急性肾损伤

Acute Kidney Injury Associates with Increased Long-Term Mortality Jean-Philippe Lafrance and Donald R. Miller Center for Health Quality, Outcomes, and Economic Research, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts; and Boston University School of Public Health, Boston, Massachusetts ABSTRACT Acute kidney injury (AKI) associates with higher in-hospital mortality, but whether it also associates with increased long-term mortality is unknown, particularly after accounting for residual kidney function after hospital discharge. We retrospectively analyzed data from US veteran patients who survived at least 90 d after discharge from a hospitalization. We identified AKI events not requiring dialysis from laboratory data and classified them according to the ratio of the highest creatinine during the hospitalization to the lowest creatinine measured between 90 d before hospitalization and the date of discharge. We esti- mated mortality risks using multivariable Cox regression models adjusting for demographics, comor- bidities, medication use, primary diagnosis of admission, length of stay, mechanical ventilation, and postdischarge estimated GFR (residual kidney function). Among the 864,933 hospitalized patients in the study cohort, we identified 82,711 hospitalizations of patients with AKI. In the study population of patients who survived at least 90 d after discharge, 17.4% died during follow-up (AKI 29.8%, without AKI 16.1%). The adjusted mortality risk associated with AKI was 1.41 (95% confidence interval [CI] 1.39 to 1.43) and increased with increasing AKI stage: 1.36 (95% CI 1.34 to 1.38), 1.46 (95% CI 1.42 to 1.50), and 1.59 (95% CI 1.54 to 1.65; P � 0.001 for trend). In conclusion, AKI that does not require dialysis associates with increased long-term mortality risk, independent of residual kidney function, for patients who survive 90 d after discharge. Long-term mortality risk is highest among the most severe cases of AKI. J Am Soc Nephrol 21: 345–352, 2010. doi: 10.1681/ASN.2009060636 Acute kidney injury (AKI) affects up to 15.3% of all hospitalized patients.1,2 Regardless of the underly- ing cause, AKI is associated with significantly in- creased in-hospital morbidity, mortality, and costs.2–16 The majority of previous studies linking AKI to mortality examined in-hospital mortality only and did not address postdischarge morbidity and mortality.2,4,7,8,10,11,13–16 Studies examining postdischarge mortality have focused primarily on critically ill patients with AKI that requires dialysis.9 Consequently, it remains unclear whether AKI that does not require dialysis is associated with a higher long-term risk for all-cause mortality. One of the challenges of long-term mortality studies is to estimate the mortality risk indepen- dently associated with AKI from risk associated with chronic kidney disease (CKD). Some patients have incomplete recovery of their kidney function after AKI, and CKD is associated with a higher risk for mortality.17,18 To evaluate the independent long-term mortality risk of AKI, it is essential to adjust for postdischarge kidney function. The ob- jective of this study was to estimate the postdis- charge, long-term mortality risk associated with Received June 19, 2009. Accepted October 13, 2009. Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Jean-Philippe Lafrance, Center for Health Quality, Outcomes, and Economic Research, Edith Nourse Rog- ers Memorial Veterans Hospital, 200 Springs Road, building 70, Bedford, MA 01730. Phone: 781-687-2865; Fax: 781-687-3106; E-mail: jplaf@bu.edu Copyright � 2010 by the American Society of Nephrology CLINICAL EPIDEMIOLOGY www.jasn.org J Am Soc Nephrol 21: 345–352, 2010 ISSN : 1046-6673/2102-345 345 AKI while adjusting for residual kidney function in a large cohort of US veterans. RESULTS We identified 864,933 patients who had a first hospitalization during our study period and met the inclusion criteria. The cohort was predominantly male (4.9% female), and the mean age was 61.8 yr. From this cohort, we identified 82,711 hospi- talizations of patients with AKI (9.6% of the cohort), catego- rized as follows: Acute Kidney Injury Network (AKIN) stage I, 52,338; stage II, 19,771; and stage III, 10,602. Baseline charac- teristics for patients with and without AKI are presented in Table 1 . As expected, patients with AKI had more comorbidi- ties compared with patients without AKI. Mechanical ventila- tionwas alsomore prevalent and the hospital length of staywas longer for patients with AKI. The mean number of creatinine values for each patient was 3.5 at baseline and 1.1 after discharge. Baseline creatinine val- ues were missing in 5.0% of patients without AKI (by defini- tion, no baseline creatinine values was missing in the AKI group), and 57.2% had at least one creatinine value before admission (versus 60.5% in theAKI group). The proportions of patients with postdischarge values in the group without AKI were 23, 38, and 48% within 30, 60, and 90 d respectively, whereas the corresponding proportions were 38, 55, and 65% in the AKI group. The latest creatinine value before discharge was�1.3 mg/dl (115 �mol/L) in 89% of patients with at least one inpatient value in the group without AKI and 78% in the AKI group. Because we included the latest inpatient value in the postdischarge creatinine assessment when a postdischarge creatinine was missing, 89.8% of those without AKI and 100% of the AKI group had a “postdischarge” value before imputa- tion. During follow-up (mean duration 2.34 yr [1.43]), 150,231 (17.4%) patients died. The crude cumulative risk for death was higher in the group with AKI (29.8%) than in the group with- out AKI (16.1%). Crude and adjusted hazard ratios (HRs) ob- tained from the Cox proportional hazards regression models are presented in Table 2. Whereas each successive addition of covariates to the model reduced the mortality risk estimate, AKI remained associated with a 41% increased risk for all- cause mortality in the fully adjusted model (adjusted HR 1.41; 95% confidence interval [CI] 1.39 to 1.43). A risk gradient was found among the three AKI categories (adjusted HR 1.39 ver- sus 1.51 versus 1.71, for AKIN stages I, II, and III, respectively, compared with no AKI), with severity of AKI associated with increasing risk for death (P � 0.001 for trend). Unadjusted Kaplan-Meier survival curves stratified by AKIN categories of AKI are presented in Figure 1. As shown in Table 3, mortality risks were lower in patients who had lower baseline estimated GFR (eGFR; adjusted HR 1.45 versus 1.35 versus 1.31 versus 1.23 for eGFR�90, 60 to 89, 45 to 59, and 30 to 44 ml/min per 1.73 m2, respectively). AKI- associated mortality HR also decreased with older age and was slightly lower in patients with diabetes compared with those without diabetes (Table 3). Between baseline and postdischarge periods, eGFR de- creased by a median of 1.5% (0.4 to 16.7%). In 56.4% of the patients, this decrease, if any, was� 10%, and they were con- sidered to have recovered from AKI or to have maintained their kidney function. Among those patients, AKI was also as- sociated with a higher mortality risk (adjusted HR 1.47; 95% CI 1.43 to 1.51). Mortality risk also varied with baseline eGFR (Table 4) with risk decreasing with lower baseline eGFR. Both sensitivity analyses in which we included patients who were readmitted in the first 30 d after discharge or in which we did not include the latest inpatient creatinine value as a post- discharge value showed similar results to the main model (ad- justed HR 1.40 [95%CI 1.38 to 1.42] and 1.44 [95%CI 1.42 to 1.46], respectively). The complete case analysis showed similar results (adjusted HR 1.33; 95% CI 1.31 to 1.35). The fourth sensitivity analysis, in whichwe limited the sample to survivors at 6 mo after discharge (n� 201,879) and started follow-up at that time, also showed a higher mortality risk associated with AKI (crude HR 1.19 [95% CI 1.18 to 1.21]; HR adjusted for demographics, comorbidities, and hospitalization details 1.14 [95%CI 1.12 to 1.16]; and fully adjustedHR 1.13 [95%CI 1.11 to 1.14]). DISCUSSION This study evaluated long-term mortality risk with AKI not requiring dialysis in a large adult cohort with relatively long follow-up. To our knowledge, this is the first study to attempt to disentangle the direct association of AKI with mortality in- dependent of the short-term loss of kidney function induced by AKI. We have shown that AKI is associated with a higher mortality risk in patients who survived for at least 90 d after hospital discharge and that the risk increases continuously with increasing severity of AKI. The association of AKI and higher in-hospital mortality has been clearly demonstrated, and the magnitude of the associa- tion seems to depend on the population.2–16 Postdischarge mortality has also been evaluated in patients with severe AKI requiring renal replacement therapies.9 Our results are consis- tent with the few studies that reported long-term mortality in patients with less severe forms of AKI.3,5,12,15,19,20 In patients admitted to an intensive care unit, the 1-yr mortality was found to be higher in patients with mild and severe renal dys- function but not with moderate dysfunction.3 In the same study, when the sample was restricted to patients who were discharged alive, the crude cumulative risk for death was more than two times higher in patients with moderate and severe AKI than in those without AKI (4.5, 11.4, and 12.6% for no AKI, moderate AKI, and severe AKI, respectively); however, those riskswere not evaluated in amultivariatemodel andwere not adjusted for kidney function after the event. Among elderly CLINICAL EPIDEMIOLOGY www.jasn.org 346 Journal of the American Society of Nephrology J Am Soc Nephrol 21: 345–352, 2010 Medicare beneficiaries who were discharged alive after an acutemyocardial infarction, patients with AKI had a 10 to 39% increased risk for death during a 10-yr period, depending on the severity and definition of AKI, compared with patients without AKI.19,20 AKI after percutaneous coronary interven- tion5,12 or cardiothoracic surgery21,22 has also been associated with long-termmortality. In another study, patients with tem- porary worsening of renal function after abdominal aortic an- eurysm surgery (defined as a return to within 10% of the esti- mated baseline creatinine clearance 3 d after surgery) had 50% higher long-term mortality risk compared with those with no AKI.15 In two studies in which data on patients without AKI were not available, the 3-yr survival ranged from 50 to 73% in patients who were discharged alive.23,24 Early studies have Table 1. Baseline characteristics of study participants Baseline Characteristic With AKI (n � 82,711) No AKI (n � 782,222) Demographics age (yr; mean � SD) 66.3 � 12.4 61.3 � 13.7 female gender (%) 3.2 5.0 race (%) white 71.6 72.0 black 21.7 20.5 Hispanic 4.0 4.0 other 1.9 2.0 Follow-up time (yr; mean � SD) 2.08 � 1.42 2.36 � 1.43 eGFR (ml/min per 1.73 m2; median �first and third quartiles�) baseline 93.8 (71.0, 122.2) 86.3 (70.3, 103.8) after discharge 75.0 (56.3, 96.7) 81.5 (65.8, 97.9) Concurrent conditions before admission (%) previous AKIa 1.1 0.3 cancer 14.6 10.5 cardiac and vascular diseasesb 37.5 28.9 CKD 4.5 2.0 chronic obstructive pulmonary disease 4.3 4.3 diabetes 33.6 22.9 hypertension 61.1 48.7 neurodegenerative diseasesc 5.0 3.9 mental health disordersd 25.2 31.3 hospitalization in previous month 0.9 0.4 hospitalization in previous yeare 8.0 6.1 Medication use before admission (%) ACEIs/ARBs 40.8 28.5 � blockers 29.5 23.7 diuretics 35.4 23.0 NSAIDs 25.6 26.9 other nephrotoxic drugs 13.8 10.9 platelet aggregation inhibitors 26.9 21.6 Hospitalization details hospitalization primary diagnosis (%) circulatory 20.8 20.2 digestive 11.8 8.3 infectious 2.3 1.1 neoplasms 7.6 5.1 respiratory 10.2 6.5 other 47.2 58.9 mechanical ventilationf 6.45 0.4 length of stay (d; median �first and third quartiles�) 10 (5, 27) 4 (2, 8) Hospitalization between 30 and 90 d after discharge (%) 13.7 10.0 ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; NSAID, nonsteroidal anti-inflammatory drug. aDefined as the presence of at least one ICD-9-CM diagnostic code 584.xx in the 2 yr before the index admission date. bInclude congestive heart failure, ischemic disease, arrhythmia, peripheral vascular disease, stroke, and valvular disease. cInclude Parkinson disease, Alzheimer disease, other dementia, and multiple sclerosis. dInclude major depression, posttraumatic stress disorder, anxiety disorder, schizophrenia, bipolar disorder, alcohol abuse, and drug abuse. eExcludes hospitalizations in the previous month. fDefined by the presence of ICD-9-CM procedure code 96.04 or 96.7x during hospitalization. CLINICAL EPIDEMIOLOGYwww.jasn.org J Am Soc Nephrol 21: 345–352, 2010 Acute Kidney Injury and Mortality 347 shown that kidney function can remain impaired after AKI evenwhen the creatinine had returned to baseline levels.25 This lower “kidney reserve” combined with an ongoing progressive damage caused by “rarefaction” of peritubular capillaries may be possible biologic pathways explaining our findings.26More- over, experimental studies have shown that AKI can injure other organs such as the heart and the lungs27–29; however, until further studies evaluate long-term eGFR decline and causes of death after AKI, these pathways underlying the long- term mortality risk remain speculative. Our results showing an adjusted mortality risk increase from 1.36 to 1.59 with AKIN stage I to stage III is consistent with previous evaluations of the correlation between AKI clas- sification and in-hospital mortality.11,13,21,30 This suggests that the predictive power of AKI classification is persistent with time, as we show in Figure 1. In one study, AKI classification did not predict 60-d and 6-mo mortality, but it was probably due to lack of statistical power.30 Because CKD is a strong predictor ofmortality, we expected a dramatic lowering of the mortality risk estimate when post- discharge eGFR was added to the multivariate model, but we found that the HR dropped only from 1.45 to 1.41. The effect was greater in thosewithAKIN stage III (from1.71 to 1.59), for which the proportion of patients with CKD induced by AKI is probably higher. Comparable results in the sample restricted to the patients who recovered ormaintained their kidney func- tion compared with the whole sample (1.41 versus 1.47) pro- vide further evidence that adjustment for residual kidney func- tion did work effectively in the main model. The long-termmortality risk inpatientswhorecover fromAKI has not been studied extensively. In most studies in which renal recovery was assessed, it was defined as being dialysis indepen- dent, which has no bearing in our study population.31 As previ- ously mentioned, a temporary worsening of kidney function was associatedwithmortality.15 Similarly, long-termmortality risks in patients who had AKI after cardiac surgery and recovered at dis- charge were previously found to be comparable to patients who did not recover.22 In another study, recovery of renal function occurred in 92.5% of the AKI cases.30 This is considerably higher than the 30.9% we found in our study, mostly because our defi- nition of renal recovery was more restrictive. Age is a known risk factor for AKI10,16; however, our results Table 2. HR (95% CI) of all-cause mortality associated with AKI Parameter Crude �Demographicsa �Comorbidities and Medication Useb �Hospitalization Detailsc �Postdischarge eGFR Categoriesd No AKI (n � 782,222) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) 1.00 (reference) With AKI (n � 82,711) 2.10 (2.07 to 2.13) 1.70 (1.68 to 1.73) 1.55 (1.53 to 1.57) 1.45 (1.43 to 1.47) 1.41 (1.39 to 1.43) By AKIN stage of AKIe I (n � 52,338) 2.01 (1.98 to 2.04) 1.62 (1.59 to 1.65) 1.48 (1.45 to 1.50) 1.39 (1.37 to 1.42) 1.36 (1.34 to 1.38) II (n � 19,771) 2.20 (2.15 to 2.26) 1.80 (1.75 to 1.84) 1.61 (1.57 to 1.66) 1.51 (1.47 to 1.55) 1.46 (1.42 to 1.50) III (n � 10,602) 2.35 (2.27 to 2.43) 1.98 (1.92 to 2.05) 1.81 (1.74 to 1.87) 1.71 (1.65 to 1.77) 1.59 (1.54 to 1.65) aModel adjusted for age, gender, race, and VA priority status. bModel adjusted for demographics and previous AKI, rheumatoid arthritis, arrhythmia, cerebrovascular disease, congestive heart failure, CKD, previous cancer, chronic obstructive pulmonary disease, cardiovascular disease, diabetes, hyperlipidemia, hypertension, liver disease, osteoarthritis, peptic ulcer disease, peripheral vascular disease, valvular disease, low back pain, inflammatory bowel disease, multiple sclerosis, history of seizures, Parkinson disease, Alzheimer disease, other dementia, major depression, posttraumatic stress disorder, anxiety disorder, schizophrenia, bipolar disorder, alcohol abuse, drug abuse, tobacco use disorder, previous hospitalizations (previous month and previous year), angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, � blockers, calcium-channel blockers, corticosteroids, diuretics, immunosuppressants, nitrates, nonsteroidal anti-inflammatory drugs, oral anticoagulants, platelet aggregation inhibitors, and other nephrotoxic drugs. cModel adjusted for demographics, comorbidities, and medication use and index admission primary diagnosis, mechanical ventilation use, and hospital length of stay. dModel fully adjusted for demographics, comorbidities and medication use, and hospitalization details and postdischarge eGFR categories. eAKIN categories are defined by the ratio of the highest creatinine to the lowest creatinine. AKIN I is a ratio �1.5 and �2, AKIN II is a ratio �2 and �3, and AKIN III is a ratio �3. 0 1 2 3 4 0 20 40 60 80 100 Follow−up time (years) Cu m ul at ive p ro ba bi lity o f s ur viv al (% ) No AKI AKIN I AKIN II AKIN III 782222 601772 443730 296128 138820782222 601772 52338 37234 25798 16441 775852338 37234 19771 13692 9210 5712 263319771 13692 10602 7173 4639 2723 120010602 7173 Number at risk No AKI AKIN I AKIN II AKIN III Figure 1. Unadjusted Kaplan-Meier survival curves by AKIN categories are shown. Time is calculated from 90 d after dis- charge of the index admission. AKIN categories are defined by the ratio of the highest creatinine to the lowest creatinine. AKIN I is a ratio �1.5 and �2, AKIN II is a ratio �2 and �3, and AKIN III is a ratio �3. Log-rank test: P � 0.001. CLINICAL EPIDEMIOLOGY www.jasn.org 348 Journal of the American Society of Nephrology J Am Soc Nephrol 21: 345–352, 2010 suggest that experiencing AKI is more strongly associated with mortality in younger than older age groups. This may be ex- plained by the fact that inducing AKI in a younger individual requires a more severe insult than in an older one, and this severe insult is also probably associated with a higher risk for mortality despite extensive covariate adjustment. Moreover, because age is in itself a strong risk factor for mortality among all patients, AKI would have a smaller attributable fraction in older patients and therefore a smaller observed relative risk for mortality. For all of these reasons, various age distributions in different studies should be taken into account when compar- ing estimates of association between AKI and long-term mortality. A similar pattern to age can be seen with eGFR be- fore AKI. Indeed, CKD is also recognized as a risk factor for AKI, and CKD stages are independently associated with mortality.18,32 Heterogeneous definitions of AKI are an important issue in research pertaining to AKI. Traditionally, large observational studies used International Classification of Diseases, Ninth Re- vision, Clinical Modification (ICD-9-CM) codes to identify AKI, but it is recogniz