Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Radiocontrast-induced nephropathy Mandeep R. Mehra MD, Kaveh Sharif MD & Frederick R. Bode MD To cite this article: Mandeep R. Mehra MD, Kaveh Sharif MD & Frederick R. Bode MD (1992) Radiocontrast-induced nephropathy, Postgraduate Medicine, 92:8, 215-223, DOI: 10.1080/00325481.1992.11701561 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701561
Published online: 17 May 2016.
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Date: 02 July 2016, At: 19:05
-(£tME cred~ article
Radiocontrast-induced nephropathy Prevention is better than cure
Mandeep R. Mehra, MD Kaveh Sharif, MD Frederick R. Bode, MD
Downloaded by [Monash University Library] at 19:05 02 July 2016
Preview Administration of radiographic contrast material is a common yet preventable cause of acute renal failure. Who is at risk for this complication? What preventive measures can be taken? Drs Mehra, Sharif, and Bode address these questions and compare the conventional Ionic agents with the newer nonionic agents.
Radiocontrast-induced nephropathy is defined as a rise in the serum creatinine level of at least 1 mgldL over the baseline value 24 to 48 hours after challenge with a contrast medium. It commonly occurs after major angiographic procedures such as cardiac catheterization; however, significant exposure may follow seemingly benign diagnostic tests such as contrast-enhanced computed tomography. In an era of burgeoning invasive strategies, radiocontrastinduced nephropathy continues to be a major cause of procedurerelated morbidity. According to Hou and colleagues, 1 it accounts for up to 12% of episodes of hospital-acquired renal failure. The incidence has been reported to range from 2% in low-risk patients to as high as 10% in highrisk patients. 2'3 Adverse effects are directly related to the patient's underlying disease and are generally seen in patients who are seriously ill.
There is no definitive treatment for radiocontrast-induced nephropathy. Although most cases resolve spontaneously, some require short-term or even longterm dialytic support. Clearly, prevention is better than cure; however, pharmacologic strategies aimed at prevention have been disappointing. The biggest challenge in dealing with radiocontrast-induced nephropathy is to eliminate the use of contrast media by developing sufficiently accurate alternative imaging methods. The immediate challenge is to increase physicians' awareness of the possibility of radiocontrastinduced nephropathy so that appropriate risk stratification, optimal test selection, and adequate patient preparation with minimum use of contrast material are achieved. Other goals are to increase understanding of the mechanisms of radiocontrastinduced nephropathy (see box on page 216) and to identify appro-
VOL 92/NO 8/DECEMBER 1992/POSTGRADUATE MEDICINE • RADIOCONTRAST-INDUc.D NIIPHROMTHY
priate preventive pharmacologic measures. The role of diabetes mellitus in radiocontrast-induced nephropathy and the protective effects of mannitol and saline hydration are controversial. Perhaps the biggest controversy, however, is whether the new, nonionic contrast media are less toxic to the kidneys than the older, ionic media.
Risk factors Underlying renal insufficiency is the principal predisposing factor for radiocontrast-induced nephropathy. Risk of renal injury correlates directly with the patient's serum creatinine level. Risk is 4% with a serum creatinine level of less than 1.1 mgldL but 20% with a serum creatinine level greater than 2.0 mgldL. 4 Sixty percent of cases are nonoliguric; clinically significant oliguria or anuria develops in 40% of patients with radiocontrastinduced nephropathy. 5 Other important risk factors include low-output class N congestive heart failure, multiple contrast challenges within a 72hour period, administration of high doses of contrast media, and dehydration. Age greater than 60 years, hyperuricemia, hypertension, proteinuria, and periphcontinued
215
Underlying renal insufficiency is the principal predisposing factor for radiocontrast-induced nephropathy.
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Potential mechanisms of radiocontrast-induced nephropathy The mechanisms of radiocontrast-induced nephropathy are not completely understood. In experimental situations, intrarenal or intravenous injection of radiocontrast media causes a brief initial increase in renal blood flow, followed by a profound reduction in glomerular filtration rate and renal blood flow. These hemodynamic consequences are more pronounced in the sodium-depleted state. Direct tubular injury may also play a significant role in radiocontrast-induced nephropathy. However, in this complex interplay of mediating factors, the common denominator appears to be injury to the medullary thick ascending loop of Henle, a site that is actively involved in oxygen-dependent electrolyte transport but is the nephron site with the least amount of oxygen delivered to it. Thus, efforts targeted at reducing oxygen demand for active electrolyte transport and improving medullary renal blood flow may reduce the risk of radiocontrastinduced nephropathy. These objectives are currently fulfilled by adequate hydration with saline solution before the procedure and administration ofloop diuretics and mannitol.l.l Other potential mechanisms include altered glomerular perm-selectivity, intraluminal obstruction, and immunologic mechanisms such as hypersensitivity to contrast media. A role for intravascular calcium flux, adenosine, and oxy-
216
gen free radicals has been suggested by results of animal studies.3'4 Data from such studies suggest that endogenous adenosine and calcium action are essential for the adverse effects of contrast material on renal blood flow. Infusion of radiocontrast media results in an increase in intrarenal generation of adenosine and activation of calcium-dependent vasoconstriction. 3 Intrarenal administration of contrast media causes an increase in urinary Tamm-Horsfall protein mediated in part by oxygen free radical damage to the kidney. 4 Tamm-Horsfall protein may thus be a marker for contrast-induced renal injury. As understanding of the crucial role of molecular elements increases, more definitive clinical strategies may emerge. These may include the use of calcium antagonists, adenosine antagonists, and oxygen free radical scavenging agents. Rd'amces I. Bn:zis M, Epstein FH. A closer look at radiocontrast-induced nephropathy. (Editorial) N EnglJ Med 1989;320(3):179-81 2. Byrd L, Sherman RL. Radiocontrast-induced acute renal failure: a clinical and pathophysiologic review. Medicine (Baltimore) 1979; 58(3):270-9 3. Deray G, Martinez F, Cacoub P, et al. A role for adenosine, calcium and ischemia in radiocontrast-induced intrarenal vasoconstriction. AmJ Nephrol1990;10(4):316-22 4. Bakris GL, Gaber AO, Jones JD. Oxygen free radical involvement in urinary Tamm-Horsfall protein excretion after intrarenal injection of contrast medium. Radiology 1990;175(1):57-60
IIADIOCOIITRAST-INDUCD Nm'HROPATHY • VOL 92/NO 8/DECEMBER 1992/POSTGRAOUATE MEDICINE
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Use of nonsteroidal anti-inflammatory drugs may increase the risk of radiocontrast-induced nephropathy.
eral vascular disease are probably not clinically important risk factors but are merely characteristic of the patient population undergoing contrast-dependent procedures and may be markers of underlying renal disease. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of radiocontrast-induced nephropathy (table 1). Multiple myeloma has been identified as an important risk factor for radiocontrast-induced nephropathy; however, studies have reported an aggregate incidence of less than 5o/o. 6•7 Case reports abound, and we urge caution in the use of contrast media in patients with plasma cell dyscrasias. Results of studies are contradictory regarding the role of diabetes mellitus in radiocontrastinduced nephropathy in the absence of renal insufficiency. In a recent study by Parfrey and colleagues/ nonazotemic diabetic patients were determined to be at low risk for clinically important radiocontrast-induced nephropathy. The presence of proteinuria does not appear to increase the risk of renal toxicity. 8 However, in a study of 394 patients undergoing femoral arteriography, Laurin and associates9 found that diabetes, especially when insulin-
Table 1. Risk factors for radiocontrast-induced nephropathy
Principal Underlying renal insufficiency (serum creatinine > 1.5 mg/dl) Low-output class IV congestive heart failure Multiple contrast challenges within 72 hr Dose of dye used Potential Diabetes mellitus (especially with renal dysfunction) Plasma cell dyscrasias (eg, multiple myeloma) Dehydration Use of nephrotoxic drugs (eg, NSAIDs)
Other* Advanced age (>60 yr) Hypertension Hyperuricemia Proteinuria Peripheral vascular disease NSAIDs. nonsteroidal anti-inflammatory drugs. "These factors probably reflect presence of underlying renal insufficiency.
dependent, was a significant independent risk factor in radiocontrast-induced nephropathy, even in nonazotemic patients. Taliercio and colleagues5 had previously identified insulindependent diabetes as a significant independent risk factor for radiocontrast-induced nephropathy. Awareness of the possibility of renal injury following contrast exposure in nonazotemic diabetic patients is important, especially in insulin-dependent patients. Extreme caution is needed in
choosing a contrast-dependent test in this population. Prevention Imaging methods that do not require the use of contrast medium should be considered for patients at high risk for renal injury. If contrast challenge is necessary, the lowest possible dose of contrast medium should be used. The patient's clinical condition, including comorbid factors, must be stabilized as much as possible before the procedure. Drugs that are potentially nephrotoxic, such
continued
VOL 92/NO 8/DECEMBER 1992/POSTGRAOUATE MEDICINE • RADIOCONTRAST·INDUCaD N.PHROMT11Y
217
Use of nonionic contrast media does not appear to substantially reduce the risk of radiocontrast-induced nephropathy.
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Preventing radiocontrast-induced. nephropathy Using a solution of 500 mL of 20% mannitol to which 100 mg of furosemide (Lasix) is added for each mg/dL serum creatinine, start infusion at a rate of 20 mL/hr 1 hour before contrast challenge. Continue infusion up to 6 hours after contrast challenge. Replace urine output milliliter for milliliter using 5% dextrose in water and a 0.45N saline solution to which 30 mEq of potassium per liter is added. It is important to make sure that no volume depletion occurs during contrast challenge.
Table 2. Commonly available contrast media
Generic name Ionic
Diatrizoate lothalamate loxaglate lodipamide
Non ionic
Metrizamide lohexol lopamidol
Adapted.from Berkseth and Kjellstrand.'3
as NSAIDs, should be discontinued. Saline and fluid depletion must be avoided. Adequate hydration with a half-normal saline solution is necessary to establish a urine output of75 mL or more per hour. 10 Use of mannitol and diuretics to prevent radiocontrastinduced nephropathy has been advocated, but firm data are lacking. Small uncontrolled studies have shown there is some benefit. 11 •12 Berkseth and Kjellstrand 13 have proposed a protocol for the use of fluids, mannitol, and/or diuretics (see box above). This protocol is specifically recommended for patients with a baseline serum creatinine level greater than 2 mgldL; however, it can be used for any patient judged to be at significant risk as long as the
use of mannitol and/or diuretics is not contraindicated. If additional radiocontrast exposures are necessary, the serum creatinine level must be monitored and allowed to return to baseline level before rechallenge.
Ionic versus nonionic media The introduction of nonionic, low-osmolar contrast media was heralded as a major technological advance. It was believed that reduction of risk of radiocontrastinduced nephropathy would be one of the many benefits. This notion has generated tremendous controversy and uncertainty. Compared with ionic media, nonionic media possess lower osmolality, lower chemotoxicity, and higher hydrophilicity. Some
ionic and nonionic contrast media that are commercially available are listed in table 2. A large-scale nationwide controlled trial from Japan prospectively compared ionic and nonionic contrast media with respect to overall prevalence of adverse reactions. 14 This study found a significantly lower incidence of adverse reactions with nonionic (3.1 %) than with ionic (12.6%) media. However, there was no concrete evidence of a reduction in risk of radiocontrast-induced nephropathy. Nonionic media are very expensive. If cost were not a factor, they would have replaced ionic media universally. Nonionic media virtually eliminate pain and reduce the chance of allergic reac-
continued on page 222 218
RADIOCONTRAST-INDUCaD .....ROMTHY • VOL 92/NO 8/DECEMBER 1992/POSTGRADUATE MEDICINE
The best screening test for radiocontrastinduced nephropathy Is measurement of the serum creatinine level.
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plicating factors must dictate their use.
Mandeep R. Mehra, MD Kaveh Sharif, MD Frederick R. Bode, MD Dr Mehra (pictured) is a fellow in cardiovascular medicine, Alton Ochsner Medical Foundation, New Orleans. Dr Sharif is a resident in internal medicine, Mount Carmel Medical Center, Columbus, Ohio. Dr Bode is program director, internal medicine residency, Mount Carmel Medical Center, and clinical associate professor of medicine, Ohio State University College of Medicine, Columbus.
tion. They have lower neurotoxicity and fewer adverse hemodynamic effects than ionic media. However, nonionic media do not appear to substantially reduce the risk of radiocontrast-induced nephropathy. 1 Therefore, until concrete data become available to prove a risk reduction, this factor should not determine the use of low-osmolar media. Other com-
222
Dose The link between the dose of contrast medium and eventual nephropathy has been debated. Although some studies have suggested that there is no relationship, they may have lacked the statistical power to demonstrate the relationship because of the low incidence of radiocontrastinduced nephropathy in the study groups. A recent study has convincingly established that dose is an independent risk factor.15 The least risk appears to accompany use of less than 30 mL of dye; risk may be significantly increased even with use of 30 to 100 mL of dye. Cigarroa and colleagues 16 have proposed a formula to calculate the optimal dose: the contrast material "limit" should equal 5 mL of contrast per kilogram of body weight (maximum, 300 mL) divided by the serum creatinine value (mgldL). Diagnosis and management Diverse imaging techniques and a wide variety of contrast media may cause radiocontrast-induced nephropathy. Nonoliguric or oliguric renal failure may occur. Oliguria is usually resistant to
loop diuretics such as furosemide (Lasix). The best screening test for radiocontrast-induced nephropathy is measurement of the serum creatinine level, which begins to rise in the first 24 to 48 hours after the procedure, peaks by the fourth day, and eventually returns to baseline level in 7 to 10 days. Short-term dialysis may be required, most likely in patients with a baseline serum creatinine level of more than 4 mgldL. A rise in serum creatinine level of at least 1 mgl dL over baseline value, 24 to 48 hours following contrast challenge, is considered diagnostic. 17 Urine sediment findings are typically nonspecific and include casts, epithelial cells, debris, and urate or calcium oxalate crystals. Proteinuria is unusual but may occur. 18 The fractional excretion of sodium is less than 1o/o in as many as 30% of patients, but it may exceed 1o/o. Thus, the sensitivity of this finding is not dear. Persistent visualization of the kidneys on plain ftlms 24 to 48 hours after contrast challenge has been thought to have a sensitivity of83o/o and specificity of93o/o. This has aptly been termed "the persistent nephrograrn." 19 The clinical utility of this procedure has not been corroborated in subsequent studies, and it ap-
RADIOCONTRAST-INDUC.D NIIPHROPATHY • VOL 92/NO 8/DECEMBER 1992/POSTGRADUATE MEDICINE
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pears to be plagued by a large number of false-positive and false-negative results. 20 Management of radiocontrastinduced nephropathy is similar to that of acute renal failure. Daily monitoring of fluid balance, body weight, electrolytes, and serum creatinine is usually all that is required. Some patients may be candidates for acute short-term dialysis, bur that is rarely needed.
Summary
The principal predisposing factor in radiocontrast-induced nephropathy appears to be underlying renal insufficiency. Identifying patients at risk is of paramount importance when a diagnostic study is being chosen. Contrast-reliant studies should be avoided, if possible, in high-risk patients. If challenge with a contrast medium is essential, appropriate risk stratification and adequate patient preparation should be done beforehand. Ultimately, prevention is a better approach
than cure. lUI
-®
Earn credit on this article.
See CME Qui"
The authors thank Joan Allen for her secretarial support and Nagaraja Sridhar, MD, and Janet Tremaine for their review of the manuscript.
Address for correspondence: Mandeep R. Mehra, MD, Alton Ochsner Medical Foundation, 1516 Jefferson Hwy, New Orleans, LA 70 121.
References 1. Hou SH, Bushinsky DA, Wuh JB, et al. Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983;74(2):243-8 2. Parfn:y PS, Griffiths SM, Barrett BJ, et al. Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both: a prospective controlled study. N Engl J Med 1989;320(3):143-9 3. Schwab SJ, Hlatky MA, Pieper KS, et al. Contrast nephrotoxicity: a randomized controlled trial of a nonionic and an ionic radiographic contrast agent. N Engl J Med 1989; 320(3): 149-53 4. Davicbon CJ, Hlatky M, Morris KG, et al. Cardiovascular and renal toxicity of a nonionic radiographic contrast agent after cardiac catheterization: a prospective trial. Ann Intern Med 1989;110(2):119-24 5. Taliercio CP, Vlietstra RE, Fuher LD, et al. Risks for renal dysfunction with cardiac angiography. Ann Intern Med 1986; I 04(4):50 1-4 6. Defronzo RA, Humphrey RL, Wright JR, et al. Acute renal failure in multiple myeloma. Medicine (Baltimore) 1975;54(3):209-23 7. Myas GH Jr, Witten DM. Acute renal failure after excretory urography in multiple myeloma. AJR 1971;113(3):583-8 8. Shieh SD, Hirsch SR, Boshell BR, et al. Low risk of contrast media-induced acute renal failure in nonawtemic type 2 diabetes mellitus. Kidney lnt 1982;21(5):739-43 9. Laurin EM, Freeman NJ, Schoenfeld AH, et al. Radiocontrast-associated renal dysfunction: incidence and risk factors. AJR 1991; 157(1 ):49-58 10. Brezis M, Epstein FH. A closer look at radiocontrast-induced nephropathy. (Editorial) N EngiJ Med 1989;320(3):179-81 II. Old CW, Lehmer LM. Prevention of ra-
VOL 92/NO 8/DECEMBER 1992/POSTGRADUATE MEDICINE • RADIOCOIITRAST-INDUC.D N.PHROPATHY
diocontrast induced acute renal failure with mannitol. (Letter) Lancet 1980;1(8173):885 12. Anto HR, Chou SY, Porush JG, et al. Infusion intravenous pyelography and renal limelion: effects of hypertonic mannitol in patients with chronic renal insufficiency. Arch Intern Med 1981;141(12):1652-6 13. Berkseth RO, Kjellnrand CM. Radiologic contrast-induced nephropathy. Med Clin North Am 1984;68(2):351-70 14. Katayama H, Yamaguchi K, Kozuka T, et al. Adverse reactions to ionic and nonionic contrast media: a report from the Japanese Committee on the Safety of Contrast Media. Radiology 1990;175(3):621-8 15. Manske CL, SprafkaJM, Suony Jf, et al. Contrast nephropathy in awtemic diabetic patients undergoing coronary angiography. Am J Med 1990;89(5):615-20 16. Cigarroa RG, Lange RA, Williams RH, et al. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. Am J Med 1989;86(6 Pt I ):649-52 17. Misson Rf, Cuder RE. Radiocontrastinduced renal failure. West J Med 1985;142(5): 657-64 18. Tejler L, Almen T, Holds S. Proteinuria following nephroangiography. I. Clinical experiences. Acta Radio( Diagn (Stockh) 1977; 18(6): 634-40 19. Older RA, Korobkin M, Cleew: DM, et al. Contrast-induced acute renal failure: persistent nephrogram as clue to early detection. AJR 1980; 134(Feb):339-42 20. Byrd L, Sherman RL. Radiocontrastinduced acute renal failure: a clinical and pathophysiologic review. Medicine (Baltimore) 1979; 58(3):270-9
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ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Radiocontrast-induced nephropathy Mandeep R. Mehra MD, Kaveh Sharif MD & Frederick R. Bode MD To cite this article: Mandeep R. Mehra MD, Kaveh Sharif MD & Frederick R. Bode MD (1992) Radiocontrast-induced nephropathy, Postgraduate Medicine, 92:8, 215-223, DOI: 10.1080/00325481.1992.11701561 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701561
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Monash University Library]
Date: 02 July 2016, At: 19:05
-(£tME cred~ article
Radiocontrast-induced nephropathy Prevention is better than cure
Mandeep R. Mehra, MD Kaveh Sharif, MD Frederick R. Bode, MD
Downloaded by [Monash University Library] at 19:05 02 July 2016
Preview Administration of radiographic contrast material is a common yet preventable cause of acute renal failure. Who is at risk for this complication? What preventive measures can be taken? Drs Mehra, Sharif, and Bode address these questions and compare the conventional Ionic agents with the newer nonionic agents.
Radiocontrast-induced nephropathy is defined as a rise in the serum creatinine level of at least 1 mgldL over the baseline value 24 to 48 hours after challenge with a contrast medium. It commonly occurs after major angiographic procedures such as cardiac catheterization; however, significant exposure may follow seemingly benign diagnostic tests such as contrast-enhanced computed tomography. In an era of burgeoning invasive strategies, radiocontrastinduced nephropathy continues to be a major cause of procedurerelated morbidity. According to Hou and colleagues, 1 it accounts for up to 12% of episodes of hospital-acquired renal failure. The incidence has been reported to range from 2% in low-risk patients to as high as 10% in highrisk patients. 2'3 Adverse effects are directly related to the patient's underlying disease and are generally seen in patients who are seriously ill.
There is no definitive treatment for radiocontrast-induced nephropathy. Although most cases resolve spontaneously, some require short-term or even longterm dialytic support. Clearly, prevention is better than cure; however, pharmacologic strategies aimed at prevention have been disappointing. The biggest challenge in dealing with radiocontrast-induced nephropathy is to eliminate the use of contrast media by developing sufficiently accurate alternative imaging methods. The immediate challenge is to increase physicians' awareness of the possibility of radiocontrastinduced nephropathy so that appropriate risk stratification, optimal test selection, and adequate patient preparation with minimum use of contrast material are achieved. Other goals are to increase understanding of the mechanisms of radiocontrastinduced nephropathy (see box on page 216) and to identify appro-
VOL 92/NO 8/DECEMBER 1992/POSTGRADUATE MEDICINE • RADIOCONTRAST-INDUc.D NIIPHROMTHY
priate preventive pharmacologic measures. The role of diabetes mellitus in radiocontrast-induced nephropathy and the protective effects of mannitol and saline hydration are controversial. Perhaps the biggest controversy, however, is whether the new, nonionic contrast media are less toxic to the kidneys than the older, ionic media.
Risk factors Underlying renal insufficiency is the principal predisposing factor for radiocontrast-induced nephropathy. Risk of renal injury correlates directly with the patient's serum creatinine level. Risk is 4% with a serum creatinine level of less than 1.1 mgldL but 20% with a serum creatinine level greater than 2.0 mgldL. 4 Sixty percent of cases are nonoliguric; clinically significant oliguria or anuria develops in 40% of patients with radiocontrastinduced nephropathy. 5 Other important risk factors include low-output class N congestive heart failure, multiple contrast challenges within a 72hour period, administration of high doses of contrast media, and dehydration. Age greater than 60 years, hyperuricemia, hypertension, proteinuria, and periphcontinued
215
Underlying renal insufficiency is the principal predisposing factor for radiocontrast-induced nephropathy.
Downloaded by [Monash University Library] at 19:05 02 July 2016
Potential mechanisms of radiocontrast-induced nephropathy The mechanisms of radiocontrast-induced nephropathy are not completely understood. In experimental situations, intrarenal or intravenous injection of radiocontrast media causes a brief initial increase in renal blood flow, followed by a profound reduction in glomerular filtration rate and renal blood flow. These hemodynamic consequences are more pronounced in the sodium-depleted state. Direct tubular injury may also play a significant role in radiocontrast-induced nephropathy. However, in this complex interplay of mediating factors, the common denominator appears to be injury to the medullary thick ascending loop of Henle, a site that is actively involved in oxygen-dependent electrolyte transport but is the nephron site with the least amount of oxygen delivered to it. Thus, efforts targeted at reducing oxygen demand for active electrolyte transport and improving medullary renal blood flow may reduce the risk of radiocontrastinduced nephropathy. These objectives are currently fulfilled by adequate hydration with saline solution before the procedure and administration ofloop diuretics and mannitol.l.l Other potential mechanisms include altered glomerular perm-selectivity, intraluminal obstruction, and immunologic mechanisms such as hypersensitivity to contrast media. A role for intravascular calcium flux, adenosine, and oxy-
216
gen free radicals has been suggested by results of animal studies.3'4 Data from such studies suggest that endogenous adenosine and calcium action are essential for the adverse effects of contrast material on renal blood flow. Infusion of radiocontrast media results in an increase in intrarenal generation of adenosine and activation of calcium-dependent vasoconstriction. 3 Intrarenal administration of contrast media causes an increase in urinary Tamm-Horsfall protein mediated in part by oxygen free radical damage to the kidney. 4 Tamm-Horsfall protein may thus be a marker for contrast-induced renal injury. As understanding of the crucial role of molecular elements increases, more definitive clinical strategies may emerge. These may include the use of calcium antagonists, adenosine antagonists, and oxygen free radical scavenging agents. Rd'amces I. Bn:zis M, Epstein FH. A closer look at radiocontrast-induced nephropathy. (Editorial) N EnglJ Med 1989;320(3):179-81 2. Byrd L, Sherman RL. Radiocontrast-induced acute renal failure: a clinical and pathophysiologic review. Medicine (Baltimore) 1979; 58(3):270-9 3. Deray G, Martinez F, Cacoub P, et al. A role for adenosine, calcium and ischemia in radiocontrast-induced intrarenal vasoconstriction. AmJ Nephrol1990;10(4):316-22 4. Bakris GL, Gaber AO, Jones JD. Oxygen free radical involvement in urinary Tamm-Horsfall protein excretion after intrarenal injection of contrast medium. Radiology 1990;175(1):57-60
IIADIOCOIITRAST-INDUCD Nm'HROPATHY • VOL 92/NO 8/DECEMBER 1992/POSTGRAOUATE MEDICINE
Downloaded by [Monash University Library] at 19:05 02 July 2016
Use of nonsteroidal anti-inflammatory drugs may increase the risk of radiocontrast-induced nephropathy.
eral vascular disease are probably not clinically important risk factors but are merely characteristic of the patient population undergoing contrast-dependent procedures and may be markers of underlying renal disease. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of radiocontrast-induced nephropathy (table 1). Multiple myeloma has been identified as an important risk factor for radiocontrast-induced nephropathy; however, studies have reported an aggregate incidence of less than 5o/o. 6•7 Case reports abound, and we urge caution in the use of contrast media in patients with plasma cell dyscrasias. Results of studies are contradictory regarding the role of diabetes mellitus in radiocontrastinduced nephropathy in the absence of renal insufficiency. In a recent study by Parfrey and colleagues/ nonazotemic diabetic patients were determined to be at low risk for clinically important radiocontrast-induced nephropathy. The presence of proteinuria does not appear to increase the risk of renal toxicity. 8 However, in a study of 394 patients undergoing femoral arteriography, Laurin and associates9 found that diabetes, especially when insulin-
Table 1. Risk factors for radiocontrast-induced nephropathy
Principal Underlying renal insufficiency (serum creatinine > 1.5 mg/dl) Low-output class IV congestive heart failure Multiple contrast challenges within 72 hr Dose of dye used Potential Diabetes mellitus (especially with renal dysfunction) Plasma cell dyscrasias (eg, multiple myeloma) Dehydration Use of nephrotoxic drugs (eg, NSAIDs)
Other* Advanced age (>60 yr) Hypertension Hyperuricemia Proteinuria Peripheral vascular disease NSAIDs. nonsteroidal anti-inflammatory drugs. "These factors probably reflect presence of underlying renal insufficiency.
dependent, was a significant independent risk factor in radiocontrast-induced nephropathy, even in nonazotemic patients. Taliercio and colleagues5 had previously identified insulindependent diabetes as a significant independent risk factor for radiocontrast-induced nephropathy. Awareness of the possibility of renal injury following contrast exposure in nonazotemic diabetic patients is important, especially in insulin-dependent patients. Extreme caution is needed in
choosing a contrast-dependent test in this population. Prevention Imaging methods that do not require the use of contrast medium should be considered for patients at high risk for renal injury. If contrast challenge is necessary, the lowest possible dose of contrast medium should be used. The patient's clinical condition, including comorbid factors, must be stabilized as much as possible before the procedure. Drugs that are potentially nephrotoxic, such
continued
VOL 92/NO 8/DECEMBER 1992/POSTGRAOUATE MEDICINE • RADIOCONTRAST·INDUCaD N.PHROMT11Y
217
Use of nonionic contrast media does not appear to substantially reduce the risk of radiocontrast-induced nephropathy.
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Preventing radiocontrast-induced. nephropathy Using a solution of 500 mL of 20% mannitol to which 100 mg of furosemide (Lasix) is added for each mg/dL serum creatinine, start infusion at a rate of 20 mL/hr 1 hour before contrast challenge. Continue infusion up to 6 hours after contrast challenge. Replace urine output milliliter for milliliter using 5% dextrose in water and a 0.45N saline solution to which 30 mEq of potassium per liter is added. It is important to make sure that no volume depletion occurs during contrast challenge.
Table 2. Commonly available contrast media
Generic name Ionic
Diatrizoate lothalamate loxaglate lodipamide
Non ionic
Metrizamide lohexol lopamidol
Adapted.from Berkseth and Kjellstrand.'3
as NSAIDs, should be discontinued. Saline and fluid depletion must be avoided. Adequate hydration with a half-normal saline solution is necessary to establish a urine output of75 mL or more per hour. 10 Use of mannitol and diuretics to prevent radiocontrastinduced nephropathy has been advocated, but firm data are lacking. Small uncontrolled studies have shown there is some benefit. 11 •12 Berkseth and Kjellstrand 13 have proposed a protocol for the use of fluids, mannitol, and/or diuretics (see box above). This protocol is specifically recommended for patients with a baseline serum creatinine level greater than 2 mgldL; however, it can be used for any patient judged to be at significant risk as long as the
use of mannitol and/or diuretics is not contraindicated. If additional radiocontrast exposures are necessary, the serum creatinine level must be monitored and allowed to return to baseline level before rechallenge.
Ionic versus nonionic media The introduction of nonionic, low-osmolar contrast media was heralded as a major technological advance. It was believed that reduction of risk of radiocontrastinduced nephropathy would be one of the many benefits. This notion has generated tremendous controversy and uncertainty. Compared with ionic media, nonionic media possess lower osmolality, lower chemotoxicity, and higher hydrophilicity. Some
ionic and nonionic contrast media that are commercially available are listed in table 2. A large-scale nationwide controlled trial from Japan prospectively compared ionic and nonionic contrast media with respect to overall prevalence of adverse reactions. 14 This study found a significantly lower incidence of adverse reactions with nonionic (3.1 %) than with ionic (12.6%) media. However, there was no concrete evidence of a reduction in risk of radiocontrast-induced nephropathy. Nonionic media are very expensive. If cost were not a factor, they would have replaced ionic media universally. Nonionic media virtually eliminate pain and reduce the chance of allergic reac-
continued on page 222 218
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The best screening test for radiocontrastinduced nephropathy Is measurement of the serum creatinine level.
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plicating factors must dictate their use.
Mandeep R. Mehra, MD Kaveh Sharif, MD Frederick R. Bode, MD Dr Mehra (pictured) is a fellow in cardiovascular medicine, Alton Ochsner Medical Foundation, New Orleans. Dr Sharif is a resident in internal medicine, Mount Carmel Medical Center, Columbus, Ohio. Dr Bode is program director, internal medicine residency, Mount Carmel Medical Center, and clinical associate professor of medicine, Ohio State University College of Medicine, Columbus.
tion. They have lower neurotoxicity and fewer adverse hemodynamic effects than ionic media. However, nonionic media do not appear to substantially reduce the risk of radiocontrast-induced nephropathy. 1 Therefore, until concrete data become available to prove a risk reduction, this factor should not determine the use of low-osmolar media. Other com-
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Dose The link between the dose of contrast medium and eventual nephropathy has been debated. Although some studies have suggested that there is no relationship, they may have lacked the statistical power to demonstrate the relationship because of the low incidence of radiocontrastinduced nephropathy in the study groups. A recent study has convincingly established that dose is an independent risk factor.15 The least risk appears to accompany use of less than 30 mL of dye; risk may be significantly increased even with use of 30 to 100 mL of dye. Cigarroa and colleagues 16 have proposed a formula to calculate the optimal dose: the contrast material "limit" should equal 5 mL of contrast per kilogram of body weight (maximum, 300 mL) divided by the serum creatinine value (mgldL). Diagnosis and management Diverse imaging techniques and a wide variety of contrast media may cause radiocontrast-induced nephropathy. Nonoliguric or oliguric renal failure may occur. Oliguria is usually resistant to
loop diuretics such as furosemide (Lasix). The best screening test for radiocontrast-induced nephropathy is measurement of the serum creatinine level, which begins to rise in the first 24 to 48 hours after the procedure, peaks by the fourth day, and eventually returns to baseline level in 7 to 10 days. Short-term dialysis may be required, most likely in patients with a baseline serum creatinine level of more than 4 mgldL. A rise in serum creatinine level of at least 1 mgl dL over baseline value, 24 to 48 hours following contrast challenge, is considered diagnostic. 17 Urine sediment findings are typically nonspecific and include casts, epithelial cells, debris, and urate or calcium oxalate crystals. Proteinuria is unusual but may occur. 18 The fractional excretion of sodium is less than 1o/o in as many as 30% of patients, but it may exceed 1o/o. Thus, the sensitivity of this finding is not dear. Persistent visualization of the kidneys on plain ftlms 24 to 48 hours after contrast challenge has been thought to have a sensitivity of83o/o and specificity of93o/o. This has aptly been termed "the persistent nephrograrn." 19 The clinical utility of this procedure has not been corroborated in subsequent studies, and it ap-
RADIOCONTRAST-INDUC.D NIIPHROPATHY • VOL 92/NO 8/DECEMBER 1992/POSTGRADUATE MEDICINE
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pears to be plagued by a large number of false-positive and false-negative results. 20 Management of radiocontrastinduced nephropathy is similar to that of acute renal failure. Daily monitoring of fluid balance, body weight, electrolytes, and serum creatinine is usually all that is required. Some patients may be candidates for acute short-term dialysis, bur that is rarely needed.
Summary
The principal predisposing factor in radiocontrast-induced nephropathy appears to be underlying renal insufficiency. Identifying patients at risk is of paramount importance when a diagnostic study is being chosen. Contrast-reliant studies should be avoided, if possible, in high-risk patients. If challenge with a contrast medium is essential, appropriate risk stratification and adequate patient preparation should be done beforehand. Ultimately, prevention is a better approach
than cure. lUI
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The authors thank Joan Allen for her secretarial support and Nagaraja Sridhar, MD, and Janet Tremaine for their review of the manuscript.
Address for correspondence: Mandeep R. Mehra, MD, Alton Ochsner Medical Foundation, 1516 Jefferson Hwy, New Orleans, LA 70 121.
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