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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

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 health care provider?” at annual study visits. Responses were linked to the previous year CKD risk stage based on GFR and proteinuria. Repeated measures 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: 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.

INTRODUCTION AND OBJECTIVE:In patients with primary hyperoxaluria type 1 (PH1), recurrent kidney stones are a major cause of morbidity; nephrocalcinosis (NC) has been shown to be associated with ki...

1. Bernarda Viteri, MD* 2. Jeffrey M. Saland, MD† 1. *Children’s Hospital of Philadelphia, Philadelphia, PA 2. †Mount Sinai Kravis Children’s Hospital, New York, NY Thrombotic microangiopathy (TMA) was described by Moschcowitz in 1924, and the term hemolytic uremic syndrome (HUS) appeared by 1955 to describe a series of patients with small-vessel renal thrombi, thrombocytopenia, and hemolytic anemia. During the 1970s an association was noted between enteric Escherichia coli infections and HUS, and in 1983 the specific trigger of Shiga toxin–producing E coli (STEC) was recognized. This recognition led to classification of HUS as “diarrhea positive” or “diarrhea negative,” although this terminology is no longer popular. Other secondary forms of HUS are known, including HUS associated with invasive pneumococcal infection, human immunodeficiency virus, systemic lupus erythematosus, or uncommon reactions to medications such as cyclosporine. More recently, the term atypical HUS (aHUS) has been used to describe a rare form of HUS occurring in susceptible individuals, most often from defects in regulation of the alternative pathway of complement, whereas typical HUS largely refers to STEC-HUS or pneumococcal HUS. In patients with bloody diarrhea, it is imperative that front-line providers understand the importance of testing for STEC. In many parts of the world STEC O157:H7 is the most common pathogen leading to HUS, but it certainly is not the only one as many other organisms besides E coli have been causally implicated with HUS. Testing for STEC is evolving quickly. Stool culture, various assays for the Shiga toxin, and most recently DNA testing of stool are all being used, each method with its own strengths and limitations. The most crucial issue is timeliness because the window of opportunity …

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.

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.

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.

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 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 ( 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. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_05_30_Schwartz.mp3

Autoinflammatory disease can result from monogenic errors of immunity. We describe herein the first example of a patient with early-onset widespread autoinflammation resulting from a mosaic, heterozygous, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of over twenty-five cytokines. By first-of-its-kind custom single-cell RNA sequencing, we examine mosaicism with single cell resolution. We uncover that JAK1 transcription is predominantly restricted to a single allele across different immune cells, introducing the concept of a mutational “transcriptotype” that differs from the genotype. Functionally, the S703I mutation not only increased JAK1 kinase activity, but also resulted in transactivation of partnering JAKs, independently of its catalytic domain. Further, S703I JAK1 was not solely hypermorphic for cytokine signaling, but neomorphic as well, as it enabled downstream signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, which led to rapid resolution of her clinical disease. Together, these findings represent an unprecedented degree of personalized medicine with the concurrent discovery of fundamental biological principles.

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.

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. Keywords: Arsenic, Lead, Cadmium, Mercury, Mixture, Childhood, Kidney, Systolic blood pressure, Blood urea nitrogen, Glomerular filtration

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.

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.

The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) guideline for management of dyslipidemia in chronic kidney disease (CKD) was published in 2003. Since then, considerable evidence, including randomized controlled trials of statin therapy in adults with CKD, has helped better define medical treatments for dyslipidemia. In light of the new evidence, KDIGO (Kidney Disease: Improving Global Outcomes) formed a work group for the management of dyslipidemia in patients with CKD. This work group developed a new guideline that contains substantial changes from the prior KDOQI guideline. KDIGO recommends treatment of dyslipidemia in patients with CKD primarily based on risk for coronary heart disease, which is driven in large part by age. The KDIGO guideline does not recommend using low-density lipoprotein cholesterol level as a guide for identifying individuals with CKD to be treated or as treatment targets. Initiation of statin treatment is no longer recommended in dialysis patients. To assist US practitioners in interpreting and applying the KDIGO guideline, NKF-KDOQI convened a work group to write a commentary on this guideline. For the most part, our work group agreed with the recommendations of the KDIGO guideline, although we describe several areas in which we believe the guideline statements are either too strong or need to be more nuanced, areas of uncertainty and inconsistency, as well as additional research recommendations. The target audience for the KDIGO guideline includes nephrologists, primary care practitioners, and non-nephrology specialists such as cardiologists and endocrinologists. As such, we also put the current recommendations into the context of other clinical practice recommendations for cholesterol treatment.

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.

Summary Background and objectives In adults, increased carotid intima-media thickness (cIMT) as assessed by ultrasonography is a valid predictor of cardiovascular events. Children with CKD are known to be at increased cardiovascular risk. This study sought to identify cardiovascular risk factors associated with increased cIMT in children with CKD. Design, setting, participants, & measurements This was a cross-sectional analysis of cIMT obtained after 12 months of follow-up of 101 children aged 2–18 years with mild to moderate CKD (median GFR 42.9 ml/min per 1.73 m2) in the Chronic Kidney Disease in Children cohort study enrolled between April 2005 and September 2009 and 97 healthy pediatric controls between January 2003 and December 2008. An average of six standardized B-mode ultrasound measurements constituted the overall cIMT measurement. Results The median cIMT was 0.43 mm (interquartile range, 0.38–0.48) compared with 0.41 mm in healthy controls (P=0.03 for difference). After multivariable adjustment, the median cIMT was 0.02 mm (95% confidence interval [CI], 0.01–0.05) larger than that of the healthy controls. In a multivariable linear regression analysis, dyslipidemia and hypertension were associated with 0.05 mm (95% CI, 0.01–0.08) and 0.04 mm (95% CI, 0.003–0.08) greater mean cIMT, respectively. Body mass index, CKD etiology, GFR, birth weight, pubertal status, calcium, phosphorus, sex, and race were not associated with cIMT. Conclusions cIMT is significantly elevated among children with CKD, as is the prevalence of other cardiovascular risk factors. Of these risk factors, hypertension and dyslipidemia are significantly associated with increased cIMT.

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.

CKD continues to detract from the success of improved survival in pediatric liver transplantation, and its presence is likely under recognized. Here we review the literature regarding the prevalence, etiology, and management of renal dysfunction in pediatric liver transplant recipients. Long-term studies suggest the prevalence of CKD to be 25-38% by 5-10 yr post-transplant. While important, sole use of serum creatinine overestimates renal function in this population. Screening for and treatment of persistent proteinuria and hypertension as well as minimization of nephrotoxic insults are the mainstays to delay or prevent CKD progression. Office-based blood pressure measures are less sensitive than ABPM, which is specifically recommended by the American Heart Association for its ability to diagnose masked hypertension in pediatric liver transplant recipients. Long-term risk of CKD is predominantly secondary to CNI toxicity. CNI minimization protocols have shown promise in slowing progression of CKD while maintaining graft function, but large-scale randomized control trials with long-term follow-up are needed.

Summary Background and objectives Although prevalence of traditional cardiovascular risk factors (CVRF) has been described in children with CKD, the frequency with which these CVRF occur concomitantly and the clinical characteristics associated with multiple CVRF are unknown. This study determined the prevalence and characteristics of multiple CVRF in children in the Chronic Kidney Disease in Children study. Design, setting, participants, & measurements Using cross-sectional data from first follow-up visits, we determined the prevalence of four CVRF: hypertension (casual BP >95th percentile or self-reported hypertension with concurrent use of anti-hypertensive medication), dyslipidemia (triglycerides >130 mg/dl, HDL 160 mg/dl, or use of lipid-lowering medication), obesity (BMI >95th percentile), and abnormal glucose metabolism (fasting glucose >110 mg/dl, insulin >20 μIU/ml, or HOMA-IR >2.20, >3.61, or >3.64 for those at Tanner stage 1, 2 to 3, or 4 to 5, respectively) in 250 children (median age 12.2 years, 74% Caucasian, median iohexol-based GFR 45.2 ml/min per 1.73 m2). Results Forty-six percent had hypertension, 44% had dyslipidemia, 15% were obese, and 21% had abnormal glucose metabolism. Thirty-nine percent, 22%, and 13% had one, two, and three or more CVRF, respectively. In multivariate ordinal logistic regression analysis, glomerular disease and nephrotic-range proteinuria were associated with 1.96 (95% confidence interval, 1.04 to 3.72) and 2.04 (95% confidence interval, 0.94 to 4.43) higher odds of having more CVRF, respectively. Conclusions We found high prevalence of multiple CVRF in children with mild to moderate CKD. Children with glomerular disease may be at higher risk for future cardiovascular events.

Melamine, a man-made non-nutritive substance containing nitrogen, can falsely elevate measures of protein content in foodstuffs. Several manufacturers of powdered infant formula in China apparently added melamine to raise the measured protein content and thereby exposed thousands of infants and young children to very high levels of melamine. Such exposure resulted in cases of acute kidney failure and nephrolithiasis. This Editorial from members of the world-wide Pediatric Nephrology community provides a common-sense approach to the care of infants who may have been exposed to powdered infant formula in 2007-2008.

Background and objectives: A male infant with a family history of thrombotic microangiopathy developed atypical hemolytic uremic syndrome (aHUS). Design, setting, participants, & measurements: Case report. Results: Genetic analysis demonstrated a heterozygous mutation (S1191L) of CFH, the gene coding complement factor H (CFH). The child suffered many episodes of HUS, each treated with plasma exchange. In time, despite initiation of a prophylactic regimen of plasma exchange, his renal function declined significantly. At the age of 4 yr he received a (split liver) combined liver-kidney transplant (LKT) with preoperative plasma exchange and enoxaparin anticoagulation. Initial function of both grafts was excellent and is maintained for nearly 2 yr. Conclusions: This report adds to the small but growing number of individuals in whom LKT has provided a favorable outcome for aHUS associated with CFH mutation, expands the technique of using a split liver graft, and describes the unique histologic features of subclinical liver disease in HUS.

Chronic renal insufficiency (CRI) is associated with a characteristic dyslipidemia. Findings in children with CRI largely parallel those in adults. Moderate hypertriglyceridemia, increased triglyceride-rich lipoproteins (TRL) and reduced high-density lipoproteins (HDL) are the most usual findings, whereas total and low-density lipoprotein cholesterol (LDL-C) remain normal or modestly increased. Qualitative abnormalities in lipoproteins are common, including small dense LDL, oxidized LDL, and cholesterol-enriched TRL. Measures of lipoprotein lipase and hepatic lipase activity are reduced, and concentrations of apolipoprotein C-III are markedly elevated. Still an active area of research, major pathophysiological mechanisms leading to the dyslipidemia of CRI include insulin resistance and nonnephrotic proteinuria. Sources of variability in the severity of this dyslipidemia include the degree of renal impairment and the modality of dialysis. The benefits of maintaining normal body weight and physical activity extend to those with CRI. In addition to multiple hypolipidemic pharmaceuticals, fish oils are also effective as a triglyceride-lowering agent, and the phosphorous binding agent sevelamer also lowers LDL-C. Emerging classes of hypolipidemic agents and drugs affecting sensitivity to insulin may impact future treatment. Unfortunately, cardiovascular benefit has not been convincingly demonstrated by any trial designed to study adults or children with renal disease. Therefore, it is not possible at this time to endorse general recommendations for the use of any agent to treat dyslipidemia in children with chronic kidney disease.

Provides an update on the metabolic syndrome in childhood.The metabolic syndrome is increasingly recognized among children. It is nearly exclusively encountered in overweight and obese individuals and is associated with atherosclerosis. Development and clustering of cardiovascular risk factors is influenced by many characteristics including heritable traits, prenatal and infantile influences, diet, physical activity, and socioeconomic status.Epidemiological data have become mature in this area. Efforts to design and implement systems to prevent and treat the metabolic syndrome are required.

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).

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.

Adult stature and peak bone mass are achieved through childhood growth and development. Multiple factors impair this process in children undergoing solid organ transplantation, including chronic illness, pretransplant osteodystrophy, use of medications with negative impact on bone, and post-transplant renal dysfunction. While growth delay and short stature remain common, the most severe forms of transplant-related bone disease, fracture and avascular necrosis, appear to have become less common in the pediatric age group. Osteopenia is very prevalent in adult transplant recipients and probably also in pediatrics, but its occurrence and sequelae are difficult to study in these groups due to methodological shortfalls of planar densitometry related to short stature and altered patterns of growth and development. Although the effect on lifetime peak bone mass is not clear, data from adult populations suggest an elevated long-term risk of bone disease in children receiving transplants. Optimal management of pretransplantation osteodystrophy, attention to post-transplant renal insufficiency among both renal and non-renal transplant patients, reduction of steroid dose in select patients, and supplementation with calcium plus vitamin D during expected periods of maximal bone loss may improve bone health. Careful research is required to determine the role of bisphosphonate therapy in pediatric transplantation.

The purpose of the present study was to examine the clearance of methotrexate (MTX) by high-flux hemodialysis (HD) in pediatric oncology patients. We present three patients who experienced nephrotoxicity and prolonged exposure to toxic MTX concentrations following high-dose infusions during treatment for osteogenic sarcomas. Each patient was successfully treated with high-flux HD, followed by carboxypeptidase G2 (CPDG2) in two cases. Minimal systemic toxicity occurred. We review the literature and discuss guidelines for early and aggressive treatment for this complication of high-dose MTX therapy. Clinically important removal of MTX depends upon prompt initiation of HD after detection of nephrotoxicity and delayed clearance of MTX. Therapy is indicated in cases where compassionate use of CPDG(2) may not be available, or while awaiting its delivery.

Autism spectrum disorder (ASD) and intellectual disability (ID) can be caused by mutations in a large number of genes. One example is SHANK3 on the terminal end of chromosome 22q. Loss of one functional copy of SHANK3 results in 22q13 deletion syndrome or Phelan-McDermid syndrome (PMS) and causes a monogenic form of ASD and/or ID with a frequency of 0.5% to 2% of cases. SHANK3 is the critical gene in this syndrome, and its loss results in disruption of synaptic function. With chromosomal microarray analyses now a standard of care in the assessment of ASD and developmental delay, and with the emergence of whole exome and whole genome sequencing in this context, identification of PMS in routine clinical settings will increase significantly. However, PMS remains a rare disorder, and the majority of physicians have never seen a case. While there is agreement about core deficits of PMS, there have been no established parameters to guide evaluation and medical monitoring of the syndrome. Evaluations must include a thorough history and physical and dysmorphology examination. Neurological deficits, including the presence of seizures and structural brain abnormalities should be assessed as well as motor deficits. Endocrine, renal, cardiac, and gastrointestinal problems all require assessment and monitoring in addition to the risk of recurring infections, dental and vision problems, and lymphedema. Finally, all patients should have cognitive, behavioral, and ASD evaluations. The objective of this paper is to address this gap in the literature and establish recommendations to assess the medical, genetic, and neurological features of PMS.

Background: Pediatric renal allograft recipients often suffer from osteopenia and the potential for increased fractures. Although modern densitometers are widely available, their use in children is complicated by lack of optimal interpretive criteria. Methods: We reviewed dual energy X-ray absorptiometry (DEXA) studies in 33 patients with functional renal allografts 4.4 ± 3.6 years after transplantation. We interpreted our data using three previously described methods of assigning bone mineral density (BMD) Z scores. Results: BMD was directly related to age, height, weight, body surface area, and pubertal status (p

Patients with end-stage renal disease (ESRD) due to atypical HUS (aHUS) now have several potential options that can enable successful kidney transplantation. This editorial addresses these options by considering key factors that are important when making an individual treatment decision.

2011 has been a special year for hemolytic uremic syndrome (HUS): on the one hand, the dramatic epidemic of Shiga toxin producing E. coli -associated HUS in Germany brought the disease to the attention of the general population, on the other hand it has been the year when eculizumab, the first complement blocker available for clinical practice, was demonstrated as the potential new standard of care for atypical HUS. Here we review the therapeutic options presently available for the various forms of hemolytic uremic syndrome and show how recent knowledge has changed the therapeutic approach and prognosis of atypical HUS.

Chronic kidney disease (CKD) is progressive in nature and characterized by decreasing kidney function over time (1–3). The natural history of CKD has been studied predominantly in adult populations (4); substantially less is known about the progression of CKD in children (5). The Chronic Kidney Disease in Children (CKiD) cohort study assembled a large cohort of children with CKD for prospective, longitudinal measurement of glomerular filtration rate (GFR) to specifically address the lack of knowledge in this area. CKD resulting from glomerular disease or injury has been associated with an accelerated decline in kidney function compared with CKD resulting from nonglomerular (predominantly structural urologic disease) CKD (5). Even among individuals with a specific diagnosis, little to no progression may occur over extended periods, whereas marked progression may occur in the most susceptible individuals (6–9). Analyses of GFR using traditional regression methods (e.g., lognormal regression) aimed at detecting rigid shifts of the entire distribution of values associated with exposures are often overly simplistic and could fail to detect meaningful differences. Specifically, classical regression analysis of a log-transformed outcome under the standard assumption of a common scale yields a single estimate for the relative effect of an exposure and might mask effect heterogeneity. Here, we show that parametric methods based on the generalized gamma (GG) distribution offer an attractive, alternative approach for characterizing the effect of an exposure on GFR decline. GG models, which are characterized by 3 parameters—location (β), scale (σ), and shape (κ)—allow for determination of heterogeneous effects of an exposure on the percentiles of the distributions of different groups (10). Heterogeneous effects of an exposure across different percentiles of the distribution can be characterized by allowing the exposure variable to modify not only β, but also σ and κ. Furthermore, the GG distribution incorporates as a particular case the classic lognormal regression, in which β depends on covariates, σ is common across exposure groups, and κ takes the fixed value of 0. Relative percentiles (RPs) (i.e., ratios of the values of the outcome below which a certain percentage of individuals are observed in different groups) derived from the GG model are useful for fully characterizing differences between exposure groups; in particular, effects of exposures can be different at different percentiles of the distribution of values. To illustrate the use of GG models and RPs as measures of heterogeneous effects of exposures, we used data collected by the CKiD cohort study to characterize the longitudinal changes in GFR in children with glomerular versus nonglomerular CKD.

Left ventricular hypertrophy (LVH) associates with increased risk for cardiovascular disease. Hypertension leads to LVH in adults, but its role in the pathogenesis of LVH in children is not as well established. To examine left ventricular mass and evaluate factors associated with LVH in children with stages 2 through 4 chronic kidney disease (CKD), we analyzed cross-sectional data from children who had baseline echocardiography (n = 366) and underwent ambulatory BP monitoring (n = 226) as a part of the observational Chronic Kidney Disease in Children (CKiD) cohort study. At baseline, 17% of children had LVH (11% eccentric and 6% concentric) and 9% had concentric remodeling of the left ventricle. On the basis of a combination of ambulatory and casual BP assessment (n = 198), 38% of children had masked hypertension (normal casual but elevated ambulatory BP) and 18% had confirmed hypertension (both elevated casual and ambulatory BP). There was no significant association between LVH and kidney function. LVH was more common in children with either confirmed (34%) or masked (20%) hypertension compared with children with normal casual and ambulatory BP (8%). In multivariable analysis, masked (odds ratio 4.1) and confirmed (odds ratio 4.3) hypertension were the strongest independent predictors of LVH. In conclusion, casual BP measurements alone are insufficient to predict the presence of LVH in children with CKD. The high prevalence of masked hypertension and its association with LVH supports early echocardiography and ambulatory BP monitoring to evaluate cardiovascular risk in children with CKD.

A 3-year-old girl with Alport syndrome presented with decompensated heart failure from hypertension-induced cardiomyopathy 6 months following renal biopsy. Selective renal angiography revealed a large left renal arteriovenous fistula (AVF) with poor perfusion to the left renal parenchyma. The AVF was treated by transcatheter embolization using an Amplatzer vascular plug. Her blood pressure normalized after embolization, and her cardiac function normalized over the following 4 months.

A 12-month-old boy and his 16-year-old aunt became acutely ill 6 months apart and were diagnosed to have atypical hemolytic uremic syndrome (aHUS). Genetic analysis revealed heterozygous R1215Q mutation in complement factor H (CFH) in both patients. The same mutation was found in five healthy adult relatives indicating incomplete penetrance of the disease. The patients developed terminal renal failure and experienced reversible neurological symptoms in spite of plasma exchange (PE) therapy. In both cases, liver-kidney transplantation was successfully performed 6 months after the onset of the disease. To minimize complement activation and prevent thrombotic microangiopathy or overt thrombotic events due to the malfunctioning CFH, extensive PE with fresh frozen plasma was performed pre- and perioperatively and anticoagulation was started a few hours after the operation. No circulatory complications appeared and all four grafts started to function immediately. Also, no recurrence or other major clinical setbacks have appeared during the postoperative follow-up (15 and 9 months) and the grafts show excellent function. While more experience is needed, it seems that liver-kidney transplantation combined with pre- and perioperative PE is a rational option in the management of patients with aHUS caused by CFH mutation. © 2008 The Authors.

Introduction Medical student clerkships are designed to provide students with an opportunity to develop a critical, problem-oriented approach to patient care. Given the time constraints of traditional medical student clerkships, it is not feasible during a short clinical rotation to expose students to all of the pathologic entities within a particular discipline. This is especially true at multiple, often distant clinical sites with varied patient populations. Methods To address this in Pediatrics, we created a series of web-supported case seminars to review a variety of common problems. The teaching cases for the core Pediatric Clerkship are based on the Council on Medical Student Education in Pediatrics Curriculum. Each case is organized to include case objectives, suggested references, a case presentation, and guiding questions. Students prepare for teaching sessions by reviewing the case's objectives, patient presentation, and guiding questions on-line. Seminar sessions use these cases for the review of the clinical approach to patients, organization of data, generation of a differential diagnosis, and management for a variety of pediatric conditions. Sessions are entirely small-group, interactive, and case-based. The curriculum is web-supported and uses multimedia resources to ensure that the cases are standardized and can be delivered efficiently across multiple and distant clinical sites. Results Their quality and presentation have been assessed using anonymous, written evaluations by each student. Responses to this method of teaching have been extremely positive. Students have reported that the teaching is of high caliber and that the topics are high yield. They were also impressed by both the format and the level of interactivity of the sessions. Discussion The cases have now been used as the primary teaching tool in the Pediatric Clerkship for four years. They are continually being refined to incorporate contemporary medical topics and further address LCME mandates.

A male child initially presented with atypical hemolytic uremic syndrome (HUS) at the age of 4 months and progressed within weeks to end stage renal disease (ESRD). At the age of 2 years he received a live-related kidney transplant from his mother, which, despite initial good function, was lost to recurrent disease after 2 weeks. Complement factor H analysis showed low serum levels and the presence of two mutations on different alleles (c.2918G > A, Cys973Tyr and c.3590T > C, Val1197Ala). His survival on dialysis was at risk because of access failure and recurrent bacteremic episodes. Therefore, at the age of 5 years he received a combined liver-kidney transplant with pre-operative plasma exchange. Initial function of both grafts was excellent and this has been maintained for over 2 years. This report suggests that despite setbacks in previous experience, combined liver-kidney transplantation offers the prospect of a favorable long-term outcome for patients with HUS associated with complement factor H mutations.

Dyslipidemia increases the risk of cardiovascular events among individuals with renal disease, and there is a growing body of evidence that it hastens the progression of renal disease itself. Children with nephrotic syndrome or renal transplants have easily recognized hyperlipidemia. Among those with chronic renal insufficiency or end-stage renal disease, detection of dyslipidemia requires more careful analysis and knowledge of normal pediatric ranges. Disordered lipoprotein metabolism results from complex interactions among many factors, including the primary disease process, use of medications such as corticosteroids, the presence of malnutrition or obesity, and diet. The systematic treatment of dyslipidemia in children with chronic renal disease is controversial because conclusive data regarding the risks and benefits are lacking. Hepatic 3-methylglutaryl coenzyme A reductase inhibitors (statins), fibrates, plant stanols, bile acid-binding resins, and dietary manipulation are options for individualized treatment. Prospective investigations are required to guide clinical management.

Three neonates presented with malignant hypertension during the first week of life; 2 of them had congestive heart failure. Although none had indwelling umbilical artery catheters, unilateral renovascular lesions were diagnosed by nuclear perfusion scans. Angiotensin-converting enzyme inhibitor therapy produced rapid recovery. Hypertension must be included in the differential diagnosis of infants presenting with congestive heart failure and acidosis. Ultrasonography is not sensitive enough to exclude renovascular lesions. We emphasize the importance of early diagnosis and treatment.