X-linked hypophosphatemia, obesity and arterial hypertension: data from the XLH21 study.

BACKGROUND: The underlying mechanisms of obesity in X-linked hypophosphatemia (XLH) are not known. We aimed to evaluate whether FGF21, an endocrine FGF involved in the regulation of carbohydrate-lipid metabolism, could be involved. METHODS: We performed a prospective multicenter cross-sectional study comparing FGF23, Klotho, and FGF21 levels in teenagers with XLH compared to healthy controls (VITADOS cohort) after matching for age, gender, and puberty. Non-parametric tests were performed (results presented as median (min-max)). RESULTS: A total of 40 XLH teenagers (n = 20 Standard Of Care, SOC, n = 20 burosumab) were included. While patients receiving burosumab displayed increased BMI as compared to patients receiving SOC, systolic blood pressure expressed as percentile was progressively and significantly lower when comparing the three groups: 77 (4-99) in SOC, 47 (9-98) in burosumab, and 28 (1-94) in controls (p = 0.007). When compared to patients receiving SOC, patients receiving burosumab displayed significantly increased phosphate and 1,25(OH)2D levels. We found increased Klotho levels in patients receiving burosumab. No differences were found for either carbohydrate-lipid biomarkers or FGF21 between the three groups. A total of 21 XLH patients (53%) had insulin resistance (HOMA > 2.4, N = 10 SOC, N = 11 burosumab). CONCLUSION: FGF21 does not explain obesity/overweight in XLH. Of note, this study was performed in France in 2018-2019, early after the approval authorizing burosumab only in case of severe XLH despite SOC. As such, the data on systolic blood pressure highlighting a possible impact of burosumab to decrease blood pressure as well as increase Klotho levels deserve further studies given their potential effect on long-term cardiovascular risk. A higher resolution version of the Graphical abstract is available as Supplementary information.

Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy.

Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the CTNS gene encoding cystinosin, and leads to end-stage renal disease within the second decade. The cornerstone of management relies on cysteamine therapy to decrease lysosomal cystine accumulation in target organs. However, despite cysteamine therapy, patients display severe bone symptoms, and the concept of "cystinosis metabolic bone disease" is currently emerging. Even though its exact pathophysiology remains unclear, at least five distinct but complementary entities can explain bone impairment in addition to CKD-MBD: long-term consequences of renal Fanconi syndrome, malnutrition and copper deficiency, hormonal disturbances, myopathy, and intrinsic/iatrogenic bone defects. Direct effects of both CTNS mutation and cysteamine on osteoblasts and osteoclasts are described. Thus, the main objective of this manuscript is not only to provide a clinical update on bone disease in cystinosis, but also to summarize the current experimental evidence demonstrating a functional impairment of bone cells in this disease and to discuss new working hypotheses that deserve future research in the field.

Intermittent cholecalciferol supplementation in children and teenagers followed in pediatric nephrology: data from a prospective single-center single-arm open trial.

Vitamin D deficiency is frequent in pediatric nephrology. The 2017 European guidelines recommend keeping 25OH vitamin D (25-D) levels within the 75-120 nmol/L range, ideally with daily supplementation. Intermittent supplementation with D3 has also been proposed. We aimed to assess the influence of our local protocol of intermittent vitamin D supplementation on the evolution of 25-D levels between baseline and 2 months. VITATOL is a prospective single-center study performed in our tertiary unit in children and teenagers followed for chronic kidney disease (CKD), kidney transplantation, or stable chronic nephrotic syndrome with 25-D levels below 75 nmol/L. Intermittent oral cholecalciferol (100,000 IU) was administered depending on baseline vitamin D levels and body weight. The primary outcome was the change in 25-D levels between baseline and 2 months. Secondary outcomes were the evolution of the main mineral biomarkers. Thirty-seven patients were included. Two months after beginning supplementation, corresponding to a median(min-max) of 46 (14-79) days after the last dose of vitamin D, 25-D levels increased from 50 to 76 nmol/L (p < 0.001), 18 patients having 25-D levels within the target range and 2 above. All patients displayed 25-D levels above 50 nmol/L. There were no significant changes in phosphate, PTH, alkaline phosphatase, and FGF23 levels before and after supplementation. Calcium levels increased from 2.39 to 2.44 mmol/L (p = 0.017), but no differences in calciuria and urinary calcium/creatinine ratio were observed.Conclusion: This vitamin D supplementation protocol using intermittent moderate doses of cholecalciferol seems efficient in 54% of cases, with neither significant overdose nor hypercalciuria. What is Known: • Vitamin D deficiency is frequent in pediatric nephrology. • The 2017 European guidelines recommend keeping 25OH vitamin D levels within the 75-120 nmol/L range ideally with daily supplementation, but intermittent supplementation with D3 has also been proposed. What is New: • We assessed the influence of a local protocol of intermittent vitamin D supplementation on the evolution of 25-D levels between baseline and 2 months in children and teenagers followed in pediatric nephrology. • The intermittent cholecalciferol supplementation protocol seems efficient in 54% of cases, with neither significant overdose nor hypercalciuria.

Fludrocortisone as a new tool for managing tubulopathy after pediatric renal transplantation: a series of cases.

BACKGROUND: The management of tubulopathies after renal transplantation (RTx) may require high doses of sodium and bicarbonate, reducing the quality of life and therapeutic compliance of the patient. Some studies on adult patients have highlighted the benefits of fludrocortisone (fludro) in the treatment of severe tubulopathies. METHODS: This study was a retrospective review of the medical charts of 15 children, aged 12.4 (range 3.6-17.4) years who received fludro after RTx. RESULTS: With the administration of fludro, both sodium bicarbonate and chloride supplementation decreased, from 10 (range 0-14) to 0 (0-5) g/day, and from 9 (0-20) to 0 (0-3) g/day, respectively (both p < 0.001). Serum potassium also significantly decreased (4.6 ± 0.4 vs. 3.3 ± 0.6 mmol/L; p < 0.001), but there was no significant effect on renal function. Both systolic and diastolic blood pressure increased significantly. Fludro therapy was stopped in six patients due to side-effects (arterial hypertension, hypokalemia during acute diarrhea, gastric pain, n = 3), parental decision (n = 1), inefficacy and/or non-compliance (n = 1) and scheduled withdrawal (n = 1). Four of these patient had subsequent increasing requirements for bicarbonate and/or sodium supplementation, which ultimately required the re-introduction of fludro in two of these patients. CONCLUSIONS: Based on our findings, fludro would appear to be an effective therapy in most cases of severe tubulopathy after RTx. Further prospective studies are required to validate this indication and to determine the optimal dose and timing of treatment to avoid side-effects as well as the clinical and biological follow-up.

[Online hemodiafiltration in children and hypoparathyroidism: a single-centre series of cases]. / Hémodiafiltration online et hypoparathyroïdie chez l'enfant : une série de cas monocentrique.

BACKGROUND: Due to technical requirements and cost, hemodiafiltration (HDF) is not widely used in pediatrics. We have been using online HDF (oHDF) since 2009 and we observed low parathyroid hormone (PTH) levels despite the accurate management of CKD-MBD. METHODS: We reviewed the medical charts and parameters of mineral metabolism assessed on a before/after session basis in the 6 children undergoing chronic oHDF in our centre. RESULTS: We observed low (<80pg/mL) PTH levels in all 6 patients and very low (<45pg/mL) PTH levels in 5, two of them presenting with pathological fractures. These low PTH levels were reversed after decreasing calcium concentration to 1.25 mmol/L in the dialysate, suggesting that high-efficiency oHDF may expose children to calcium during sessions in a too important amount when using 1.5 mmol/L dialysates. Last, C-terminal FGF23 levels before sessions were relatively low (<1600RU/mL), with a 32% clearance by oHDF. CONCLUSION: PTH levels should be closely monitored in pediatric oHDF and solutions with a calcium concentration of 1.25 mmol/L should be used as first line in these patients.