Edward D. Siew

The Outcome of Neutrophil Gelatinase-Associated Lipocalin-Positive Subclinical Acute Kidney Injury: A Multicenter Pooled Analysis of Prospective Studies

OBJECTIVES The aim of this study was to test the hypothesis that, without diagnostic changes in serum creatinine, increased neutrophil gelatinase-associated lipocalin (NGAL) levels identify patients with subclinical acute kidney injury (AKI) and therefore worse prognosis. BACKGROUND Neutrophil gelatinase-associated lipocalin detects subclinical AKI hours to days before increases in serum creatinine indicate manifest loss of renal function. METHODS We analyzed pooled data from 2,322 critically ill patients with predominantly cardiorenal syndrome from 10 prospective observational studies of NGAL. We used the terms NGAL(-) or NGAL(+) according to study-specific NGAL cutoff for optimal AKI prediction and the terms sCREA(-) or sCREA(+) according to consensus diagnostic increases in serum creatinine defining AKI. A priori-defined outcomes included need for renal replacement therapy (primary endpoint), hospital mortality, their combination, and duration of stay in intensive care and in-hospital. RESULTS Of study patients, 1,296 (55.8%) were NGAL(-)/sCREA(-), 445 (19.2%) were NGAL(+)/sCREA(-), 107 (4.6%) were NGAL(-)/sCREA(+), and 474 (20.4%) were NGAL(+)/sCREA(+). According to the 4 study groups, there was a stepwise increase in subsequent renal replacement therapy initiation-NGAL(-)/sCREA(-): 0.0015% versus NGAL(+)/sCREA(-): 2.5% (odds ratio: 16.4, 95% confidence interval: 3.6 to 76.9, p < 0.001), NGAL(-)/sCREA(+): 7.5%, and NGAL(+)/sCREA(+): 8.0%, respectively, hospital mortality (4.8%, 12.4%, 8.4%, 14.7%, respectively) and their combination (4-group comparisons: all p < 0.001). There was a similar and consistent progressive increase in median number of intensive care and in-hospital days with increasing biomarker positivity: NGAL(-)/sCREA(-): 4.2 and 8.8 days; NGAL(+)/sCREA(-): 7.1 and 17.0 days; NGAL(-)/sCREA(+): 6.5 and 17.8 days; NGAL(+)/sCREA(+): 9.0 and 21.9 days; 4-group comparisons: p = 0.003 and p = 0.040, respectively. Urine and plasma NGAL indicated a similar outcome pattern. CONCLUSIONS In the absence of diagnostic increases in serum creatinine, NGAL detects patients with likely subclinical AKI who have an increased risk of adverse outcomes. The concept and definition of AKI might need re-assessment.

Urine Neutrophil Gelatinase-Associated Lipocalin Moderately Predicts Acute Kidney Injury in Critically Ill Adults

Urine neutrophil gelatinase-associated lipocalin (uNGAL) has shown promise as a biomarker for the early detection of acute kidney injury (AKI) in fixed models of injury, but its ability to predict AKI and provide prognostic information in critically ill adults is unknown. We prospectively studied a heterogeneous population of 451 critically ill adults, 64 (14%) and 86 (19%) of whom developed AKI within 24 and 48 h of enrollment, respectively. Median uNGAL at enrollment was higher among patients who developed AKI within 48 h compared with those who did not (190 versus 57 ng/mg creatinine, P < 0.001). The areas under the receiver operating characteristic curves describing the relationship between uNGAL level and the occurrence of AKI within 24 and 48 h were 0.71 (95% Confidence Intervals [CI]: 0.63 to 0.78) and 0.64 (95% CI: 0.57 to 0.71), respectively. Urine neutrophil gelatinase-associated lipocalin remained independently associated with the development of AKI after adjustment for age, serum creatinine closest to enrollment, illness severity, sepsis, and intensive care unit (ICU) location, although it only marginally improved the predictive performance of the clinical model alone. A Cox proportional hazards model using time to first dialysis, adjusted for APACHE II score, suggested that uNGAL independently predicts severe AKI during hospitalization [HR 2.60, 95% CI:1.55 to 4.35]. In summary, although a single measurement of uNGAL exhibited moderate predictive utility for the development and severity of AKI in a heterogeneous ICU population, its additional contribution to conventional clinical risk predictors appears limited.

Biological Markers of Acute Kidney Injury

An abrupt change in serum creatinine, the most common indicator of acute kidney injury (AKI), is strongly linked to poor outcomes across multiple clinical settings. Despite endless attempts to distill the magnitude and timing of a changing serum creatinine into a standardized metric, singular focus on this traditional functional marker obligates the characterization of AKI to remain, at best, retrospective and causally noninformative. The resultant inability to meaningfully segregate critical aspects of injury such as type, onset, propagation, and recovery from ongoing decrements in renal function has hindered successful translation of promising therapeutics. Over the past decade, however, the emerging field of clinical proteomics reinvigorates hope of identifying novel plasma and urine biomarkers to characterize cause and course of kidney injury. Efforts to validate these markers for use in clinical studies now show early promise but face important obstacles including interpretive difficulties inherent in using serum creatinine as a sole comparator for diagnostic performance, a need to better evaluate the incremental performance of new markers above established clinical and biochemical predictors, a relative lack of power to sufficiently examine hard clinical end points, and a potential over-reliance on use alone of receiver operating curves for assessing biomarker utility. Here, we discuss efforts to address these barriers and further ascertain the clinical value of new markers.

Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury

Studies of acute kidney injury usually lack data on pre-admission kidney function and often substitute an inpatient or imputed serum creatinine as an estimate for baseline renal function. In this study, we compared the potential error introduced by using surrogates such as (1) an estimated glomerular filtration rate of 75 ml/min per 1.73 m(2) (suggested by the Acute Dialysis Quality Initiative), (2) a minimum inpatient serum creatinine value, and (3) the first admission serum creatinine value, with values computed using pre-admission renal function. The study covered a 12-month period and included a cohort of 4863 adults admitted to the Vanderbilt University Hospital. Use of both imputed and minimum baseline serum creatinine values significantly inflated the incidence of acute kidney injury by about half, producing low specificities of 77-80%. In contrast, use of the admission serum creatinine value as baseline significantly underestimated the incidence by about a third, yielding a low sensitivity of 39%. Application of any surrogate marker led to frequent misclassification of patient deaths after acute kidney injury and differences in both in-hospital and 60-day mortality rates. Our study found that commonly used surrogates for baseline serum creatinine result in bi-directional misclassification of the incidence and prognosis of acute kidney injury in a hospital setting.

Diagnosis of Acute Kidney Injury Using Functional and Injury Biomarkers: Workgroup Statements from the Tenth Acute Dialysis Quality Initiative Consensus Conference

Acute kidney injury (AKI) commonly occurs in hospitalized patients and is independently and strongly associates with morbidity and mortality. The clinical benefits of a timely and definitive diagnosis of AKI have not been fully realized due to limitations imposed by the use of serum creatinine and urine output to fulfill diagnostic criteria. These restrictions often lead to diagnostic delays, potential misclassification of actual injury status, and provide little information regarding underlying cause. Novel biomarkers of damage have shown ability to reflect ongoing kidney injury and help further refine existing Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN) diagnostic criteria. A comprehensive review of the published literature to date was performed using previously published methodology of the Acute Dialysis Quality Initiative (ADQI) working group to establish consensus statements regarding (i) the overall implementation of injury biomarkers in the concept of AKI diagnosis, (ii) their clinical use, and (iii) future research. On the basis of published data on the ability of novel damage biomarkers to provide diagnostic and prognostic information on AKI, we recommend that novel damage biomarkers may, in the appropriate clinical setting and context (situation consistent with AKI), be used to diagnose AKI even in the absence of changes in serum creatinine or the presence of oliguria as described in the existing RIFLE/AKIN criteria for diagnosis of AKI. Adding injury biomarkers as a criterion for AKI will complement the ability of RIFLE/AKIN to define AKI. Promising diagnostic injury markers include neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18) and liver-type fatty acid binding protein (L-FABP). However, there are currently insufficient data on damage biomarkers to support their use for AKI staging. Rigorous validation studies measuring the association between the novel damage biomarker(s) and clinically relevant outcomes are needed.

Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome.

Objectives: To determine whether prehospital statin use is associated with a lower risk of sepsis, acute lung injury/acute respiratory distress syndrome, and mortality in critically ill patients. We also investigated the effect of combined prehospital use of both statins and aspirin. Design: Cross-sectional analysis of a prospective cohort. Patients: A total of 575 critically ill patients admitted to the medical or surgical intensive care unit of an academic tertiary-care hospital. Interventions: None. Measurements and Main Results: Of 575 patients, 149 (26%) were on statin therapy before hospitalization. A multivariable analysis including age, gender, current tobacco use, prehospital aspirin use, race, and Acute Physiology and Chronic Health Evaluation II score revealed that patients on statin therapy before hospitalization were less likely to have or develop severe sepsis (odds ratio 0.62, 95% confidence interval 0.40–0.96) or acute lung injury/acute respiratory distress syndrome (odds ratio 0.60, 95% confidence interval 0.36–0.99) during the first four intensive care unit days. In-hospital mortalities for patients with and without prehospital statin use (odds ratio 1.06, 95% confidence interval 0.62–1.83) were similar. Patients who had prehospital use of both statins and aspirin had the lowest rates of severe sepsis, acute lung injury/acute respiratory distress syndrome, and mortality. Conclusions: Prehospital use of statins may be protective against sepsis and acute lung injury. This effect may be potentiated by prehospital aspirin use.

Elevated Urinary IL-18 Levels at the Time of ICU Admission Predict Adverse Clinical Outcomes

BACKGROUND AND OBJECTIVES Urine IL-18 (uIL-18) has demonstrated moderate capacity to predict acute kidney injury (AKI) and adverse outcomes in defined settings. Its ability to predict AKI and provide prognostic information in broadly selected, critically ill adults remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The study prospectively evaluated the capacity of uIL-18 measured within 24 hours of intensive care unit (ICU) admission to predict AKI, death, and receipt of acute dialysis in a large mixed-adult ICU population. RESULTS Of 451 patients, 86 developed AKI within 48 hours of enrollment and had higher median uIL-18 levels [426 (interquartile range [IQR]: 152 to 1183) pg/mg creatinine] compared with those without AKI [248 (IQR: 120 to 559) pg/mg]. The area under the receiver operating characteristic curve for uIL-18 predicting subsequent AKI within 24 hours was 0.62 (95% CI: 0.54 to 0.69) and improved modestly to 0.67 (95% CI: 0.53 to 0.81) in patients whose enrollment eGFR was >or=75 ml/min per 1.73 m(2). The highest median uIL-18 levels were observed in patients with sepsis at enrollment [508 (IQR: 230 to 1281) pg/mg], those receiving acute dialysis [571 (IQR: 161 to 1614) pg/mg] or dying [532 (IQR: 210 to 1614) pg/mg] within 28 days of ascertainment. After adjustment for a priori selected clinical predictors, uIL-18 remained independently predictive of composite outcome of death or acute dialysis within 28 days of ascertainment (odds ratio, 1.86 [95% CI: 1.31 to 2.64]). CONCLUSIONS uIL-18 did not reliably predict AKI development, but did predict poor clinical outcomes in a broadly selected, critically ill adult population.

Outpatient Nephrology Referral Rates after Acute Kidney Injury

AKI associates with an increased risk for the development and progression of CKD and mortality. Processes of care after an episode of AKI are not well described. Here, we examined the likelihood of nephrology referral among survivors of AKI at risk for subsequent decline in kidney function in a US Department of Veterans Affairs database. We identified 3929 survivors of AKI hospitalized between January 2003 and December 2008 who had an estimated GFR (eGFR) <60 ml/min per 1.73 m(2) 30 days after peak injury. We analyzed time to referral considering improvement in kidney function (eGFR ≥60 ml/min per 1.73 m(2)), dialysis initiation, and death as competing risks over a 12-month surveillance period. Median age was 73 years (interquartile range, 62-79 years) and the prevalence of preadmission kidney dysfunction (baseline eGFR <60 ml/min per 1.73 m(2)) was 60%. Overall mortality during the surveillance period was 22%. The cumulative incidence of nephrology referral before dying, initiating dialysis, or experiencing an improvement in kidney function was 8.5% (95% confidence interval, 7.6-9.4). Severity of AKI did not affect referral rates. These data demonstrate that a minority of at-risk survivors are referred for nephrology care after an episode of AKI. Determining how to best identify survivors of AKI who are at highest risk for complications and progression of CKD could facilitate early nephrology-based interventions.

The growth of acute kidney injury: a rising tide or just closer attention to detail?

Acute kidney injury (AKI), previously termed acute renal failure, is associated with increased mortality, prolonged hospital stay, and accelerated chronic kidney disease (CKD). Over the past 2 decades, dramatic rises in the incidences of AKI have been reported, particularly within the United States. The question arises as to whether these changes reflect actual increases in disease incidence, or are potentially explained by the introduction of consensus definitions that rely on small standardized changes in serum creatinine, changes in coding and reimbursement, or increasingly available and more liberal use of dialysis. In this review, we explore the secular trends in AKI incidence in North America and Western Europe and its potential contributors.

The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods

BackgroundThe incidence of acute kidney injury (AKI) has been increasing over time and is associated with a high risk of short-term death. Previous studies on hospital-acquired AKI have important methodological limitations, especially their retrospective study designs and limited ability to control for potential confounding factors.MethodsThe Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) Study was established to examine how a hospitalized episode of AKI independently affects the risk of chronic kidney disease development and progression, cardiovascular events, death, and other important patient-centered outcomes. This prospective study will enroll a cohort of 1100 adult participants with a broad range of AKI and matched hospitalized participants without AKI at three Clinical Research Centers, as well as 100 children undergoing cardiac surgery at three Clinical Research Centers. Participants will be followed for up to four years, and will undergo serial evaluation during the index hospitalization, at three months post-hospitalization, and at annual clinic visits, with telephone interviews occurring during the intervening six-month intervals. Biospecimens will be collected at each visit, along with information on lifestyle behaviors, quality of life and functional status, cognitive function, receipt of therapies, interim renal and cardiovascular events, electrocardiography and urinalysis.ConclusionsASSESS-AKI will characterize the short-term and long-term natural history of AKI, evaluate the incremental utility of novel blood and urine biomarkers to refine the diagnosis and prognosis of AKI, and identify a subset of high-risk patients who could be targeted for future clinical trials to improve outcomes after AKI.