Advances in pediatric acute kidney injury pathobiology: a report from the 26th Acute Disease Quality Initiative (ADQI) conference.

BACKGROUND: In the past decade, there have been substantial advances in our understanding of the pathobiology of pediatric acute kidney injury (AKI). In particular, animal models and studies focused on the relationship between kidney development, nephron number, and kidney health have identified a number of heterogeneous pathophysiologies underlying AKI. Despite this progress, gaps remain in our understanding of the pathobiology of pediatric AKI. METHODS: During the 26th Acute Disease Quality Initiative (ADQI) Consensus conference, a multidisciplinary group of experts discussed the evidence and used a modified Delphi process to achieve consensus on recommendations for opportunities to advance translational research in pediatric AKI. The current state of research understanding as well as gaps and opportunities for advancement in research was discussed, and recommendations were summarized. RESULTS: Consensus was reached that to improve translational pediatric AKI advancements, diverse teams spanning pre-clinical to epidemiological scientists must work in concert together and that results must be shared with the community we serve with patient involvement. Public and private research support and meaningful partnerships with adult research efforts are required. Particular focus is warranted to investigate the pediatric nuances of AKI, including the effect of development as a biological variable on AKI incidence, severity, and outcomes. CONCLUSIONS: Although AKI is common and associated with significant morbidity, the biologic basis of the disease spectrum throughout varying nephron developmental stages remains poorly understood. An incomplete understanding of factors contributing to kidney health, the diverse pathobiologies underlying AKI in children, and the historically siloed approach to research limit advances in the field. The recommendations outlined herein identify gaps and outline a strategic approach to advance the field of pediatric AKI via multidisciplinary translational research.

Advances in pediatric acute kidney injury pharmacology and nutrition: a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference.

BACKGROUND: In the past decade, there have been substantial advances in our understanding of pediatric AKI. Despite this progress, large gaps remain in our understanding of pharmacology and nutritional therapy in pediatric AKI. METHODS: During the 26th Acute Disease Quality Initiative (ADQI) Consensus Conference, a multidisciplinary group of experts reviewed the evidence and used a modified Delphi process to achieve consensus on recommendations for gaps and advances in care for pharmacologic and nutritional management of pediatric AKI. The current evidence as well as gaps and opportunities were discussed, and recommendations were summarized. RESULTS: Two consensus statements were developed. (1) High-value, kidney-eliminated medications should be selected for a detailed characterization of their pharmacokinetics, pharmacodynamics, and pharmaco-"omics" in sick children across the developmental continuum. This will allow for the optimization of real-time modeling with the goal of improving patient care. Nephrotoxin stewardship will be identified as an organizational priority and supported with necessary resources and infrastructure. (2) Patient-centered outcomes (functional status, quality of life, and optimal growth and development) must drive targeted nutritional interventions to optimize short- and long-term nutrition. Measures of acute and chronic changes of anthropometrics, body composition, physical function, and metabolic control should be incorporated into nutritional assessments. CONCLUSIONS: Neonates and children have unique metabolic and growth parameters compared to adult patients. Strategic investments in multidisciplinary translational research efforts are required to fill the knowledge gaps in nutritional requirements and pharmacological best practices for children with or at risk for AKI.

Global and Regional White Matter Fractional Anisotropy in Children with Chronic Kidney Disease.

OBJECTIVE: To investigate the associations between neurocognition and white matter integrity in children with chronic kidney disease (CKD). STUDY DESIGN: This cross-sectional study included 17 boys (age 6-16 years) with a diagnosis of mild to moderate (stages 1-3, nondialysis/nontransplant) CKD because of congenital anomalies of the kidney and urinary tract and 20 typically developing community controls. Participants underwent 3T neuroimaging and diffusion-weighted magnetic resonance imaging to assess white matter fractional anisotropy. Multivariable linear regression models were used to evaluate the impact of each group (controls vs CKD) on white matter fractional anisotropy, adjusting for age. Associations between white matter fractional anisotropy and neurocognitive abilities within the CKD group were also evaluated using regression models that were adjusted for age. The false discovery rate was used to account for multiple comparisons; wherein false discovery values <0.10 were considered significant. RESULTS: Global white matter fractional anisotropy was reduced in patients with CKD relative to controls (standardized estimate = -0.38, 95% CI -0.69:-0.07), driven by reductions within the body of the corpus callosum (standardized estimate = -0.44, 95% CI -0.75:-0.13), cerebral peduncle (SE = -0.37, 95% CI -0.67:-0.07), cingulum (hippocampus) (standardized estimate = -0.45, 95% CI -0.75:-0.14), and posterior limb of the internal capsule (standardized estimate = -0.46, 95% CI -0.76:-0.15). Medical variables and neurocognitive abilities were not significantly associated with white matter fractional anisotropy. CONCLUSIONS: White matter development is vulnerable in children with CKD because of congenital causes, even prior to the need for dialysis or transplantation.

Early pediatric chronic kidney disease is associated with brain volumetric gray matter abnormalities.

BACKGROUND: The impact of pediatric chronic kidney disease (pCKD) on the brain remains poorly defined. The objective of this study was to compare brain morphometry between children with early-stage pCKD and typically developing peers using structural magnetic resonance imaging (MRI). METHODS: The sample age range was 6-16 years. A total of 18 children with a diagnosis of pCKD (CKD stages 1-3) due to congenital anomalies of the kidney and urinary tract and 24 typically developing peers were included. Volumetric data from MRI and neurocognitive testing were compared using linear models including pCKD status, age, maternal education level, and socioeconomic status. RESULTS: Cerebellar gray matter volume was significantly smaller in pCKD, t(38) = -2.71, p = 0.01. In contrast, cerebral gray matter volume was increased in pCKD, t(38) = 2.08, p = 0.04. Reduced cerebellum gray matter volume was associated with disease severity, operationalized as estimated glomerular filtration rate (eGFR), t(14) = 2.21, p = 0.04 and predicted lower verbal fluency scores in the pCKD sample. Enlarged cerebral gray matter in the pCKD sample predicted lower scores on mathematics assessment. CONCLUSIONS: This study provides preliminary evidence for a morphometric underpinning to the cognitive deficits observed in pCKD. IMPACT: The impact of pediatric chronic kidney disease (CKD) on the brain remains poorly defined, with no data linking brain morphometry and observed cognitive deficits noted in this population. We explored the relationship between brain morphometry (using structural magnetic resonance imaging), cognition, and markers of CKD. Cerebellar and cerebral gray matter volumes are different in early CKD. Volumetric decreases in cerebellar gray matter are predicted by lower eGFR, suggesting a link between disease and brain morphometry. Reduced cerebellar gray matter predicted lower verbal fluency for those with pCKD. Enlarged cerebral gray matter in the pCKD sample predicted lower mathematics performance.

A prospective multi-center quality improvement initiative (NINJA) indicates a reduction in nephrotoxic acute kidney injury in hospitalized children.

Nephrotoxic medication (NTMx) exposure is a common cause of acute kidney injury (AKI) in hospitalized children. The Nephrotoxic Injury Negated by Just-in time Action (NINJA) program decreased NTMx associated AKI (NTMx-AKI) by 62% at one center. To further test the program, we incorporated NINJA across nine centers with the goal of reducing NTMx exposure and, consequently, AKI rates across these centers. NINJA screens all non-critically ill hospitalized patients for high NTMx exposure (over three medications on the same day or an intravenous aminoglycoside over three consecutive days), and then recommends obtaining a daily serum creatinine level in exposed patients for the duration of, and two days after, exposure ending. Additionally, substitution of equally efficacious but less nephrotoxic medications for exposed patients starting the day of exposure was recommended when possible. The main outcome was AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria (increase of 50% or 0.3 mg/dl over baseline). The primary outcome measure was AKI episodes per 1000 patient-days. Improvement was defined by statistical process control methodology and confirmed by Autoregressive Integrated Moving Average (ARIMA) modeling. Eight consecutive bi-weekly measure rates in the same direction from the established baseline qualified as special cause change for special process control. We observed a significant and sustained 23.8% decrease in NTMx-AKI rates by statistical process control analysis and by ARIMA modeling; similar to those of the pilot single center. Thus, we have successfully applied the NINJA program to multiple pediatric institutions yielding decreased AKI rates.

Late onset neonatal acute kidney injury: results from the AWAKEN Study.

BACKGROUND: Most studies of neonatal acute kidney injury (AKI) have focused on the first week following birth. Here, we determined the outcomes and risk factors for late AKI (>7d). METHODS: The international AWAKEN study examined AKI in neonates admitted to an intensive care unit. Late AKI was defined as occurring >7 days after birth according to the KDIGO criteria. Models were constructed to assess the association between late AKI and death or length of stay. Unadjusted and adjusted odds for late AKI were calculated for each perinatal factor. RESULTS: Late AKI occurred in 202/2152 (9%) of enrolled neonates. After adjustment, infants with late AKI had higher odds of death (aOR:2.1, p = 0.02) and longer length of stay (parameter estimate: 21.9, p < 0.001). Risk factors included intubation, oligo- and polyhydramnios, mild-moderate renal anomalies, admission diagnoses of congenital heart disease, necrotizing enterocolitis, surgical need, exposure to diuretics, vasopressors, and NSAIDs, discharge diagnoses of patent ductus arteriosus, necrotizing enterocolitis, sepsis, and urinary tract infection. CONCLUSIONS: Late AKI is common, independently associated with poor short-term outcomes and associated with unique risk factors. These should guide the development of protocols to screen for AKI and research to improve prevention strategies to mitigate the consequences of late AKI.

Model for Medical Student Introductory Telemedicine Education.

Background: Several medical specialty organizations and the American Telemedicine Association have developed specialty-specific guidelines and tips for optimal telemedicine use. Formal introductory education for medical students appears to lag behind these other developments. Introduction: Leaders at the University of Iowa Hospitals and Clinics recognized that students would benefit from an introductory educational program pertinent across all specialties to prepare them for future telemedicine use. The program objective was to introduce a short educational intervention highlighting basic principles to improve knowledge and help students gain confidence with telemedicine technology. Materials and Methods: The program consists of three modules, a video, and a simulation session. The first module presents telemedicine history, current uses, terminology, Medicare-Medicaid rules, and legal issues. The second addresses efficacy, ethical concerns, and best practices. The third reviews steps for success, including environment (sound, lighting, color, and camera placement), communication tips, documentation, and follow-up. The video demonstrates an ideal telemedicine visit. A short quiz follows each module. A 1-h simulation session utilizes case scenarios, telemedicine software, and peripheral equipment. A retrospective pretest and posttest were used to gauge success. Results: One hundred fifty-three second year medical students completed the program during 2017. Ninety-three (60%) completed the questionnaire. Posttest results showed higher (positive) mean scores for all questions addressed in the program regarding basic telemedicine knowledge and confidence issues. Conclusion: This program model was effective in improving basic knowledge and confidence in telemedicine among second-year medical students. We speculate that they are more informed and prepared for future telemedicine rotations and practices.

Vesicoureteral reflux and the extracellular matrix connection.

Primary vesicoureteral reflux (VUR) is a common pediatric condition due to a developmental defect in the ureterovesical junction. The prevalence of VUR among individuals with connective tissue disorders, as well as the importance of the ureter and bladder wall musculature for the anti-reflux mechanism, suggest that defects in the extracellular matrix (ECM) within the ureterovesical junction may result in VUR. This review will discuss the function of the smooth muscle and its supporting ECM microenvironment with respect to VUR, and explore the association of VUR with mutations in ECM-related genes.

The nephrologist of tomorrow: towards a kidney-omic future.

Omics refers to the collective technologies used to explore the roles and relationships of the various types of molecules that make up the phenotype of an organism. Systems biology is a scientific discipline that endeavours to quantify all of the molecular elements of a biological system. Therefore, it reflects the knowledge acquired by omics in a meaningful manner by providing insights into functional pathways and regulatory networks underlying different diseases. The recent advances in biotechnological platforms and statistical tools to analyse such complex data have enabled scientists to connect the experimentally observed correlations to the underlying biochemical and pathological processes. We discuss in this review the current knowledge of different omics technologies in kidney diseases, specifically in the field of pediatric nephrology, including biomarker discovery, defining as yet unrecognized biologic therapeutic targets and linking omics to relevant standard indices and clinical outcomes. We also provide here a unique perspective on the field, taking advantage of the experience gained by the large-scale European research initiative called "Systems Biology towards Novel Chronic Kidney Disease Diagnosis and Treatment" (SysKid). Based on the integrative framework of Systems biology, SysKid demonstrated how omics are powerful yet complex tools to unravel the consequences of diabetes and hypertension on kidney function.

Preterm neonatal urinary renal developmental and acute kidney injury metabolomic profiling: an exploratory study.

BACKGROUND: Acute kidney injury (AKI) staging has been developed in the adult and pediatric populations, but these do not yet exist for the neonatal population. Metabolomics was utilized to uncover biomarkers of normal and AKI-associated renal function in preterm infants. The study comprised 20 preterm infants with an AKI diagnosis who were matched by gestational age and gender to 20 infants without an AKI diagnosis. METHODS: Urine samples from pre-term newborn infants collected on day 2 of life were analyzed using broad-spectrum nuclear magnetic resonance (NMR) metabolomics. Multivariate analysis methods were used to identify metabolite profiles that differentiated AKI and no AKI, and to identify a metabolomics profile correlating with gestational age in infants with and without AKI. RESULTS: There was a clear distinction between the AKI and no-AKI profiles. Two previously identified biomarkers of AKI, hippurate and homovanillate, differentiated AKI from no-AKI profiles. Pathway analysis revealed similarities to cholinergic neurons, prenatal nicotine exposure on pancreatic ß cells, and amitraz-induced inhibition of insulin secretion. Additionally, a pH difference was noted. Both pH and the metabolites were found to be associated with AKI; however, only the metabotype was a significant predictor of AKI. Pathways for the no-AKI group that correlated uniquely with gestational age included aminoacyl-t-RNA biosynthesis, whereas pathways in the AKI group yielded potential metabolite changes in pyruvate metabolism. CONCLUSIONS: Metabolomics was able to differentiate the urinary profiles of neonates with and without an AKI diagnosis and metabolic developmental profiles correlated with gestational age. Further studies in larger cohorts are needed to validate these results.

Neutrophil Phenotype Correlates With Postoperative Inflammatory Outcomes in Infants Undergoing Cardiopulmonary Bypass.

OBJECTIVES: Infants with congenital heart disease frequently require cardiopulmonary bypass, which causes systemic inflammation. The goal of this study was to determine if neutrophil phenotype and activation status predicts the development of inflammatory complications following cardiopulmonary bypass. DESIGN: Prospective cohort study. SETTING: Tertiary care PICU with postoperative cardiac care. PATIENTS: Thirty-seven patients 5 days to 10 months old with congenital heart disease requiring cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Laboratory and clinical data collected included length of mechanical ventilation, acute kidney injury, and fluid overload. Neutrophils were isolated from whole blood at three time points surrounding cardiopulmonary bypass. Functional analyses included measurement of cell surface protein expression and nicotinamide adenine dinucleotide phosphate oxidase activity. Of all patients studied, 40.5% displayed priming of nicotinamide adenine dinucleotide phosphate oxidase activity in response to N-formyl-Met-Leu-Phe stimulation 24 hours post cardiopulmonary bypass as compared to pre bypass. Neonates who received steroids prior to bypass demonstrated enhanced priming of nicotinamide adenine dinucleotide phosphate oxidase activity at 48 hours. Patients who displayed priming post cardiopulmonary bypass were 8.8 times more likely to develop severe acute kidney injury as compared to nonprimers. Up-regulation of neutrophil surface CD11b levels pre- to postbypass occurred in 51.4% of patients, but this measure of neutrophil priming was not associated with acute kidney injury. Subsequent analyses of the basal neutrophil phenotype revealed that those with higher basal CD11b expression were significantly less likely to develop acute kidney injury. CONCLUSIONS: Neutrophil priming occurs in a subset of infants undergoing cardiopulmonary bypass. Acute kidney injury was more frequent in those patients who displayed priming of nicotinamide adenine dinucleotide phosphate oxidase activity after cardiopulmonary bypass. This pilot study suggests that neutrophil phenotypic signature could be used to predict inflammatory organ dysfunction.

Early urinary biomarkers of acute kidney injury in preterm infants.

BACKGROUND: Acute kidney injury (AKI) in the neonatal intensive care setting is multifactorial and is associated with significant morbidity and mortality. This study evaluates the utility of novel urinary biomarkers to predict the development and/or severity AKI in preterm infants. METHODS: We performed a case-control study on a prospective cohort of preterm infants (<32 wk), to compare seven urine biomarkers between 25 infants with AKI and 20 infants without AKI. RESULTS: Infants with AKI had significantly higher neutrophil gelatinase-associated lipocalin (NGAL) (median, control (CTRL) vs. AKI; 0.598 vs. 4.24 µg/ml; P < 0.0001). In contrast, urinary epidermal growth factor (EGF) levels were significantly lower in infants who developed AKI compared to controls (median, CTRL vs. AKI; 0.016 vs. 0.006 µg/ml; P < 0.001). The area under the curve (AUC) for NGAL for prediction of stage I AKI on the day prior to AKI diagnosis (day-1) was 0.91, and for the prediction of stage II/III, AKI was 0.92. Similarly, urine EGF was a predictor of renal injury on day -1 (AUC: 0.97 for stage I and 0.86 for stage II/III AKI). CONCLUSION: Urinary biomarkers may be useful to predict AKI development prior to changes in serum creatinine (SCr) in preterm infants.

Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study.

BACKGROUND: Cross-sectional studies of children with prevalent nephrotic syndrome (NS) have shown 25-vitamin D (25(OH)D) deficiency rates of 20-100 %. Information on 25(OH)D status in incident patients or following remission is limited. This study aimed to assess 25(OH)D status of incident idiopathic NS children at presentation and longitudinally with short-term observation. METHODS: Multicenter longitudinal study of children (2-18 years old) from 14 centers across the Midwest Pediatric Nephrology Consortium with incident idiopathic NS. 25(OH)D levels were assessed at diagnosis and 3 months later. RESULTS: Sixty-one children, median age 5 (3, 11) years, completed baseline visit and 51 completed second visit labs. All 61 (100 %) had 25(OH)D < 20 ng/ml at diagnosis. Twenty-seven (53 %) had 25(OH)D < 20 ng/ml at follow-up. Fourteen (28 %) children were steroid resistant. Univariate analysis showed that children prescribed vitamin D supplements were less likely to have 25(OH)D deficiency at follow-up (OR 0.2, 95 % CI 0.04, 0.6). Steroid response, age, and season did not predict 25(OH)D deficiency. Multivariable linear regression modeling showed higher 25(OH)D levels at follow-up by 13.2 ng/ml (SE 4.6, p < 0.01) in children supplemented with vitamin D. CONCLUSIONS: In this incident idiopathic NS cohort, all children at diagnosis had 25(OH)D deficiency and the majority continued to have a deficiency at 2-4 months. Supplemental vitamin D decreased the odds of 25(OH)D deficiency at follow-up, supporting a role for supplementation in incident NS.

Rare variants in tenascin genes in a cohort of children with primary vesicoureteric reflux.

BACKGROUND: Primary vesicoureteral reflux (PVUR) is the most common malformation of the kidney and urinary tract, and reflux nephropathy is a major cause of chronic kidney disease in children. Recently, we reported mutations in the tenascin XB gene (TNXB) as a cause of PVUR with joint hypermobility. METHODS: To define the role of rare variants in tenascin genes in the etiology of PVUR, we screened a cohort of patients with familial PVUR (FPVUR) and non-familial PVUR (NFPVUR) for rare missense variants inTNXB and the tenascin C gene (TNC) after excluding mutations in ROBO2 and SOX17. RESULTS: The screening procedure identified 134 individuals from 112 families with PVUR; two families with mutations in ROBO2 were excluded from further analysis. Rare missense variants in TNXB were found in the remaining 110 families, of which 5/55 (9%) families had FPVUR and 2/55 (4%) had NFPVUR. There were no differences in high-grade reflux or renal parenchymal scarring between patients with and without TNXB variants. All patients with TNXB rare variants who were tested exhibited joint hypermobility. Overall we were able to identify causes of FPVUR in 7/57 (12%) families (9% in TNXB and 3% in ROBO2). CONCLUSIONS: In conclusion, the identification of a rare missense variant in TNXB in combination with a positive family history of VUR and joint hypermobility may represent a non-invasive method to diagnose PVUR and warrants further evaluation in other cohorts.

Congenital nephrotic syndrome in an infant with ALG1-congenital disorder of glycosylation.

Congenital nephrotic syndrome (NS) in the newborn is most frequently related to mutations in genes specific for structural integrity of the glomerular basement membrane and associated filtration structures within the kidney, resulting in massive leakage of plasma proteins into the urine. Occurrence of congenital NS in a multi-system syndrome is less common. We describe the case of an infant with deteriorating neurological status, seizures, edema, and proteinuria who was found to have a mutation in gene ALG1 and a renal biopsy consistent with congenital NS. Furthermore, we briefly review rare existing case reports documenting congenital NS in patients with mutations in ALG1, and treatment strategies, including novel use of peritoneal dialysis.

HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome.

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.