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Mortality prediction by acute kidney injury biomarkers in comparison with serum creatinine
Abstract
Objectives:
To investigate the performance of acute kidney injury (AKI) biomarkers for mortality prediction.
Materials and methods:
Cutoff values of urinary L-type fatty acid-binding protein (L-FABP) and N-acetyl-β-d-glucosaminidase (NAG) for AKI diagnosis in ICU were determined in the derivation cohort. The performance of these AKI biomarkers for mortality prediction was evaluated in the validation cohort with stratification of serum-creatinine based AKI diagnosis.
Results:
Mortality in the AKI patients diagnosed by serum creatinine was increased remarkably when urinary L-FABP and NAG were positive.
Conclusions:
These AKI biomarkers can specifically detect high-risk patients among creatinine-base diagnosed AKI.
... Urine NAG can specifically detect clinical outcome of renal tubular damage in high-risk patients (Hiruma et al. 2014;Damman et al. 2011). ...
Aim: There are limited studies on renal involvement in beta-thalassemia patients. The aim of the present study was to investigate renal dysfunctions in pediatric patients with transfusion dependent beta thalassemia major (TD-βTM), using both conventional and early markers of glomerular and tubular dysfunctions and corralate findings to iron chelation therapy, deferasirox. Neutrofil-gelatinase associated lipocalin (NGAL) is an emerging biomarker in early diagnosis of acute kidney injury and also elevated urine NGAL is a good predictor of chronic kidney disease. We aimed to evaluate urine NGAL/creatinin ratio in thalassemia patients and corralate findings with normal controls.
Methods: Fifty-three TD-βTM patients (aged 5-19 years) and 47 healthy controls (aged 3.5-18 years) were enrolled in this study. All patients were regularly transfused and all of them were using oral chelator; deferasirox. In addition to conventional renal biochemistries, serum cystatin C were measured with immunoturbodimetric technique. Fresh second morning urine samples collected and analysed for sodium, potassium, calcium, protein, creatinine, glucose, phosphate, uric acid, β2-microglobulin and NGAL. NGAL was measured with immunosorbent assay (ELISA). We calculated glomerular filtration rate by Schwartz formula, fractional excretion of sodium, tubular phosphorus reabsorption and uric acid excretion. Serum ferritin concentration was also measured to asses iron overload.
Results: The mean age of our patients were 145±45 month, and controls were 158±140 month. A considerable number of patients demonstrated impaired renal functions. Glomerular hyperfiltration was detected in 9.5%, proteinuria in 40% , hypercalciuria in 60% increased urinary excretion of β-2 mikroglobulin in 62%, increased uric acid excretion in 58% of thalassemia patients. We detected renal tubular and glomerular dysfunctions is associated with especially pretransfusional low hemoglobine levels. We detected no relationship with deferasirox treatment doses and period with renal patologies. Mean levels of plasma cystatin C were elevated in the patient cohort compared to controls ( 0.9+0.2 and 0.78 + 0.06 mg/L, respectively, p<0.05) , Specificially ; 26/53 thalassemia patients (%49) presented with abnormally elevated serum cystatin C. Mean levels of urine NGAL/creatinin ratio was found to be elevated in patients compared to controls (85 + 88 and 31 + 38 ng/mg kreatinin, respectively, p<0.001). In thalassemia group negative significant correlation between ürine NGAL/creatinin ratio and pretransfusional hemoglobine levels was found (r=-0.35, p<0.01). And also we detected urine NGAL/creatinin ratio was corralate with other renal parametries; such as serum cystatin c/creatinin, urine β-2MG/creatinin, urine Ca/creatinin values.
Conclusions: Our data confirm high frequency of glomerular and tubular dysfunctions in TD-βTM pediatric patients, and renal patologies was associated especially pretransfusional low hemoglobine levels. Therefore routine use of early markers of renal dysfunction such as urine NGAL is recommended for all patients.
Disclosures
No relevant conflicts of interest to declare.
... To date, many studies have tried to prevent the occurrence of AKI and find biomarkers to predict AKI 3,5 . In recent years, various laboratory parameters, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), interleukin-18 (IL- 18), and cystatin C, have been proposed as potential biomarkers of AKI [5][6][7][8] . ...
Procalcitonin (PCT) is a useful marker for the diagnosis of systemic inflammatory response syndrome. In addition, PCT is affected by renal function. However, few studies have investigated the relationship between PCT and the development of acute kidney injury (AKI). Hence, we investigated whether serum PCT levels at the time of admission were associated with the development of AKI and clinical outcomes. A total of 790 patients in whom PCT was measured on admission to the intensive care unit (ICU) were analyzed retrospectively. We attempted to investigate whether serum PCT levels measured at the time of admission could be used as a risk factor for the development of AKI in septic and nonseptic patients or as a risk factor for all-cause mortality, and diagnostic usefulness of PCT was further assessed. Serum PCT levels were significantly higher in patients with AKI than in those without AKI (P < 0.001). After multivariable adjustment for clinical factors, laboratory findings, and comorbidities, PCT as a continuous variable showed a significant association with AKI (OR 1.006, 95% CI [1.000–1.011]; P = 0.035). However, PCT was not effective in predicting mortality. The cut-off value of PCT for the prediction of AKI incidence was calculated to be 0.315 ng/ml, with sensitivity and specificity of 60.9% and 56.9%, respectively. The odds ratios (ORs) from an equation adjusted for optimum thresholds of PCT levels for developing AKI with and without sepsis were 2.422 (1.222–4.802, P = 0.011) and 1.798 (1.101–2.937, P = 0.019), respectively. However, there were no absolute differences between the pre- and posttest probabilities after including the PCT value for AKI development. This study suggests that the PCT value was higher in AKI patients than in non-AKI patients, but PCT measurement at the time of admission did not improve the prediction model for AKI.
... One showed that urine L-FABP levels predicted mortality in 5-yearold children with sepsis [24]. Another suggested that urine L-FABP levels predicted mortality in patients with acute kidney injuries [25]. A third study showed that urine L-FABP levels were associated with all-cause mortality in women with HIV infections [26]. ...
... Urine NAG can specifically detect clinical outcome of renal tubular damage in high-risk patients (Hiruma et al. 2014;Damman et al. 2011). ...
The risk of acute kidney injury is rising due to aging in the world and with the increased usage of therapeutic agents and diagnostic interventions which are highly nephrotoxic. Kidneys, however, well tolerate with the injury, and with the late rise in nitrogenous waste products such as creatinine and BUN in the blood, the organ damage is underestimated. Biomarkers are being searched to find a more specific and sensitive one for kidney injury diagnosis like cardiac troponins (I and T) which is the gold standard in diagnosing acute coronary syndrome nowadays replaced the total creatine kinase and CK-MB. However, there is still no such a marker available to take place instead of creatinine. N-Acetyl-β-d-glucosaminidase is a lysosomal enzyme that leaks into urine which is mainly originated from the proximal tubular cells. This enzyme is defined as being more specific and sensitive to renal tubular injury than creatinine especially with its isoenzymes and when combined with other renal biomarkers, for example, NGAL and Kim-1. N-Acetyl-β-d-glucosaminidase is stable in urine, and the variation among individuals is minimal that the spot urine sample is adequate for the assay practically with colorimetric and spectrophotometric methods with its high reproducibility. Endothelins are paracrine hormones that stimulate myocardial contraction and other smooth muscle contraction such as uterus, bronchus, and stomach. They also promote vascular smooth muscle cell growth. Besides they stimulate secretion in kidney, liver, and adrenals. Endothelins are implicated in many pathophysiological conditions such as hypertension, myocardial infarctus, subarachnoidal hemorrhage, and kidney failure.
... Urine NAG can specifically detect clinical outcome of renal tubular damage in high-risk patients (Hiruma et al. 2014;Damman et al. 2011). ...
The risk of acute kidney injury is rising due to aging in the world and with the increased usage of therapeutic agents and diagnostic interventions which are highly nephrotoxic. Kidneys, however, well tolerate with the injury, and with the late rise in nitrogenous waste products such as creatinine and BUN in the blood, the organ damage is underestimated. Biomarkers are being searched to find a more specific and sensitive one for kidney injury diagnosis like cardiac troponins (I and T) which is the gold standard in diagnosing acute coronary syndrome nowadays replaced the total creatine kinase and CK-MB. However, there is still no such a marker available to take place instead of creatinine. N-Acetyl-β-d-glucosaminidase is a lysosomal enzyme that leaks into urine which is mainly originated from the proximal tubular cells. This enzyme is defined as being more specific and sensitive to renal tubular injury than creatinine especially with its isoenzymes and when combined with other renal biomarkers, for example, NGAL and Kim-1. N-Acetyl-β-d-glucosaminidase is stable in urine, and the variation among individuals is minimal that the spot urine sample is adequate for the assay practically with colorimetric and spectrophotometric methods with its high reproducibility. Endothelins are paracrine hormones that stimulate myocardial contraction and other smooth muscle contraction such as uterus, bronchus, and stomach. They also promote vascular smooth muscle cell growth. Besides they stimulate secretion in kidney, liver, and adrenals. Endothelins are implicated in many pathophysiological conditions such as hypertension, myocardial infarctus, subarachnoidal hemorrhage, and kidney failure.
Blood urea nitrogen (BUN) and serum creatinine (SCr) are not very sensitive and specific markers of kidney function in acute kidney injury (AKI) as they are influenced by many renal and nonrenal factors independent of kidney function. A biomarker that is released into the blood or urine by the injured kidney and is analogous to the troponin release by injured myocardial cells after myocardial ischemia or infarction, may be a more sensitive and specific early marker of AKI than BUN and SCr. Numerous biomarkers of AKI have been detected in the urine or serum of patients with AKI. Urine IL-18, urine NGAL, urine KIM-1, and urine L-FABP are biomarkers of renal tubular injury in early AKI and identify patients with AKI before the rise in BUN or SCr. Urine IL-18, urine NGAL, and urine KIM-1 are biomarkers of poor prognosis in patients with AKI. A combination of urinary TIMP2 and IGFBP7, which is known as NephroCheck is the first FDA-approved biomarker of AKI. Urinary [TIMP2] × [IGFBP7] of greater than 0.3 is an early biomarker of AKI and predicts outcomes. In the future, the combined use of functional and damage markers may advance the field of biomarkers of AKI. More studies are required to definitively demonstrate the association between early kidney damage biomarkers and clinical outcomes and to determine whether randomization to a treatment for AKI based on high structural/damage biomarker levels results in an improvement in kidney function and improves clinical outcomes.
Accompanied with the broad application of interventional therapy, the incidence of acute kidney injury (AKI) has been recently increasing in clinical renal medicine. The pathogenesis of AKI is diverse and complex. In the context of the requirements for the diagnosis and treatment of a renal disorder, a large number of studies have explored biological markers and their usefulness to the early diagnosis and treatment of AKI, including glomerular injury, renal tubular injury, and others. These biomarkers provide an important basis for early monitoring of AKI, but are still not quite sufficient. More ideal biomarkers are needed to be identified. Therefore, future studies are necessary to explore more effective biomarkers for AKI clinical practice, which would play an important role in the early diagnosis and intervention treatment of AKI. This review summarizes the important biomarkers identified by previous studies and aims to highlight the advancements that might provide new methods for early clinical diagnosis and effective therapeutic options, along with prediction of response to treatment for AKI.
Introduction The lack of a standard definition for acute kidney injury has resulted in a large variation in the reported incidence and associated mortality. RIFLE, a newly developed international consensus classification for acute kidney injury, defines three grades of severity – risk (class R), injury (class I) and failure (class F) – but has not yet been evaluated in a clinical series.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases.When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
Background Acute kidney injury (AKI) remains associated with high morbidity and mortality, despite progress in medical care. Although
the RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease) and AKIN (Acute Kidney Injury Network) criteria, based on
serum creatinine and urine output, were a step forward in diagnosing AKI, a reliable tool to differentiate between true parenchymal
and pre-renal azotaemia in clinical practice is still lacking. In the last decade, many papers on the use of new urinary and
serum biomarkers for the diagnosis and prognostication of AKI have been published. Thus, the question arises which biomarker
is a reliable differential diagnostic tool under which circumstances.
Acute kidney injury (AKI) occurring in patients admitted to the ICU may result in impaired renal function on long-term follow-up after ICU discharge. The damage induced by subclinical or manifest episodes of AKI may, in fact, produce an irreversible loss of a variable amount of renal mass with deleterious effects on overall renal function. This may be the case even though baseline glomerular filtration rate appears to return to normal but renal reserve is impaired. This may have an important effect on long-term outcomes, including progression to chronic kidney disease. Acute kidney insults should not be considered as isolated episodes but rather a sequence of progressive events that can lead to progressive deterioration of kidney tissue and eventual declines in renal function.
The concept of acute kidney syndromes has shifted in recent years from acute renal failure to acute kidney injury (AKI). AKI implies injury or damage but not necessarily dysfunction. The human kidney has an important glomerular function reserve, and dysfunction becomes evident only when more than 50% of the renal mass is compromised. Recent AKI classifications include even slight changes in serum creatinine, acknowledging that this condition is associated with worse outcomes. This, however, still represents a functional criterion for AKI and implies a glomerular filtration rate alteration that may be a late phenomenon in the time course of the syndrome. An early diagnosis of AKI by using tubular damage biomarkers preceding filtration function loss is possible today. Some studies have shown evidence that there is an additional value of new biomarkers not only because they allow a diagnosis to be made earlier but also because they allow a kidney injury to be diagnosed even in the absence of subsequent dysfunction. Only recently, tubular damage without glomerular function loss was demonstrated to be associated with worse renal and overall outcomes. For this condition, the term 'subclinical' AKI has been introduced, challenging the traditional view that a kidney problem is clinically relevant, only when a loss of filtration function becomes apparent. A new domain of AKI diagnosis could then include functional criteria and damage criteria. This may have an impact on the epidemiology, prevention, and management of AKI.
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.
In the development of novel therapeutic strategies for kidney disease, new renal biomarkers for early detection and accurate evaluation of renal injury are urgently required for both acute kidney injury (AKI) and chronic kidney disease (CKD). Fatty acid-binding protein 1 (FABP1) is expressed in renal proximal tubule cells and shed into urine in response to hypoxia caused by decreased peritubular capillary blood flow. To clarify the role of urinary FABP1 in kidney disease, we established human FABP1 transgenic mice and evaluated the responses of FABP1 to several AKI and CKD models. Moreover, there are accumulating clinical data that urinary FABP1 can detect human AKI earlier than serum creatinine and can distinguish the risk population for AKI. Investigation with "humanized" FABP1 transgenic mice and measurement of clinical samples allowed us to develop urinary FABP1 as a new renal biomarker. Further clinical studies are necessary to confirm the potential of urinary FABP1 for clinical application.
This paper presents the form and validation results of APACHE II, a severity of disease classification system. APACHE II uses a point score based upon initial values of 12 routine physiologic measurements, age, and previous health status to provide a general measure of severity of disease. An increasing score (range 0 to 71) was closely correlated with the subsequent risk of hospital death for 5815 intensive care admissions from 13 hospitals. This relationship was also found for many common diseases. When APACHE II scores are combined with an accurate description of disease, they can prognostically stratify acutely ill patients and assist investigators comparing the success of new or differing forms of therapy. This scoring index can be used to evaluate the use of hospital resources and compare the efficacy of intensive care in different hospitals or over time.
Receiver operating characteristic (ROC) curves are used to describe and compare the performance of diagnostic technology and diagnostic algorithms. This paper refines the statistical comparison of the areas under two ROC curves derived from the same set of patients by taking into account the correlation between the areas that is induced by the paired nature of the data. The correspondence between the area under an ROC curve and the Wilcoxon statistic is used and underlying Gaussian distributions (binormal) are assumed to provide a table that converts the observed correlations in paired ratings of images into a correlation between the two ROC areas. This between-area correlation can be used to reduce the standard error (uncertainty) about the observed difference in areas. This correction for pairing, analogous to that used in the paired t-test, can produce a considerable increase in the statistical sensitivity (power) of the comparison. For studies involving multiple readers, this method provides a measure of a component of the sampling variation that is otherwise difficult to obtain.
There is no consensus definition of acute renal failure (ARF) in critically ill patients. More than 30 different definitions have been used in the literature, creating much confusion and making comparisons difficult. Similarly, strong debate exists on the validity and clinical relevance of animal models of ARF; on choices of fluid management and of end-points for trials of new interventions in this field; and on how information technology can be used to assist this process. Accordingly, we sought to review the available evidence, make recommendations and delineate key questions for future studies.
We undertook a systematic review of the literature using Medline and PubMed searches. We determined a list of key questions and convened a 2-day consensus conference to develop summary statements via a series of alternating breakout and plenary sessions. In these sessions, we identified supporting evidence and generated recommendations and/or directions for future research.
We found sufficient consensus on 47 questions to allow the development of recommendations. Importantly, we were able to develop a consensus definition for ARF. In some cases it was also possible to issue useful consensus recommendations for future investigations. We present a summary of the findings. (Full versions of the six workgroups' findings are available on the internet at http://www.ADQI.net)
Despite limited data, broad areas of consensus exist for the physiological and clinical principles needed to guide the development of consensus recommendations for defining ARF, selection of animal models, methods of monitoring fluid therapy, choice of physiological and clinical end-points for trials, and the possible role of information technology.
The lack of a standard definition for acute kidney injury has resulted in a large variation in the reported incidence and associated mortality. RIFLE, a newly developed international consensus classification for acute kidney injury, defines three grades of severity--risk (class R), injury (class I) and failure (class F)--but has not yet been evaluated in a clinical series.
We performed a retrospective cohort study, in seven intensive care units in a single tertiary care academic center, on 5,383 patients admitted during a one year period (1 July 2000-30 June 2001).
Acute kidney injury occurred in 67% of intensive care unit admissions, with maximum RIFLE class R, class I and class F in 12%, 27% and 28%, respectively. Of the 1,510 patients (28%) that reached a level of risk, 840 (56%) progressed. Patients with maximum RIFLE class R, class I and class F had hospital mortality rates of 8.8%, 11.4% and 26.3%, respectively, compared with 5.5% for patients without acute kidney injury. Additionally, acute kidney injury (hazard ratio, 1.7; 95% confidence interval, 1.28-2.13; P < 0.001) and maximum RIFLE class I (hazard ratio, 1.4; 95% confidence interval, 1.02-1.88; P = 0.037) and class F (hazard ratio, 2.7; 95% confidence interval, 2.03-3.55; P < 0.001) were associated with hospital mortality after adjusting for multiple covariates.
In this general intensive care unit population, acute kidney 'risk, injury, failure', as defined by the newly developed RIFLE classification, is associated with increased hospital mortality and resource use. Patients with RIFLE class R are indeed at high risk of progression to class I or class F. Patients with RIFLE class I or class F incur a significantly increased length of stay and an increased risk of inhospital mortality compared with those who do not progress past class R or those who never develop acute kidney injury, even after adjusting for baseline severity of illness, case mix, race, gender and age.
The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in acute renal failure (ARF) has not been well described. The relationship between urinary N-acetyl-beta-(D)-glucosaminidase activity (NAG) and kidney injury molecule-1 (KIM-1) level and adverse clinical outcomes was evaluated prospectively in a cohort of 201 hospitalized patients with ARF. NAG was measured by spectrophotometry, and KIM-1 was measured by a microsphere-based Luminex technology. Mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score was 16, 43% had sepsis, 39% required dialysis, and hospital mortality was 24%. Urinary NAG and KIM-1 increased in tandem with APACHE II and Multiple Organ Failure scores. Compared with patients in the lowest quartile of NAG, the second, third, and fourth quartile groups had 3.0-fold (95% confidence interval [CI] 1.3 to 7.2), 3.7-fold (95% CI 1.6 to 8.8), and 9.1-fold (95% CI 3.7 to 22.7) higher odds, respectively, for dialysis requirement or hospital death (P < 0.001). This association persisted after adjustment for APACHE II, Multiple Organ Failure score, or the combined covariates cirrhosis, sepsis, oliguria, and mechanical ventilation. Compared with patients in the lowest quartile of KIM-1, the second, third, and fourth quartile groups had 1.4-fold (95% CI 0.6 to 3.0), 1.4-fold (95% CI 0.6 to 3.0), and 3.2-fold (95% CI 1.4 to 7.4) higher odds, respectively, for dialysis requirement or hospital death (P = 0.034). NAG or KIM-1 in combination with the covariates cirrhosis, sepsis, oliguria, and mechanical ventilation yielded an area under the receiver operator characteristic curve of 0.78 (95% CI 0.71 to 0.84) in predicting the composite outcome. Urinary markers of kidney injury such as NAG and KIM-1 can predict adverse clinical outcomes in patients with ARF.
Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI.
Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results.
The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed.
We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.
Acute kidney injury (AKI) is a common clinical problem with significant clinical and economic consequences. A number of studies point to a rising incidence of AKI in the hospital and in the intensive care unit over the past several years, and an increase in the degree of co-morbidity associated with it. Recent evidence suggests that there has been some improvement in outcomes over time. Nevertheless, the mortality associated with AKI remains unacceptably high, and further work is needed. Recently developed consensus definitions will be useful in this regard.
Acute kidney injury (AKI) is a major complication of cardiac bypass surgery. We examined whether levels of liver fatty acid-binding protein (L-FABP) can be an early biomarker for ischemic injury by measuring this protein in the urine of 40 pediatric patients prior to and following cardiopulmonary bypass surgery. AKI was defined as a 50% increase in the serum creatinine from baseline, which was normally not seen until 24-72 h after surgery. Enzyme-linked immunosorbent assay analysis showed increased L-FABP levels (factored for creatinine excretion) of about 94- and 45-fold at 4 and 12 h, respectively, following surgery in the 21 patients who developed AKI with western blot analysis, confirming L-FABP identity. Univariate logistic regression analyses showed that both bypass time and urinary L-FABP were significant independent risk indicators for AKI. After excluding bypass time from the model and using a stepwise multivariate logistic regression analysis, urinary L-FABP levels at 4 h after surgery were an independent risk indicator with the area under the receiver-operating characteristic curve 0.810, sensitivity 0.714, and specificity 0.684 for a 24-fold increase in urinary L-FABP. Our study shows that urinary L-FABP levels represent a sensitive and predictive early biomarker of AKI after cardiac surgery.
According to guidelines published by Kidney Disease: Improving Global Outcomes, patients at risk of acute kidney injury (AKI) should be managed according to their susceptibilities and exposures. Clinical evaluation of a patient's risk of acute loss of renal function is of undisputed importance. However, such evaluations can be hindered by the complex presentations of critically ill patients and the lack of methods to detect early kidney damage. In this regard, a tool for diagnosis and stratification of patients at risk of AKI would complement clinical assessments and enable improved therapeutic decision-making. Emerging evidence suggests that 15-20% of patients who do not fulfil current serum-creatinine-based consensus criteria for AKI are nevertheless likely to have acute tubular damage, which is associated with adverse outcomes. This evidence supports reassessment of the concept and evolution of the definition of AKI to incorporate biomarkers of tubular damage.
An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
Urinary liver-type fatty acid-binding proteins (uL-FABP) have recently been recognized as a useful biomarker for predicting contrast-induced nephropathy. Although accumulating studies have evaluated short-term outcomes, its prognostic value for long-term renal prognosis in patients undergoing coronary angiography (CAG) has not been fully examined. This study aimed to evaluate the predictive value of uL-FABP for long-term renal outcome in patients with ischemic heart disease (IHD). Consecutive 24 patients with impaired renal function (serum creatinine >1.2 mg/dL) who underwent CAG were enrolled. uL-FABP was measured before CAG, 24 and 48 h after CAG. The changes in estimated glomerular filtration rate (eGFR) throughout CAG and at 1 year later were compared with the uL-FABP levels. The patients with a greater decrease in eGFR 1 year later had higher uL-FABP levels at all points, but only the value at 48 h after CAG reached statistical significance (lower vs. higher decreased eGFR group, 4.61 ± 3.87 vs. 17.71 ± 12.96; P < 0.01). Measurement of uL-FABP at 48 h after CAG (48h-uL-FABP) showed better correlation with the change in eGFR (pre-CAG uL-FABP vs. 48h-uL-FABP: R = 0.27, P = 0.20 vs. R = 0.65, P < 0.01). Moreover, the high-pre and high-48h-uL-FABP group showed a significantly larger decrease in eGFR compared with the high-pre and low-48h-uL-FABP group (change in eGFR; 8.12 ± 4.06 vs. 1.25 ± 2.23 mL/min/1.73 m(2), P < 0.01), although the baseline eGFR levels were similar between these two groups. In this pilot study, measurement of uL-FABP levels at 48 h after CAG may be useful in detecting renal damage, and in predicting 1-year renal outcome in IHD patients undergoing CAG.
Over the last decade there has been considerable progress in the discovery and development of biomarkers of kidney disease, and several have now been evaluated in different clinical settings. Although there is a growing literature on the performance of various biomarkers in clinical studies, there is limited information on how these biomarkers would be utilized by clinicians to manage patients with acute kidney injury (AKI). Recognizing this gap in knowledge, we convened the 10th Acute Dialysis Quality Initiative meeting to review the literature on biomarkers in AKI and their application in clinical practice. We asked an international group of experts to assess four broad areas for biomarker utilization for AKI: risk assessment, diagnosis, and staging; differential diagnosis; prognosis and management; and novel physiological techniques including imaging. This article provides a summary of the key findings and recommendations of the group, to equip clinicians to effectively use biomarkers in AKI.Kidney International advance online publication, 9 October 2013; doi:10.1038/ki.2013.374.
Interleukin 18 (IL-18) has been proposed as a biomarker for the early detection of acute kidney injury (AKI), but a broad range of its predictive accuracy has been reported.
Meta-analysis of diagnostic test studies.
Various clinical settings of AKI, including after cardiac surgery, after contrast infusion, in the emergency department, or in the intensive care unit.
Prospective studies that investigated the diagnostic accuracy of IL-18 level to predict AKI.
Increasing or increased urinary IL-18 excretion.
The primary outcome was AKI development, mainly based on serum creatinine level (definition varied across studies). The other outcome was in-hospital mortality.
We analyzed data from 23 studies and 7 countries involving 4,512 patients. Of these studies, 18 could be included in the meta-analysis. Across all settings, the diagnostic odds ratio (DOR) for urinary IL-18 level to predict AKI was 4.22 (95% CI, 2.90-6.14), with sensitivity and specificity of 0.58 and 0.75, respectively. The area under the receiver operating characteristic curve (AUROC) of urinary IL-18 level to predict AKI was 0.70 (95% CI, 0.66-0.74). Subgroup analysis showed the DOR/AUROC of urinary IL-18 was 5.32 (95% CI, 2.92-9.70)/0.72 (95% CI, 0.68-0.76) in cardiac surgery patients and 3.65 (95% CI, 1.88-7.10)/0.66 (95% CI, 0.62-0.70) in intensive care unit or coronary care unit patients. After stratification for age, IL-18 level had better diagnostic accuracy in children and adolescents versus adults: 8.12 (95% CI, 3.79-17.41)/0.78 (95% CI, 0.75-0.82) versus 3.31 (95% CI, 2.28-4.80)/0.66 (95% CI, 0.62-0.70). There was no significant difference in predictive performance of urinary IL-18 level among various times.
Various clinical settings; different definition of AKI and serum creatinine level as the reference standard test for the diagnosis of AKI.
Urinary IL-18 is a useful biomarker of AKI with moderate predictive value across all clinical settings.
Background:
Urinary liver-type fatty acid-binding protein (L-FABP) is a proximal tubular injury candidate biomarker for early detection of acute kidney injury (AKI), with variable performance characteristics depending on clinical settings.
Study design:
Meta-analysis of diagnostic test studies assessing the performance of urinary L-FABP in AKI.
Setting & population:
Literature search in MEDLINE, EMBASE, Scopus, Google Scholar, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov using search terms "liver-type fatty acid-binding protein" and "L-FABP."
Selection criteria for studies:
Studies of humans investigating the performance characteristics of urinary L-FABP for the early diagnosis of AKI and AKI-related outcomes, including dialysis requirement and mortality.
Predictor:
Urinary L-FABP.
Outcomes:
Diagnosis of AKI, dialysis requirement, and in-hospital death.
Results:
15 prospective cohort and 2 case-control studies were identified. Only 7 cohort studies could be meta-analyzed. The estimated sensitivity of urinary L-FABP level for the diagnosis of AKI was 74.5% (95% CI, 60.4%-84.8%), and specificity was 77.6% (95% CI, 61.5%-88.2%). The estimated sensitivity of urinary L-FABP level for predicting dialysis requirement was 69.1% (95% CI, 34.6%-90.5%), and specificity was 42.7% (95% CI, 3.1%-94.5%); for in-hospital mortality, sensitivity and specificity were 93.2% (95% CI, 66.2%-99.0%) and 78.8% (95% CI, 27.0%-97.4%), respectively.
Limitations:
Paucity and low quality of studies, different clinical settings, and variable definitions of AKI.
Conclusions:
Although urinary L-FABP may be a promising biomarker for early detection of AKI and prediction of dialysis requirement and in-hospital mortality, its potential value needs to be validated in large studies and across a broader spectrum of clinical settings.
Background and objectives:
Baseline creatinine (BCr) is frequently missing in AKI studies. Common surrogate estimates can misclassify AKI and adversely affect the study of related outcomes. This study examined whether multiple imputation improved accuracy of estimating missing BCr beyond current recommendations to apply assumed estimated GFR (eGFR) of 75 ml/min per 1.73 m(2) (eGFR 75).
Design, setting, participants, & measurements:
From 41,114 unique adult admissions (13,003 with and 28,111 without BCr data) at Vanderbilt University Hospital between 2006 and 2008, a propensity score model was developed to predict likelihood of missing BCr. Propensity scoring identified 6502 patients with highest likelihood of missing BCr among 13,003 patients with known BCr to simulate a "missing" data scenario while preserving actual reference BCr. Within this cohort (n=6502), the ability of various multiple-imputation approaches to estimate BCr and classify AKI were compared with that of eGFR 75.
Results:
All multiple-imputation methods except the basic one more closely approximated actual BCr than did eGFR 75. Total AKI misclassification was lower with multiple imputation (full multiple imputation + serum creatinine) (9.0%) than with eGFR 75 (12.3%; P<0.001). Improvements in misclassification were greater in patients with impaired kidney function (full multiple imputation + serum creatinine) (15.3%) versus eGFR 75 (40.5%; P<0.001). Multiple imputation improved specificity and positive predictive value for detecting AKI at the expense of modestly decreasing sensitivity relative to eGFR 75.
Conclusions:
Multiple imputation can improve accuracy in estimating missing BCr and reduce misclassification of AKI beyond currently proposed methods.
Prerenal acute kidney injury (AKI) is thought to be a reversible loss of renal function without structural damage. Although prerenal and intrinsic AKI frequently coexist in clinical situations, serum creatinine and urine output provide no information to support their differentiation. Recently developed biomarkers reflect tubular epithelial injury; therefore, we evaluated urinary biomarker levels in an adult mixed intensive care unit (ICU) cohort of patients who had been clinically evaluated as having prerenal AKI. Urinary L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), N-acetyl-β-D-glucosaminidase (NAG), and albumin in patients with prerenal AKI showed modest but significantly higher concentrations than in patients with non-AKI. We also conducted a proof-of-concept experiment to measure urinary biomarker excretion in prerenal AKI caused by volume depletion. Compared with cisplatinum and ischemia-reperfusion models in mice, volume depletion in mice caused a modest secretion of L-FABP and NGAL into urine with more sensitive response of L-FABP than that of NGAL. Although no histological evidence of structural damage was identified by light microscopy, partial kidney hypoxia was found by pimonidazole incorporation in the volume depletion model. Thus, our study suggests that new AKI biomarkers can detect mild renal tubular damage in prerenal acute kidney injury.Kidney International advance online publication, 1 August 2012; doi:10.1038/ki.2012.266.
Urinary L-type fatty acid-binding protein (L-FABP) has not been evaluated for adult post-cardiac surgery acute kidney injury (AKI) to date. This study was undertaken to evaluate a biomarker panel consisting of urinary L-FABP and N-acetyl-β-D-glucosaminidase (NAG), a more established urinary marker of kidney injury, for AKI diagnosis in adult post-cardiac surgery patients.
This study prospectively evaluated 77 adult patients who underwent cardiac surgery at 2 general hospitals. Urinary L-FABP and NAG were measured before surgery, at intensive care unit arrival after surgery (0 hours), 4, and 12 hours after arrival. The AKI was diagnosed by the Acute Kidney Injury Network criteria.
Of 77 patients, 28 patients (36.4%) developed AKI after surgery. Urinary L-FABP and NAG were significantly increased. However, receiver operating characteristic (ROC) analysis revealed that the biomarkers' performance was statistically significant but limited for clinical translation (area under the curve of ROC [AUC-ROC] for L-FABP at 4 hours 0.72 and NAG 0.75). Urinary L-FABP showed high sensitivity and NAG detected AKI with high specificity. Therefore, we combined these 2 biomarkers, which revealed that this combination panel can detect AKI with higher accuracy than either biomarker measurement alone (AUC-ROC 0.81). Moreover, this biomarker panel improved AKI risk prediction significantly compared with predictions made using the clinical model alone.
When urinary L-FABP and NAG are combined, they can detect AKI adequately, even in a heterogeneous population of adult post-cardiac surgery AKI. Combining 2 markers with different sensitivity and specificity presents a reasonable strategy to improve the diagnostic performance of biomarkers.
Acute kidney injury (AKI) is a common complication after cardiac surgery. Urinary liver-type fatty acid-binding protein (L-FABP) reflects the presence of renal tubular injury. The aim of the present study was to evaluate the utility of urinary L-FABP compared with other urinary biomarkers for the early detection of postoperative AKI among adult patients undergoing cardiac surgery.
Patients were divided into the AKI (n=48) and non-AKI groups (n=37) according to whether they developed postoperative AKI within 48h after surgery. Changes in various biomarkers were evaluated. Urine and serum samples were obtained from each patient at the following time points: before the operation, immediately after the operation, and 3, 6, 18, 24, and 48h postoperatively. The urinary L-FABP level was significantly higher in the AKI group than in the non-AKI group at every time point, while other biomarkers did not show such a tendency. The biomarker with the largest area under the curve at every time point for predicting the onset of AKI was urinary L-FABP. On multiple logistic regression analysis, the urinary L-FABP level before operation and within the first 6h after cardiac surgery was significantly associated with the onset of AKI.
Urinary L-FABP is a useful biomarker for early detection of AKI and is a good early predictor of the onset of AKI.
It has been suggested that fluid accumulation may delay recognition of acute kidney injury. We sought to determine the impact of fluid balance on the incidence of nondialysis requiring acute kidney injury in patients with acute lung injury and to describe associated outcomes, including mortality.
Analysis of the Fluid and Catheter Treatment Trial, a factorial randomized clinical trial of conservative vs. liberal fluid management and of management guided by a central venous vs. pulmonary artery catheter.
Acute Respiratory Distress Syndrome Network hospitals.
One thousand patients.
None.
The incidence of acute kidney injury, defined as an absolute rise in creatinine of ≥0.3 mg/dL or a relative change of >50% over 48 hrs, was examined before and after adjustment of serum creatinine for fluid balance. The incidence of acute kidney injury before adjustment for fluid balance was greater in those managed with the conservative fluid protocol (57% vs. 51%, p = .04). After adjustment for fluid balance, the incidence of acute kidney injury was greater in those managed with the liberal fluid protocol (66% vs. 58%, p = .007). Patients who met acute kidney injury criteria after adjustment of creatinine for fluid balance (but not before) had a mortality rate that was significantly greater than those who did not meet acute kidney injury criteria both before and after adjustment for fluid balance (31% vs. 12%, p < .001) and those who had acute kidney injury before but not after adjustment for fluid balance (31% vs. 11%, p = .005). The mortality of those patients meeting acute kidney injury criteria after but not before adjustment for fluid balance was similar to patients with acute kidney injury both before and after adjustment for fluid balance (31% vs. 38%, p = .18).
Fluid management influences serum creatinine and therefore the diagnosis of acute kidney injury using creatinine-based definitions. Patients with "unrecognized" acute kidney injury that is identified after adjusting for positive fluid balance have higher mortality rates, and patients who have acute kidney injury before but not after adjusting for fluid balance have lower mortality rates. Future studies of acute kidney injury should consider potential differences in serum creatinine caused by changes in fluid balance and the impact of these differences on diagnosis and prognosis.
Biomarkers for detection of acute kidney injury and prediction of mortality will be useful to improve the outcomes of critically ill patients. Although several promising acute kidney injury biomarkers have been reported, evaluation in heterogeneous disease-oriented populations is necessary to confirm their reliability before their translation to clinical use. This study was undertaken to evaluate the reliability of new acute kidney injury biomarkers including urinary L-type fatty acid-binding protein with heterogeneous intensive care unit populations.
Prospective observational cohort study.
Single-center study, 15-bed medical-surgical mixed intensive care unit at a university hospital.
Three hundred thirty-nine adult critically ill patients who had been admitted to the intensive care unit were studied prospectively.
None.
Five urinary biomarkers (L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, interleukin-18, N-acetyl-β-D-glucosaminidase, and albumin) were measured at intensive care unit admission. By the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria, 131 patients (39%) were diagnosed as acute kidney injury. Urinary L-type fatty acid-binding protein detected acute kidney injury better than the other biomarkers did (the area under the receiver operating characteristic curves for L-type fatty acid-binding protein 0.75, neutrophil gelatinase-associated lipocalin 0.70, interleukin-18 0.69, N-acetyl-β-D-glucosaminidase 0.62, albumin 0.69). Urinary L-type fatty acid-binding protein predicted later-onset acute kidney injury after intensive care unit admission with the highest area under the receiver operating characteristic curve value of 0.70. Furthermore, L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, and interleukin-18 were able to predict 14-day mortality with higher area under the receiver operating characteristic curves than acute kidney injury detection (area under the receiver operating characteristic curve for L-type fatty acid-binding protein 0.90, neutrophil gelatinase-associated lipocalin 0.83, interleukin-18 0.83). The combination of L-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin improved mortality prediction (area under the receiver operating characteristic curve 0.93).
This prospective observational study with a cohort of heterogeneous patients treated in a mixed intensive care unit revealed that new acute kidney injury biomarkers have a significantly and moderately predictive use for acute kidney injury diagnosis and that urinary L-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin can serve as new biomarkers of mortality prediction in critical care.
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.
Neutrophil gelatinase-associated lipocalin detects subclinical AKI hours to days before increases in serum creatinine indicate manifest loss of renal function.
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.
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.
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.
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.
Purpose of review:
Acute kidney injury (AKI) is a major clinical problem in hospitalized patients. Effective treatment and early diagnosis of this syndrome are not currently available. This review focuses on recent studies examining the biological characteristics and the diagnostic and prognostic value of a novel biomarker--neutrophil gelatinase-associated lipocalin (NGAL)--in the two major patient populations at risk for AKI.
Recent findings:
NGAL is one of the most intensively investigated novel renal biomarkers with promising data from animal experiments and clinical studies comprising more than 3500 cardiac surgery or critically ill patients. NGAL was discovered using unbiased transcriptomic approaches and was identified as the gene with the earliest and highest rise of mRNA and protein concentration in renal tissue, urine and plasma following various renal insults. Within minutes to a few hours after a renal insult, NGAL is induced in and released from the injured distal nephron. The average sensitivity and specificity of NGAL--measured 1-3 days prior to current AKI consensus diagnosis--was 76 and 77% respectively for cardiac surgery patients and 73 and 80% respectively for patients admitted to the intensive care unit.
Summary:
NGAL appears to fulfill many characteristics of an appropriate 'real-time' biomarker for AKI detection.
Purpose of review:
Acute kidney injury (AKI) remarkably increases the mortality of critically ill patients treated in ICUs. Recently, several renal biomarkers have been developed for the early detection of AKI. We review the potential of urinary L-type fatty acid-binding protein (L-FABP) as a new renal biomarker for AKI diagnosis in critical care.
Recent findings:
In the kidney, L-FABP is expressed in renal proximal tubular epithelial cells and shed into urine rapidly in response to renal insults. By using human L-FABP transgenic mice, we reported that urinary L-FABP can detect AKI sensitively and reflect its severity accurately in animal models of AKI and sepsis. In clinical evaluations, the good performance of urinary L-FABP was demonstrated not only in pediatric postcardiopulmonary bypass surgery AKI and contrast media-induced AKI but also in septic shock patients complicated with AKI.
Summary:
Recent data suggest that urinary L-FABP can contribute to the development of new AKI diagnostic tools in critical care. Combining with other renal markers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), optimal threshold determination for distinguishing AKI from chronic renal failure should be explored before translation to the clinical.
Neutrophil gelatinase-associated lipocalin (NGAL) appears to be a promising biomarker for the early diagnosis of acute kidney injury (AKI); however, a wide range in its predictive value has been reported.
Meta-analysis of diagnostic test studies using custom-made standardized data sheets sent to each author.
Different clinical settings of AKI.
MEDLINE, EMBASE, and CENTRAL databases and congress abstracts were searched for studies reporting the value of NGAL to predict AKI.
Plasma/serum and urine NGAL within 6 hours from the time of insult (if known) or 24-48 hours before the diagnosis of AKI if the time of insult was not known.
The primary outcome was AKI, defined as an increase in serum creatinine level > 50% from baseline within 7 days or contrast-induced nephropathy (creatinine increase > 25% or concentration > 0.5 mg/dL in adults or > 50% increase in children within 48 hours). Other outcomes predicted using NGAL were renal replacement therapy initiation and in-hospital mortality.
Using a hierarchical bivariate generalized linear model to calculate the diagnostic odds ratio (DOR) and sample size-weighted area under the curve for the receiver-operating characteristic (AUC-ROC), we analyzed data from 19 studies and 8 countries involving 2,538 patients, of whom 487 (19.2%) developed AKI. Overall, the DOR/AUC-ROC of NGAL to predict AKI was 18.6 (95% CI, 9.0-38.1)/0.815 (95% CI, 0.732-0.892). The DOR/AUC-ROC when standardized platforms were used was 25.5 (95% CI, 8.9-72.8)/0.830 (95% CI, 0.741-0.918) with a cutoff value > 150 ng/mL for AKI compared with 16.7 (95% CI, 7.1-39.7)/0.732 (95% CI, 0.656-0.830) for "research-based" NGAL assays. In cardiac surgery patients, the DOR/AUC-ROC of NGAL was 13.1 (95% CI, 5.7-34.8)/0.775 (95% CI, 0.669-0.867); in critically ill patients, 10.0 (95% CI, 3.0-33.1)/0.728 (95% CI, 0.615-0.834); and after contrast infusion, 92.0 (95% CI, 10.7-794.1)/0.894 (95% CI, 0.826-0.950). The diagnostic accuracy of plasma/serum NGAL (17.9 [95% CI, 6.0-53.7]/0.775 [95% CI, 0.679-0.869]) was similar to that of urine NGAL (18.6 [95% CI, 7.2-48.4]/0.837 [95% CI, 0.762-0.906]). We identified age to be an effective modifier of NGAL value with better predictive ability in children (25.4 [95% CI, 8.9-72.2]/0.930 [95% CI, 0.883-0.968]) compared with adults (10.6 [95% CI, 4.8-23.4]/0.782 [95% CI, 0.689-0.872]). NGAL level was a useful prognostic tool with regard to the prediction of renal replacement therapy initiation (12.9 [95% CI, 4.9-33.9]/0.782 [95% CI, 0.648-0.917]) and in-hospital mortality (8.8 [95% CI, 1.9-40.8]/0.706 [95% CI, 0.530-0.747]).
Serum creatinine level was used for AKI definition.
NGAL level appears to be of diagnostic and prognostic value for AKI.
Acute kidney injury (AKI) is associated with significantly increased morbidity and mortality. To provide a uniformly accepted definition, the RIFLE classification was introduced by the Acute Dialysis Quality Initiative, recently modified by the Acute Kidney Injury Network (AKIN), suggesting staging of AKI based on dynamic changes within 48 h. This study compares these two classification systems with regard to outcome.
Cohort analysis of SAPS 3 database.
Sixteen thousand seven hundred and eighty-four ICU patients from 303 ICUs were analysed. Classification was performed according to RIFLE (Risk, Injury, Failure) or according to AKIN (stage 1, 2, 3) without including a requirement of renal replacement therapy in the analysis. Changes of serum creatinine as well as urinary output were assessed for both AKIN and RIFLE during the first 48 h of ICU admission. Primary endpoint was hospital mortality.
Incidence of AKI in our population of critically ill patients was found to range between 28.5 and 35.5% when applying AKIN and RIFLE criteria, respectively, associated with increased hospital mortality averaging 36.4%. Observed-to-expected mortality ratios revealed excess mortality conferred by any degree of AKI increasing from 0.81 for patients classified as non-AKI up to 1.31 and 1.23 with AKIN stage 3 or RIFLE Failure, respectively. AKIN misclassified 1,504 patients as non-AKI compared to RIFLE which misclassified 504 patients.
Acute kidney injury classified by either RIFLE or AKIN is associated with increased hospital mortality. Despite presumed increased sensitivity by the AKIN classification, RIFLE shows better robustness and a higher detection rate of AKI during the first 48 h of ICU admission.
Although diagnosis and staging of acute kidney injury uses serum creatinine, acute changes in creatinine lag behind both renal injury and recovery. The risk for mortality increases when acute kidney injury accompanies sepsis; therefore, we sought to explore the limitations of serum creatinine in this setting. In mice, induction of sepsis by cecal ligation and puncture in bilaterally nephrectomized mice increased markers of nonrenal organ injury and serum TNF-alpha. Serum creatinine, however, was significantly lower in septic animals than in animals subjected to bilateral nephrectomy and sham cecal ligation and puncture. Under these conditions treatment with chloroquine decreased nonrenal organ injury markers but paradoxically increased serum creatinine. Sepsis dramatically decreased production of creatinine in nephrectomized mice, without changes in body weight, hematocrit, or extracellular fluid volume. In conclusion, sepsis reduces production of creatinine, which blunts the increase in serum creatinine after sepsis, potentially limiting the early detection of acute kidney injury. This may partially explain why small absolute increases in serum creatinine levels are associated with poor clinical outcomes. These data support the need for new biomarkers that provide better measures of renal injury, especially in patients with sepsis.
Estimation of glomerular filtration rate (GFR) is limited by differences in creatinine generation among ethnicities. Our previously reported GFR-estimating equations for Japanese had limitations because all participants had a GFR less than 90 mL/min/1.73 m2 and serum creatinine was assayed in different laboratories.
Diagnostic test study using a prospective cross-sectional design. New equations were developed in 413 participants and validated in 350 participants. All samples were assayed in a central laboratory.
Hospitalized Japanese patients in 80 medical centers. Patients had not participated in the previous study.
Measured GFR (mGFR) computed from inulin clearance.
Estimated GFR (eGFR) by using the modified isotope dilution mass spectrometry (IDMS)-traceable 4-variable Modification of Diet in Renal Disease (MDRD) Study equation using the previous Japanese Society of Nephrology Chronic Kidney Disease Initiative (JSN-CKDI) coefficient of 0.741 (equation 1), the previous JSN-CKDI equation (equation 2), and new equations derived in the development data set: modified MDRD Study using a new Japanese coefficient (equation 3), and a 3-variable Japanese equation (equation 4).
Performance of equations was assessed by means of bias (eGFR - mGFR), accuracy (percentage of estimates within 15% or 30% of mGFR), root mean squared error, and correlation coefficient.
In the development data set, the new Japanese coefficient was 0.808 (95% confidence interval, 0.728 to 0.829) for the IDMS-MDRD Study equation (equation 3), and the 3-variable Japanese equation (equation 4) was eGFR (mL/min/1.73 m2) = 194 x Serum creatinine(-1.094) x Age(-0.287) x 0.739 (if female). In the validation data set, bias was -1.3 +/- 19.4 versus -5.9 +/- 19.0 mL/min/1.73 m2 (P = 0.002), and accuracy within 30% of mGFR was 73% versus 72% (P = 0.6) for equation 3 versus equation 1 and -2.1 +/- 19.0 versus -7.9 +/- 18.7 mL/min/1.73 m(2) (P < 0.001) and 75% versus 73% (P = 0.06) for equation 4 versus equation 2 (P = 0.06), respectively.
Most study participants had chronic kidney disease, and some may have had changing GFRs.
The new Japanese coefficient for the modified IDMS-MDRD Study equation and the new Japanese equation are more accurate for the Japanese population than the previously reported equations.
Urinary N-acetyl-beta-D-glucosaminidase (NAG) activities were assayed in every urine void throughout 24 hours in 17 normal people and in four patients with renal disease. The variation in NAG activity due to changing rates of urine flow was almost eliminated by factoring enzyme activity by the urinary creatinine concentration. Random samples of urine may thus be used for assay. The results of NAG assay in 36 patients with acute and chronic renal diseases showed that NAG was a sensitive indicator of renal damage. This simple test may be valuable in detecting or monitoring renal disease.
Methods of evaluating and comparing the performance of diagnostic tests are of increasing importance as new tests are developed and marketed. When a test is based on an observed variable that lies on a continuous or graded scale, an assessment of the overall value of the test can be made through the use of a receiver operating characteristic (ROC) curve. The curve is constructed by varying the cutpoint used to determine which values of the observed variable will be considered abnormal and then plotting the resulting sensitivities against the corresponding false positive rates. When two or more empirical curves are constructed based on tests performed on the same individuals, statistical analysis on differences between curves must take into account the correlated nature of the data. This paper presents a nonparametric approach to the analysis of areas under correlated ROC curves, by using the theory on generalized U-statistics to generate an estimated covariance matrix.
Administration of contrast agents can cause a decrease in renal function and, occasionally, end-stage renal disease. Liver-type fatty acid-binding protein (L-FABP) is an intracellular carrier protein of free fatty acids that is expressed in proximal tubules of the human kidney. Whether urinary excretion of L-FABP can predict the occurrence of contrast medium-induced nephropathy was studied.
Sixty-six patients (46 men, 20 women; mean age, 60.0 years) undergoing nonemergency coronary angiography or intervention at 1 of our institutions who had a serum creatinine (Cr) level greater than 1.2 mg/dL (> 106 micromol/L) and less than 2.5 mg/dL (< 221 micromol/L) and 30 healthy volunteers (21 men, 9 women; mean age, 56.5 years) were included. Urinary L-FABP levels were measured before and after coronary angiography with the use of monoclonal antibodies. Contrast medium-induced nephropathy is defined as an increase in serum Cr level of greater than 0.5 mg/dL (> 44 micromol/L) or a relative increase of more than 25% at 2 to 5 days after the procedure.
Contrast medium-induced nephropathy occurred in 13 of 66 patients (19.7%). Before angiography, urinary L-FABP levels were significantly greater in these 13 patients (contrast medium-induced nephropathy group; 18.5 +/- 12.8 microg/g Cr; range, 5.8 to 33.6 microg/g Cr) than in the remaining 53 patients (non-contrast medium-induced nephropathy group; 7.4 +/- 4.4 microg/g Cr; range, 2.8 to 13.8 microg/g Cr; P < 0.01) or healthy volunteers (5.4 +/- 4.4 microg/g Cr; range, 1.0 to 10.0 microg/g Cr; P < 0.01). The next day and 2 days after angiography, urinary L-FABP levels increased significantly to 46.8 +/- 30.5 microg/g Cr (range, 12.0 to 84.5 microg/g Cr; P < 0.01) and 38.5 +/- 28.5 microg/g Cr (range, 9.5 to 70.5 microg/g Cr; P < 0.01) in the contrast medium-induced nephropathy group, respectively. After 14 days, serum Cr returned to the baseline level, but urinary L-FABP level remained high (34.5 +/- 30.0 microg/g Cr; range, 4.0 to 68.0 microg/g Cr). However, urinary L-FABP levels in the non-contrast medium-induced nephropathy group changed little throughout the experimental period.
Urinary L-FABP level can serve clinically as a predictive marker for contrast medium-induced nephropathy.
To apply the RIFLE criteria "risk," "injury," and "failure" for severity of acute kidney injury to patients admitted to the intensive care unit and to evaluate the significance of other prognostic factors.
Retrospective analysis of the Riyadh Intensive Care Program database.
Riyadh Intensive Care Unit Program database of 41,972 patients admitted to 22 intensive care units in the United Kingdom and Germany between 1989 and 1999.
Acute kidney injury as defined by the RIFLE classification occurred in 15,019 (35.8%) patients; 7,207 (17.2%) patients were at risk, 4,613 (11%) had injury, and 3,199 (7.6%) had failure. It was found that 797 (2.3%) patients had end-stage dialysis-dependent renal failure when admitted to an intensive care unit.
None.
: Patients with risk, injury, and failure classifications had hospital mortality rates of 20.9%, 45.6%, and 56.8%, respectively, compared with 8.4% among patients without acute kidney injury. Independent risk factors for hospital mortality were age (odds ratio 1.02); Acute Physiology and Chronic Health Evaluation II score on admission to intensive care unit (odds ratio 1.10); presence of preexisting end-stage disease (odds ratio 1.17); mechanical ventilation (odds ratio 1.52); RIFLE categories risk (odds ratio 1.40), injury (odds ratio 1.96), and failure (odds ratio 1.59); maximum number of failed organs (odds ratio 2.13); admission after emergency surgery (odds ratio 3.08); and nonsurgical admission (odds ratio 3.92). Renal replacement therapy for acute kidney injury was not an independent risk factor for hospital mortality.
The RIFLE classification was suitable for the definition of acute kidney injury in intensive care units. There was an association between acute kidney injury and hospital outcome, but associated organ failure, nonsurgical admission, and admission after emergency surgery had a greater impact on prognosis than severity of acute kidney injury.
The Acute Dialysis Quality Initiative Group has published a consensus definition/classification system for acute kidney injury (AKI) termed the RIFLE criteria. The Acute Kidney Injury Network (AKIN) group has recently proposed modifications to this system. It is currently unknown whether there are advantages between these criteria.
We interrogated the Australian New Zealand Intensive Care Society (ANZICS) Adult Patient Database (APD) for all adult admissions to 57 ICUs from 1 January 2000 to 31 December 2005. We compared the performance of the RIFLE and AKIN criteria for diagnosis and classification of AKI and for robustness of hospital mortality.
We included 120 123 critically ill patients, of which 27.8% had a primary diagnosis of sepsis. We found only small differences (<1%) in the number of patients classified as having some degree of kidney injury using either the AKIN or RIFLE definition or classification systems. AKIN slightly increased the number of patients classified as Stage I injury (category R in RIFLE) (from 16.2 to 18.1%) but decreased the number of patients classified as having Stage II injury (category I in RIFLE) (13.6% versus 10.1%). The area under the ROC curve for hospital mortality was 0.66 for RIFLE and 0.67 for AKIN in all patients and it was 0.65 for both in septic patients.
Compared to the RIFLE criteria, the AKIN criteria do not materially improve the sensitivity, robustness and predictive ability of the definition and classification of AKI in the first 24 h after admission to ICU.
The receiver operating characteristic (ROC) curve is used to evaluate a biomarker's ability for classifying disease status. The Youden Index (J), the maximum potential effectiveness of a biomarker, is a common summary measure of the ROC curve. In biomarker development, levels may be unquantifiable below a limit of detection (LOD) and missing from the overall dataset. Disregarding these observations may negatively bias the ROC curve and thus J. Several correction methods have been suggested for mean estimation and testing; however, little has been written about the ROC curve or its summary measures. We adapt non-parametric (empirical) and semi-parametric (ROC-GLM [generalized linear model]) methods and propose parametric methods (maximum likelihood (ML)) to estimate J and the optimal cut-point (c *) for a biomarker affected by a LOD. We develop unbiased estimators of J and c * via ML for normally and gamma distributed biomarkers. Alpha level confidence intervals are proposed using delta and bootstrap methods for the ML, semi-parametric, and non-parametric approaches respectively. Simulation studies are conducted over a range of distributional scenarios and sample sizes evaluating estimators' bias, root-mean square error, and coverage probability; the average bias was less than one percent for ML and GLM methods across scenarios and decreases with increased sample size. An example using polychlorinated biphenyl levels to classify women with and without endometriosis illustrates the potential benefits of these methods. We address the limitations and usefulness of each method in order to give researchers guidance in constructing appropriate estimates of biomarkers' true discriminating capabilities.
Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis
- R C Bone
- R A Balk
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