sodium bicarbonate (150-166 mEq/L): 3ml/kg/hr for 1 hour before and 1 ml/kg/hr post procedure.
RenalGuard is a device which creates high urine output and fluid balancing. Two trials have studied the potential role of forced diuresis and matching hydration compared to standard hydration. This strategy is aimed at reducing contrast exposure and uptake by renal tubular cells by accelerating urinary excretion of contrast agents. In both the trials a forced diuresis and matched volume repletion decreased the incidence of contrast nephropathy.(16, 17)
More than 40 trials using NAC have been completed in the last decade and have reported inconsistent results. Over a dozen meta-analyses have attempted to assimilate the available data. These show great heterogeneity and conflicting results from the available clinical trials. The Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT) in many ways may have closed the debate on the use of NAC as it failed to show any benefit with the additional short term use of NAC (1200mg bd before and after procedure).(18-20)
Since statins improve endothelial dysfunction and reduce oxidative stress it is plausible that they may reduce the risk of CIN. In fact this notion is supported by several observational studies and small RCTs.(21, 22) In the NAPLES II trial patients undergoing elective coronary angiography or percutaneous coronary intervention in a native coronary artery were randomly assigned to receive atorvastatin treatment at a dose of 80 mg before the intervention or placebo.(23) CIN, defined as an increase >10% of serum cystatin C concentration (an established marker of AKI) within 24 hours after contrast exposure, occurred in 4.5% patients in the atorvastatin group and in 17.8% patients in the control group (P=0.005; odds ratio=0.22; 95% confidence interval, 0.07–0.69). Another RCT, the Statin Contrast Induced Nephropathy Prevention [PRATO-ACS], published in 2014 showed that high-dose rosuvastatin given on admission to statin-naive patients with acute coronary syndrome who are scheduled for an early invasive procedure prevented CIN.(24) Han et al randomized 2998 patients with DM and CKD who were scheduled to have angiography to receive Rosuvavtatin (2 days prior to procedure and 3 days after) or no statin. The primary endpoint of the study was the development of CIN, defined as an increase in serum creatinine concentration by 44.2 mmol/l or 0.25% above baseline at 72 h after exposure to contrast medium. Patients randomized to the rosuvastatin group had a significantly lower incidence of CIN than controls (2.3% vs. 3.9%, respectively; p< 0.01).(25, 26)
Many other interventions have been attempted with unproven benefit. These include Ascorbic acid, atrial Natriuretic peptide, mannitol, theophylline and sodium citrate. There is also general lack of data to support interventions like prophylactic haemodialysis, ischemic preconditioning and withholding ACE inhibitors or Metformin. There is some emerging evidence that transradial coronary procedures may have lower risk of CIN compared to transfemoral.(27)
CIN is a reversible form of acute kidney injury with poorly understood underlying pathophysiology. No specific treatment exists and prevention is the key. Despite the huge amount of published data the optimal strategy to prevent CIN remains elusive. Notwithstanding initial enthusiasm there is lack of conclusive evidence to support the routine use of NAC. However, where there is no contraindication to volume expansion, hydration preferably with isotonic fluids remains an appropriate preventative strategy. Novel fluid management systems like RenalGuard and the prophylactic use of high dose statins are a new area of interest.
1. Maeder M, Klein M, Fehr T, Rickli H. Contrast nephropathy: review focusing on prevention. Journal of the American College of Cardiology. 2004;44(9):1763-71. Epub 2004/11/03.
2. Tepel M, Aspelin P, Lameire N. Contrast-induced nephropathy: a clinical and evidence-based approach. Circulation. 2006;113(14):1799-806. Epub 2006/04/12.
3. Persson PB, Hansell P, Liss P. Pathophysiology of contrast medium-induced nephropathy. Kidney Int. 2005;68(1):14-22. Epub 2005/06/16.
4. Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003;348(6):491-9. Epub 2003/02/07.
5. Brar SS, Shen AY, Jorgensen MB, Kotlewski A, Aharonian VJ, Desai N, et al. Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: a randomized trial. JAMA. 2008;300(9):1038-46. Epub 2008/09/05.
6. Rudnick MR, Goldfarb S, Wexler L, Ludbrook PA, Murphy MJ, Halpern EF, et al. Nephrotoxicity of ionic and nonionic contrast media in 1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidney Int. 1995;47(1):254-61. Epub 1995/01/01.
7. Rich MW, Crecelius CA. Incidence, risk factors, and clinical course of acute renal insufficiency after cardiac catheterization in patients 70 years of age or older. A prospective study. Arch Intern Med. 1990;150(6):1237-42. Epub 1990/06/01.
8. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. Journal of the American College of Cardiology. 2004;44(7):1393-9. Epub 2004/10/07.
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10. Reed M, Meier P, Tamhane UU, Welch KB, Moscucci M, Gurm HS. The relative renal safety of iodixanol compared with low-osmolar contrast media: a meta-analysis of randomized controlled trials. JACC Cardiovasc Interv. 2009;2(7):645-54. Epub 2009/07/25.
11. Kushner FG, Hand M, Smith SC, Jr., King SB, 3rd, Anderson JL, Antman EM, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology. 2009;54(23):2205-41. Epub 2009/11/28.
12. Trivedi HS, Moore H, Nasr S, Aggarwal K, Agrawal A, Goel P, et al. A randomized prospective trial to assess the role of saline hydration on the development of contrast nephrotoxicity. Nephron Clin Pract. 2003;93(1):C29-34. Epub 2002/11/02.
13. Weisbord SD, Palevsky PM. Prevention of contrast-induced nephropathy with volume expansion. Clin J Am Soc Nephrol. 2008;3(1):273-80. Epub 2007/11/09.
14. Hoste EA, De Waele JJ, Gevaert SA, Uchino S, Kellum JA. Sodium bicarbonate for prevention of contrast-induced acute kidney injury: a systematic review and meta-analysis. Nephrol Dial Transplant. 2010;25(3):747-58. Epub 2009/08/26.
15. Klima T, Christ A, Marana I, Kalbermatter S, Uthoff H, Burri E, et al. Sodium chloride vs. sodium bicarbonate for the prevention of contrast medium-induced nephropathy: a randomized controlled trial. Eur Heart J. 2012;33(16):2071-9. Epub 2012/01/24.
16. Briguori C, Visconti G, Focaccio A, Airoldi F, Valgimigli M, Sangiorgi GM, et al. Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II): RenalGuard System in high-risk patients for contrast-induced acute kidney injury. Circulation. 2011;124(11):1260-9. Epub 2011/08/17.
17. Marenzi G, Ferrari C, Marana I, Assanelli E, De Metrio M, Teruzzi G, et al. Prevention of contrast nephropathy by furosemide with matched hydration: the MYTHOS (Induced Diuresis With Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy Prevention) trial. JACC Cardiovasc Interv. 2012;5(1):90-7. Epub 2012/01/11.
18. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT). Circulation. 2011;124(11):1250-9. Epub 2011/08/24.
19. Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008;148(4):284-94. Epub 2008/02/20.
20. O'Sullivan S, Healy DA, Moloney MC, Grace PA, Walsh SR. The role of N--acetylcysteine in the prevention of contrast-induced nephropathy in patients undergoing peripheral angiography: a structured review and meta-analysis. Angiology. 2013;64(8):576-82. Epub 2012/11/29.
21. Toso A, Maioli M, Leoncini M, Gallopin M, Tedeschi D, Micheletti C, et al. Usefulness of atorvastatin (80 mg) in prevention of contrast-induced nephropathy in patients with chronic renal disease. Am J Cardiol. 2010;105(3):288-92. Epub 2010/01/28.
22. Xinwei J, Xianghua F, Jing Z, Xinshun G, Ling X, Weize F, et al. Comparison of usefulness of simvastatin 20 mg versus 80 mg in preventing contrast-induced nephropathy in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Am J Cardiol. 2009;104(4):519-24. Epub 2009/08/08.
23. Quintavalle C, Fiore D, De Micco F, Visconti G, Focaccio A, Golia B, et al. Impact of a high loading dose of atorvastatin on contrast-induced acute kidney injury. Circulation. 2012;126(25):3008-16. Epub 2012/11/14.
24. Leoncini M, Toso A, Maioli M, Tropeano F, Villani S, Bellandi F. Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: Results from the PRATO-ACS Study (Protective Effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome). Journal of the American College of Cardiology. 2014;63(1):71-9. Epub 2013/10/01.
25. Han Y, Zhu G, Han L, Hou F, Huang W, Liu H, et al. Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. Journal of the American College of Cardiology. 2014;63(1):62-70. Epub 2013/10/01.
26. Alpert MA. Do statins reduce the risk of contrast-induced acute kidney injury in patients undergoing coronary angiography or percutaneous coronary interventions? Journal of the American College of Cardiology. 2014;63(1):80-2. Epub 2013/10/01.
27. Kooiman J, Seth M, Dixon S, Wohns D, Lalonde T, Rao SV, et al. Risk of Acute Kidney Injury After Percutaneous Coronary Interventions Using Radial Versus Femoral Vascular Access: Insights From the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. Circ Cardiovasc Interv. 2014. Epub 2014/02/27.
Number of hits: 9437
Comments: 2
Excellent review |
Well done |
By: Conrad Murphy |
12 May 2014 at 12:16:33 |
Thank you Dr Murphy |
Regards, Adnan |
By: Adnan Nadir |
28 May 2014 at 18:31:58 |
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