RANKL, but Not R-Spondins, Is Involved in Vascular Smooth Muscle Cell Calcification through LGR4 Interaction.

Vascular calcification has a global health impact that is closely linked to bone loss. The Receptor Activator of Nuclear Factor Kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system, fundamental for bone metabolism, also plays an important role in vascular calcification. The Leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a novel receptor for RANKL, regulates bone remodeling, and it appears to be involved in vascular calcification. Besides RANKL, LGR4 interacts with R-spondins (RSPOs), which are known for their roles in bone but are less understood in vascular calcification. Studies were conducted in rats with chronic renal failure fed normal or high phosphorus diets for 18 weeks, with and without control of circulating parathormone (PTH) levels, resulting in different degrees of aortic calcification. Additionally, vascular smooth muscle cells (VSMCs) were cultured under non-calcifying (1 mM phosphate) and calcifying (3 mM phosphate) media with different concentrations of PTH. To explore the role of RANKL in VSMC calcification, increasing concentrations of soluble RANKL were added to non-calcifying and calcifying media. The effects mediated by RANKL binding to its receptor LGR4 were investigated by silencing the LGR4 receptor in VSMCs. Furthermore, the gene expression of the RANK/RANKL/OPG system and the ligands of LGR4 was assessed in human epigastric arteries obtained from kidney transplant recipients with calcification scores (Kauppila Index). Increased aortic calcium in rats coincided with elevated systolic blood pressure, upregulated Lgr4 and Rankl gene expression, downregulated Opg gene expression, and higher serum RANKL/OPG ratio without changes in Rspos gene expression. Elevated phosphate in vitro increased calcium content and expression of Rankl and Lgr4 while reducing Opg. Elevated PTH in the presence of high phosphate exacerbated the increase in calcium content. No changes in Rspos were observed under the conditions employed. The addition of soluble RANKL to VSMCs induced genotypic differentiation and calcification, partly prevented by LGR4 silencing. In the epigastric arteries of individuals presenting vascular calcification, the gene expression of RANKL was higher. While RSPOs show minimal impact on VSMC calcification, RANKL, interacting with LGR4, drives osteogenic differentiation in VSMCs, unveiling a novel mechanism beyond RANKL-RANK binding.

Nutritional Assessment and Support in Children with Chronic Kidney Disease: The Benefits of Working with a Registered Dietitian.

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.

Long-term complications of primary distal renal tubular acidosis.

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.

Transcriptomic clustering of critically ill COVID-19 patients.

BACKGROUND: Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a severe disease, termed coronavirus disease 2019 (COVID-19), with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms and their modulation has shown a mortality benefit. METHODS: In a cohort of 56 critically ill COVID-19 patients, peripheral blood transcriptomes were obtained at admission to an intensive care unit (ICU) and clustered using an unsupervised algorithm. Differences in gene expression, circulating microRNAs (c-miRNAs) and clinical data between clusters were assessed, and circulating cell populations estimated from sequencing data. A transcriptomic signature was defined and applied to an external cohort to validate the findings. RESULTS: We identified two transcriptomic clusters characterised by expression of either interferon-related or immune checkpoint genes, respectively. Steroids have cluster-specific effects, decreasing lymphocyte activation in the former but promoting B-cell activation in the latter. These profiles have different ICU outcomes, despite no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in two external validation cohorts (with 50 and 60 patients), yielding similar results. CONCLUSIONS: These results reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19 with the aim to ultimately personalise their therapies.

Evaluation of urinary acidification in children: Clinical utility.

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.

IGHG3 hinge length variation was associated with the risk of critical disease and death in a Spanish COVID-19 cohort.

IgG3 would play an important role in the immune adaptive response against SARS-CoV-2, and low plasma levels might increase the risk of COVID-19 severity and mortality. The IgG3 hinge sequence has a variable repeat of a 15 amino acid exon with common 4-repeats (M) and 3-repeats (S). This length IGHG3 polymorphism might affect the IgG3 effector functions. The short hinge length would reduce the IgG3 flexibility and impairs the neutralization and phagocytosis compared to larger length-isoforms. We genotyped the IGHG3 length polymorphism in patients with critical COVID-19 (N = 516; 107 death) and 152 moderate-severe but no-critical cases. Carriers of the S allele had an increased risk of critical ICU and mortality (p < 0.001, OR = 2.79, 95% CI = 1.66-4.65). This adverse effect might be explained by a less flexibility and reduced ability to induce phagocytosis or viral neutralization for the short length allele. We concluded that the IgG3 hinge length polymorphism could be a predictor of critical COVID-19 and the risk of death. This study was based on a limited number of patients from a single population, and requires validation in larger cohorts.

Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

Background: Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19. Methods: Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. Results: About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings. Conclusions: COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype. Funding: Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).

Patients with severe COVID-19 often need mechanical ventilation to help them breathe and other types of intensive care. The outcome for many of these patients depends on how their immune system reacts to the infection. If the inflammatory response triggered by the immune system is too strong, this can cause further harm to the patient. One gene that plays an important role in inflammation is IFIH1 which encodes a protein that helps the body to recognize viruses. There are multiple versions of this gene which each produce a slightly different protein. It is possible that this variation impacts how the immune system responds to the virus that causes COVID-19. To investigate, Amado-Rodríguez, Salgado del Riego et al. analyzed the IFIH1 gene in 227 patients admitted to an intensive care unit in Spain for severe COVID-19 between March and December 2020. They found that patients with a specific version of the gene called TT experienced less inflammation and were more likely to survive the infection. Physicians typically treat patients with moderate to severe COVID-19 with corticosteroid drugs that reduce the inflammatory response. However, Amado-Rodríguez, Salgado del Riego et al. found that patients with the TT version of the IFIH1 gene were at greater risk of dying if they received corticosteroids. The team then applied the distribution of IFIH1 variants among different ethnic ancestries to data from a previous clinical trial, and simulated the effects of corticosteroid treatment. This 'mock' clinical trial supported their findings from the patient-derived data, which were also validated by laboratory experiments on immune cells from individuals with the TT gene. The work by Amado-Rodríguez, Salgado del Riego et al. suggests that while corticosteroids benefit some patients, they may cause harm to others. However, a real-world clinical trial is needed to determine whether patients with the TT version of the IFIH1 gene would do better without steroids.

Cellular and Molecular Alterations Underlying Abnormal Bone Growth in X-Linked Hypophosphatemia.

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.

SARS-CoV-2 Spike Protein in Intestinal Cells of a Patient with Coronavirus Disease 2019 Multisystem Inflammatory Syndrome.

A previously healthy 12-year-old boy had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related multisystem inflammatory syndrome (MIS-C) that was rapidly fatal. Autopsy revealed the presence of a large intracardiac thrombus. SARS-CoV-2 spike protein was detected in intestinal cells, supporting the hypothesis that viral presence in the gut may be related to the immunologic response of MIS-C.

Systemic Jak1 activation causes extrarenal calcitriol production and skeletal alterations provoking stunted growth.

Mineral homeostasis is regulated by a complex network involving endocrine actions by calcitriol, parathyroid hormone (PTH), and FGF23 on several organs including kidney, intestine, and bone. Alterations of mineral homeostasis are found in chronic kidney disease and other systemic disorders. The interplay between the immune system and the skeletal system is not fully understood, but cytokines play a major role in modulating calcitriol production and function. One of the main cellular signaling pathways mediating cytokine function is the Janus kinase (JAK)--signal transducer and activator of transcription (STAT) pathway. Here, we used a mouse model (Jak1S645P+/- ) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans, and shows altered mineral metabolism, with higher fibroblast growth factor 23 (FGF23) levels, lower PTH levels, and higher calcitriol levels. The higher calcitriol levels are probably due to extrarenal calcitriol production. Furthermore, systemic Jak1/Stat3 activation led to growth impairment and skeletal alterations. The growth plate in long bones showed decreased chondrocyte proliferation rates and reduced height of terminal chondrocytes. Furthermore, we demonstrate that Jak1 is also involved in bone remodeling early in life. Jak1S645P+/- animals have decreased bone and cortical volume, imbalanced bone remodeling, reduced MAP kinase signaling, and local inflammation. In conclusion, Jak1 plays a major role in bone health probably both, directly and systemically by regulating mineral homeostasis. Understanding the role of this signaling pathway will contribute to a better knowledge in bone growth and in mineral physiology, and to the development of selective Jak inhibitors as osteoprotective agents.

Variant-genetic and transcript-expression analysis showed a role for the chemokine-receptor CCR5 in COVID-19 severity.

The chemokine receptor CCR5 has been implicated in COVID-19. CCR5 and its ligands are overexpressed in patients. The pharmacological targeting of CCR5 would improve the COVID-19 severity. We sought to investigate the role of the CCR5-Δ32 variant (rs333) in COVID-19. The CCR5-Δ32 was genotyped in 801 patients (353 in the intensive care unit, ICU) and 660 healthy controls, and the deletion was significantly less frequent in hospitalysed COVID-19 than in healthy controls (p = 0.01, OR = 0.66, 95%CI = 0.49-0.88). Of note, we did not find homozygotes among the patients, compared to 1% of the controls. The CCR5 transcript was measured in leukocytes from 85 patients and 40 controls. We found a significantly higher expression of the CCR5 transcript among the patients, with significant difference when comparing the non-deletion carriers (controls = 35; patients = 81; p = 0.01). ICU-patients showed non-significantly higher expression than no-ICU cases. Our study points to CCR5 as a genetic marker for COVID-19. The pharmacological targeting of CCR5 should be a promising treatment for COVID-19.

Kidney function in patients with primary distal renal tubular acidosis.

BACKGROUND: Recent reports indicate that chronic reduction of glomerular filtration rate (GFR) is common in patients with distal renal tubular acidosis (DRTA). Factors responsible for decreased GFR need clarification. METHODS: We reviewed records of 25 patients with genetically confirmed DRTA included in the RenalTube database. Patients < 18 years at diagnosis and having at least one annual follow-up were selected and classified in two groups according to GFR ≥ 90 (normal GFR) or < 90 mL/min/1.73 m2 (low GFR) after median follow-up of 8.8 years. RESULTS: Eighteen and seven patients had normal and low GFR (X ± SEM, 121.16 ± 28.87 and 71.80 ± 10.60 mL/min/1.73 m2, respectively, p < 0.01). At diagnosis, these 2 subgroups did not differ in sex, age, underlying mutated gene, GFR, height SDS, or percentage of ultrasound nephrocalcinosis. Serum creatinine (SCr) was different but likely due to median ages of presentation being 0.6 and 4.0 in normal and low GFR patients, respectively. On the last recorded visit, no differences between both groups were found in serum bicarbonate, serum potassium, or alkali dosage. Height SDS of patients with normal GFR was - 0.15 ± 0.47 whereas it was - 1.06 ± 0.60 in the low GFR group (p = 0.27). Interestingly, 23% of the whole group had low birth weight (LBW; < 2500 g), equating to 20% and 29% in the normal and low GFR patients, respectively (p = 0.65). CONCLUSIONS: Our findings confirm the risk of kidney function reduction in patients with DRTA of pediatric age onset, suggesting that low GFR is related with less favorable growth outcome and discloses the high frequency of LBW in primary DRTA, a hitherto unrecognized feature.

Evolución de tubulopatías renales primarias diagnosticadas en edad pediátrica / Outcome of primary tubular tubulopathies diagnosed in pediatric age

ANTECEDENTES Y OBJETIVO: Las tubulopatías primarias son raras y se presentan habitualmente en la edad pediátrica. Avances recientes en diagnóstico genético y tratamiento han cambiado su historia natural. Este estudio presenta el espectro clínico de una serie de tubulopatías primarias diagnosticadas en una Unidad de Nefrología Pediátrica y ofrece datos de seguimiento a largo plazo sobre crecimiento, filtrado glomerular estimado y complicaciones intercurrentes. PACIENTES Y MÉTODOS: Estudio observacional en 53 pacientes con tubulopatías primarias y defecto genético identificado: síndrome de Gitelman (36%), acidosis tubular renal distal (15%), cistinuria (11%), raquitismo hipofosfatémico ligado al X (7%), síndrome de Dent-Lowe (7%), cistinosis (6%), y uno o 2 casos de otras tubulopatías. Se recogieron datos demográficos, analíticos y clínicos al diagnóstico, durante la evolución y en el momento del estudio. RESULTADOS: La edad (mediana y rango intercuartílico) al diagnóstico fue de 5,08 años (1,33-8,50). Las manifestaciones de presentación más frecuentes fueron descompensaciones metabólicas asociadas a procesos intercurrentes (40%) y talla baja (38%). La talla (media ± DE) fue de -1,39 ± 1,49 al diagnóstico y 1,07 ± 1,54 tras un seguimiento de 18,92 (6,25-24,33) años. Dieciséis (32%) desarrollaron filtrado glomerular estimado < 90 mL/min/1,73 m2. Tres pacientes requirieron reemplazo renal sustitutivo. Once enfermos tuvieron descompensaciones metabólicas que requirieron hospitalización, 9 cólicos nefríticos y/o cálculos renales y 10 problemas mentales. Seis de 8 pacientes con acidosis tubular renal desarrollaron sordera neurosensorial. CONCLUSIONES: Las tubulopatías primarias son un grupo heterogéneo de enfermedades que ocasionan afectación del crecimiento, reversible en gran medida con tratamiento, riesgo de reducción de filtrado glomerular estimado e importantes complicaciones extrarrenales derivadas o asociadas

BACKGROUND AND OBJECTIVE: Primary tubulopathies are rare and usually present at pediatric age. Recent advances in genetic diagnosis and treatment have changed its natural history. This study provides the clinical spectrum of a series of primary tubulopathies diagnosed in a Pediatric Nephrology Unit and to offer long-term follow-up data regarding growth, estimated glomerular filtration and intercurrent complications. PATIENTS AND METHODS: Observational study in 53 patients with primary tubulopathies and identified genetic defect: Gitelman syndrome (36%), distal renal tubular acidosis (15%), cystinuria (11%), X-linked hypophosphatemic rickets (7%), Dent-syndrome Lowe (7%), cystinosis (6%), and 1-2 cases of other tubulopathies. Demographic, analytical and clinical data were collected at diagnosis, during evolution and at the time of the study. RESULTS: The age (median and interquartile range) at diagnosis was 5.08 years (1.33-8.50). The most frequent presentation manifestations were metabolic decompensations associated with intercurrent processes (40%) and short stature (38%). Height (mean±SD) was - 1.39 ± 1.49 at diagnosis and 1.07 ± 1.54 after a follow-up of 18.92 (6.25-24.33) years. Sixteen (32%) developed an estimated glomerular filtration < 90 ml / min / 1.73 m2. Three patients required replacement renal replacement. Eleven patients had metabolic decompensations that required hospitalization, 9 renal colic and / or kidney stones and 10 mental problems. Six of 8 patients with distal renal tubular acidosis developed sensorineural deafness. CONCLUSIONS: Primary tubulopathies are a heterogeneous group of diseases that cause growth impairment, largely reversible with treatment, risk of estimated glomerular filtration reduction and significant extrarenal complications derived or associated

Phenotypic characterization of X-linked hypophosphatemia in pediatric Spanish population.

BACKGROUND: X-linked hypophosphatemia (XLH) is a hereditary rare disease caused by loss-of-function mutations in PHEX gene leading tohypophosphatemia and high renal loss of phosphate. Rickets and growth retardation are the major manifestations of XLH in children, but there is a broad phenotypic variability. Few publications have reported large series of patients. Current data on the clinical spectrum of the disease, the correlation with the underlying gene mutations, and the long-term outcome of patients on conventional treatment are needed, particularly because of the recent availability of new specific medications to treat XLH. RESULTS: The RenalTube database was used to retrospectively analyze 48 Spanish patients (15 men) from 39 different families, ranging from 3 months to 8 years and 2 months of age at the time of diagnosis (median age of 2.0 years), and with XLH confirmed by genetic analysis. Bone deformities, radiological signs of active rickets and growth retardation were the most common findings at diagnosis. Mean (± SEM) height was - 1.89 ± 0.19 SDS and 55% (22/40) of patients had height SDS below-2. All cases had hypophosphatemia, serum phosphate being - 2.81 ± 0.11 SDS. Clinical manifestations and severity of the disease were similar in both genders. No genotype-phenotype correlation was found. Conventional treatment did not attenuate growth retardation after a median follow up of 7.42 years (IQR = 11.26; n = 26 patients) and failed to normalize serum concentrations of phosphate. Eleven patients had mild hyperparathyroidism and 8 patients nephrocalcinosis. CONCLUSIONS: This study shows that growth retardation and rickets were the most prevalent clinical manifestations at diagnosis in a large series of Spanish pediatric patients with XLH confirmed by mutations in the PHEX gene. Traditional treatment with phosphate and vitamin D supplements did not improve height or corrected hypophosphatemia and was associated with a risk of hyperparathyroidism and nephrocalcinosis. The severity of the disease was similar in males and females.

The Formation of the Epiphyseal Bone Plate Occurs via Combined Endochondral and Intramembranous-Like Ossification.

The formation of the epiphyseal bone plate, the flat bony structure that provides strength and firmness to the growth plate cartilage, was studied in the present study by using light, confocal, and scanning electron microscopy. Results obtained evidenced that this bone tissue is generated by the replacement of the lower portion of the epiphyseal cartilage. However, this process differs considerably from the usual bone tissue formation through endochondral ossification. Osteoblasts deposit bone matrix on remnants of mineralized cartilage matrix that serve as a scaffold, but also on non-mineralized cartilage surfaces and as well as within the perivascular space. These processes occur simultaneously at sites located close to each other, so that, a core of the sheet of bone is established very quickly. Subsequently, thickening and reshaping occurs by appositional growth to generate a dense parallel-fibered bone structurally intermediate between woven and lamellar bone. All these processes occur in close relationship with a cartilage but most of the bone tissue is generated in a manner that may be considered as intramembranous-like. Overall, the findings here reported provide for the first time an accurate description of the tissues and events involved in the formation of the epiphyseal bone plate and gives insight into the complex cellular events underlying bone formation at different sites on the skeleton.

Outcome of primary tubular tubulopathies diagnosed in pediatric age.

BACKGROUND AND OBJECTIVE: Primary tubulopathies are rare and usually present at pediatric age. Recent advances in genetic diagnosis and treatment have changed its natural history. This study provides the clinical spectrum of a series of primary tubulopathies diagnosed in a Pediatric Nephrology Unit and to offer long-term follow-up data regarding growth, estimated glomerular filtration (eGFR) and intercurrent complications. PATIENTS AND METHODS: Observational study in 53 patients with primary tubulopathies and identified genetic defect: Gitelman syndrome (36%), distal renal tubular acidosis (15%), cystinuria (11%), X-linked hypophosphatemic rickets (7%), Dent-syndrome Lowe (7%), cystinosis (6%), and 1-2 cases of other tubulopathies. Demographic, analytical and clinical data were collected at diagnosis, during evolution and at the time of the study. RESULTS: The age (median and interquartile range) at diagnosis was 5.08 years (1.33-8.50). The most frequent presentation manifestations were metabolic decompensations associated with intercurrent processes (40%) and short stature (38%). Height (mean ±â€¯SD) was -1.39 ±â€¯1.49 at diagnosis and 1.07 ±â€¯1.54 after a follow-up of 18.92 (6.25-24.33) years. Sixteen (32%) developed an eGFR <90 ml/min/1.73 m2. Three patients required replacement renal replacement. Eleven patients had metabolic decompensations that required hospitalization, 9 renal colic and/or kidney stones and 10 mental problems. Six of 8 patients with distal renal tubular acidosis developed sensorineural deafness. CONCLUSIONS: Primary tubulopathies are a heterogeneous group of diseases that cause growth impairment, largely reversible with treatment, risk of eGFR reduction and significant extrarenal complications derived or associated.

Outcome of primary tubular tubulopathies diagnosed in pediatric age. / Evolución de tubulopatías renales primarias diagnosticadas en edad pediátrica.

BACKGROUND AND OBJECTIVE: Primary tubulopathies are rare and usually present at pediatric age. Recent advances in genetic diagnosis and treatment have changed its natural history. This study provides the clinical spectrum of a series of primary tubulopathies diagnosed in a Pediatric Nephrology Unit and to offer long-term follow-up data regarding growth, estimated glomerular filtration and intercurrent complications. PATIENTS AND METHODS: Observational study in 53 patients with primary tubulopathies and identified genetic defect: Gitelman syndrome (36%), distal renal tubular acidosis (15%), cystinuria (11%), X-linked hypophosphatemic rickets (7%), Dent-syndrome Lowe (7%), cystinosis (6%), and 1-2 cases of other tubulopathies. Demographic, analytical and clinical data were collected at diagnosis, during evolution and at the time of the study. RESULTS: The age (median and interquartile range) at diagnosis was 5.08 years (1.33-8.50). The most frequent presentation manifestations were metabolic decompensations associated with intercurrent processes (40%) and short stature (38%). Height (mean±SD) was -1.39±1.49 at diagnosis and 1.07±1.54 after a follow-up of 18.92 (6.25-24.33) years. Sixteen (32%) developed an estimated glomerular filtration<90ml / min / 1.73m2. Three patients required replacement renal replacement. Eleven patients had metabolic decompensations that required hospitalization, 9 renal colic and / or kidney stones and 10 mental problems. Six of 8 patients with distal renal tubular acidosis developed sensorineural deafness. CONCLUSIONS: Primary tubulopathies are a heterogeneous group of diseases that cause growth impairment, largely reversible with treatment, risk of estimated glomerular filtration reduction and significant extrarenal complications derived or associated.

The Interferon-induced transmembrane protein 3 gene (IFITM3) rs12252 C variant is associated with COVID-19.

BACKGROUND AND AIMS: The interferon-induced transmembrane proteins play an important antiviral role by preventing viruses from traversing the cellular lipid bilayer. IFITM3 gene variants have been associated with the clinical response to influenza and other viruses. Our aim was to determine whether the IFITM3 rs12252 polymorphism was associated with the risk of developing severe symptoms of COVID-19 in our population. METHODS: A total of 288 COVID-19 patients who required hospitalization (81 in the intensive care unit) and 440 age matched controls were genotyped with a Taqman assay. Linear regression models were used to compare allele and genotype frequencies between the groups, correcting for age and sex. RESULTS: Carriers of the minor allele frequency (rs12252 C) were significantly more frequent in the patients compared to controls after correcting by age and sex (p = 0.01, OR = 2.02, 95%CI = 1.19-3.42). This genotype was non-significantly more common among patients who required ICU. CONCLUSIONS: The IFITM3 rs12252 C allele was a risk factor for COVID-19 hospitalization in our Caucasian population. The extent of the association was lower than the reported among Chinese, a population with a much higher frequency of the risk allele.