Tubular Reabsorption Of Phosphate Research Articles

Clinical Spectrum of Hereditary Hypophosphatemic Rickets With Hypercalciuria (HHRH).

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) represents an FGF23-independent disease caused by biallelic variants in the solute carrier family 34-member 3 (SLC34A3) gene. HHRH is characterized by chronic hypophosphatemia and an increased risk for nephrocalcinosis and rickets/osteomalacia, muscular weakness, and secondary limb deformity. Biochemical changes, but no relevant skeletal changes, have been reported for heterozygous SLC34A3 carriers. Therefore, we assessed the characteristics of individuals with biallelic and monoallelic SLC34A3 variants. In 8 index patients and 5 family members, genetic analysis was performed using a custom gene panel. The skeletal assessment comprised biochemical parameters, areal bone mineral density (aBMD), and bone microarchitecture. Pathogenic SLC34A3 variants were revealed in 7 of 13 individuals (2 homozygous, 5 heterozygous), whereas 3 of 13 carried monoallelic variants of unknown significance. Whereas both homozygous individuals had nephrocalcinosis, only one displayed a skeletal phenotype consistent with HHRH. Reduced to low-normal phosphate levels, decreased tubular reabsorption of phosphate (TRP), and high-normal to elevated values of 1,25-OH2 -D3 accompanied by normal cFGF23 levels were revealed independently of mutational status. Interestingly, individuals with nephrocalcinosis showed significantly increased calcium excretion and 1,25-OH2 -D3 levels but normal phosphate reabsorption. Furthermore, aBMD Z-score <-2.0 was revealed in 4 of 8 heterozygous carriers, and HR-pQCT analysis showed a moderate decrease in structural parameters. Our findings highlight the clinical relevance also of monoallelic SLC34A3 variants, including their potential skeletal impairment. Calcium excretion and 1,25-OH2 -D3 levels, but not TRP, were associated with nephrocalcinosis. Future studies should investigate the effects of distinct SLC34A3 variants and optimize treatment and monitoring regimens to prevent nephrocalcinosis and skeletal deterioration. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

PTH and FGF23 Exert Interdependent Effects on Renal Phosphate Handling: Evidence From Patients With Hypoparathyroidism and Hyperphosphatemic Familial Tumoral Calcinosis Treated With Synthetic Human PTH 1-34.

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) both influence blood phosphate levels by regulating urinary phosphate reabsorption. Clinical data suggest that adequate renal phosphate handling requires the presence of both FGF23 and PTH, but robust evidence is lacking. To investigate whether the phosphaturic effects of PTH and FGF23 are interdependent, 11 patients with hypoparathyroidism, which features high blood phosphate in spite of concomitant FGF23 elevation, and 1 patient with hyperphosphatemic familial tumoral calcinosis (HFTC), characterized by deficient intact FGF23 action and resulting hyperphosphatemia, were treated with synthetic human PTH 1-34 (hPTH 1-34). Biochemical parameters, including blood phosphate, calcium, intact FGF23 (iFGF23), nephrogenic cAMP, 1,25(OH)2 vitamin D (1,25D), and tubular reabsorption of phosphate (TRP), were measured at baseline and after hPTH 1-34 treatment. In patients with hypoparathyroidism, administration of hPTH 1-34 increased nephrogenic cAMP, which resulted in serum phosphate normalization followed by a significant decrease in iFGF23. TRP initially decreased and returned to baseline. In the patient with HFTC, hPTH 1-34 administration also increased nephrogenic cAMP, but this did not produce changes in phosphate or TRP. No changes in calcium were observed in any of the studied patients, although prolonged hPTH 1-34 treatment did induce supraphysiologic 1,25D levels in the patient with HFTC. Our results indicate that PTH and FGF23 effects on phosphate regulation are interdependent and both are required to adequately regulate renal phosphate handling. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.

FGF23-related hypophosphatemic rickets/osteomalacia: diagnosis and new treatment.

FGF23 is a phosphaturic hormone produced by bone. FGF23 reduces serum phosphate by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption. After the identification of FGF23, several kinds of hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) have been shown to be caused by excessive actions of FGF23. Circulatory FGF23 is high in patients with these hypophosphatemic diseases while FGF23 is rather low in those with chronic hypophosphatemia from other causes such as vitamin D deficiency. These results indicate that FGF23 measurement is useful for the differential diagnosis of hypophosphatemia. Chemiluminescent enzyme immunoassay for FGF23 has been approved for clinical use in Japan. The first choice treatment for patients with TIO is complete removal of responsible tumors. However, it is not always possible to find and completely remove responsible tumors. Phosphate and active vitamin D have been used for patients with hypophosphatemic diseases caused by excessive actions of FGF23 including TIO patients with unresectable tumors. However, these medications have limited effects and several adverse events. The inhibition of excessive FGF23 actions has been considered to be a novel therapy for these hypophosphatemic diseases. Human MAB for FGF23, burosumab, has been shown to improve biochemical abnormalities, roentgenological signs of rickets, growth, fracture healing and impaired mineralization in patients with XLH. Burosumab has been approved in several countries including Europe, North America and Japan. Long-term effects of burosumab need to be addressed in future studies.

Increase in phosphaturia by inhibition of renal sodium-dependent phosphate cotransporter NPT2a

Numerous mechanisms are involved in maintaining serum phosphate concentration in the normal range, mainly by regulating phosphate absorption in the gut and tubular phosphate reabsorption in the kidney. In the gut, phosphate is absorbed by passive paracellular diffusion and active transcellular transport, mainly via NPT2b, the major sodium phosphate cotransporter in the small intestine.1 Active phosphate absorption is enhanced by 1,25(OH)2 vitamin D. Intestinal phosphate absorption can be reduced by several approaches,1 including reduction of dietary phosphate intake, chelation of phosphate in the gut lumen,2 specific inhibition of NPT2b activity by small-molecule inhibitors,3 nonspecific inhibition of NPT2b by niacin or its derivative nicotinamide,2 and reduction of passive paracellular phosphate flux via inhibition of the sodium/hydrogen exchanger 3.

One-year follow-up results of patients with prenatally diagnosed hydronephrosis and evaluation of renal functions

Introduction: Hydronephrosis is the most common urologic anomaly detected in the fetus. Obstructive uropathy can cause long-term mortality and morbidity by leading to renal damage and decreasing renal functions. Objective: We aimed to determine the etiological reasons and frequency of prenatal determined hydronephrosis, also to evaluate the association between some (clinical and laboratory) parameters and renal functions during study. Patients and method: 48 patients with antenatally detected hydronephrosis were followed prospectively. The ultrasonography scan and renal functioning tests were performed on day 3rd-7th of life and repeated on week 4th-6th, months 3rd, 6th and 12nd. Results: The degree of hydronephrosis at the end of study was decreased significantly when compared to antenatal hydronephrosis severity (p&lt;0.05). Transient hydronephrosis was diagnosed in 22 (28.9%) of 76 renal unit with prenatal hydronephrosis. Ureteropelvic junction obstruction was the most common cause of antenatal hydronephrosis. Positive correlations between the end study glomerular filtration rate (GFR) and tubular reabsorption of phosphate, blood urea nitrogen and creatinine levels were found at the end of the study. Some significant negative correlations between the end study GFR and fractional excretions of K+ and Mg++ were found at several periods of the study. Conclusion: Transient hydronephrosis is one of the most important reasons of prenatally detected hydronephrosis. The patients with antenatal hydronephrosis must be followed-up closely. Tubular functioning test may be impaired in early stages. The episodic evaluation of tubular functions may predict renal damage before the development of renal failure.

Burosumab in X-linked hypophosphatemia and perspective for chronic kidney disease.

Perturbations in phosphate and vitamin D homeostasis impacts skeletal health in children and adults. Study of inherited and acquired hypophosphatemic syndromes led to the discovery of fibroblast growth factor 23 (FGF23) as a potent regulator of phosphate and vitamin D metabolism, and advanced our understanding of the pathophysiology of mineral and bone disorder in chronic kidney disease (CKD-MBD). Here, we review a recently approved therapy for patients with X-linked hypophosphatemia (XLH) using a novel anti-FGF23 antibody, burosumab, and discuss the implications of such targeted therapy in CKD. In children and adults with XLH, burosumab treatment significantly increased renal tubular phosphate reabsorption and normalized serum phosphorus concentrations. Prolonged treatment with burosumab showed a favorable safety profile, improved healing of rickets in children, and fractures and pseudofractures in adults. FGF23 excess in CKD is independently associated with left ventricular hypertrophy and cardiovascular mortality. Research strategies to lower FGF23 in animal models of CKD are rapidly advancing and a question that remains to be answered is whether FGF23 blockade will offer a new targeted intervention for disordered mineral metabolism in CKD. Findings from recently concluded clinical trials in adults and children with XLH provide evidence for improved skeletal health with burosumab therapy with normalization of phosphate and vitamin D metabolism. Targeted anti-FGF23 antibody treatment of XLH has emerged as a novel therapeutic strategy to treat an inherited disorder of FGF23 excess.

Nephropathic Cystinosis: A Distinct Form of CKD-Mineral and Bone Disorder that Provides Novel Insights into the Regulation of FGF23.

The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD-mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD-mineral and bone disorder. We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis. The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3-5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate. Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.

Mediation of the relationship between proteinuria and serum phosphate: Insight from the KNOW-CKD study.

Proteinuria and hyperphosphatemia are risk factors for cardiovascular disease in patients with chronic kidney disease (CKD). Although the interaction between proteinuria and the serum phosphate level is well established, the mechanistic link between the two, particularly the extent to which this interaction is mediated by phosphate-regulating factors, remains poorly understood. In this study, we examined the association between proteinuria and the serum phosphate level, as well as potential mediators, including circulating fibroblast growth factor (FGF23)/klotho, the 24-h urinary phosphate excretion rate to glomerular filtration rate ratio (EP/GFR), and the 24-h tubular phosphate reabsorption rate to GFR ratio (TRP/GFR). The analyses were performed with data from 1793 patients in whom 24-h urine protein and phosphate, serum phosphate, FGF23, and klotho levels were measured simultaneously, obtained from the KoreaN cohort study for Outcome in patients With Chronic Kidney Disease (KNOW-CKD). Multivariable linear regression and mediation analyses were performed. Total, direct, and indirect effects were also estimated. Patients with high serum phosphate levels were found to be more likely to exhibit greater proteinuria, higher FGF23 levels, and lower klotho levels. The 24-h EP/GFR increased and the 24-h TRP/GFR decreased with increasing proteinuria and CKD progression. Simple mediation analyses showed that 15.4% and 67.9% of the relationship between proteinuria and the serum phosphate level were mediated by the FGF23/klotho ratio and 24-h EP/GFR, respectively. Together, these two factors accounted for 73.1% of the relationship between serum markers. These findings suggest that proteinuria increases the 24-h EP/GFR via the FGF23/klotho axis as a compensatory mechanism for the increased phosphate burden well before the reduction in renal function is first seen.

P0042SPECTRUM OF RENAL INVOLVEMENT IN CHILDREN WITH HNF1B NEPHROPATHY

Abstract Background and Aims Hepatocyte nuclear factor 1 gene (HNF1B) encodes for HNF-1ß, a transcription factor that is expressed early in embryonic development and plays a key role for tissue-specific regulations of gene expression in various organs such as the kidneys, urogenital tract, liver, biliary ducts and pancreas. HNF1B disease (MIM 137920) is recognized to represent an autosomal dominant syndromal disorder comprising variable phenotype with renal and extrarenal manifestations. Renal phenotype in HNF1B nephropathy is highly heterogeneous. The aim of the study was to evaluate the clinical characteristics of renal involvement in children with genetically proven HNF1B nephropathy. Method Five children (2M/3F) from unrelated families with heterozygous HNF1β mutations and kidney disorders were examined. We evaluated serum levels of electrolytes, magnesium (Mg), phosphorus (P), uric acid, acid-base composition; urinary excretion of Ca, P, creatinine (Cr); fractional excretion (FE) of Mg, urate (Ur), Na, K; tubular maximum phosphate reabsorption per GFR (TmP/GFR), and urinary β-2 microglobulin. Molecular genetic analysis was performed using by next generation sequencing. Results Cortical or medullary bilateral renal cysts were detected in all five children with HNF1B nephropathy. Kidney hypoplasia, medullary nephrocalcinosis, and low-grade proteinuria (&amp;lt;0.5 g/m2/d) revealed in 2\5 (40%) of cases. One child had vesicoureteral reflux. All patients with HNF1B nephropathy had normal serum level of uric acid and all electrolytes, including Mg. Increased FE of Mg and urinary excretion of β-2 microglobulin was found in all cases. Increased FE of Ur, Na and K revealed in 4\5 (80%) of subjects. Decreased TmP/GFR had 3\5 (60%) of cases. At the first examination of patients aged 1.0 (IQR: 1.0; 2.0) years all of them already had decreased eGFR to CKD stage 2-3. Conclusion The present study demonstrates that patients with HNF1B-associated disease had wide spectrum of renal involvement. The most prevalent features of HNF1B nephropathy in our children were bilateral renal cysts, defects of proximal tubular function with wasting of electrolytes and progression to CKD stage 2-3 at early age.

P0904EFFECT OF EMPAGLIFLOZIN ON SERUM MARKERS OF OSTEOCYTE AND OSTEOBLAST FUNCTION AND ALBUMINURIA IN DIABETIC AND NON-DIABETIC PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Sodium-glucose co-transporter 2 (SGLT2) inhibitors are new class of oral antidiabetic drugs that show potent cardio- and nephroprotective actions. Despite having a favorable safety profile the treatment with SGLT2 inhibitors has been associated with several side-effects including increased risk of fractures. Although the pathomechanism of this complication has not been elucidated these drugs may inhibit tubular reabsorption of phosphate which may stimulate a secretion of fibroblast growth factor 23 (FGF23). The study was designed to assess the effect of SGLT2 inhibitor on markers of calcium-phosphate metabolism, bone turnover and early glomerular injury in diabetic and non-diabetic patients with stage 3 chronic kidney disease (CKD). Method 41 patients with chronic kidney disease including 23 without diabetes (13 M, 11F, age 52.9±0.7 years, estimated glomerular filtration rate (eGFR) 38.6±10.8 ml/min/1.73 m2) and 18 with type 2 diabetes (12 M, 6F, age 58.8±1.4 years, eGFR 38.8±7.7 ml/min/1.73 m2) were recruited. Main inclusion criteria were CKD stage 3 and urine albumin secretion &amp;gt;100 mg/g creatinine. All subjects received oral empagliflozin 10 mg once daily for 7 days. Serum calcium, phosphorus, parathormone (PTH), calcitriol, bone alkaline phosphatase (BAP), FGF23 and urine calcium, phosphate and albumin were measured at baseline and after 7 days of empagliflozin treatment. Results Plasma calcitriol, serum and urine calcium, phosphorus and BAP did not change significantly during the administration of empagliflozin. Urine phosphate/creatinine ratio was similar in both subgroups at baseline and did not change during empagliflozin administration. Plasma PTH was higher in non-diabetics than in diabetics both at baseline and after empagliflozin. The increase of PTH after empagliflozin tended to be higher in diabetic patients (p=0.07). There was only a trend towards an increase of serum FGF23 in both non-diabetic and diabetic subgroup (by 4.2±0.2 vs. 9.3±1.1 pg/mL, ns). BAP was significantly higher at baseline in diabetic patients but did not significantly change after empagliflozin in the subgroups. Albumin/creatinine ratio decrease after empagliflozin administration was significant only in non-diabetic patients (-62±17 vs. -2±8 mg/g in diabetic patients, p=0.03 for difference). Conclusion Our study showed no effect of short-time administration of empagliflozin on calcium-phosphate and bone metabolism markers in patients with both diabetic and non-diabetic CKD. Empagliflozin decreased albuminuria significantly only in non-diabetic CKD that may suggest a potentially greater nephroprotective effect of this SGLT2 inhibitor in non-diabetic than in diabetic nephropathy.

Kidney and vascular function in adult patients with hereditary fructose intolerance

Objective: Previous studies have shown that patients with hereditary fructose intolerance (HFI) are characterized by a greater intrahepatic triglyceride content, despite a fructose-restricted diet. The present study aimed to examine the long-term consequences of HFI on other aldolase-B-expressing organs, i.e. the kidney and vascular endothelium.Methods: Fifteen adult HFI patients were compared to healthy control individuals matched for age, sex and body mass index. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) and endothelial function by peripheral arterial tonometry, skin laser doppler flowmetry and the endothelial function biomarkers soluble E-selectin [sE-selectin] and von Willebrand factor. Serum creatinine and cystatin C were measured to estimate the glomerular filtration rate (eGFR). Urinary glucose and amino acid excretion and the ratio of tubular maximum reabsorption of phosphate to GFR (TmP/GFR) were determined as measures of proximal tubular function. Results: Median systolic blood pressure was significantly higher in HFI patients (127 versus 122 mmHg, p = .045). Pulse pressure and cf-PWV did not differ between the groups (p = .37 and p = .49, respectively). Of all endothelial function markers, only sE-selectin was significantly higher in HFI patients (p = .004). eGFR was significantly higher in HFI patients than healthy controls (119 versus 104 ml/min/1.73m2, p = .001, respectively). All measurements of proximal tubular function did not differ significantly between the groups.Conclusions: Adult HFI patients treated with a fructose-restricted diet are characterized by a higher sE-selectin level and slightly higher systolic blood pressure, which in time could contribute to a greater cardiovascular risk. The exact cause and, hence, clinical consequences of the higher eGFR in HFI patients, deserves further study.

MON-366 X Linked Hypophosphatemic Rachitism: Case Report in Adult Patient

BACKGROUND: X linked hypophosphatemia (XLH) is a rare genetic disorder, with an estimated prevalence of 1: 20,000 live births resulting from a mutation in the PHEX gene (phosphate regulatory endopeptidase), which causes increased levels of circulating fibroblast growth factor 23 (FGF23), reducing both renal reabsorption of phosphate and serum levels of 1,25-dihydroxyvitamin D3, causing chronic hypophosphatemia, rickets and osteomalacy. CLINICAL CASE: a 34 year old female with a height of 1.34 meters whose past medical history began at the age of three years old with a diagnosis of short stature, associated with genu varum and low serum phosphate levels. She received treatment with phosphate salts and calcitriol until eleven years old. During childhood, she underwent several surgical procedures to correct the genu varum. After stopping the treatment, she has presented four fractures in the lower extremities: bilateral femur, tibia and fibula that have required six surgical interventions (osteotomy, osteosynthesis and external fixation); the last surgery was performed in June of 2019; in addition, she has had multiple dental abscesses that required several oral surgeries. Current laboratory tests report: calcium 8.89 mg/dL (8.6-10), 24-hour urine calcium 72.17 mg (100-300) with urinary volume 1470 ml/24 h, serum creatinine 0.44 mg/dL (0.51-0.95), urine creatinine 43.72 mg/dL (29-226), serum phosphate 1.78 mg/dL (2.5-4.5), urine phosphate 17.75 mg/dL (40-136) PTH 86 pg/mL (15-65), alkaline phosphatase 134 ug/ dL (35-104), 25OH vitamin D 23 ng/mL (30-40). Tubular resorption of phosphate corrected for glomerular filtration rate (TmP/GFR:) 1.6 mg/dL (<2.8), Tubular Reabsorption of Phosphate (TRP) 89.96% (>80). Densitometry revealed a normal bone mineral density (BMD) in lumbar spine and hip. Radiographs of the lower limbs showed a difference of 19 mm of the right lower limb in anatomical length and 13 mm in functional length. A HLX genetic panel was performed, with a result of a definitely pathogenic Gene PHEX linked to chromosome X, with a pathological mutation 22 151 705 G> A p Trp456. The patient started treatment with calcitriol and dibasic phosphorus one month ago because of bone and muscle pain, stiffness, functional limitation, periodontal disease, recent hip fracture and indication of left hip replacement. She is candidate for burosumab (Anti-FGF23 Monoclonal Antibody) treatment.CONCLUSIONS: We present the case of adult patient with X-linked hypophosphatemia. Early treatment with phosphate is essential to avoid bone deformities. In adult patients, identifying pain, fractures or requirement of bone surgery, are indications for continuing treatment to improve quality of life, either with phosphate and calcitriol or with the new option, burosumab for pain control, improving functionality and stiffness.

SUN-345 Use of Anti-FGF23 Monoclonal Antibody in the Treatment of Children and Adolescents with X-Linked Hypophosphatemic Rickets

Background: X-linked hypophosphataemia is the most common heritable form of rickets in children, disorder caused by mutations in PHEX, leading to elevated secretion of FGF23, renal phosphate wasting with consequent hypophosphataemia, diminish synthesis of 1,25(OH)2 vitamin D, rickets/osteomalacia, and disproportionate short stature. Conventional treatment with oral phosphate supplementation and active vitamin D heals rickets, prevents progressive growth failure, but in a substantial proportion of patients treatment is unsuccessful and/or associated with adverse effects. Since 2018, burosumab, a human monoclonal antibody against FGF23, was approved for the treatment of X-linked hypophosphataemia.Aim: We report a pilot experience on the efficacy and safety of treatment with burosumab in children and adolescents with X-linked hypophosphataemia (XLH). Methods and patients: Eight XLH patients (5 males) (5 pre pubertal and 3 Tanner IV) with an age range from 2.9 to 16.2 years, were recruited, 6/8 had family history of XLH, the remaining two were confirmed with molecular study. All discontinue conventional therapy at least 7 days before treatment with Burosumab which was administered every 2 weeks SC for 6 months, at a starting dose of 0.8 mg/kg/dose. Growth velocity, Thacher Rickets Severity Score, fasting serum calcium (mg/dl), phosphorus (P)(mg/dl), alkaline phosphatase (ALP)(IU/L), PTH (pg/dl), 25OH Vitamin D (ng/ml) and tubular phosphate reabsorption (TPR) (X±SD) were evaluated at basal, 3, and 6 months of treatment. Results: All patients had normal 25OH2 Vitamin D: 35.3±8.6 ng/ml at the start of therapy and had significantly improvement of serum P: basal 2.2±0.51, 3 months: 3.24±0.43 and at 6 months 3.01±0.38 mg/dl (p<0.005). The mean serum ALP level decreased from 686.9±410.8 to 535.8±302.4 and 402.5±106.7 IU/L (p<0.05) respectively. TPR normalized during treatment: 67.3±9, 86±3.1, and 86.9±6.1 %(p<0.001). The severity of rickets, as well, showed a significant improvement: 4.0±2.0, 2.3±1.2, and 1.0±0.8 (p<0.005), respectively. The non-pubertal children increased their growth velocity from 3.7±1.2 cm/yr to 7.0±1.4, and 7.9±2.0 cm/yr (p<0.05) respectively. Serum calcium and PTH levels did not show any significantly variation. Mild adverse events such as local reactions and headaches were observed. Conclusions: 1) Treatment with burosumab restores phosphate metabolism, 2) Growth and the Thacher Rickets Severity Score improved during treatment, 3) all patients showed a good safety profile with only minor adverse events. This is the first report of children with XLH treated with burosumab in Latin-America.

Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) GALNT3, which encodes a protein responsible for FGF23 glycosylation; and (3) KL, the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.

SAT-069 Advantages of Next Generation Sequencing (NGS) in Hypophosphatemic Disorders Diagnosis. First Case of SLC9A3R1 Gene Pathogenic Variant Detected in a Pediatric Patient

Background: Hereditary hypophosphatemic rickets (HHR) is a group of inherited disorders characterized by hypophosphatemia due to renal-phosphate wasting and impairment of vitamin D metabolism, rickets and disproportioned short stature. Different genetic defects are known to cause HHR, but similar clinical and biochemical features were reported. Dominant-X-linked HR (XLHR) is the most frequent form, with an incidence of 1 in 20.000, although dominant and recessive autosomal forms are also described. XLHR is caused by inactivating mutations in the PHEX gene (located at Xp22.1), encoding a endopeptidase which regulates the phosphaturic secretion. Affected individuals present with a broad phenotypic spectrum, ranging from isolated hypophosphatemia up to severe symptoms of rickets. Therefore NGS studies represent an useful tool for molecular diagnosis characterization Aim: to develop a reliable NGS diagnostic tool for HHR and related disorders. Patients and Methods: we develop a NGS panel including 13 genes related with HHR or other hypophosphatemic disorders, using Illumina TruSeq Custom Amplicon technology.We analyzed 12 patients which have been sent to our laboratory for molecular genetic testing under suspicion of HHR based on clinical phenotype and laboratory studies but with no proven mutation in PHEX gene by Sanger sequencing or MLPA analysis or other hypophosphatemic disorder. Results: A previously reported pathogenic variant (p.Arg153Gln) was found in SLC9A3R1 gene encoding NHERF1cotransporter, which interact with phosphate and sodium renal transporter NaPi2a in a 13 months old girl. There are only 5 reported cases with alterations in this gene and all of them were adult patients with nephrolithiasis. The patient was referred to our hospital due to hypercalcemia. She had poor weight gain and laboratory findings showed high serum calcium (16,6 mg/dl), mild serum phosphate (3.9 mg/dl), very low parathyroid hormone (PTH) (< 3 ng/ml), normal 25OHvit D (40 ng/ml) levels, and elevated urinary calcium/ creatinine rate (2), and low phosphate tubular reabsorption (85%). Ultrasound showed nephrolithiasis. Since she had hypophosphatemia and renal phosphate wasting with symptomatic severe PTH independent hypercalcemia probably secondary to excessive calcitriol production with hypercalciuria, a molecular alteration of CYP24A1 or SLC34A1genes was suspected. Conclusion: NGS allowed to report for the first time the identification of a mutation in the SLC9A3R1 gene in a pediatric patient. An early diagnosis might improve long term outcome starting the right therapy to avoid progression of nephrolithiasis and nephrocalcinosis and chronic renal failure.

Positive Response to One-Year Treatment With Burosumab in Pediatric Patients With X-Linked Hypophosphatemia.

X-linked hypophosphatemia (XLH) causes significant burden in pediatric patients in spite of maintained treatment with phosphate supplements and vitamin D derivatives. Administration of burosumab has shown promising results in clinical trial but studies assessing its effect in the everyday practice are missing. With this aim, we analyzed the response to one-year treatment with burosumab, injected subcutaneously at 0.8 mg/kg every 2 weeks, in five children (three females) aged from 6 to 16 years, with genetically confirmed XLH. Patients were being treated with phosphate and vitamin D analogs until the beginning of burosumab treatment. In all children, burosumab administration led to normalization of serum phosphate in association with marked increase of tubular reabsorption of phosphate and reduction of elevated serum alkaline phosphatase levels. Baseline height of patients, from −3.56 to −0.46 SD, increased in the three prepubertal children (+0.84, +0.89, and +0.16 SD) during burosumab treatment. Growth improvement was associated with reduction in body mass index (−1.75, −1.47, and −0.17 SD, respectively), suggesting a salutary effect of burosumab on physical activity and body composition. Burosumab was well-tolerated, mild local pain at the injection site and transient and mild headache following the initial doses of burosumab being the only reported undesirable side effects. No patient exhibited hyperphosphatemia, progression of nephrocalcinosis, worsening of metabolic control or developed hyperparathyroidism. Mild elevation of serum PTH present at the beginning of treatment in one patient 4 was not modified by burosumab administration. These results indicate that in the clinical setting, beyond the strict conditions and follow-up of clinical trials, burosumab treatment for 1 year exerts positive effects in pediatric patients with XLH without major adverse events.

Anorexia Nervosa with Markedly High Bone Turnover and Hyperphosphatemia During Refeeding Rectified by Denosumab.

We describe a unique case of hyperphosphatemia associated with a very high bone turnover rate in a 51-year-old postmenopausal woman with undiagnosed anorexia nervosa (AN) who presented with a low-trauma hip fracture. In view of her severely malnourished state, she was not fit for surgery. She was treated according to a refeeding protocol that mandated bed rest. Contrary to expectation, she developed sustained hyperphosphatemia and borderline hypercalcemia. Bone remodelling markers, both resorption and formation, were markedly elevated. Parathyroid hormone (PTH) was low-normal at 1.7pmol/L, C-terminal fibroblast growth factor 23 (FGF23) was high at 293RU/ml, but tubular maximum reabsorption of phosphate (TmPO4/GFR) was elevated at 1.93mmol/L. Denosumab 60mg was administered that was followed by: rapid normalisation of serum phosphate; normalisation of resorption markers, transient hypocalcaemia with secondary hyperparathyroidism, and normalisation of both TmPO4/GFR and C-terminal FGF23. We speculate that prolonged immobilization as part of AN management led to a high remodelling state followed by hyperphosphatemia and high-normal calcium with appropriate suppression of PTH and that marked hyperphosphatemia and high TmP/GFR despite high FGF23 indicates the necessity of PTH adequacy for excess FGF23 to lower TmP/GFR.

Renal phosphate loss in Iraqi chronic myeloid leukemia patients treated by imatinib mesylate

BACKGROUND: The use of BCR-ABL tyrosine kinase inhibitor imatinib mesylate improved outcomes for patients with chronic myeloid leukemia (CML). Hypophosphatemia is found to be associated with imatinib mesylate use; the exact mechanism of this is not clear yet but mostly related to a drug-induced proximal renal tubular defect.OBJECTIVE: The objective was to measure the renal phosphate loss in CML patients treated by imatinib mesylate.PATIENTS AND METHODS: A cross-sectional study included 40 patients (25 females) who were already diagnosed cases and treated with imatinib mesylate (400 mg/day). The mean age was 40.2 ± 7.8 years. The study was conducted at the medical city teaching hospital, Baghdad, hematology outpatient clinic from July 2016 to December 2016. Serum and random urine samples were measured phosphate and creatinine in serum and urine, respectively. Serum and urine phosphate were measured using the colorimetric method, whereas serum and urine creatinine were calculated by the kinetic method. Fractional excretion of phosphate and tubular maximum of phosphate reabsorption were calculated. After the completion of the study, we tested ten newly diagnosed patients at 0- and 3 months of treatment.RESULTS: Sixteen patients (40%) developed hypophosphatemia. The fractional excretion of phosphate increased (FEPO4 = 21.1%) with a comparable reduction in tubular reabsorption of phosphate to the glomerular filtration rate (Tmpi/GFR = 2.3 mg/dl). There was a significant direct correlation between SPO4 level and white blood cell count (R = 0.451; P = 0.001). The mean intact parathyroid hormone and Vitamin D levels were normal for the study group. All ten newly diagnosed cases developed hypophosphatemia at 3 months. This was statistically significant (P = 0.002). There increase in FEPO4 and decrease in Tmpi/GFR was statistically significant (P < 0.001 and 0.002), respectively.CONCLUSION: Hypophosphatemia while using imatinib mesylate is due to increased urinary phosphate excretion.

Oral Iron for Prevention and Treatment of Rickets and Osteomalacia in Autosomal Dominant Hypophosphatemia.

ABSTRACT Autosomal dominant hypophosphatemia (ADH) causes rickets, osteomalacia, and taurodontism due to heterozygous mutations in FGF23, which inhibit the inactivation (cleavage) of the encoded protein, the hormone fibroblast growth factor 23 (FGF23). Iron deficiency increases FGF23 mRNA expression and recent evidence suggests that the recurrent, late-onset, or waxing-waning hypophosphatemic phenotype may be linked to synchronous variations in iron status. The fact that most adult symptomatic ADH patients are females during reproductive age supports the notion of a gene-environmental interaction. Practically all symptomatic hypophosphatemic patients described in the recent literature were also iron deficient (with/without anemia) at presentation, when measured. Given its interaction with FGF23, correcting iron deficiency should therefore also correct FGF23 excess. Following the original report of successful phenotype reversal in an iron-deficient ADH child using oral iron supplementation in 2015, more evidence has emerged that supports the use of the element iron to restore homoeostasis of the element phosphorus (in addition to its own). We put into perspective the recent evidence and add 14 years observational data on the original case that demonstrates the correlation of serum phosphorus and renal tubular phosphate reabsorption in mass per unit volume of glomerular filtrate (TmP/GFR) with serum ferritin. Presentation and relapse of ADH, 12 years apart, occurred during iron deficiency, and the onset of menstrual periods was associated with relapse. Here we propose management guidance for patients affected by ADH throughout the lifespan based on iron stores. Because ferritin correlates best with hypophosphatemia historically, and in long-term observation of the originally treated case, it should be used as the monitoring tool and kept in the normal range. Women with ADH who are of reproductive age and other risk groups require supplementation with oral iron using WHO guidelines. Treatment of this form of FGF23 excess may not require phosphate and active vitamin D, or burosumab. © 2020 American Society for Bone and Mineral Research

2491. Virologic Response of Switching Tenofovir Disoproxil Fumarate (TDF)-Based Regimen to Abacavir (ABC)-Based Regimen vs. Lopinavir/Ritonavir(LPV/r) Plus Lamivudine(3TC) in HIV-Infected Patients with TDF-Induced Nephrotoxicity at 24 Weeks: A Prospective, Open-Label, Randomized, Controlled Trial

BackgroundTenofovir disoproxil fumarate (TDF)-induced nephrotoxicity is a well-recognized complication and one of the reasons for treatment switching in HIV-infected patients. Salvage regimens in renal impairment such as abacavir(ABC)-based regimen or two-drug regimens such as boosted protease inhibitor (PI) plus lamivudine (3TC) are the options for switching. However, ABC is contraindicated in patients with a high risk for cardiovascular disease. In resource-limited setting, only some PIs such as lopinavir and atazanavir are available options.MethodsWe conducted a prospective, open-label, randomized controlled trial in a tertiary center in Bangkok. We recruited HIV-infected adults who had viral suppression, with TDF-induced proximal tubulopathy and/or a significant decrease in estimated glomerular filtration rate(eGFR). The patients were randomized to receive ABC/3TC plus efavirenz (ABC-based regimen) or LPV/r+3TC. The primary outcome was the proportion of patients with viral suppression at 24 weeks. The secondary outcomes were the immunologic response, recovery of eGFR, proximal tubular function and change in lipid profile at 24 weeks.ResultsBetween August 2018 - February 2019, we screened 87 patients and enrolled 24 patients were randomly assigned to the ABC-based regimen and 23 patients to LPV/r+3TC regimen. In the intention-to-treat population, virologic response at 24 weeks was noted in 21 (87.5%) patients assigned to ABC-based regimen and 19 (82.6%) patients assigned to LPV/r+3TC regimen (P = 0.635). There were no differences in the improvement of the percentage change of eGFR, fractional excretion of phosphate, renal tubular reabsorption of phosphate (TmP/GFR), fractional excretion of uric and UPCI at 24 weeks. Triglyceride levels were significantly increased in LPV/r+3TC regimen compared with ABC-based regimen at 24 weeks (91.32% vs. 20.46%; P = 0.001).ConclusionOur study showed no difference in virologic suppression after switching to ABC-based regimen or LPV/r+3TC regimen in patients with TDF-induced nephrotoxicity. There was no difference in percentage change of eGFR, recovery of proximal tubular function in both arms after discontinuation of TDF. There was a significant change in triglyceride levels in LPV/r +3TC regimen.Disclosures All authors: No reported disclosures.