Updated consensus guidelines on the management of Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.

Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1.

Introduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels. Methods: We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran). Results: In the lumasiran/lumasiran group (n = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group (n = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs). Conclusion: Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes.

FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring.

FOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.

Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an investigational RNA interference (RNAi) therapeutic agent, reduces hepatic oxalate production by targeting glycolate oxidase. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with PH1 who were 6 years of age or older to receive subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and at months 1, 2, 3, and 6). The primary end point was the percent change in 24-hour urinary oxalate excretion from baseline to month 6 (mean percent change across months 3 through 6). Secondary end points included the percent change in the plasma oxalate level from baseline to month 6 (mean percent change across months 3 through 6) and the percentage of patients with 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6. RESULTS: A total of 39 patients underwent randomization; 26 were assigned to the lumasiran group and 13 to the placebo group. The least-squares mean difference in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was -53.5 percentage points (P<0.001), with a reduction in the lumasiran group of 65.4% and an effect seen as early as month 1. The between-group differences for all hierarchically tested secondary end points were significant. The difference in the percent change in the plasma oxalate level (lumasiran minus placebo) was -39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had 24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of the normal range at month 6, as compared with 0% in the placebo group (P<0.001). Mild, transient injection-site reactions were reported in 38% of lumasiran-treated patients. CONCLUSIONS: Lumasiran reduced urinary oxalate excretion, the cause of progressive kidney failure in PH1. The majority of patients who received lumasiran had normal or near-normal levels after 6 months of treatment. (Funded by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number, NCT03681184.).

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function.

Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.

Timing of patient-reported renal replacement therapy planning discussions by disease severity among children and young adults with chronic kidney disease.

BACKGROUND: Preparing children with chronic kidney disease (CKD) for renal replacement therapy (RRT) begins with a discussion about transplant and dialysis, but its typical timing in the course of CKD management is unclear. We aimed to describe participant-reported RRT planning discussions by CKD stage, clinical and sociodemographic characteristics, in the Chronic Kidney Disease in Children (CKiD) cohort. METHODS: Participants responded to the question "In the past year, have you discussed renal replacement therapy with your doctor or healthcare provider?" at annual study visits. Responses were linked to the previous year CKD risk stage based on GFR and proteinuria. Repeated measure logistic models estimated the proportion discussing RRT by stage, with modification by sex, age, race, socioeconomic status, and CKD diagnosis (glomerular vs. non-glomerular). RESULTS: A total of 721 CKiD participants (median age = 12, 62% boys) contributed 2856 person-visits. Proportions of person-visits reporting RRT discussions increased as CKD severity increased (10% at the lowest disease stage and 87% at the highest disease stage). After controlling for CKD risk stage, rates of RRT discussions did not differ by sex, age, race, and socioeconomic status. CONCLUSIONS: Despite participant-reported RRT discussions being strongly associated with CKD severity, a substantial proportion with advanced CKD reported no discussion. While recall bias may lead to underreporting, it is still meaningful that some participants with severe CKD did not report or remember discussing RRT. Initiating RRT discussions early in the CKD course should be encouraged to foster comprehensive preparation and to align RRT selection for optimal health and patient preferences.

Secondhand smoke exposure and higher blood pressure in children and adolescents participating in NHANES.

We assessed the relationship between acute and intermittent secondhand tobacco smoke (SHS) exposure with child and adolescent blood pressure (BP). We analyzed cross-sectional data from 3579 children and adolescents aged 8-17 years participating in the National Health and Nutrition Examination Survey (NHANES) collected between 2007 and 2012, with SHS exposure assessed via serum cotinine (a biomarker for acute exposures) and urine NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, a biomarker for intermittent exposures). BP percentiles and z-scores were calculated according to the 2017 guidelines established by the American Academy of Pediatrics. We used weighted linear regression accounting for the complex sampling weights from NHANES and adjusting for socio-demographic and clinical characteristics. Overall, 56% of the children were non-Hispanic white with a mean age of 12.6 years. There was approximately equal representation of boys and girls. Approximately 15.9% of participants lived in homes where smoking was present. In adjusted models, an interquartile range (IQR) increase in urinary NNAL was associated with 0.099 (95% CI: 0.033, 0.16) higher diastolic blood pressure (DBP) z-score, and with a 0.094 (95% CI: 0.011, 0.18) higher systolic blood pressure (SBP) z-score. The odds of being in the hypertensive range was 1.966 (95% CI: 1.31, 2.951) times greater among children with high NNAL exposures compared to those with undetectable NNAL. For serum cotinine, an IQR increase was associated with 0.097 (95% CI: 0.020, 0.17) higher DBP z-scores, but was not significantly associated with SBP z-scores. The associations of cotinine and NNAL with BP also differed by sex. Our findings provide the first characterization of the relationship between a major tobacco-specific metabolite, NNAL, and BP z-scores in a nationally representative population of US children.

Grip strength in children with chronic kidney disease.

BACKGROUND: The relationship between muscle strength and chronic kidney disease (CKD) in children is unknown. This study aims to quantify the association between grip strength (GS) and kidney function and to explore factors associated with grip strength in children and adolescents with CKD. METHODS: We included 411 children (699 GS assessments) of the Chronic Kidney Disease in Children (CKiD) study. They were matched by age, sex, and height to a healthy control from the National Health and Nutrition Examination Survey to quantify the relationship between GS and CKD. Linear mixed models were used to identify factors associated with GS among CKD patients. RESULTS: Median GS z-score was - 0.72 (IQR - 1.39, 0.11) among CKD patients with CKD stages 2 through 5 having significantly lower GS than CKD stage 1. Compared with healthy controls, CKiD participants had a decreased GS z-score (- 0.53 SD lower, 95% CI - 0.67 to - 0.39) independent of race/ethnicity and body mass index. Factors associated with reduced GS included longer duration of CKD, pre-pubertal status, delayed puberty, neuropsychiatric comorbidities, need of feeding support, need for alkali therapy, and hemoglobin level. Decreased GS was also associated with both a lower frequency and intensity of physical activity. CONCLUSIONS: CKD is associated with impaired muscle strength in children independent of growth retardation and BMI. Exposure to CKD for a prolonged time is associated with impaired muscle strength. Potential mediators of the impact of CKD on muscle strength include growth retardation, acidosis, poor nutritional status, and low physical activity. Additional studies are needed to assess the efficacy of interventions targeted at these risk factors.

Change in Dyslipidemia with Declining Glomerular Filtration Rate and Increasing Proteinuria in Children with CKD.

BACKGROUND AND OBJECTIVES: Dyslipidemia, a risk factor for cardiovascular disease, is common in CKD but its change over time and how that change is influenced by concurrent progression of CKD have not been previously described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the CKD in Children study we prospectively followed children with progressive CKD and utilized multivariable, linear mixed-effects models to quantify the longitudinal relationship between within-subject changes in lipid measures (HDL cholesterol, non-HDL cholesterol, triglycerides) and within-subject changes in GFR, proteinuria, and body mass index (BMI). RESULTS: A total of 508 children (76% nonglomerular CKD, 24% glomerular CKD) had 2-6 lipid measurements each, with a median follow-up time of 4 (interquartile range [IQR], 2.1-6.0) years. Among children with nonglomerular CKD, dyslipidemia was common at baseline (35%) and increased significantly as children aged; 43% of children with glomerular CKD had dyslipidemia at baseline and demonstrated persistent levels as they aged. Longitudinal increases in proteinuria were independently associated with significant concomitant increases in non-HDL cholesterol (nonglomerular: 4.9 [IQR, 3.4-6.4] mg/dl; glomerular: 8.5 [IQR, 6.0-11.1] mg/dl) and triglycerides (nonglomerular: 3% [IQR, 0.8%-6%]; glomerular: 5% [IQR, 0.6%-9%]). Decreases in GFR over follow-up were significantly associated with concomitant decreases of HDL cholesterol in children with nonglomerular CKD (-1.2 mg/dl; IQR, -2.1 to -0.4 mg/dl) and increases of non-HDL cholesterol in children with glomerular CKD (3.9 mg/dl; IQR, 1.4-6.5 mg/dl). The effects of increased BMI also affected multiple lipid changes over time. Collectively, glomerular CKD displayed stronger, deleterious associations between within-subject change in non-HDL cholesterol (9 mg/dl versus 1.2 mg/dl; P<0.001) and triglycerides (14% versus 3%; P=0.004), and within-subject change in BMI; similar but quantitatively smaller differences between the two types of CKD were noted for associations of within-subject change in lipids to within-subject change in GFR and proteinuria. CONCLUSIONS: Dyslipidemia is a common and persistent complication in children with CKD and it worsens in proportion to declining GFR, worsening proteinuria, and increasing BMI.

Combined exposure to lead, cadmium, mercury, and arsenic and kidney health in adolescents age 12-19 in NHANES 2009-2014.

BACKGROUND: Occupational and environmental exposures to toxic metals are established risk factors for the development of hypertension and kidney disease in adults. There is some evidence of developmental metal nephrotoxicity in children and from animal studies; however, to our knowledge no previous studies have examined associations between co-exposure to nephrotoxic environmental metals and children's kidney health. OBJECTIVE: The objective of this study was to assess the association between co-exposure to lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As), measured in urine and blood, and kidney parameters in US adolescents. METHODS: We performed a cross-sectional analysis of a subsample of 2709 children aged 12-19 participating in the National Health and Nutrition Examination Survey (NHANES) between 2009 and 2014. We analyzed urine levels of 4 nephrotoxic metals selected a priori (As, Cd, Pb and Hg), Umix, and 3 nephrotoxic metals in blood (Cd, Pb, and Hg), Bmix, using a weighted quantile sum (WQS) approach. We applied WQS regression to analyze the association of Bmix and Umix with estimated glomerular filtration rate (eGFR), serum uric acid (SUA), urine albumin, blood urea nitrogen (BUN), and systolic blood pressure (SBP), adjusting for sex, race/ethnicity, age, head of household's education level, height, BMI, serum cotinine, and NHANES cohort year. Umix and urine albumin models were also adjusted for urine creatinine, and Bmix models were also adjusted for fish consumption. Subanalyses included stratification by sex and an arsenic-only model including six speciated forms of As measured in urine. RESULTS: In WQS regression models, each decile increase of Umix was associated with 1.6% (95% CI: 0.5, 2.8) higher BUN, 1.4% (95% CI: 0.7, 2.0) higher eGFR, and 7.6% (95% CI: 2.4, 13.1) higher urine albumin. The association between Umix and BUN was primarily driven by As (72%), while the association with eGFR was driven by Hg (61%), and Cd (17%), and the association with urine albumin was driven by Cd (37%), Hg (33%), and Pb (25%). There was no significant relationship between Umix and SUA or SBP. In WQS models using the combined blood metals, Bmix, each decile increase of Bmix was associated with 0.6% (95% CI: 0.0, 1.3) higher SUA; this association was driven by Pb (43%), Hg (33%), and Cd (24%) and was marginally significant (p = 0.05). No associations were observed between Bmix and urine albumin, eGFR, BUN, or SBP. CONCLUSIONS: The findings suggest metals including As, Pb, Hg, Cd and their combinations may affect renal parameters, although potential reverse causation cannot be ruled out due to the cross-sectional study design. Implications of early life low-level exposure to multiple metals on kidney function may have far-reaching consequences later in life in the development of hypertension, kidney disease, and renal dysfunction. Longitudinal studies should further evaluate these relationships.

A novel de novo frameshift mutation in NR0B1 and low prenatal estriol in adrenal hypoplasia congenita.

Mutations in the gene NR0B1 have been associated with several clinical phenotypes of X-linked adrenal hypoplasia congenita (AHC). The degree and onset of adrenal insufficiency and involvement of hypogonadotropic hypogonadism is variable and may not be concordant with the identified mutation. We review a patient with AHC in which prenatal estriol levels were low, presenting with early-onset mineralocorticoid deficiency in the newborn period followed by glucocorticoid deficiency 2 years later. The reported child is hemizygous for a novel mutation that is deemed de novo in the ligand-binding site of the protein (DAX1) expressed by NR0B1. The identified frameshift mutation results in a T407N/fs protein change. Low prenatal estriol levels may represent a sensitive marker of potentially fatal disorders associated with adrenal insufficiency and should be utilized more frequently. Additionally, accurate reporting of mutations in NR0B1 and the associated phenotype are important to eventually establish a genotype-phenotype correlation that may help anticipate guidance in AHC.

Perinatal and childhood exposure to environmental chemicals and blood pressure in children: a review of literature 2007-2017.

Exposure to environmental chemicals during periods of renal development from embryogenesis to birth and through childhood can inform critical windows of nephrotoxicity, including changes in childhood blood pressure. This review assessed recent studies that examined the relationship of air pollution, metals, and other organic pollutants with children's blood pressure outcomes. We restricted this review to peer-reviewed studies published in English between January 2007 and July 2017. We identified a total of 36 articles that estimated associations with childhood blood pressure, of which 14 studies examined the effects of air pollution, 10 examined metals, and 12 examined other organic pollutants including phthalates (n = 4), Bisphenol A (n = 3), polychlorinated biphenols (n = 2), organophosphate pesticides (n = 2), or perfluoroalkyl acids (n = 1). Similar to the established relationship between tobacco smoke exposure and childhood blood pressure, the majority of studies that examined air pollutants, particularly exposure to PM10 and PM2.5, reported associations with increased childhood blood pressure. The literature reported conflicting evidence for metals, and putative evidence of the effects of exposure to phthalates, Bisphenol A, polychlorinated biphenols, and pesticides. Overall, our review underscores the need for additional studies that assess the impact of nephrotoxicant exposure during early life, particularly the perinatal period, and blood pressure in childhood.

Waist Circumference and Body Mass Index in Children with Chronic Kidney Disease and Metabolic, Cardiovascular, and Renal Outcomes.

OBJECTIVE: To describe the prevalence of obesity as estimated by waist circumference (WC) and body mass index (BMI) and compare associations of WC and BMI with indicators of metabolic, cardiovascular, and renal health in children with chronic kidney disease (CKD). STUDY DESIGN: Cross-sectional analysis stratified by CKD etiology (nonglomerular or glomerular) of 737 subjects. The kappa statistic was used to assess agreement between the 2 measures of obesity. Linear regression models were performed using WC and BMI as separate independent variables. Dependent variables included lipid measures, insulin resistance, blood pressure, left ventricular mass index, proteinuria, and estimated glomerular filtration rate. Associations were scaled to SD and interpreted as the change in dependent variable associated with a 1-SD change in WC or BMI. RESULTS: There was good agreement (kappa statistic = 0.68) between WC and BMI in identifying obesity. Approximately 10% of subjects had obesity by 1 measure but not the other. BMI was more strongly associated with estimated glomerular filtration rate than WC. BMI was more strongly associated with left ventricular mass index in the nonglomerular CKD group compared with WC, but both had significant associations. The associations between WC and BMI with the remainder of the dependent variables were not significantly different. CONCLUSIONS: Measurement of WC added limited information to BMI in this cohort. Further longitudinal study is needed to determine how WC and BMI compare in predicting outcomes, particularly for children with CKD identified as having obesity by 1 measure but not the other.

Environmental exposures and pediatric kidney function and disease: A systematic review.

BACKGROUND: Environmental chemical exposures have been implicated in pediatric kidney disease. No appraisal of the available evidence has been conducted on this topic. METHODS: We performed a systematic review of the epidemiologic studies that assessed association of environmental exposures with measures of kidney function and disease in pediatric populations. The search period went through July 2016. RESULTS: We found 50 studies that met the search criteria and were included in this systematic review. Environmental exposures reviewed herein included lead, cadmium, mercury, arsenic, fluoride, aflatoxin, melamine, environmental tobacco, bisphenol A, dental procedures, phthalates, ferfluorooctanoic acid, triclosan, and thallium/uranium. Most studies assessed environmental chemical exposure via biomarkers but four studies assessed exposure via proximity to emission source. There was mixed evidence of association between metal exposures, and other non-metal environmental exposures and pediatric kidney disease and other kidney disease biomarkers. The evaluation of causality is hampered by the small numbers of studies for each type of environmental exposure, as well as lack of study quality and limited prospective evidence. CONCLUSION: There is a need for well-designed epidemiologic studies of environmental chemical exposures and kidney disease outcomes.

Albuminuria, Proteinuria, and Renal Disease Progression in Children with CKD.

BACKGROUND AND OBJECTIVES: The role of albuminuria as an indicator of progression has not been investigated in children with CKD in the absence of diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Children were enrolled from 49 centers of the CKD in Children study between January of 2005 and March of 2014. Cross-sectional multivariable linear regression (n=647) was used to examine the relationship between urine protein-to-creatinine (UP/C [milligrams per milligram]) and albumin-to-creatinine (ACR [milligrams per gram]) with eGFR (milliliters per minute per 1.73 m2). Parametric time-to-event analysis (n=751) was used to assess the association of UP/C, ACR, and urine nonalbumin-to-creatinine (Unon-alb/cr [milligrams per gram]) on the time to the composite endpoint of initiation of RRT or 50% decline in eGFR. RESULTS: The median follow-up time was 3.4 years and 202 individuals experienced the event. Participants with a UP/C≥0.2 mg/mg and ACR≥30 mg/g had a mean eGFR that was 16 ml/min per 1.73 m2 lower than those with a UP/C<0.2 mg/mg and ACR<30 mg/g. Individuals with ACR<30 mg/g, but a UP/C≥0.2 mg/mg, had a mean eGFR that was 9.3 ml/min per 1.73 m2 lower than those with a UP/C<0.2 mg/mg and ACR<30 mg/g. When categories of ACR and Unon-alb/cr were created on the basis of clinically meaningful cutoff values of UP/C with the same sample sizes for comparison, the relative times (RTs) to the composite end-point were almost identical when comparing the middle (RT=0.31 for UP/C [0.2-2.0 mg/mg], RT=0.38 for ACR [56-1333 mg/g], RT=0.31 for Unon-alb/cr [118-715 mg/g]) and the highest (RT=0.08 for UP/C [>2.0 mg/mg], RT=0.09 for ACR [>1333 mg/g], RT=0.07 for Unon-alb/cr [>715 mg/g]) levels to the lowest levels. A similar trend was seen when categories were created on the basis of clinically meaningful cutoff values of ACR (<30, 30-300, >300 mg/g). CONCLUSIONS: In children with CKD without diabetes, the utility of an initial UP/C, ACR, and Unon-alb/cr for characterizing progression is similar.

Transient antenatal Bartter's Syndrome and X-linked polyhydramnios: insights from the genetics of a rare condition.

The discovery that mutations in MAGED2 cause a rare and transient form of antenatal Bartter's Syndrome may have implications beyond the very small number of affected families. Understanding the mechanism by which this severe form of Bartter's Syndrome resolves after birth could also provide new insights into the regulation of tubular transport and the response to tissue hypoxia.

Impaired postprandial lipemic response in chronic kidney disease.

Dyslipidemia in chronic kidney disease (CKD) is usually characterized by hypertriglyceridemia. Here we studied postprandial lipemia in children and young adults to determine whether an increasing degree of CKD results in a proportional increase in triglyceride and chylomicron concentration. Secondary goals were to determine whether subnephrotic proteinuria, apolipoprotein (apo)C-III and insulin resistance modify the CKD effect. Eighteen fasting participants (mean age of 15 years, mean glomerular filtration rate (GFR) of 50 ml/min/1.73 m(2)) underwent a postprandial challenge with a high fat milkshake. Triglycerides, apoB-48, insulin, and other markers were measured before and 2, 4, 6, and 8 hours afterward. Response was assessed by the incremental area under the curve of triglycerides and of apoB-48. The primary hypothesis was tested by correlation to estimated GFR. Significantly, for every 10 ml/min/1.73 m(2) lower estimated GFR, the incremental area under the curve of triglycerides was 17% greater while that of apoB-48 was 16% greater. Univariate analyses also showed that the incremental area under the curve of triglycerides and apoB-48 were significantly associated with subnephrotic proteinuria, apoC-III, and insulin resistance. In multivariate analysis, CKD and insulin resistance were independently associated with increased area under the curve and were each linked to increased levels of apoC-III. Thus, postprandial triglyceride and chylomicron plasma excursions are increased in direct proportion to the degree of CKD. Independent effects are associated with subclinical insulin resistance and increased apoC-III is linked to both CKD and insulin resistance.

Can transition to adult care for transplant recipients be improved by intensified services while patients are still in pediatrics?

Context-Transferring out of pediatrics is a vulnerable time for transplant recipients. Use of a transition coordinator before and after transfer improves outcomes, although it is unclear whether placing a transition coordinator in pediatrics alone is beneficial. Objective-To determine if incorporating a transition coordinator in pediatrics only is associated with stable outcomes for kidney transplant recipients. Design-A retrospective chart review was conducted on outcomes for kidney transplant recipients who shifted service location between 2008 and 2012. Setting-A pediatric and adult transplant unit. Patients-Twenty-two patients transferred during the study period. Intervention-Twelve patients received more intensified preparation from the team's social worker, whose role was aligned with a transition coordinator position; 10 patients received standard care. Main Outcome Measures-The primary outcome was medication adherence, using a validated measure, standard deviations of tacrolimus blood levels. A standard deviation greater than 2.5 has been established as a threshold associated with poor outcomes such as rejection. Standard deviation of tacrolimus levels was compared for 1 year before and 1 year after transfer. Results-Medication adherence worsened from 1 year before (2.03 [SD, 0.75]) to 1 year after transfer (2.95 [SD, 1.38]; t = -;3.07, P = .007). A repeated-measures analysis of variance indicated that this pattern was the same for patients who did and patients who did not receive intensified services in pediatrics (F1,16 = 1.07, P = .32).

Biliary Atresia Is Associated With Hypertension.

OBJECTIVES: The improved survival of pediatric liver transplant recipients is accompanied by an increase in long-term comorbidities. A recently highlighted concern, hypertension, is associated with chronic kidney disease (CKD) in this population and can result in other target-organ damage during childhood. The prevalence of hypertension in pediatric liver transplantation is imprecisely known. In addition, individual etiologies of liver failure may convey different risks of hypertension. We sought to study the effect of liver transplantation on the prevalence of hypertension and CKD in patients with biliary atresia (BA). METHODS: We conducted a retrospective chart review of 160 patients with BA followed at the Mount Sinai Medical Center, New York, from 1987 to 2012. Data were accumulated from the initial and subsequent visits at approximately 6 months, 1, 3, 5, 10, and 15 years of age. Hypertension was defined as systolic blood pressure >95th percentile for age, sex, height, and/or use of antihypertensive medication. Renal function was examined over time. Data were stratified by liver transplantation status at the time of visit. RESULTS: A high prevalence of hypertension was observed from the initial visit through age 10, independent of transplant status (transplanted: 48% initial visit and 13% after 10 years vs nontransplanted: 55% initial visit and 17% after 10 years [P = ns for transplant status]). Mean estimated glomerular filtration rate (eGFR) was lower among liver transplant patients as compared with nontransplant patients and declined posttransplant. The incidence of CKD was higher among transplant patients. CONCLUSIONS: Hypertension is common among children with BA, independent of liver transplant status. Transplant patients had significantly reduced renal function, which continued to decline over time. Hypertension was not associated with reduced eGFR.