Rajit K. Basu

Epidemiology of Acute Kidney Injury in Critically Ill Children and Young Adults

BACKGROUND The epidemiologic characteristics of children and young adults with acute kidney injury have been described in single‐center and retrospective studies. We conducted a multinational, prospective study involving patients admitted to pediatric intensive care units to define the incremental risk of death and complications associated with severe acute kidney injury. METHODS We used the Kidney Disease: Improving Global Outcomes criteria to define acute kidney injury. Severe acute kidney injury was defined as stage 2 or 3 acute kidney injury (plasma creatinine level ≥2 times the baseline level or urine output <0.5 ml per kilogram of body weight per hour for ≥12 hours) and was assessed for the first 7 days of intensive care. All patients 3 months to 25 years of age who were admitted to 1 of 32 participating units were screened during 3 consecutive months. The primary outcome was 28‐day mortality. RESULTS A total of 4683 patients were evaluated; acute kidney injury developed in 1261 patients (26.9%; 95% confidence interval [CI], 25.6 to 28.2), and severe acute kidney injury developed in 543 patients (11.6%; 95% CI, 10.7 to 12.5). Severe acute kidney injury conferred an increased risk of death by day 28 after adjustment for 16 covariates (adjusted odds ratio, 1.77; 95% CI, 1.17 to 2.68); death occurred in 60 of the 543 patients (11.0%) with severe acute kidney injury versus 105 of the 4140 patients (2.5%) without severe acute kidney injury (P<0.001). Severe acute kidney injury was associated with increased use of mechanical ventilation and renal‐replacement therapy. A stepwise increase in 28‐day mortality was associated with worsening severity of acute kidney injury (P<0.001 by log‐rank test). Assessment of acute kidney injury according to the plasma creatinine level alone failed to identify acute kidney injury in 67.2% of the patients with low urine output. CONCLUSIONS Acute kidney injury is common and is associated with poor outcomes, including increased mortality, among critically ill children and young adults. (Funded by the Pediatric Nephrology Center of Excellence at Cincinnati Childrens Hospital Medical Center and others; AWARE ClinicalTrials.gov number, NCT01987921.)

Derivation and validation of the renal angina index to improve the prediction of acute kidney injury in critically ill children.

Reliable prediction of severe acute kidney injury (AKI) has the potential to optimize treatment. Here we operationalized the empiric concept of renal angina with a renal angina index (RAI) and determined the predictive performance of RAI. This was assessed on admission to the pediatric intensive care unit, for subsequent severe AKI (over 200% rise in serum creatinine) 72 h later (Day-3 AKI). In a multicenter four cohort appraisal (one derivation and three validation), incidence rates for a Day 0 RAI of 8 or more were 15-68% and Day-3 AKI was 13-21%. In all cohorts, Day-3 AKI rates were higher in patients with an RAI of 8 or more with the area under the curve of RAI for predicting Day-3 AKI of 0.74-0.81. An RAI under 8 had high negative predictive values (92-99%) for Day-3 AKI. RAI outperformed traditional markers of pediatric severity of illness (Pediatric Risk of Mortality-II) and AKI risk factors alone for prediction of Day-3 AKI. Additionally, the RAI outperformed all KDIGO stages for prediction of Day-3 AKI. Thus, we operationalized the renal angina concept by deriving and validating the RAI for prediction of subsequent severe AKI. The RAI provides a clinically feasible and applicable methodology to identify critically ill children at risk of severe AKI lasting beyond functional injury. The RAI may potentially reduce capricious AKI biomarker use by identifying patients in whom further testing would be most beneficial.

Sepsis-Associated Acute Kidney Injury

Acute kidney injury (AKI) is an epidemic problem. Sepsis has long been recognized as a foremost precipitant of AKI. Sepsis-associated AKI (SA-AKI) portends a high burden of morbidity and mortality in both children and adults with critical illness. Although our understanding of its pathophysiology is incomplete, SA-AKI likely represents a distinct subset of AKI contributed to by a unique constellation of hemodynamic, inflammatory, and immune mechanisms. SA-AKI poses significant clinical challenges for clinicians. To date, no singular effective therapy has been developed to alter the natural history of SA-AKI. Rather, current strategies to alleviate poor outcomes focus on clinical risk identification, early detection of injury, modifying clinician behavior to avoid harm, early appropriate antimicrobial therapy, and surveillance among survivors for the longer-term sequelae of kidney damage. Recent evidence has confirmed that patients no longer die with AKI, but from AKI. To improve the care and outcomes for sufferers of SA-AKI, clinicians need a robust appreciation for its epidemiology and current best-evidence strategies for prevention and treatment.

Combining Functional and Tubular Damage Biomarkers Improves Diagnostic Precision for Acute Kidney Injury After Cardiac Surgery

BACKGROUND Increases in serum creatinine (ΔSCr) from baseline signify acute kidney injury (AKI) but offer little granular information regarding its characteristics. The 10th Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) suggested that combining AKI biomarkers would provide better precision for AKI course prognostication. OBJECTIVES This study investigated the value of combining a functional damage biomarker (plasma cystatin C [pCysC]) with a tubular damage biomarker (urine neutrophil gelatinase-associated lipocalin [uNGAL]), forming a composite biomarker for prediction of discrete characteristics of AKI. METHODS Data from 345 children after cardiopulmonary bypass (CPB) were analyzed. Severe AKI was defined as Kidney Disease Global Outcomes Initiative stages 2 to 3 (≥100% ΔSCr) within 7 days of CPB. Persistent AKI lasted >2 days. SCr in reversible AKI returned to baseline ≤48 h after CPB. The composite of uNGAL (>200 ng/mg urine Cr = positive [+]) and pCysC (>0.8 mg/l = positive [+]), uNGAL+/pCysC+, measured 2 h after CPB initiation, was compared to ΔSCr increases of ≥50% for correlation with AKI characteristics by using predictive probabilities, likelihood ratios (LR), and area under the curve receiver operating curve (AUC-ROC) values [Corrected]. RESULTS Severe AKI occurred in 18% of patients. The composite uNGAL+/pCysC+ demonstrated a greater likelihood than ΔSCr for severe AKI (+LR: 34.2 [13.0:94.0] vs. 3.8 [1.9:7.2]) and persistent AKI (+LR: 15.6 [8.8:27.5] versus 4.5 [2.3:8.8]). In AKI patients, the uNGAL-/pCysC+ composite was superior to ΔSCr for prediction of transient AKI. Biomarker composites carried greater probability for specific outcomes than ΔSCr strata. CONCLUSIONS Composites of functional and tubular damage biomarkers are superior to ΔSCr for predicting discrete characteristics of AKI.

Renal angina: an emerging paradigm to identify children at risk for acute kidney injury

Acute kidney injury (AKI) leads to high rates of morbidity and independently increases mortality risk. Therapy for AKI is likely limited by the inability to reliably diagnose AKI in its early stages, and, importantly, small changes in serum creatinine may be associated with poor outcomes and severe AKI. Whereas AKI biomarker research seeks to identify more sensitive and timely indices of kidney dysfunction, AKI lacks physical signs and symptoms to trigger biomarker assessment in at-risk patients, limiting biomarker efficacy. Accurate models of AKI prediction are unavailable. Severity of illness (SOI) scoring systems and organ dysfunction scores (OD), which stratify patients by prediction of mortality risk, are AKI reactive, not predictive. Kidney-specific severity scores do not account for AKI progression, and stratification models of AKI severity are not predictive of AKI. Thus, there is a need for a kidney scoring system that can help predict the development of AKI. This review highlights the concept of renal angina, a combination of patient risk factors and subtle AKI, as a methodology to predict AKI progression. Fulfillment of renal angina criteria will improve the efficiency of AKI prediction by biomarkers, in turn expediting early therapy and assisting in creation of AKI-predictive scoring systems.

An update and review of acute kidney injury in pediatrics.

Objectives: To inform the pediatric intensivist of recent advancements in acute kidney injury diagnosis and management. Data Sources: Studies were identified from MEDLINE (OVID), PubMed, and the Cochrane Library for topics relevant to acute kidney injury. We also reviewed bibliographies of relevant studies. Data Extraction, Synthesis, and Outline Review: Because of the lack of prospective trials, a majority of information is extracted from observational and retrospective data. The pathophysiology section reviews acute kidney injury mechanisms and highlights data regarding distal injury from experimental acute kidney injury. The epidemiology section focuses on incidence and outcomes of acute kidney injury, highlighting new strategies for diagnosis. The management section cites studies investigating hemodynamic optimization, nutrition, and fluid management, including the indications and impact of continuous renal replacement therapy in fluid overload. Conclusions: There is limited data-driven evidence in pediatrics regarding effective therapy for acute kidney injury, a significant problem in the pediatric intensive care unit extending length of stay, ventilator days, and overall mortality. Sublethal kidney injury may be contributing to overall morbidity. We conclude that prospective clinical trials are needed to evaluate specific diagnostic aids, such as biomarkers, and therapeutic strategies, such as early initiation of continuous renal replacement therapy in children with fluid overload.

Validation of a gene expression-based subclassification strategy for pediatric septic shock

Objective:Septic shock heterogeneity has important implications for clinical trial implementation and patient management. We previously addressed this heterogeneity by identifying three putative subclasses of children with septic shock based exclusively on a 100-gene expression signature. Here we attempted to prospectively validate the existence of these gene expression-based subclasses in a validation cohort. Design:Prospective observational study involving microarray-based bioinformatics. Setting:Multiple pediatric intensive care units in the United States. Patients:Separate derivation (n = 98) and validation (n = 82) cohorts of children with septic shock. Interventions:None other than standard care. Measurements and Main Results:Gene expression mosaics of the 100 class-defining genes were generated for 82 individual patients in the validation cohort. Using computer-based image analysis, patients were classified into one of three subclasses (“A,” “B,” or “C”) based on color and pattern similarity relative to reference mosaics generated from the original derivation cohort. After subclassification, the clinical database was mined for phenotyping. Subclass A patients had higher illness severity relative to subclasses B and C as measured by maximal organ failure, fewer intensive care unit-free days, and a higher Pediatric Risk of Mortality score. Patients in subclass A were characterized by repression of genes corresponding to adaptive immunity and glucocorticoid receptor signaling. Separate subclass assignments were conducted by 21 individual clinicians using visual inspection. The consensus classification of the clinicians had modest agreement with the computer algorithm. Conclusions:We have validated the existence of subclasses of children with septic shock based on a biologically relevant, 100-gene expression signature. The subclasses have relevant clinical differences.

Incorporation of Biomarkers with the Renal Angina Index for Prediction of Severe AKI in Critically Ill Children

BACKGROUND AND OBJECTIVES Novel AKI biomarkers carry variable performance for prediction of AKI in patients with heterogeneous illness. Until utility is demonstrated in critically ill patients outside of the cardiopulmonary bypass population, AKI biomarkers are unlikely to gain widespread implementation. Operationalization of an AKI risk stratification methodology, termed renal angina, was recently reported to enhance prediction at the time of intensive care unit admission for persistent severe AKI. The renal angina index (RAI) was developed to provide the clinical context to direct AKI biomarker testing. This study tested the hypothesis that incorporation of AKI biomarkers in patients fulfilling renal angina improves the prediction of persistent severe AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a multicenter study of 214 patients admitted to the pediatric intensive care unit with sepsis, the discrimination of plasma neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-8 (MMP-8), and neutrophil elastase-2 (Ela-2) were determined individually and in combination with the RAI for severe AKI. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated. RESULTS Individual biomarkers demonstrated marginal discrimination for severe AKI (area under curve [AUC]: NGAL, 0.72; MMP-8, 0.68; Ela-2, 0.72), inferior to prediction by the clinical model of the RAI (AUC=0.80). Incorporation of each biomarker significantly added to the renal angina model AKI prediction (AUC=0.80, increased to 0.84-0.88; P<0.05 for each). The inclusion of each biomarker with the RAI demonstrated NRI (0.512, 0.428, and 0.545 for NGAL, MMP-8, and Ela-2, respectively; all P<0.03) and IDI (0.075 for Ela-2). The inclusion of both Ela-2 and NGAL with RAI demonstrated an NRI of 0.871 (P<0.001) and an IDI of 0.1 (P=0.01). CONCLUSIONS This study shows that incorporation of AKI biomarkers into the RAI improves discrimination for severe AKI. The RAI optimizes the utility of AKI biomarkers in a heterogeneous, critically ill patient population.

Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology in Critically Ill Children (AWARE): study protocol for a prospective observational study

BackgroundAcute kidney injury (AKI) is associated with poor outcome in critically ill children. While data extracted from retrospective study of pediatric populations demonstrate a high incidence of AKI, the literature lacks focused and comprehensive multicenter studies describing AKI risk factors, epidemiology, and outcome. Additionally, very few pediatric studies have examined novel urinary biomarkers outside of the cardiopulmonary bypass population.Methods/DesignThis is a prospective observational study. We anticipate collecting data on over 5000 critically ill children admitted to 31 pediatric intensive care units (PICUs) across the world during the calendar year of 2014. Data will be collected for seven days on all children older than 90 days and younger than 25 years without baseline stage 5 chronic kidney disease, chronic renal replacement therapy, and outside of 90 days of a kidney transplant or from surgical correction of congenital heart disease. Data to be collected includes demographic information, admission diagnoses and co-morbidities, and details on fluid and vasoactive resuscitation used. The renal angina index will be calculated integrating risk factors and early changes in serum creatinine and fluid overload. On days 2–7, all hemodynamic and pertinent laboratory values will be captured focusing on AKI pertinent values. Daily calculated values will include % fluid overload, fluid corrected creatinine, and KDIGO AKI stage. Urine will be captured twice daily for biomarker analysis on Days 0–3 of admission. Biomarkers to be measured include neutrophil gelatinase lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (l-FABP), and interleukin-18 (IL-18). The primary outcome to be quantified is incidence rate of severe AKI on Day 3 (Day 3 – AKI). Prediction of Day 3 – AKI by the RAI and after incorporation of biomarkers with RAI will be analyzed.DiscussionThe Assessment of Worldwide Acute Kidney Injury, Renal Angina and Epidemiology (AWARE) study, creates the first prospective international pediatric all cause AKI data warehouse and biologic sample repository, providing a broad and invaluable resource for critical care nephrologists seeking to study risk factors, prediction, identification, and treatment options for a disease syndrome with high associated morbidity affecting a significant proportion of hospitalized children.Trial registrationClinicalTrials.gov: NCT01987921

Acute kidney injury based on corrected serum creatinine is associated with increased morbidity in children following the arterial switch operation.

Background and Objectives: Evaluate risk factors for and impact of acute kidney injury on children following the arterial switch operation. Design: Single-center retrospective chart review. Setting: A tertiary children’s hospital. Patients: A total of 92 patients receiving the arterial switch operation from 1997 to 2008 at severe acute kidney injury was defined as a 100% serum creatinine rise over baseline. Results: Of 92 patients, 18 (20%) developed severe acute kidney injury. Neither patient age or weight nor cardiopulmonary bypass time correlated with the development of acute kidney injury. Acute kidney injury was associated with the following: higher postoperative day 1 (POD1) fluid balance, higher inotrope scores (POD1 and POD2), and longer: postoperative ICU length of stay (p = 0.005), overall ICU length of stay (p = 0.05), and postoperative hospital length of stay (p = 0.006). The time to peak creatinine for acute kidney injury patients was between POD1 and POD2. Correction of serum creatinine for fluid balance increased the population defined as severe acute kidney injury and strengthened the association of acute kidney injury with postoperative morbidity. Conclusions: Acute kidney injury following the arterial switch operation is associated with increased morbidity. In this single center, single population, and homogenous cohort of patients, the development of acute kidney injury was not correlated with age, size, or cardiopulmonary bypass time, but was still associated with prolonged duration of ventilation and hospitalization. Notably, the failure to correct serum creatinine for fluid balance underestimates the prevalence and impact of acute kidney injury.