contents TIB Kidney dysfunction is a serious compli- cation that can occur following the admin- istration of contrast media (CM). Although the incidence of contrast nephropathy (CN) is low in the general population (1 - 2%) it poses a serious risk to those with impaired kidney function. Other risks include diabetes, old age and dehydration. The first step in prevention is to identify patients at risk. In such patients a small dose of non-ionic iso-osmolar CM togeth- er with adequate hydration (preferably an intravenous infusion of 0.45% or 0.9% normal saline) and oral N-acetylcysteine (NAC) dramatically reduces CN. Although the disease occurs infrequently with nor- mal kidney function, its frequency increas- es with decreasing kidney function, ranging from 5% in patients with mild kidney insufficiency to 50% in those with severe dysfunction and diabetes. Given that CN is associated with increased morbidity, mor- tality and prolonged hospitalisation, and possibly with long-term kidney impair- ment, there is great interest in its preven- tion.1 Epidemiology Although definitions may vary, a com- monly accepted and applied definition is a > 25% increase in serum creatinine level that occurs within 48 hours of contrast exposure.2 Once CN occurs, kidney func- tion remains depressed for 1 - 3 weeks but returns to normal or near normal in most cases.3 The presence of predisposing risk factors (Table I) increases the risk of CN and in the elderly patient multiple risk fac- tors may be present. The most important risk factors seem to be the presence of pre- existing kidney insufficiency, diabetes mel- litus and the volume of contrast used. The use of non-ionic agents4 appears to lower the incidence of CN and this has been con- firmed in animal models.5 Pathophysiology The mechanism by which contrast administration induces kidney injury is uncertain. A combination of the following factors appears to be most feasible: • Reduced renal blood flow and medullary ischaemia related to an inhibition of prostacyclin production and stimulation of the renin-angiotensin system.6 • Direct nephrotoxicity and uric acid pre- cipitation.7 • Red blood cell sludging.8 • The generation of reactive oxygen species.9 Preventive strategies First and foremost is the ever-impor- tant fact that the decision to perform the procedure must be debated continuously. Without contrast there would be no nephrotoxicity and the decision to perform the intervention must take into cognisance the risks for and outcomes of CN. Prevention or mitigation of renal fail- ure after the administration of a radi- ographic contrast agent has been notably difficult. Previous studies have attempted to identify methods to reduce the incidence of CN, particularly in high-risk groups. Pretreatment with diuretics such as furosemide,10,11 or with drugs thought to prevent vasoconstriction, such as calcium channel blockers, adenosine receptor blockers, dopamine, aminophylline,12 endothelin antagonists,13 and atrial natriur- tic peptide, have not provided clear benefit and may even be harmful. Volume expansion with intravenous 0.45% or 0.9% saline (2 - 3 litres prior to the procedure and continued after) has been found to be safe and effective but has not eliminated the condition. The use of low osmolar, non-ionic con- trast agents in patients with mild renal insufficiency has been shown to moderate- ly reduce the risk of CN. In a randomised trial involving more than 1 100 patients, Rudnick et al.14 demonstrated acute nephrotoxicity in 7% of patients receiving the ionic agent diatrizoic acid and in 3% using the non-ionic agent iohexol (p < 0.002). Such data have been confirmed in other studies and the effect is especially noticeable in those with kidney insufficien- cy and those with diabetes. REVIEW ARTICLE 14 SA JOURNAL OF RADIOLOGY • October 2005 Practical issues in the preven- tion and treatment of contrast nephrotoxicity G Bihl MB BCh, MMed, FCP(SA) Winelands Kidney and Dialysis Centre Somerset West Table I. Risk factors for contrast-associated nephropathy CCoonnffiirrmmeedd SSuussppeecctteedd Serum creatinine > 150 µmol/l Hypertension Diabetic nephropathy Abnormal liver function Metformin Older age Class III/IV congestive heart failure Concomitant use of loop diuretics Multiple myeloma . Volume and osmolality of contrast media used Repeat contrast within 48 hours Intracardiac injection Nephrotoxic drugs (NSAIDS, chemotherapy, cyclosporin A) pg14-16 9/28/05 1:22 PM Page 14 N-Acetylcysteine (ACC 200, Salmucol, Parvolex) a thiol-containing antioxidant, has been used to treat a variety of pul- monary diseases and to treat acute parac- etamol poisoning. Recently this agent has been used successfully to amend the toxic effects of experimentally and clinically induced ischaemia-reperfusion injuries in the heart, kidney, lung and liver.15-17 Oxidants activate a signal-transduction cascade and molecular response that may engage the cell-death pathway and provoke apoptosis. Such pathways seem to be sensi- tive to the prevailing redox state of the cell and are inhibited by NAC. Studies have shown that NAC inhibits cell death induced by ischaemia-reperfusion injury in the kid- ney, liver and lung, and promotes pathways that lead to repair and survival whenever cells are under oxidant stress. In a randomised study, Tepel et al. 18 administered NAC at a dose of 1 200 mg/day (in divided doses per os) on the day before and on the day of the procedure in all high-risk patients, especially those with kidney insufficiency. In this study all patients received saline intravenously and low-osmolality, non-ionic agents were administered. The expected decline in renal function in these patients was significantly reduced. These data are supported by data from Kay et al.19 who used a similar dosing schedule and showed a lower serum creati- nine and higher creatinine clearance in those pre-treated with NAC. Haemodialysis does not remove the contrast agent given and may increase the risk of CN. A recent study20 concluded that in patients with moderate to severe kidney insufficiency undergoing coronary inter- ventions, periprocedural haemofiltration given in an ICU setting appeared to prevent deterioration in kidney function related to the administration of a contrast agent.20 This is a plausible modality to use in high- risk patients requiring intervention although it does increase the costs of the overall procedure significantly. It is important to realise that not every increase in serum creatinine following con- trast administration is due to the contrast agent. Atheroembolic disease with a rapid decline in renal function or a more slow and indolent decline needs to be consid- ered in the differential diagnosis. In those patients requiring dialysis following coro- nary angiography, atheroembolic emboli may be a fairly common cause of kidney insufficiency. Clinical recommen- dations The algorithm proposed in Fig. 1 sug- gests a practical approach to CN preven- tion, realising that patients with pre-exist- ing renal impairment alone or three or more of the risk factors detailed in Table I pose a significant risk for CN. Normal kidney function. In patients with normal serum creatinine adequate hydration is all that is necessary. Although serum creatinine levels may be normal, dia- betics, elderly patients and those with reduced muscle mass may have a normal U&E although their creatinine clearance may be reduced thereby imparting a risk for CN.21 A calculated creatinine clearance using the Cockroft-Gault formula [(140-Age) x ideal body weight (kg)] [0.8 x serum creatinine (µmol/l)] would easily identify such patients. Preventive measures as for moderate insuf- ficiency could then be instituted. Moderate/ severe kidney insufficiency (creatinine 150 µmol/l - 250 µmol/l, creati- nine clearance < 50 ml/min). • Intravenous volume administration with saline 0.45% or 0.9% for 12 hours before and 6 hours after the procedure. REVIEW ARTICLE 15 SA JOURNAL OF RADIOLOGY • October 2005 EEnnssuurree aa pprree--pprroocceedduurraall cchheecckklliisstt iiss ccoommpplleetteedd If high risk for CN, reconsider the procedure or consider other non-nephrotoxic investigations DDiissccuussss ddiissccoonnttiinnuuaattiioonn ooff nnoonn--eesssseennttiiaall mmeeddiiccaattiioonnss wwiitthh rreeffeerrrriinngg cclliinniicciiaann:: NSAIDS Diuretics Metformin EEnnssuurree aaddeeqquuaattee hhyyddrraattiioonn ((uunnlleessss ccoonnttrraaiinnddiiccaatteedd)) 0.45% or 0.9% saline at 1ml/kg/hr 6-12 hours before and 12-24 hours after NN--AAcceettyyllccyysstteeiinnee Consider this medication in ALL patients. 600mg bd po the day before and on the day CCoonnttrraasstt aaggeenntt Low osmolar or non-ionic iso-osmolar As low a dose as possible. Avoid re-administration UUrreeaa aanndd eelleeccttrroollyytteess Prior to procedure if high risk Repeat at 48-72 hours if an inpatient Repeat at 3-6 days if an outpatient Encourage oral hydration Fig. 1. Recommended peri-procedural methods to prevent contrast nephropathy. pg14-16 9/28/05 1:22 PM Page 15 • Low-osmolality, non-ionic contrast agents with judicious dose limitation. • Acetylcysteine 600 mg twice daily on the day before and on the day of the proce- dure. Severe kidney insufficiency (creatinine > 250 μmol/l, creatinine < 30 ml/min) Consider that there is a risk of irre- versible kidney failure in such patients despite the abovementioned preventive measures. Such a risk should be discussed with the patient prior to the intervention and the need for the intervention should be debated. In such patients it is imperative to discuss risks with the patient while ensur- ing adequate hydration; preferably perform the procedure pre-dialysis in those patients receiving chronic dialysis (as dialysis dehy- drates patients and may modestly remove contrast), use low-volume iso-osmolar contrast, and monitor renal function close- ly for 3 - 5 days following transplant. Practical implications • Provide generous intravenous hydration, except in the presence of heart failure. • Avoid postprocedural volume depletion. • Avoid mannitol and furosemide in patients with kidney insufficiency. • Minimise contrast volume. • Allow a 5-day interval between 2 proce- dures requiring contrast. • Minimise the development of hypoten- sion and hypoxia. • Eliminate the administration of other nephrotoxic drugs, e.g. non-steroidal anti -inflammatory drugs (NSAIDs). Conclusion Successful prediction and prevention of CN would diminish the morbidity and mortality associated with acute kidney fail- ure related to the administration of con- trast agents. Patient convenience and med- ical care costs would also be optimised by negating the need for prolonged admission, long-term monitoring of kidney function, and the possibility of end-stage kidney fail- ure. References 1. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. J Am Soc Nephrol 2000;11:177-182. 2. Porter G. Contrast medium-associated nephropa- thy. Invest Radiol 1993; 28: suppl. 4, S11-18. 3. Berns AS. Nephrotoxicity of contrast media. Kidney Int 1989; 36: 730-740. 4. Esplugas E, Cequier A. Comparative tolerability of contrast media used for coronary interventions. Drug Sa,f 2002; 25: 1079-1098. 5. Soejima K, Uozumi J, Kanou T. Non-ionic contrast media are less nephrotoxic than ionic contrast media to rat renal cortical slices. Toxicol Lett 2003; 143(1): 17-25. 6. Katzberg RW, Morris TW, Burgener FA. Renal renin and hemodynamic responses to selective renal artery catheterisation and angiography. Invest Radiol 1977; 12: 381-388. 7. Davidson CJ, Hlatky M. Cardiovascular and renal toxicity of a non-ionic radiographic contrast agent after cardiac catherterisation: a prospective trial. Ann Intern Med 1989; 110: 119-124. 8. Gabern GL, Read RC. Red cell factors in renal damage from hypertonic solutions. Proc Soc Exp Biol Med 1961; 107: 165-169. 9. Sandhu C, Newman DJ, Morgan R. The role of oxygen free radicals in contrast induced nephro- toxicity. Acad Radiol 2002; 9: Suppl 2, S436-437. 10. Solomon R, Werner C, Mann D, D’Elia J, Silva P. Effects of saline, mannitol, and furosemide on acute decreases in renal function induced by radio- contrast agents. N Engl J Med 1994; 331: 1416- 1420. 11. Stevens MA, McCullough PA, Tobin KJ. A prospec- tive randomised trial of prevention measures in patients at high risk for contrast nephropathy:results of the PRINCE study. Prevention of Radiocontrast Induced Nephropathy Clincal Evaluation. J Am Coll Cardiol 1999; 33: 403-411. 12. Abizaid AS, Clark CE, Mintz GS. Effects of dopamine and aminophylline on contrast-induced acute renal failure after coronary angioplasty in patients with pre-existing renal insufficiency. Am J Cardiol.1999; 83: 260-263. 13. Wang A, Holcslaw T, Bashore TM, et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000; 57: 1675-1680. 14. Rudnick MR, Goldfarb S, Wexler L. Nephrotoxicity of ionic and non-ionic contrast media in 1196 patients: a randomised trial. Kidney Int 1995; 47: 254-261. 15. Arstall MA, Yang J, Stafford I, Betts WH, Horowitz JD. N-acetylcysteine in combination with nitro- glycerin and streptokinase for treatment of evolv- ing acute myocardial infarction: safety and bio- chemical effects. Circulation 1995; 92: 2855-2862. 16. DiMari J, Megyesi J, Udvarhelyi N, Price P, Davis R, Safirstein RL. N-acetyl cysteine ameliorates ischemic renal failure. Am J Physiol 1997; 272: F292-F298. 17. Weinbroum AA, Rudick V, Ben-Abraham R, Karchevski E. N-acetyl-L-cysteine for preventing lung reperfusion injury after liver ischemia-reper- fusion: a possible dual protective mechanism in a dose-response study. Transplantation 2000; 69: 853-859. 18. Tepel M, van Der Giet M, Laufer U. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343: 180-184. 19. Kay J, Chow WH, Chan TK. Acetylcysteine for pre- vention of acute deterioration of renal function following elective coronary angiography and inter- vention. A randomised control trial. JAMA 2003; 289: 553-559. 20. Marenzi G, Marana I, Lauri G. The prevention of radio-contrast-agent-induced nephropathy by hemofiltration. N Engl J Med 2003; 349: 1333- 1340. 21. Curhan GC. Prevention of contrast nephropathy. JAMA 2003; 289: 606-608. REVIEW ARTICLE 16 SA JOURNAL OF RADIOLOGY • October 2005 SONOGRAPHERS SONOGRAPHERS WWANTED FOR SECURE, FANTED FOR SECURE, FAMILAMILYY-FRIENDL-FRIENDLYY, , RELAXED LIFESTYLE IN PERRELAXED LIFESTYLE IN PERTH, TH, WESTERN WESTERN AAUSTRALIAUSTRALIA Perth’s largest employer of radiographers and sonographers is looking for at least 3 qualified sonographers and is offering : • Excellent hourly rates of pay and working conditions • Family-friendly hours and locations of practices • Attractive leave, travel allowance and training conditions • Payment of relocation costs • Payment of first 2 weeks accommodation costs whilst you are settling in For further details please email Niels Andersen at : info@premiermigration.com.au. pg14-16 10/2/05 9:08 AM Page 16