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1.  Adjudication of etiology of acute kidney injury: experience from the TRIBE-AKI multi-center study 
BMC Nephrology  2014;15:105.
Background
Adjudication of patient outcomes is a common practice in medical research and clinical trials. However minimal data exists on the adjudication process in the setting of Acute Kidney Injury (AKI) as well as the ability to judge different etiologies (e.g. Acute Tubular Necrosis (ATN), Pre-renal Azotemia (PRA)).
Methods
We enrolled 475 consecutive patients undergoing cardiac surgery at four sites of the Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) study. Three expert nephrologists performed independent chart review, utilizing clinical variables and retrospective case report forms with pre intra and post-operative data, and then adjudicated all cases of AKI (n = 67). AKI was defined as a > 50% increase in serum creatinine for baseline (RIFLE Risk). We examined the patterns of AKI diagnoses made by the adjudication panel as well as association of these diagnoses with pre and postoperative kidney injury biomarkers.
Results
There was poor agreement across the panel of reviewers with their adjudicated diagnoses being independent of each other (Fleiss’ Kappa = 0.046). Based on the agreement of the two out of three reviewers, ATN was the adjudicated diagnosis in 41 cases (61%) while PRA occurred in 13 (19%). Neither serum creatinine or any other biomarker of AKI (urine or serum), was associated with an adjudicated diagnosis of ATN within the first 24 post-operative hours.
Conclusion
The etiology of AKI after cardiac surgery is probably multi-factorial and pure forms of AKI etiologies, such as ATN and PRA may not exist. Biomarkers did not appear to correlate with the adjudicated etiology of AKI; however the lack of agreement among the adjudicators impacted these results.
Trial registration
Clinicaltrials.gov: NCT00774137
doi:10.1186/1471-2369-15-105
PMCID: PMC4091753  PMID: 24996668
Acute kidney injury; Acute tubular necrosis; Cardio-thoracic surgery; Adjudication
2.  Prophylactic Perioperative Sodium Bicarbonate to Prevent Acute Kidney Injury Following Open Heart Surgery: A Multicenter Double-Blinded Randomized Controlled Trial 
PLoS Medicine  2013;10(4):e1001426.
In a double-blinded randomized controlled trial, Anja Haase-Fielitz and colleagues find that an infusion of sodium bicarbonate during open heart surgery did not reduce the risk for acute kidney injury, compared with saline control.
Background
Preliminary evidence suggests a nephroprotective effect of urinary alkalinization in patients at risk of acute kidney injury. In this study, we tested whether prophylactic bicarbonate-based infusion reduces the incidence of acute kidney injury and tubular damage in patients undergoing open heart surgery.
Methods and Findings
In a multicenter, double-blinded (patients, clinical and research personnel), randomized controlled trial we enrolled 350 adult patients undergoing open heart surgery with the use of cardiopulmonary bypass. At induction of anesthesia, patients received either 24 hours of intravenous infusion of sodium bicarbonate (5.1 mmol/kg) or sodium chloride (5.1 mmol/kg). The primary endpoint was the proportion of patients developing acute kidney injury. Secondary endpoints included the magnitude of acute tubular damage as measured by urinary neutrophil gelatinase-associated lipocalin (NGAL), initiation of acute renal replacement therapy, and mortality. The study was stopped early under recommendation of the Data Safety and Monitoring Committee because interim analysis suggested likely lack of efficacy and possible harm. Groups were non-significantly different at baseline except that a greater proportion of patients in the sodium bicarbonate group (66/174 [38%]) presented with preoperative chronic kidney disease compared to control (44/176 [25%]; p = 0.009). Sodium bicarbonate increased urinary pH (from 6.0 to 7.5, p<0.001). More patients receiving bicarbonate (83/174 [47.7%]) developed acute kidney injury compared with control patients (64/176 [36.4%], odds ratio [OR] 1.60 [95% CI 1.04–2.45]; unadjusted p = 0.032). After multivariable adjustment, a non-significant unfavorable group difference affecting patients receiving sodium bicarbonate was found for the primary endpoint (OR 1.45 [0.90–2.33], p = 0.120]). A greater postoperative increase in urinary NGAL in patients receiving bicarbonate infusion was observed compared to control patients (p = 0.011). The incidence of postoperative renal replacement therapy was similar but hospital mortality was increased in patients receiving sodium bicarbonate compared with control (11/174 [6.3%] versus 3/176 [1.7%], OR 3.89 [1.07–14.2], p = 0.031).
Conclusions
Urinary alkalinization using sodium bicarbonate infusion was not found to reduce the incidence of acute kidney injury or attenuate tubular damage following open heart surgery; however, it was associated with a possible increase in mortality. On the basis of these findings we do not recommend the prophylactic use of sodium bicarbonate infusion to reduce the risk of acute kidney injury. Discontinuation of growing implementation of this therapy in this setting seems to be justified.
Trial registration
ClinicalTrials.gov NCT00672334
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Open heart surgery is a type of cardiac surgery that is used to treat patients with severe heart disease, where the patient's chest is cut open and surgery is performed on the internal structures of the heart. During open heart surgery, surgeons may use a technique called cardiopulmonary bypass to temporarily take over the function of the heart and lungs. This type of surgery may be used to prevent heart attack or heart failure in patients with conditions such as angina, atherosclerosis, congenital heart disease, or valvular heart disease. There are a number of complications associated with open heart surgery and one of these is the rapid loss of kidney function, known as acute kidney injury (AKI), and formerly known as acute renal failure. Symptoms of AKI can be variable, with diagnosis of AKI based on laboratory findings (such as elevated blood urea nitrogen and creatinine), or clinical signs such as inability of the kidneys to produce sufficient amounts of urine. Globally, more than 10 million people are affected by AKI each year. AKI occurs in about one quarter of patients undergoing cardiac surgery and is associated with longer stays in the hospital and an increased risk of death. Treatment of AKI includes administration of intravenous fluids, diuretics, and, in severe cases, patients may require kidney dialysis.
Why Was This Study Done?
The mechanism for why AKI occurs during cardiac surgery is complex and thought to involve multiple factors relating to blood circulation, the immune system, and toxins released by the kidneys. In addition to treating AKI after it occurs, it is important to identify patients who are at risk for developing AKI prior to cardiac surgery and then apply techniques to prevent AKI during cardiac surgery. A number of interventions have been tested for preventing AKI during cardiac surgery, but there is currently no strong evidence for a standard way to prevent AKI. One intervention that has potential for preventing AKI is the administration of sodium bicarbonate during cardiac surgery. Sodium bicarbonate causes alkalinization of the urine, and it is thought that this could reduce the effect of toxins in the kidneys. A previous pilot study showed promising effects for sodium bicarbonate to reduce the likelihood of AKI. In a follow-up to this pilot study, here the researchers have performed an international randomized controlled trial to test whether administration of sodium bicarbonate compared to sodium chloride (saline) during cardiac surgery can prevent AKI.
What Did the Researchers Do and Find?
350 patients undergoing open heart surgery with at least one risk factor for developing AKI were recruited across four sites in different countries (Germany, Canada, Ireland, and Australia). These patients were randomly assigned to receive either sodium bicarbonate (treatment) or saline control solution, given as a continuous infusion into the blood stream for 24 hours during surgery. Neither the researchers nor the patients were aware of which patients were assigned to the treatment group. The researchers measured the occurrence of AKI within the first 5 days after surgery and they found that a greater proportion of those patients receiving sodium bicarbonate developed AKI, as compared to those patients receiving saline control. On the basis of these findings the study was terminated before planned recruitment was completed. A key issue with this study is that a greater proportion of the patients in the sodium bicarbonate group had chronic kidney disease prior to open heart surgery. After adjusting for this difference in the statistical analysis, the researchers observed that the difference between the groups was not significant—that is, it could have happened by chance. The authors also observed that a significantly greater proportion of patients receiving sodium bicarbonate died in the hospital after surgery compared to patients receiving saline control.
What Do These Findings Mean?
These findings suggest that giving an infusion of sodium bicarbonate to induce alkalinization of the urine during open heart surgery is not a useful treatment for preventing AKI. Furthermore, this treatment may even increase the likelihood of death. The researchers do not recommend the use of sodium bicarbonate infusion to reduce the risk of AKI after open heart surgery and stress the need for discontinuation of this therapy. Key limitations of this research study are the early termination of the study and the greater proportion of patients with chronic kidney disease prior to surgery.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001426.
The Renal Association, a professional association for kidney doctors and researchers, provides information about acute kidney injury
The International Society for Nephrology and the International Federation of Kidney Foundations provide information about preventing acute kidney injury around the world and jointly initiated World Kidney Day
MedlinePlus has information on open heart surgery
doi:10.1371/journal.pmed.1001426
PMCID: PMC3627643  PMID: 23610561
3.  Urine interleukin-6 is an early biomarker of acute kidney injury in children undergoing cardiac surgery 
Critical Care  2010;14(5):R181.
Introduction
Interleukin-6 (IL-6) is a proinflammatory cytokine that increases early in the serum of patients with acute kidney injury (AKI). The aim of this study was to determine whether urine IL-6 is an early biomarker of AKI and determine the source of urine IL-6. Numerous proteins, including cytokines, are filtered by the glomerulus and then endocytosed and metabolized by the proximal tubule. Since proximal tubule injury is a hallmark of AKI, we hypothesized that urine IL-6 would increase in AKI due to impaired proximal tubule metabolism of filtered IL-6.
Methods
Urine was collected in 25 consecutive pediatric patients undergoing cardiac bypass surgery (CPB). AKI was defined as a 50% increase in serum creatinine at 24 hours (RIFLE (Risk, Injury, Failure, Loss, End stage), R). Mouse models of AKI and freshly isolated proximal tubules were also studied.
Results
Urine IL-6 increased at six hours in patients with AKI versus no AKI (X2 = 8.1750; P < 0.0042). Urine IL-6 > 75 pg/mg identified AKI with a sensitivity of 88%. To assess whether increased urine IL-6 occurs in functional versus structural renal failure, mouse models of pre-renal azotemia after furosemide injection (no tubular injury), ischemic AKI (tubular injury) and cisplatin AKI (tubular injury) were studied. Urine IL-6 did not significantly increase in pre-renal azotemia but did increase in ischemic and cisplatin AKI. To determine if circulating IL-6 appears in the urine in AKI, recombinant human (h)IL-6 was injected intravenously and urine collected for one hour; urine hIL-6 increased in ischemic AKI, but not pre-renal azotemia. To determine the effect of AKI on circulating IL-6, serum hIL-6 was determined one hour post-intravenous injection and was increased in ischemic AKI, but not pre-renal azotemia. To directly examine IL-6 metabolism, hIL-6 was added to the media of normal and hypoxic isolated proximal tubules; hIL-6 was reduced in the media of normal versus injured hypoxic proximal tubules.
Conclusions
Urine IL-6 increases early in patients with AKI. Animal studies demonstrate that failure of proximal tubule metabolism of IL-6 results in increased serum and urine IL-6. Impaired IL-6 metabolism leading to increased serum IL-6 may contribute to the deleterious systemic effects and increased mortality associated with AKI.
doi:10.1186/cc9289
PMCID: PMC3219287  PMID: 20942931
4.  Proteomic Identification of Early Biomarkers of Acute Kidney Injury After Cardiac Surgery in Children 
Background
Serum creatinine is a delayed marker of acute kidney injury (AKI). Our purpose was to discover and validate novel early urinary biomarkers of AKI after cardiac surgery.
Study Design
Diagnostic test study.
Setting & Participants
Children undergoing cardiopulmonary bypass surgery. The test set included 15 subjects with AKI and 15 matched controls (median age 1.5 years) among 45 subjects without AKI. The validation set included 365 children (median age 1.9 years).
Index Tests
Biomarkers identified by proteomic profiling: α1-microglobulin, α1-acid glycoprotein, and albumin.
Reference Test
AKI, defined as a 50% or greater increase in serum creatinine from baseline within three days of surgery.
Results
Proteomic profiling by SELDI-TOF MS revealed three protein peaks that consistently appeared within 2 hours in children who developed AKI after cardiopulmonary bypass surgery. The proteins were identified as α1-microglobulin, α1-acid glycoprotein, and albumin. Using clinical assays, the results were confirmed in a test set and validated in an independent prospective cohort. In the validation set, 135 (37%) developed AKI, in whom there was a progressive increase in urinary biomarker concentrations with severity of AKI. The area under the curve (AUC) for urinary α1-microglobulin, α1-acid glycoprotein, and albumin at 6 hours after cardiac surgery were 0.84 (CI 0.79–0.89), 0.87 (CI 0.83–0.91), and 0.76 (CI 0.71–0.81) respectively. Subjects with increasing quartiles of biomarkers demonstrated increasing length of hospital stay and duration of AKI (P<0.001).
Limitations
Single center study of children with normal kidney function at recruitment. The SELDI-TOF MS technique has limited sensitivity for the detection of proteins above the 20 kDa range.
Conclusions
Urinary α1-microglobulin, α1-acid glycoprotein, and albumin represent early, accurate, inexpensive and widely available biomarkers of AKI after cardiac surgery. They also offer prognostic information on duration of AKI and length of hospitalization after cardiac surgery.
doi:10.1053/j.ajkd.2010.04.014
PMCID: PMC2943007  PMID: 20599305
5.  Urinary Biomarkers of Acute Kidney Injury in Patients with Liver Cirrhosis 
ISRN Nephrology  2014;2014:376795.
Acute kidney injury (AKI) is a common complication in cirrhotic patients. Serum creatinine is a poor biomarker for detection of renal impairment in cirrhotic patients. This study aimed to evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) and urinary interleukin-18 (IL-18) as early biomarkers of acute kidney injury in cirrhotic patients. 160 patients with cirrhosis admitted to the Liver Units at Zagazig University Hospitals were classified into three groups: (I) nonascitic patients, (II) ascitic patients without renal impairment, and (III) ascitic patients with renal impairment. Patients with renal impairment were further divided into four subgroups: [A] prerenal azotemia, [B] chronic kidney disease (CKD), [C] hepatorenal syndrome (HRS), and [D] acute tubular necrosis (ATN). Significant elevation of both urinary NGAL and urinary IL-18 in cirrhotic patients with renal impairment especially in patients with ATN was observed. Urinary NGAL and urinary IL-18 have the ability to differentiate between AKI types in patients with cirrhosis. This could improve risk stratification for patients admitted to the hospital with cirrhosis, perhaps leading to early ICU admission, transplant evaluation, and prompt initiation of HRS therapy and early management of AKI.
doi:10.1155/2014/376795
PMCID: PMC4045442  PMID: 24967242
6.  Hsp72 Is a Novel Biomarker to Predict Acute Kidney Injury in Critically Ill Patients 
PLoS ONE  2014;9(10):e109407.
Background and Objectives
Acute kidney injury (AKI) complicates the course of disease in critically ill patients. Efforts to change its clinical course have failed because of the fail in the early detection. This study was designed to assess whether heat shock protein (Hsp72) is an early and sensitive biomarker of acute kidney injury (AKI) compared with kidney injury molecule (Kim-1), neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) biomarkers.
Methods
A total of 56 critically ill patients fulfilled the inclusion criteria. From these patients, 17 developed AKI and 20 were selected as controls. In AKI patients, Kim-1, IL-18, NGAL, and Hsp72 were measured from 3 days before and until 2 days after the AKI diagnosis and in no-AKI patients at 1, 5 and 10 days after admission. Biomarker sensitivity and specificity were determined. To validate the results obtained with ROC curves for Hsp72, a new set of critically ill patients was included, 10 with AKI and 12 with no-AKI patients.
Results
Urinary Hsp72 levels rose since 3 days before the AKI diagnosis in critically ill patients; this early increase was not seen with any other tested biomarkers. Kim-1, IL-18, NGAL, and Hsp72 significantly increased from 2 days before AKI and remained elevated during the AKI diagnosis. The best sensitivity/specificity was observed in Kim-1 and Hsp72: 83/95% and 100/90%, respectively, whereas 1 day before the AKI diagnosis, the values were 100/100% and 100/90%, respectively. The sensibility, specificity and accuracy in the validation test for Hsp72 were 100%, 83.3% and 90.9%, respectively.
Conclusions
The biomarker Hsp72 is enough sensitive and specific to predict AKI in critically ill patients up to 3 days before the diagnosis.
doi:10.1371/journal.pone.0109407
PMCID: PMC4196900  PMID: 25313566
7.  Repulsive guidance cue semaphorin 3A in urine predicts the progression of acute kidney injury in adult patients from a mixed intensive care unit 
Backgrounds
Predicting the development of acute kidney injury (AKI) in the critical care setting is challenging. Although several biomarkers showed somewhat satisfactory performance for detecting established AKI even in a heterogeneous disease-oriented population, identification of new biomarkers that predict the development of AKI accurately is urgently required.
Methods
A single-center prospective observational cohort study was undertaken to evaluate for the first time the reliability of the newly identified biomarker semaphorin 3A for AKI diagnosis in heterogeneous intensive care unit populations. In addition to five urinary biomarkers of L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), IL-18, albumin and N-acetyl-β-d-glucosaminidase (NAG), urinary semaphorin 3A was measured at intensive care unit (ICU) admission.
Results and conclusion
Three hundred thirty-nine critically ill adult patients were recruited for this study. Among them, 131 patients (39%) were diagnosed with AKI by the RIFLE criteria and 66 patients were diagnosed as AKI at post-ICU admission (later-onset AKI). Eighty-four AKI patients showed worsening severity during 1 week observation (AKI progression). Although L-FABP, NGAL and IL-18 showed significantly higher area under the curve (AUC)-receiver operating characteristic (ROC) values than semaphorin 3A in detecting established AKI, semaphorin 3A was able to detect later-onset AKI and AKI progression with similar AUC-ROC values compared with the other five biomarkers [AUC-ROC (95% CI) for established AKI 0.64 (0.56–0.71), later-onset AKI 0.71 (0.64–0.78), AKI progression 0.71 (0.64–0.77)]. Urinary semaphorin 3A was not increased in non-progressive established AKI, while the other biomarkers were elevated regardless of further progression. Finally, sepsis did not have any impact on semaphorin 3A while the other urinary biomarkers were increased with sepsis. Semaphorin 3A is a new biomarker of AKI which may have a distinct predictive use for AKI progression when compared with other AKI biomarkers.
doi:10.1093/ndt/gft414
PMCID: PMC3888311  PMID: 24166457
acute kidney injury; AKI progression; biomarker; mixed ICU; semaphorin 3A
8.  Diagnosing drug-induced AIN in the hospitalized patient: A challenge for the clinician  
Clinical Nephrology  2014;81(6):381-388.
Drug-induced acute interstitial nephritis (AIN) is a relatively common cause of hospital-acquired acute kidney injury (AKI). While prerenal AKI and acute tubular necrosis (ATN) are the most common forms of AKI in the hospital, AIN is likely the next most common. Clinicians must differentiate the various causes of hospital-induced AKI; however, it is often difficult to distinguish AIN from ATN in such patients. While standardized criteria are now used to classify AKI into stages of severity, they do not permit differentiation of the various types of AKI. This is not a minor point, as these different AKI types often require different therapeutic interventions. Clinicians assess and differentiate AIN from these other AKI causes by utilizing clinical assessment, various imaging tests, and certain laboratory data. Gallium scintigraphy has been employed with mixed results. While a few serum tests, such as eosinophilia may be helpful, examination of the urine with tests such as dipstick urinalysis, urine chemistries, urine eosinophils, and urine microscopy are primarily utilized. Unfortunately, these tools are not always sufficient to definitively clinch the diagnosis, making it a challenging task for the clinician. As a result, kidney biopsy is often required to accurately diagnose AIN and guide management.
doi:10.5414/CN108301
PMCID: PMC4326856  PMID: 24691017
urine microscopy; eosinophiluria; leukocytes; white blood cell cast; acute kidney injury; acute interstitial nephritis; acute tubular necrosis
9.  Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study 
Critical Care  2011;15(3):R146.
Introduction
In adults, small (< 50%) serum creatinine (SCr) increases predict mortality. It is unclear whether different baseline serum creatinine (bSCr) estimation methods affect findings of acute kidney injury (AKI)-outcome associations. We characterized pediatric AKI, evaluated the effect of bSCr estimation approaches on AKI-outcome associations and evaluated the use of small SCr increases to predict AKI development.
Methods
We conducted a retrospective cohort database study of children (excluding postoperative cardiac or renal transplant patients) admitted to two pediatric intensive care units (PICUs) for at least one night in Montreal, QC, Canada. The AKI definition was based on the Acute Kidney Injury Network staging system, excluding the requirement of SCr increase within 48 hours, which was impossible to evaluate on the basis of our data set. We estimated bSCr two ways: (1) the lowest SCr level in the three months before admission or the average age- and gender-based norms (the standard method) or (2) by using average norms in all patients. Outcomes were PICU mortality and length of stay as well as required mechanical ventilation. We used multiple logistic regression analysis to evaluate AKI risk factors and the association between AKI and mortality. We used multiple linear regression analysis to evaluate the effect of AKI on other outcomes. We calculated diagnostic characteristics for early SCr increase (< 50%) to predict AKI development.
Results
Of 2,106 admissions (mean age ± SD = 5.0 ± 5.5 years; 47% female), 377 patients (17.9%) developed AKI (using the standard bSCr method) during PICU admission. Higher Pediatric Risk of Mortality score, required mechanical ventilation, documented infection and having a bSCr measurement were independent predictors of AKI development. AKI was associated with increased mortality (adjusted odds ratio (OR) = 3.7, 95% confidence interval (95% CI) = 2.1 to 6.4, using the standard bSCr method; OR = 4.5, 95% CI = 2.6 to 7.9, using normative bSCr values in all patients). AKI was independently associated with longer PICU stay and required mechanical ventilation. In children with no admission AKI, the initial percentage SCr increase predicted AKI development (area under the curve = 0.67, 95% CI = 0.60 to 0.74).
Conclusions
AKI is associated with increased mortality and morbidity in critically ill children, regardless of the bSCr used. Paying attention to small early SCr increases may contribute to early AKI diagnosis in conjunction with other new AKI biomarkers.
doi:10.1186/cc10269
PMCID: PMC3219018  PMID: 21663616
10.  Exosomal Fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury 
Kidney international  2006;70(10):1847-1857.
Urinary exosomes containing apical membrane and intracellular fluid are normally secreted into the urine from all nephron segments, and may carry protein markers of renal dysfunction and structural injury. We aimed to discover biomarkers in urinary exosomes to detect acute kidney injury (AKI) which has a high mortality and morbidity. Animals were injected intravenously with cisplatin. Urinary exosomes were isolated by differential centrifugation. Protein changes were evaluated by two-dimensional difference in gel electrophoresis and changed proteins were identified by MALDI-TOF-TOF or LC-MS/MS. The identified candidate biomarkers were validated by western blotting in individual urine samples from rats subjected to cisplatin injection; bilateral ischemia and reperfusion (I/R); volume depletion (VD); and ICU patients with and without AKI. We identified 18 proteins that were increased and 9 proteins that were decreased 8 hr after cisplatin. Most of the candidates could not be validated by western blotting. However, exosomal Fetuin-A increased 52.5-fold at day 2 (1 day before serum creatinine increase and tubule damage) and remained elevated 51.5-fold at day 5 (peak renal injury) after cisplatin injection. By immuno-electron microscopy and elution studies, Fetuin-A was located inside urinary exosomes. Urinary Fetuin-A was increased 31.6-fold in the early phase (2~8hr) of ischemia/reperfusion, but not in prerenal azotemia. Urinary exosomal Fetuin-A also increased in three ICU patients with AKI compared to the patients without AKI. We conclude that 1) Proteomic analysis of urinary exosomes can provide biomarker candidates for the diagnosis of AKI; 2) Urinary Fetuin-A might be a predictive biomarker of structural renal injury.
doi:10.1038/sj.ki.5001874
PMCID: PMC2277342  PMID: 17021608
exosomes; AKI; rats; ICU patients; cisplatin; ischemia; sepsis; mass spectrometry
11.  Association of inflammatory and endothelial cell activation biomarkers with acute kidney injury after sepsis 
SpringerPlus  2014;3:207.
Objective
Acute kidney injury (AKI) is a sequela of sepsis associated with increased morbidity and mortality. We sought to determine if individuals with elevated baseline levels of inflammation and endothelial cell activation are at increased risk for future AKI after sepsis.
Methods
We conducted an analysis of individuals developing sepsis in the national 30,239 subject REGARDS cohort. Biomarkers measured at the beginning of an 8-year observation period included high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor (TNF-α), E-selectin, inter-cellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and urinary Albumin-to-creatinine ratio (ACR). We defined subsequent sepsis as hospitalization for a serious infection with ≥2 Systemic Inflammatory Response Syndrome (SIRS) criteria. We excluded patients with prior dialysis or kidney transplantation, or those receiving less than two serum creatinine (sCr) measurements during hospitalization. We defined AKI as an increase in sCr ≥0.3 mg/dL from the initial sCr measurement, or the initiation of hemodialysis. Using logistic regression, we evaluated the associations between AKI and biomarker quartiles, adjusting for comorbidities.
Results
We identified 212 sepsis cases encompassing 41 (19.3%) AKI. Elapsed time from biomarker measurement to sepsis episode was 3.1 years (IQR 1.6-4.5). Compared with non-AKI, AKI individuals exhibited higher TNF-α (9.4 vs. 6.2 pg/mL, p = 0.003) and ACR (504.82 vs 61.81 mg/g, p < 0.001). hsCRP, IL-6, E-selectin, ICAM-1 and VCAM-1 were similar between AKI and non-AKI. After adjustment for confounders, AKI after sepsis was more likely in those with higher E-selectin (adjusted ORs 2.91 (0.95-8.93), 1.99 (0.61-6.47), 4.01 (1.30-12.35), test of linear trend p = 0.04), and higher ACR (adjusted ORs 2.29 (0.99-5.30), 10.67 (3.46-32.90), test of linear trend p < 0.001). Baseline hsCRP, TNF-α, IL-6, VCAM-1 and ICAM-1 were not associated with AKI after sepsis.
Conclusion
Elevated baseline levels of E-selectin and ACR are associated with future AKI in the setting of sepsis. Baseline inflammatory and endothelial activation biomarkers may be useful for predicting future risk of AKI in sepsis.
doi:10.1186/2193-1801-3-207
PMCID: PMC4018475  PMID: 24826374
Acute kidney injury (AKI); Biomarkers; Endothelium; Inflammation; Sepsis
12.  Performance of Urinary Liver-Type Fatty Acid–Binding Protein in Acute Kidney Injury: A Meta-analysis 
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
Human studies investigating the performance characteristics of urinary L-FABP for 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 studies and 2 case-control studies were identified. Only 7 cohort studies could be meta-analyzed. The estimated sensitivity of urinary L-FABP for diagnosis of AKI was 74.5% (95% CI, 60.4-84.8), and the specificity was 77.6% (95% CI, 61.5-88.2). The estimated sensitivity of urinary L-FABP for predicting dialysis requirement was 69.1% (95% CI, 34.6-90.5), and the specificity was 42.7% (95% CI, 3.1-94.5); for in-hospital mortality, sensitivity and specific 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 diagnosis of AKI, and for predicting dialysis requirement and in-hospital mortality, its potential value needs to be validated in large studies and across a broader spectrum of clinical settings.
doi:10.1053/j.ajkd.2012.10.016
PMCID: PMC3578035  PMID: 23228945
L-FABP; biomarker; AKI; systematic review; meta-analysis
13.  Plasma and urine neutrophil gelatinase-associated lipocalin in the diagnosis of new onset acute kidney injury in critically ill patients 
Critical Care  2014;18(4):R137.
Introduction
Neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a useful early diagnostic biomarker of acute kidney injury (AKI) where the timing of the insult is certain. However, NGAL is not well validated in adult critical care practice because of indeterminate timing of injury. Therefore, we sought to establish the predictive ability of both urine and plasma NGAL to detect AKI in ICU patients.
Method
This prospective observational study was performed in a busy large district general hospital mixed surgical-medical ICU in Reading, UK. Consecutive adult admissions to the ICU, with absence of chronic kidney disease, renal transplant or AKI as defined by RIFLE criteria were included. Blood and urine specimens were collected at admission and every 24 hours until 72 hours and tested for NGAL. The purpose of the study was to assess whether urinary NGAL (uNGAL) or plasma NGAL (pNGAL) can predict the occurrence of AKI at an earlier point of time than the conventional markers, that is creatinine and urine output as is used in RIFLE criteria.
Results
Over a 12-month period, 194 patients were enrolled. In total, 59 (30.4%) patients developed AKI. The admission pNGAL and uNGAL were significantly higher in the patients who developed AKI compared to the non-AKI patients (436 ng/mL (240, 797) versus 168 ng/mL (121.3, 274.3) P <0.001 and 342 ng/mL (61.5, 1,280) versus 34.5 ng/mL (11.5, 107.75) P <0.001 respectively). Hospital mortality was higher in the AKI group (17% versus 4%). Plasma NGAL performed fairly on admission (AUROC 0.77) and thereafter performance improved at 24 and 48 hours (AUROC 0.88 and 0.87) following ICU admission. Urine NGAL had a fair predictive value on admission (AUROC 0.79) and at 24 hours (AUROC 0.78) and was good at 48 hours (AUROC 0.82).
Conclusions
In critically ill patients without pre-existing kidney disease, both pNGAL and uNGAL measured at admission can predict AKI (defined by RIFLE criteria) occurrence up to 72 hours post-ICU admission and their performance (AUROC) was fair. The accuracy of NGAL appeared to improve slightly as patients progressed through their ICU stay. Serial measurements of NGAL (both pNGAL and uNGAL) may be of added value in an ICU setting to predict the occurrence of AKI.
doi:10.1186/cc13958
PMCID: PMC4226989  PMID: 24985156
14.  Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial 
PLoS Medicine  2014;11(2):e1001601.
Martin Gallagher and colleagues examine the long-term outcomes of renal replacement therapy (RRT) dosing in patients with acute kidney injury randomized to normal vs. augmented RRT.
Please see later in the article for the Editors' Summary
Background
The incidence of acute kidney injury (AKI) is increasing globally and it is much more common than end-stage kidney disease. AKI is associated with high mortality and cost of hospitalisation. Studies of treatments to reduce this high mortality have used differing renal replacement therapy (RRT) modalities and have not shown improvement in the short term. The reported long-term outcomes of AKI are variable and the effect of differing RRT modalities upon them is not clear. We used the prolonged follow-up of a large clinical trial to prospectively examine the long-term outcomes and effect of RRT dosing in patients with AKI.
Methods and Findings
We extended the follow-up of participants in the Randomised Evaluation of Normal vs. Augmented Levels of RRT (RENAL) study from 90 days to 4 years after randomization. Primary and secondary outcomes were mortality and requirement for maintenance dialysis, respectively, assessed in 1,464 (97%) patients at a median of 43.9 months (interquartile range [IQR] 30.0–48.6 months) post randomization. A total of 468/743 (63%) and 444/721 (62%) patients died in the lower and higher intensity groups, respectively (risk ratio [RR] 1.04, 95% CI 0.96–1.12, p = 0.49). Amongst survivors to day 90, 21 of 411 (5.1%) and 23 of 399 (5.8%) in the respective groups were treated with maintenance dialysis (RR 1.12, 95% CI 0.63–2.00, p = 0.69). The prevalence of albuminuria among survivors was 40% and 44%, respectively (p = 0.48). Quality of life was not different between the two treatment groups. The generalizability of these findings to other populations with AKI requires further exploration.
Conclusions
Patients with AKI requiring RRT in intensive care have high long-term mortality but few require maintenance dialysis. Long-term survivors have a heavy burden of proteinuria. Increased intensity of RRT does not reduce mortality or subsequent treatment with dialysis.
Trial registration
www.ClinicalTrials.gov NCT00221013
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. Chronic kidney disease (caused, for example, by diabetes) gradually destroys the kidneys' filtration units (the nephrons), eventually leading to life-threatening end-stage kidney disease. However, the kidneys can also stop working suddenly because of injury, infection, or poisoning. Acute kidney injury (AKI) is much more common than end-stage kidney disease and its incidence is increasing worldwide. In the US, for example, the number of hospitalizations that included an AKI diagnosis rose from 4,000 in 1996 to 23,000 in 2008. Moreover, nearly half of patients with AKI will die shortly after the condition develops. Symptoms of AKI include changes in urination, swollen feet and ankles, and tiredness. Treatments for AKI aim to prevent fluid and waste build up in the body and treat the underlying cause (e.g., severe infection or dehydration) while allowing the kidneys time to recover. In some patients, it is sufficient to limit the fluid intake and to reduce waste build-up by eating a diet that is low in protein, salt, and potassium. Other patients need renal replacement therapy (RRT), life-supporting treatments such as hemodialysis and hemofiltration, two processes that clean the blood by filtering it outside the body.
Why Was This Study Done?
The long-term outcomes of AKI (specifically, death and chronic kidney disease) and the effects of different RRT modalities on these outcomes are unclear. A recent controlled trial that randomly assigned patients with AKI who were managed in intensive care units (ICUs) to receive two different intensities of continuous hemodiafiltration (a combination of hemodialysis and hemofiltration) found no difference in all-cause mortality (death) at 90 days. Here, the researchers extend the follow-up of this trial (the Randomized Evaluation of Normal vs. Augmented Levels of renal replacement therapy [RENAL] study) to investigate longer-term mortality, the variables that predict mortality, treatment with long-term dialysis (an indicator of chronic kidney disease), and functional outcomes in patients with AKI treated with different intensities of continuous RRT.
What Did the Researchers Do and Find?
For the Prolonged Outcomes Study of RENAL (POST-RENAL), the researchers extended the follow-up of the RENAL participants up to 4 years. Over an average follow-up of 43.9 months, 63% of patients in the lower intensity treatment group died compared to 62% of patients in the higher intensity group. Overall, a third of patients who survived to 90 days died during the extended follow-up. Among the survivors to day 90, 5.1% and 5.8% of patients in the lower and higher intensity groups, respectively, were treated with maintenance dialysis during the extended follow-up. Among survivors who consented to analysis, 40% and 44% of patients in the lower and higher intensity groups, respectively, had albuminuria (protein in the urine, an indicator of kidney damage). Patients in both groups had a similar quality life (determined through telephone interviews). Finally, increasing age, APACHE III score (a scoring system that predicts the survival of patients in ICU), and serum creatinine level (an indicator of kidney function) at randomization were all predictors of long-term mortality.
What Do These Findings Mean?
These findings indicate that patients with AKI in ICUs who require RRT have a high long-term mortality. They show that few survivors require maintenance dialysis for chronic kidney disease but that there is a substantial rate of albuminuria among survivors despite relative preservation of kidney function. The findings also suggest that the intensity of RRT has no significant effect on mortality or the need for dialysis. Because these findings were obtained in a randomized controlled trial, they may not be generalizable to other patient populations. Moreover, although data on mortality and maintenance dialysis were available for all the trial participants, clinical and biochemical outcomes were only available for some participants and may not be representative of all the participants. Despite these study limitations, these findings suggest that survivors of AKI may be at a high risk of death or of developing chronic kidney disease. Survivors of AKI are, therefore, at high risk of further illness and long-term albuminuria reduction strategies may offer a therapeutic intervention for this group of patients.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001601.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about the kidneys and about all aspects of kidney disease and its treatment; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The Mayo Clinic provides information for patients about acute kidney injury
Wikipedia has a page on acute kidney injury (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers, including a link to a video about acute kidney injury
World Kidney Day, a joint initiative between the International Society of Nephrology and the International Federation of Kidney Foundations (IFKF), aims to raise awareness about kidneys and kidney disease; its website provides information about acute kidney injury
The MedlinePlus Encyclopedia has a pages about acute kidney failure and about renal dialysis
The UK National Institute for Health and Care Excellence (NICE) recently published new guidelines on the treatment of acute kidney injury; a clinical practice guideline for acute kidney injury produced by KDIGO (a not-for-profit organization that aims to improve the care and outcomes of kidney disease patients worldwide through the development and implementation of global clinical practice guidelines) is available; the Acute Kidney Injury app provides a fast and simple way to explore guidelines on the diagnosis, prevention, and management of AKI
doi:10.1371/journal.pmed.1001601
PMCID: PMC3921111  PMID: 24523666
15.  Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts outcomes 
Kidney international  2011;80(4):10.1038/ki.2011.41.
In established acute kidney injury (AKI), serum creatinine poorly differentiates prerenal and intrinsic AKI. A damage-associated nephron biomarker, neutrophil gelatinase-associated lipocalin (NGAL) could be a better discriminator. We tested the hypothesis that urinary NGAL distinguishes intrinsic and prerenal AKI, and tested its performance in the prediction of a composite outcome that included progression to a higher RIFLE (“risk, injury, failure, loss of function, end stage renal disease”) severity class, dialysis, or death. We measured urinary NGAL in 161 hospitalized patients with established AKI using a standardized clinical platform. We excluded 16 patients with postrenal obstruction or insufficient clinical information. Of the remaining 145 patients, 75 patients had intrinsic AKI, 32 patients had prerenal AKI, and 38 patients could not be classified. We found that urinary NGAL levels effectively discriminated intrinsic AKI from prerenal AKI (ROC 0.87, CI 0.81-0.94). An NGAL level >104 μg/L indicated intrinsic AKI (likelihood ratio 5.97), while an NGAL level <47 μg/L made intrinsic AKI unlikely (likelihood ratio 0.2). Patients experiencing the composite outcome had higher median urinary NGAL levels on inclusion (248.2 vs. 68.3 μg/L, p<0.001). In logistic regression analysis, NGAL independently predicted the composite outcome, when corrected for demographics, co-morbidities, creatinine, and RIFLE class. Hence, urinary NGAL is useful in classifying and stratifying patients with established AKI.
doi:10.1038/ki.2011.41
PMCID: PMC3870593  PMID: 21412214
16.  Urine interleukin-18 in prediction of acute kidney injury: a systemic review and meta-analysis 
Journal of Nephrology  2014;28:7-16.
Background
Interleukin-18 (IL-18) mediates ischemic acute tubular necrosis; it has been proved as a rapid, reliable, and affordable test marker for the early detection of acute kidney injury (AKI), but its predictive accuracy varies greatly.
Methods
MEDLINE and EMBASE, Cochrane Library, Ovid, and Springerlink (from inception to November 15, 2013) were searched for relevant studies (in English) investigating diagnostic accuracy of urine IL-18 to predict AKI in various clinical settings. The text index was increasing or increased urine IL-18 level and the main outcome was the development of AKI, which was primarily based on serum creatinine level [using risk, injury, failure, loss and end-stage renal disease (RIFLE), acute kidney injury network, or modified pediatric RIFLE criteria in pediatric patients]. Pooled estimates of diagnostic odds ratio (OR), sensitivity and specificity were calculated. Summary receiver operating characteristic curves were used to calculate the measures of accuracy and Q point value (Q*). Remarkable heterogeneity was explored further by subgroup analysis based on the different clinical settings.
Results
We analyzed data from 11 studies of 3 countries covering 2,796 patients. These studies were marked by limitations of threshold and non-threshold effect heterogeneity. Across all settings, the diagnostic OR for urine IL-18 level to predict AKI was 5.11 [95 % confidence interval (CI) 3.22–8.12], with sensitivity and specificity respectively at 0.51 and 0.79. The area under the ROC curve of urine IL-18 level to predict AKI was 0.77 (95 % CI 0.71–0.83). Subgroup analysis showed that urine IL-18 level in pediatric patients (<18 years) and early AKI predictive time (<12 h) were more effective in predicting AKI, with diagnostic ORs of 7.51 (2.99–18.88), 8.18 (2.19–30.51), respectively.
Conclusion
Urine IL-18 holds promise as a biomarker in the prediction of AKI but has only moderate diagnostic value.
doi:10.1007/s40620-014-0113-9
PMCID: PMC4322238  PMID: 24899123
Interleukin-18; Acute kidney injury; Predictive value; Systemic review
17.  Recovery process in patients followed-up due to acute kidney injury 
Hippokratia  2013;17(3):239-242.
Introduction: Acute kidney injury (AKI) may result in complete recovery in some of the patients and partial recovery in others. AKI episodes may accelerate the progression to chronic kidney disease and end-stage renal failure, while risk for morbidity and mortality is high following AKI. Discharge of patients from the hospital, independently from dialysis is a crucial outcome. Many patients without a need for dialysis, require follow-up for various durations and different treatments. The objective of this study was to compare mean recovery time of the patients followed-up due to prerenal, renal and postrenal AKIs.
Method: In this prospective observational study, a total of 159 patients hospitalized in Bulent Ecevit Hospital, clinic of nephrology or monitored in the other wards and intensive care unit due to AKI, between June 2011 and January 2012, were enrolled. The cases were divided into three groups as prerenal, renal and postrenal, and monitored with the daily visits and renal function testing.
Results: Prerenal AKI was seen by 54%, while renal AKI was observed by 34% and post-renal AKI by 12%. Incidence of chronic kidney disease was 17.6%. Totally 43 patients required hemodialysis (27%). Of these patients, 23 were in the prerenal AKI (53.4%), 15 in the renal AKI (34.8%) and 5 (11.6%) in the postrenal AKI group. Blood urea nitrogen (BUN) and creatinine levels were dropped to the basal values only in the prerenal AKI group, on the seventh day of treatment. These levels remained higher in the postrenal and renal groups on the 7th day of treatment compared to the basal values. BUN levels decreased to the normal values on average 7th day in the postrenal, while remained higher in the renal group.
Conclusion: Prerenal AKI patients recovered in seven days with a proper treatment, although AKI patients due to other reasons should be followed-up for a longer time.
PMCID: PMC3872460  PMID: 24470734
Acute kidney injury; prerenal; renal; postrenal acute kidney injury; recovery time
18.  Predictive models for kidney disease: improving global outcomes (KDIGO) defined acute kidney injury in UK cardiac surgery 
Critical Care  2014;18(6):606.
Introduction
Acute kidney injury (AKI) risk prediction scores are an objective and transparent means to enable cohort enrichment in clinical trials or to risk stratify patients preoperatively. Existing scores are limited in that they have been designed to predict only severe, or non-consensus AKI definitions and not less severe stages of AKI, which also have prognostic significance. The aim of this study was to develop and validate novel risk scores that could identify all patients at risk of AKI.
Methods
Prospective routinely collected clinical data (n = 30,854) were obtained from 3 UK cardiac surgical centres (Bristol, Birmingham and Wolverhampton). AKI was defined as per the Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines. The model was developed using the Bristol and Birmingham datasets, and externally validated using the Wolverhampton data. Model discrimination was estimated using the area under the ROC curve (AUC). Model calibration was assessed using the Hosmer–Lemeshow test and calibration plots. Diagnostic utility was also compared to existing scores.
Results
The risk prediction score for any stage AKI (AUC = 0.74 (95% confidence intervals (CI) 0.72, 0.76)) demonstrated better discrimination compared to the Euroscore and the Cleveland Clinic Score, and equivalent discrimination to the Mehta and Ng scores. The any stage AKI score demonstrated better calibration than the four comparison scores. A stage 3 AKI risk prediction score also demonstrated good discrimination (AUC = 0.78 (95% CI 0.75, 0.80)) as did the four comparison risk scores, but stage 3 AKI scores were less well calibrated.
Conclusions
This is the first risk score that accurately identifies patients at risk of any stage AKI. This score will be useful in the perioperative management of high risk patients as well as in clinical trial design.
doi:10.1186/s13054-014-0606-x
PMCID: PMC4258283
19.  The histopathology of septic acute kidney injury: a systematic review 
Critical Care  2008;12(2):R38.
Introduction
Sepsis is the most common trigger of acute kidney injury (AKI) in critically ill patients; understanding the structural changes associated with its occurrence is therefore important. Accordingly, we systematically reviewed the literature to assess current knowledge on the histopathology of septic AKI.
Methods
A systematic review of the MEDLINE, EMBASE and CINHAL databases and bibliographies of the retrieved articles was performed for all studies describing kidney histopathology in septic AKI.
Results
We found six studies reporting the histopathology of septic AKI for a total of only 184 patients. Among these patients, only 26 (22%) had features suggestive of acute tubular necrosis (ATN). We found four primate studies. In these, seven out of 19 (37%) cases showed features of ATN. We also found 13 rodent studies of septic AKI. In total, 23% showed evidence of ATN. In two additional studies performed in a dog model and a sheep model there was no evidence of ATN on histopathologic examination. Overall, when ATN was absent, studies reported a wide variety of kidney morphologic changes in septic AKI – ranging from normal (in most cases) to marked cortical tubular necrosis.
Conclusion
There are no consistent renal histopathological changes in human or experimental septic AKI. The majority of studies reported normal histology or only mild, nonspecific changes. ATN was relatively uncommon.
doi:10.1186/cc6823
PMCID: PMC2447560  PMID: 18325092
20.  Urinary Cystatin C and Acute Kidney Injury After Cardiac Surgery 
Background
Acute Kidney Injury (AKI) is common following cardiac surgery and is associated with adverse patient outcomes. Urinary cystatin C (CysC) is a biomarker of proximal tubule function and may rise earlier in AKI than serum creatinine.
Study Design
Prospective cohort study
Settings & Participants
The TRIBE AKI (Translational Research Investigating Biomarker Endpoints in AKI) Consortium prospectively enrolled 1,203 adults and 299 children at 8 institutions from 2007–2009.
Index Test
Urinary CysC (mg/L) within the first 12 hours after surgery
Outcome
Serum Creatinine based AKI was defined as AKI Network stage 1 (Mild AKI) as well as a doubling of serum creatinine from the pre-operative value or the need for dialysis during hospitalization (Severe AKI).
Other Measurements
Analyses were adjusted for characteristics used clinically for AKI risk stratification including age, sex, race, eGFR, diabetes, hypertension, heart failure, non-elective surgery, cardiac catheterization within 72 hours, type of surgery, myocardial infarction, and cardiopulmonary bypass time greater than 120 minutes.
Results
Urinary CysC measured in the early post-operative period (0–6 and 6–12 hours postoperatively) correlated with both mild and severe AKI in adults and children. However after analyses were adjusted for other factors the effect was attenuated for both forms of AKI in both cohorts.
Limitations
Limited numbers of patients with severe AKI and short-term dialysis
Conclusions
Urinary CysC values are not significantly associated with the development of AKI following cardiac surgery in adults and children.
doi:10.1053/j.ajkd.2012.12.006
PMCID: PMC3627833  PMID: 23332602
Acute kidney injury Biomarkers; Cystatin C; Dialysis; Peri-operative
21.  Urine Catalytic Iron and Neutrophil Gelatinase-Associated Lipocalin as Companion Early Markers of Acute Kidney Injury after Cardiac Surgery: A Prospective Pilot Study 
Cardiorenal Medicine  2013;3(1):7-16.
Background
Open heart surgery with cardiopulmonary bypass is recognized as a common cause of acute kidney injury (AKI). The conventional biomarker creatinine is not sensitive enough to detect AKI until a significant decline in renal filtration has occurred. Urine neutrophil gelatinase-associated lipocalin (NGAL), part of an acute response to the release of tissue iron from cells, is an early biomarker and a predictor of AKI in a variety of clinical settings. We sought to evaluate the relationship between urine catalytic iron (unbound iron) and NGAL over the course of AKI due to cardiac surgery.
Methods
Fourteen patients who underwent open heart surgery had the following measured: serum creatinine (0, 12, 24, 48 and 72 h postoperatively), urine NGAL and urine catalytic iron (0, 8, 24 and 48 h postoperatively). Urine NGAL and urine catalytic iron were quantified by immunoassay and bleomycin-detectable iron assay, respectively. AKI was defined by the Acute Kidney Injury Network (AKIN) criteria.
Results
Urine catalytic iron increased significantly (p < 0.05) within 8 h and peaked at 24 h postoperatively in patients who developed AKI (n = 8, baseline 101.96 ± 177.48, peak 226.35 ± 238.23 nmol/l, p = 0.006), but not in non-AKI patients (n = 6, baseline 131.08 ± 116.21, peak 163.99 ± 109.62 nmol/l, p = 0.380). Urine NGAL levels also peaked at 24 h with significant increase observed only in AKI patients: AKI – baseline 34.88 ± 26.47, peak 65.50 ± 27.03 ng/ml, p = 0.043; non-AKI – baseline 59.33 ± 31.72, peak 71.00 ± 31.76 ng/ml, p = 0.100. The correlation between baseline levels of urine catalytic iron and NGAL and peak levels of urine catalytic iron and NGAL was r = 0.86, p < 0.0001.
Conclusion
Urine catalytic iron appears to rise and fall in concert with NGAL in patients undergoing cardiac surgery and may be indicative of early AKI. Future research into the role that catalytic iron plays in acute organ injury syndromes and its potential diagnostic and therapeutic implications is warranted.
doi:10.1159/000346815
PMCID: PMC3743453  PMID: 23946721
Catalytic iron; Marker; Neutrophil gelatinase-associated lipocalin; Acute kidney injury; Heart surgery
22.  Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury 
Critical Care  2013;17(1):R25.
Introduction
Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
Methods
We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
Results
Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
Conclusions
Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.
Trial registration
ClinicalTrials.gov number NCT01209169.
doi:10.1186/cc12503
PMCID: PMC4057242  PMID: 23388612
23.  Development and Standardization of a Furosemide Stress Test to Predict the Severity of Acute Kidney Injury 
Critical Care  2013;17(5):R207.
Introduction
In the setting of early acute kidney injury (AKI), no test has been shown to definitively predict the progression to more severe stages.
Methods
We investigated the ability of a furosemide stress test (FST) (one-time dose of 1.0 or 1.5 mg/kg depending on prior furosemide-exposure) to predict the development of AKIN Stage-III in 2 cohorts of critically ill subjects with early AKI. Cohort 1 was a retrospective cohort who received a FST in the setting of AKI in critically ill patients as part of Southern AKI Network. Cohort 2 was a prospective multicenter group of critically ill patients who received their FST in the setting of early AKI.
Results
We studied 77 subjects; 23 from cohort 1 and 54 from cohort 2; 25 (32.4%) met the primary endpoint of progression to AKIN-III. Subjects with progressive AKI had significantly lower urine output following FST in each of the first 6 hours (p<0.001). The area under the receiver operator characteristic curves for the total urine output over the first 2 hours following FST to predict progression to AKIN-III was 0.87 (p = 0.001). The ideal-cutoff for predicting AKI progression during the first 2 hours following FST was a urine volume of less than 200mls(100ml/hr) with a sensitivity of 87.1% and specificity 84.1%.
Conclusions
The FST in subjects with early AKI serves as a novel assessment of tubular function with robust predictive capacity to identify those patients with severe and progressive AKI. Future studies to validate these findings are warranted.
doi:10.1186/cc13015
PMCID: PMC4057505  PMID: 24053972
24.  Human miRNome Profiling Identifies MicroRNAs Differentially Present in the Urine after Kidney Injury 
Clinical chemistry  2013;59(12):10.1373/clinchem.2013.210245.
BACKGROUND
Extracellular microRNAs (miRNAs) have been proposed as potentially robust and stable biomarkers of various disease conditions. The primary objective of this study was to identify miRNAs differentially occurring in the urine that could serve as potential biomarkers of acute kidney injury (AKI), because traditional AKI markers have limitations with respect to sensitivity, specificity, and timeliness of diagnosis.
METHODS
We profiled 1809 miRNAs in pooled urine samples from 6 patients with AKI and from 6 healthy controls. We measured the 378 stably detectable miRNAs in the 12 samples individually and selected the top 7 miRNAs that were most different in the urine of patients with AKI compared with the non-AKI control individuals. These miRNAs were assessed in a larger cohort of patients with AKI (n = 98:71 AKI patients in the intensive care unit (ICU) and 27 kidney transplantation patients with biopsy-proven tubular injury) and patients without AKI (n = 97: 74 healthy volunteers and 23 ICU patients without AKI).
RESULTS
We identified 4 miRNAs capable of significantly differentiating patients with AKI from individuals without AKI: miR-21 (P = 0.0005), miR-200c (P < 0.0001), miR-423 (P = 0.001), and miR-4640 (P = 0.0355). The combined cross-validated area under the ROC curve for these 4 miRNAs was 0.91. The imprecision with respect to miRNA isolation and reverse transcription efficiency was <9% across 224 samples.
CONCLUSIONS
In this study we determined the entire miRNome of human urine and identified a panel of miRNAs that are both detectable noninvasively and diagnostically sensitive indicators of kidney damage.
doi:10.1373/clinchem.2013.210245
PMCID: PMC3870155  PMID: 24153252
25.  Determinants of Acute Kidney Injury Duration After Cardiac Surgery: An Externally Validated Tool 
The Annals of thoracic surgery  2011;93(2):570-576.
Background
Acute kidney injury (AKI) duration following cardiac surgery is associated with poor survival in a dose-dependent manner. However, it is not known what peri-operative risk factors contribute to prolonged AKI and delayed recovery. We sought to identify peri-operative risk factors that predict duration of AKI, a complication that effects short and long term survival.
Methods
We studied 4,987 consecutive cardiac surgery patients from 2002 through 2007. AKI was defined as a ≥0.3 (mg/dL) or ≥50% increase in SCr from baseline. Duration of AKI was defined by the number of days AKI was present. Step-wise multivariable negative binomial regression analysis was conducted using peri-operative risk factors for AKI duration. C-index was estimated by Kendall’s tau.
Results
AKI developed in 39% of patients with a median duration of AKI at 3 days and ranged from 1 to 108 days. Patients without AKI had duration of zero days. Independent predictors of AKI duration included baseline patient and disease characteristics, operative and post-operative factors. Prediction for mean duration of AKI was developed using coefficients from the regression model and externally validated the model on 1,219 cardiac surgery patients in a separate cardiac surgery cohort (TRIBE-AKI). The C-index was 0.65 (p<0.001) for the derivation cohort and 0.62 (p<0.001) for the validation cohort.
Conclusion
We identified and externally validated peri-operative predictors of AKI duration. These risk-factors will be useful to evaluate a patient’s risk for the tempo of recovery from AKI after cardiac surgery and subsequent short and long term survival. The level of awareness created by working with these risk factors have implications regarding positive changes in processes of care that have the potential to decrease the incidence and mitigate AKI.
doi:10.1016/j.athoracsur.2011.11.004
PMCID: PMC3761881  PMID: 22206952
acute kidney injury; cardiac surgery; risk model; risk prediction; Statistics; risk analysis/modeling; Surgery; complications; Kidney; CABG; Heart Valve surgery

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