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.

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.).

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.

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.

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.

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.

KDOQI US commentary on the 2013 KDIGO Clinical Practice Guideline for Lipid Management in CKD.

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.

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.

The kidney in pediatric liver transplantation: an updated perspective.

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.

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.

Methods for characterizing differences in longitudinal glomerular filtration rate changes between children with glomerular chronic kidney disease and those with nonglomerular chronic kidney disease.

The rate of decline of glomerular filtration rate (GFR) in children with chronic kidney disease (CKD) can vary, even among those with similar diagnoses. Classic regression methods applied to the log-transformed GFR (i.e., lognormal) quantify only rigid shifts in a given outcome. The generalized gamma distribution offers an alternative approach for characterizing the heterogeneity of effect of an exposure on a positive, continuous outcome. Using directly measured GFR longitudinally assessed between 2005 and 2010 in 529 children enrolled in the Chronic Kidney Disease in Children Study, the authors characterized the effect of glomerular CKD versus nonglomerular CKD diagnoses on the outcome, measured as the annualized GFR ratio. Relative percentiles were used to characterize the heterogeneity of effect of CKD diagnosis across the distribution of the outcome. The rigid shift assumed by the classic mixed models failed to capture the fact that the greatest difference between the glomerular and nonglomerular diagnosis' annualized GFR ratios was in children who exhibited the fastest GFR declines. Although this difference was enhanced in children with an initial GFR level of 45 mL/minute/1.73 m(2) or less, the effect of diagnosis on outcome was not significantly modified by level. Generalized gamma models captured heterogeneity of effect more richly and provided a better fit to the data than did conventional lognormal models.

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.

Dyslipidemia in children with chronic kidney disease.

Dyslipidemia, a known risk factor for atherosclerosis, is frequent among both adults and children with chronic kidney disease. Here, we describe the prevalence and pattern of dyslipidemia from a cross-sectional analysis of 391 children aged 1-16 years, enrolled in the multicenter Chronic Kidney Disease in Children (CKiD) study, with a median glomerular filtration rate (GFR), measured by the plasma disappearance of iohexol, of 43 ml/min per 1.73 m2. Multivariate analysis was applied to adjust for age, gender, body mass index (BMI), GFR, and the urinary protein/creatinine ratio. Proteinuria was in the nephrotic range in 44 and the BMI exceeded the 95th percentile in 57 patients of this cohort. Baseline lipid analysis found a high prevalence of hypertriglyceridemia in 126, increased non-HDL-C in 62, and reduced HDL-C in 83. Overall, 177 children had dyslipidemia, of whom 79 had combined dyslipidemia. Lower GFR was associated with higher triglycerides, lower HDL-C, and higher non-HDL-C. Nephrotic-range proteinuria was significantly associated with dyslipidemia and combined dyslipidemia. Compared with children with a GFR>50, children with a GFR<30 had significantly increased odds ratios for any dyslipidemia or for combined dyslipidemia. Hence, among children with moderate chronic kidney disease, dyslipidemia is common and is associated with lower GFR, nephrotic proteinuria, and non-renal factors including age and obesity.

Liver-kidney transplantation to cure atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome is often associated with mutations in genes encoding complement regulatory proteins and secondary disorders of complement regulation. Progression to kidney failure and recurrence with graft loss after kidney transplantation are frequent. The most common mutation is in the gene encoding complement factor H. Combined liver-kidney transplantation may correct this complement abnormality and prevent recurrence when the defect involves genes encoding circulating proteins that are synthesized in the liver, such as factor H or I. Good outcomes have been reported when surgery is associated with intensified plasma therapy. A consensus conference to establish treatment guidelines for atypical hemolytic uremic syndrome was held in Bergamo in December 2007. The recommendations in this article are the result of combined clinical experience, shared research expertise, and a review of the literature and registry information. This statement defines groups in which isolated kidney transplantation is extremely unlikely to be successful and a combined liver-kidney transplant is recommended and also defines those for whom kidney transplant remains a viable option. Although combined liver-kidney or isolated liver transplantation is the preferred therapeutic option in many cases, the gravity of risk associated with the procedure has not been eliminated completely, and assessment of risk and benefit requires careful and individual attention.

Postrenal biopsy AVM leading to severe hypertension and dilated cardiomyopathy.

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 position statement on kidney disease from powdered infant formula-based melamine exposure in Chinese infants.

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.