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Concomitant drugs with exposure to contrast media
http://www.kidney-international.org & 2006 International Society of Nephrology
Concomitant drugs with exposure to contrast media C Erley1 1
St Joseph-Krankenhaus, Medizinische Abt. II, Nephrologie und Dialyse, Berlin, Germany
The increasing number of radiological procedures performed in old patients with high co-morbidity may be one of the problems physicians have to deal with when regarding the increasing number of acute renal failures. A key question when addressing the patients scheduled to receive iodinated contrast media (CM) is which concomitant medications prescribed to the patient are potentially harmful or helpful in terms of the risk of contrast-induced nephropathy. This overview summarizes the knowledge of concomitant medications in the setting of CM application and gives suggestion for prescription. In general, due to the unique (yet not fully understood and of high complexity) mechanism of renal damage proposed for a variety of nephrotoxic drugs including CM, physicians should carefully monitor patients’ renal function and hydration status whenever concomitant nephrototoxic drugs are used. Recommendations are to monitor kidney function with more sensitive measurements of glomerular filtration rate (i.e. cystatin C). Kidney International (2006) 69, S20–S24. doi:10.1038/sj.ki.5000370 KEYWORDS: contrast media nephrotoxicity; concomitant drugs; prevention; NSAIDs
The increasing number of radiological procedures performed in old patients with high co-morbidity may be one of the problems physicians have to deal with when regarding the increasing number of acute renal failures.1–3 A key question when addressing the patients scheduled to receive iodinated contrast media (CM) is which concomitant medications prescribed to the patient are potentially harmful or helpful in terms of the risk of contrast-induced nephropathy (CIN). The main factors contributing to CIN are renal vasoconstriction, medullary hypoxia, and low medullary pH with formation of free radicals and superoxide. Ischemia prior to application of CM increases their toxicity,4 and renal ischemia enhances adenosine generation leading to renal vasoconstriction.5–7 The knowledge of CIN and of concomitant drug use are based on a few studies performed in humans and some clinical observations coming from limited, sometimes inhomogeneous and not comparable patient populations, and on a large number of in vitro and animal experiments. Information on the mechanism leading to CIN is confined to the general consensus that arterial vasoconstriction plays a fundamental role. A variety of vasoactive substances may modulate the CM-induced vasoconstriction, including prostaglandins, atrial natriuretic peptide (ANP), adenosine, endothelin, vasopressin, noradrenaline, and angiotensin.8 Measuring the increase of these substances after CM exposure and the use of their antagonists (i.e. misoprostol, bosentan, ace-inhibitors, alpha-blockers, etc.) may help to investigate the degree of involvement in the process of developing CIN.9–14 In contrast to the experimental studies, in clinical practice, the direct or indirect inhibition of renal vasoconstriction (i.e. with dopamine or endothelin antagonists) has yielded discouraging and unconvincing results. The following drugs are suspected to have a potential negative effect on the risk probability of CIN due to their effect on renal integrity. DRUGS INFLUENCING THE RENAL HEMODYNAMICS AND THE TUBULOGLOMERULAR FEEDBACK
Correspondence: C Erley, St Joseph-Krankenhaus, Medizinische Abt. II, Nephrologie und Dialyse, Ba¨umerplan 24, 12101 Berlin. E-mail: [email protected] S20
Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors cause acute renal failure and chronic renal injury (analgesic nephropathy). Inhibition of the production of vasodilatory prostaglandines by indomethacin increases both the adenosine effect in the kidney,15 as well as the vasoconstriction induced by CM.16–18 Although there are no randomized studies in humans to confirm the Kidney International (2006) 69, S20–S24
C Erley: Concomitant drugs
increased risk of CIN from the concomitant use of NSAIDs or cyclooxygenase-inhibitors (Cox-inhibitors), case reports from the literature19,20 and the clinical expertise of every nephrologists will confirm this association. In a recent study, 8% of patients with CIN still received a comedication with NSAID.21 Epidemiological studies showed a 54% increase in the rate of acute renal failure in elderly patients taking NSAIDs22 and 37% of all drug-induced renal failures could be related to the use of NSAID. The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs,23 and these drugs should be handled the same way. Many patients receive CM for evaluation of pain and must be considered to be at risk from NSAID-induced vasoconstriction especially as these drugs are widely used without prescription. Discontinuation of NSAID’s and Cox-2 inhibitors before CM application is recommended, substituting narcotics or alternative pain treatment, depending on the suspected source of the pain. Even the use of aspirin in this setting has to be evaluated, as a decline in glomerular filtration rate about 50% under 100 mg aspirine has been described.24 Atrial natriuretic peptide is a potent endogenous natriuretic and diuretic substance. Exogenous administration of h-atrial natriuretic peptide increases glomerular filtration rate and renal blood flow in clinical acute renal failure. In randomized human studies, no beneficial effect has been shown when given as a prophylactic agent, and thus should be avoided since it has a high likelihood of having the same effects as diuretics.25,26 Endothelin antagonist has been successfully given in rat models of CIN13,27 although in a carefully performed randomized human study exacerbation of radiocontrast nephrotoxicity has been seen28 and thus should be avoided. Antihypertensive therapy in general should be continued since most prophylactic protocols call for hydration with salt and water, which is likely to raise a hypertensive patient’s blood pressure. Blood pressure medications, in general, can be problematic if the action of the antihypertensive drug is to induce a blood pressure that is 25–30 mm Hg lower than the usual pressure for a given patient. It is not uncommon for the medical staff to resume a prescribed medication in a hospital setting for a patient only to find that the effect of the medication is to lower the pressure excessively because of outpatient noncompliance. For patients on antihypertensive medications the importance of following the patient’s blood pressure before, during, and after contrast exposure should be evident. The increased oxidative stress from hypotension in the setting of contrast administration can contribute to CIN. Any patient presenting with an unacceptably low blood pressure, the blood pressure should be increased before the administration of CM. Renal dysfunction that accompanies antihypertensive therapy is a result of the lowering of blood pressure and is independent of the agent used. Angiotensin-converting enzyme inhibitors and angiotensinreceptor blockers are more commonly associated with this complication, since any decline in intraglomerular pressure Kidney International (2006) 69, S20–S24
due to blood-pressure lowering will be exaggerated by concomitant vasodilatation of the efferent side of the glomerular circulation.29 Small clinical studies with captopril initiated to reduce the angiotensin-mediated medullary ischemia after CM application showed different results.30–31 Dipyridamol is a nucleoside uptake blocker that enhances the renal hemodynamic effects of CM.32,33 It has been proposed that increased renal adenosine levels as a result of enhanced adenosin triphosphate hydrolysis may be a major factor in the development of acute renal failure after CM application, and this is corroborated by the finding that application of CM increases urinary adenosine.33,32 Although not investigated so far the concomitant use of dipyridamol in case of CM application should be avoided. Dopamine was used in the so-called ‘renal dose’ for years in order to prevent CIN and increase renal blood flow. Newer randomized studies34 and meta-analyses35 failed to show any positive effects in most kinds of renal failure including those induced by CM application. Furthermore, interindividual variation in the pharmacokinetics of dopamine typically results in poor correlation between blood levels and administered dose, making accurate and reliable delivery of dopamine difficult. Finally, dopamine is a proximal tubular diuretic that increases Na ( þ ) delivery to tubular cells, thus increasing their oxygen demands. Accordingly, even if dopamine were able to preferentially increase renal blood flow, there is no guarantee that it would restore renal parenchymal oxygen homeostasis. Some investigators even suspect that dopamine might increase patients mortality when administered in order to prevent renal blood flow, which could be related to the positive chronotrop effects of this catecholamine.36 Nevertheless, it is of no discussion that in some clinical situations, dopamine administered in a dose where it might exert positive inotropic effects could increase diuresis and improve renal function especially in patients with severe heart failure. Fenoldopam (Fenoldopam mesylate), a specific agonist of the dopamine-1 receptor, preserves renal blood flow after iodinated contrast administration, and has shown promise in ameliorating contrast nephropathy in observational and small randomized trials. Nevertheless, within larger randomized placebo-controlled studies, it failed to have any effect on CIN.37 As one potential reason for the failure of this agent to reduce the incidence of renal dysfunction was that the higher doses were associated with systemic hypotension. The drug is being restudied using the Flow Medica catheter system that delivers the drug directly into the kidneys. DRUGS THAT MIGHT CAUSE TUBULAR TOXICITY
Diuretics have been shown in randomized trials to have no prophylactic benefit, in fact a negative effect.38–40 Diuretics have been used in oliguric forms of acute renal failure with no effects on mortality.41 Some studies even suggest that nonoliguric patients had a better outcome and the authors favor the use of diuretics.42 In fact, there are no studies showing a positive effect when stopping diuretics in patients, S21
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that is with severe heart failure. Diuretics may need to be administered if either hypertension from volume overload or decompensate congestive heart failure occurs. So no general recommendation could be given, but physicians have to keep in mind the danger of hyperkalemia in case of spironolactone administration, especially if kidney function declines after CM application,43 and the danger of hypovolemia under the use of diuretics. Mannitol has been shown in randomized trials to be harmful if administered with the contrast agent for prevention of CIN.39 The difficult clinical issue is the neurosurgical patient receiving mannitol who needs a contrast study. There are no studies to answer that question, thus the conservative approach would be to hold the mannitol for several hours prior to and following the contrast. Evaluation for adequate hydration is important in this setting and more difficult to evaluate given the mannitol-induced urine flow and the neurosurgical constraints. Aminoglycosides are well known to cause an interstitial, medullary renal injury. The mechanism is not fully understood, but concomitant use of this class of drugs in the setting of contrast administration could be problematic. Nevertheless, close monitoring of the dose and careful adjustment has been shown to minimize the risk of renal failure.44 Several investigations recommend a once-a-dayschedule45 without testing this practice in the presence of other nephrotoxic medications. After about 6–8 h, the contrast will have been eliminated in those with healthy renal filtration. In patients with advanced renal failure, the time delay to safely resume the aminoglycoside may be more than 24 h. Without randomized studies to guide this recommendation, contrast administration during administration of aminoglycosidses should be avoided. Vancomycin the worldwide increase in the incidence of resistant Gram-positive infections has renewed the interest and increased the use in the T-glycopeptide antibiotics. The incidence of nephrotoxicity associated with vancomycin is low (5–15%) when the drug is used alone, but there is clinical and experimental evidence that vancomycin can enhance the nephrotoxic potential of aminoglycosides.46 In case of CM application, physicians should be aware of a concomitant nephrotoxicity and closely monitor drug levels. The use of newer less nephrotoxic drugs (quinupristin/dalfopristin and linezolid) should be discussed. Tacrolimus and cyclosporin A are immunosuppressive medications that reportedly cause renal injury by free-radical mediated injury to the medulla of the kidney. These drugs cannot be discontinued, but consideration as to the dosing of the drugs in relationship to the contrast administration is warranted. Amphotericin B is a commonly used antimycotic agent, and is included in most protocols to treat fever in case of leucopenia. Up to 93% of the patients receiving amphotericin develop renal insufficiency.47 Mechanisms of nephrotoxicity include acute renal vasoconstriction and distal tubular epithel damage. There is no direct investigation about the S22
concomitant use of amphotericin in case of CM application, but given the high number of radiological procedures performed in neutropenic patients receiving antimycotic therapy it seems to be worth to discuss this point. One recent study in patients with malignant hematologic disorders undergoing bone marrow transplantation showed that the use of CM together with amphotericin is one of the main reasons for a loss of effective renal plasma flow in patients after bone marrow transplantation and total body irradiation.48 Dehydration due to the loss of concentrating ability of the kidney under amphotericin and the development of renal tubular acidosis may play a role in this setting. Recommendation is careful hydration of the patients together with intensive monitoring of kidney function (cystatin C) and of the acid–base status. In case of known renal insufficiency, the use to newer less nephrotixic agents (i.e. caspofungin) is recommended. In summary, due to the unique (yet not fully understood and of high complexity) mechanism of renal damage proposed for a variety of nephrotoxic drugs including CM, physicians should carefully monitor patients renal function and hydration status whenever concomitant nephrototoxic drugs are used. Recommendations are to monitor kidney function with more sensitive measurements of glomerular filtration rate (i.e. cystatin C), as a huge number of studies exists showing that creatinine levels are of low value to detect acute renal failure especially in elderly patients.49–53 DRUGS THAT MIGHT ENHANCE THEIR TOXICITY AFTER CONTRAST MEDIA APPLICATION
Metformin reportedly can cause lactic acidosis associated with acute renal failure in patients with type II diabetes. There are no definitive studies to identify cause and effect. One has to notice that a meta-analysis by the Cochrane library with pooled data from 176 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 35 619 patient-years of metformin use or in 30 002 patients-years in the non-metformin group.54 The authors conclude that: there is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other antihyperglycemic treatments if prescribed under the study conditions, taking into account contra-indications. Randomized studies of the concomitant use of CM are lacking. Nevertheless, the Food and Drug Administration has recommended that metformin should be withheld the day of the contrast procedure, and generally recommended for another 2–3 days. Alternative diabetic care may be required. Uncontrolled diabetes could induce volume depletion and thus increase the risk of CIN by a mechanism of renal ischemia. The recommendation includes the need to control the patient’s blood glucose levels and withhold the metformin before and after the contrast. Statins have been recommended in patients with renal impairment. Rhabdomyolysis leading to renal failure has been reported, but it appears to be very rare, except in Kidney International (2006) 69, S20–S24
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patients also receiving cyclosporin, nicotinic acid, or gemfibrozil.55 Although there are some case reports about statins and exacerbated myotoxicity in patients with chronic renal failure.56,57 The effect of statins on CIN is unknown. Preprocedure statin use was associated with significant reduction in CIN in two retrospective studies performed by the same group.58,59 Experimental studies exist for a model of postischemic acute renal failure.60 Larger studies are needed to clarify the benefit of statins in this setting. So far statins should be continued during CM application. REFERENCES 1. McCullough PA, Wolyn R, Rocher LL et al. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med 1997; 103: 368–375. 2. Rihal CS, Textor SC, Grill DE et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002; 105: 2259–2264. 3. Freeman RV, O’Donnell M, Share D et al. Nephropathy requiring dialysis after percutaneous coronary intervention and the critical role of an adjusted contrast dose. Am J Cardiol 2002; 90: 1068–1073. 4. Cederholm C, Almen T, Bergqvist D et al. Acute renal failure in rats. Interaction between contrast media and temporary renal arterial occlusion. Acta Radiol 1989; 30: 321–326. 5. Deray G, Dubois M, Martinez F et al. Renal effects of radiocontrast agents in rats: a new model of acute renal failure. Am J Nephrol 1990; 10: 507–513. 6. Osswald H, Schmidt HJ, Kemper R. Tissue content of adenosine, inosine and hypoxanthine in the rat kidney after ischemia and postischemic recirculation. Pflugers Arch 1977; 371: 45–49. 7. Osswald H, Schmitz HJ, Heidenreich O. Adenosine response of the rat kidney after saline loading, sodium restriction and hemorrhagia. Pflugers Arch 1975; 357: 323–333. 8. Katzberg RW. Urography into the 21st century: new contrast media, renal handling, imaging characteristics, and nephrotoxicity. Radiology 1997; 204: 297–312. 9. Caldicott WJ, Hollenberg NK, Abrams HL. Characteristics of response of renal vascular bed to contrast media. Evidence for vasoconstriction induced by renin–angiotensin system. Invest Radiol 1970; 5: 539–547. 10. Workman RJ, Shaff MI, Jackson RV et al. Relationship of renal hemodynamic and functional changes following intravascular contrast to the renin–angiotensin system and renal prostacyclin in the dog. Invest Radiol 1983; 18: 160–166. 11. Larson TS, Hudson K, Mertz JI et al. Renal vasoconstrictive response to contrast medium. The role of sodium balance and the renin-angiotensin system. J Lab Clin Med 1983; 101: 385–391. 12. Heyman SN, Clark BA, Kaiser N et al. Radiocontrast agents induce endothelin release in vivo and in vitro. J Am Soc Nephrol 1992; 3: 58–65. 13. Oldroyd SD, Haylor JL, Morcos SK. Bosentan, an orally active endothelin antagonist: effect on the renal response to contrast media. Radiology 1995; 196: 661–665. 14. Russo D, Minutolo R, Cianciaruso B et al. Early effects of contrast media on renal hemodynamics and tubular function in chronic renal failure. J Am Soc Nephrol 1995; 6: 1451–1458. 15. Haas JA, Osswald H. Adenosine induced fall in glomerular capillary pressure: effect of ureteral obstruction and aortic constriction in the Munich–Wistar rat kidney. Naunyn Schmiedebergs Arch Pharmacol 1981; 317: 86–89. 16. Cantley LG, Spokes K, Clark B et al. Role of endothelin and prostaglandins in radiocontrast-induced renal artery constriction. Kidney Int 1993; 44: 1217–1223. 17. Heyman SN, Brezis M, Reubinoff CA et al. Acute renal failure with selective medullary injury in the rat. J Clin Invest 1988; 82: 401–412. 18. Heyman SN, Brezis M, Epstein FH et al. Early renal medullary hypoxic injury from radiocontrast and indomethacin. Kidney Int 1991; 40: 632–642. 19. Dzgoeva FU, Milovanov I, Kutyrina IM. Acute kidney failure related to the use of X-ray contrast agents and indomethacin: the risk factors and mechanisms of its development]. Ter Arkh 1995; 67: 36–39. 20. Carvallo A, Rakowski TA, Argy Jr WP, Schreiner GE. Acute renal failure following drip infusion pyelography. Am J Med 1978; 65: 38–45.
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Weisbord SD, Bruns FJ, Saul MI, Palevsky PM. Provider use of preventive strategies for radiocontrast nephropathy in high-risk patients. Nephron Clin Pract 2004; 96: c56–c62. Griffin MR, Yared A, Ray WA. Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons. Am J Epidemiol 2000; 151: 488–496. Swan SK, Rudy DW, Lasseter KC et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet: a randomized, controlled trial. Ann Intern Med 2000; 133: 1–9. Segal R, Lubart E, Leibovitz A et al. Early and late effects of low-dose aspirin on renal function in elderly patients. Am J Med 2003; 115: 462–466. Kurnik BR, Weisberg LS, Cuttler IM, Kurnik PB. Effects of atrial natriuretic peptide versus mannitol on renal blood flow during radiocontrast infusion in chronic renal failure. J Lab Clin Med 1990; 116: 27–36. Kurnik BR, Allgren RL, Genter FC et al. Prospective study of atrial natriuretic peptide for the prevention of radiocontrast-induced nephropathy. Am J Kidney Dis 1998; 31: 674–680. Oldroyd S, Slee SJ, Haylor J et al. Role for endothelin in the renal responses to radiocontrast media in the rat. Clin Sci Colch 1994; 87: 427–434. Wang A, Holcslaw T, Bashore TM et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000; 57: 1675–1680. Palmer BF. Renal dysfunction complicating the treatment of hypertension. N Engl J Med 2002; 347: 1256–1261. Toprak O, Cirit M, Bayata S et al. The effect of pre-procedural captopril on contrast-induced nephropathy in patients who underwent coronary angiography]. Anadolu Kardiyol Derg 2003; 3: 98–103. Gupta RK, Kapoor A, Tewari S et al. Captopril for prevention of contrast-induced nephropathy in diabetic patients: a randomised study. Indian Heart J 1999; 51: 521–526. Katholi RE, Taylor GJ, McCann WP et al. Nephrotoxicity from contrast media: attenuation with theophylline. Radiology 1995; 195: 17–22. Arend LJ, Bakris GL, Burnett JCJ et al. Role for intrarenal adenosine in the renal hemodynamic response to contrast media. J Lab Clin Med 1987; 110: 406–411. Bellomo R, Chapman M, Finfer S et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Lancet 2000; 356: 2139–2143. Friedrich JO, Adhikari N, Herridge MS, Beyene J. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med 2005; 142: 510–524. Chertow GM, Sayegh MH, Allgren RL, Lazarus JM. Is the administration of dopamine associated with adverse or favorable outcomes in acute renal failure? Auriculin Anaritide Acute Renal Failure Study Group. Am J Med 1996; 101: 49–53. Stone GW, McCullough PA, Tumlin JA et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial. JAMA 2003; 290: 2284–2291. Weinstein JM, Heyman S, Brezis M. Potential deleterious effect of furosemide in radiocontrast nephropathy. Nephron 1992; 62: 413–415. Solomon R, Werner C, Mann D et al. Effects of saline, mannitol, and furosemide on acute decreases in renal function induced by radiocontrast agents. N Engl J Med 1994; 331: 1416–1420. Stevens MA, McCullough PA, Tobin KJ et al. A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy: results of the P.R.I.N.C.E. Study. Prevention of Radiocontrast Induced Nephropathy Clinical Evaluation. J Am Coll Cardiol 1999; 33: 403–411. Cantarovich F, Rangoonwala B, Lorenz H et al. High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Am J Kidney Dis 2004; 44: 402–409. Shilliday I, Quinn K, Allison M. Loop diuretics in the management of acute renal failure: a prospective, double-blind, placebo-controlled, randomized study. Nephrol Dialysis Transplant 1997; 12: 2592–2596. Juurlink DN, Mamdani MM, Lee DS et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351: 543–551. Moore RD, Smith CR, Lipsky JJ et al. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984; 100: 352–357. Ali MZ, Goetz MB. A meta-analysis of the relative efficacy and toxicity of single daily dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997; 24: 796–809.
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Goetz MB, Sayers J. Nephrotoxicity of vancomycin and aminoglycoside therapy separately and in combination. J Antimicrob Chemother 1993; 32: 325–334. Butler WT, Bennett JE, Alling DW et al. Nephrotoxicity of amphotericin B; early and late effects in 81 patients. Ann Intern Med 1964; 61: 175–187. Miralbell R, Sancho G, Bieri S et al. Renal insufficiency in patients with hematologic malignancies undergoing total body irradiation and bone marrow transplantation: a prospective assessment. Int J Radiat Oncol Biol Phys 2004; 58: 809–816. McDougal WS. Early detection of acute renal failure by serum cystatin C. J Urol 2005; 174: 1024–1025. Larsson A, Helmersson J, Hansson LO, Basu S. Increased serum cystatin C is associated with increased mortality in elderly men. Scand J Clin Lab Invest 2005; 65: 301–305. Herget-Rosenthal S, Pietruck F, Volbracht L et al. Serum cystatin C – a superior marker of rapidly reduced glomerular filtration after uninephrectomy in kidney donors compared to creatinine. Clin Nephrol 2005; 64: 41–46. Grubb A, Bjork J, Lindstrom V et al. A cystatin C-based formula without anthropometric variables estimates glomerular filtration rate better than creatinine clearance using the Cockcroft–Gault formula. Scand J Clin Lab Invest 2005; 65: 153–162.
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Larsson A, Cystatin C. an emerging glomerular filtration rate marker. Scand J Clin Lab Invest 2005; 65: 89–91. Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. The Cochrane Database of Systematic Reviews Art. No.: CD002967. Doi: 10.1002/14651858.CD002967.[3]. 2003. Paiva H, Thelen KM, Van Coster R et al. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther 2005; 78: 60–68. Al Shohaib S. Simvastatin-induced rhabdomyolysis in a patient with chronic renal failure. Am J Nephrol 2000; 20: 212–213. Moro H, Tsukada H, Tanuma A et al. Rhabdomyolysis after simvastatin therapy in an HIV-infected patient with chronic renal failure. AIDS Patient Care STDS 2004; 18: 687–690. Khanal S, Attallah N, Smith DE et al. Statin therapy reduces contrastinduced nephropathy: an analysis of contemporary percutaneous interventions. Am J Med 2005; 118: 843–849. Attallah N, Yassine L, Musial J et al. The potential role of statins in contrast nephropathy. Clin Nephrol 2004; 62: 273–278. Gueler F, Rong S, Park JK et al. Postischemic acute renal failure is reduced by short-term statin treatment in a rat model. J Am Soc Nephrol 2002; 13: 2288–2298.
Kidney International (2006) 69, S20–S24
Concomitant drugs with exposure to contrast media C Erley1 1
St Joseph-Krankenhaus, Medizinische Abt. II, Nephrologie und Dialyse, Berlin, Germany
The increasing number of radiological procedures performed in old patients with high co-morbidity may be one of the problems physicians have to deal with when regarding the increasing number of acute renal failures. A key question when addressing the patients scheduled to receive iodinated contrast media (CM) is which concomitant medications prescribed to the patient are potentially harmful or helpful in terms of the risk of contrast-induced nephropathy. This overview summarizes the knowledge of concomitant medications in the setting of CM application and gives suggestion for prescription. In general, due to the unique (yet not fully understood and of high complexity) mechanism of renal damage proposed for a variety of nephrotoxic drugs including CM, physicians should carefully monitor patients’ renal function and hydration status whenever concomitant nephrototoxic drugs are used. Recommendations are to monitor kidney function with more sensitive measurements of glomerular filtration rate (i.e. cystatin C). Kidney International (2006) 69, S20–S24. doi:10.1038/sj.ki.5000370 KEYWORDS: contrast media nephrotoxicity; concomitant drugs; prevention; NSAIDs
The increasing number of radiological procedures performed in old patients with high co-morbidity may be one of the problems physicians have to deal with when regarding the increasing number of acute renal failures.1–3 A key question when addressing the patients scheduled to receive iodinated contrast media (CM) is which concomitant medications prescribed to the patient are potentially harmful or helpful in terms of the risk of contrast-induced nephropathy (CIN). The main factors contributing to CIN are renal vasoconstriction, medullary hypoxia, and low medullary pH with formation of free radicals and superoxide. Ischemia prior to application of CM increases their toxicity,4 and renal ischemia enhances adenosine generation leading to renal vasoconstriction.5–7 The knowledge of CIN and of concomitant drug use are based on a few studies performed in humans and some clinical observations coming from limited, sometimes inhomogeneous and not comparable patient populations, and on a large number of in vitro and animal experiments. Information on the mechanism leading to CIN is confined to the general consensus that arterial vasoconstriction plays a fundamental role. A variety of vasoactive substances may modulate the CM-induced vasoconstriction, including prostaglandins, atrial natriuretic peptide (ANP), adenosine, endothelin, vasopressin, noradrenaline, and angiotensin.8 Measuring the increase of these substances after CM exposure and the use of their antagonists (i.e. misoprostol, bosentan, ace-inhibitors, alpha-blockers, etc.) may help to investigate the degree of involvement in the process of developing CIN.9–14 In contrast to the experimental studies, in clinical practice, the direct or indirect inhibition of renal vasoconstriction (i.e. with dopamine or endothelin antagonists) has yielded discouraging and unconvincing results. The following drugs are suspected to have a potential negative effect on the risk probability of CIN due to their effect on renal integrity. DRUGS INFLUENCING THE RENAL HEMODYNAMICS AND THE TUBULOGLOMERULAR FEEDBACK
Correspondence: C Erley, St Joseph-Krankenhaus, Medizinische Abt. II, Nephrologie und Dialyse, Ba¨umerplan 24, 12101 Berlin. E-mail: [email protected] S20
Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors cause acute renal failure and chronic renal injury (analgesic nephropathy). Inhibition of the production of vasodilatory prostaglandines by indomethacin increases both the adenosine effect in the kidney,15 as well as the vasoconstriction induced by CM.16–18 Although there are no randomized studies in humans to confirm the Kidney International (2006) 69, S20–S24
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increased risk of CIN from the concomitant use of NSAIDs or cyclooxygenase-inhibitors (Cox-inhibitors), case reports from the literature19,20 and the clinical expertise of every nephrologists will confirm this association. In a recent study, 8% of patients with CIN still received a comedication with NSAID.21 Epidemiological studies showed a 54% increase in the rate of acute renal failure in elderly patients taking NSAIDs22 and 37% of all drug-induced renal failures could be related to the use of NSAID. The effects of COX-2 inhibition on renal function are similar to those observed with nonselective NSAIDs,23 and these drugs should be handled the same way. Many patients receive CM for evaluation of pain and must be considered to be at risk from NSAID-induced vasoconstriction especially as these drugs are widely used without prescription. Discontinuation of NSAID’s and Cox-2 inhibitors before CM application is recommended, substituting narcotics or alternative pain treatment, depending on the suspected source of the pain. Even the use of aspirin in this setting has to be evaluated, as a decline in glomerular filtration rate about 50% under 100 mg aspirine has been described.24 Atrial natriuretic peptide is a potent endogenous natriuretic and diuretic substance. Exogenous administration of h-atrial natriuretic peptide increases glomerular filtration rate and renal blood flow in clinical acute renal failure. In randomized human studies, no beneficial effect has been shown when given as a prophylactic agent, and thus should be avoided since it has a high likelihood of having the same effects as diuretics.25,26 Endothelin antagonist has been successfully given in rat models of CIN13,27 although in a carefully performed randomized human study exacerbation of radiocontrast nephrotoxicity has been seen28 and thus should be avoided. Antihypertensive therapy in general should be continued since most prophylactic protocols call for hydration with salt and water, which is likely to raise a hypertensive patient’s blood pressure. Blood pressure medications, in general, can be problematic if the action of the antihypertensive drug is to induce a blood pressure that is 25–30 mm Hg lower than the usual pressure for a given patient. It is not uncommon for the medical staff to resume a prescribed medication in a hospital setting for a patient only to find that the effect of the medication is to lower the pressure excessively because of outpatient noncompliance. For patients on antihypertensive medications the importance of following the patient’s blood pressure before, during, and after contrast exposure should be evident. The increased oxidative stress from hypotension in the setting of contrast administration can contribute to CIN. Any patient presenting with an unacceptably low blood pressure, the blood pressure should be increased before the administration of CM. Renal dysfunction that accompanies antihypertensive therapy is a result of the lowering of blood pressure and is independent of the agent used. Angiotensin-converting enzyme inhibitors and angiotensinreceptor blockers are more commonly associated with this complication, since any decline in intraglomerular pressure Kidney International (2006) 69, S20–S24
due to blood-pressure lowering will be exaggerated by concomitant vasodilatation of the efferent side of the glomerular circulation.29 Small clinical studies with captopril initiated to reduce the angiotensin-mediated medullary ischemia after CM application showed different results.30–31 Dipyridamol is a nucleoside uptake blocker that enhances the renal hemodynamic effects of CM.32,33 It has been proposed that increased renal adenosine levels as a result of enhanced adenosin triphosphate hydrolysis may be a major factor in the development of acute renal failure after CM application, and this is corroborated by the finding that application of CM increases urinary adenosine.33,32 Although not investigated so far the concomitant use of dipyridamol in case of CM application should be avoided. Dopamine was used in the so-called ‘renal dose’ for years in order to prevent CIN and increase renal blood flow. Newer randomized studies34 and meta-analyses35 failed to show any positive effects in most kinds of renal failure including those induced by CM application. Furthermore, interindividual variation in the pharmacokinetics of dopamine typically results in poor correlation between blood levels and administered dose, making accurate and reliable delivery of dopamine difficult. Finally, dopamine is a proximal tubular diuretic that increases Na ( þ ) delivery to tubular cells, thus increasing their oxygen demands. Accordingly, even if dopamine were able to preferentially increase renal blood flow, there is no guarantee that it would restore renal parenchymal oxygen homeostasis. Some investigators even suspect that dopamine might increase patients mortality when administered in order to prevent renal blood flow, which could be related to the positive chronotrop effects of this catecholamine.36 Nevertheless, it is of no discussion that in some clinical situations, dopamine administered in a dose where it might exert positive inotropic effects could increase diuresis and improve renal function especially in patients with severe heart failure. Fenoldopam (Fenoldopam mesylate), a specific agonist of the dopamine-1 receptor, preserves renal blood flow after iodinated contrast administration, and has shown promise in ameliorating contrast nephropathy in observational and small randomized trials. Nevertheless, within larger randomized placebo-controlled studies, it failed to have any effect on CIN.37 As one potential reason for the failure of this agent to reduce the incidence of renal dysfunction was that the higher doses were associated with systemic hypotension. The drug is being restudied using the Flow Medica catheter system that delivers the drug directly into the kidneys. DRUGS THAT MIGHT CAUSE TUBULAR TOXICITY
Diuretics have been shown in randomized trials to have no prophylactic benefit, in fact a negative effect.38–40 Diuretics have been used in oliguric forms of acute renal failure with no effects on mortality.41 Some studies even suggest that nonoliguric patients had a better outcome and the authors favor the use of diuretics.42 In fact, there are no studies showing a positive effect when stopping diuretics in patients, S21
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that is with severe heart failure. Diuretics may need to be administered if either hypertension from volume overload or decompensate congestive heart failure occurs. So no general recommendation could be given, but physicians have to keep in mind the danger of hyperkalemia in case of spironolactone administration, especially if kidney function declines after CM application,43 and the danger of hypovolemia under the use of diuretics. Mannitol has been shown in randomized trials to be harmful if administered with the contrast agent for prevention of CIN.39 The difficult clinical issue is the neurosurgical patient receiving mannitol who needs a contrast study. There are no studies to answer that question, thus the conservative approach would be to hold the mannitol for several hours prior to and following the contrast. Evaluation for adequate hydration is important in this setting and more difficult to evaluate given the mannitol-induced urine flow and the neurosurgical constraints. Aminoglycosides are well known to cause an interstitial, medullary renal injury. The mechanism is not fully understood, but concomitant use of this class of drugs in the setting of contrast administration could be problematic. Nevertheless, close monitoring of the dose and careful adjustment has been shown to minimize the risk of renal failure.44 Several investigations recommend a once-a-dayschedule45 without testing this practice in the presence of other nephrotoxic medications. After about 6–8 h, the contrast will have been eliminated in those with healthy renal filtration. In patients with advanced renal failure, the time delay to safely resume the aminoglycoside may be more than 24 h. Without randomized studies to guide this recommendation, contrast administration during administration of aminoglycosidses should be avoided. Vancomycin the worldwide increase in the incidence of resistant Gram-positive infections has renewed the interest and increased the use in the T-glycopeptide antibiotics. The incidence of nephrotoxicity associated with vancomycin is low (5–15%) when the drug is used alone, but there is clinical and experimental evidence that vancomycin can enhance the nephrotoxic potential of aminoglycosides.46 In case of CM application, physicians should be aware of a concomitant nephrotoxicity and closely monitor drug levels. The use of newer less nephrotoxic drugs (quinupristin/dalfopristin and linezolid) should be discussed. Tacrolimus and cyclosporin A are immunosuppressive medications that reportedly cause renal injury by free-radical mediated injury to the medulla of the kidney. These drugs cannot be discontinued, but consideration as to the dosing of the drugs in relationship to the contrast administration is warranted. Amphotericin B is a commonly used antimycotic agent, and is included in most protocols to treat fever in case of leucopenia. Up to 93% of the patients receiving amphotericin develop renal insufficiency.47 Mechanisms of nephrotoxicity include acute renal vasoconstriction and distal tubular epithel damage. There is no direct investigation about the S22
concomitant use of amphotericin in case of CM application, but given the high number of radiological procedures performed in neutropenic patients receiving antimycotic therapy it seems to be worth to discuss this point. One recent study in patients with malignant hematologic disorders undergoing bone marrow transplantation showed that the use of CM together with amphotericin is one of the main reasons for a loss of effective renal plasma flow in patients after bone marrow transplantation and total body irradiation.48 Dehydration due to the loss of concentrating ability of the kidney under amphotericin and the development of renal tubular acidosis may play a role in this setting. Recommendation is careful hydration of the patients together with intensive monitoring of kidney function (cystatin C) and of the acid–base status. In case of known renal insufficiency, the use to newer less nephrotixic agents (i.e. caspofungin) is recommended. In summary, due to the unique (yet not fully understood and of high complexity) mechanism of renal damage proposed for a variety of nephrotoxic drugs including CM, physicians should carefully monitor patients renal function and hydration status whenever concomitant nephrototoxic drugs are used. Recommendations are to monitor kidney function with more sensitive measurements of glomerular filtration rate (i.e. cystatin C), as a huge number of studies exists showing that creatinine levels are of low value to detect acute renal failure especially in elderly patients.49–53 DRUGS THAT MIGHT ENHANCE THEIR TOXICITY AFTER CONTRAST MEDIA APPLICATION
Metformin reportedly can cause lactic acidosis associated with acute renal failure in patients with type II diabetes. There are no definitive studies to identify cause and effect. One has to notice that a meta-analysis by the Cochrane library with pooled data from 176 comparative trials and cohort studies revealed no cases of fatal or nonfatal lactic acidosis in 35 619 patient-years of metformin use or in 30 002 patients-years in the non-metformin group.54 The authors conclude that: there is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other antihyperglycemic treatments if prescribed under the study conditions, taking into account contra-indications. Randomized studies of the concomitant use of CM are lacking. Nevertheless, the Food and Drug Administration has recommended that metformin should be withheld the day of the contrast procedure, and generally recommended for another 2–3 days. Alternative diabetic care may be required. Uncontrolled diabetes could induce volume depletion and thus increase the risk of CIN by a mechanism of renal ischemia. The recommendation includes the need to control the patient’s blood glucose levels and withhold the metformin before and after the contrast. Statins have been recommended in patients with renal impairment. Rhabdomyolysis leading to renal failure has been reported, but it appears to be very rare, except in Kidney International (2006) 69, S20–S24
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patients also receiving cyclosporin, nicotinic acid, or gemfibrozil.55 Although there are some case reports about statins and exacerbated myotoxicity in patients with chronic renal failure.56,57 The effect of statins on CIN is unknown. Preprocedure statin use was associated with significant reduction in CIN in two retrospective studies performed by the same group.58,59 Experimental studies exist for a model of postischemic acute renal failure.60 Larger studies are needed to clarify the benefit of statins in this setting. So far statins should be continued during CM application. REFERENCES 1. McCullough PA, Wolyn R, Rocher LL et al. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med 1997; 103: 368–375. 2. Rihal CS, Textor SC, Grill DE et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation 2002; 105: 2259–2264. 3. Freeman RV, O’Donnell M, Share D et al. Nephropathy requiring dialysis after percutaneous coronary intervention and the critical role of an adjusted contrast dose. Am J Cardiol 2002; 90: 1068–1073. 4. Cederholm C, Almen T, Bergqvist D et al. Acute renal failure in rats. Interaction between contrast media and temporary renal arterial occlusion. Acta Radiol 1989; 30: 321–326. 5. Deray G, Dubois M, Martinez F et al. Renal effects of radiocontrast agents in rats: a new model of acute renal failure. Am J Nephrol 1990; 10: 507–513. 6. Osswald H, Schmidt HJ, Kemper R. Tissue content of adenosine, inosine and hypoxanthine in the rat kidney after ischemia and postischemic recirculation. Pflugers Arch 1977; 371: 45–49. 7. Osswald H, Schmitz HJ, Heidenreich O. Adenosine response of the rat kidney after saline loading, sodium restriction and hemorrhagia. Pflugers Arch 1975; 357: 323–333. 8. Katzberg RW. Urography into the 21st century: new contrast media, renal handling, imaging characteristics, and nephrotoxicity. Radiology 1997; 204: 297–312. 9. Caldicott WJ, Hollenberg NK, Abrams HL. Characteristics of response of renal vascular bed to contrast media. Evidence for vasoconstriction induced by renin–angiotensin system. Invest Radiol 1970; 5: 539–547. 10. Workman RJ, Shaff MI, Jackson RV et al. Relationship of renal hemodynamic and functional changes following intravascular contrast to the renin–angiotensin system and renal prostacyclin in the dog. Invest Radiol 1983; 18: 160–166. 11. Larson TS, Hudson K, Mertz JI et al. Renal vasoconstrictive response to contrast medium. The role of sodium balance and the renin-angiotensin system. J Lab Clin Med 1983; 101: 385–391. 12. Heyman SN, Clark BA, Kaiser N et al. Radiocontrast agents induce endothelin release in vivo and in vitro. J Am Soc Nephrol 1992; 3: 58–65. 13. Oldroyd SD, Haylor JL, Morcos SK. Bosentan, an orally active endothelin antagonist: effect on the renal response to contrast media. Radiology 1995; 196: 661–665. 14. Russo D, Minutolo R, Cianciaruso B et al. Early effects of contrast media on renal hemodynamics and tubular function in chronic renal failure. J Am Soc Nephrol 1995; 6: 1451–1458. 15. Haas JA, Osswald H. Adenosine induced fall in glomerular capillary pressure: effect of ureteral obstruction and aortic constriction in the Munich–Wistar rat kidney. Naunyn Schmiedebergs Arch Pharmacol 1981; 317: 86–89. 16. Cantley LG, Spokes K, Clark B et al. Role of endothelin and prostaglandins in radiocontrast-induced renal artery constriction. Kidney Int 1993; 44: 1217–1223. 17. Heyman SN, Brezis M, Reubinoff CA et al. Acute renal failure with selective medullary injury in the rat. J Clin Invest 1988; 82: 401–412. 18. Heyman SN, Brezis M, Epstein FH et al. Early renal medullary hypoxic injury from radiocontrast and indomethacin. Kidney Int 1991; 40: 632–642. 19. Dzgoeva FU, Milovanov I, Kutyrina IM. Acute kidney failure related to the use of X-ray contrast agents and indomethacin: the risk factors and mechanisms of its development]. Ter Arkh 1995; 67: 36–39. 20. Carvallo A, Rakowski TA, Argy Jr WP, Schreiner GE. Acute renal failure following drip infusion pyelography. Am J Med 1978; 65: 38–45.
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