Kidney function assessment in the critically ill child: is it time to leave creatinine behind?

The accurate diagnosis of acute kidney injury (AKI) is especially problematic in critically ill patients in whom renal function is in an unsteady state, rendering creatinine-based baseline assessment measures of renal function potentially inadequate. Herrero-Morin and colleagues performed a cross-sectional analysis of the ability of cystatin C and β2 microglobulin to reflect creatinine clearance in pediatric patients with AKI. The aim of this commentary is to review the current state of AKI clinical and translational research in the light of the results presented in that study

Consensus-based recommendations on priority activities to address acute kidney injury in children: A modified Delphi consensus statement

Importance: Increasing evidence indicates that acute kidney injury (AKI) occurs frequently in children and young adults and is associated with poor short-term and long-term outcomes. Guidance is required to focus efforts related to expansion of pediatric AKI knowledge. Objective: To develop expert-driven pediatric specific recommendations on needed AKI research, education, practice, and advocacy. Evidence Review: At the 26th Acute Disease Quality Initiative meeting conducted in November 2021 by 47 multiprofessional international experts in general pediatrics, nephrology, and critical care, the panel focused on 6 areas: (1) epidemiology; (2) diagnostics; (3) fluid overload; (4) kidney support therapies; (5) biology, pharmacology, and nutrition; and (6) education and advocacy. An objective scientific review and distillation of literature through September 2021 was performed of (1) epidemiology, (2) risk assessment and diagnosis, (3) fluid assessment, (4) kidney support and extracorporeal therapies, (5) pathobiology, nutrition, and pharmacology, and (6) education and advocacy. Using an established modified Delphi process based on existing data, workgroups derived consensus statements with recommendations. Findings: The meeting developed 12 consensus statements and 29 research recommendations. Principal suggestions were to address gaps of knowledge by including data from varying socioeconomic groups, broadening definition of AKI phenotypes, adjudicating fluid balance by disease severity, integrating biopathology of child growth and development, and partnering with families and communities in AKI advocacy. Conclusions and Relevance: Existing evidence across observational study supports further efforts to increase knowledge related to AKI in childhood. Significant gaps of knowledge may be addressed by focused efforts

Acute kidney injury in critically ill newborns: What do we know? What do we need to learn?

Outcomes in critically ill neonates have improved over the past three decades, yet high residual mortality and morbidity rates exist. Acute kidney injury (AKI) is not just an innocent by-stander in the critically ill patient. Research on incidence and outcomes of AKI in the critically ill neonatal population is scarce. The objective of this publication is to (a) review original articles on the short- and long-term outcomes after neonatal AKI, (b) highlight key articles on adults and children with AKI in order to demonstrate how such insights might be applied to neonates, and (c) suggest clinical research studies to fill the gaps in our understanding of neonatal AKI. To date, observational studies suggest high rates of AKI and poor outcomes in critically ill neonates. Neonates with AKI are at risk of developing chronic kidney disease and hypertension. Large prospective studies are needed to test definitions and to better understand risk factors, incidence, independent outcomes, and mechanisms that lead to poor short- and long-term outcomes. Early biomarkers of AKI need to be explored in critically ill neonates. Infants with AKI need to be followed for sequelae after AKI

Phenotype standardization for drug-induced kidney disease.

Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition

Proactive monitoring of pediatric hemodialysis vascular access: Effects of ultrasound dilution on thrombosis rates

Proactive monitoring of pediatric hemodialysis vascular access: Effects of ultrasound dilution on thrombosis rates.BackgroundHemodialysis vascular access thrombosis (VAT) is a significant cause of morbidity for hemodialysis patients and results, in part, from decreased access flow potentially caused by venous outflow stenosis. We have previously shown ultrasound dilution (UD) to be a practical and reliable predictor of venous outflow in children receiving hemodialysis.MethodsThe current study is the first to our knowledge to assess the impact of a proactive UD monitoring program upon VAT in pediatric patients. Nine patients experienced 18 VAT over the two-year study. Mean values for variables potentially associated with VAT were compared to values from a size-matched seven patient group without VAT during the study period. VAT rates were compared between the year-before (pre-UD era) and year-after (UD era) UD was initiated. During the latter half of the UD era (rapid referral period), patients with VA flow rate (QAcorr) <650 mL/min/1.73 m2 were referred for balloon angioplasty within 48 hours.ResultsMean QAcorr was lower for patients with subsequent VAT (562 ± 290 mL/min/1.73 m2) versus patients without VAT (1005 ± 372 mL/min/1.73 m2; P = 0.02). The VAT rate was significantly lower in the UD era (4.1 VAT/100 patient-months) versus the pre-UD era (11.0 VAT/100 patient-months; P = 0.03). The decrease in VAT rates was caused predominantly in the rapid referral period, where the VAT rate dropped to 0.96 VAT/100 patient-months (P < 0.001). Cost of vascular access management was 65% higher ($1264 vs.$765/patient-month) in the pre-UD era, reflecting the increased cost for treatment of VAT.ConclusionsMonthly QAcorr <650 mL/min/1.73 m2 is predictive of imminent VAT in children receiving hemodialysis. Prompt referral for angioplasty of VA with QAcorr <650 mL/min/1.73 m2 leads to decreased VAT rates in children

Renal recovery

Acute kidney injury (AKI) research in the past decade has mostly focused upon development of a standard AKI definition, validation of early novel biomarkers to predict AKI prior to serum creatinine rise and predict AKI severity, and assessment of aspects of renal replacement therapies and their impact on survival. Given the independent association between AKI and mortality in the acute phase, such focus makes imminent sense. More recently, the recognition that AKI is associated with subsequent development of chronic kidney disease and end-stage renal disease, with the attendant increase in mortality, has led to interest in the clinical epidemiology and the mechanistic understanding of renal recovery after an AKI episode in critically ill patients. We review the current knowledge surrounding renal recovery after an AKI episode, including renal replacement therapy initiation timing and modality impact, biomarker assessment and mechanistic targets to guide potential future clinical trials

Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study

INTRODUCTION: Serum creatinine is a late marker of acute kidney injury (AKI). Urine neutrophil gelatinase-associated lipocalin (uNGAL) is an early marker of AKI, where the timing of kidney injury is known. It is unknown whether uNGAL predicts AKI in the general critical care setting. We assessed the ability of uNGAL to predict AKI development and severity in critically ill children. METHODS: This was a prospective cohort study of critically ill children. Children aged between 1 month and 21 years who were mechanically ventilated and had a bladder catheter inserted were eligible. Patients with end-stage renal disease or who had just undergone kidney transplantation were excluded. Patients were enrolled within 24 to 48 hours of initiation of mechanical ventilation. Clinical data and serum creatinine were collected daily for up to 14 days from enrollment, and urine was collected once daily for up to 4 days for uNGAL measurement. AKI was graded using pRIFLE (pediatric modified Risk, Injury, Failure, Loss, End Stage Kidney Disease) criteria. Day 0 was defined as the day on which the AKI initially occurred, and pRIFLEmax was defined as the worst pRIFLE AKI grade recorded during the study period. The χ(2 )test was used to compare associations between categorical variables. Mann-Whitney and Kruskal-Wallis tests were used to compare continuous variables between groups. Diagnostic characteristics were evaluated by calculating sensitivity and specificity, and constructing receiver operating characteristic curves. RESULTS: A total of 140 patients (54% boys, mean ± standard deviation Pediatric Risk of Mortality II score 15.0 ± 8.0, 23% sepsis) were included. Mean and peak uNGAL concentrations increased with worsening pRIFLEmax status (P < 0.05). uNGAL concentrations rose (at least sixfold higher than in controls) in AKI, 2 days before and after a 50% or greater rise in serum creatinine, without change in control uNGAL. The parameter uNGAL was a good diagnostic marker for AKI development (area under the receiver operating characteristic curve [AUC] 0.78, 95% confidence interval [CI] 0.62 to 0.95) and persistent AKI for 48 hours or longer (AUC 0.79, 95% CI 0.61 to 0.98), but not for AKI severity, when it was recorded after a rise in serum creatinine had occurred (AUC 0.63, 95% CI 0.44 to 0.82). CONCLUSION: We found uNGAL to be a useful early AKI marker that predicted development of severe AKI in a heterogeneous group of patients with unknown timing of kidney injury

Rationale and Design of the Genetic Contribution to Drug Induced Renal Injury (DIRECT) Study

IntroductionNephrotoxicity from drugs accounts for 18% to 27% of cases of acute kidney injury. Determining a genetic predisposition may potentially be important in minimizing risk. The aims of this study are as follows: to determine whether a genetic predisposition exists for the development of drug-induced kidney disease (DIKD), using genome-wide association and whole-genome sequencing studies; to describe the frequency, course, risk factors, resolution and outcomes of DIKD cases; to investigate the role of ethnic/racial variability in the genetics of DIKD; and to explore the use of different tools establishing causality of DIKD.MethodsA total of 800 patients will be enrolled worldwide and blood samples for DNA collected. Data on the patient risk factors, vital signs, laboratory parameters, drug exposure, and DIKD course will be recorded. A panel of nephrologists will adjudicate all cases. Genome-wide association studies will be conducted using population controls matched on biogeographic ancestry to determine whether there is a genetic predisposition to DIKD. The primary endpoint is the identification of specific drug-related polymorphisms associated with DIKD. Secondary endpoints include the following: frequency of DIKD by causal drug and drug combinations; DIKD genetic variability; exploration of causality assessment tools; risk factor identification; description of the course of DIKD, including mortality and dialysis dependency at hospital discharge and 28 and 90 days post-event.ResultsData are currently being analyzed. Results are pending.DiscussionThe Genetic Contribution to Drug Induced Renal Injury (DIRECT) study will be the first observational cohort study to investigate the genetic determinants of DIKD. If the trial is positive, its findings will potentially translate into safer patient outcomes, by genotypic individualization of therapy and minimization of harm