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.

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.

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.

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.

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.

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.

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.

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.

Ambulatory blood pressure and increased left ventricular mass in children at risk for hypertension.

OBJECTIVE: To relate ambulatory blood pressure (ABP) to cardiac target organ measurement in children at risk for primary hypertension (HTN). STUDY DESIGN: Left ventricular mass index (LVMI) and ABP were measured concomitantly in children (6 to 18 years) at risk for hypertension using a cross-sectional study design. RESULTS: LVMI showed a significant positive correlation with 24-hour systolic blood pressure (SBP) load, SBP index (SBPI), and standard deviation score (SDS). When subjects were stratified by LVMI percentile, there were significant differences in SBP load, 24-hour SBPI, and 24-hour SSDS. The odds ratio (OR) of having elevated LVMI increased by 54% for each incremental increase of SDS in 24-hour SSDS after controlling for race and BMI (OR = 1.54, unit = 1 SDS, CI = 1.1, 2.15, P = .011) and increased by 88% for each increase of 0.1 in BPI (OR = 1.88, CI = 1.03, 3.45, P = .04). Subjects with stage 3 HTN had significantly greater mean LVMI compared with normal subjects (P = .002 by ANOVA; LMVI, 31.6 +/- 7.9 versus 39.5 +/- 10.4). CONCLUSIONS: As systolic ABP variables increase, there is greater likelihood for increased LVMI. Staging based on ABPM allows assessment of cardiovascular risk in children with primary hypertension.

Serum uric acid and ambulatory blood pressure in children with primary hypertension.

Hyperuricemia is associated with primary hypertension (HTN) in adults and children. Furthermore, uric acid levels during childhood are associated with blood pressure (BP) levels in adulthood. We measured 24-h ambulatory BP and serum uric acid (SUA) in 104 children referred for possible hypertension. Mean age was 13.7 +/- 2.6 y (range, 7-18 y) with 67 males and 37 females; 74 were African-American, 29 Caucasian and one Asian. SUA was associated with age (r = 0.38, p = 0.0001) and BMI Z-score (r = 0.23, p = 0.021). SUA was significantly associated with mean ambulatory systolic (S) and diastolic (D) BP. Mean ambulatory BP was normalized to gender- and height-specific reference standards using BP index. SUA was significantly associated with 24-h DBP index and nocturnal DBP index after adjusting for age, gender, race, BMI Z-score and urinary sodium excretion. SUA was also significantly associated with 24-h DBP load and nocturnal DBP load. Uric acid was significantly associated with increased likelihood for diastolic HTN (OR = 2.1, CI = 1.2, 3.7; p = 0.0063) after adjusting for other co-variables. Among children at risk for HTN, the likelihood for diastolic HTN (as defined by ambulatory blood pressure monitoring) increases significantly as SUA increases. SUA may be associated with increased severity of HTN during youth.

Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group.

Improvements in childhood cancer therapy have led to increasing numbers of long-term survivors. These survivors are at risk for a variety of late effects due to the disease itself, treatment exposures (surgery, chemotherapy, and radiotherapy), underlying medical problems, and health behaviors. The COG LTFU Guidelines are risk-based, exposure-related recommendations for the identification and management of late effects due to therapies utilized in the treatment of childhood cancer, and are designed for asymptomatic survivors presenting for routine medical follow-up 2 or more years after completion of cancer therapy. The COG Guidelines Task Force on Urinary Tract Complications conducted an extensive review of the medical literature via MEDLINE. Specific treatment exposures which were reviewed include nephrectomy, chemotherapy regimens known to be nephrotoxic (cisplatin, carboplatin, ifosfamide, and methotrexate), and renal irradiation. Literature sources were ranked according to the strength of evidence and are cited in the review. This review summarizes the literature that supported the recommendations for cancer survivors at risk for nephrotoxicity previously outlined in the Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent and Young Adult Cancers (COG LTFU Guidelines).

Induction therapy for pediatric focal proliferative lupus nephritis: cyclophosphamide versus mycophenolate mofetil.

PURPOSE OF THE STUDY: Although cyclophosphamide has been used with success in children, mycophenolate may be a better alternative with less toxicity. The objective of this study is to determine the efficacy of mycophenolate compared with cyclophosphamide as induction therapy in children with class III lupus nephritis. METHODS: We retrospectively studied pediatric patients with class III lupus nephritis from two pediatric centers from January 1991 to December 2005 who were treated either with monthly cyclophosphamide or mycophenolate mofetil for the first 6 months. Thirteen patients were studied, with seven patients in the cyclophosphamide group and six patients in the mycophenolate group. RESULTS: At 6 months, in the cyclophosphamide group, no patient had achieved complete remission, while 57% were in partial remission. In the mycophenolate group, 66% had achieved complete remission, 17% were in partial remission, and 17% were not in remission. DISCUSSION: In a small group of children with class III lupus nephritis, we observed a trend of more patients in the mycophenolate group achieving remission at 6 months. However, the long-term benefit of using mycophenolate as an induction agent is still unclear.

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.

BK virus-induced tubulointerstitial nephritis in a child with acute lymphoblastic leukemia.

We report a case of BK virus-induced tubulointerstitial nephritis in a child with acute lymphoblastic leukemia. Primary BK virus infection was exacerbated by chemotherapy-induced immunodeficiency. Careful administration of chemotherapy and anti-viral therapy prevented further damage. This diagnosis should be considered in children who experience renal dysfunction during cancer treatment.