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CJASN ePress. Published on December 19, 2014 as doi: 10.2215/CJN.01240214 Article

Long-Term Risk of Upper Gastrointestinal Hemorrhage after Advanced AKI

| Pei-Chen Wu,*† Chih-Jen Wu,†‡§ Cheng-Jui Lin,† Vin-Cent Wu,¶ for the National Taiwan University Study Group on Acute Renal Failure Group

Abstract Background and objectives There are few reports on temporary -requiring AKI as a risk factor for future upper gastrointestinal bleeding (UGIB). This study sought to explore the long-term association between dialysis- *Graduate Institute of Clinical Medicine, requiring AKI and UGIB. College of Medicine, National Taiwan Design, setting, participants, & measurements This nationwide cohort study used data from the Taiwan National University, Taipei, † Health Insurance Research Database. Patients who recovered from dialysis-requiring AKI and matched controls Taiwan; Division of Nephrology, were selected from hospitalized patients age $18 years between 1998 and 2006. The cumulative incidences of fi Department of long-term de novo UGIB were calculated, and the risk factors of UGIB and mortality were identi ed using time- Internal Medicine, varying Cox proportional hazard models adjusted for subsequent CKD and ESRD after AKI. Mackay Memorial Hospital, Taipei, ‡ Results A total of 4565 AKI-recovery patients and the same number of matched patients without AKI were Taiwan; Department – of Medicine, Mackay analyzed. After a median follow-up time of 2.33 years (interquartile range, 0.97 4.81 years), the incidence rates of Medical College, UGIB were 50 (by stringent criterion) and 69 (by lenient criterion) per 1000 patient-years in the AKI-recovery Taipei, Taiwan; group and 31 (by stringent criterion) and 48 (by lenient criterion) per 1000 patient-years in the non-AKI group §Graduate Institute of (both P,0.001). When compared with patients in the non-AKI group, the multivariate hazard ratio (HR) for Medical Sciences and Department of UGIB was 1.30 (95% confidence interval [95% CI], 1.14 to 1.48) for dialysis-requiring AKI, 1.83 (95% CI, 1.53 to , Pharmacology, 2.20) for time-varying CKD, and 2.31 (95% CI, 1.92 to 2.79) for time-varying ESRD (all P 0.001). Finally, the College of Medicine, risk for long-term mortality increased after UGIB (HR, 1.24; 95% CI, 1.12 to 1.38) and dialysis-requiring AKI Taipei Medical University, Taipei, (HR, 1.66; 95% CI, 1.54 to 1.78). | Taiwan; Department of Early Childhood Conclusions Recovery from dialysis-requiring AKI was associated with future UGIB and mortality. Care and Education, Clin J Am Soc Nephrol 10: ccc–ccc, 2014. doi: 10.2215/CJN.01240214 Mackay Junior College of Medicine, Nursing and Management, Taipei, Taiwan; and ¶ Introduction 13.4% to 26% (18,19). However, few reports have ad- Departments of The risk of upper gastrointestinal bleeding (UGIB) in Internal Medicine, dressed the effect of AKI, especially temporary dialysis- National Taiwan patients with CKD (1) or ESRD is reportedly greater requiring AKI, on the long-term risk of gastrointestinal University Hospital, than that observed in the general population (1,2). Ad- hemorrhage. We hypothesized that dialysis-requiring Taipei, Taiwan ditionally, patients with ESRD who developed UGIB AKI is an independent risk factor for UGIB. Specifi- have higher mortality than those without ESRD who cally, we sought to determine the incidence and risk Correspondence: developed UGIB (3–6). While several uremia-specific factors of UGIB after AKI using a nationwide inpatient Dr.Vin-CentWu, factors, including platelet dysfunction and impaired Department of cohort. Medicine, National platelet-vessel wall interaction (7,8), have been postu- Taiwan University lated to increase the risk of UGIB and mucosal abnor- Hospital, 7 Chung- malities of the , some studies Materials and Methods Shan South Road, suggest that repeated anticoagulant exposure (8) and Data Source Zhong-Zheng District, Taipei 100, Taiwan. the frequent use of ulcerogenic agents, such as nonste- This population-based cohort study was based on Email: q91421028@ roidal anti-inflammatory drugs (NSAIDs) (1,9) and an- medical information from Taiwan’s National Health ntu.edu.tw tiplatelets (10), also have important roles. Insurance (NHI), a nationwide compulsory healthcare Because of the advances in critical care medicine and program that covers outpatient visits, hospital admis- dialysis technologies, an increasing number of hospi- sions, prescriptions, interventional procedures, disease talized patients could be discharged alive after AKI profiles, and vital status. The study cohort consisted of (11–17). Acute gastrointestinal hemorrhage, especially 2.6 million patients hospitalized between 1998 and in the upper gastrointestinal tract, is the most frequent 2006, representing nearly 10% of all NHI enrollees. cause of bleeding after AKI (18). The incidence of short- Because all personal information was de-identified term acute gastrointestinal bleeding in hospital stay in the database to protect privacy, no informed consent varies widely in patients with AKI, ranging from was required and the study was exempt from a full ethical www.cjasn.org Vol 10 March, 2014 Copyright © 2014 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology

review by the institutional review board of the National Taiwan stringent criterion and a lenient criterion as previously re- University Hospital (201212021RINC). ported (Table 1) (20,21). By the stringent criterion, UGIB was defined using ICD-9-CM codes that specified the lesions re- – Study Population sponsible for the hemorrhage (e.g., Mallory Weiss syndrome, fi This study included patients age $18 years who developed gastric ulcer with hemorrhage). UGIB de ned by the lenient fi de novo dialysis-requiring AKI during their index admissions criterion encompassed that de ned by the stringent criterion (identified by the procedure codes for acute dialysis) and and ICD-9-CM codes that did not specify the cause of the subsequently recovered from dialysis for 30 days after dis- bleeding (e.g., plus chronic gastric ulcer without charge (Figure 1). Comorbidities were identified from at least mention of hemorrhage, gastrointestinal hemorrhage plus three outpatient visits or one inpatient claim within 1 year upper gastrointestinal endoscopy performed). Each patient fi preceding the index admission. All diagnoses were obtained was followed from the date of discharge to the rst docu- from International Classification of Diseases, 9th Revision, mented UGIB event and was censored at death or the end of fi Clinical Modification (ICD-9-CM), codes. We excluded pa- the study (December 31, 2008), whichever occurred rst. tients who had AKI or ESRD within 1 year before admission and patients with UGIB or peptic ulcers before or during Research Variables admission. Also excluded were patients who underwent re- The Charlson comorbidity index (22) was calculated us- nal transplantation, vascular access creation for long-term ing preadmission comorbidities. The following were recorded dialysis, or peritoneal-dialysis implantation; those during index hospitalization: intensive care unit admission, . who were hospitalized for 180 days; and those who did categories of major surgeries and acute organ dysfunction, . not survive for 30 days after discharge (Figure 2). UGIB and specific acute comorbidities that might be associated and peptic ulcers were excluded by ICD-9 codes (Supple- with AKI (e.g., severe sepsis, , myocardial infarction, fi mental Table 1). AKI was de ned by ICD-9 codes for AKI hepatorenal syndrome, obstructive uropathy, and exposure 3 (584. , 634.3, 635.3, 636.3, 637.3, 638.3, 639.3, 669.3, 958.5), as to contrast material). well as by procedure codes for acute dialysis. ESRD was After recovery from acute dialysis, the renal function status fi “ identi ed under the NHI Scheme by catastrophic illness was evaluated in mutually exclusive subgroups of non-CKD, fi ” certi cates for ESRD on which the commencement dates CKD, advanced CKD, and ESRD. Because GFR could not be of long-term dialysis for at least 3 months were recorded. obtained from our insurance database, CKD was defined by For comparison, we constructed a control group (non-AKI ICD-9 codes (23) and advanced CKD was defined by codes group), which was selected from the remaining hospitalized for CKD plus simultaneous erythropoiesis-stimulating agent patients who did not have a history of AKI, dialysis, and (ESA) treatment. On the basis of the regulation of NHI, ESA UGIB before and during the index admission and were can be prescribed only in anemic patients with CKD who matched with the study group (AKI-recovery group) on a 1:1 have a hematocrit level of #28% and a serum ratio basis according to age, sex, calendar year of index ad- level of .6 mg/dl (i.e., advanced CKD). Renal status was mission, and propensity scores before and during the index assessed in two overlapping periods: within 0–90 days of hospitalization. discharge and long term after discharge (at some time from the day of discharge to the day of UGIB, death, or Outcome Measures the end of the study). Patients were labeled as having ad- Our primary outcome was postdischarge nonvariceal vanced CKD or ESRD in certain periods according to the UGIB, which was identified using two modified criteria: a timing of the commencement of ESA or long-term dialysis.

Figure 1. | Schematic diagram of study design. H2RA, histamine-2 receptor antagonist; LMWH, low-molecular-weight heparin; NSAID, nonsteroidal anti-inflammatory drugs; PPI, proton-pump inhibitor; UGIB, upper gastrointestinal bleeding. Clin J Am Soc Nephrol 10: ccc–ccc, March, 2014 Long-Term UGI Bleeding After AKI, Wu et al. 3

Figure 2. | Detailed flowchart for enrollees.

Taking into account the potential confounders of UGIB, Mann–Whitney U tests to compare continuous variables we also obtained information on pertinent disorders (e.g., and chi-squared tests for categorical ones. myocardial infarction, atrial fibrillation) and medications For simplicity and specificity, the following analyses were from the day of discharge to the day of UGIB, death, or the made under the condition of UGIB defined by the stringent end of the study. The select medications were proton-pump criterion; the outcome defined by the lenient criterion was inhibitors, histamine-2 receptor antagonists, systemic cortico- used only in the sensitivity analysis. Taking into consider- steroids, NSAIDs, aspirin, clopidogrel, warfarin, heparin, and ation the higher risk of developing CKD or ESRD after AKI low-molecular-weight heparin (LMWH) (Supplemental Table and the strong correlations of CKD/ESRD with UGIB and 2). The prevalence of Helicobacter pylori was assessed mortality, we used a Cox proportional hazards model with according to treatment with triple or quadruple eradication ther- CKD/ESRD as time-dependent covariates (15,25,26), denoted apy (24), defined as a proton-pump inhibitor or histamine-2 by time-varying CKD/ESRD, to account for the effects of receptor antagonist, plus clarithromycin or metronidazole, CKD/ESRD developing at some time during follow-up on plus amoxicillin or tetracycline, with or without bismuth. the risks of UGIB and mortality. Comorbidities and postdis- charge medications (use versus nonuse) were also incorpo- Statistical Analyses rated into the analysis. Variable selection was performed by To reduce the bias in assessing the detrimental effects of using stepwise multiple regression, with a p-to-enter and AKI, we constructed a comparable non-AKI group using the p-to-leave both equal to 0.15. Final results of multivariate propensity score method in an attempt to make an unbiased analyses were summarized by hazard ratios (HRs) and estimate of all the confounders predicting dialysis. Contin- 95% confidence intervals (CIs). uous variables are described as mean6SD or median (inter- After obtaining the Cox regression equation, we estimated quartile range) as appropriate; discrete variables are presented the hazard function along with the time for a reference pa- as counts and percentages. We used independent t tests or tient who did not have AKI during the index hospitalization; 4 Clinical Journal of the American Society of Nephrology

Table 1. Nonvariceal upper gastrointestinal bleeding defined by modified stringent and lenient criteria

1. Stringent criteria: diagnosis in group A 2. Lenient criteria: one of the following: Any diagnosis in group A Any diagnosis in group B (hematemesis/GI bleeding) plus at least one in group C (upper GI illness) Any diagnosis in group B (hematemesis/GI bleeding) plus upper gastrointestinal endoscopy performed (Taiwan procedure codes: 28015C, 28016C, 28010B) 3. Exclude diagnosis in group D and associated endoscopic procedure (47025B, 47067B, 47078B) Group A: Specific diagnosis for nonvariceal UGIB, according to ICD-9 code 530.21: Ulcer of with bleeding 530.7: Gastroesophageal laceration-hemorrhage syndrome (Mallory–Weiss syndrome) 530.82: Esophageal hemorrhage 531.03: Gastric ulcer, acute with hemorrhage 531.23: Gastric ulcer, acute with hemorrhage and perforation 531.43: Gastric ulcer, chronic or unspecified with hemorrhage 531.63: Gastric ulcer, chronic or unspecified with hemorrhage and perforation 532.03: Duodenal ulcer, acute with hemorrhage 532.23: Duodenal ulcer, acute with hemorrhage and perforation 532.43: Duodenal ulcer, chronic or unspecified with hemorrhage 532.63: Duodenal ulcer, chronic or unspecified with hemorrhage and perforation 533.03: Peptic ulcer, acute with hemorrhage 533.23: Peptic ulcer, acute with hemorrhage and perforation 533.43: Peptic ulcer, chronic or unspecified with hemorrhage 533.63: Peptic ulcer, chronic or unspecified with hemorrhage and perforation 534.03: Gastrojejunal ulcer, acute with hemorrhage 534.23: Gastrojejunal ulcer, acute with hemorrhage and perforation 534.43: Gastrojejunal ulcer, chronic or unspecified with hemorrhage 534.63: Gastrojejunal ulcer, chronic or unspecified with hemorrhage and perforation 535. 3 1: and with hemorrhage 537.83: of stomach and with hemorrhage 537.84: Dieulafoy lesion (hemorrhagic) of stomach and duodenum Group B: Diagnosis for gastrointestinal bleeding but not specific for location, according to ICD-9 code 578.0: Hematemesis 578.3: Gastrointestinal hemorrhage Group C: Diagnosis for upper but not specific for bleeding, according to ICD-9 code 530–538: Disease of esophagus, stomach, and duodenum Group D: Diagnosis specific for esophageal variceal bleeding 456.0: with bleeding 456.2: Esophageal varices in diseases classified elsewhere with bleeding Taiwan procedure codes 28010B: Enteroscopy 28015C: Esophagoscopy 28016C: Upper gastrointestinal endoscopy, exam 47025B: Esophageal injection of sclerosing therapy 47043B: Endoscopic control of gastric or duodenal bleeding 47067B: Endoscopic esophageal variceal ligation 47078B: Gastric variceal sclerosing therapy

GI, gastrointestinal; UGIB, upper gastrointestinal bleeding; ICD-9, International Classification of Diseases, Ninth Revision. did not have AKI, CKD, or ESRD for 10 years after discharge; P value ,0.05 was considered to represent statistically signif- and had the mean values of all the other covariates for our icant difference. study patients. On the basis of this hazard function, we further simulated and depicted 10-year survival curves of the probability of freedom from UGIB events under different Results scenarios of conditions in regard to AKI, CKD, ad- Patient Characteristics vanced CKD, and ESRD. Specifically, we stratified patients Among the 4898 patients with de novo transient dialysis- by the status of AKI during index admission and by the renal requiring AKI, 4565 were matched with the same number status after discharge. of controls without AKI (Figure 2). The average age was All analyses were performed using R software, version 2.15.2 63.6616.5 years, 56.9% of participants were male, and the (Free Software Foundation, Inc., Boston, MA). A two-sided median preadmission Charlson comorbidity index score Clin J Am Soc Nephrol 10: ccc–ccc, March, 2014 Long-Term UGI Bleeding After AKI, Wu et al. 5

was 2 (interquartile range, 0–3) (Table 2). The baseline co- patient-years in the non-AKI group (both P,0.001). The me- morbidities and the proportions of patients undergoing dian time from discharge to the first episode of UGIB operations were similar in both groups. In the AKI-recovery according to the stringent criterion was 1.37 years in the group, more patients had severe sepsis, hepatorenal syn- AKI-recovery group, which was not statistically different drome, obstructive uropathy, and exposure to contrast ma- from the 1.22 years in the non-AKI group (P=0.41). Peptic terial during hospitalization. ulcer disease with hemorrhage accounted for 66.2% and 51.7% of the UGIB events in the AKI-recovery and non- Outcomes AKI groups, respectively (P,0.001). Of note, the number As shown in Table 3, more AKI-recovery patients received of patients receiving triple or quadruple therapy for H. pylori corticosteroids, warfarin, heparin, and LMWH and had infection was small. CKD, advanced CKD, and ESRD within 0–90 days of dis- Table 4 shows the clinical predictors of UGIB after we charge and during long-term follow-up. After a median applied the time-varying Cox regression hazards model. follow-up period of 2.33 years (interquartile range, 0.97–4.81 In contrast to the non-AKI group, the AKI-recovery years), the AKI-recovery group had a higher incidence of group had a higher long-term risk for UGIB (HR, 1.30; UGIB and higher mortality. The incidence rates of UGIB 95% CI, 1.14 to 1.48), independent of the effects from were 50 (by stringent criterion) and 69 (by lenient criterion) other covariates of age, hepatic dysfunction, severe sep- per 1000 patient-years in the AKI-recovery group and 31 (by sis, corticosteroids, NSAIDs, aspirin, time-varying CKD, stringent criterion) and 48 (by lenient criterion) per 1000 advanced CKD, and ESRD. The model exhibited modest

Table 2. Clinical characteristics in the propensity score–matched AKI-recovery and non-AKI cohorts

AKI-Recovery Group Non-AKI Group Characteristic P Value (n=4565) (n=4565)

Men 2598 (56.9) 2598 (56.9) 0.99 Age (yr) 63.63616.53 63.63616.51 0.97 Preadmission comorbidities Charlson comorbidity index scorea 2(0–3) 2 (0–3) 0.99 Myocardial infarction 174 (3.8) 191 (4.2) 0.39 Congestive heart failure 553 (12.1) 531 (11.6) 0.50 Peripheral 70 (1.5) 87 (1.9) 0.20 Cerebrovascular disease 476 (10.4) 510 (11.2) 0.27 Dementia 116 (2.5) 121 (2.7) 0.79 Chronic obstructive pulmonary disease 524 (11.5) 488 (10.7) 0.24 Rheumatologic disease 55 (1.2) 70 (1.5) 0.21 Hemiplegia 62 (1.4) 71 (1.6) 0.49 Malignancy 310 (6.8) 293 (6.4) 0.50 Diabetes mellitus 1511 (33.1) 1587 (34.8) 0.10 Moderate or severe disease 274 (6) 251 (5.5) 0.32 CKD 533 (11.7) 540 (11.8) 0.85 Hypertension 2059 (45.1) 2010 (44) 0.31 Dyslipidemia 436 (9.6) 429 (9.4) 0.83 In-hospital acute comorbidities ICU admission 2972 (65.1) 2995 (65.6) 0.63 Operation categories Cardiothoracic 191 (4.2) 171 (3.7) 0.31 Upper gastrointestinal 28 (0.6) 29 (0.6) 0.99 Lower gastrointestinal 96 (2.1) 81 (1.8) 0.29 Hepatobiliary 58 (1.3) 54 (1.2) 0.78 Acute organ dysfunction Cardiovascular 326 (7.1) 307 (6.7) 0.46 Respiratory 855 (18.7) 843 (18.5) 0.77 Hepatic 86 (1.9) 84 (1.8) 0.94 Neurologic 80 (1.8) 94 (2.1) 0.32 Hematologic 70 (1.5) 82 (1.8) 0.37 Severe sepsis 835 (18.3) 527 (11.5) ,0.001 Shock 335 (7.3) 296 (6.5) 0.12 Myocardial infarction 271 (5.9) 372 (8.1) ,0.001 Hepatorenal syndrome 9 (0.2) 0 (0) 0.004 Obstructive uropathy 110 (2.4) 5 (0.1) ,0.001 Exposure to contrast material 1082 (23.7) 922 (20.2) ,0.001

Unless otherwise noted, values are the number (percentage) of participants. ICU, intensive care unit. aMedian (25th–75th percentile). 6 Clinical Journal of the American Society of Nephrology

Table 3. Long-term outcomes and conditions pertinent to outcome after discharge

AKI-Recovery Group Non-AKI Group Variable P Value (n=4565) (n=4565)

Medications PPI 1288 (28.2) 770 (16.9) ,0.001 Histamine-2 receptor antagonist 989 (21.7) 991 (21.7) 0.98 Corticosteroids 1979 (43.4) 1752 (38.4) ,0.001 Long-term usea of steroids 289 (6.3) 225 (4.9) 0.004 NSAIDs 2294 (50.3) 2577 (56.5) ,0.001 Long-term usea of NSAIDs 379 (8.3) 498 (10.9) ,0.001 Aspirin 1051 (23) 1141 (25) 0.03 Long-term usea of aspirin 393 (8.6) 550 (12.0) ,0.001 Clopidogrel 624 (13.7) 576 (12.6) 0.15 Warfarin 421 (9.2) 248 (5.4) ,0.001 Heparin 988 (21.6) 454 (9.9) ,0.001 Low-molecular-weight heparin 259 (5.7) 152 (3.3) ,0.001 Helicobacter pylori eradication therapy 8 (0.2) 6 (0.1) 0.79 Renal status within 0–90 d of discharge ,0.001 CKD 578 (12.7) 116 (2.5) Advanced CKD 87 (1.9) 7 (0.2) ESRDb 72 (1.6) 0 (0) Renal status during long-term follow-up ,0.001 CKD 751 (16.5) 314 (6.9) Advanced CKD 101 (2.2) 33 (0.7) ESRD 896 (19.6) 57 (1.2) Comorbidities during long-term follow-up Myocardial infarction 41 (0.9) 20 (0.4) 0.01 Atrial fibrillation 57 (1.2) 76 (1.7) 0.12 Outcomes UGIB event (lenient criterion) 949 (20.8) 706 (15.5) ,0.001 UGIB event (stringent criterion) 702 (15.4) 464 (10.2) ,0.001 Median time after discharge (yr) 1.37 1.22 0.41 PUD with hemorrhage 465 (66.2) 240 (51.7) ,0.001 Gastric ulcer bleeding 252 (35.9) 139 (30.0) Duodenal ulcer bleeding 149 (21.2) 62 (13.4) Mortality 2557 (56.0) 1496 (32.8) ,0.001

Unless otherwise noted, values are the number (percentage) of participants. PPI, proton-pump inhibitor; NSAIDs, nonsteroidal anti- inflammatory drugs; PUD, . aDefined as drug prescription in 3 consecutive months. bDefined by the commencement dates of long-term dialysis at 31–90 days of discharge. discrimination with a c statistic of 0.70 and an adjusted Probability of Freedom from UGIB in the Long Term under R2 value of 0.08. Furthermore, the strength of the associ- Different Scenarios of Morbid Conditions in Regard to AKI, ation between AKI recovery and long-term UGIB was CKD, and ESRD stronger when time-varying CKD/ESRD was not incor- Our simulation results (Figure 3) showed AKI recovery had porated into the analysis (HR, 1.71; 95% CI, 1.52 to 1.93; an ominous long-term association with the risk of UGIB com- P,0.001). Warfarin, heparin, and LMWH were not pre- pared with a reference hospitalized patient without AKI, dictive of UGIB. CKD, and ESRD for the whole period of 10 years after dis- For sensitivity analysis, we replaced UGIB defined by the charge. Overall, the long-term UGIB-free probability of pa- stringent criterion with UGIB defined by the lenient criterion tients recovering from advanced AKI is sandwiched between and conducted the time-varying Cox regression model again. that of the reference patient and that of patients with CKD The analysis showed that AKI recovery was significantly after discharge. Patients with ESRD during follow-up had associated with long-term UGIB as well (HR, 1.23; 95% CI, lower long-term UGIB-free probability than did those with 1.10 to 1.36; P,0.001), with a c statistic of 0.69 and an ad- advanced CKD and CKD. There was a trend that the risks for justed R2 value of 0.09. UGIB appeared to be higher among patients whose renal We also analyzed the risk factors for mortality by applying status changed to a worse category during follow-up. the Cox regression model with time-varying covariates. AKI recovery (HR, 1.66; 95% CI, 1.54 to 1.78) and UGIB (HR, 1.24; 95% CI, 1.12 to 1.38) were significantly associated with long- Discussion term mortality. The model’spredictionabilitywasgood To our knowledge, our study is the first to identify that (c statistic=0.77; adjusted R2=0.35). hospitalized patients surviving temporary acute dialysis have Clin J Am Soc Nephrol 10: ccc–ccc, March, 2014 Long-Term UGI Bleeding After AKI, Wu et al. 7

Table 4. Independent predictors of upper gastrointestinal bleeding(defined by stringent criterion) after dialysis-requiring AKI

Variable Hazard Ratio (95% Confidence Interval) P Value

Age (per decade) 1.20 (1.15 to 1.25) ,0.001 AKI-recovery groupa 1.30 (1.14 to 1.48) ,0.001 Premorbid moderate/severe 1.57 (1.25 to 1.95) ,0.001 Acute hepatic dysfunction 1.59 (1.10 to 2.29) 0.01 Severe sepsis 1.29 (1.08 to 1.54) 0.01 Long-term use of corticosteroids 1.28 (1.01 to 1.62) 0.04 NSAIDs 1.58 (1.32 to 1.89) ,0.001 Aspirin 1.71 (1.36 to 2.14) ,0.001 Time-varyingb CKD 1.83 (1.53 to 2.20) ,0.001 Time-varyingb advanced CKD 2.10 (1.31 to 3.36) 0.002 Time-varyingb ESRD 2.31 (1.92 to 2.79) ,0.001

aIn contrast to non-AKI group. b“Time-varying” denotes some time during follow-up.

higher long-term risk for UGIB and mortality than those number of patients receiving heparin and LMWH was sim- without a history of dialysis-requiring AKI. After adjustment ilar to that of ESRD patients, the presence of ESRD might for age, comorbidities, and postdischarge drugs, hospitaliza- mask the salient effects of heparin and LMWH. tion for dialysis-requiring AKI remains a significant risk factor Consistent with the results from our cohorts suggesting for future UGIB, even though the AKI event is momentary. In that peptic ulcer disease with hemorrhage was the most our statistical models, both CKD and ESRD were handled as prominent cause of UGIB in AKI-recovery patients (66.2%), time-dependent covariates so that the association between one other study reported that gastroduodenal ulcers account- AKI and subsequent UGIB was independent of the develop- ed for around 60% of UGIB cases viewed with endoscopy in ment or progression of CKD/ESRD. Moreover, the strength patients with CKD (29). In another recent population-based of the association between AKI and UGIB was stronger when study, peptic ulcer disease (35.2%) and gastroduodenitis CKD/ESRD was not considered, and there was a trend that with hemorrhage (29.1%) were the leading causes of UGIB the risks for UGIB were higher among patients with worse in patients with ESRD (21,30). In brief, the role of peptic renal status during follow-up. These findings are consistent ulcer disease with hemorrhage might be more prominent with the hypothesis that part of the connection between AKI in patients recovering from advanced AKI. Although AKI and subsequent UGIB is mediated through the development involves some degree of inflammation (31–33), an “immu- of CKD/ESRD after AKI. noparalysis” state, similar to that ensuing from sepsis and The crude incidence rates of UGIB in our patients with critical illness (34,35), may coexist and make the effects of H. dialysis-requiring AKI were 50 and 69 per 1000 patient-years pylori more pernicious. Our study showed, however, that a according to the stringent and lenient criteria, respectively. small portion of patients received H. pylori eradication ther- To our knowledge, this is the only study estimating the long- apy. According to a population-based study in Taiwan, term incidence of UGIB in patients with AKI based on both H. pylori eradication therapy was given in 24.5%, 31.1%, inpatient and outpatient claims. In comparison, the incidence and 17.1% of patients with uncomplicated, bleeding, and of UGIB requiring hospitalization in patients with ESRD was perforated peptic ulcer disease, respectively, and the num- reported to be 23–42 per 1000 patient-years (2,9). However, bers of prescriptions did not change significantly between these reports retrieved data only from more severe UGIB 1997 and 2006 (36). Our results suggested that the preva- that required hospitalization. It is important to stress that lence of H. pylori infection might be low in this patient pop- approximately 40% of UGIB events reported in the United ulation or that our patients were undertreated. The role and States Medicare records were managed in an outpatient set- prevalence of H. pylori infection in UGIB after advanced AKI ting (27). By also incorporating outpatient claims, a recent require further evaluation. population-based study of nearly 1 million patients with This study provides evidence that patients recovering from ESRD reported an incidence rate of 57 and 328 UGIB epi- dialysis-requiring AKI have a higher risk of UGIB, although a sodes per 1000 patient-years, according to the stringent and compelling mechanism linking the two is lacking. Despite all lenient definitions, respectively (21). Despite the lack of a the statistical efforts, our study might overfit this finding or head-to-head comparison, the incidence of UGIB in patients UGIB might be an underappreciated late hazard of advanced recovering from advanced AKI is seemingly lower than that AKI through an as-yet-unknown mechanism. Our study has observed in patients with ESRD, but it is still much greater other limitations. The most important stems from the ret- than the occurrence in the general population, for which an rospective analysis of administrative billing claims. Previous overall incidence of 89–112 UGIB events per 100,000 patient- studies have shown the NHI Research Database is of ac- years was reported (28). Patients with ESRD receiving he- ceptable quality in providing epidemiologic data, including modialysis are frequently exposed to anticoagulants, which studies of CKD (37). Although GFR was unobtainable from undoubtedly augment the bleeding risk. In our study, hep- the ICD codes, which added difficulty in identifying the arin and LMWH were not predictive of UGIB. Because the CKD stage, a meta-analysis suggested that CKD codes are 8 Clinical Journal of the American Society of Nephrology

Figure 3. | Future 10-year probability of freedom from upper gastrointestinal bleeding was lower among patients with worse renal status during follow up. The simulation curves (A) were depicted based on different scenarios of morbid conditions with regard to AKI, CKD, ad- vanced CKD, and ESRD (B). Clin J Am Soc Nephrol 10: ccc–ccc, March, 2014 Long-Term UGI Bleeding After AKI, Wu et al. 9

insensitive but reasonably specific (38). Since 2004, the rate 5. Sood P, Kumar G, Nanchal R, Sakhuja A, Ahmad S, Ali M, Kumar of misdiagnosing CKD may have been modest in Taiwan N, Ross EA: Chronic kidney disease and end-stage renal disease predict higher risk of mortality in patients with primary upper because a CKD prevention program has made nearly all gastrointestinal bleeding. Am J Nephrol 35: 216–224, 2012 patients with CKD diagnosis undergo a nephrology consul- 6. Wu CY, Wu MS, Kuo KN, Wang CB, Chen YJ, Lin JT: Long-term tation (39,40). peptic ulcer rebleeding risk estimation in patients undergoing The second limitation is that we did not analyze the dose haemodialysis: A 10-year nationwide cohort study. Gut 60: and frequency of ulcerogenic drugs in predicting UGIB after 1038–1042, 2011 7. Mannucci PM, Tripodi A: Hemostatic defects in liver and renal AKI. In one study, although the use of ulcerogenic agents dysfunction. Hematology (Am Soc Hematol Educ Program) fi was a signi cant risk factor for peptic ulcer rebleeding in 2012: 168–173, 2012 patients with ESRD, a dose-dependent response pattern was 8. Kaw D, Malhotra D: Platelet dysfunction and end-stage renal not found (6). The effect of the dose and frequency of ulcero- disease. Semin Dial 19: 317–322, 2006 genic agents on UGIB after advanced AKI remains unsolved. 9. Wasse H, Gillen DL, Ball AM, Kestenbaum BR, Seliger SL, Sherrard D, Stehman-Breen CO: Risk factors for upper gastroin- Another limitation is that our database does not contain testinal bleeding among end-stage renal disease patients. Kidney data regarding smoking, which is a risk factor for UGIB in Int 64: 1455–1461, 2003 patients with ESRD (9). In light of the idea from the joint 10. Cheung J, Yu A, LaBossiere J, Zhu Q, Fedorak RN: Peptic ulcer modeling of multiple diseases (41), we captured the effect bleeding outcomes adversely affected by end-stage renal disease. of smoking through investigating its proxies, namely Gastrointest Endosc 71: 44–49, 2010 11. Waikar SS, Winkelmayer WC: Chronic on acute renal failure: chronic obstructive pulmonary disease, lung cancer, myo- long-term implications of severe . JAMA 302: cardial infarction, and diabetes mellitus, which are highly 1227–1229, 2009 related to smoking (42,43). We found that AKI was asso- 12. Wu VC, Huang TM, Lai CF, Shiao CC, Lin YF, Chu TS, Wu PC, ciated with UGIB independent of the effects of these prox- Chao CT, Wang JY, Kao TW, Young GH, Tsai PR, Tsai HB, Wang fi CL, Wu MS, Chiang WC, Tsai IJ, Hu FC, Lin SL, Chen YM, Tsai TJ, ies, suggesting smoking might not have a signi cant role Ko WJ, Wu KD: Acute-on-chronic kidney injury at hospital dis- in UGIB after AKI. charge is associated with long-term dialysis and mortality. Kid- In conclusion, the current study found that dialysis-requiring ney Int 80: 1222–1230, 2011 AKI was associated with a higher risk of long-term UGIB, and 13. Wu VC, Ko WJ, Chang HW, Chen YW, Lin YF, Shiao CC, Chen that UGIB was a significant predictor of long-term mortality YM, Chen YS, Tsai PR, Hu FC, Wang JY,Lin YH, Wu KD; National Taiwan University Surgical ICU Acute Renal Failure Study Group after AKI. The high accumulation rates of NSAIDs and anti- (NSARF): Risk factors of early redialysis after weaning from platelets use after AKI augmented the possibility of UGIB. These postoperative acute renal replacement therapy. Intensive Care findings are of clinical importance for physicians who care for Med 34: 101–108, 2008 patients surviving advanced AKI. 14. Wu VC, Wang CH, Wang WJ, Lin YF, Hu FC, Chen YW, Chen YS, WuMS,LinYH,KuoCC,HuangTM,ChenYM,TsaiPR,Ko WJ, Wu KD; NSARF Study Group: Sustained low-efficiency dialysis Acknowledgments versus continuous veno-venous hemofiltration for postsurgical We would like to thank Dr. Ju-Yeh Yang for her experience in using acute renal failure. Am J Surg 199: 466–476, 2010 the US Renal Data System to evaluate UGIB in patients with ESRD; 15. Wu VC, Wu CH, Huang TM, Wang CY, Lai CF, Shiao CC, Chang Professor Likwang Chen for her offering of the database and statistical CH, Lin SL, Chen YY,Chen YM, Chu TS, Chiang WC, Wu KD, Tsai support; and Drs. Chi-Feng Pan, Tao-Min Huang, Che-Hsiung Wu, PR, Chen L, Ko WJ; NSARF Group: Long-term risk of coronary events after AKI. J Am Soc Nephrol 25: 595–605, 2014 and Tai-Shuan Lai for their dedication to data interpretation and re- 16. Wu VC, Young GH, Huang PH, Lo SC, Wang KC, Sun CY, Liang vision of the statistical models. CJ, Huang TM, Chen JH, Chang FC, Chen YL, Kuo YS, Chen JB, This study was supported by the following grants: National Sci- Chen JW, Chen YM, Ko WJ, Wu KD; NSARF group: In acute ence Council (NSC)-102-2314-B-002-140-MY2, NSC 101-2314-B-002- kidney injury, indoxyl sulfate impairs human endothelial pro- 132-MY3,NSC 101-2314-B-002-085-MY3,NSC100-2314-B-002-119,and genitor cells: Modulation by statin. Angiogenesis 16: 609–624, 2013 NSC-100-2314-B-002-147-MY3; National Taiwan University Hospi- 17. Huang TM, Wu VC, Young GH, Lin YF, Shiao CC, Wu PC, Li WY, tal (NTUH)-103-082, NTUH-103-S-2467, NTUH-102-CGN03, NTUH- YuHY, Hu FC, Lin JW, Chen YS, Lin YH, Wang SS, Hsu RB, Chang 102-S2097, NTUH-101-M1953, and NTUH-100-N1776; and National FC, Chou NK, Chu TS, Yeh YC, Tsai PR, Huang JW, Lin SL, Chen Health Research Institute (NHRI)-PH-101-SP-09 and NHRI-PH-102- YM, Ko WJ, Wu KD; National Taiwan University Hospital Study SP-09. Group of Acute Renal Failure: Preoperative predicts adverse renal outcomes after coronary artery bypass grafting. J Am Soc Nephrol 22: 156–163, 2011 Disclosures 18. Fiaccadori E, Maggiore U, Clima B, Melfa L, Rotelli C, Borghetti None. A: Incidence, risk factors, and prognosis of gastrointestinal hemorrhage complicating acute renal failure. Kidney Int 59: 1510–1519, 2001 References 19. Klouche K, Cristol JP, Kaaki M, Turc-Baron C, Canaud B, Beraud 1. Luo JC, Leu HB, Huang KW, Huang CC, Hou MC, Lin HC, Lee FY, JJ: Prognosis of acute renal failure in the elderly. Nephrol Dial Lee SD: Incidence of bleeding from gastroduodenal ulcers in Transplant 10: 2240–2243, 1995 patients with end-stage renal disease receiving . 20. Targownik LE, Nabalamba A: Trends in management and out- CMAJ 183: E1345–E1351, 2011 comes of acute nonvariceal upper gastrointestinal bleeding: 2. Kuo CC, Kuo HW, Lee IM, Lee CT, Yang CY: The risk of upper 1993-2003. Clin Gastroenterol Hepatol 4: 1459–1466, 2006 gastrointestinal bleeding in patients treated with hemodialysis: 21. Yang JY, Lee TC, Montez-Rath ME, Paik J, Chertow GM, Desai M, a population-based cohort study. BMC Nephrol 14: 15, 2013 Winkelmayer WC: Trends in acute nonvariceal upper gastrointestinal 3. Boyle JM, Johnston B: Acute upper gastrointestinal hemorrhage bleeding in dialysis patients. J Am Soc Nephrol 23: 495–506, 2012 in patients with chronic renal disease. Am J Med 75: 409–412, 22. Charlson ME, Pompei P, Ales KL, MacKenzie CR: A new method 1983 of classifying prognostic comorbidity in longitudinal studies: 4. Tsai CJ, Hwang JC: Investigation of upper gastrointestinal hem- Development and validation. J Chronic Dis 40: 373–383, 1987 orrhage in chronic renal failure. J Clin Gastroenterol 22: 2–5, 23. Hsu TW, Liu JS, Hung SC, Kuo KL, Chang YK, Chen YC, Hsu CC, 1996 Tarng DC: Renoprotective effect of -angiotensin- 10 Clinical Journal of the American Society of Nephrology

system blockade in patients with predialysis advanced chronic Williams HC, Woolf AD, Lopez AD, Davis A: UK health perfor- kidney disease, hypertension, and anemia. JAMA Intern Med 174: mance: Findings of the Global Burden of Disease Study 2010. 347–354, 2014 Lancet 381: 997–1020, 2013 24. Wu CY, Kuo KN, Wu MS, Chen YJ, Wang CB, Lin JT: Early Heli- 35. Sundar KM, Sires M: Sepsis induced immunosuppression: Im- cobacter pylori eradication decreases risk of gastric cancer in plications for secondary and complications. Indian J patients with peptic ulcer disease. 137: 1641– Crit Care Med 17: 162–169, 2013 1648, e1–e2, 2009 36. Wu CY, Wu CH, Wu MS, Wang CB, Cheng JS, Kuo KN, Lin JT: A 25. Wang WJ, Chao CT,Huang YC, Wang CY,Chang CH, Huang TM, nationwide population-based cohort study shows reduced hos- Lai CF, Huang HY, Shiao CC, Chu TS, Chen YM, Wu VC, Ko WJ, pitalization for peptic ulcer disease associated with H pylori Wu KD; National Taiwan University Study Group on Acute Renal eradication and proton pump inhibitor use. Clin Gastroenterol Failure: The impact of acute kidney injury with temporary dialysis Hepatol 7: 427–431, 2009 on the risk of fracture. J Bone Miner Res 29: 676–684, 2014 37. Kuo HW, Tsai SS, Tiao MM, Yang CY: Epidemiological features of 26. Lai TS, Wang CY, Pan SC, Huang TM, Lin MC, Lai CF, Wu CH, Wu CKD in Taiwan. Am J Kidney Dis 49: 46–55, 2007 VC, Chien KL; National Taiwan University Hospital Study Group 38. Grams ME, Plantinga LC, Hedgeman E, Saran R, Myers GL, on Acute Renal Failure (NSARF): Risk of developing severe sepsis Williams DE, Powe NR; CDC CKD Surveillance Team: Validation after acute kidney injury: A population-based cohort study. Crit of CKD and related conditions in existing data sets: A systematic Care 17: R231, 2013 review. Am J Kidney Dis 57: 44–54, 2011 27. Cooper GS, Kou TD, Wong RC: Outpatient management of non- 39. Wu IW, Wang SY, Hsu KH, Lee CC, Sun CY, Tsai CJ, Wu MS: variceal upper gastrointestinal hemorrhage: unexpected mortality Multidisciplinary predialysis education decreases the incidence in Medicare beneficiaries. Gastroenterology 136: 108–114, 2009 of dialysis and reduces mortality—a controlled cohort study 28. Loperfido S, Baldo V, Piovesana E, Bellina L, Rossi K, Groppo M, based on the NKF/DOQI guidelines. Nephrol Dial Transplant 24: Caroli A, Dal Bo` N, Monica F, Fabris L, Salvat HH, Bassi N, 3426–3433, 2009 Okolicsanyi L: Changing trends in acute upper-GI bleeding: A 40. Hwang SJ, Tsai JC, Chen HC: Epidemiology, impact and pre- population-based study. Gastrointest Endosc 70: 212–224, 2009 ventive care of chronic kidney disease in Taiwan. Nephrology 29. Chalasani N, Cotsonis G, Wilcox CM: Upper gastrointestinal (Carlton) 15[Suppl 2]: 3–9, 2010 bleeding in patients with chronic renal failure: Role of vascular 41. Best N, Hansell AL: Geographic variations in risk: Adjusting for ectasia. Am J Gastroenterol 91: 2329–2332, 1996 unmeasured confounders through joint modeling of multiple 30. Yang JY, Lee TC, Montez-Rath ME, Chertow GM, Winkelmayer diseases. Epidemiology 20: 400–410, 2009 WC: Risk factors of short-term mortality after acute nonvariceal 42. Centers for Disease Control and Prevention: Health effects of upper gastrointestinal bleeding in patients on dialysis: A cigarette smoke. http://www.cdc.gov/tobacco/data_statistics/ population-based study. BMC Nephrol 14: 97, 2013 fact_sheets/health_effects/effects_cig_smoking/. Accessed June 31. Grams ME, Rabb H: The distant organ effects of acute kidney 8, 2014 injury. Kidney Int 81: 942–948, 2012 43. U.S. Department of Health and Human Services: 2014 Surgeon 32. White LE, Hassoun HT: Inflammatory mechanisms of organ General’s Report: The health consequences of smoking—50 crosstalk during ischemic acute kidney injury. Int J Nephrol 2012: years of progress. http://www.cdc.gov/tobacco/data_statistics/ 505197, 2012 sgr/50th-anniversary/index.htm. Accessed February 6, 2014. 33. Yap SC, Lee HT: Acute kidney injury and extrarenal organ dys- function: New concepts and experimental evidence. Anesthesi- Received: February 3, 2014 Accepted: November 11, 2014 ology 116: 1139–1148, 2012 34. Murray CJ, Richards MA, Newton JN, Fenton KA, Anderson HR, Atkinson C, Bennett D, Bernabe´ E, Blencowe H, Bourne R, Published online ahead of print. Publication date available at www. Braithwaite T,Brayne C, Bruce NG, Brugha TS, Burney P,Dherani cjasn.org. M, Dolk H, Edmond K, Ezzati M, Flaxman AD, Fleming TD, Freedman G, Gunnell D, Hay RJ, Hutchings SJ, Ohno SL, Lozano This article contains supplemental material online at http://cjasn. R, Lyons RA, Marcenes W, Naghavi M, Newton CR, Pearce N, asnjournals.org/lookup/suppl/doi:10.2215/CJN.01240214/-/ Pope D, Rushton L, Salomon JA, Shibuya K, Vos T, Wang H, DCSupplemental. Supplemental Data: ICD-9, procedure, and drug codes pertinent to study design

Supplementary Table 1: Exclusion criteria of the enrollees ICD-9 codes Procedure codes Upper gastrointestinal 530.21, 530.7, 530.82, 531, bleeding and peptic 532, 533, 534, 535.X1, ulcers 537.83, 537.84 Acute kidney injury 584.X, 634.3, 635.3, 636.3, 637.3, 638.3, 639.3, 669.3, 958.5 Acute dialysis 58001C, 58019C, 58020C, 58021C, 58022C, 58023C, 58024C, 58025C, 58027C, 58029C, 58007C, 58014C, 58018C, 58002C, 58011A, 58011B, 58011C, 58017A, 58017B, 58017C, 58026C, 58028C End-stage renal disease “Catastrophic illness certificates”

Supplementary Table 2: Anatomic therapeutic chemical (ATC) classification codes for select medications Class of medication ATC codes Proton pump inhibitors A02BC Histamine-2 receptor antagonists A02BA Systemic corticosteroids H02AB, H02BX, M01BA Non-steroidal anti-inflammatory drugs M01AB, M01AC, M01AE, M01AH Aspirin B01AC06 Clopidogrel B01AC04 Warfarin B01AA03 Heparin B01AB01 Low-molecular weight heparin B01AB04, B01AB05, B01AB06, B01AB10