Primary Hyperoxaluria

Primary hyperoxalurias (PH) are inborn errors in the metabolism of glyoxylate and oxalate. PH type 1, the most common form, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine, glyoxylate aminotransferase (AGT) resulting in overproduction and excessive urinary excretion of oxalate. Recurrent urolithiasis and nephrocalcinosis are the hallmarks of the disease. As glomerular filtration rate decreases due to progressive renal damage, oxalate accumulates leading to systemic oxalosis. Diagnosis is often delayed and is based on clinical and sonographic findings, urinary oxalate assessment, DNA analysis, and, if necessary, direct AGT activity measurement in liver biopsy tissue. Early initiation of conservative treatment, including high fluid intake, inhibitors of calcium oxalate crystallization, and pyridoxine in responsive cases, can help to maintain renal function in compliant subjects. In end-stage renal disease patients, the best outcomes have been achieved with combined liver-kidney transplantation which corrects the enzyme defect

Hyperparathyroidism Is an Independent Risk Factor for Allograft Dysfunction in Pediatric Kidney Transplantation

Allograft outcome; Hyperparathyroidism; Kidney transplantationResultado del aloinjerto; Hiperparatiroidismo; Trasplante de riñónResultat de l'aloempelt; Hiperparatiroïdisme; Trasplantament de ronyóIntroduction Little is known about the consequences of deranged chronic kidney disease–mineral and bone disorder (CKD-MBD) parameters on kidney allograft function in children. We examined a relationship between these parameters over time and allograft outcome. Methods This registry study from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) collected data at baseline, months 1, 3, 6, 9, and 12 after transplant; and every 6 months thereafter up to 5 years. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤30 ml/min per 1.73 m2 or a ≥50% decline from eGFR at month 1 posttransplant was performed. Associations of parathyroid hormone (PTH), calcium, phosphate, and 25-hydroxyvitamin D (25(OH)D) with allograft outcome were investigated using conventional stratified Cox proportional hazards models and further verified with marginal structural models with time-varying covariates. Results We report on 1210 patients (61% boys) from 16 European countries. The composite end point was reached in 250 grafts (21%), of which 11 (4%) were allograft losses. In the conventional Cox proportional hazards models adjusted for potential confounders, only hyperparathyroidism (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.82–4.74) and hyperphosphatemia (HR, 1.94; 95% CI, 1.28–2.92) were associated with the composite end point. Marginal structural models showed similar results for hyperparathyroidism (HR, 2.74; 95% CI, 1.71–4.38), whereas hyperphosphatemia was no longer significant (HR, 1.35; 95% CI, 0.87–2.09), suggesting that its association with graft dysfunction can be ascribed to a decline in eGFR. Conclusion Hyperparathyroidism is a potential independent risk factor for allograft dysfunction in children.This study was supported by a research grant from the European Society for Paediatric Nephrology to AP. The authors gratefully acknowledge the funding of the Cooperative European Paediatric Renal Transplant Initiative Registry by a grant from the Dietmar Hopp Stiftung, the European Society for Paediatric Nephrology, and the German Society for Paediatric Nephrology and by grants from the pharmaceutical companies Astellas and Novartis

Inherited renal tubular dysgenesis: the first patients surviving the neonatal period

Renal tubular dysgenesis (RTD) is a clinical disorder either acquired during fetal development or inherited as an autosomal recessive condition. Inherited RTD is caused by mutations in the genes encoding the components of the renin-angiotensin system angiotensinogen, renin, angiotensin-converting enzyme and angiotensin II receptor type 1. Inherited RTD is characterized by early onset oligohydramnios, skull ossification defects, preterm birth and neonatal pulmonary and renal failure. The histological hallmark is the absence or poor development of proximal tubules. So far, all patients died either in utero or shortly after birth. We report the first patients with inherited RTD surviving the neonatal period and still being alive. Genetic and functional analysis of the renin-angiotensin system contributes to the diagnosis of RTD. In conclusion, the clinical diagnosis of inherited RTD is easily missed after birth without renal biopsy or information on affected family members. Genetic and functional analysis of the renin-angiotensin system contributes to correct diagnosi

Safety and Efficacy of Cinacalcet in Children Aged Under 3 Years on Maintenance Dialysis

Introduction: Secondary hyperparathyroidism (sHPT) is particularly severe in rapidly growing infants in dialysis. Although cinacalcet is effective and licensed in dialysis in children aged &gt;3 years, its efficacy and safety for children aged &lt;3 years is unknown. Methods: We identified 26 children aged &lt;3 years who were on dialysis and treated with cinacalcet between 2009 and 2021 in 8 European pediatric centers. Results: Median (interquartile range) age at the start of cinacalcet was 18 (interquartile range: 11–27) months, serum parathyroid hormone (PTH) was 792 (411–1397) pg/ml, corresponding to 11.6 (5.9–19.8) times the upper limit of normal (ULN). Serum calcium was 2.56 (2.43–2.75) mmol/l, and serum phosphate 1.47 (1.16–1.71) mmol/l. Serum 25-OH vitamin D (25–OHD) was 70 (60–89) nmol/l, 3 children were vitamin D deficient (&lt;50 nmol/l). The initial cinacalcet dose was 0.4 (0.2–0.8) mg/kg/d and the maximum dose was 1.1 (0.6–1.2) mg/kg/d. The median follow-up under cinacalcet was 1.2 (0.7–2.0) years. PTH decreased to 4.3 (2.2–7.8) times the ULN after 6 months, to 2.0 (1.0–5.3) times ULN after 12 months, and to 1.6 (0.5–3.4) times thereafter (P = 0.017/0.003/&lt;0.0001, log-transformed PTH). Seven of the 26 infants developed 10 hypocalcemic episodes &lt;2.10 mmol/l. Oral calcium intake was 84% (66%–117%) of recommended nutrient intake at start, 100% (64%–142%) at 3 months and declined to 78% (65%–102%) at 12 months of therapy. Three children developed clinical signs of precocious puberty.Conclusion: Cinacalcet efficiently controlled severe sHPT in children aged &lt;3 years and was associated with hypocalcemic episodes (similar to what is observed in older children) and precious puberty, thereby mandating meticulous control of calcium (considering nutrition, supplementation, and dialysate) and endocrine changes.</p

Safety and Efficacy of Cinacalcet in Children Aged Under 3 Years on Maintenance Dialysis

Introduction: Secondary hyperparathyroidism (sHPT) is particularly severe in rapidly growing infants in dialysis. Although cinacalcet is effective and licensed in dialysis in children aged &gt;3 years, its efficacy and safety for children aged &lt;3 years is unknown. Methods: We identified 26 children aged &lt;3 years who were on dialysis and treated with cinacalcet between 2009 and 2021 in 8 European pediatric centers. Results: Median (interquartile range) age at the start of cinacalcet was 18 (interquartile range: 11–27) months, serum parathyroid hormone (PTH) was 792 (411–1397) pg/ml, corresponding to 11.6 (5.9–19.8) times the upper limit of normal (ULN). Serum calcium was 2.56 (2.43–2.75) mmol/l, and serum phosphate 1.47 (1.16–1.71) mmol/l. Serum 25-OH vitamin D (25–OHD) was 70 (60–89) nmol/l, 3 children were vitamin D deficient (&lt;50 nmol/l). The initial cinacalcet dose was 0.4 (0.2–0.8) mg/kg/d and the maximum dose was 1.1 (0.6–1.2) mg/kg/d. The median follow-up under cinacalcet was 1.2 (0.7–2.0) years. PTH decreased to 4.3 (2.2–7.8) times the ULN after 6 months, to 2.0 (1.0–5.3) times ULN after 12 months, and to 1.6 (0.5–3.4) times thereafter (P = 0.017/0.003/&lt;0.0001, log-transformed PTH). Seven of the 26 infants developed 10 hypocalcemic episodes &lt;2.10 mmol/l. Oral calcium intake was 84% (66%–117%) of recommended nutrient intake at start, 100% (64%–142%) at 3 months and declined to 78% (65%–102%) at 12 months of therapy. Three children developed clinical signs of precocious puberty.Conclusion: Cinacalcet efficiently controlled severe sHPT in children aged &lt;3 years and was associated with hypocalcemic episodes (similar to what is observed in older children) and precious puberty, thereby mandating meticulous control of calcium (considering nutrition, supplementation, and dialysate) and endocrine changes.</p

An Expert Perspective on Phosphate Dysregulation With a Focus on Chronic Hypophosphatemia

Because of their rarity, diseases characterized by chronic hypophosphatemia can be underrecognized and suboptimally managed, resulting in poor clinical outcomes. Moreover, serum phosphate may not be measured routinely in primary care practice. Authors participated in several working sessions to advance the understanding of phosphate homeostasis and the causes, consequences, and clinical implications of chronic hypophosphatemia. Phosphate levels are regulated from birth to adulthood. Dysregulation of phosphate homeostasis can result in hypophosphatemia, which becomes chronic if phosphate levels cannot be normalized. Chronic hypophosphatemia may be underrecognized as serum phosphate measurement is not always part of routine analysis in the primary care setting and results might be misinterpreted, for instance, due to age-specific differences not being accounted for and circadian variations. Clinical consequences of chronic hypophosphatemia involve disordered endocrine regulation, affect multiple organ systems, and vary depending on patient age and the underlying disorder. Signs and symptoms of chronic hypophosphatemic diseases that manifest during childhood or adolescence persist into adulthood if the disease is inadequately managed, resulting in an accumulation of clinical deficits and a progressive, debilitating impact on quality of life. Early identification and diagnosis of patients with chronic hypophosphatemia is crucial, and clinical management should be started as soon as possible to maximize the likelihood of improving health outcomes. Furthermore, in the absence of a universally accepted description for "chronic hypophosphatemia," a definition is proposed here that aims to raise awareness of these diseases, facilitate diagnosis, and guide optimal phosphate management strategies by improving monitoring and assessment of patient response to treatment. (c) 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).Peer reviewe

Long-term outcomes of peritoneal dialysis started in infants below 6 months of age: An experience from two tertiary centres.

peer reviewedBACKGROUND: Little data are available for infants who started renal replacement therapy before 6 months of age. Because of extra-renal comorbidities and uncertain outcomes, whether renal replacement therapy in neonates is justified remains debatable. METHODS: We performed a retrospective analysis of all patients who began chronic peritoneal dialysis below 6 months between 2007 and 2017 in two tertiary centres. Results are presented as median (min;max). RESULTS: Seventeen patients (10 boys) were included (8 prenatal diagnoses, 6 premies), with the following diagnoses: congenital anomalies of kidney and urinary tract (n=9), oxalosis (n=5), congenital nephrotic syndrome (n=2) and renal vein thrombosis (n=1). Five patients had associated comorbidities. At peritoneal dialysis initiation, age was 2.6 (0.1;5.9) months, height-standard deviation score (SDS) -1.3 (-5.7;1.6) and weight-SDS -1.4 (-3.6;0.6). Peritoneal dialysis duration was 12 (2;32) months, and at peritoneal dialysis discontinuation height-SDS was -1.0 (-4.3;0.7) weight-SDS -0.7 (-3.2;0.2), parathyroid hormone 123 (44;1540) ng/L, and hemoglobin 110 (73;174) g/L. During the first 6 months of peritoneal dialysis, the median time of hospitalisation stay was 69 (15;182) days. Ten patients presented a total of 27 peritonitis episodes. Reasons for peritoneal dialysis discontinuation were switch to hemodialysis (n=6), transplantation (n=6), recovery of renal function (n=2) and death (n=1). After a follow-up of 4.3 (1.7;10.3) years, 12 patients were transplanted, 2 patients were still on peritoneal dialysis, 2 patients were dialysis free with severe chronic kidney disease and 1 patient had died. Seven patients displayed neurodevelopmental delay, of whom five needed special schooling. CONCLUSION: We confirm that most infants starting peritoneal dialysis before 6 months of age will be successfully transplanted and will have a favourable growth outcome. Their quality of life will be impacted by recurrent hospitalisations and neurodevelopmental delay is frequent

Knowledge and beliefs of endocrine disruptors in pediatrics: all hands on deck!

Endocrine disruptors (ED) are ubiquitous pollutants, possibly implicated in chronic disease. Exposure of vulnerable populations; including neonates, infants and children; must therefore be limited. Informing parents is now a public health challenge. We conducted a quantitative cross-sectional study at the Lyon Mother and child Hospital. We used questionnaires to assess the beliefs and knowledge about ED of parents and pediatric healthcare professionals in the pediatric ward in Lyon, France. A total of 746 questionnaires were completed: 444 for professionals and 302 for parents. The majority of both populations had already heard of ED but only 10% of parents and 5% of professionals felt sufficiently informed. Professionals answered better than parents (73% vs. 60%). The main source of information was similar: media. Only 20% of professionals had read a scientific article about ED and 4% have followed a training. Environmental exposure and EDs is an increasing concern for parents but specific knowledge remains scare for parents and professionals. Specific training is needed

Osteocalcin signaling in myofibers is necessary and sufficient for optimum adaptation to exercise

Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity