Mortality Associated With Nephropathy After Radiographic Contrast Exposure

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1 ORIGINAL ARTICLE MORTALITY ASSOCIATED WITH NEPHROPATHY AFTER RADIOGRAPHIC CONTRAST EXPOSURE Mortality Associated With Nephropathy After Radiographic Contrast Exposure AARON M. FROM, MD; BRIAN J. BARTHOLMAI, MD; AMY W. WILLIAMS, MD; STEPHEN S. CHA, MS; AND FURMAN S. MCDONALD, MD, MPH OBJECTIVE: To define outcomes from contrast-induced nephropathy (CIN) after both intra-arterial and intravenous administration of contrast medium. PATIENTS AND METHODS: We performed a retrospective casematched cohort study at Mayo Clinic s site in Rochester, MN, from April 1, 24, to March 31, 26. All contrast procedures were evaluated for inclusion. was defined as creatinine elevation of 25% or more after contrast exposure or of more than.5 mg/dl within 7 days of contrast exposure. Cases of CIN were matched 1:3 with controls by age, sex, preprocedure creatinine elevation, diabetes mellitus, and type of imaging procedure. RESULTS: A total of 89 patients who developed CIN were matched to 2427 patients who did not develop CIN after contrast exposure. In multivariate analyses, CIN was significantly associated with 3-day mortality (odds ratio, 3.37; 95% confidence interval [CI], ; P<.1) and overall mortality (hazard ratio, 1.57; 95% CI, ; P<.1) after adjustment for heart failure, hypertension, medications, total hydration, iodine load, prior contrast exposure, and all matched variables during the study period. Intravenous contrast administration was a risk factor for 3-day mortality (odds ratio, 2.91; 95% CI, ; P=.2) and overall mortality (hazard ratio, 3.2; 95% CI, ; P<.1) compared with intra-arterial administration of contrast after adjustment for heart failure, hypertension, medications, total hydration, iodine load, prior contrast exposure, and all matched variables during the study period. CONCLUSION: after administration of contrast medium is associated with increased mortality. This risk is higher in patients in whom contrast medium is administered intravenously than in those in whom it is administered intraarterially. Mayo Clin Proc. 28;83(1): CI = confidence interval; CIN = contrast-induced nephropathy; HR = hazard ratio; OR = odds ratio Few studies have evaluated outcomes after the development of contrast-induced nephropathy (CIN). 1-3 These studies focus mainly on patients undergoing coronary catheterization and neglect the many patients in whom contrast medium is administered intravenously for computed tomography. This study aimed to evaluate the outcomes of CIN that develop after both intra-arterial and intravenous contrast exposure. PATIENTS AND METHODS After approval by the Mayo Clinic Institutional Review Board, all patients in whom contrast medium was administered intravenously or intra-arterially at Mayo Clinic s site in Rochester, MN, from April 1, 24, to March 31, 26, were identified. Patients who underwent computed tomography or noncardiac interventional radiographic procedures requiring intravenous contrast or intra-arterial contrast medium were identified by searching the radiology information system database that records all procedures performed in the Department of Radiology. Coronary angiography cases were obtained from the Mayo Clinic Catheterization Laboratory, which maintains a computer registry of all coronary angiography procedures. Contrastinduced nephropathy was defined as creatinine elevation of 25% or more after contrast exposure or of more than.5 mg/dl within 7 days of contrast exposure. Because previous reports suggested that CIN can occur up to 1 week after contrast exposure, 2,4-7 we included cases of intravenous contrast medium administered to patients 17 years old or older with at least one creatinine value available within 7 days before and after exposure. In patients with more than one exposure during the study period, the last exposure was used with adjustment for prior exposure during the study period. The maximum creatinine value before contrast exposure was used in the analyses. The highest creatinine value after the contrast exposure was used as the postexposure creatinine value in the analyses. As described previously, 8 patients with precontrast creatinine values above 8 mg/dl (to convert to mmol/l, multiply by 88.4) or a history of dialysis were excluded. Contrast iodine load (grams) was calculated using the equation: (iodine concentration [g/ml] volume of contrast [ml]). Comorbid diseases were identified using a coding system maintained for record identification at Mayo From the Division of Cardiovascular Diseases (A.M.F.), Department of Radiology (B.J.B.), Division of Nephrology and Hypertension (A.W.W.), Division of Biostatistics (S.S.C.), and Divisions of General Internal Medicine and Hospital Internal Medicine (F.S.M.), Mayo Clinic, Rochester, MN. This study was supported in part by a grant from the Mayo Small Grants Program administered by the Division of General Internal Medicine Research Committee, Mayo Clinic, Rochester, MN, which reviewed the design of the study before data collection but did not otherwise participate in the conduct of the study; nor in collection, management, analysis, or interpretation of the data; nor preparation, review, or approval of the manuscript. Individual reprints of this article are not available. Address correspondence to Aaron M. From, MD, Division of Cardiovascular Diseases, Mayo Clinic, 2 First St SW, Rochester, MN 5595 (from.aaron@mayo.edu). 28 Mayo Foundation for Medical Education and Research Mayo Clin Proc. October 28;83(1):

2 Clinic that closely approximates the International Classification of Diseases, Ninth Revision codes. The codes, which are not based on hospital billing codes, were assigned by coders primarily according to physician diagnoses for outpatient visits and from discharge diagnoses for hospitalizations. Fluid administration was determined by summing the total of all fluids (oral and intravenous) administered 1 day before and on the date of contrast exposure. β-blockers, diuretics, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aspirin therapies were determined by searching the electronic medical records 7 days before contrast administration. Glomerular filtration rate was estimated using the 4-variable Modification of Diet in Renal Disease equation This equation uses race (African American: yes or no) as a variable. DATA COLLECTION Dialysis information was obtained from the Mayo Dialysis Database. This database contains date of dialysis for patients who undergo dialysis in a local affiliated dialysis center. For patients initiating dialysis after administration of contrast medium, the first dialysis date in the database was used. Mortality data were collected in May 27. Survival status was initially determined from the Mayo Clinic registration database. For patients with no record of death in the registration database, mortality was determined with the use of Accurint (LexisNexis, Philadelphia, PA), an institutionally approved fee-based Internet research and location service. 12 STUDY OUTCOMES AND STATISTICAL ANALYSES Outcomes studied included CIN, 3-day mortality, and overall mortality. The association of CIN and any prior conditions was determined using conditional logistic regression model analysis. The 3-day mortality and the overall survival analyses were based on 89 cases and 2427 controls. Survival analysis methodology (Kaplan-Meier, log-rank test) was used to assess the association between mortality and CIN. Unconditional logistic regression modeling was used to determine the odds ratio (OR) and 95% confidence interval (CI) for each factor toward 3-day mortality. Cox proportional hazards regression model was used to determine the hazard ratio (HR) and 95% CI of each factor toward mortality over time. All analyses were performed using SAS version (SAS Institute, Cary, NC). P<.5 was considered statistically significant. RESULTS Overall, 936 patients who developed CIN after contrast exposure were identified, of whom 89 (86%) could be matched to controls (1 case to 3 controls). Controls comprised 2427 patients who did not develop CIN after contrast exposure. Among patients with CIN, no patient had only a.5 mg/dl elevation of creatinine, 544 patients had only a 25% increase in postcontrast creatinine values, and 265 patients had both an increase of.5 mg/dl and a 25% increase in creatinine values. Low-osmolar contrast media were used in 95% of the cases. As shown in Table 1, cases were well matched to 3 controls by age, sex, prior creatinine value, diabetes mellitus, and type of study. Compared with patients without CIN, patients with CIN were more likely to have higher creatinine clearance, to have lower iodine load, to be hypertensive, to have chronic heart failure, and to be taking angiotensin-converting enzyme inhibitors and diuretics. Analysis of patients who had prior contrast exposure revealed that, among 132 patients in the study group, 55 patients (42%) met criteria for CIN before the last contrast exposure. Among 45 patients in the control group, 38 patients (9%) met criteria for CIN before the last contrast exposure. Among patients undergoing noncardiac interventional radiographic procedures, intra-arterial contrast medium was administered to 47%; in the remaining 53%, contrast medium was administered intravenously. Further, in patients undergoing computed tomographic angiography, contrast medium was administered intravenously. RISK OF DIALYSIS Dialysis was required in.6% of the entire group (2 patients). Among patients who developed CIN, dialysis was initiated in.2% (2 patients) compared with % (no patients) of those who did not develop CIN (P=.1). In the 2 patients who underwent dialysis, therapy was initiated 122 days after contrast exposure in one patient and 539 days after contrast exposure in the second. RISK OF MORTALITY Thirty-day mortality was 7.8% (253 patients) for the entire group. Using Kaplan-Meier survival estimation, the 3-day mortality for patients who developed CIN was 15.6% (95% CI, 13.%-18.% in 126 patients) compared with 5.2% (95% CI, 4.2%-6.9% in 127 patients) among those who did not develop CIN (P<.1) (Figure 1). In unconditional multivariate logistic regression modeling, CIN was significantly associated with 3-day mortality (OR, 3.37; 95% CI, ; P<.1) after adjustment for heart failure, hypertension, medications, total hydration, iodine load, prior contrast exposure, and all matched variables during the study period (Table 2). Also, CIN was associated with 1-year mortality in multivariate logistic regression modeling (OR, 1.84; 95% CI, ; P<.1) after adjustment for all factors in Table Mayo Clin Proc. October 28;83(1):

3 TABLE 1. Univariate Analyses of Baseline Characteristics a,b CIN present CIN absent P Characteristic (n=89) (n=2427) value c Matched variables Age, y 64±16 64±16.9 Male 46 (5) 1218 (5) >.99 Average prior creatinine value, mg/dl 1.1±.3 1.1±.3.27 Diabetes mellitus 182 (22) 546 (22) >.99 Computed tomography 586 (72) 1758 (72) >.99 Computed tomographic angiography 69 (9) 27 (9) >.99 Noncardiac angiography or venography 37 (5) 111 (5) >.99 Coronary catheterization 117 (14) 351 (14) >.99 Unmatched variables Creatinine clearance, ml/min d 7.2± ±22..3 Iodine load, g 36.± ± Total hydration, ml e 191± ± Prior contrast exposure 132 (16) 45 (17).72 Hypertension 396 (49) 193 (45).2 Chronic heart failure 149 (18) 279 (11) <.1 ACE inhibitors 176 (22) 458 (19).1 ARBs 88 (11) 26 (8).4 Acetylsalicylic acid 15 (19) 458 (19).76 β-blockers 197 (24) 575 (24).58 Diuretics 251 (31) 59 (24) <.1 NSAIDs 69 (9) 233 (1).19 a Continuous variables are expressed as mean ± SD; categorical variables are expressed as number (percentage). ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CIN = contrast-induced nephropathy; NSAID = nonsteroidal anti-inflammatory drug. b SI conversion factors: To convert creatinine values to µmol/l, multiply by 88.4; to convert creatinine clearance values to ml/s per m 2, multiply by.167. c Creatinine clearance was available in 2817 patients (87%). d Total hydration was available in 1277 patients (39%). e P values are derived from conditional logistic analysis using 4854 pairs; CIN was the outcome variable. Overall mortality for the entire group was 24.8% (85 patients) and was 31.8% (257 patients) among patients with CIN vs 22.6% (548 patients) among those without CIN (P<.1). Mean ± SD time to death or latest follow-up was 16.3±33.4 months. In a multivariate proportional hazards model that accounts for time to follow-up, CIN was significantly associated with overall mortality (HR, 1.57; 95% CI, ; P<.1) after adjustment for heart failure, hypertension, medications, total hydration, iodine Survival (%) Year No. at risk FIGURE 1. Mortality stratified by contrast-induced nephropathy load, prior contrast exposure, and all matched variables during the study period (Table 2). To further define the association between CIN and mortality, patients were stratified by creatinine clearance before contrast exposure. After stratification, 3-day and overall mortality were increased in stage II and stage III kidney disease for patients with CIN compared with patients without CIN (Table 3). COMPARISON OF OUTCOMES BY ROUTE OF CONTRAST ADMINISTRATION Figure 2 shows the rates of 3-day mortality according to the type of procedure and route of contrast administration with stratification by diabetes or elevated creatinine levels (preprocedure creatinine elevation, >1.5 mg/dl). To determine whether CIN was independently associated with mortality in patients in whom contrast medium was administered intravenously, we analyzed the 27 patients in whom contrast medium was administered intravenously (the subset of patients who underwent computed tomography, computed tomographic angiography, and noncardiac venography). In multivariate proportional hazard modeling adjusting for heart failure, hypertension, medications, total hydration, iodine load, prior contrast exposure, and all matched variables during the study period, CIN was Mayo Clin Proc. October 28;83(1):

4 TABLE 2. Thirty-Day Mortality and Overall Mortality a 3-day mortality Overall mortality Variable OR (95% CI) P value HR (95% CI) P value Age 1.2 ( ) ( ) <.1 Male 1.16 ( ) ( ).9 Prior creatinine value 1.48 ( ) ( ).52 Diabetes mellitus.88 ( ) ( ).32 Computed tomography 5.6 ( ) < ( ) <.1 Computed tomographic angiography 2.15 ( ) ( ).68 Noncardiac angiography or venography 4.93 ( ) ( ) < ( ) < ( ) <.1 Iodine load 1. ( ) ( ).97 Total hydration b 1. (1.-1.).9 1. (1.-1.).11 Prior contrast exposure 1.52 ( ) ( ) <.1 Hypertension.69 (.5-.94).2.76 (.65-.9).11 Chronic heart failure 1.2 (.8-1.8) ( ).4 ACE inhibitors 1.1 ( ) ( ).32 ARBs 1.9 ( ) ( ).37 Acetylsalicylic acid.65 ( ).3.67 ( ) <.1 β-blocker 1.27 ( ) ( ).49 Diuretics 1.8 ( ) ( ).4 NSAIDs 1.13 ( ) ( ).71 a ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CI = confidence interval; HR = hazard ratio; NSAID = nonsteroidal anti-inflammatory drug; OR = odds ratio. b Total hydration was available in 1277 patients (39%). an independent risk factor for 3-day mortality (OR, 3.4; 95% CI, ; P<.1) and overall mortality (HR, 1.57; 95% CI, ; P<.1). Finally, to determine whether intravenous contrast administration was associated with increased mortality compared with intra-arterial administration, patients who underwent computed tomography, computed tomographic angiography, or noncardiac venography (all underwent intravenous contrast administration) were compared with the group of patients who underwent coronary angiography or noncardiac angiography (all underwent intra-arterial contrast administration). Intravenous contrast administration was a risk factor for 3-day mortality (OR, 2.91; 95% CI, ; P=.2) and overall mortality (HR, 3.2; 95% CI, ; P<.1) compared with intraarterial administration of contrast after adjustment for heart failure, hypertension, medications, total hydration, iodine load, prior contrast exposure, and all matched variables during the study period. DISCUSSION The current study shows that, in this large cohort of patients, CIN after contrast exposure was associated with an increased risk of death. The mortality associated with CIN was higher among patients who underwent intravenous contrast administration than among patients who underwent intra-arterial contrast administration. Previous studies have established that elevated baseline creatinine levels and diabetes are associated with CIN. 1-3,13-15 It is interesting that, within our cohort, patients who developed CIN were more likely to be treated with diuretics TABLE 3. Mortality Stratified by CrCl Before Contrast Exposure a 3-day mortality Overall mortality Total No. All, With CIN c, All, With CIN c, GFR (CrCl) b of patients No. (%) OR (95% CI) No. (%) HR (95% CI) Stage I ( 9 ml/min) (9) 1.63 ( ) 111 (25) 1.17 ( ) Stage II (6-9 ml/min) (7) 3.71 ( ) 31 (23) 1.58 ( ) Stage III (3-6 ml/min) (9) 3.53 ( ) 29 (27) 1.76 ( ) Stage IV and V (<3 ml/min) 6 1 (17) NA 2 (33) NA a CrCl = creatinine clearance; CIN = contrast-induced nephropathy; GFR = glomerular filtration rate; HR = hazard ratio; NA = not applicable because of low number of patients and outcomes; OR = odds ratio. b Available in 2817 patients (87%). c Unadjusted ratios. 198 Mayo Clin Proc. October 28;83(1):

5 A 5 B 5 3-d mortality (%) * * d mortality (%) * C 5 D 5 3-d mortality (%) d mortality (%) FIGURE 2. Thirty-day mortality rates with different types of radiographic procedures and routes of contrast administration, stratified by presence of diabetes mellitus (DM) and elevated creatinine (Cr) levels (pre-exposure Cr level >1.5 mg/dl [to convert to µmol/l, multiply by 88.4]). A, Computed tomography with intravenous contrast; B, Coronary angiography with intra-arterial contrast; C, Noncoronary venography with intravenous contrast; D, Noncardiac angiography with intra-arterial contrast. Any P value <.5 was considered statistically significant. * = statistically significant. and were more likely to have a history of heart failure (Table 1). This fact could be a clue to an unrecognized tubular dysfunction that predisposes patients to renal dysfunction. Few studies have examined the risks of mortality after contrast exposure, 1-3 and even fewer have examined CIN after intravenous contrast administration Our data suggest that CIN after intravenous contrast administration is a serious complication. It is surprising that the use of intravenous contrast material was associated with an almost 3-fold increase in the risk of death compared with intra-arterial contrast. Further, in our original database of 12,618 patients with precontrast and postcontrast creatinine values (from which the patients in the current study were obtained), intravenous contrast was administered to 767 (81%) of 947 patients with CIN compared with 9549 (82%) of 11,671 patients without CIN (P=.53). Because the use of intravenous contrast medium was the same in patients with and without CIN (in an unselected and unmatched cohort), we suspect that intravenous contrast administration is independently associated with poor outcome and not just a surrogate marker of CIN. We are uncertain of the mechanism for this association. Recent studies that define risks and outcomes of acute renal decline after contrast exposure focus almost exclusively on angiographic interventions of the heart or other vessels, which require only intra-arterial contrast material. 1-3,8,19-22 Data from the current study and few data from previous research on this topic indicate that more research should focus on patients in whom contrast medium is administered intravenously. LIMITATIONS The current study has several limitations. Data were collected retrospectively and are subject to the methodological limitations inherent in retrospective studies. This is not a consecutive group of patients in whom contrast material was administered; the decision to perform a postprocedure creatinine check was made entirely by the primary physician, and it is possible that some patients who had CIN after contrast exposure were missed or that the cohort overrepresents patients who required postprocedure creatinine checks because of indefinable clinical characteristics. Further, this study identifies patients with all-cause increases in the serum creatinine concentration among patients who Mayo Clin Proc. October 28;83(1):

6 had been exposed to contrast medium. It is possible that factors other than contrast exposure led to the increase in creatinine value and that the creatinine increase alone explains the higher mortality rates shown regardless of contrast exposure. STRENGTHS Once CIN was defined, assessment of mortality in those with CIN and those without was matched to important variables and assessed longitudinally from the time of contrast administration, making these groups comparable. Further, to our knowledge, this is the first study to focus on a large group of patients in whom contrast material was administered for computed tomography and on their mortality after contrast administration in relationship to the development of CIN. Also, the patient group represents a real world population; therefore, the data could apply to patients of practicing physicians. CONCLUSION was associated with increased mortality. Among patients who developed CIN, this risk was significantly higher after intravenous than after intra-arterial administration of contrast medium. Further study of the effects and prevention of CIN in patients in whom contrast material is administered intravenously is warranted. We sincerely thank Dale Kuisle, Edward Asmann, and Barbara Abbott for help with data collection. REFERENCES 1. Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation. 22;15(19): McCullough PA, Wolyn R, Rocher LL, Levin RN, O Neill WW. Acute renal failure after coronary intervention: incidence, risk factors, and relationship to mortality. Am J Med. 1997;13(5): Gruberg L, Mintz GS, Mehran R, et al. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol. 2;36(5): Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospitalacquired renal insufficiency: a prospective study. Am J Med. 1983;74(2): Pannu N, Wiebe N, Tonelli M; Alberta Kidney Disease Network. Prophylaxis strategies for contrast-induced nephropathy. JAMA. 26;295 (23): Kandzari DE, Rebeiz AG, Wang A, Sketch MH Jr. Contrast nephropathy: an evidence-based approach to prevention. Am J Cardiovasc Drugs. 23;3(6): Maeder M, Klein M, Fehr T, Rickli H. Contrast nephropathy: review focusing on prevention. J Am Coll Cardiol. 24;44(9): Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 24;291(19): Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D; Modification of Diet in Renal Disease Study Group. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;13(6): Poggio ED, Wang X, Weinstein DM, et al. Assessing glomerular filtration rate by estimation equations in kidney transplant recipients. Am J Transplant. 26;6(1): National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 22;39(2)(suppl 1):S1-S Accurint Web site. Manage risk with more intelligence. Accessed August 13, Weisberg LS, Kurnik PB, Kurnik BR. Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney Int. 1994;45(1): Parfrey 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;32(3): Weinrauch LA, Healy RW, Leland OS Jr, et al. Coronary angiography and acute renal failure in diabetic azotemic nephropathy. Ann Intern Med. 1977;86(1): Warren SE, Bott JC, Thornfeldt C, Swerdlin AH, Steinberg SM. Hazards of computerized tomography: renal failure following contrast injection. Surgical Neurol. 1978;1(5): Byrd LH, Sherman RL, Stenzel KH, Rubin AL. Computerized tomography-induced acute renal failure [letter]. Arch Intern Med. 1979; 139(4): Shafi T, Chou SY, Porush JG, Shapiro WB. Infusion intravenous pyelography and renal function: effects in patients with chronic renal insufficiency. Arch Intern Med. 1978;138(8): Recio-Mayoral A, Chaparro M, Prado B, et al. The reno-protective effect of hydration with sodium bicarbonate plus N-acetylcysteine in patients undergoing emergency percutaneous coronary intervention: the RENO Study. J Am Coll Cardiol. 27 Mar 27;49(12): Epub 27 Mar Briguori C, Airoldi F, D Andrea D, et al. Renal Insufficiency Following Contrast Media Administration Trial (REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation. 27 Mar 13;115(1): Epub 27 Feb Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrastinduced nephropathy in primary angioplasty. N Engl J Med. 26;354: Schmidt P, Pang D, Nykamp D, Knowlton G, Jia H. N-acetylcysteine and sodium bicarbonate versus N-acetylcysteine and standard hydration for the prevention of radiocontrast-induced nephropathy following coronary angiography. Ann Pharmacother. 27 Jan;41(1):46-5. Epub 26 Dec Mayo Clin Proc. October 28;83(1):