mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy.

BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis. METHODS: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.

Long-term renal function after treatment for unilateral, nonsyndromic Wilms tumor. A report from the St. Jude Lifetime Cohort Study.

BACKGROUND: The impact of specific treatment modalities on long-term renal function and blood pressure among adult survivors of Wilms tumor (WT) has not been well documented. METHODS: Among 40 WT survivors and 35 noncancer controls, we estimated the glomerular filtration rate (eGFR) using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equations with and without cystatin C, obtained 24-hour ambulatory blood pressure readings, and, among survivors only, measured 99m Tc diethylenetriamine pentaacetic acid (DTPA) plasma clearance. Survivors were treated with unilateral nephrectomy and nonnephrotoxic chemotherapy. Twenty received whole abdomen radiation therapy (WART) [median -16.5 Gray (Gy)], and 20 received no radiation therapy. Pairwise comparisons between survivors treated with and without WART, and each group to controls were performed using two-sample t tests. RESULTS: Twenty-six (65%) WT survivors were female, and 33 (83%) were non-Hispanic white. GFR estimated with creatinine or creatinine + cystatin C was decreased among irradiated survivors compared with controls. No irradiated or unirradiated participant had an eGFR (creatinine + cystatin C) < 60 mL/min/1.73 m2 . The prevalence of hypertension was significantly increased among unirradiated (25%) and irradiated survivors (35%) compared with controls (0%). Of the 24-hour ambulatory blood pressure monitoring parameters evaluated, only mean sleep period diastolic blood pressure load of those who received WART was significantly different from that of controls. CONCLUSIONS: Chronic kidney disease was infrequent in long-term survivors of unilateral nonsyndromic WT, whether treated with WART or no radiation. The prevalence of hypertension was increased in both groups compared with controls, emphasizing the need for ongoing monitoring of renal and cardiovascular health.

Acute kidney injury risk-based screening in pediatric inpatients: a pragmatic randomized trial.

BACKGROUND: Pediatric acute kidney injury (AKI) is common and associated with increased morbidity, mortality, and length of stay. We performed a pragmatic randomized trial testing the hypothesis that AKI risk alerts increase AKI screening. METHODS: All intensive care and ward admissions of children aged 28 days through 21 years without chronic kidney disease from 12/6/2016 to 11/1/2017 were included. The intervention alert displayed if calculated AKI risk was > 50% and no serum creatinine (SCr) was ordered within 24 h. The primary outcome was SCr testing within 48 h of AKI risk > 50%. RESULTS: Among intensive care admissions, 973/1909 (51%) were randomized to the intervention. Among those at risk, more SCr tests were ordered for the intervention group than for controls (418/606, 69% vs. 361/597, 60%, p = 0.002). AKI incidence and severity were the same in intervention and control groups. Among ward admissions, 5492/10997 (50%) were randomized to the intervention, and there were no differences between groups in SCr testing, AKI incidence, or severity of AKI. CONCLUSIONS: Alerts based on real-time prediction of AKI risk increased screening rates in intensive care but not pediatric ward settings. Pragmatic clinical trials provide the opportunity to assess clinical decision support and potentially eliminate ineffective alerts.

Urinary apolipoprotein AI in children with kidney disease.

BACKGROUND: Although high-density lipoprotein (HDL) modulates many cell types in the cardiovascular system, little is known about HDL in the kidney. We assessed urinary excretion of apolipoprotein AI (apoAI), the main protein in HDL. METHODS: We enrolled 228 children with various kidney disorders and 40 controls. Urinary apoAI, albumin, and other markers of kidney damage were measured using ELISA, apoAI isoforms with Western blot, and renal biopsies stained for apoAI. RESULTS: Patients followed in nephrology clinic had elevated urinary apoAI vs. controls (median 0.074 µg/mg; interquartile range (IQR) 0.0160-0.560, vs. 0.019 µg/mg; IQR 0.004-0.118, p < 0.001). Patients with tubulopathies, renal dysplasia/congenital anomalies of the kidney and urogenital tract, glomerulonephritis, and nephrotic syndrome (NS) in relapse had the greatest elevations (p ≤ 0.01). Patients with NS in remission, nephrolithiasis, polycystic kidney disease, transplant, or hypertension were not different from controls. Although all NS in relapse had higher apoAI excretion than in remission (0.159 vs. 0.0355 µg/mg, p = 0.01), this was largely driven by patients with focal segmental glomerulosclerosis (FSGS). Many patients, especially with FSGS, had increased urinary apoAI isoforms. Biopsies from FSGS patients showed increased apoAI staining at proximal tubule brush border, compared to diffuse cytoplasmic distribution in minimal change disease. CONCLUSIONS: Children with kidney disease have variably increased urinary apoAI depending on underlying disease. Urine apoAI is particularly elevated in diseases affecting proximal tubules. Kidney disease is also associated with high molecular weight (HMW) apoAI isoforms in urine, especially FSGS. Whether abnormal urinary apoAI is a marker or contributor to renal disease awaits further study.

CLCN2 chloride channel mutations in familial hyperaldosteronism type II.

Primary aldosteronism, a common cause of severe hypertension 1 , features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II) 2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of a mutation encoding an identical p.Arg172Gln substitution; all relatives with early-onset primary aldosteronism carried the CLCN2 variant found in the proband. CLCN2 encodes a voltage-gated chloride channel expressed in adrenal glomerulosa that opens at hyperpolarized membrane potentials. Channel opening depolarizes glomerulosa cells and induces expression of aldosterone synthase, the rate-limiting enzyme for aldosterone biosynthesis. Mutant channels show gain of function, with higher open probabilities at the glomerulosa resting potential. These findings for the first time demonstrate a role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. They establish the cause of a substantial fraction of early-onset primary aldosteronism.

Electronic health record-based predictive models for acute kidney injury screening in pediatric inpatients.

BackgroundAcute kidney injury (AKI) is common in pediatric inpatients and is associated with increased morbidity, mortality, and length of stay. Its early identification can reduce severity.MethodsTo create and validate an electronic health record (EHR)-based AKI screening tool, we generated temporally distinct development and validation cohorts using retrospective data from our tertiary care children's hospital, including children aged 28 days through 21 years with sufficient serum creatinine measurements to determine AKI status. AKI was defined as 1.5-fold or 0.3 mg/dl increase in serum creatinine. Age, medication exposures, platelet count, red blood cell distribution width, serum phosphorus, serum transaminases, hypotension (ICU only), and pH (ICU only) were included in AKI risk prediction models.ResultsFor ICU patients, 791/1,332 (59%) of the development cohort and 470/866 (54%) of the validation cohort had AKI. In external validation, the ICU prediction model had a c-statistic=0.74 (95% confidence interval 0.71-0.77). For non-ICU patients, 722/2,337 (31%) of the development cohort and 469/1,474 (32%) of the validation cohort had AKI, and the prediction model had a c-statistic=0.69 (95% confidence interval 0.66-0.72).ConclusionsAKI screening can be performed using EHR data. The AKI screening tool can be incorporated into EHR systems to identify high-risk patients without serum creatinine data, enabling targeted laboratory testing, early AKI identification, and modification of care.

Measurement of glomerular filtration rate by dynamic contrast-enhanced magnetic resonance imaging using a subject-specific two-compartment model.

Measuring glomerular filtration rate (GFR) by dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) as part of standard of care clinicalMRIexams (e.g., in pediatric solid tumor patients) has the potential to reduce diagnostic burden. However, enthusiasm for this relatively newGFRtest may be curbed by the limited amount of cross-calibration studies with referenceGFRtechniques and the vast variety ofMRtracer model algorithms causing confusion on the choice of model. To advanceMRI-basedGFRquantification via improvedGFRmodeling and comparison with associated(99m)Tc-DTPA-GFR, 29 long-term Wilms' tumor survivors (19.0-43.3 years, [median 32.0 ± 6.0 years]) treated with nephrectomy, nonnephrotoxic chemotherapy ± radiotherapy underwentMRIwith Gd-DTPAadministration and a(99m)Tc-DTPA GFRtest. ForDCE-MRI-basedGFRestimation, a subject-specific two-compartment (SS-2C) model was developed that uses individual hematocrit values, automatically defines subject-specific uptake intervals, and fits tracer-uptake curves by incorporating these measures. The association between reference(99m)Tc-DTPA GFRandMR-GFRs obtained bySS-2C, three published 2C uptake, and inflow-outflow models was investigated via linear regression analysis. Uptake intervals varied from 64 sec to 141 sec [96 sec ± 21 sec] and hematocrit values ranged from 30% to 49% [41% ± 4%]; these parameters can therefore not be assumed as constants in 2C modeling. OurMR-GFRestimates using theSS-2C model showed accordingly the highest correlation with(99m)Tc-DTPA-GFRs (R(2) = 0.76,P < 0.001) compared with other models (R(2)-range: 0.36-0.66). In conclusion,SS-2C modeling ofDCE-MRIdata improved the association betweenGFRobtained by(99m)Tc-DTPAand Gd-DTPA DCE-MRIto such a degree that this approach could turn into a viable, diagnosticGFRassay without radiation exposure to the patient.

Acute Kidney Injury Incidence in Noncritically Ill Hospitalized Children, Adolescents, and Young Adults: A Retrospective Observational Study.

BACKGROUND: Acute kidney injury (AKI) has been characterized in high-risk pediatric hospital inpatients, in whom AKI is frequent and associated with increased mortality, morbidity, and length of stay. The incidence of AKI among patients not requiring intensive care is unknown. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 13,914 noncritical admissions during 2011 and 2012 at our tertiary referral pediatric hospital were evaluated. Patients younger than 28 days or older than 21 years of age or with chronic kidney disease (CKD) were excluded. Admissions with 2 or more serum creatinine measurements were evaluated. FACTORS: Demographic features, laboratory measurements, medication exposures, and length of stay. OUTCOME: AKI defined as increased serum creatinine level in accordance with KDIGO (Kidney Disease: Improving Global Outcomes) criteria. Based on time of admission, time interval requirements were met in 97% of cases, but KDIGO time window criteria were not strictly enforced to allow implementation using clinically obtained data. RESULTS: 2 or more creatinine measurements (one baseline before or during admission and a second during admission) in 2,374 of 13,914 (17%) patients allowed for AKI evaluation. A serum creatinine difference ≥0.3mg/dL or ≥1.5 times baseline was seen in 722 of 2,374 (30%) patients. A minimum of 5% of all noncritical inpatients without CKD in pediatric wards have an episode of AKI during routine hospital admission. LIMITATIONS: Urine output, glomerular filtration rate, and time interval criteria for AKI were not applied secondary to study design and available data. The evaluated cohort was restricted to patients with 2 or more clinically obtained serum creatinine measurements, and baseline creatinine level may have been measured after the AKI episode. CONCLUSIONS: AKI occurs in at least 5% of all noncritically ill hospitalized children, adolescents, and young adults without known CKD. Physicians should increase their awareness of AKI and improve surveillance strategies with serum creatinine measurements in this population so that exacerbating factors such as nephrotoxic medication exposures may be modified as indicated.

Renal teratogens.

In utero exposure to certain drugs early in pregnancy may adversely affect nephrogenesis. Exposure to drugs later in pregnancy may affect the renin-angiotensin system, which could have an impact on fetal or neonatal renal function. Reduction in nephron number and renal function could have adverse consequences for the child several years later. Data are limited on the information needed to guide decisions for patients and providers regarding the use of certain drugs in pregnancy. The study of drug nephroteratogenicity has not been systematized, a large, standardized, global approach is needed to evaluate the renal risks of in utero drug exposures.

Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.

OBJECTIVES: To determine if interventions during the pre-hemolytic uremic syndrome (HUS) diarrhea phase are associated with maintenance of urine output during HUS. DESIGN: Prospective observational cohort study. SETTINGS: Eleven pediatric hospitals in the United States and Scotland. PARTICIPANTS: Children younger than 18 years with diarrhea-associated HUS (hematocrit level <30% with smear evidence of intravascular erythrocyte destruction), thrombocytopenia (platelet count <150 × 10³/mm³), and impaired renal function (serum creatinine concentration > upper limit of reference range for age). INTERVENTIONS: Intravenous fluid was given within the first 4 days of the onset of diarrhea. OUTCOME MEASURE: Presence or absence of oligoanuria (urine output ≤ 0.5 mL/kg/h for >1 day). RESULTS: The overall oligoanuric rate of the 50 participants was 68%, but was 84% among those who received no intravenous fluids in the first 4 days of illness. The relative risk of oligoanuria when fluids were not given in this interval was 1.6 (95% confidence interval, 1.1-2.4; P = .02). Children with oligoanuric HUS were given less total intravenous fluid (r = -0.32; P = .02) and sodium (r = -0.27; P = .05) in the first 4 days of illness than those without oligoanuria. In multivariable analysis, the most significant covariate was volume infused, but volume and sodium strongly covaried. CONCLUSIONS: Intravenous volume expansion is an underused intervention that could decrease the frequency of oligoanuric renal failure in patients at risk of HUS.

Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis.

Post-streptococcal acute glomerulonephritis (PSAGN) is one of the most important and intriguing conditions in the discipline of pediatric nephrology. Although the eventual outcome is excellent in most cases, PSAGN remains an important cause of acute renal failure and hospitalization for children in both developed and underdeveloped areas. The purpose of this review is to describe both the typical and less common clinical features of PSAGN, to outline the changes in the epidemiology of PSAGN over the past 50 years, and to explore studies on the pathogenesis of the condition with an emphasis on the search for the elusive nephritogenic antigen.

Impact of continuous renal replacement therapy on oxygenation in children with acute lung injury after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Acute lung injury (ALI) continues to carry a high mortality rate in children after allogeneic hematopoietic stem cell transplant (HSCT). Continuous renal replacement therapy (CRRT) is often used for these patients for various indications including renal failure and fluid overload, and may have a beneficial effect on oxygenation and survival. Therefore, we sought to determine the effect of CRRT on oxygenation in mechanically ventilated pediatric allogeneic HSCT patients with ALI, and to document survival to intensive care unit discharge in this at-risk population receiving both mechanical ventilation and CRRT. PROCEDURE: Retrospective analysis of a pediatric allogeneic HSCT cohort admitted to intensive care unit of a single pediatric oncology center from 1994 to 2006 who received CRRT during a course of mechanical ventilation for ALI. RESULTS: Thirty post-HSCT mechanically ventilated children with ALI who underwent CRRT were included. There was a significant improvement in PaO(2)/FiO(2) with median increase of 31 and 43 in the 24 and 48 hr intervals after initiation of CRRT compared with the 24 hr interval before CRRT (P = 0.0008 and 0.0062, respectively). This improvement in PaO(2)/FiO(2) correlated significantly with reduction of fluid balance achieved after initiation of CRRT (P = 0.0001). There was a trend not reaching statistical significance in improvement in mean airway pressure 48 hr after CRRT in survivors compared to non-survivors. CONCLUSIONS: CRRT improved oxygenation in mechanically ventilated pediatric allogeneic HSCT patients with ALI.

Outcomes of hematopoietic stem cell transplant patients who received continuous renal replacement therapy in a pediatric oncology intensive care unit.

OBJECTIVES: To assess the long-term benefits of continuous renal replacement therapy (CRRT) in this patient population and to analyze factors associated with survival. Hematopoietic stem cell transplantation is being utilized as curative therapy for a variety of disorders. However, organ dysfunction is commonly associated with this therapy. Continuous renal replacement therapy (CRRT) is increasingly being used in the treatment of this multiorgan dysfunction. DESIGN: Retrospective cohort study. SETTING: A free-standing, tertiary care, pediatric oncology hospital. PATIENTS: Twenty-nine allogeneic hematopoietic stem cell transplantation patients who underwent 33 courses of CRRT in the intensive care unit between January 2003 and December 2007. INTERVENTIONS: Cox proportional hazards regressions models were used to examine the relationship between demographic and clinical variables and length of survival. MEASUREMENTS AND MAIN RESULTS: The median length of survival post CRRT initiation was 31 days; only one patient survived >6 mos. Factors associated with increased risk of death included: higher bilirubin and blood urea nitrogen levels before and at 48 hrs into CRRT, lower Pao2/Fio2 ratios at 48 hrs of CRRT, and higher C-reactive protein levels, as well as lower absolute neutrophil counts at CRRT end. CONCLUSION: In this single-center study, CRRT was not associated with long-term survival in pediatric allogeneic hematopoietic stem cell transplantation patients. Clinical data exist, both before and during CRRT, that may be associated with length of survival. Lower C-reactive protein levels at CRRT end were associated with longer survival, suggesting that the ability to attenuate inflammation during CRRT may afford a survival advantage. These findings require confirmation in a prospective study.

Work up of the child with hypertension.

This paper outlines the work up of children with hypertension. In those with confirmed hypertension, the initial work up should be focused on the evaluation for renal parenchymal and renovascular disease. Secondary evaluation should be focused on history and clinical findings. Consideration of angiography should be made in children with severe hypertension and no evidence of renal parenchymal disease, with hypertension requiring more than a single antihypertensive agent to achieve adequate BP control, or with confirmed BP > 99th percentile for sex/age/height percentile. Screening for endocrinopathies should be directed by compatible history and findings on physical examination and should not be a part of a routine initial work up. In any child diagnosed with hypertension, attempts should be made to evaluate for end-organ disease and co-morbid conditions, particularly left ventricular hypertrophy. Pediatricians should establish a degree of comfort in the evaluation and management of hypertension; however, children with severe and complicated hypertension should be referred to a specialist well versed and practiced in the evaluation and management of this disease.

Left ventricular geometry in children and adolescents with primary hypertension.

BACKGROUND: Children with hypertension (HTN) are at increased risk for left ventricular hypertrophy (LVH). Increased left ventricular (LV) mass (LVM) by the process of remodeling in response to volume or pressure loading may be eccentric (increased LV diameter) or concentric (increased wall thickness). Our objective was to classify LV geometry among children with primary HTN and examine differences in ambulatory blood pressure (ABP). METHODS: Subjects aged 7-18 years with suspected HTN were enrolled in this cross-sectional study. ABP and LVM index (LVMI) were measured within the same 24-h period. LV geometry was classified as normal, concentric remodeling, concentric LVH, or eccentric LVH. RESULTS: Children with LVH had significantly higher ambulatory systolic BP (SBP) and diastolic blood pressure (BP) (DBP) levels and body mass index (BMI) Z-score. Sixty-eight children had HTN based upon ABP monitoring (ABPM). Thirty-eight percent of the hypertensive subjects had LVH, with equal distribution in the concentric and eccentric groups. There were significant differences in the 24-h DBP parameters when the eccentric LVH group was compared to the normal geometry and concentric LVH groups. Relative wall thickness (RWT) was inversely associated with night time DBP parameters. These relationships persisted after controlling for BMI Z-score. CONCLUSIONS: Although the risk for LVH is associated with increased SBP and BMI Z-score, those with eccentric LVH had significantly higher DBP.

Blood aldosterone-to-renin ratio, ambulatory blood pressure, and left ventricular mass in children.

OBJECTIVE: To assess the blood aldosterone-to-renin ratio (ARR) and its relationship to ambulatory blood pressure (ABP) and left ventricular mass (LVM) in children. STUDY DESIGN: A cross-sectional clinical study was conducted in 102 children (71.6% African American; 62.7% male) ranging in age from 7 to 18 years (mean, 13.6 years; median, 14 years). ABP (24-hour monitoring) was expressed as blood pressure index (BPI; mean blood pressure/95th percentile by sex and height). LVM was measured by echocardiography and expressed as an index (LVMI = g/height [m](2.7)). Regression analyses were used to estimate associations. RESULTS: African-American children had significantly lower serum aldosterone concentration and plasma renin activity compared with European-American children (aldosterone: 5.9 ng/dL vs 11.4 ng/dL, P < .0001; renin: 1.6 ng/mL/hour vs 2.8 ng/mL/hour, P = .01). However, ARR was not significantly different by race. ARR was not associated with 24-hour ABP but was significantly associated with LVMI (beta = 0.4 g/m(2.7); P = .02) after adjustment for the ratio of 24-hour urine Na to creatinine excretion, body mass index z- score, and ABP index. CONCLUSIONS: The data indicated a significant association between ARR and LVMI, but not ABP, in children, suggesting early cardiac remodeling associated with a high ARR.

Comparison of ambulatory blood pressure reference standards in children evaluated for hypertension.

OBJECTIVE: The purpose of this study was to systematically compare methods for standardization of blood pressure levels obtained by ambulatory blood pressure monitoring (ABPM) in a group of 111 children studied at our institution. METHODS: Blood pressure indices, blood pressure loads and standard deviation scores were calculated using the original ABPM and the modified reference standards. Bland-Altman plots and kappa statistics for the level of agreement were generated. RESULTS: Overall, the agreement between the two methods was excellent; however, approximately 5% of children were classified differently by one as compared with the other method. CONCLUSION: Depending on which version of the German Working Group's reference standards is used for interpretation of ABPM data, the classification of the individual as having hypertension or normal blood pressure may vary.