Renal Phosphate Loss Research Articles

Effects of SLC34A3 or SLC34A1 variants on calcium and phosphorus homeostasis.

Variants in SLC34A1 and SLC34A2 genes, which encode co-transporters NaPi2a and NaPi2c, respectively, can lead to hypophosphatemia due to renal phosphate loss. This condition results in hypercalcitriolemia and hypercalciuria, leading to formation of kidney stones and nephrocalcinosis. Phenotype is highly variable. Management includes hyperhydration, dietary modifications, and/or phosphate supplementation. Thiazides and azoles may be used, but randomized studies are needed to confirm their clinical efficacy. We conducted a retrospective study in the pediatric nephrology unit at Grenoble University Hospital from January 2010 to December 2023. The study aimed to describe clinical and biological symptoms of patients with confirmed SLC34A1 and SLC34A3 gene variants and their outcomes. A total of 11 patients (9 females) from 6 different families had variants in the SLC34A1 (5 patients) and SLC34A3 (6 patients) genes. Median age at diagnosis was 72 [1-108] months. Average follow-up duration was 8.1 ± 4.5years. Presenting symptom was nephrocalcinosis (4 cases), followed by renal colic (3 cases). At diagnosis, 90% of patients had hypercalciuria and 45% had hypercalcitriolemia. Management included hyperhydration and dietary advice. All patients showed favorable outcomes with normal growth and school attendance. One patient with an SLC34A3 variant showed regression of nephrocalcinosis. Kidney function remained normal. Clinical and biological manifestations of SLC34 gene variants are highly variable, even among siblings; therefore, management must be personalized. Hygienic and dietary measures (such as hyperhydration, a low sodium diet, and age-appropriate calcium intake) result in favorable outcomes in most cases. Use of azoles (e.g., fluconazole) appears to be a promising therapeutic option.

#2015 Burosumab therapy in adult patients with X-linked hypophosphatemia: a three-year follow-up study

Abstract Background and Aims X-linked hypophosphatemic rickets (XLH) arises from mutations in the PHEX gene, resulting in elevated FGF23 levels, renal phosphate loss, hypophosphatemia, low vitamin D, heightened alkaline phosphatase (AP), and associated bone disorders. In challenging the conventional therapy of vitamin D and phosphate supplements, Burosumab, a monoclonal antibody against FGF23, has shown promise in normalizing phosphate and vitamin D levels in pediatric patients. However, its effectiveness in adult patients with established bone lesions remains an area of investigation. This study aims to present the three-year outcomes of Burosumab therapy on both biochemical and clinical aspects in adult XLH patients. Method The study assessed the efficacy of Burosumab in adult XLH patients (age >18, drug-naïve) before and continuously over three years post-therapy. Monthly assessments of biochemical parameters (phosphatemia, alkaline phosphatase, Tubular Maximum Reabsorption of Phosphate per Glomerular Filtration Rate, TMP/GFR) were conducted before the monthly administration of Burosumab, while clinical improvements were monitored every six months using established tests, including the six-minute walk test, UP and go timed test, and WOMAC Index. Burosumab was administered monthly at a consistent dosage of 1 mg/kg throughout the entire follow-up period. Results In a cohort of five genetically diagnosed XLH patients (average age 45 ± 10 years, average weight 60 ± 10 kg), the average monthly Burosumab dose was 60 ± 10 mg. Baseline values and subsequent changes in Ps, TMP/GFR, WOMAC Index, six-minute walk, and UP and go test are presented in Table 1 and Fig. 1. Importantly, no significant adverse events were reported during the initial year of treatment. Conclusion Burosumab therapy demonstrated excellent tolerability and yielded substantial improvements in biochemical parameters (Ps and TMP/GFR), maintaining stability over the entire three-year follow-up. Alkaline phosphatase levels, initially elevated, exhibited a progressive reduction in the second and third years, eventually reaching values within the normal range. Functional indices, reflective of enhanced strength (improved walk test and UP and go timed test) and diminished pain (optimal WOMAC test score), showcased notable improvements in the first year, persisting with stability during the follow-up period, with the exception of the walk test, which demonstrated a gradual and sustained enhancement. The findings suggest that Burosumab is a well-tolerated and effective therapeutic option for adult XLH patients. The observed reduction in alkaline phosphatase after a year of treatment implies a normalization of bone turnover, while the progressive improvement in the walk test indicates a sustained clinical enhancement likely associated with the chronic positive effects of maintaining biochemical stability.

#5571 THERAPY WITH BUROSUMAB IN ADULT PATIENTS WITH X-LINKED HYPOPHOSPHATEMIA: A YEAR OF FOLLOW-UP

Abstract Background and Aims X-linked hypophosphatemic rickets (XLH) is a genetic disorder secondary to the mutation of the PHEX gene that results in increased circulating levels of FGF23. Increased FGF23 causes hypophosphatemia secondary to renal phosphate loss. Clinically, the disease is characterized by reduced growth, bone alterations, weakness, chronic pain and reduced mobility. From a biochemical point of view, patients have hypophosphatemia, increased values of alkaline phosphatase, increased fraction excretion of phosphate (FEP). Recently, therapy with Burosumab, a monoclonal antibody against FGF23, has been introduced. Burosumab by reducing the receptor availability of circulating FGF23 reduces its activity. This leads to a normalization of serum phosphate and in paediatric patients an improvement of the clinical phenotype. In adult patients, the effectiveness of therapy in improving the clinical outcome and quality of life is being investigated. The purpose of the study was to evaluate the efficacy in improving the biochemical, bone and clinical picture of adult patients with XLH in therapy with Burosumab for one year. Method We enrolled patients with XLH naive for Burosumab therapy. In all we evaluated the biochemical aspects (phospahatemia, alkaline phosphatase, FEP), bone Radiographic Global Impression of Change score and clinical improvements (six-minute walk test, UP and go timed test, WOMAC Index) pre therapy and after a year of therapy. Burosumab was administered monthly at a dose of 1 mg/Kg. Results We enrolled 5 patients (45 ± 10 year old, weight 60 ± 10 Kg, Burosumab dose 60 ±10 mg) with genetic diagnosis of XLH. The comparison between pre therapy and post-one-year therapy showed in all patients: increase in average phosphatemia (pre 1.9± 0.5 mg/dl vs post 3.4 ±0.6 mg/dl p = 0.003), reduction in FEP (pre 50 ±15% vs 20 ±10% p = 0.004), reduction of UP and go timed test (pre 20± 5 sec vs post 11 ±5 sec p = 0.005) increase of the distance in the six minutes’ walk test (pre 150 ± 30 meters vs post 250 ± 50 meters p = 0.01), improvement of the WOMAC test (pre 15± 3 vs post 5± 2; p = 0.008) and reduction of the Radiographic Global Impression of Change score (pre -2 ±0.5 and post 2± 0.4; p = 0.001). The serum value of alkaline phosphate was high and it did not change with the Burosumab therapy (pre 200±50 UI/L vs post 220±60 UI/L; p: n.s. n.v. 33–98 UI/L). No patients had significant complications during the first year of treatment. Conclusion The therapy with Burosumab was well tolerated by patients. It resulted in a marked improvement in the biochemical picture associated with a better quality of life identified by increased strength (improved walk test and UP and go timed test) reduction of pain (best WOMAC test) and bone damage score. In conclusion, Burosumab may be a good and safe therapy option for adults’ patients with XLH.

TUMOR INDUCED OSTEOMALACIA: A CASE REPORT

Background:Tumor-induced osteomalacia (TIO), which is also known as oncogenic osteomalacia, is an uncommon paraneoplastic syndrome characterized by a renal phosphate loss causing hypophosphatemia, leading to rickets in children and osteomalacia in adults. It is caused by mesenchymal tumors, which secrete FGF-23 (fibroblast growth factor-23) and rarely other phosphotonins. It can present with a wide range of symptoms and there is often a delay in its diagnosis. Early diagnosis is important and surgical excision can cure the disease in most patients, thus preventing the complications.We report a case of TIO, who was diagnosed at an early stage and underwent curative surgery. Case presentation: A 30 years old female presented with pain in both legs, more severe in the left leg since about 1 year. She also had difficulty in walking, low back ache, muscle pain, mild pain in both the knee joints as well. On examination, she had limping gait, muscle power in the left leg was grade 3-4 otherwise, there was no significant findings on examination. Blood investigations showed elevated alkaline phosphatase (ALP)- 387IU/ml, low serum phosphorus- 1.2mg/dl, normal calcium - 9.8mg/dl, 25-OH Vitamin D- 24.69ng/ml, Parathyroid hormone (PTH)- 61pg/ml.Other blood tests were unremarkable. X- rays of both the legs and pelvis showed a classicalpseudo-fracture in proximal part of both the fibulae and proximal part of the right femur. This suggested hypophosphatemicosteomalacia. TmP/GFR was found to be very low (1.4mg/dl), which confirmed renal phosphate wasting. Later we got Fibroblast growth factor – 23 (FGF-23)- 617RU/ml, which was elevated. This confirmed FGF-23 related hypophosphatemicosteomalacia. In view of the patients age, onset of symptoms, lack of family history, absence of dental and hearing abnormalities, we suspected an acquired rather than a genetic cause. The patient underwent whole body Gallium-68 DOTANOC PET scan, which revealed somatostatin receptor expressing soft tissue density lesion in subcutaneous plane in the mid- anterior right leg, suggestive of FGF-23 secreting mesenchymal tumor.The patient was initially treated with replacement dose of oral phosphorus and calcitriol, along with calcium and vitamin D supplements. Later the patient underwent surgery for excision of the tumor in the right leg. The tumor was around 2cm size and the histopathology was suggestive of gaint cell rich tumor- possibly a phosphaturic mesenchymal tumor. Post surgery, the patient had significant improvement in her symptoms, gait improved and pain reduced. The serum phosphorus level was 3.8mg/dl post-operatively. The serum phosphorus level was maintained without phosphorus replacement. The patient was advised to repeat FGF-23 levels, but the patient failed to get it done. Conclusion: The diagnosis of TIO requires high index of suspicion and should always be looked as a differential diagnosis when we are evaluating a patient with osteomalacia. A detailed history and examination followed by a step wise biochemical evaluation and imaging is important to diagnose TIO in early stages. Surgical resection of the causative tumor will lead to definitve cure of the disease in most patients and avoids the complications like osteoporosis and fractures, thus improving the quality of life of the patients.

Reflections on TRP and TP/GFR in the definition of renal phosphate loss: conceptual review.

Fractional tubular reabsorption of phosphate (TRP) has been used for over 60years to establish the existence of renal phosphate loss. It is a parameter of corrected volume per decilitre of glomerular filtration rate (GFR). Later, a mass parameter per dl GFR called TP/GFR (tubular PO4 reabsorption per dl GFR) was devised which some authors have sought to substitute for TRP. The aim of the present work is to attempt to demonstrate that TRP and TP/GFR are similar parameters and, in certain aspects, TRP is more effective for diagnosis. Data were gathered on the metabolism of phosphate corresponding to a group of healthy children without hypophosphatemia (n = 47), a group of patients with idiopathic hypercalciuria (n = 27), and ten patients diagnosed with X-linked hypophosphatemia (XLH). The TRP, the TP/GFR, and the percent tubular reabsorption of phosphate were calculated. All the patients with XLH presented TRP values lower than 95ml/dl GFR and of TP/GFR equal to or lower than 2.8mg/dl GFR. In the total sample, a direct correlation was observed between TRP and TP/GFR (r = 0.65; p = 0.01). The TRP and the percent tubular reabsorption of phosphate values were the same in the three groups (r = 1; p = 0.01). TRP and TP/GFR are similar parameters. TRP is more effective than TP/GFR given that in renal hypophosphatemia it is always below 95% and above 95% in reduced phosphatemia and normal kidney proximal tubular function. There is no solid reason for using TP/GFR rather than TRP. A higher resolution version of the Graphical abstract is available as Supplementary information.

Mild Hypophosphatemia-Associated Conditions in Children: The Need for a Comprehensive Approach.

To better understand the causes of hypophosphatemia in children, we evaluated all serum phosphate tests performed in a tertiary hospital with unexpected but persistent temporary or isolated hypophosphatemia over an 18 year period. We collected 29,279 phosphate tests from 21,398 patients, of which 268 (1.2%) had at least one result showing hypophosphatemia. We found that endocrinopathies (n = 60), tumors (n = 10), and vitamin D deficiency (n = 3) were the medical conditions most commonly associated with mild hypophosphatemia, but in many patients the cause was unclear. Among patients with endocrinopathies, those with diabetes mellitus were found to have lower mean serum phosphate levels (mean 3.4 mg/dL) than those with short stature (3.7 mg/dL) or thyroid disorders (3.7 mg/dL). In addition, we found a correlation between glycemia and phosphatemia in patients with diabetes. However, despite the potential relevance of monitoring phosphate homeostasis and the underlying etiologic mechanisms, renal phosphate losses were estimated in less than 5% of patients with hypophosphatemia. In the pediatric age group, malignancies, hypovitaminosis D, and endocrine disorders, mostly diabetes, were the most common causes of hypophosphatemia. This real-world study also shows that hypophosphatemia is frequently neglected and inadequately evaluated by pediatricians, which emphasizes the need for more education and awareness about this condition to prevent its potentially deleterious consequences.

Impact of X-Linked Hypophosphatemia on Muscle Symptoms

X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets and deficiency of renal tubular phosphate transport in humans. XLH is caused by the inactivation of mutations within the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene and follows an X-dominant transmission. It has an estimated frequency of 1 case per 20,000, and over 300 distinct pathogenic variations have been reported that result in an excess of fibroblast growth factor 23 (FGF23) in the serum. Increased levels of FGF23 lead to renal phosphate loss, decreased serum 1,25-dihydroxyvitamin D, and increased metabolism of 1,25-dihydoxyvitamin D, resulting in hypophosphatemia. Major clinical manifestations include rickets, bone deformities, and growth retardation that develop during childhood, and osteomalacia-related fractures or pseudo-fractures, degenerative osteoarthritis, enthesopathy, dental anomalies, and hearing loss during adulthood, which can affect quality of life. In addition, fatigue is also a common symptom in patients with XLH, who experience decreased motion, muscle weakness, and pain, contributing to altered quality of life. The clinical and biomedical characteristics of XLH are extensively defined in bone tissue since skeletal deformations and mineralization defects are the most evident effects of high FGF23 and low serum phosphate levels. However, despite the muscular symptoms that XLH causes, very few reports are available on the effects of FGF23 and phosphate in muscle tissue. Given the close relationship between bones and skeletal muscles, studying the effects of FGF23 and phosphate on muscle could provide additional opportunities to understand the interactions between these two important compartments of the body. By describing the current literature on XLH and skeletal muscle dysfunctions, the purpose of this review is to highlight future areas of research that could contribute to a better understanding of XLH muscular disability and its management.

PSAT219 Renal Phosphate Wasting Caused by ENPP-1 mutation.

Abstract Background Increased renal phosphate loss can be Fibroblast Growth Factor-23 (FGF-23) dependent or independent. FGF-23 reduces expression of Sodium-Phosphate co-transporters, responsible for phosphate reabsorption; and by inhibition of 1-alpha hydroxylation of 25-OH-D3. Reduced serum concentration of 1, 25-OH2-D3 results in secondary hyperparathyroidism. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) mutation is one of the rarest causes of hypophosphatemia, which causes FGF-23 dependent hypophosphatemia. Case description 31-year-old female referred to endocrinology for evaluation of recurrent nephrolithiasis despite normalization of PTH and serum Calcium (Ca) after right inferior parathyroid adenoma resection. Repeated renal stone analysis revealed calcium phosphate as the major stone composition. Patient achieved mid parental height, denied history of calcium or phosphate metabolism disorders/ rickets in the family. Physical exam was not suggestive of rickets and skeletal survey showed normal bone mineralization. Initial labs following parathyroid adenoma resection showed normal Ca 9.7 mg/dl, PTH 47 pg/ml, Phosphorus (Ph) 2.3 mg/dl, 25-OH-D3 51 ng/ml, albumin 3.9 g/dl, Mg 1.8 mg/dl. Repeat fasting labs six months later revealed Ca 9 mg/dl, Ph 1.7 mg/dl, 25-OH-D3 52 ng/ml, PTH 67.5 pg/ml and albumin 3.7 g/dl. Persistent low serum phosphate was evaluated further by a 24-hour urine collection which revealed high urine phosphate of 828 mg/day, Ca 181 mg/day, Mg 23 mg/day and creatinine was 1485 mg/day. Tubular reabsorption of phosphorus was 77% (normal: >80%), indicating renal phosphate wasting. Serum FGF-23 on two different days was >180 RU/ml. Next-generation sequencing tested positive for heterozygous ENPP-1 gene mutation variant c1441C>T (p. Arg481Trp). Patient was started on oral Phosphorus supplementation & calcitriol. Repeat labs showed normalization of Ph 2.4 mg/dl. Audiology evaluation suggested mild sensorineural hearing loss. Heart calcium score was zero. Discussion ENPP1 gene mutation's clinical presentations can vary from no symptoms, hypophosphatemic rickets to death in the first six months of life from generalized arterial calcification. ENPP1 is an enzyme, which degrades ATP into adenosine monophosphate (AMP) and pyrophosphate (PPi). PPI is an inhibitor of hydroxyapatite crystallization in vascular tissue and organs, while Ph is a pro-mineralization factor. ENPP1 gene mutation results in a low concentration of PPi, predisposing the patient to pathological calcification. It is speculated that ENPP-1 modulates FGF-23 secretion. FGF-23 elevation in these patients is a protective response, as hypophosphatemia prevents pathological calcification. Treatment target is to keep phosphate at low end of normal. In our patient, ENPP- 1 mutation likely contributed to recurrent renal stones and possible parathyroid adenoma. Evaluation of genetic mutations is necessary to decide for or against FGF-23 antibody/Burosumab treatment. In ENPP-1 mutation. Burosumab should be avoided as it can bind to FGF-23 resulting in pathological calcification. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Persistently Augmented FGF-23 Serum Values in a Surgically Resolved Oncogenic Osteomalacia Patient with No Tumor and Inflammatory Activity

Objective: Oncogenic osteomalacia is a paraneoplastic syndrome characterized by severe hypophosphatemia, hyperphosphaturia, and osteomalacia subordinated to renal loss of phosphate. It is caused by overproduction of phosphatonin fibroblast growth factor-23 by benign mesenchymal tumors which, when surgically eliminated, returns to basal levels. Methods: We report a case of a patient with oncogenic osteomalacia from a sacrum mesenchymal tumor whose FGF-23 levels remain elevated two years after successful surgical treatment. Results: A 53-year-old man with severe difficulty to walk and stand, severe hypophosphatemia, hyperphosphaturia, and raised levels of alkaline phosphatase and FGF-23 was diagnosed with oncogenic osteomalacia after a thorough process of elimination of causes of hyphosphatemia were excluded. Despite systemic chemotherapy, surgical removal of sacrum, primary mesenchymal tumor, phosphate and calcium supplementation, and no evidence of tumor recurrence, the serum concentration of FGF-23 remains elevated two years after discharge. Conclusions: The possible underlying mechanisms of sustained FGF-23 serum concentrations in this patient suggest the presence of molecular alterations in the FGF/FGFR signaling pathway.

39-Year-Old Woman With Severe Weakness

39-Year-Old Woman With Severe Weakness

Enfermedades metabólicas óseas: osteomalacia

The term osteomalacia traditionally refers to a characteristic skeletal disease that is documented radiologically or histologically, not just the clinical or biochemical abnormalities. Osteomalacia is currently defined as a mineralization defect in the recently formed bone matrix, leading to accumulation of osteoid. The principal causes of osteomalacia are a vitamin D disorder, renal phosphate loss, or uncommon causes related to a direct abnormality in the mineralization process.Osteomalacia causes greater bone fragility, with the appearance of spontaneous fissures or fractures. Although it is an uncommon entity, it should be suspected when faced with symptoms of diffuse osteoarticular pain. In very advanced forms, an X-ray will show biconcave vertebrae or long bone deformity with pseudofractures or Looser's zones. A transiliac crest bone biopsy with double tetracycline labeling and its histomorphometric evaluation is the most precise way of diagnosing osteomalacia. However, it is not usually performed in clinical practice as it is an invasive technique. Therefore, a diagnosis tends to be made based on a combination of clinical and laboratory data and radiological findings. The treatment is what is indicated for the underlying pathology that triggered the osteomalacia, although vitamin D supplementation may be considered the essential pillar of therapy.

Evaluation of proximal tubule functions in children with COVID-19: a prospective analytical study.

BackgroundThere are limited numbers of studies focusing on renal effects of coronavirus disease 2019 (COVID-19) infection and proximal tubular dysfunction in children with COVID-19 infections. The purpose of this study was to evaluate the functions of the proximal tubule in hospitalized children with confirmed acute COVID-19.MethodsThe children who were hospitalized for confirmed COVID-19 were included in this prospective descriptive analysis. The presence of at least two of the following four abnormalities was used to diagnose proximal tubule injury: abnormal tubular reabsorption of phosphate, normoglycemic glycosuria, hyperuricosuria, and proteinuria.ResultsA total of 115 patients were included in the study. About a third of the individuals had elevated blood creatinine levels or proteinuria. In addition, abnormal renal tubular phosphate loss measured by renal tubular phosphate loss was found in 10 (8.7%) patients, as was hyperuricosuria in 28.6%. As a result, total proximal tubular dysfunction was found in 24 (20.9%) patients.ConclusionsOne in every five children with acute COVID-19 infections had proximal tubular dysfunction, according to our data. Although, the rate of proximal tubular dysfunction was lower than in adults, it should be noted. The recovery of proximal tubular function in children with COVID-19 should be followed.

Tumor Induced Osteomalacia - Long Term Medical Treatment When Surgery Is Risky

Introduction: Tumor induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by bone pain, muscle weakness and fractures caused by production of a phosphaturic factor by rare mesenchymal bone or soft tissue tumors that causes isolated renal phosphate loss and osteomalacia. Low phosphate (iP), high bone alkaline phosphatase (BAP), and normal or low 125 dihydroxy D, are salient biochemical findings. Fibroblast derived growth factor (FGF 23) may be high or inappropriately normal. Gallium-68 Dotatate (DoT) imaging has become the imaging method of choice. Long term medical management may be required when removal of the tumor is risky or not feasable. Case Report: 65 yr old woman with carcinoid tumor of the right lung and a bony lesion in the T3 vertebral body diagnosed with TIO. She was initially screened for osteoporosis after traumatic rib fractures. Bone scan and SPECT-CT revealed numerous foci of increased uptake. She had elevated alkaline phosphatase 186 IU/L (0–140) and PTH 83 pg/ml (15–65) with a low phosphate 1.5 mg/dl (2.5–4.5), along with normal FGF23 level 102 RU/ml Ref Range < + 180 RU/ml. DoT and PET CT imaging for TIO evaluation showed a foci of increased uptake right lower lobe of her lung, and “osseous metastatic disease” in the right scapula, vertebral body, iliac, and pubic ramus. Sclerosis of T3 vertebral body was noted in the area of intense Gallium Dotatate uptake. Transbronchial excision of the lesion showed a well differentiated neuroendocrine carcinoma. Chromogranin A and 24 hour urine for 5HIAA were normal. She responded well to medical therapy with oral phosphate, calcium and calcitriol. Follow up, DoT and FDG PET showed persistent intense uptake in the sclerotic lesion on T3 vertebral body, while the rest of the hot spots resolved. Sclerotic T3 lesion is likely the primary lesion that is responsible for the TIO. Neuroendocrine tumor of the lung may be a mere association. Biopsy of the T3 lesion was not feasible and excision was considered risky to the patient. Discussion: Our case illustrates that awareness is the key to early diagnosis of TIO. FGF 23 in some TIO cases may be inappropriately normal in commercial assays and even in research labs. Measurement of fibronectin 1 (FN1) and FGF receptor 1 fusion gene which is noted in up to 60% of tumors are not commercially available. While DoT and PET CT are imaging modality of choice, CT and MRI may be useful to define the anatomy of the lesion. Long term medical management may be necessary when removal of primary lesion is not possible or risky. Most tumors are benign while some may prove to be malignant.

Phenotypic characterization of X-linked hypophosphatemia in pediatric Spanish population

BackgroundX-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.ResultsThe 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.ConclusionsThis 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.

Hypophosphatemia is an independent risk factor for AKI among hospitalized patients with COVID-19 infection

Background This study sought to investigate incidence and risk factors for acute kidney injury (AKI) in hospitalized COVID-19. Methods In this retrospective study, we enrolled 823 COVID-19 patients with at least two evaluations of renal function during hospitalization from four hospitals in Wuhan, China between February 2020 and April 2020. Clinical and laboratory parameters at the time of admission and follow-up data were recorded. Systemic renal tubular dysfunction was evaluated via 24-h urine collections in a subgroup of 55 patients. Results In total, 823 patients were enrolled (50.5% male) with a mean age of 60.9 ± 14.9 years. AKI occurred in 38 (40.9%) ICU cases but only 6 (0.8%) non-ICU cases. Using forward stepwise Cox regression analysis, we found eight independent risk factors for AKI including decreased platelet level, lower albumin level, lower phosphorus level, higher level of lactate dehydrogenase (LDH), procalcitonin, C-reactive protein (CRP), urea, and prothrombin time (PT) on admission. For every 0.1 mmol/L decreases in serum phosphorus level, patients had a 1.34-fold (95% CI 1.14–1.58) increased risk of AKI. Patients with hypophosphatemia were likely to be older and with lower lymphocyte count, lower serum albumin level, lower uric acid, higher LDH, and higher CRP. Furthermore, serum phosphorus level was positively correlated with phosphate tubular maximum per volume of filtrate (TmP/GFR) (Pearson r = 0.66, p < .001) in subgroup analysis, indicating renal phosphate loss via proximal renal tubular dysfunction. Conclusion The AKI incidence was very low in non-ICU patients as compared to ICU patients. Hypophosphatemia is an independent risk factor for AKI in patients hospitalized for COVID-19 infection.

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.

320. UK-HOPS (HIV Osteoporosis Prevention and Screening)-Gaps in the Care of HIV Patients with Bone Disease

BackgroundWith increasing life expectancy among people living with Human Immunodeficiency Virus (HIV), long-term complications such as osteoporosis/osteopenia and fractures are frequently seen. Although screening guidelines exist for bone disease in the HIV population, quantitative and qualitative gaps exist in screening and prevention. Bone disease in HIV is multifactorial, and FRAX may not accurately predict fracture risk. The aim of our study is to describe diagnostic features of bone disease and estimate the population at risk, and evaluate the frequency of screening, referral and treatment in patients attending an HIV Clinic.MethodsWe performed a retrospective analysis of 1220 patients with HIV infection ≥40 years of age who attended the HIV clinic under the Ryan White program, during January 2016 to December 2018, at University of Kentucky. We obtained demographic details (Table 1), comorbidities, laboratory testing, bone mineral density (BMD) testing and specialty bone clinic referral data from electronic health records, applying ICD -10 and CPT codes. We estimated the frequency of BMD measurement and prevalence of risk factors for bone disease specific to this population.ResultsBMD testing was performed in only 158 (13%) patients (CMS targets 60% for testing at-risk populations). Of these patients, 76 (48%) had osteopenia and 59 (37%) had osteoporosis; 22 (14%) received treatment (Figure 1). Seven patients with osteoporosis/osteopenia and fracture had bone biopsy, with low bone turnover in four (57%). Potential risk factors for secondary osteoporosis are presented in Table 2; at least one factor was present in 98% of patients. Fracture prevalence was likely underestimated because the ICD-10 /CPT coding was available only in 23 (2%) patients.ConclusionBone disease is under-recognized and undertreated, and targeted screening programs are needed for earlier diagnosis and management in this population. Bisphosphonates may not be optimal first-line therapy for all HIV patients with bone loss. In addition to stress or fragility fractures and worsening osteoporosis, metabolic bone work-up should be performed in patients with secondary osteoporosis related to CKD, renal phosphate loss, prior bisphosphonate/Tenofovir/glucocorticoid treatment. Disclosures All authors: No reported disclosures.

MON-490 Iatrogenic Hypophosphatemia Presenting as Low Bone Mass

Introduction: The incidence of osteomalacia is 1 in every 1000 individuals and the most common cause is vitamin D deficiency. Hypophosphatemia is a less recognized but important etiology of osteomalacia. Here we describe a case who was referred to Endocrinology for osteoporosis but was found to have medication induced hypophosphatemic osteomalacia. Case: A 68 years old woman from Thailand with known past medical history of chronic hepatitis B infection, Sjogren’s syndrome, lung cancer s/p lobectomy had screening DEXA scan which showed T score of -2.9SD at Forearm. She was referred to Endocrinology for osteoporosis work up. She reported at least 8-month long history of myalgia and noticed pain in the chest wall exacerbated by motion such as rolling in bed for the last few months. Blood work showed normal calcium, robust vitamin D and high bone specific alkaline phosphatase levels. Phosphorus levels were noted to be in the range of 1.4 to 2.1 mg/dl for 2 years before the presentation and fractional excretion of phosphorous was 71%. Bone scan showed foci of increased radiotracer uptake in multiple ribs which correlated to the site of prior thoracotomy. Patient was taking adefovir 10 mg daily for 4 years for hepatitis B infection which is known to cause increased renal phosphate loss similar to Fanconi’s syndrome. The medication was changed and phosphate repletion was started which alleviated the symptoms promptly. Discussion: This case emphasizes on the importance of considering osteomalacia as a potential cause of low bone mass. Adefovir is commonly used for hepatitis B treatment and is known to cause renal phosphate loss at higher doses like 20-40 mg a day. This case illustrates that it can cause similar phosphoturic effect even at lower doses if used over a long period of time as a result of the cumulative dose effect of this drug. It is important to be cognizant of this side effect of Adefovir as it is a widely used medication and monitor patients for hypophosphatemia while undergoing therapy.

Physiopathologie et diagnostic des rachitismes/ostéomalacies vitamino-résistants

Vitamin resistant rickets and osteomalacia are rare disorders, usually associated with abnormal serum calcium and/or phosphate. Rickets correspond to mineralization abnormalities on the bone of a growing skeleton, as opposed to osteomalacia, an abnormality of mineralization of an adult bone. Renal phosphate loss is the main cause of vitamin-resistant rickets/osteomalacia, and is linked to a dysregulation of the FGF-23 pathway. The diagnosis of rickets or osteomalacia is based on clinical history, phosphocalcic metabolism assessment and, if necessary, molecular characterization. This diagnosis must be rapid to initiate the most appropriate treatment and discuss new treatments such as burosumab if necessary. This review aims to do an overview of the pathophysiology of vitamin-resistant rickets/osteomalacia (especially related to renal phosphate loss) and to describe the different subtypes of rickets and their differential diagnosis.

Genetic Causes of Rickets.

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches.