Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Background. The purpose of this study is to evaluate the effectiveness and safety of switching from immediate-release (IR) to extended-release (ER) cysteamine in patients with nephropathic cystinosis (NC) in Spain. Methods. We conducted an observational, retrospective, multicentre study in NC patients who received IR cysteamine for at least 12 months, switched to ER cysteamine, and received it for at least 6 months before inclusion. Results. Data were collected from nine patients (four children, five adults) 36 months before and after the switch. Despite the highly selected population, an improvement in growth, particularly in children and a significant reduction in hospitalization days was observed. A decrease in halitosis, body odour and gastrointestinal effects was reported in most of the patients who suffered before the switch, and the use of proton pump inhibitors (PPIs) decreased in some patients. The estimated glomerular filtration rate (eGFR) remained stable in patients with preserved kidney function. No significant changes in white blood cell (WBC) cystine levels were observed after the switch. There was no significant difference in the cysteamine dose received. However, some patients were receiving <50% of the recommended dose of cysteamine before and after the switch and showed elevated levels of WBC cystine. Conclusions. Switching from IR to ER cysteamine in clinical practice reduces hospital stays, improves nutritional status and growth in paediatric patients and could help to enhance treatment tolerability by reducing side effects. Furthermore, the dosing of ER cysteamine could promote therapeutic compliance and positively affect the quality of life of the NC population.

Bartter syndrome (BS) is a salt-losing hereditary tubulopathy characterized by hypokalemic metabolic alkalosis with secondary hyperaldosteronism. Confirmatory molecular diagnosis may be difficult due to genetic heterogeneity and overlapping of clinical symptoms. The aim of our study was to describe the different molecular findings in patients with a clinical diagnosis of classic BS. We included 27 patients (26 families) with no identified pathogenic variants in CLCNKB . We used a customized Ion AmpliSeq Next-Generation Sequencing panel including 44 genes related to renal tubulopathies. We detected pathogenic or likely pathogenic variants in 12 patients (44%), reaching a conclusive genetic diagnosis. Variants in SLC12A3 were found in 6 (Gitelman syndrome). Median age at diagnosis was 14.6 years (range 0.1–31), with no history of prematurity or polyhydramnios. Serum magnesium level was low in 2 patients (33%) but urinary calcium excretion was normal or low in all, with no nephrocalcinosis. Variants in SLC12A1 were found in 3 (BS type 1); and in KCNJ1 in 1 (BS type 2). These patients had a history of polyhydramnios in 3 (75%), and the mean gestational age was 34.2 weeks (SD 1.7). The median age at diagnosis was 1.8 years (range 0.1–6). Chronic kidney disease and nephrocalcinosis were present in 1 (25%) and 3 (75%) patients, respectively. A variant in CLCN5 was found in one patient (Dent disease), and in NR3C2 in another patient (Geller syndrome). Genetic diagnosis of BS is heterogeneous as different tubulopathies can present with a similar clinical picture. The use of gene panels in these diseases becomes more efficient than the study gene by gene with Sanger sequencing.

Background: An unbalanced dietary pattern, characterized by high animal protein content: may worsen metabolic control, accelerate renal deterioration and consequently aggravate the stage of the chronic kidney disease (CKD) in pediatric patients with this condition. Aim: to assess the effect of a registered dietitian (RD) intervention on the CKD children’s eating habits. Methods: Anthropometric and dietetic parameters, obtained at baseline and 12 months after implementing healthy eating and nutrition education sessions, were compared in 16 patients (50% girls) of 8.1 (1–15) years. On each occasion, anthropometry, 3-day food records and a food consumption frequency questionnaire were carried out. The corresponding relative intake of macro- and micronutrients was contrasted with the current advice by the European Food Safety Authority (EFSA) and with consumption data obtained using the Spanish dietary guidelines. Student’s paired t-test, Wilcoxon test and Mc Nemar test were used. Results: At Baseline 6% were overweight, 69% were of normal weight and 25% were underweight. Their diets were imbalanced in macronutrient composition. Following nutritional education and dietary intervention 63%, 75% and 56% met the Dietary Reference Values requirements for fats, carbohydrates and fiber, respectively, but not significantly. CKD children decreased protein intake (p < 0.001), increased dietary fiber intake at the expense of plant-based foods consumption (p < 0.001) and a corresponding reduction in meat, dairy and processed food intake was noticed. There were no changes in the medical treatment followed or in the progression of the stages. Conclusions: RD-led nutrition intervention focused on good dieting is a compelling helpful therapeutic tool to improve diet quality in pediatric CKD patients.

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone. X-linked hypophosphatemia (XLH) is the most prevalent inherited phosphate wasting disorder due to mutations in the PHEX gene, which cause elevated circulating FGF23 levels. Clinically, it is characterized by growth impairment and defective mineralization of bones and teeth. Treatment of XLH is challenging. Since 2018, neutralizing antibodies against FGF23 have dramatically improved the therapy of XLH patients, although not all patients fully respond to the treatment, and it is very costly. C-terminal fragments of FGF23 have recently emerged as blockers of intact FGF23 signaling. Here, we analyzed the effect on growth and bone of a short 26 residues long C-terminal FGF23 (cFGF23) fragment and two N-acetylated and C-amidated cFGF23 peptides using young XLH mice (Phex C733RMhda mice). Although no major changes in blood parameters were observed after 7 days of treatment with these peptides, bone length and growth plate structure improved. The modified peptides accelerated the growth rate probably by improving growth plate structure and dynamics. The processes of chondrocyte proliferation, death, hypertrophy, and the cartilaginous composition in the growth plate were partially improved in young treated XLH mice. In conclusion, these findings contribute to understand the role of FGF23 signaling in growth plate metabolism and show that this may occur despite continuous hypophosphatemia.

Given the relatively recent introduction of burosumab in the management of X-linked hypophosphatemia (XLH), there is limited real-world data to guide its use in clinical practice. As a group of European physicians experienced with burosumab treatment in clinical practice, we convened with the objective of sharing these practice-based insights on the use of burosumab in children and adolescents with XLH. We attended two virtual meetings, then discussed key questions via Within3, a virtual online platform. Points of discussion related to patient selection criteria, burosumab starting dose, dose titration and treatment monitoring. Our discussions revealed that criteria for selecting children with XLH varied across Europe from all children above 1 year to only children with overt rickets despite conventional treatment being eligible. We initiated burosumab dosing according to guidance in the Summary of Product Characteristics, an international consensus statement from 2019 and local country guidelines. Dose titration was primarily guided by serum phosphate levels, with some centers also using the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR). We monitored response to burosumab treatment clinically (growth, deformities, bone pain and physical functioning), radiologically (rickets and deformities) and biochemically (serum phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, urine calcium-creatinine ratio and TmP/GFR). Key suggestions made by our group were initiation of burosumab treatment in children as early as possible, from the age of 1 year, particularly in those with profound rickets, and a need for clinical studies on continuation of burosumab throughout adolescence and into adulthood.

Fibroblast growth factor 23 (FGF23) was identified at the turn of the century as the long-sought circulating phosphatonin in human pathology. Since then, several clinical and experimental studies have investigated the metabolism of FGF23 and revealed its relevant pathogenic role in various diseases. Most of these studies have been performed in adult individuals. However, the mineral metabolism of the child is, to a large extent, different from that of the adult because, in addition to bone remodeling, the child undergoes a specific process of endochondral ossification responsible for adequate mineralization of long bones’ metaphysis and growth in height. Vitamin D metabolism is known to be deeply involved in these processes. FGF23 might have an influence on bones’ growth as well as on the high and age-dependent serum phosphate concentrations found in infancy and childhood. However, the interaction between FGF23 and vitamin D in children is largely unknown. Thus, this review focuses on the following aspects of FGF23 metabolism in the pediatric age: circulating concentrations’ reference values, as well as those of other major variables involved in mineral homeostasis, and the relationship with vitamin D metabolism in the neonatal period, in vitamin D deficiency, in chronic kidney disease (CKD) and in hypophosphatemic disorders.

The clinical manifestations of primary distal renal tubular acidosis usually begin in childhood, but the disease is caused by a genetic defect that persists throughout life. This review focuses on the complications of distal tubular acidosis that occur or remain long-term such as nephrocalcinosis and urolithiasis, growth impairment, bone mineralization, severe hypokalemia, kidney cysts, and progressive kidney failure, as well as other persistent manifestations that occur independent of acidosis but are associated with some inherited forms of the disease. The pathogenic factors responsible for kidney failure are discussed in particular because it is a complication to which different publications have recently drawn attention and which affects a high percentage of adults with primary distal renal tubular acidosis. The need to maintain optimal metabolic control of the disease and scheduled clinical follow-up throughout life and the importance of organizing protocols for the transition of patients to adult nephrology services are emphasized.

The diagnosis of Alport syndrome is a challenge in the pediatric age, due to the absence of expected clinical phenotypes of the disease, its classic characterization of a rare disease and the very restricted practice of renal biopsies with routine analysis of the sample by electron microscopy during infancy. The clinical and genetic characteristics of 6 pediatric patients (4 women) diagnosed with Alport syndrome in two hospital centers between 2018 and 2021 are reported. All patients presented a clearly different clinical debut and none presented auditory or ophthalmological complications. Half had no family history of chronic kidney disease. No kidney biopsy performed confirmed the diagnosis. All patients were genetically confirmed and were the index case in the family study. This series illustrates the presence of unexpected clinical phenotypes in Alport syndrome and reflects the need for the incorporation of the genetic study for its diagnosis.El diagnóstico del síndrome de Alport supone un reto en la edad pediátrica, debido a la ausencia de fenotipos clínicos esperados de la enfermedad, su clásica caracterización de entidad rara y la práctica muy restringida de biopsias renales con análisis rutinario de la muestra por microscopía electrónica durante la infancia. Se presentan las características clínicas y genéticas de 6 pacientes pediátricos (4 mujeres) diagnosticados de síndrome de Alport en dos centros hospitalarios entre 2018 y 2021. Todos los pacientes presentaron un debut clínico claramente diferente y ninguno presentó complicaciones auditivas ni oftalmológicas. La mitad carecía de antecedentes familiares de enfermedad renal crónica. Ninguna biopsia renal realizada confirmó el diagnóstico. Todos los pacientes fueron confirmados genéticamente y fueron el caso índice del estudio familiar. Esta serie ilustra la presencia de fenotipos clínicos inesperados en el síndrome de Alport y refleja la necesidad de incorporar el estudio genético para su diagnóstico.

The uptake of the current concept of chronic kidney disease (CKD) by the public, physicians and health authorities is low. Physicians still mix up CKD with chronic kidney insufficiency or failure. In a recent manuscript, only 23% of participants in a cohort of persons with CKD had been diagnosed by their physicians as having CKD while 29% has a diagnosis of cancer and 82% had a diagnosis of hypertension. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. A prevalent view is that for those in whom kidneys fail, the problem is "solved" by dialysis or kidney transplantation. However, the main burden of CKD is accelerated aging and all-cause and cardiovascular premature death. CKD is the most prevalent risk factor for lethal COVID-19 and the factor that most increases the risk of death in COVID-19, after old age. Moreover, men and women undergoing KRT still have an annual mortality which is 10-100-fold higher than similar age peers, and life expectancy is shortened by around 40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth global cause of death by 2040 and the second cause of death in Spain before the end of the century, a time when 1 in 4 Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded CIBER network research structure in Spain. Leading Spanish kidney researchers grouped in the kidney collaborative research network REDINREN have now applied for the RICORS call of collaborative research in Spain with the support of the Spanish Society of Nephrology, ALCER and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true. However, only the highest level of research funding through the CIBER will allow to adequately address the issue before it is too late. (C) 2021 Sociedad Espanola de Nefrologia. Published by Elsevier Espana, S.L.U.

The diagnosis of Alport syndrome is a challenge in the pediatric age, due to the absence of expected clinical phenotypes of the disease, its classic characterization of a rare disease and the very restricted practice of renal biopsies with routine analysis of the sample by electron microscopy during infancy. The clinical and genetic characteristics of 6 pediatric patients (4 women) diagnosed with Alport syndrome in two hospital centers between 2018 and 2021 are reported. All patients presented a clearly different clinical debut and none presented auditory or ophthalmological complications. Half had no family history of chronic kidney disease. No kidney biopsy performed confirmed the diagnosis. All patients were genetically confirmed and were the index case in the family study. This series illustrates the presence of unexpected clinical phenotypes in Alport syndrome and reflects the need for the incorporation of the genetic study for its diagnosis.

ABSTRACT Background Small cohort studies have reported high parathyroid hormone (PTH) levels in patients with Bartter syndrome and lower serum phosphate levels have anecdotally been reported in patients with Gitelman syndrome. In this cross-sectional study, we assessed PTH and phosphate homeostasis in a large cohort of patients with salt-losing tubulopathies. Methods Clinical and laboratory data of 589 patients with Bartter and Gitelman syndrome were provided by members of the European Rare Kidney Diseases Reference Network (ERKNet) and the European Society for Paediatric Nephrology (ESPN). Results A total of 285 patients with Bartter syndrome and 304 patients with Gitelman syndrome were included for analysis. Patients with Bartter syndrome type I and II had the highest median PTH level (7.5 pmol/L) and 56% had hyperparathyroidism (PTH >7.0 pmol/L). Serum calcium was slightly lower in Bartter syndrome type I and II patients with hyperparathyroidism (2.42 versus 2.49 mmol/L; P = .038) compared to those with normal PTH levels and correlated inversely with PTH (rs −0.253; P = .009). Serum phosphate and urinary phosphate excretion did not correlate with PTH. Overall, 22% of patients had low serum phosphate levels (phosphate—standard deviation score < −2), with the highest prevalence in patients with Bartter syndrome type III (32%). Serum phosphate correlated with tubular maximum reabsorption of phosphate/glomerular filtration rate (TmP/GFR) (rs 0.699; P < .001), suggesting renal phosphate wasting. Conclusions Hyperparathyroidism is frequent in patients with Bartter syndrome type I and II. Low serum phosphate is observed in a significant number of patients with Bartter and Gitelman syndrome and appears associated with renal phosphate wasting.

X-linked hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets, is caused by inactivating mutations of the phosphate-regulating endopeptidase gene (PHEX). XLH is mainly characterized by short stature, bone deformities and rickets, while in hypophosphatemia, normal or low vitamin D levels and low renal phosphate reabsorption are the principal biochemical aspects. The cause of growth impairment in patients with XLH is not completely understood yet, thus making the study of the growth plate (GP) alterations necessary. New treatment strategies targeting FGF23 have shown promising results in normalizing the growth velocity and improving the skeletal effects of XLH patients. However, further studies are necessary to evaluate how this treatment affects the GP as well as its long-term effects and the impact on adult height.

The kidney plays a fundamental role in acid-base homeostasis by reabsorbing the filtered bicarbonate and by generating new bicarbonate, to replace that consumed in the buffering of non-volatile acids, a process that leads to the acidification of urine and the excretion of ammonium (NH4 +). Therefore, urine pH (UpH) and urinary NH4 + (UNH4 +) are valuable parameters to assess urinary acidification. The adaptation of automated plasma NH4 + quantification methods to measure UNH4 + has proven to be an accurate and feasible technique, with diverse potential indications in clinical practice. Recently, reference values for spot urine NH4 +/creatinine ratio in children have been published. UpH and UNH4 +, aside from their classical application in the study of metabolic acidosis, have shown to be useful in the identification of incomplete distal renal tubular acidosis (dRTA), an acidification disorder, without overt metabolic acidosis, extensively described in adults, and barely known in children, in whom it has been found to be associated to hypocitraturia, congenital kidney abnormalities and growth impairment. In addition, a low UNH4 + in chronic kidney disease (CKD) is a risk factor for glomerular filtration decay and mortality in adults, even in the absence of overt metabolic acidosis. We here emphasize on the need of measuring UpH and UNH4 + in pediatric population, establishing reference values, as well as exploring their application in metabolic acidosis, CKD and disorders associated with incomplete dRTA, including growth retardation of unknown cause.

This manuscript discusses mineral and bone disorders of chronic kidney disease (MBD-CKD) in pediatric patients with special emphasis on the underlying pathophysiology, the causes and clinical profile of growth retardation, the alterations in the growth plate, the strategies to optimize growth and the medical recommendations for prevention and treatment.

Distal renal tubular acidosis (dRTA) is characterized by an impaired ability of the distal tubule to excrete acid, leading to metabolic acidosis. Associated complications include bone disease, growth failure, urolithiasis and hypokalaemia. Due to its rarity, there is limited evidence to guide diagnosis and management; however, available data strongly suggest that metabolic control of the acidosis by alkali supplementation can halt or revert almost all complications. Despite this, cohort studies show that adequate metabolic control is present in only about half of patients, highlighting problems with treatment provision or adherence. With these clinical practice points the authors, part of the working groups tubulopathies in the European Rare Kidney Disease Reference network and inherited kidney diseases of the European Society for Paediatric Nephrology, aim to provide guidance for the management of patients with dRTA to facilitate adequate treatment and establish an initial best practice standard against which treatment of patients can be audited.