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1.  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
2.  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
3.  Clinical Analysis of Cause, Treatment and Prognosis in Acute Kidney Injury Patients 
PLoS ONE  2014;9(2):e85214.
Acute kidney injury (AKI) is characterized by an abrupt decline in renal function, resulting in an inability to secrete waste products and maintain electrolyte and water balance, and is associated with high risks of morbidity and mortality. This study retrospectively analyzed clinical data, treatment, and prognosis of 271 hospitalized patients (172 males and 99 females) diagnosed with AKI from December, 2008 to December, 2011. In addition, this study explored the association between the cause of AKI and prognosis, severity and treatment of AKI. The severity of AKI was classified according to the Acute Kidney Injury Network (AKIN) criteria. Renal recovery was defined as a decrease in a serum creatinine level to the normal value. Prerenal, renal, and postrenal causes accounted for 36.5% (99 patients), 46.5% (126 patients) and 17.0% (46 patients), respectively, of the incidence of AKI. Conservative, surgical, and renal replacement treatments were given to 180 (66.4%), 30 (11.1%) and 61 patients (22.5%), respectively. The overall recovery rate was 21.0%, and the mortality rate was 19.6%. Levels of Cl−, Na+ and carbon dioxide combining power decreased with increasing severity of AKI. Cause and treatment were significantly associated with AKI prognosis. Likewise, the severity of AKI was significantly associated with cause, treatment and prognosis. Multivariate logistic regression analysis found that respiratory injury and multiple organ dysfunction syndrome (MODS) were associated with AKI patient death. Cause, treatment and AKIN stage are associated with the prognosis of AKI. Respiratory injury and MODS are prognostic factors for death of AKI patients.
doi:10.1371/journal.pone.0085214
PMCID: PMC3931618  PMID: 24586237
4.  Acute kidney injury: Global health alert 
Journal of Nephropathology  2013;2(2):90-97.
Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, increase awareness of AKI by governments, the public, general and family physicians and other health care professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI.
doi:10.12860/JNP.2013.15
PMCID: PMC3891141  PMID: 24475433
Acute kidney injury; World Kidney Day; Morbidity; Mortality
5.  Diagnosis of kidney damage using novel acute kidney injury biomarkers: assessment of kidney function alone is insufficient 
Critical Care  2011;15(4):170.
Acute kidney injury (AKI) is a syndrome that is associated with a major burden of morbidity and mortality in a variety of high risk patient populations, many of them cared for by intensivists. Following renal transplantation, delayed graft function (DGF) caused by severe acute tubular necrosis (ATN), defined by a requirement for dialysis during the initial post-transplant week, complicates postoperative management, and if prolonged (>14 days), adversely affects allograft survival. Neutrophil gelatinase-associated lipocalin (NGAL) and other novel biomarkers can detect AKI earlier than serum creatinine, and can predict AKI severity in high risk patient populations, including kidney transplant recipients. Hollmen and colleagues now demonstrate that elevated urine NGAL in deceased kidney donors is a significant risk factor for prolonged post-transplant DGF in recipients. These findings have clear implications with regard to potentially improved assessment of deceased donor suitability for potential renal allograft donation. These findings are also consistent with the growing evidence that severe ATN diagnosed by markedly elevated levels of AKI biomarkers is a useful predictor of the requirement for acute renal replacement therapy in AKI patients.
doi:10.1186/cc10251
PMCID: PMC3226312  PMID: 21740601
6.  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
7.  Kidneys in chronic liver diseases 
Acute kidney injury (AKI), defined as an abrupt increase in the serum creatinine level by at least 0.3 mg/dL, occurs in about 20% of patients hospitalized for decompensating liver cirrhosis. Patients with cirrhosis are susceptible to developing AKI because of the progressive vasodilatory state, reduced effective blood volume and stimulation of vasoconstrictor hormones. The most common causes of AKI in cirrhosis are pre-renal azotemia, hepatorenal syndrome and acute tubular necrosis. Differential diagnosis is based on analysis of circumstances of AKI development, natriuresis, urine osmolality, response to withdrawal of diuretics and volume repletion, and rarely on renal biopsy. Chronic glomerulonephritis and obstructive uropathy are rare causes of azotemia in cirrhotic patients. AKI is one of the last events in the natural history of chronic liver disease, therefore, such patients should have an expedited referral for liver transplantation. Hepatorenal syndrome (HRS) is initiated by progressive portal hypertension, and may be prematurely triggered by bacterial infections, nonbacterial systemic inflammatory reactions, excessive diuresis, gastrointestinal hemorrhage, diarrhea or nephrotoxic agents. Each type of renal disease has a specific treatment approach ranging from repletion of the vascular system to renal replacement therapy. The treatment of choice in type 1 hepatorenal syndrome is a combination of vasoconstrictor with albumin infusion, which is effective in about 50% of patients. The second-line treatment of HRS involves a transjugular intrahepatic portosystemic shunt, renal vasoprotection or systems of artificial liver support.
doi:10.3748/wjg.v18.i24.3035
PMCID: PMC3386317  PMID: 22791939
Acute kidney injury; Liver cirrhosis; Chronic renal failure; Chronic liver disease
8.  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
9.  Some biomarkers of acute kidney injury are increased in pre-renal acute injury 
Kidney International  2012;81(12):1254-1262.
Pre-renal acute kidney injury (AKI) is assumed to represent a physiological response to underperfusion. Its diagnosis is retrospective after a transient rise in plasma creatinine, usually associated with evidence of altered tubular transport, particularly that of sodium. In order to test whether pre-renal AKI is reversible because injury is less severe than that of sustained AKI, we measured urinary biomarkers of injury (cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), γ-glutamyl transpeptidase, IL-18, and kidney injury molecule-1 (KIM-1)) at 0, 12, and 24 h following ICU admission. A total of 529 patients were stratified into groups having no AKI, AKI with recovery by 24 h, recovery by 48 h, or the composite of AKI greater than 48 h or dialysis. Pre-renal AKI was identified in 61 patients as acute injury with recovery within 48 h and a fractional sodium excretion <1%. Biomarker concentrations significantly and progressively increased with the duration of AKI. After restricting the AKI recovery within the 48 h cohort to pre-renal AKI, this increase remained significant. The median concentration of KIM-1, cystatin C, and IL-18 were significantly greater in pre-renal AKI compared with no-AKI, while NGAL and γ-glutamyl transpeptidase concentrations were not significant. The median concentration of at least one biomarker was increased in all but three patients with pre-renal AKI. Thus, the reason why some but not all biomarkers were increased requires further study. The results suggest that pre-renal AKI represents a milder form of injury.
doi:10.1038/ki.2012.23
PMCID: PMC3365288  PMID: 22418979
acute kidney injury; acute renal failure; creatinine
10.  New Biomarkers for the Quick Detection of Acute Kidney Injury 
ISRN Nephrology  2012;2013:394582.
Acute kidney injury (AKI) is a common and strong problem in the diagnosis of which based on measurement of BUN and serum creatinine. These traditional methods are not sensitive and specific for the diagnosis of AKI. AKI is associated with increased morbidity and mortality in critically ill patients and a quick detection is impossible with BUN and serum creatinine. A number of serum and urinary proteins have been identified that may messenger AKI prior to a rise in BUN and serum creatinine. New biomarkers of AKI, including NGAL, KIM-1, cystatin-C, IL-18, and L-FABP, are more favourable tests than creatinine which have been identified and studied in several experimental and clinical training. This paper will discuss some of these new biomarkers and their potential as useful signs of AKI. We searched the literature using PubMed and MEDLINE with acute kidney injury, urine, and serum new biomarkers and the articles were selected only from publication types in English.
doi:10.5402/2013/394582
PMCID: PMC4045421  PMID: 24967225
11.  Biomarkers of Acute Kidney Injury 
The diagnosis of acute kidney injury (AKI) is usually based on measurements of blood urea nitrogen (BUN) and serum creatinine. BUN and serum creatinine are not very sensitive or specific for the diagnosis of AKI because they are affected by many renal and nonrenal factors that are independent of kidney injury or kidney function. Biomarkers of AKI that are made predominantly by the injured kidney have been discovered in preclinical studies. In clinical studies of patients with AKI, some of these biomarkers (eg, interleukin-18, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1) have been shown to increase in the urine before the increase in serum creatinine. These early biomarkers of AKI are being tested in different types of AKI and in larger clinical studies. Biomarkers of AKI may also predict long-term kidney outcomes and mortality.
doi:10.1053/j.ackd.2008.04.003
PMCID: PMC3287955  PMID: 18565474
Biomarkers; Acute kidney injury; Interleukin-18; Neutrophil gelatinase-associated lipocalin; Kidney injury molecule-1; Cystatin C
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.  Sensitivity and Specificity of a Single Emergency Department Measurement of Urinary Neutrophil Gelatinase–Associated Lipocalin for Diagnosing Acute Kidney Injury 
Annals of internal medicine  2008;148(11):810-819.
Background
A single serum creatinine measurement cannot distinguish acute kidney injury from chronic kidney disease or prerenal azotemia.
Objective
To test the sensitivity and specificity of a single measurement of urinary neutrophil gelatinase–associated lipocalin (NGAL) and other urinary proteins to detect acute kidney injury in a spectrum of patients.
Design
Prospective cohort study.
Setting
Emergency department of Columbia University Medical Center, New York, New York.
Participants
635 patients admitted to the hospital with acute kidney injury, prerenal azotemia, chronic kidney disease, or normal kidney function.
Measurements
Diagnosis of acute kidney injury was based on the RIFLE (risk, injury, failure, loss, and end-stage) criteria and assigned by researchers who were blinded to experimental measurements. Urinary NGAL was measured by immunoblot, N-acetyl-β-D-glucosaminidase (NAG) by enzyme measurement, α1-microglobulin and α1-acid glycoprotein by immunonephelometry, and serum creatinine by Jaffe kinetic reaction. Experimental measurements were not available to treating physicians.
Results
Patients with acute kidney injury had a significantly elevated mean urinary NGAL level compared with the other kidney function groups (416 μg/g creatinine [SD, 387]; P = 0.001). At a cutoff value of 130 μg/g creatinine, sensitivity and specificity of NGAL for detecting acute injury were 0.900 (95% CI, 0.73 to 0.98) and 0.995 (CI, 0.990 to 1.00), respectively, and positive and negative likelihood ratios were 181.5 (CI, 58.33 to 564.71) and 0.10 (CI, 0.03 to 0.29); these values were superior to those for NAG, α1-microglobulin, α1-acid glycoprotein, fractional excretion of sodium, and serum creatinine. In multiple logistic regression, urinary NGAL level was highly predictive of clinical outcomes, including nephrology consultation, dialysis, and admission to the intensive care unit (odds ratio, 24.71 [CI, 7.69 to 79.42]).
Limitations
All patients came from a single center. Few kidney biopsies were performed.
Conclusion
A single measurement of urinary NGAL helps to distinguish acute injury from normal function, prerenal azotemia, and chronic kidney disease and predicts poor inpatient outcomes.
PMCID: PMC2909852  PMID: 18519927
14.  Kidney and Urinary Tract Involvement in Kawasaki Disease 
Kawasaki disease (KD) is a systemic vasculitis and can develop multiple organ injuries including kidney and urinary tract involvement. These disorders include pyuria, prerenal acute kidney injury (AKI), renal AKI caused by tubulointerstitial nephritis (TIN), hemolytic uremic syndrome (HUS), and immune-complex mediated nephropathy, renal AKI associated with either Kawasaki disease shock syndrome or unknown causes, acute nephritic syndrome (ANS), nephrotic syndrome (NS), renal tubular abnormalities, renal abnormalities in imaging studies, and renal artery lesions (aneurysms and stenosis). Pyuria is common in KD and originates from the urethra and/or the kidney. TIN with AKI and renal tubular abnormalities probably result from renal parenchymal inflammation caused by T-cell activation. HUS and renal artery lesions are caused by vascular endothelial injuries resulting from vasculitis. Some patients with ANS have immunological abnormalities associated with immune-complex formation. Nephromegaly and renal parenchymal inflammatory foci are detected frequently in patients with KD by renal ultrasonography and renal scintigraphy, respectively. Although the precise pathogenesis of KD is not completely understood, renal vasculitis, immune-complex mediated kidney injuries, or T-cell immune-regulatory abnormalities have been proposed as possible mechanisms for the development of kidney and urinary tract injuries.
doi:10.1155/2013/831834
PMCID: PMC3833317  PMID: 24288547
15.  Acute kidney injury biomarkers: renal angina and the need for a renal troponin I 
BMC Medicine  2011;9:135.
Acute kidney injury (AKI) in hospitalized patients is independently associated with increased morbidity and mortality in pediatric and adult populations. Continued reliance on serum creatinine and urine output to diagnose AKI has resulted in our inability to provide successful therapeutic and supportive interventions to prevent and mitigate AKI and its effects. Research efforts over the last decade have focused on the discovery and validation of novel urinary biomarkers to detect AKI prior to a change in kidney function and to aid in the differential diagnosis of AKI. The aim of this article is to review the AKI biomarker literature with a focus on the context in which they should serve to add to the clinical context facing physicians caring for patients with, or at-risk for, AKI. The optimal and appropriate utilization of AKI biomarkers will only be realized by understanding their characteristics and placing reasonable expectations on their performance in the clinical arena.
doi:10.1186/1741-7015-9-135
PMCID: PMC3287120  PMID: 22189039
16.  Risk factors for acute kidney injury following orthotopic liver transplantation: the impact of changes in renal function while patients await transplantation 
BMC Nephrology  2010;11:30.
Background
Acute kidney injury (AKI) occurs commonly in the setting of orthotopic liver transplantation (OLT). To date, the correlation between AKI post-OLT and pre-operative changes in renal function has not been rigorously examined.
Methods
To determine the impact of pre-OLT changes in renal function on AKI post-OLT, as well as to identify risk factors for AKI, we analyzed the prospectively maintained NIDDK Liver Transplantation Database, which includes patients who received their first OLT between April 15, 1990, and June 30, 1994. We used the AKI Network definition of AKI.
Results
Surprisingly, univariate analysis revealed that worsening renal function while awaiting OLT was protective to the development of AKI post-OLT. Independent predictors of AKI were increased body mass index, increased Childs-Pugh-Turcott score, decreased urine output during cross-clamp, improved renal function while awaiting OLT, increased post-operative stroke volume, non-Caucasian race, and post-operative use of tacrolimus.
Conclusions
The correlation between improving renal function pre-OLT and AKI post-OLT may represent true protection (via ischemic pre-conditioning) or, alternatively, a masking of milder forms of AKI (via improved renal perfusion through correction of the cirrhotic milieu). These results highlight the complex interaction between liver and kidney disease, and suggest that not only the etiology but also the course of pre-OLT renal dysfunction may be a critical determinant of renal function post-OLT.
doi:10.1186/1471-2369-11-30
PMCID: PMC2991287  PMID: 21059264
17.  Biomarkers of Acute Kidney Injury 
Journal of Toxicology  2011;2011:328120.
Acute kidney injury (AKI) is a common problem in both the inpatient and outpatient setting and often results from drug toxicities. Traditional methods of identifying AKI, through measurement of blood urea nitrogen and serum creatinine, are problematic in that they are slow to detect decreases in glomerular filtration rate (GFR) and are influenced by a variety of factors that are not related to GFR changes. The problems inherent in a creatinine-based diagnosis of AKI have impeded the development of proper therapeutics in AKI and posed problems in evaluating nephrotoxicity of drugs and other chemical exposures. In recent years, a number of new biomarkers of AKI with more favorable test characteristics than creatinine have been identified and studied in a variety of experimental and clinical settings. This review will consider the most well-established biomarkers and appraise the literature, with particular attention given to the use of biomarkers in identifying toxin-mediated AKI.
doi:10.1155/2011/328120
PMCID: PMC3205656  PMID: 22131986
18.  Incidence, risk factors and prediction of post-operative acute kidney injury following cardiac surgery for active infective endocarditis: an observational study 
Critical Care  2013;17(5):R220.
Introduction
Cardiac surgery is frequently needed in patients with infective endocarditis (IE). Acute kidney injury (AKI) often complicates IE and is associated with poor outcomes. The purpose of the study was to determine the risk factors for post-operative AKI in patients operated on for IE.
Methods
A retrospective, non-interventional study of prospectively collected data (2000–2010) included patients with IE and cardiac surgery with cardio-pulmonary bypass. The primary outcome was post-operative AKI, defined as the development of AKI or progression of AKI based on the acute kidney injury network (AKIN) definition. We used ensemble machine learning (“Super Learning”) to develop a predictor of AKI based on potential risk factors, and evaluated its performance using V-fold cross validation. We identified clinically important predictors among a set of risk factors using Targeted Maximum Likelihood Estimation.
Results
202 patients were included, of which 120 (59%) experienced a post-operative AKI. 65 (32.2%) patients presented an AKI before surgery while 91 (45%) presented a progression of AKI in the post-operative period. 20 patients (9.9%) required a renal replacement therapy during the post-operative ICU stay and 30 (14.8%) died during their hospital stay. The following variables were found to be significantly associated with renal function impairment, after adjustment for other risk factors: multiple surgery (OR: 4.16, 95% CI: 2.98-5.80, p<0.001), pre-operative anemia (OR: 1.89, 95% CI: 1.34-2.66, p<0.001), transfusion requirement during surgery (OR: 2.38, 95% CI: 1.55-3.63, p<0.001), and the use of vancomycin (OR: 2.63, 95% CI: 2.07-3.34, p<0.001), aminoglycosides (OR: 1.44, 95% CI: 1.13-1.83, p=0.004) or contrast iodine (OR: 1.70, 95% CI: 1.37-2.12, p<0.001). Post-operative but not pre-operative AKI was associated with hospital mortality.
Conclusions
Post-operative AKI following cardiopulmonary bypass for IE results from additive hits to the kidney. We identified several potentially modifiable risk factors such as treatment with vancomycin or aminoglycosides or pre-operative anemia.
doi:10.1186/cc13041
PMCID: PMC4056899  PMID: 24093498
19.  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
20.  Spectrum of acute kidney injury in the Himalayan region 
Indian Journal of Nephrology  2012;22(5):363-366.
Acute kidney injury (AKI) is common in hospitalized patients and is an important cause of mortality. This is a descriptive study of AKI in patients from Himachal Pradesh, India, located in Western Himalayan region. Over a period of 1 year, 102 patients with clinical and laboratory evidence of azotemia were included. Out of 102 patients, 84.3% had community acquired AKI and 15.7% had hospital acquired AKI. Medical causes were leading contributors (85.3%), with septicemia being the main factor (33.3%). Multiorgan failure was present in 59.8% patients. The overall mortality was 29.2%, and community acquired AKI was associated with higher mortality as compared to hospital-acquired AKI (22.5% vs 6.7%). AKI is still common in community and associated with high mortality. Septicemia, volume depletion and nephrotoxins were the leading cause of AKI in our study. Our study highlights the presence of hypotension, multiorgan failure and oliguria with mortality. Community-acquired AKI had higher mortality than hospital-acquired AKI.
doi:10.4103/0971-4065.103914
PMCID: PMC3544058  PMID: 23326047
Acute kidney injury; community-acquired acute kidney injury; hospital-acquired acute kidney injury; Western Himalayas
21.  Neutrophil gelatinase-associated lipocalin: a promising biomarker for human acute kidney injury 
Biomarkers in medicine  2010;4(2):265-280.
Acute kidney injury (AKI) is a common and serious condition, the diagnosis of which depends on serum creatinine measurements. Unfortunately, creatinine is a delayed and unreliable indicator of AKI. The lack of early biomarkers has crippled our ability to translate promising experimental therapies to human AKI. Fortunately, understanding the early stress response of the kidney to acute injuries has revealed a number of potential biomarkers. The discovery, translation and validation of neutrophil gelatinase-associated lipocalin, arguably the most promising novel AKI biomarker, are reviewed in this article. Neutrophil gelatinase-associated lipocalin is emerging as an excellent standalone troponin-like biomarker in the plasma and urine for the prediction of AKI, monitoring clinical trials in AKI and for the prognosis of AKI in several common clinical scenarios.
doi:10.2217/bmm.10.12
PMCID: PMC2893148  PMID: 20406069
acute kidney injury; acute renal failure; biomarkers; lipocalin; nephrotoxicity; neutrophil gelatinase-associated lipocalin
22.  Lessons for Successful Study Enrollment from the VA/NIH Acute Renal Failure Trial Network (ATN) Study 
Background
Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. The VA/NIH Acute Renal Failure Trial Network (ATN) Study was designed to compare strategies of renal replacement therapy (RRT) in critically ill subjects with acute kidney injury (AKI).
Design
Reasons for subject non-enrollment into the ATN Study were systematically monitored and categorized as modifiable or non-modifiable.
Results
4339 subjects were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible based on exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible subjects; surrogate unavailability accounted for 1/3 of these exclusions. Delayed identification of potential subjects, physician refusal, and involvement in competing trials accounted for 4.4%, 2.7%, and 2.3% of exclusions. Comfort measures only (CMO) status, chronic illness, chronic kidney disease (CKD), and obesity excluded 11.8%, 7.8%, 7.6%, and 5.9% of potential subjects. Modification of an enrollment window reduced the loss of subjects from 6.6% to 2.3%.
Conclusions
The ATN Study’s enrollment efficiency compared favorably with previous ICU intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent in the critically ill with AKI highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper subject recruitment, but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials involving the critically ill with AKI.
doi:10.2215/CJN.05621207
PMCID: PMC2440269  PMID: 18385390
Acute Kidney Injury; Clinical Trial; Research Design; Recruitment; Enrollment; Critical Care; External Validity
23.  Update on the diagnosis and management of acute kidney injury 
Acute kidney injury (AKI) is an independent risk factor for morbidity and mortality. This review provides essential information for the diagnosis and management of AKI. Blood urea nitrogen and serum creatinine are used for the diagnosis of AKI. The review also focuses on recent studies on the diagnosis of AKI using the RIFLE (R-renal risk, I-injury, F-failure, L-loss of kidney function, E-end stage kidney disease) and Acute Kidney Injury Network criteria, and serum and urine AKI biomarkers. Dialysis is the only Food and Drug Administration-approved therapy for AKI. Recent studies on the dose of dialysis in AKI are reviewed.
doi:10.2147/IJNRD.S8641
PMCID: PMC3108768  PMID: 21694939
acute kidney injury; biomarkers; interleukin-18
24.  A Case of Severe Acute Kidney Injury by Near-Drowning 
Journal of Korean Medical Science  2012;27(2):218-220.
Acute kidney injury (AKI) secondary to near-drowning is rarely described and poorly understood. Only few cases of severe isolated AKI resulting from near-drowning exist in the literature. We report a case of near-drowning who developed to isolated AKI due to acute tubular necrosis (ATN) requiring dialysis. A 21-yr-old man who recovered from near-drowning in freshwater 3 days earlier was admitted to our hospital with anuria and elevated level of serum creatinine. He needed five sessions of hemodialysis and then renal function recovered spontaneously. Renal biopsy confirmed ATN. We review the existing literature on near-drowning-induced AKI and discuss the possible pathogenesis.
doi:10.3346/jkms.2012.27.2.218
PMCID: PMC3271299  PMID: 22323873
Acute Kidney Injury; Acute Tubular Necrosis; Hemodialysis; Near Drowning
25.  Biomarkers of Nephrotoxic Acute Kidney Injury 
Toxicology  2008;245(3):182-193.
Acute kidney injury (AKI) is a common condition with significant associated morbidity and mortality. Epidemiologic data suggest that a significant proportion of AKI cases are at least partially attributable to nephrotoxin exposure. This is not surprising given intrinsic renal susceptibility to toxicant-induced injury, a consequence of the unique physiologic and biochemical properties of the normally functioning kidney. A number of pathophysiologic mechanisms have been identified that mediate toxic effects on the kidney, resulting in a variety of clinical syndromes ranging from subtle changes in tubular function to fulminant renal failure. Unfortunately, standard metrics used to diagnosis and monitor kidney injury, such as blood urea nitrogen and serum creatinine, are insensitive and nonspecific, resulting in delayed diagnosis and intervention. Considerable effort has been made to identify biomarkers that will allow the earlier diagnosis of AKI. Further characterization of these candidate biomarkers will clarify their utility in the setting of acute nephrotoxicity, define new diagnostic and prognostic paradigms for kidney injury, facilitate clinical trials, and lead to novel effective therapies.
doi:10.1016/j.tox.2007.12.024
PMCID: PMC4038970  PMID: 18294749

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