De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

Over Three Decades of Growth Hormone Treatment in Children With Chronic Kidney Disease-Associated Growth Failure Before and After Kidney Transplantation.

BACKGROUND: Growth retardation and short final height is a common complication of chronic kidney disease (CKD) beginning in childhood, with profound deleterious effects on quality of life, mental health, and social achievement. Despite optimal treatments of causative factors for growth retardation in children with CKD, more than 50% of patients reach end-stage renal failure with a height >2 SD below the mean, and most do not demonstrate "catch-up" growth after receiving a kidney transplant. Four decades ago, recombinant human growth hormone (rhGH) treatment was introduced after studies showed increased growth velocity and improved height SDS in uremic subjects. Since then, an abundance of published data showed significant improvements in health-related quality of life, and most studies revealed no significant adverse effects. Clinical practice guidelines recommended rhGH treatment in CKD Stages 3-5D and after transplantation. Despite these guidelines, this therapy remained underutilized. Most commonly cited barriers to the implementation of rhGH treatment were the need for daily injections, financial challenges, physicians' unfamiliarity with guidelines, and fear of adverse events. CONCLUSIONS: rhGH has been shown to improve growth and final height in short children with CKD, with minimal adverse effects. Despite data of its successful use generated over 3 decades, this treatment is underutilized. More judicious utilization of the treatment should emphasize educating patients, their care givers, and members of the multidisciplinary treating team. Additional studies are needed to assess the longer-term rhGH treatment in larger cohorts of patients, leading to additional supportive data and clearer recommendations.

Patient-Reported Outcomes Over 24 Months in Pediatric CKD: Findings From the MyKidneyHealth Cohort Study.

RATIONALE & OBJECTIVE: The lived experience of children with chronic kidney disease (CKD) is poorly characterized. We examined the associations between patient-reported outcome (PRO) scores measuring their fatigue, sleep health, psychological distress, family relationships, and global health with clinical outcomes over time in children, adolescents, and younger adults with CKD and investigated how the PRO scores of this group compare with those of other children, adolescents, and younger adults. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 212 children, adolescentss, and adults aged 8 to 21 years with CKD and their parents recruited from 16 nephrology programs across North America. PREDICTORS: CKD stage, disease etiology, and sociodemographic and clinical variables. OUTCOME: PRO scores over 2 years. ANALYTICAL APPROACH: We compared PRO scores in the CKD sample with a nationally representative general pediatric population (ages 8 to 17 years). Change of PROs over time and association of sociodemographic and clinical variables with PROs were assessed using multivariable regression models. RESULTS: For all time points, 84% of the parents and 77% of the children, adolescents, and younger adults completed PRO surveys . The baseline PRO scores for the participants with CKD revealed a higher burden of fatigue, sleep-related impairment, psychological distress, impaired global health, and poorer family relationships compared with the general pediatric population, with median score differences≥1 SD for fatigue and global health. The baseline PRO scores did not differ by CKD stage or glomerular versus nonglomerular etiology. Over 2 years, PROs were stable with a<1-point annual change on average on each measure and intraclass correlation coefficients ranging from 0.53 to 0.79, indicating high stability. Hospitalization and parent-reported sleep problems were associated with worse fatigue, psychological health, and global health scores (all P<0.04). LIMITATIONS: We were unable to assess responsiveness to change with dialysis or transplant. CONCLUSIONS: Children with CKD experience a high yet stable burden of impairment across numerous PRO measures, especially fatigue and global health, independent of disease severity. These findings underscore the importance of assessing PROs, including fatigue and sleep measures, in this vulnerable population. PLAIN-LANGUAGE SUMMARY: Children with chronic kidney disease (CKD) have many treatment demands and experience many systemic effects. How CKD impacts the daily life of a child is poorly understood. We surveyed 212 children, adolescents, and younger adults with CKD and their parents over 24 months to assess the participants' well-being over time. Among children, adolescents, and younger adults with CKD we found a very high and persistent burden of psychological distress that did not differ by degree of CKD or type of kidney disease. The participants with CKD endorsed greater impairment in fatigue and global health compared with healthy children, adolescents, and younger adults, and parent-reported sleep problems were associated with poorer patient-reported outcome (PRO) scores across all domains. These findings emphasize the importance of including PRO measures, including fatigue and sleep measures, into routine clinical care to optimize the lived experience of children with CKD.

Racial-ethnic diversity in ambulatory blood pressure monitoring in children with chronic kidney disease.

BACKGROUND: Black adults with chronic kidney disease (CKD) have higher rates of hypertension as compared to White adults with CKD. Little is known of how race and ethnicity associate with the prevalence of hypertension in pediatric CKD patients. The aim was to compare ambulatory blood pressure monitoring (ABPM) results for patients with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study across racial-ethnic groups. METHODS: Patients from the CKiD study who identified as non-Hispanic White, non-Hispanic Black, or Hispanic were included to analyze differences in ABPM results across these racial-ethnic groups. The outcomes were fitted using 3 progressively adjusted models. RESULTS: This study included 501 CKiD participants with at least one successful ABPM study. Compared to White participants, Black participants had 4.2 mmHg higher mean sleep systolic blood pressure and 2.7 mmHg higher mean sleep diastolic blood pressure (p = 0.001 and p = 0.004, respectively). Additionally, Black participants had higher odds of abnormal wake systolic load (OR 1.88, 1.21-2.91, p = 0.005), wake diastolic load (OR 1.68, 1.03-2.73, p = 0.04), sleep systolic load (OR 2.19, 1.36-3.5, p = 0.001), sleep diastolic load (OR 2.01, 1.28-3.15, p = 0.002), systolic non-dipping (OR 2.02, 1.31-3.10, p = 0.001), and diastolic non-dipping (OR 2.69, 1.60-4.51, p < 0.001). Compared to White participants, Hispanic participants demonstrated only a lower sleep diastolic load (OR 0.54, 0.31-0.95, p = 0.03). CONCLUSIONS: Black children with CKD have higher absolute nocturnal blood pressures and higher rates of abnormal dipping. Further studies are needed to determine the etiology of these differences and the clinical implications of racial-ethnic differences in ABPM outcomes within the pediatric CKD population. A higher resolution version of the Graphical abstract is available as Supplementary information.

AT1R Activating Autoantibodies in Hematopoietic Stem Cell Transplantation.

Angiotensin II type 1 receptor activating autoantibodies (AT1R-AAs) have gained attention in solid organ transplant as non-HLA antibodies associated with rejection, vasculopathy, and graft dysfunction. These antibodies have also been reported in the context of pre-eclampsia, scleroderma, and isolated hypertension. Here, we present 3 post-hematopoietic stem cell transplant (HSCT) cases with patients demonstrating elevated levels of AT1R-AAs detected within the first year post-HSCT. All patients had hypertension, and 2 patients exhibited profound diarrhea and hypokalemia. The hypertension, in all cases, was refractory to multiple classes of antihypertensives. Upon autoantibody identification, an angiotensin receptor blocker, losartan, was promptly initiated, and all patients showed blood pressure improvement. The 2 patients with electrolyte disturbances had rapid normalization of these levels and resolution of the diarrhea. These cases demonstrate a previously unreported association of elevated AT1R-AA levels in post-HSCT patients with a rapid response to angiotensin receptor blockade initiation.

Impaired osteocyte maturation in the pathogenesis of renal osteodystrophy.

Pediatric renal osteodystrophy is characterized by skeletal mineralization defects, but the role of osteoblast and osteocyte maturation in the pathogenesis of these defects is unknown. We evaluated markers of osteocyte maturation and programmed cell death in iliac crest biopsy samples from pediatric dialysis patients and healthy controls. We evaluated the relationship between numbers of fibroblast growth factor 23 (FGF23)-expressing osteocytes and histomorphometric parameters of skeletal mineralization. We confirmed that chronic kidney disease (CKD) causes intrinsic changes in bone cell maturation using an in vitro model of primary osteoblasts from patients with CKD and healthy controls. FGF23 co-localized with the early osteocyte marker E11/gp38, suggesting that FGF23 is a marker of early osteocyte maturation. Increased numbers of early osteocytes and decreased osteocyte apoptosis characterized CKD bone. Numbers of FGF23-expressing osteocytes were highest in patients with preserved skeletal mineralization indices, and packets of matrix surrounding FGF23-expressing osteocytes appeared to have entered secondary mineralization. Primary osteoblasts from patients with CKD retained impaired maturation and mineralization characteristics in vitro. Addition of FGF23 did not affect primary osteoblast mineralization. Thus, CKD is associated with intrinsic changes in osteoblast and osteocyte maturation, and FGF23 appears to mark a relatively early stage in osteocyte maturation. Improved control of renal osteodystrophy and FGF23 excess will require further investigation into the pathogenesis of CKD-mediated osteoblast and osteocyte maturation failure.

A biphasic dialytic strategy for the treatment of neonatal hyperammonemia.

BACKGROUND: Neonates with inborn errors of metabolism (IEM) often develop hyperammonemia which, if not corrected quickly, may result in poor neurologic outcomes. As pharmacologic therapy cannot rapidly lower ammonia levels, dialysis is frequently required. Both hemodialysis (HD) and standard-dose continuous renal replacement therapy (CRRT) are effective; however, HD may be followed by post-dialytic ammonia rebound, and standard-dose CRRT may not effect a rapid enough decrease in ammonia levels. CASE-DIAGNOSIS/TREATMENT: We present two cases of IEM-associated neonatal hyperammonemia in which we employed a biphasic, high-dose CRRT treatment strategy, initially using dialysate flow rates of 5,000 mL/h (approximately 40,000 mL/h/1.73 m(2)) in order to rapidly decrease ammonia levels, then decreasing the dialysate flow rates to 500 mL/h (approximately 4,000 mL/h/1.73 m(2)) in order to prevent ammonia rebound. CONCLUSIONS: This biphasic dialytic treatment strategy for neonatal hyperammonemia effected rapid ammonia reduction without rebound and accomplished during a single dialysis run without equipment changes.

Growth in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children Study.

BACKGROUND: Growth failure is common among children with chronic kidney disease (CKD). We examined the relationship of growth parameters with glomerular filtration rate (GFR), CKD diagnosis, sex and laboratory results in children with CKD. METHODS: Baseline data from 799 children (median age 11.0 years, median GFR 49.9 mL/min/1.73 m(2)) participating in the Chronic Kidney Disease in Children Study were examined. Growth was quantified by age-sex-specific height, weight, body mass index (BMI-age), and height-age-sex-specific BMI (BMI-height-age) standard deviation scores (SDS). RESULTS: Median height and weight SDS were -0.55 [interquartile range (IQR) -1.35 to 0.19] and 0.03 (IQR -0.82 to 0.97), respectively. Girls with non-glomerular CKD were the shortest (median height SDS -0.83; IQR -1.62 to -0.02). Compared to those with a serum bicarbonate (CO2) level of ≥ 22 mEq/L, children with CO2 of <18 mEq/L had a height SDS that was on average 0.67 lower [95 % confidence interval (CI) -0.31 to -1.03]. Only 23 % of children with a height SDS of ≤-1.88 were prescribed growth hormone therapy. Forty-six percent of children with glomerular CKD were overweight or obese (BMI-height-age ≥ 85th percentile). CONCLUSIONS: Growth outcomes in a contemporary cohort of children with CKD remain suboptimal. Interventions targeting metabolic acidosis and overcoming barriers to recombinant human growth hormone usage may improve growth in this population.

The impact of short stature on health-related quality of life in children with chronic kidney disease.

OBJECTIVES: To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) and short stature (SS) with that of children with CKD and normal height (NH), to evaluate the impact of catch-up growth and growth hormone (GH) use on HRQoL, and to describe the concordance of perceptions of HRQoL between children with SS and NH and their parents. STUDY DESIGN: Four hundred eighty-three children and/or parents enrolled in the multicenter Chronic Kidney Disease in Children study who had completed the Pediatric Quality of Life Inventory (Version 4.0) on at least 2 Chronic Kidney Disease in Children study visits composed this substudy population. Participants were dichotomized into NH or SS groups. The demographic characteristics that varied at baseline (sex, glomerular filtration rate, and parent education) were controlled for in the main analysis evaluating the impact of catch-up growth and use of GH on HRQoL. RESULTS: Multivariate modeling (controlling for confounding variables) revealed a significant association between both catch-up growth and GH use on parent-proxy reports of child physical functioning (P < .05) and social functioning (P < .05). Older children with CKD (15-17 years old) had significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children (8-14 years old). CONCLUSION: The finding that height gains and GH use are associated with increases in physical and social functioning by parent report provides additional support for interventions to improve height in children with CKD. The importance of evaluating both the parent and child perceptions of HRQoL is supported by our results.

Hemoglobin differences by race in children with CKD.

BACKGROUND: There are known racial disparities in the prevalence of anemia in adults with chronic kidney disease (CKD), but these differences have not been well described in children. STUDY DESIGN: Cohort study, cross-sectional analysis. SETTING & PARTICIPANTS: The Chronic Kidney Disease in Children (CKiD) Study is a multicenter prospective cohort study of children with mild to moderate CKD. This analysis included 429 children of African American or white race. PREDICTOR: Race. OUTCOMES & MEASUREMENTS: This study examined the association of race with hemoglobin level. Both multiple linear regression and generalized gamma modeling techniques were used to characterize the association between race and hemoglobin level. RESULTS: 79% of the cohort was white, 21% was African American. Neither median hemoglobin level nor frequency of erythropoiesis-stimulating agent use differed by race. In multivariate analysis, lower levels of iohexol-measured glomerular filtration rate, African American race, and glomerular disease (vs nonglomerular disease) as the underlying cause of CKD were independently associated with decreased hemoglobin levels; independent of glomerular filtration rate and CKD diagnosis, African American children had average hemoglobin levels that were 0.6 g/dL (95% CI, -0.9 to -0.2 g/dL) lower than those of white children. Generalized gamma modeling showed that differences in hemoglobin levels observed by race become more pronounced when moving from high to low in the overall hemoglobin level distribution. LIMITATIONS: Cross-sectional analysis cannot establish causality, and data for iron stores were not available for all patients. CONCLUSIONS: African American compared with white children have lower hemoglobin values in CKD independent of the underlying cause of CKD. These racial differences in hemoglobin levels appear to increase at the lower end of the hemoglobin level distribution in this population.

Adrenocorticotropic Hormone for Childhood Nephrotic Syndrome: The ATLANTIS Randomized Trial.

BACKGROUND AND OBJECTIVES: There is renewed interest in adrenocorticotropic hormone (ACTH) for the treatment of nephrotic syndrome. We evaluated the efficacy and safety of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome in a randomized trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants aged 2-20 years old with frequently relapsing or steroid-dependent nephrotic syndrome were enrolled from 16 sites in the United States and randomized 1:1 to ACTH (repository corticotropin injection) or no relapse-preventing treatment. ACTH treatment regimen was 80 U/1.73 m2 administered twice weekly for 6 months, followed by 40 U/1.73 m2 administered twice weekly for 6 months. The primary outcome was disease relapse during the first 6 months. Participants in the control group were offered crossover to ACTH treatment if they relapsed within 6 months. Secondary outcomes were relapse after ACTH dose reduction and treatment side effects. RESULTS: The trial was stopped at a preplanned interim analysis after enrollment of 31 participants because of a lack of discernible treatment efficacy. Fourteen out of 15 (93%) participants in the ACTH arm experienced disease relapse in the first 6 months, with a median time to first relapse of 23 days (interquartile range, 9-32), compared with 15 out of 16 (94%) participants and at a median of 21 days (interquartile range, 14-51) in the control group. There was no difference in the proportion of relapsed patients (odds ratio, 0.93; 95% confidence interval, 0.05 to 16.40; P>0.99) or time to first relapse (hazard ratio, 1.03; 95% confidence interval, 0.50 to 2.15; P=0.93). Thirteen out of 16 participants in the control group crossed over to ACTH treatment. Three out of 28 participants completed 12 months of ACTH treatment; the others exited the trial because of frequent relapses or side effects. There were no disease relapses after ACTH dose reduction among the three participants. Most side effects were mild and similar to side effects of corticosteroids. CONCLUSIONS: ACTH at 80 U/1.73 m2 administered twice weekly was ineffective at preventing disease relapses in pediatric nephrotic syndrome.

Early skeletal and biochemical alterations in pediatric chronic kidney disease.

BACKGROUND AND OBJECTIVES: The relationship between parathyroid hormone, fibroblast growth factor 23 (FGF-23), and indices of bone turnover and mineralization in children with early CKD is unknown; thus, this study characterizes the features of renal osteodystrophy and their relationship to biochemical markers of mineral metabolism. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-two patients 2-21 years of age with predialysis CKD underwent tetracycline-labeled bone biopsy. Anthropomorphic measurements and biochemical values were obtained at the time of biopsy. RESULTS: Serum phosphorus levels were increased in 4% of patients with stage 3 CKD and 43% of those with stage 4/5 CKD. Parathyroid hormone concentrations were elevated in 36% of patients with stage 2, 71% with stage 3, and 93% with stage 4/5 CKD, whereas FGF-23 values were elevated in 81% of all patients, regardless of CKD stage. Bone turnover was normal in all patients with stage 2, but was increased in 13% with stage 3 and 29% with stage 4/5 CKD. Defective mineralization was present in 29% of patients with stage 2, 42% with stage 3, and 79% with stage 4/5 CKD. Defective skeletal mineralization was associated with lower serum calcium levels and increased parathyroid hormone concentrations. CONCLUSIONS: Elevated circulating FGF-23 levels and defects in skeletal mineralization early in the course of CKD suggest that factors other than the traditional markers of mineral deficiency play a crucial role in the development of renal bone disease.

Patterns of FGF-23, DMP1, and MEPE expression in patients with chronic kidney disease.

Fibroblast growth factor 23 (FGF-23), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) are skeletal proteins involved in the regulation of phosphate homeostasis and bone metabolism. Circulating FGF-23 levels are increased in patients with chronic kidney disease (CKD); however, FGF-23 skeletal expression and its regulation by DMP1 and MEPE have yet to be evaluated. Thus, expression of these three proteins was characterized by immunohistochemistry in 32 pediatric and young adult patients with CKD stages 2-5. When compared to normal controls, bone FGF-23 and DMP1 expression were increased in all stages of CKD; significant differences in bone FGF-23 and DMP1 expression were not detected between pre-dialysis CKD and dialysis patients. Bone MEPE expression in CKD did not differ from controls. FGF-23 was expressed in osteocyte cell bodies located at the trabecular periphery. DMP1 was widely expressed in osteocyte cell bodies and dendrites throughout bone. MEPE was also expressed throughout bone, but only in osteocyte cell bodies. Bone FGF-23 expression correlated directly with plasma levels of the protein (r=0.43, p<0.01) and with bone DMP1 expression (r=0.54, p<0.01) and expression of both proteins were inversely related to osteoid accumulation. Bone MEPE expression was inversely related to bone volume. In conclusion, skeletal FGF-23 and DMP1 expression are increased in CKD and are related to skeletal mineralization. The patterns of expression of FGF-23, MEPE, and DMP1 differ markedly in trabecular bone, suggesting that individual osteocytes may have specialized functions. Increases in bone FGF-23 and DMP1 expression suggest that osteocyte function is altered early in the course of CKD.

Type III mixed cryoglobulinemia and antiphospholipid syndrome in a patient with partial DiGeorge syndrome.

We studied a 14 year-old boy with partial DiGeorge syndrome (DGS), status post complete repair of Tetralogy of Fallot, who developed antiphospholipid syndrome (APS) and type III mixed cryoglobulinemia. He presented with recurrent fever and dyspnea upon exertion secondary to right pulmonary embolus on chest computed tomography (CT). Coagulation studies revealed homozygous methylene tetrahydrofolate reductase 677TT mutations, elevated cardiolipin IgM antibodies, and elevated beta(2)-glycoprotein I IgM antibodies. Infectious work-up revealed only positive anti-streptolysin O (ASO) and anti-DNAse B titers. Autoimmune studies showed strongly positive anti-platelet IgM, elevated rheumatoid factor (RF), and positive cryocrit. Renal biopsy for evaluation of proteinuria and hematuria showed diffuse proliferative glomerulonephritis (DPGN) with membranoproliferative features consistent with cryoglobulinemia. Immunofixation showed polyclonal bands. Our patient was treated successfully with antibiotics, prednisone, and mycophenolate mofetil (MMF). This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection.

Hypertension in hypophosphatemic rickets--role of secondary hyperparathyroidism.

Hypertension has been anecdotally reported in children with familial hypophosphatemic rickets (XLH). To better identify and characterize the clinical and laboratory features of hypertensive XLH children, we reviewed the medical records of 41 XLH children, all treated with phosphate and vitamin D analogues. Eight children, who were originally normotensive, developed hypertension during the 2nd decade of life. At diagnosis of hypertension all had persistent secondary/tertiary hyperparathyroidism (HPTD), defined as high serum parathyroid hormone (PTH) for 12 months or longer. Seven had nephrocalcinosis (NC). Analysis of data showed that of 11 children with HPTD, 8 developed hypertension compared with 0 among 30 without HPTD (P<0.001). Of 40 children studied, 18 had NC that was significantly associated with both HPTD (P<0.01) and hypertension (P<0.025). At diagnosis of hypertension, serum calcium was elevated in 2. Plasma renin activity was high in 3 of 4 patients in whom it was measured. Doppler ultrasonography or renal scan was normal in the 5 children studied. Early echocardiography showed left ventricular hypertrophy in only 2 of 5 children studied. In 3 patients who underwent parathyroidectomy, hypertension persisted and 1 progressed to renal failure. Serum creatinine remained normal in all others. Successful treatment of hypertension consisted of beta-adrenergic blockers, angiotensin converting enzyme inhibitors, and Ca channel blockers as monotherapy or in combination. We conclude that hypertension in treated XLH children is closely associated with HPTD. Emphasis should therefore be placed on prevention of the development of HPTD as a complication of XLH treatment, and close monitoring for hypertension in those who do develop HPTD.