View source for Contrast induced nephropathy

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'''''Synonyms and keywords:''''' CIN

==Overview==
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.<ref name="pmid16436769">{{cite journal |author=Barrett BJ, Parfrey PS |title=Clinical practice. Preventing nephropathy induced by contrast medium |journal=N. Engl. J. Med. |volume=354 |issue=4 |pages=379–86 |year=2006 |pmid=16436769 |doi=10.1056/NEJMcp050801}}</ref>

==Pathophysiology==

The exact mechanism of development of nephropathy following contrast administration is not clearly understood. Several studies put forth two main theories:
*'''Renal medullary hypoxia secondary to renal vasoconstriction'''where vasoconstriction occurs due to contrast induced release of adenosine and possible endothelin as well as high osmolality of contrast substance <ref name="pmid8301922">{{cite journal |author=Cantley LG, Spokes K, Clark B, McMahon EG, Carter J, Epstein FH |title=Role of endothelin and prostaglandins in radiocontrast-induced renal artery constriction |journal=[[Kidney International]] |volume=44 |issue=6 |pages=1217–23 |year=1993 |month=December |pmid=8301922 |doi= |url= |accessdate=2011-03-06}}</ref> <ref name="pmid7892462">{{cite journal |author=Katholi RE, Taylor GJ, McCann WP, Woods WT, Womack KA, McCoy CD, Katholi CR, Moses HW, Mishkel GJ, Lucore CL |title=Nephrotoxicity from contrast media: attenuation with theophylline |journal=[[Radiology]] |volume=195 |issue=1 |pages=17–22 |year=1995 |month=April |pmid=7892462 |doi= |url=http://radiology.rsnajnls.org/cgi/pmidlookup?view=long&pmid=7892462 |accessdate=2011-03-06}}</ref> <ref name="pmid11126837">{{cite journal |author=Pflueger A, Larson TS, Nath KA, King BF, Gross JM, Knox FG |title=Role of adenosine in contrast media-induced acute renal failure in diabetes mellitus |journal=[[Mayo Clinic Proceedings. Mayo Clinic]] |volume=75 |issue=12 |pages=1275–83 |year=2000 |month=December |pmid=11126837 |doi= |url= |accessdate=2011-03-06}}</ref>. Other causes related to volume depletion or heart failure are also lead to renal vasoconstriction by stimulation of renin-angiotensin cascade and associated with impaired nitric oxide generation. Thereby potentiates medullary ischemia which is induced by the contrast media <ref name="pmid20602168">{{cite journal |author=Rosenstock JL, Gilles E, Geller AB, Panagopoulos G, Mathew S, Malieckal D, DeVita MV, Michelis MF |title=Impact of heart failure on the incidence of contrast-induced nephropathy in patients with chronic kidney disease |journal=[[International Urology and Nephrology]] |volume=42 |issue=4 |pages=1049–54 |year=2010 |month=December |pmid=20602168 |doi=10.1007/s11255-010-9798-  |url=http://dx.doi.org/10.1007/s11255-010-9798-4 |accessdate=2011-03-06}}</ref> <ref name="pmid8083347">{{cite journal |author=Agmon Y, Peleg H, Greenfeld Z, Rosen S, Brezis M |title=Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat |journal=[[The Journal of Clinical Investigation]] |volume=94 |issue=3 |pages=1069–75 |year=1994 |month=September |pmid=8083347 |pmc=295165 |doi=10.1172/JCI117421 |url= |accessdate=2011-03-06}}</ref>. Normally the metabolic rate and thereby oxygen consumption in renal medulla is high resulting from active salt reabsorption by medullary thick ascending limbs of Henle's loop. Hence renal vasoconstriction, increased blood-contrast viscosity, and a leftward shift of the oxygen-hemoglobin dissociation curve may all contribute to intrarenal hypoxia, imbalance between oxygen demand and supply thereby playing a major role in radiocontrast-induced outer medullary hypoxic damage<ref name="pmid10548380">{{cite journal |author=Heyman SN, Reichman J, Brezis M |title=Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia |journal=[[Investigative Radiology]] |volume=34 |issue=11 |pages=685–91 |year=1999 |month=November |pmid=10548380 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0020-9996&volume=34&issue=11&spage=685 |accessdate=2011-03-06}}</ref>

*'''Cytotoxic effects of contrast''' can cause renal tubular injury <ref name="pmid15845795">{{cite journal |author=Heinrich MC, Kuhlmann MK, Grgic A, Heckmann M, Kramann B, Uder M |title=Cytotoxic effects of ionic high-osmolar, nonionic monomeric, and nonionic iso-osmolar dimeric iodinated contrast media on renal tubular cells in vitro |journal=[[Radiology]] |volume=235 |issue=3 |pages=843–9 |year=2005 |month=June |pmid=15845795 |doi=10.1148/radiol.2353040726 |url=http://radiology.rsnajnls.org/cgi/pmidlookup?view=long&pmid=15845795 |accessdate=2011-03-08}}</ref> and also by generation of free oxygen radicals such as superoxide anion, hydrogen peroxide, hydroxyl radicals and hypochlorous acid. The endothelial dysfunction discussed above is also partly due to oxygen free-radical generation during post ischemic reperfusion as they decrease bioavailibility of nitric oxide leading to vasoconstriction. These reactive species also exerts their oxidative and nitrosative effects on the sulf hydrylic groups and aromatic rings of proteins, cellular membrane lipids and nucleic acids and contribute to vasoconstriction. This occurs through the nitrosation of tyrosine residues of enzymes, such as prostacycline synthase and nitric oxide synthase, which are involved in the synthesis of medulla vasodilators <ref name="pmid16033768">{{cite journal |author=Detrenis S, Meschi M, Musini S, Savazzi G |title=Lights and shadows on the pathogenesis of contrast-induced nephropathy: state of the art |journal=[[Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association]] |volume=20 |issue=8 |pages=1542–50 |year=2005 |month=August |pmid=16033768 |doi=10.1093/ndt/gfh868 |url=http://ndt.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=16033768 |accessdate=2011-03-08}}</ref>. Mitochondrial injury/cytochrome-c release and plasma membrane damage may be other causes of renal injury as shown in animal experiments <ref name="pmid12787403">{{cite journal |author=Zager RA, Johnson AC, Hanson SY |title=Radiographic contrast media-induced tubular injury: evaluation of oxidant stress and plasma membrane integrity |journal=[[Kidney International]] |volume=64 |issue=1 |pages=128–39 |year=2003 |month=July |pmid=12787403 |doi=10.1046/j.1523-1755.2003.00059.x |url=http://dx.doi.org/10.1046/j.1523-1755.2003.00059.x |accessdate=2011-03-08}}</ref>. Reduction in creatinine clearence was also seen with increase in adenosine excreation on administration of low osmolality, non-ionic contrast and with use of theophylline the fall in creatinine clearance declined <ref name="pmid7892462">{{cite journal |author=Katholi RE, Taylor GJ, McCann WP, Woods WT, Womack KA, McCoy CD, Katholi CR, Moses HW, Mishkel GJ, Lucore CL |title=Nephrotoxicity from contrast media: attenuation with theophylline |journal=[[Radiology]] |volume=195 |issue=1 |pages=17–22 |year=1995 |month=April |pmid=7892462 |doi= |url=http://radiology.rsnajnls.org/cgi/pmidlookup?view=long&pmid=7892462 |accessdate=2011-03-08}}</ref>.

==Predictors of Contrast-Induced Nephropathy==
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] - [http://www.intmed.mcw.edu/clincalc/creatinine.html online calculator]), preexisting [[diabetes]], and reduced intravascular volume.<ref name="pmid9375704">{{cite journal | author=McCullough PA, Wolyn R, Rocher LL, Levin RN, O'Neill WW | title=Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality | journal=Am J Med | year=1997 | pages=368-75 | volume=103 | issue=5  | id=PMID 9375704}}</ref><ref name="pmid10334456">{{cite journal | author=Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, Legako RD, Leon DF, Murray JA, Nissen SE, Pepine CJ, Watson RM, Ritchie JL, Gibbons RJ, Cheitlin MD, Gardner TJ, Garson A Jr, Russell RO Jr, Ryan TJ, Smith SC Jr | title=ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions | journal=J Am Coll Cardiol | year=1999 | pages=1756-824 | volume=33 | issue=6  | id=PMID 10334456}}</ref>

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)<ref name="pmid15464318">{{cite journal |author=Mehran R, Aymong ED, Nikolsky E, ''et al'' |title=A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation |journal=J. Am. Coll. Cardiol. |volume=44 |issue=7 |pages=1393–9 |year=2004 |pmid=15464318 |doi=10.1016/j.jacc.2004.06.068}}</ref>:

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]] ([http://www.intmed.mcw.edu/clincalc/creatinine.html 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:<br>
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 is believed to be of great importance in contrast-induced nephropathy. Ideally, the contrast agent should be iso-osmolar to [[blood]]. Modern iodinated contrast agents are non-ionic, the older ionic types caused more adverse effects and are not used much anymore.

Iso-osmolar, nonionic contrast media may be the best according to a [[randomized controlled trial]].<ref name="pmid12571256">{{cite journal |author=Aspelin P, Aubry P, Fransson S, Strasser R, Willenbrock R, Berg K |title=Nephrotoxic effects in high-risk patients undergoing angiography |journal=N Engl J Med |volume=348 |issue=6 |pages=491-9 |year=2003 |pmid=12571256}}</ref>

Hypo-osmolar, non-ionic contrast agents are beneficial if iso-osmolar, nonionic contrast media is not available due to costs.<ref name="pmid2643042">{{cite journal |author=Schwab S, Hlatky M, Pieper K, Davidson C, Morris K, Skelton T, Bashore T |title=Contrast nephrotoxicity: a randomized controlled trial of a nonionic and an ionic radiographic contrast agent |journal=N Engl J Med |volume=320 |issue=3 |pages=149-53 |year=1989 |pmid=2643042}}</ref>

==Prevention==
===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 creatinne of at least 1.1 mg/dL (97.2 µmol/L) .<ref name="pmid15150204">{{cite journal |author=Merten G, Burgess W, Gray L, Holleman J, Roush T, Kowalchuk G, Bersin R, Van Moore A, Simonton C, Rittase R, Norton H, Kennedy T |title=Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial |journal=JAMA |volume=291 |issue=19 |pages=2328-34 |year=2004 |pmid=15150204}}</ref> 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<ref name="pmid17309916">{{cite journal |author=Briguori C, Airoldi F, D'Andrea D, Bonizzoni E, Morici N, Focaccio A, Michev I, Montorfano M, Carlino M, Cosgrave J, Ricciardelli B, Colombo A |title=Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies |journal=Circulation |volume=115 |issue=10 |pages=1211-7 |year=2007 |pmid=17309916}}</ref>.  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]].<ref name="pmid11822926">{{cite journal |author=Mueller C, Buerkle G, Buettner H, Petersen J, Perruchoud A, Eriksson U, Marsch S, Roskamm H |title=Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty |journal=Arch Intern Med |volume=162 |issue=3 |pages=329-36 |year=2002 |pmid=11822926}}</ref>.

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.<ref name="pmid7969280">{{cite journal |author=Solomon R, Werner C, Mann D, D'Elia J, Silva P |title=Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents |journal=N. Engl. J. Med. |volume=331 |issue=21 |pages=1416–20 |year=1994 |pmid=7969280 |doi=|url=http://content.nejm.org/cgi/content/full/331/21/1416}}</ref>

===Methylxanthines===
[[Adenosine]] antagonists such as the [[methylxanthine]]s [[theophylline]] and [[aminophylline]], may help<ref name="pmid17512638"/> although studies have conflicting results.<ref name="pmid15911721">{{cite journal |author=Bagshaw SM, Ghali WA |title=Theophylline for prevention of contrast-induced nephropathy: a systematic review and meta-analysis |journal=Arch. Intern. Med. |volume=165 |issue=10 |pages=1087-93 |year=2005 |pmid=15911721 |doi=10.1001/archinte.165.10.1087}}</ref> The best studied dose is 200 mg of theophylline given IV 30 minutes before contrast administration.<ref name="pmid12745095">{{cite journal |author=Huber W, Schipek C, Ilgmann K, ''et al'' |title=Effectiveness of theophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency |journal=Am. J. Cardiol. |volume=91 |issue=10 |pages=1157–62 |year=2003 |pmid=12745095 |doi=10.1016/S0002-9149(03)00259-5 }}</ref><ref name="pmid12034949">{{cite journal |author=Huber W, Ilgmann K, Page M, ''et al'' |title=Effect of theophylline on contrast material-nephropathy in patients with chronic renal insufficiency: controlled, randomized, double-blinded study |journal=Radiology |volume=223 |issue=3 |pages=772–9 |year=2002 |pmid=12034949 |doi=}}</ref>

===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.<ref name="pmid12578487">{{cite journal |author=Kay J, Chow W, Chan T, Lo S, Kwok O, Yip A, Fan K, Lee C, Lam W |title=Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial |journal=JAMA |volume=289 |issue=5 |pages=553-8 |year=2003 |pmid=12578487}}</ref>.  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<ref name="pmid16807414">{{cite journal |author=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 |title=N-acetylcysteine and contrast-induced nephropathy in primary angioplasty |journal=N Engl J Med |volume=354 |issue=26 |pages=2773-82 |year=2006 |pmid=16807414}}</ref>.

Since publication of the meta-analyses, two small and underpowered negative studies, one of IV NAC<ref name="pmid17414730">{{cite journal |author=Haase M, Haase-Fielitz A, Bagshaw SM, ''et al'' |title=Phase II, randomized, controlled trial of high-dose N-acetylcysteine in high-risk cardiac surgery patients |journal=Crit. Care Med. |volume=35 |issue=5 |pages=1324–31 |year=2007 |pmid=17414730 |doi=10.1097/01.CCM.0000261887.69976.12}}</ref> and one of 600 mg give four times around coronary angiography<ref name="pmid17509426">{{cite journal |author=Seyon RA, Jensen LA, Ferguson IA, Williams RG |title=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 |journal=Heart & lung : the journal of critical care |volume=36 |issue=3 |pages=195–204 |year=2007 |pmid=17509426 |doi=10.1016/j.hrtlng.2006.08.004}}</ref>, found [[statistical significance|statistically insignificant]] trends towards benefit.

Some authors believe the benefit is not overwhelming.<ref name="pmid15547209">{{cite journal | author=Gleeson TG, Bulugahapitiya S | title=Contrast-induced nephropathy | journal=AJR Am J Roentgenol | year=2004 | pages=1673-89 | volume=183 | issue=6  | id=PMID 15547209}}</ref> The strongest results were from an [[Blind experiment|unblinded]] [[randomized controlled trial]] that used NAC intravenously.<ref name="pmid12821233">{{cite journal |author=Baker CS, Wragg A, Kumar S, De Palma R, Baker LR, Knight CJ |title=A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study |journal=J. Am. Coll. Cardiol. |volume=41 |issue=12 |pages=2114–8 |year=2003 |pmid=12821233 |doi=}}</ref> A [[systematic review]] by [http://clinicalevidence.com Clinical Evidence] concluded that NAC is "[http://clinicalevidence.bmj.com/ceweb/about/guide.jsp likely to beneficial]" but did not recommend a specific dose.<ref name="pmid16973048">{{cite journal |author=Kellum J, Leblanc M, Venkataraman R |title=Renal failure (acute) |journal=Clinical evidence |volume= |issue=15 |pages=1191–212 |year=2006 |pmid=16973048 |doi=|url=http://clinicalevidence.bmj.com/ceweb/conditions/knd/2001/2001.jsp}}</ref> One study found that the apparent benefits of NAC may be due to its interference with the creatinine laboratory test itself.<ref name="pmid14747387">{{cite journal | author=Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK | title=The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable | journal=J Am Soc Nephrol | year=2004 | pages=407-10 | volume=15 | issue=2  | id=PMID 14747387}}</ref> 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.<ref name="pmid12821233"/>

===Prophylactic hemodialysis===
Patients with [[renal failure|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<ref name="pmid10356104">{{cite journal |author=Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW |title=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 |journal=Stroke |volume=30 |issue=6 |pages=1223–9 |year=1999 |pmid=10356104 |doi=}}</ref>

===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.<ref name="pmid7969280"/><ref name="pmid10073832">{{cite journal | author=Abizaid AS, Clark CE, Mintz GS, Dosa S, Popma JJ, Pichard AD, Satler LF, Harvey M, Kent KM, Leon MB | title=Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with preexisting renal insufficiency | journal=Am J Cardiol | year=1999 | pages=260-3, A5 | volume=83 | issue=2  | id=PMID 10073832}}</ref>

==References==
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[[Category:Nephrology]]
[[Category:Radiology]]
[[Category:Cardiology]]

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