Fibroblast growth factor-23 (FGF23) is a phosphaturic hormone that contributes to several hypophosphatemic disorders by reducing the expression of the type II sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the kidney proximal tubule and by reducing serum 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels. The FGF receptor(s) mediating the hypophosphatemic action of FGF23 in vivo have remained elusive. In this study, we show that proximal tubules express FGFR1, -3, and -4 but not FGFR2 mRNA. To determine which of these three FGFRs mediates FGF23's hypophosphatemic actions, we characterized phosphate homeostasis in FGFR3(-/-) and FGFR4(-/-) null mice, and in conditional FGFR1(-/-) mice, with targeted deletion of FGFR1 expression in the metanephric mesenchyme. Basal serum phosphorus levels and renal cortical brush-border membrane (BBM) NaPi-2a and NaPi-2c expression were comparable between FGFR1(-/-), FGFR3(-/-), and FGFR4(-/-) mice and their wild-type counterparts. Administration of FGF23 to FGFR3(-/-) mice induced hypophosphatemia in these mice (8.0 +/- 0.4 vs. 5.4 +/- 0.3 mg/dl; p < or = 0.001) and a decrease in renal BBM NaPi-2a and NaPi-2c protein expression. Similarly, in FGFR4(-/-) mice, administration of FGF23 caused a small but significant decrease in serum phosphorus levels (8.7 +/- 0.3 vs. 7.6 +/- 0.4 mg/dl; p < or = 0.001) and in renal BBM NaPi-2a and NaPi-2c protein abundance. In contrast, injection of FGF23 into FGFR1(-/-) mice had no effects on serum phosphorus levels (5.6 +/- 0.3 vs. 5.2 +/- 0.5 mg/dl) or BBM NaPi-2a and NaPi-2c expression. These data show that FGFR1 is the predominant receptor for the hypophosphatemic action of FGF23 in vivo, with FGFR4 likely playing a minor role.

Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in the pathogenesis of several hypophosphatemic disorders. FGF23 causes hypophosphatemia by decreasing the expression of sodium phosphate cotransporters (NaPi-2a and NaPi-2c) and decreasing serum 1,25(OH)2Vitamin D3 levels. We previously showed that FGFR1 is the predominant receptor for the hypophosphatemic actions of FGF23 by decreasing renal NaPi-2a and 2c expression while the receptors regulating 1,25(OH)2Vitamin D3 levels remained elusive. FIBROBLAST GROWTH FACTOR 23 (FGF23) is a phosphaturic hormone that has been implicated in several inherited and acquired hypophosphatemic disorders (15). FGF23 increases urinary phosphate excretion by decreasing renal brush-border expression of the sodium phosphate cotransporters 2a and 2c (NaPi-2a and NaPi-2c) (14, 42). In addition, FGF23 decreases the expression of 25(OH)Vitamin D-1␣-hydroxylase (CYP27B1) and increases the expression 24-hydroxylase (CYP24) resulting in low-serum 1,25(OH) 2 Vitamin D 3 levels (37, 42). The inherited hypophosphatemic disorders where FGF23 levels are increased include X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and autosomal recessive hypophosphatemic rickets (12,14,21,24,31,36,50). The increased FGF23 levels in these disorders result in severe hypophosphatemia, rickets/osteomalacia, bone pain, fractures, and growth failure in children. Serum FGF23 levels are also elevated in tumor-induced osteomalacia (8, 9).The FGF family of ligands bind to FGF receptors (FGFRs) to mediate their actions (10,17,23,34). Four FGFRs (FGFR1-4) are encoded by four genes and alternative splicing (b and c isoforms of FGFR1-3) results in tissue and ligand binding specificity (33,35). The proximal tubule, the site of most renal phosphate reabsorption (4, 46) and 25(OH)Vitamin D-1␣-hydroxylase activity (7, 13), has FGFR1, 3, and 4, but it does not express FGFR2 (14).We previously utilized FGFR-null mice with the goal of determining which receptor was responsible for the FGF23-mediated decrease in renal phosphate transport and vitamin D production. In these studies, FGF23 was administered to conditional FGFR1Ϫ/Ϫ , and FGFR4 Ϫ/Ϫ mice. FGFR1 was found to be the predominant receptor mediating the hypophosphatemic actions of FGF23 by decreasing brushborder membrane (BBM) NaPi-2a and NaPi-2c expression with FGFR4 playing an additional but relatively minor role (14). Liu et al. (29) also found that deletion of either FGFR3 or FGFR4 in a mouse model of X-linked hypophosphatemic rickets (Hyp mouse) did not correct the disturbances in phosphate homeostasis. Intriguingly, in the conditional FGFR1 Ϫ/Ϫ mice, as well as FGFR3 Ϫ/Ϫ and FGFR4 Ϫ/Ϫ mice, 1,25(OH) 2 Vitamin D 3 levels decreased comparably after administration of FGF23 (14). This implies that FGF23 regulates proximal tubular 1,25(OH) 2 Vitamin D 3 biosynthesis using a different receptor than for the inhibition of phosphate transport in the proximal tubule. 1,25(OH) 2 Vitamin D 3 is primarily synthesized in the pr...

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BackgroundChildren are recognised as at lower risk of severe COVID-19 compared with adults, but the impact of immunosuppression is yet to be determined. This study aims to describe the clinical course of COVID-19 in children with kidney disease taking immunosuppressive medication and to assess disease severity.MethodsCross-sectional study hosted by the European Rare Kidney Disease Reference Network and supported by the European, Asian and International paediatric nephrology societies. Anonymised data were submitted online for any child (age <20 years) with COVID-19 taking immunosuppressive medication for a kidney condition. Study recruited for 16 weeks from 15 March 2020 to 05 July 2020. The primary outcome was severity of COVID-19.Results113 children were reported in this study from 30 different countries. Median age: 13 years (49% male). Main underlying reasons for immunosuppressive therapy: kidney transplant (47%), nephrotic syndrome (27%), systemic lupus erythematosus (10%). Immunosuppressive medications used include: glucocorticoids (76%), mycophenolate mofetil (MMF) (54%), tacrolimus/ciclosporine A (58%), rituximab/ofatumumab (11%). 78% required no respiratory support during COVID-19 illness, 5% required bi-level positive airway pressure or ventilation. Four children died; all deaths reported were from low-income countries with associated comorbidities. There was no significant difference in severity of COVID-19 based on gender, dialysis status, underlying kidney condition, and type or number of immunosuppressive medications.ConclusionsThis global study shows most children with a kidney disease taking immunosuppressive medication have mild disease with SARS-CoV-2 infection. We therefore suggest that children on immunosuppressive therapy should not be more strictly isolated than children who are not on immunosuppressive therapy.

A range of women’s health issues are intimately related to chronic kidney disease, yet nephrologists’ confidence in counseling or managing these issues has not been evaluated. The women’s health working group of Cure Glomerulonephropathy (CureGN), an international prospective cohort study of glomerular disease, sought to assess adult nephrologists’ training in, exposure to, and confidence in managing women’s health. A 25-item electronic questionnaire was disseminated in the United States (US) and Canada via CureGN and Canadian Society of Nephrology email networks and the American Society of Nephrology Kidney News. Response frequencies were summarized using descriptive statistics. Responses were compared across provider age, gender, country of practice, and years in practice using Pearson’s chi-squared test or Fisher’s exact test. Among 154 respondents, 53% were women, 58% practiced in the US, 77% practiced in an academic setting, and the median age was 41–45 years. Over 65% of respondents lacked confidence in women’s health issues, including menstrual disorders, preconception counseling, pregnancy management, and menopause. Most provided contraception or preconception counseling to less than one woman per month, on average. Only 12% had access to interdisciplinary pregnancy clinics. Finally, 89% felt that interdisciplinary guidelines and/or continuing education seminars would improve knowledge. Participants lacked confidence in both counseling and managing women’s health. Innovative approaches are warranted to improve the care of women with kidney disease and might include the expansion of interdisciplinary clinics, the development of case-based teaching materials, and interdisciplinary treatment guidelines focused on this patient group.