Oral Phosphate Research Articles

MO525: Iron absorption and phosphate-lowering effects of ferric citrate hydrate are not influenced by gastric secretion inhibitors in patients with chronic kidney disease

Abstract BACKGROUND AND AIMS Ferric citrate hydrate (FC, Riona®), an oral iron-based phosphate binder in chronic kidney disease (CKD) patients, is also approved as an iron preparation for iron-deficiency anemia (IDA) in Japan. In the USA, ferric citrate (Auryxia®) is approved as a phosphate binder for dialysis-dependent CKD and an iron replacement product for the treatment of IDA in patients with CKD not on dialysis. Ingested iron is dissolved at a low pH of the secreted gastric acid in the stomach, which is an important process for its effective absorption [1]. Patients taking gastric acid secretion inhibitors (GASI), such as proton pump inhibitors and histamine-2 receptor antagonists, showed decreased iron absorption and increased risk of iron deficiency, which were dose- and treatment-duration-dependent [2]. The increase in the intragastric pH by concomitantly use of GASI might be affected on FC's iron absorption effect. METHOD We have conducted a retrospective study using data from two previous clinical studies to investigate FC in CKD patients with hyperphosphatemia. A 12-week, phase 3, multicenter, randomized, double-blind, placebo-controlled study in non–dialysis-dependent (ND) CKD patients (FC, n = 60, ; placebo, n = 30) (CTI-111 435) [3], and a 52-week, phase 3, multicenter, open-label, dose-titration study in CKD patients undergoing hemodialysis (HD) (FC, n = 180) (CTI-111 437) [4] were divided into with or without GASI, and levels of iron and phosphate related parameters were analyzed. RESULTS In ND patients, approximately 25% in FC (n = 14) and 50% (n = 14) in placebo used GASI. Mean [standard deviation (SD)] changes from baseline to end of treatment (EOT) in serum ferritin (ng/mL) were 109.83 (104.46) in FC with GASI, 142.68 (94.28) in FC without GASI, −22.49 (74.85) in placebo with GASI, and −3.43 (43.58) in placebo without GASI (Fig. 1a). Those in transferrin saturation (TSAT, %) were 16.64 (30.13) in FC with GASI, 17.07 (17.56) in FC without GASI, 2.86 (14.68) in placebo with GASI, and 1.31 (9.75) in placebo without GASI (Figure 1b). The mean (SD) dose of FC with or without GASI were 3240 mg/day (approximately 778 mg ferric iron) with GASI (n = 14) and 3445 mg/day (approximately 827 mg ferric iron) without GASI (n = 46), respectively. In HD patients, approximately 50% (n = 95) used GASI. Mean changes (SD) from baseline to EOT in serum ferritin (ng/mL) were 166.32 (153.70) with GASI and 155.16 (139.47) without GASI, and in TSAT (%) were 16.60 (19.44) with GASI and 16.02 (18.81) without GASI, respectively. The mean (SD) dose of FC with or without GASI were 2619 mg/day (approximately 629 mg of ferric iron) with GASI (n = 95) and 2854 mg/day (approximately 685 mg or ferric iron) without GASI (n = 85), respectively. In both studies, there were no differences in the changes from baseline to EOT in serum phosphate between with or without GASI. CONCLUSION GASI did not interfere with iron absorption and phosphate-lowering effects of FC in CKD patients with hyperphosphatemia.

MO519: Ferric Citrate Hydrate Improves Levels of Transferrin Saturation in Hemodialysis Patients With Lower Levels of Transferrin Saturation

Abstract BACKGROUND AND AIMS Iron deficiency identified by transferrin saturation (TSAT) is reported as a risk factor for all-cause mortality and cardiovascular events in non-dialysis dependent (NDD) chronic kidney disease (CKD) [1, 2] and for all-cause mortality in hemodialysis patients [3]. Ferric citrate hydrate (FC, Riona®), an oral iron-based phosphate binder in CKD patients, is also approved as an iron preparation for iron-deficiency anemia (IDA) in Japan in 2021. In the USA, ferric citrate (Auryxia®) is approved as a phosphate binder for dialysis-dependent CKD and an iron replacement product for the treatment of IDA in patients with NDD-CKD. FC or ferric citrate increased TSAT in patients with NDD-CKD and IDA [4]. However, a few data show that whether FC or ferric citrate has the similar effect in hemodialysis patients whose TSAT is <20%. Considering the additional indication of IDA in Japan, we investigated the FC's effect on TSAT by using the data obtained from the ASTRIO study [5], which was conducted in Japanese hemodialysis (HD) patients. METHOD We conducted a retrospective study using the data of ASTRIO study [5], which is a randomized, prospective, open-label, multicenter 24-week study to investigate the FC's effect on anemia management compared with non-iron-based phosphate binders (PBs) in Japanese HD patients with hyperphosphatemia. Ninety-three patients taking non-iron-based PBs were randomized 1:1 to continue PBs (control) or switch to FC. During 24-week study, serum phosphate and hemoglobin were controlled, 3.5–6.0 mg/dL and 10–12 g/dL, respectively. From 93 patients (FC, n = 48; control, n = 45), we extracted 41 patients (FC, n = 21; control, n = 20) whose TSAT at baseline was <20% and compared the levels of TSAT and other iron related parameters between FC group and control group. RESULTS In the ASTRIO study, the mean (SD) levels of TSAT (%) was 14.3 (4.0) at baseline and rapidly increased to 25.0 (11.1) at 4 weeks in the FC group. After that, the levels of TSAT were almost unchanged in the FC group, whereas, in the control group, the mean (SD) levels of TSAT were almost unchanged during the 24-week study. The mean (SD) levels of serum ferritin gradually increased until week 12 and subsequently showed to be stabilized in the FC group, whereas, in the control group, these were almost unchanged during the 24-week study (Table 1). CONCLUSION In Japanese HD patients whose TSAT was <20%, FC rapidly increased TSAT compared with control. We will also investigate the FC's effect on TSAT in HD patients from the post-marketing surveillance study, the prospective, multicenter and observational, up to maximum 2 years treatment.

MO448: Progressive Tubular Injury Caused by High Phosphate Intake is Associated With Activation of STAT3/KIM-1 Signalling and Macrophage Recruitment in Mice

Abstract BACKGROUND AND AIMS Dietary phosphate intake greatly exceeds the recommended daily allowance in the Western population. Elevated phosphate levels are linked to increased cardiovascular and all-cause mortality, impaired bone health and premature ageing. The renal effects of chronic high dietary phosphate intake for healthy individuals are still not clear. METHOD Male C57BL/6 mice received a 2% high phosphate diet (HPD) or a 0.8% normal phosphate diet (NPD) for 1 to 6 months. We collected blood, urine and kidneys to investigate phosphate metabolism and progression of kidney injury. In vitro analysis for the toxic effects of phosphate or the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor (FGF) 23 was done in HK-2 humane proximal tubule (PT) cells. RESULTS HPD in mice caused hyperphosphataemia despite increased phosphaturia. Both intact FGF23 and PTH plasma levels were significantly increased in mice on HPD at 1 month onward. Mice on HPD showed significantly increased creatinine levels and albuminuria. Histopathological analysis of the kidneys revealed increased PT injury in mice receiving HPD compared to NPD controls from 2 months onward followed by a rapid progression of organ damage from month 5 to 6. Picrosirius red staining of kidney sections showed a progressively increased accumulation of collagen fibers in renal cortex of mice on HPD, which was significant from 4 months onward and accompanied by enhanced expression of transforming growth factor-β1, collagen 1 and fibronectin. The significant induction of the tubular injury marker Havcr1, encodes for Kim-1, started already after 1 month of feeding HPD, progressed over time and was strongest after 6 months. Immunofluorescence staining revealed Kim-1 localization to damaged PT, which was most prominent after 3 and 6 months of HPD. Renal Kim-1 protein levels were positively associated with tubular injury score and tubulointerstitial fibrosis. Histological staining and quantification revealed significantly increased number of pStat3+ cells in PTs of HPD-fed mice at months 1, 2, 5 and 6, indicating activated Stat3 signaling. The number of pStat3+ cells was positively associated with Kim-1 synthesis. Inflammation cytokine array with kidney tissue lysates showed, among others, enhanced expression of monocyte chemoattractant protein (MCP)-1 and macrophage colony-stimulating factor (MCSF) in HPD-fed mice. The mRNA expression of Csf1 (encodes for MCSF) was upregulated in HPD-fed mice and most pronounced after 6 months. Ccl2 mRNA expression (encodes for MCP-1) was significantly enhanced after 3, 5 and 6 months of HPD compared to NPD. Immunofluorescence staining showed a strong and specific induction of MCP-1 in PT epithelial cells due to HPD. The HPD-induced Ccl2 expression was positively associated with Kim-1 expression indicating an interaction between pStat3/Kim-1 signalling pathway and MCP-1. Immunohistochemical staining and flow cytometry analysis revealed a significantly increased recruitment of F4/80+ macrophages in renal tissue of HPD-fed mice after 3 and 6 months. The enhanced renal macrophage recruitment in the entire HPD cohort was associated with increased MCP-1 protein synthesis and increased tubular injury score. In vitro experiments using HK-2 cells showed that stimulation with FGF23 or high phosphate, but not PTH, induced the phosphorylation of STAT3. Interestingly, only treatment with high phosphate significantly upregulated HAVCR1 and CCL2 expression. CONCLUSION Chronic oral phosphate load in mice induced progressive inflammatory kidney injury dominated by macrophages. The direct toxic effects of phosphate are mediated by Stat3/Kim-1 signalling activation in PT cells. Our data support the hypothesis that kidney injury induced by widespread high dietary phosphate intake may cause a global health problem and underline the urgent need for clinical studies on this issue.

MO818: PTH Levels and Mortality in Incident Haemodialysis Patients

Abstract BACKGROUND AND AIMS Serum intact parathyroid hormone (iPTH) is associated with the prognosis of haemodialysis (HD) patients; however, its optimal range for reducing mortality remains unknown. The aim of this study was to assess the association between different serum iPTH levels and mortality in incident HD patients. METHOD We conducted a retrospective single-centre study of incident HD patients between January 2013 and 2020. According to the iPTH level measured at baseline, patients were categorized into four groups: <150 pg/mL, 150–300 pg/mL, 301–600 pg/mL and >600 pg/mL. Clinical, analytical and demographic data were compared among groups. All-cause mortality over a mean follow-up of 3.2 years was assessed using standard survival methods. Statistical analysis was performed using SPSS (Version 23 for Mac OSX). RESULTS The mean age of 149 patients was 74.14 ± 14.17 years, 95 (63.8%) were male, 75 (50.3%) were diabetic, 85 (57%) had congestive heart failure (CHF) and 110 (73.9%) had hypertension. A total of 46 patients (30.9%) were treated with vitamin D analogues, 2 (1.3%) with calcimimetics and 25 (16.8%) with oral phosphate binders. A total of 57 (38.3%) patients had iPTH < 150 pg/mL, 44 (29.5%) 150–300 pg/mL, 35 (23.5%) 301–600 pg/mL and 13 (8.7%) > 600 pg/mL. There were no age, gender, comorbidity or HD modality differences among groups. Patients with iPTH < 150 pg/mL had higher c-reactive protein (CRP) (P = .042), higher serum bicarbonate (P = .020), lower albumin (P = .001), lower serum phosphate (P = .009) and lower bone-specific alkaline phosphatase (BAP) (P = .008). During the study follow-up period, 82 patients (55%) died. Multivariate Cox regression showed that patients with iPTH < 150 pg/mL had an increased risk of all-cause mortality when compared with those with iPTH 301–600 pg/mL {HR: 0.59, [95% confidence interval (95% CI) 0.36–0.96]; P = .035} and iPTH > 600 pg/mL [HR: 0.36, 95% CI 0.19–0.70; P = .02] in both unadjusted and adjusted models for age, albumin, diabetes, CHF and hypertension. No significant difference was found between iPTH < 150 pg/mL and iPTH 150–300 pg/mL groups. When the reference was changed to iPTH > 600 pg/mL, patients in this group had a decreased mortality risk when compared with those with iPTH < 150 pg/mL (HR: 2.75, 95% CI 1.43–5.29; P = .02) and iPTH 150–300 pg/mL (HR: 2.23, 95% CI 1.14–4.36; P = .02), but not iPTH 300–600 pg/mL. CONCLUSION In our study, the baseline iPTH level was associated with all-cause mortality in incident HD patients. Our results suggest that the optimal serum iPTH level conferring the lowest mortality risk is > 300 pg/mL in this group of patients.

Abstract #1183932: Management Challenge in Hyperphosphatemic Tumoral Calcinosis

Tumoral calcinosis (TC) is a rare metabolic disorder causing abnormal calcium salt deposition in different peri-articular soft tissue regions. The most common site is lateral hips. TC can be primary normo-phosphatemic or primary hyperphosphatemic. It can be secondary also, seen commonly in chronic renal failure. We describe a case report of 14 years old girl who presented with primary hyperphosphatemic tumoral calcinosis with recurrent swellings even after surgery and medical therapy. A 14-year-old girl presented to us with recurrent soft tissue mass and persistent hyperphosphtemia associated with pain and decreased movements. She was operated twice for this soft tissue. Her medical record stated that patient had undergone 6 surgeries till date for these periarticular swellings at multiple sites (right elbow, left hip, right hip and left knee) but it recurs after 3-4 months of surgery and progressively enlarges in size. Physical examination revealed firm tender 9 X 4 cm oval shaped swelling in the left greater trochanteric area with restriction in abduction, internal rotation and rotator movements at hip joint and 4 X 4 cm circular hard, non-sessile mass over medial aspect of left knee joint with slight difficulty in complete flexion of knee. Biochemical work up showed hyperphosphatemia with normal serum calcium and low iPTH levels, low serum 25 hydroxyvitamin-D and slightly high 1,25 vitamin D with calculated TmP/GfR of 5.7 mg/dl. C-terminal FGF23 level was grossly elevated to 1200 RU/ml. Histological evaluation of previously surgically excised soft tissue mass revealed fibrocollagenous stroma with clusters of crystalline and amorphous calcium enclosed by band of histiocytes and lymphocytes compatible with findings seen in tumoral calcinosis. Presently the patient is maintaining the near normal phosphate level with oral phosphate restricted diet and multiple phosphate binder and acetazolamide. Hyperphosphatemic Tumoral calcinosis is a disorder of dysregulated phosphate metabolism characterized by hyperphosphatemia and deposition of calcium salts in soft tissue regions of the body usually in the periarticular sites. FGF23 is a 251-amino acid peptide secreted by osteoblasts, osteocytes and erythroid precursor cells of the bone marrow that plays a critical role in phosphate regulation. In the proximal tubule of the kidney, FGF23 binds to the FGF receptor 1 (FGFR1) and its co-receptor KLOTHO, downregulating expression of the sodium-phosphate cotransporters NPT2a and NPT2c, which leads to phosphaturia. Additionally, FGF23 inhibits 1-alpha-hydroxylase and stimulates 25-vitamin D-24 hydroxylase, resulting in decreased 1,25-(OH)2-vitamin D (1,25D), the active form of vitamin D. Recently an entitity named autoimmune hyperphosphataemic tumoral calcinosis has been reported in which pathogenetic autoantibodies mediate FGF23 resistance.Treatment is to lower serum phosphorus by blocking dietary phosphate absorption and increasing renal phosphate excretion. Surgery is usually reserved for patients with significant pain or restricted movements of joint.

Comparison of Mean Bowel Cleanliness Score in Patients Undergoing Colonoscopy Prepared by Sodium Phosphate versus Polyethylene

Background: Adequate bowel preparation is essential for accurate colonoscopy. Both oral sodium phosphate (NaP) and polyethylene glycol-based lavage (PEG-ELS) are used predominantly as bowel cleansing modalities. However, NaP has gained popularity due to low drinking volume and lower costs. Objective: To compare the mean bowel cleanliness score in patients undergoing colonoscopy prepared by sodium phosphate vs. polyethylene glycol. Study Design: It’s a randomized controlled trial Settings and Duration: Department of Gastroenterology Shaikh Zayed Hospital, Lahore, 6 months after the approval of synopsis, from Nov 2019 to April 2020. Methodology: After approval from ethical review committee of the hospital, 100 cases (50 in each group) patients who presented in Department of Gastroenterology Shaikh Zayed Hospital, Lahore and who fulfilled the criteria were counselled and explained the details of the study. Written informed consent and detailed history was taken from each patient. These patients were then randomly divided into following two groups using lottery method, Group-S: Sodium phosphate and Group-P: polyethyelene glycol. Cleanliness of the colon was noted as per operational definition. All the data was noted and recorded into the attached proforma along with demographic details of the patient. All the colonoscopies were done by the endoscopists with a same single observer recording the findings to eliminate bias, and confounding variables were controlled by exclusion. Results: In our study, of 100 cases (50 in each group) 48%(n=24) in Group-S and 52%(n=26) in Group-P were between 18-50 years of age whereas 52%(n=26) in Group-S and 48%(n=24) in Group-P were between 51-70 years of age, mean+sd was calculated as 51.64+8.82 years in S and 51.24+8.67 in P groups, 50%(n=25) in Group-S and 60%(n=30) in Group-P were male whereas 50%(n=25) in Group-S and 40%(n=20) in Group-P were females. Comparison of mean bowel cleanliness score in patients undergoing colonoscopy prepared by sodium phosphate vs. polyethylene glycol shows that Group-S had 3.82+0.92 and Group-P had 2.68+0.68 cleanliness score, p value was 0.0001. The results of our study are comparable with the above study. Conclusion: We concluded that the mean bowel cleanliness score was significantly better in patients undergoing colonoscopy prepared with sodium phosphate when compared with polyethylene glycol. Keywords: Colonoscopy, Sodium phosphate, Polyethylene glycol, Bowel cleanliness

Phosphate restriction using a processed clay mineral reduces vascular pathologies and microalbuminuria in rats with chronic renal failure

BackgroundThe progression of chronic kidney disease (CKD) is associated with an increasing risk of cardiovascular morbidity and mortality due to elevated serum phosphate levels. Besides low phosphate diets and hemodialysis, oral phosphate binders are prescribed to treat hyperphosphatemia in CKD patients. This study reports on a processed clay mineral as a novel and efficient phosphate sorbent with comparable efficacy of a clinically approved phosphate binder.Methods5/6 nephrectomized rats, which develop chronic renal failure (CRF), received a high phosphate and calcium diet supplemented with either a processed Montmorillonite-Illite clay mineral (pClM) or lanthanum carbonate (LaC) for 12 weeks. Levels of plasma uremic toxins, glomerular filtration rates and microalbuminuria were determined and the histomorphology of blood vessels and smooth muscle cells was analyzed.Results5/6 nephrectomy induced an increase in plasma uremic toxins levels and progressive proteinuria. Treatment of CRF rats with pClM decreased observed vascular pathologies such as vascular fibrosis, especially in coronary vessels. The transition of vascular smooth muscle cells from a contractile to a secretory phenotype was delayed. Moreover, pClM administration resulted in decreased blood creatinine and urea levels, and increased glomerular filtration rates, reduced microalbuminuria and eventually the mortality rate in CRF rats.ConclusionOur study reveals pClM as a potent phosphate binding agent with beneficial impacts on pathophysiological processes in an animal model of CKD. pClM effectively attenuates the progression of vascular damage and loss of renal function which are the most severe consequences of chronic renal failure.

Hypophosphatemia Associated with Tumor-Induced Osteomalacia Caused by A Third Primary Tumor: A Case Report

Tumor-induced osteomalacia (TIO) is a paraneoplastic condition in which a tumor, usually of mesenchymal origin, causes osteomalacia often by producing Fibroblast Growth Factor-23 (FGF-23). FGF-23 induces hypophosphatemia through its phosphaturic action. Case Presentation: A 65-year-old male patient presented with complaints of muscle weakness, difficulty walking and severe bone pain. His medical history included distal gastrectomy for a moderate-risk gastrointestinal stromal tumor (GIST) of 4 cm in diameter, Billroth II antecholic gastroenterostomy and subsequently total thyroidectomy for Stage 1 multicentric micropapillary carcinoma (CA). Widespread lesions detected on bone scintigraphy were considered as bone metastases of GIST. Laboratory investigations revealed the following results: calcium (Ca): 8.3 mg/dL; phosphate (P): 1.5 mg/dL; Parathormone (PTH): 75 pg/mL; 25-OH vit D3: 31 ng/mL; 1-25-(OH)2 vit D3: 36 pg/mL; creatinine: 0.75 mg/dL; alkaline phosphatase (ALP): 109 IU/L, urine phosphate: 2.54 g/day. His hypophosphatemia was considered to be most probably due to TIO induced by bone metastases of GIST. Since it was not possible to remove the metastases, the patient was started on oral phosphate and calcitriol therapy. However, despite an improvement in Ca levels after the initiation of the treatment, P levels persisted around 2 mg/dL. After one year of treatment, an ulcer developed on his right first toe, which was excised and identified as “extraskeletal myxoid chondrosarcoma” on pathological examination. Following excision of the tumor, the patient’s Ca and P values returned to normal range. The development of TIO in the presence of a GIST and thyroid CA is an unusual occurrence. As a matter of fact, the cause of hypophosphatemia was TIO which induced by a third primary tumor in this patient. To the best of our knowledge, TIO due to a third primary tumor is the first and only case in the literature. Another primary tumor focus should be suspected and carefully investigated if the patient already has a primary tumor and that tumor is not among those frequently inducing TIO.

PREVALENCE OF HYPOKALEMIA AFTER BOWEL PREPARATION IN PATIENTS UNDERGOING COLORECTAL INTERVENTIONS

INTRODUCTION:-Bowel preparation is usually done before colonoscopy and other colorectal interventions. It mostly contain oral sodium phosphate or polyethylene glycol solutions.. Bowel preparation results in electrolyte shifts, requiring special precautions especially in high risk patients. It causes abdominal distension ( ileus), muscle cramps , arrhythmia, hypokalemia.This study is undertaken to determine the electrolyte imbalances and clinical outcome of the patient who underwent bowel preparation and colorectal intervention. MATERIAL AND METHODS:- We conducted our study in Department of General Surgery, Dr. B. R. A. M. Hospital Raipur C.G. over a period of 1 year.Written and informed consent was taken from all the patients. This study is hospital based,cross sectional observational study.Patient was given two liters polyethylene glycol based solution which contain polyethylene glycol,sodium chloride,potassium chloride,sodium bicarbonate,and anhydrous sodium sulfate for bowel cleansing and asked to drink the solution in 2 hrs and to feed on only clear fluids. We compared serum potassium levels before and after bowel preparation and evaluated the development of hypokalemia after bowel preparation. RESULTS:- The study was done among 71 patients who underwent bowel preparation before colorectal intervention at Dr.B.R.A.M. hospital Raipur (C.G.) in one year. 36.6% of the participants developed mild hypokalemia after bowel preparation. Most of the patients belong to age group of 41-50 years(26.8%). The duration of passage of first flatus and first feces after intervention was longer in patient with hypokalemia (1.73 and 3.30) as compared to patient with normokalemia (0.87 and 1.26). CONCLUSION :-On the basis of our study it is evident that hypokalemia can develop after bowel preparation in patients who underwent colorectal interventions.

Acute adaptation of renal phosphate transporters in the murine kidney to oral phosphate intake requires multiple signals.

Dietary inorganic phosphate (Pi) modulates renal Pi reabsorption by regulating the expression of the NaPi-IIa and NaPi-IIc Pi transporters. Here, we aimed to clarify the role of several Pi-regulatory mechanisms including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) and inositol hexakisphosphate kinases (IP6-kinases) in the acute regulation of NaPi-IIa and NaPi-IIc. Wildtype (WT) and PTH-deficient mice (PTH-KO) with/without inhibition of FGF23 signalling were gavaged with Pi/saline and examined at 1, 4 and 12h. Pi-gavage elevated plasma Pi and decreased plasma Ca2+ in both genotypes after 1h Within 1h, Pi-gavage decreased NaPi-IIa abundance in WT and PTH-KO mice. NaPi-IIc was downregulated 1h post-administration in WT and after 4h in PTH-KO. PTH increased after 1h in WT animals. After 4h Pi-gavage, FGF23 increased in both genotypes being higher in the KO group. PTHrp and dopamine were not altered by Pi-gavage. Blocking FGF23 signalling blunted PTH upregulation in WT mice and reduced NaPi-IIa downregulation in PTH-KO mice 4h after Pi-gavage. Inhibition of IP6-kinases had no effect. (1) Acute downregulation of renal Pi transporters in response to Pi intake occurs also in the absence of PTH and FGF23 signalling, (2) when FGF23 signalling is blocked, a partial contribution of PTH is revealed, (3) IP6 kinases, intracellular Pi-sensors in yeast and bacteria, are not involved, and (4) Acute Pi does not alter PTHrp and dopamine. Thus, signals other than PTH, PTHrp, FGF23 and dopamine contribute to renal adaption.

Rickets guidance: part II—management

Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormone, 25-hydroxyvitamin D3, and calciuria. An adequate calcium intake and normal 25-hydroxyvitamin D3 levels should be assured in all patients. Children with calcipenic rickets require the supplementation or pharmacological treatment with native or active vitamin D depending on the underlying pathophysiology. Treatment of phosphopenic rickets depends on the underlying pathophysiology. Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible. Burosumab, a fully humanized FGF23-antibody, was recently approved for treatment of X-linked hypophosphatemia (XLH) and TIO and shown to be superior for treatment of XLH compared to conventional treatment. Forms of hypophosphatemic rickets independent of FGF23 due to genetic defects of renal tubular phosphate reabsorption are treated with oral phosphate only, since they are associated with excessive 1,25-dihydroxyvitamin D production. Finally, forms of hypophosphatemic rickets caused by Fanconi syndrome, such as nephropathic cystinosis and Dent disease require disease-specific treatment in addition to phosphate supplements and active vitamin D. Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis.

Safety and effectiveness of ferric citrate hydrate in serum phosphorus management of patients with chronic kidney disease: a long-term, real-world, observational, post-marketing surveillance study

BackgroundFerric citrate hydrate (FC) is an oral iron-based phosphate binder that is used to treat hyperphosphatemia in patients with chronic kidney disease (CKD). This post-marketing surveillance study was performed to investigate the long-term safety and effectiveness of FC.MethodsThis prospective, multicenter, observational post-marketing surveillance study was performed in a real-world setting in Japan. The study involved CKD patients with hyperphosphatemia receiving FC who were undergoing either hemodialysis or peritoneal dialysis or were non-dialysis-dependent. Adverse drug reactions, iron- and erythrocyte-related parameters (i.e., levels of serum ferritin, transferrin saturation, and hemoglobin), and serum levels of phosphorus, corrected calcium, and intact parathyroid hormone were monitored for up to 104 weeks.ResultsSafety was evaluated in 2723 patients. Of these patients, 20.5% discontinued FC because of adverse events, and 3.9% discontinued FC because of unsatisfactory effectiveness. Iron-related parameters gradually increased after the initiation of FC treatment but stabilized after week 36. Effectiveness was analyzed in 2367 patients. Serum phosphorus immediately decreased, and the effect persisted for 104 weeks.ConclusionIn this 104 week surveillance study, no new safety concerns were noted. The safety profile was not obviously different from those in pre-approval clinical trials and the 52 week interim report of this surveillance study. The serum ferritin level of most patients was below the upper limit of the target range, and iron overload risk was not evident. Long-term FC treatment effectively controlled serum phosphorus.

Abstract 159: Glomus tumour presenting with oncogenic osteomalacia

Introduction: Tumour induced osteomalacia (TIO) is a rare paraneoplastic syndrome of mostly, benign mesenchymal tumours. Glomus tumours causing TIO is a very rare entity. We present a case of unresectable locally invasive glomus tympanicum with hypophosphatemic osteomalacia being misdiagnosed as bone metastases.Case Synopsis: 55 year old man presented with difficulty walking for the 2 years and wheel chair bound for 3 months. Past medical history revealed multiple surgeries for recurrent glomus tympanicum -left ear in 2011, 2013 and 2015. Tumour recurred in 2019-unresectable. Due to his bone pain, a Tc 99 MDP scan done showed increased tracer uptake in multiple ribs bilaterally and iliac bones which was interpreted as metastasis - given radiation therapy and chemotherapy. On examination- Lower limb power was 3/5 bilaterally. Other systemic examination was normal. Investigations showed S. Calcium of 8.5 mg/dl, S. phosphorus – 1.3 mg/dl with ALP- 424 IU/L, 25 (OH) D- 21 ng/ml, S. creatinine -0.9 mg/dl and iPTH-115 pg/ml. His 24 hour urine Calcium, Phosphorus and Creatinine were 107 mg, 588 mg and 1260 mg per day. Tubular reabsorption of phosphorus was 70% with TmP GFR of 1.1 suggesting renal phosphate wasting. MRI spine showed multiple vertebral compression fractures and insufficiency fractures of iliac bones suggestive of metabolic bone disease. FGF 23 was 555.6 RU/ml (0-150). Hence tumour induced osteomalacia was diagnosed. Ga DOTANOC showed only the Left glomus tumour and no other lesion. He was started on oral phosphate and Vitamin D. After 3 months his bone pains have reduced by 40-50%, he is walking independently and his S. Phosphorus levels have increased to 2.5 mg/dl.

Real-world effectiveness of burosumab in children with X-linked hypophosphatemic rickets.

X-linked hypophosphatemic rickets (XLH) is the most common cause of inherited rickets. Historically, XLH was treated with oral phosphate and calcitriol (conventional treatment). Burosumab, a fibroblast growth factor 23 (FGF-23) monoclonal antibody, was approved by the United States Food and Drug Administration (FDA) in 2018 for XLH treatment. Nevertheless, conventional treatment of XLH continues to be recommended by some specialists due to lack of published experience with burosumab in the clinical setting. We compared laboratory and radiographic changes observed following transition from conventional therapy to burosumab in pediatric XLH patients as part of routine care. This retrospective single-center study identified and retroactively studied twelve patients aged 1-18years old with XLH previously treated with conventional therapy and transitioned to burosumab. Laboratory studies and radiographs were obtained routinely as standard of care during two treatment periods: (1) conventional therapy and (2) burosumab treatment. Laboratory values and radiologic rickets severity scores were compared between periods. All laboratory values demonstrated improvement following 1month of burosumab treatment, findings which were sustained over the 2-year study period. Rickets severity scores and height z-scores also improved with burosumab. There were no serious adverse events with burosumab, and adverse events overall were very infrequent and mild. One patient developed an asymptomatic mild elevation of serum phosphate while taking burosumab resulting in a temporary pause in therapy. Safety and effectiveness of burosumab in treatment of XLH were demonstrated as burosumab yielded statistically significant improvement in laboratory and radiographic markers of rickets and height compared to conventional therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.

POS-748 HYPOPHOSPHATEMIA AFTER KIDNEY TRANSPLANTATION IN CHILDREN: A RETROSPECTIVE SINGLE CENTER EXPERIENCE

Hypophosphatemia is among the common complications that are seen after kidney Transplantation (KTX). It’s noticed in the first few days in most of the KTX, particularly a well-functioning graft, and its tretment may continued many months after KTX in certain conditions. Our aim is to identify hypophosphatemia after KTX, as well its potential association with Parathyroid hormone and Vitamin D. A retrospective study of children underwent KTX between 2009-2021. We collected their Baseline demographics, type of KTX, their primary kidney diseases, time after KTX of first presentation of hypophosphatemia, initial serum phosphate level, initial levels of Parathyroid hormone, 25 OH vitamin D, Calcium, and Magnesium, time of its resolution after KTX. A 38 children underwent KTX between 2009 and 2021, their baseline demographics are shown in Table 1. A 26 (68%) of children developed hypophosphatemia with a mean of occurrence at 5 days after KTX, and range of 1 to 12 days. Early (within three days) drops in serum phosphate have been found more in living KTX, which have related to immediate functioning of the allograft, and tend to be more severe, while delayed ( more than 6 days) drops are seen more with deceased KTX, as its more likely to be associated with relative delay in graft function. The average serum phosphate level in hypophosphatemia group was 0.6 mmol/l with a range of 0.28 to 0.8 mmol/l. The mean duration of requirement of phosphate supplement after KTX was 6 months days with a range of 0.5 to 39 months. All the patients were managed with oral phosphate with a mean of dose of 650 mg/day and range of 250 mg/ day to 1500 mg/day, without the requirement of intravenous supplement except in four patients from living KTX group. The associated levels of serum Phosphate, serum Calcium, serum Magnesium, 25 OH vitamin D, and PTH for both hypophosphatemic group and normal phosphate group are shown in table 2 and 3 respectively. Children with hypophosphatemia tend to have a higher mean PTH and 25(OH)2 Vitamin D level, but the difference is not statistically significant. Table 1: Baseline Demographics Tabled 1VariableValueAge at TransplantationMean 8 yearsGenderMale 22 (58 %)Weight (Kg)22Deceased donor26 (68%)Live Related donor9 (24%)Live unrelated donor3 (8%)HLA mismatches4/6Causes of Chronic kidney diseaseCAKUT16(42%)FSGS10 (26%)CNS4 (10 %)Nephronophthesis2 (6%)Nephropathic cystinosis1 (3%)ARPKD1 (3%)Unknown4 (8%) Open table in a new tab Table 2: Hypophosphatemia group Tabled 1VariableMean (range)Phosphate (mmol/l)0.6 (0.28-0.8)Calcium (mmol/l)2.22 (1.91- 2.63)Magnesium (mmol/l)0.73 (0.52- 1.17)Alkaline Phosphatase (U/l)194 ( 51- 713)Parathyroid Hormone (Pg/ml)587 (34 - 1565)25 (OH)2 Vitamin D (nmol/l)53 ( 7- 110) Open table in a new tab Table 3: Normophosphatemia group Tabled 1VariableMean (range)Phosphate (mmol/l)1.22 (0.9-1.64)Calcium (mmol/l)2.30 (2.15- 2.78)Magnesium (mmol/l)0.75 (0.55- 1.03)Alkaline Phosphatase (U/l)176 ( 55- 297)Parathyroid Hormone (Pg/ml)520 (113 - 1354)25 (OH)2 Vitamin D (nmol/l)43 ( 7- 82) Open table in a new tab Hypophosphatemia is a commonly seen after kidney transplantation particularly those with immediately functioning graft, higher PTH is a known potential contributory factor but that was observed partly in our cohort. our result should be interpreted with caution because of small sample size and retrospective design, so prospective large sample study can delineate this area more clearly.

Post-authorisation safety study of burosumab use in paediatric, adolescent and adult patients with X-linked hypophosphataemia: rationale and description.

Background:X-linked hypophosphataemia (XLH) is a rare, inherited, phosphate-wasting disorder that elevates fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D (1,25(OH)2D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH)2D supplements. However, these treatments do not correct the primary pathogenic mechanism or treat all symptoms and can be associated with adverse effects. Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody against FGF23, approved for treating XLH in several geographical regions, including Europe and Israel. Burosumab restores normal serum phosphate levels, minimising the clinical consequences of XLH. Safety data on long-term treatment with burosumab are lacking owing to the rarity of XLH. This post-authorisation safety study (PASS) aims to evaluate the safety outcomes in patients aged >1 year.Methods:The PASS is a 10-year retrospective and prospective cohort study utilising data from the International XLH Registry (NCT03193476), which includes standard diagnostic and monitoring practice data at participating centres. The PASS aims to evaluate frequency and severity of safety outcomes, frequency and outcomes of pregnancies in female patients, and safety outcomes in patients with mild to moderate kidney disease at baseline, in children, adolescents and adults treated with burosumab for XLH. It is expected that there will be at least 400 patients who will be administered burosumab.Results:Data collection started on 24 April 2019. The expected date of the final study report is 31 December 2028, with two interim reports.Conclusion:This PASS will provide data on the long-term safety of burosumab treatment for XLH patients and describe safety outcomes for patients receiving burosumab contrasted with those patients receiving other XLH treatments, to help inform the future management of XLH patients. The PASS will be the largest real-world safety study of burosumab.Registry identification:The International XLH Registry is registered with clinicaltrials.gov as NCT03193476 (https://clinicaltrials.gov/ct2/show/NCT03193476), and the PASS is registered with the European Union electronic Register of Post-Authorisation Studies as EUPAS32190 (http://www.encepp.eu/encepp/viewResource.htm?id=32191).

Burden of disease of X-linked hypophosphatemia in Japanese and Korean patients: a cross-sectional survey.

The burden of disease of X-linked hypophosphatemia (XLH) in East Asia is poorly understood. This was a cross-sectional study using an online questionnaire to evaluate health-related quality of life (HRQOL) and disease complications in Japanese and Korean patients with XLH. Adults with XLH and the caregivers of children <18 years of age with XLH in Japan and Korea were surveyed. Respondents disclosed demographic data, family history, diagnostic history, medical history, surgical history, disease-specific clinical symptoms, treatment, medications, and use of ancillary equipment. Patient-reported outcomes (PROs; the Western Ontario and McMaster Universities Osteoarthritis Index, the brief pain inventory, and the 36-item short form health survey version 2) were used to assess pain, disability, and HRQOL in adults. Of those surveyed, all 14 children (100%) and 30/32 adults (93.8%) were receiving treatment for XLH. However, despite oral phosphate and active vitamin D use, short stature, gait abnormalities, dental conditions, and decreased physical function were reported. Stapling of the growth plates was reported in 14.3% of children but no adults. Adult patients reported high rates of bone pain (59.4%) and joint pain (65.6%). Caregivers of children with XLH also reported the occurrence of bone pain (35.7%) and joint pain (35.7%). Many adult patients had a history of impaired renal function (9.5%), nephrocalcinosis (15.6%), hyperparathyroidism (15.6%), and parathyroidectomy (6.3%), all of which are associated with conventional XLH treatments. These data show that patients (both pediatric and adult) continue to have symptoms such as pain, disability, and various complications despite receiving conventional therapies.

Лекарственно-индуцированная кристаллическая нефропатия

Drug-induced (DI) crystal nephropathy (CN) is a relatively rare kidney disease that is not always easy to diagnose and potentially leads to acute kidney injury (AKI), which may lead to the need for haemodialysis and is associated with a high risk of mortality. Th e aim of the review was analysis and systematisation of data on drugs, the intake of which is associated with development of DICN, conditioning the increased risk of drug-induced AKI, on its pathophysiological mechanisms, analysis of possible methods of treatment and prevention. The search for the specifi ed keywords was carried out in the eLIBRARY.RU, PubMed®, MEDLINE, EMBASE databases, guidelines and methodological recommendations, materials of databases of adverse reactions, instructions for the medical use of drugs published within the period up to June 2021. Most often, DICN is associated with the use of such drugs as sulfadiazine, acyclovir, indinavir, triamterene, methotrexate, as well as orlistat, ciprofl oxacin, amoxicillin, oral sodium phosphate preparations, etc. Th e main pathophysiological mechanism of CN development is the precipitation of poorly soluble substances in the urine and formation of crystals. Th ereat, one part of the drug crystallises and the precipitate falls out directly into the renal tubules, the other part acts through a change in metabolism, increasing the concentration of other poorly soluble compounds in the urine. The risk factors for DICN include the risk factors for AKI as well as drug-specifi c risk factors, such as urine pH. Clinically, СN is most oft en manifested by symptoms of AKI, sometimes with development of acute renal colic and hematuria. In СN treatment, it is required to cancel the inducer drug or reduce its dose, stimulate diuresis with replenishment of the intravascular fluid volume using infusions of balanced electrolyte solutions. For the prevention of DICN, it is important to take into account all possible risk factors for its development, use adequate doses of drugs and avoid the prescription of potentially nephrotoxic drugs

Fibroblast Growth Factor 23 as Regulator of Vitamin D Metabolism.

Fibroblast growth factor 23 (FGF23) is a hormone produced by osteocytes in bone that acts on the kidneys to regulate phosphate and vitamin D metabolism.FGF23 levels were shown to be increased in the early stage of chronic kidney disease (CKD), with a slight decline in estimated glomerular filtration rate (eGFR) even when the range was restricted to above 60mL/min/1.73m2, indicating that subtle phosphate load is a stimulator of FGF23 in serum. FGF23 is also known to inhibit vitamin D activation from 25-hydroxyvitamin D (25-OH-D) to 1,25-dihydroxyvitamin D [1,25(OH)2D], while it stimulates its degradation from 25-OH-D to 24,25-dihydroxyvitamin D [24,25(OH)2D]. Previously, we demonstrated a significant and negative association of serum FGF23 with serum 1,25(OH)2D and 1,25(OH)2D/25-OH-D ratio, a putative parameter for CYP27B1, and confirmed the physiological effects of FGF23 on phosphate and vitamin D metabolism in non-CKD subjects. Elevated FGF23 by itself is reported to be associated with various adverse outcomes, including left ventricular hypertrophy, endothelial dysfunction, and activation of the renin-angiotensin-aldosterone system, leading to increased mortality even in non-CKD individuals. On the other hand, our previous study showed that the impaired incremental response of serum FGF23 in response to oral phosphate load in diabetic patients can help to significantly increase serum phosphate (Yoda et al., J Clin Endocrinol Metab 97:E2036-43, 2012) and thus may contribute to progression of vascular calcification in those patients (personal observation). It is suggested that increased serum FGF23 might be an important indicator of adverse outcomes in non-CKD as well as CKD patients.

Changes in Bone Mineral Density Following Conventional Oral Phosphonate Treatment of Hypophosphatemic Osteomalacia: A Non-Randomized Controlled Study.

PurposeThere are limited clinical studies aimed at solving the problem of the efficiency of conventional treatment with oral phosphate and calcitriol in adults with hypophosphatemic osteomalacia (HO). In addition, there still had no good non-hazardous markers to evaluate the severity of bone loss of osteomalacia before and after treatment. Therefore, the purpose of this study was to assess the efficacy of conventional treatment with a self-blended phosphate supplementation and calcitriol on patients with HO and whether bone mineral density (BMD) can be helpful for monitoring the efficacy.Patients and MethodsA total of 21 HO patients and 105 healthy controls were enrolled. All patients were tested for serum biomarkers and BMD of the lumbar spine (L1–L4), femoral neck, and total left hip. After three years of treatment, 11 of 21 HO patients were recalled for BMD measurement. According to the administration of drugs, HO patients with calcium and calcitriol were divided into three phosphate treatment groups: patients in group A (n = 3) received continuous phosphate supplementation, patients in group B (n = 5) received intermittent phosphate supplementation and patients in group C (n = 3) received no phosphate supplementation.ResultsThe diagnoses of 21 HO patients were 5 cases of hereditary hypophosphatemic rickets, 4 cases of Fanconi syndrome with the features of renal tubular acidosis and vitamin D deficiency, and 12 cases of hereditary vitamin D abnormality. The average initial serum phosphorus level of the patient group was approximately 50% lower than that of the control group. Lower BMD was significantly observed in the HO group than the control group at the lumbar spine and total hip. Continuous treatment with the phosphate supplement could increase BMD in the lumbar spine and total hip by 33.4–52.3% and in the femoral neck increased by 43.2–79.3% compared with baseline, and the effect appears to be continued once treatment is discontinued.ConclusionThese findings suggest that conventional therapy can improve bone mineral defects in patients with HO, especially in the femoral neck. Detection of BMD in HO patients is a good tool to assess the extent of bone defects and the therapeutic effect.Trial RegistrationChinese Clinical Trial Registry, ChiCTR-OOC-16010095. Registered 7 December 2016. Retrospectively registered.