1. Association of Commonly Used Medications with Prevalence and Renal Recovery after Postoperative Acute Kidney Injury Shahab Bozorgmehri, MD, MPH, CPH 1 ; Meghan Brennan, MS 2 ; Tezcan Ozrazgat Baslanti, PhD 2 ; Charles E. Hobson, MD, MHA 2 ; Azra Bihorac, MD, MS, FASN 2 1 Departments of Epidemiology, College of Public Health & Health Professions; 2 Departments of Anesthesiology and Surgery, College of Medicine, University of Florida, Gainesville, FL Introduction Acute kidney injury (AKI) is a common clinical condition in postoperative patients associated with a significantly increased risk of morbidity and mortality. 1-5 In a significant proportion of patients with AKI, drug intake can be related to the onset of AKI. 6-8 It is not known to what extent drug intake after the onset of AKI has an impact on renal outcomes. Purpose Describe the frequency of commonly administered postoperative medications. Investigate the association between commonly given postoperative medications and the prevalence of AKI episodes. Describe the frequency of commonly administered postoperative medications after the onset of AKI episodes. Assess the relationship between complete renal recovery and common postoperative medications given after the onset of AKI episodes. Methods We retrospectively studied all patients aged 18 years or older, who were hospitalized for more than 2 days (48 hours) and had any type of surgery between January 1, 2000 and December 31, 2010 at Shands Hospital at the University of Florida. We excluded patients with less than 2 serum creatinine (sCr) measurements and those who had chronic kidney disease stage 5 [established kidney failure: glomerular filtration rate (GFR) <15 mL/min/1.73 m 2, or a need for permanent renal replacement therapy (RRT)]. We also excluded patients who had a length of hospital stay over 90 days. The final cohort contained 54,768 patients. AKI was defined based on the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End stage renal disease) classification as an increase in sCr × 1.5 baseline, decrease in GFR ≥25%, or urine output <0.5 mL/kg/hour × 6 hours. 4 Renal outcome was classified into 3 categories: complete renal recovery (sCr returning to a level  50% above baseline sCr), partial renal recovery (a persistent increase in sCr with  50% above baseline sCr, but no need for RRT), and no renal recovery (a need for RRT at the time of hospital discharge or death). 4,9 We investigated the frequency of commonly administered postoperative medications before and after the AKI episodes. Univariate and multivariate logistic regression models were used to assess the relationship between commonly given medications and the prevalence of AKI episodes, and also to investigate the relationship between common postoperative medications given after the onset of AKI episodes and renal outcome. Discussion The odds of AKI was significantly increased by the use of vancomycin, aminoglycosides, amphotericin B, antivirals, trimetoprim-sulfametoxazol, beta-blockers, pressors, inotropes, nesiritide, and diuretics (Table 4). The odds of AKI was significantly decreased by the use of ACE-inhibitors, aspirin, NSAIDs, and statins (Table 4). The odds of partial or no renal recovery was higher with the use of amphotericin B, diuretics, pressors, and beta-blockers (Table 5). The impact of NSAIDS on AKI has been documented to be dose- dependent, with high plasma concentrations of NSAIDS associated with renal adverse effect. 10 However, in this study, ASA and NSAIDS were shown to significantly reduce the odds of AKI, irrespective of the baseline eGFR. Conclusion Our findings demonstrate that several commonly administered postoperative medications may be associated not only with an increased risk for AKI, but with a decreased likelihood of renal recovery after an AKI episode. While some of these findings could be explained, further research is required to corroborate them. These findings may be useful to determine risks versus benefits of common medications given to patients at risk of AKI or with new onset of AKI. Acknowledgement This study was funded by NIH NIGMS K23GM087709. References 1.Bihorac A, Yavas S, Subbiah S, et al. Long-term risk of mortality and acute kidney injury during hospitalization after major surgery. Ann Surg 2009; 249:851-8. 2.Hobson CE, Yavas S, Segal MS, et al. Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery. Circulation 2009; 119:2444-53. 3.Zavada J, Hoste E, Cartin-Ceba R, et al. A comparison of three methods to estimate baseline creatinine for RIFLE classification. Nephrol Dial Transplant 2010; 25:3911-8. 4.Bellomo R, Ronco C, Kellum JA et al. The Second International ConsensusConference of theAcute Dialysis Quality Initiative (ADQI) Group. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs. Crit Care 2004; 8: R204–R212 5.Abelha FJ, Botelho M, Fernandes V, et al. Determinants of postoperative acute kidney injury. Crit Care 2009; 13:R79. 6.Khutsishivili K, Okusa MD. Distant organ effects of acute kidney injury. Nephrology Self-Assessment Program 2009; 8(3). Available at: http://d.yimg.com/kq/groups/22411327/434588285/name/Nefrologia_ICU_ASN_2009.pdf. Accessed May 3, 2012. 7.Naughton CA. Drug-induced nephrotoxicity. Am Fam Phys 2008; 78:743-50. 8.Schetza M, Dastab J, Goldsteinc S, et al. Drug-induced acute kidney injury. Curr Opin Crit Care 2005; 11:555—65. 9.Bihorac A, Delano MJ, Schold JD, et al. Incidence, clinical predictors, genomics, and outcome of acute kidney injury among trauma patients. Ann Surg 2010; 252:158-65. 10.Harirforoosh S, Jamali F. Renal adverse effects of nonsteroidal anti-inflamatory drugs. Exp Opin Drug Safety 2009; 8:669-81. For more information regarding the study, please contact Shahab Bozorgmehri at: s.bozorgmehri@ufl.edu. Table 1. Sociodemographic and Clinical Characteristics of Study Participants CharacteristicsAll (n=54,768)No AKI(n=33,407) AKI P-value 1 P-value 2 All AKI(n=21,361)RIFLE-R(n=11,664)RIFLE-I(n=5,666)RIFLE-F(n=4,031) Sociodemographics Age,mean (SD) years 54 (18)53 (18)55(18) 55 (17)<0.00010.9572 Female Gender, n (%) 26,134 (47.7)16,214(48.5)9,920 (46.5)5,575 (47.8)2,662 (47.0)1,683 (41.7)<0.0001 Race/ethnicity, n (%) White 44,388 (82.5)27,297 (83.0)17,091 (81.6)9,489 (83.0)4,512 (81.2)3090 (78.3)<0.0001 African-American 6,829 (12.7)3,941 (12.0)2,888 (13.8)1,424 (12.4)774 (13.9)690 (17.5) Hispanic 1,613 (3.0)979 (3.0)634 (3.0)336 (2.9)180 (3.2)118 (3.0) Baseline eGFR, median (IQR) 91 (69,107)95 (77,109)84(54,103)89 (65,106)78 (50,101)63 (27,96)<0.0001 Comorbid Conditions, n (%) Congestive Heart Failure 4,761 (8.7)1,797 (5.4)2,964 (13.9)1,259 (10.8)882 (15.6)823 (20.4)<0.0001 Myocardial Infarction 3,919 (7.1)1,990 (6.0)1,929 (9.0)1,005 (8.6)515 (9.1)409 (10.1)<0.0001 Peripheral Vascular Disease 7,385 (13.5)3,991 (11.9)3,394 (15.9)1,835 (15.7)979 (17.3)580 (14.4)<0.00010.0005 Renal Disease 3,904 (7.1)1,315 (3.9)2,589 (12.1)869 (7.4)715 (12.6)1,005 (24.9)<0.0001 Chronic Pulmonary Disease 9,394 (17.1)5,175 (15.5)4,219 (19.7)2,282 (19.5)1,160 (20.5)777 (19.3)<0.00010.26 Mild Liver Disease 2,686 (4.9)1,072 (3.2)1,614 (7.6)619 (5.3)434 (7.6)561 (13.9)<0.0001 Diabetes without complications 8,687 (15.8)5,219 (15.6)3,468 (16.2)2,050 (17.6)953 (16.8)465 (11.5)0.0556<0.0001 Cancer 9,377 (17.1)5,788 (17.3)3,589 (16.8)2,167 (18.6)825 (14.5)97 (14.8)0.1123<0.0001 Hospital Complications, n (%) Sepsis 2,758 (5.0)221 (0.6)2,537 (11.9)447 (3.8)790 (13.9)1,300 (32.2)<0.0001 Shock 1,622 (2.9)307 (0.9)1,315 (6.2)292 (2.5)366 (6.4)657 (16.3)<0.0001 Wound complications 3,358 (6.1)1,355 (4.1)2,003 (9.4)898 (7.7)584 (10.3)521 (12.9)<0.0001<.0001 Postoperative infections 2,787 (5.1)1,165 (3.5)1,622 (7.6)710 (6.1)509 (9.0)403 (10.0)<0.0001 Pulmonary complications 5,061 (9.2)1,394 (4.2)3,667 (17.2)1,380 (11.8)1,263 (22.3)1,024 (25.4)<0.0001 Hospital Outcomes In-hospital mortality, n (%) 2,186 (4.0)251 (0.7)1,935 (9.1)450 (3.8)551 (9.7)934 (23.2)<0.0001 Days in hospital, median (IQR) 7 (4,13)5 (4,8)13 (7,24)10 (7,17)17 (10,29)25 (12,45)<0.0001 Days in ICU, median (IQR) 0 (0,3)0 (0,1)2 (0,9)1 (0,5)4 (0,13)9 (1,24)<0.0001 Hospital costs ($,1000), median (IQR) 48 (29,93)37 (25,57)93 (51,178)71 (42,119)123 (65,217)194 (89,366)<0.0001 Complete Renal Recovery n/a 18,306 (85.7)10,795 (92.5)4,707 (83.1)2,804 (69.5)<0.0001 IQR=Inter quarter range; eGFR= Estimated glomerular filtration rate, GFR was estimated by means of CKD-EPI equation 1 P value for comparison across AKI and No AKI, by analysis of variance (continuous variables) and chi-square (categorical variables) 2 P value for comparison across AKI-RIFLE categories, by analysis of variance (continuous variables) and chi-square (categorical variables) 3 Specialty surgeries include orthopedics, urology, ENT, OB/GYN, and plastic surgery 4 Others include transplant, ophthalmology, burn, non-operative, and trauma Table 2. Frequency of Common Medications Given prior to AKI Drug Use, n (%) No AKI during hospitalization (n=33407) AKI during hospitalization (n=21361) P-value Beta-blockers15292 (45.8)13256 (62.1) <.0001 Diuretic11191 (33.5)12158 (56.9) <.0001 Vancomycin8786 (26.3)9445 (44.2) <.0001 ASA8768 (26.2)6020 (28.2) <.0001 ACE inhibitors7598 (22.7)5441 (25.5) <.0001 Statin6892 (20.6)4957 (23.2) <.0001 NSAIDs6173 (18.5)2940 (13.8) <.0001 1 P-value for comparison between AKI and No AKI, by chi-square test Table 3. Common Medications Given after the Onset of AKI, Stratified by Renal Outcome Drug Use, n (%) All AKI (n=21361) Complete Renal Recovery (n=18306) Partial Renal Recovery (n=2442) No Renal Recovery (n=613) P- value 1 Pressors 2362 (11)1573 (8.6) 467 (19.1)322 (52.5) <.0001 Vancomycin2153 (10)1576 (8.6) 367 (15)210 (34.3) <.0001 Diuretic1984 (9.3)1441 (7.9) 409 (16.7)134 (21.9) <.0001 Beta-blocker1829 (8.5)1376 (7.5) 322 (13.2)131 (21.4) <.0001 ASA1321 (6.2)993 (5.4) 219 (9)109 (17.8) <.0001 TMP-SMX1183 (5.5)895 (4.9) 211 (8.6)77 (12.6) <.0001 ACE inhibitors,1059 (4.9)835 (4.6) 163 (6.7)61 (9.9) <.0001 1 P-value for comparison across renal outcome categories, by chi-square test Table 4. Association between Common Medications Used and AKI Drug Use Unadjusted Odds Ratio (95% Confidence Interval) P-value Adjusted 1 Odds Ratio (95% Confidence Interval) P-value Amphotericin B 10.64 (8.09-14.00)<.00014.46 (3.31-6.01)<.0001 Nesiritide9.38 (7.31-12.03)<.00012.43 (1.85-3.19)<.0001 Inotropes 6.72 (6.03-7.49)<.00012.35 (2.08-2.67)<.0001 Pressors 3.58 (3.41-3.75)<.00012.05 (1.93-2.17)<.0001 Diuretic2.62 (2.53-2.72)<.00011.72 (1.65-1.80)<.0001 Vancomycin2.22 (2.14-2.30)<.00011.60 (1.53-1.67)<.0001 Beta-blockers1.94 (1.87-2.00)<.00011.38 (1.33-1.44)<.0001 TMP-SMX2.65 (2.45-2.85)<.00011.31 (1.19-1.44)<.0001 Aminoglycosides1.31 (1.24-1.38)<.00011.28 (1.20-1.36)<.0001 Antiviral3.62 (3.30-3.97)<.00011.24 (1.11-1.39)0.0002 NSAIDs0.71 (0.67-0.74)<.00010.91 (0.81-0.96)0.0006 ACE inhibitors1.16 (1.18-1.21)<.00010.88 (0.84-0.92)<.0001 Statin1.16 (1.11-1.21)<.00010.79 (0.75-0.84)<.0001 ASA1.10 (1.06-1.14)<.00010.74 (0.70-0.77)<.0001 1 Adjusted for age, sex, race, admission service, routine elective vs. emergency admission, weekend vs. weekdays admission, Charlson comorbidity index, and baseline eGFR Table 5. Association between Common Medications Used and Partial or No Renal Recovery Drug Use Adjusted 1 Odds Ratio (95% Confidence Interval) P-value Pressors 1.75 (1.54-1.98)<.0001 Amphotericin B1.71 (1.31-2.24)<.0001 Diuretics1.53 (1.35-1.74)<.0001 Beta-blockers1.18 (1.04-1.35)0.01 Nesiritide1.20 (0.89-1.60)0.238 ASA1.13 (0.98-1.32)0.098 Aminoglycosides1.11 (0.92-1.35)0.275 Vancomycin1.09 (0.96-1.24)0.18 TMP-SMX1.07 (0.90-1.26)0.453 Antiviral1.05 (0.87-1.26)0.624 Inotropes 1.02 (0.83-1.24)0.868 Statin1.00 (0.81-1.23)0.998 ACE inhibitors0.90 (0.75-1.06)0.216 NSAIDs0.83 (0.67-1.03)0.089 1 Adjusted for age, sex, race, admission service, routine elective vs. emergency admission, weekends vs. weekdays admission, Charlson comorbidity index, and severity of AKI by RIFLE classification