Sevelamer Research Articles

The effect of sevelamer on serum calcification propensity in patients with chronic kidney disease: the results of a multicentre, double-blind, placebo-controlled, randomized clinical trial

Abstract Background The serum calcification propensity test (or T50 test) might become a standard tool for the assessment of vascular calcification risk, and T50 might be a valuable biomarker in clinical trials of treatments intended to slow the progression of vascular calcification. Literature data suggest that non-calcium-containing phosphate binders can influence T50 in chronic dialyzed patients. However, it is not clear whether similar interventions are effective in patients at earlier stages of chronic kidney disease (CKD). Methods The “FGF23 Reduction efficacy of a new Phosphate Binder in CKD” (FRENCH) trial was a multi-centre, double-blind, placebo-controlled, randomized trial of sevelamer carbonate in participants with stage 3b/4 CKD. In this subanalysis of the FRENCH data, T50 and other laboratory variables (including fetuin A, and ionized and total magnesium) were measured centrally at baseline and after 12 weeks of treatment. Results A total of 96 patients were screened; 78 (55 men and 23 women) met the inclusion criteria and were randomized to receive placebo (n=39) or sevelamer carbonate (n=39). The median [interquartile range] patient age was 66 [56-72], the median eGFR was 25 [21-30] mL/min/1.73m², and the mean T50 was 335 (82) minutes. In a linear regression model, T50 was independently associated with serum ionized magnesium, fetuin-A and bicarbonate levels; and inversely associated with phosphate concentration. The within-group changes in the mean [95% confidence interval] T50 between week 0 and week 12 were not significant in the sevelamer group or the placebo group (4.6 [-13.6; 22.8] minutes (p=0.61) and 7.8 [-16.4; 32.1] minutes (p=0.51), respectively). Furthermore, we did not observe significant changes in fetuin-A and magnesium levels. Conclusion A 12-week course of the non-calcium-containing phosphate binder sevelamer carbonate was not associated with a significant change in T50 in patients with stage 3b/4 CKD. Phosphate binders might not be an effective strategy for modifying serum calcification propensity in non-dialysis-dependent patients with CKD.

Efficacy and safety of sucroferric oxyhydroxide versus sevelamer carbonate: A systematic review and meta-analysis.

Phosphate binders are commonly used in patients receiving kidney replacement therapy (KRT), aiming to reduce and maintain serum phosphorus. Chronic kidney disease-mineral and bone disorder has been linked to reduced lifespan and worsened quality of life. This study aims to examine the efficacy and safety of sucroferric oxyhydroxide versus sevelamer carbonate in patients receiving KRT. The data sources examined were MEDLINE (PubMed), Scopus, and the Cochrane Central Register of Controlled Clinical Trials with a search deadline of October 2023. We examined randomized controlled trials that compared sucroferric oxyhydroxide versus sevelamer carbonate in the adult population receiving KRT. We performed a meta-analysis combining the data from trials, using R-studio. Inclusion criteria were met by five randomized trials. There was no statistically significant difference in the reduction of serum phosphorus between the two groups (MD: -0.07 mmol/L, 95% CI-random effects: -0.15 to 0.02). In the same line, a non-statistically significant difference was observed in serum i-PTH reduction between the two drugs (MD = -1.53 mg/dL, 95% CI = (-4.45, 1.4), p = 0.26, random effects model). No statistically significant difference was observed in all adverse events between the two groups (odds ratio: 1.11, 95% CI: 0.65-1.88, random effects model). Further analysis of gastrointestinal adverse events revealed that sevelamer carbonate increases gastrointestinal adverse events by up to 60% (odds ratio: 1.60, 95% CI: 1.31-1.97, common (fixed) effect model). This meta-analysis of randomized trials showed that both drugs, sucroferric oxyhydroxide and sevelamer equally and effectively controlled serum phosphorus levels, whereas sucroferric oxyhydroxide revealed a better profile in terms of gastrointestinal adverse events. Sucroferric oxyhydroxide is a valuable option for patients receiving KRT when sevelamer carbonate is more difficult to tolerate.

Exploring the top 30 drugs associated with drug-induced constipation based on the FDA adverse event reporting system.

This project aims to identify the top 30 drugs most commonly associated with constipation and their signal values within the FDA Adverse Event Reporting System database. We extracted adverse drug events (ADEs) related to constipation from the FAERS database spanning from January 1, 2004, to September 30, 2023. We compiled the 30 most frequently reported drugs based on the frequency of constipation events. We employed signal detection methodologies to ascertain whether these drugs elicited significant signals, including reporting odds ratio, proportional reporting ratio, multi-item gamma Poisson shrinker, and information component given by the Bayesian confidence propagation neural network. Furthermore, we conducted a time-to-onset (TTO) analysis for drugs generating significant signals using the medians, quartiles, and the Weibull shape parameter test. We extracted a total of 50, 659, 288 ADEs, among which 169,897 (0.34%) were related to constipation. We selected and ranked the top 30 drugs. The drug with the highest ranking was lenalidomide (7,730 cases, 4.55%), with the most prevalent drug class being antineoplastic and immunomodulating agents. Signal detection was performed for the 30 drugs, with constipation risk signals identified for 26 of them. Among the 26 drugs, 22 exhibited constipation signals consistent with those listed on the FDA-approved drug labels. However, four drugs (orlistat, nintedanib, palbociclib, and dimethyl fumarate) presented an unexpected risk of constipation. Ranked by signal values, sevelamer carbonate emerged as the drug with the strongest risk signal [reporting odds ratio (95% CI): 115.51 (110.14, 121.15); PRR (χ2): 83.78 (191,709.73); EBGM (EB05): 82.63 (79.4); IC (IC025): 6.37 (4.70)]. A TTO analysis was conducted for the 26 drugs that generated risk signals, revealing that all drugs exhibited an early failure type. The median TTO for orlistat was 3days, the shortest of all the drugs, while the median TTO for clozapine was 1,065days, the longest of all the drugs. Our study provides a list of drugs potentially associated with drug-induced constipation (DIC). This could potentially inform clinicians about some alternative medications to consider when managing secondary causes of constipation or caring for patients prone to DIC, thereby reducing the incidence and mortality associated with DIC.

MiRNAs and indicators of mineral metabolism in the population of dialysis patients

Introduction. Cardiovascular events are the leading cause of death in patients on renal replacement dialysis therapy. The vast majority of patients with CKD 5D have left ventricular hypertrophy (LVH), which is a predisposing factor to diastolic dysfunction, heart failure (HF), arrhythmias, and sudden cardiac death. In recent years, a significant role in the development of cardiovascular pathology in CKD has been attributed to disturbances in calcium and phosphorus homeostasis. Mineral bone correction may have a beneficial effect on LVH.Aim. To evaluate the associations between indices of mineral-bone metabolism and cardiac echocardiography parameters in patients on renal replacement therapy (RRT) with hemo- and peritoneal dialysis, receiving and not receiving phosphate binders.Materials and methods. The study included 75 patients, of whom 53 received treatment with program hemodialysis (HD), 22 with peritoneal dialysis (PD). The control group consisted of 28 healthy volunteers. 43 patients were treated with phosphate binders. Of all patients receiving treatment aimed at correcting hyperphosphatemia, 22 received sevelamer carbonate: 86% of patients took sevelamer carbonate at a dose of 4800 mg/day and 14% at a dose of 2400 mg/day. All biochemical parameters were determined on an automatic biochemical analyzer; FGF-23 was also determined by enzyme-linked immunosorbent assay (ELISA) and the level of intact PTH was determined by chemiluminescence immunoassay. Instrumental studies included echocardiography.Results. In patients with left ventricular hypertrophy (LVMM in the group of patients on hemodialysis 206.6 [120.0; 300.0], in the group on peritoneal dialysis 176.2 [134.0; 204.0]) the level of FGF-23 was significantly increased (p = 0.005). In the group of patients receiving sevelamer carbonate, there was a decrease in the incidence of left ventricular hypertrophy, lower levels of FGF-23 (12.4 ± 5.9), in contrast to the group that did not receive this drug (23 ± 7.3; p = 0.003 ) and PTH (110 ± 27 ng/ml, in the group that did not receive the drug – 340 ± 15; p = 0.01).Conclusions. The use of phosphate binders, in particular sevelamer carbonate, is associated with a decrease in left ventricular hypertrophy and lower levels of FGF-23.

#2028 Efficacy and safety of sucroferric oxyhydroxide versus sevelamer carbonate: a systematic review and meta-analysis

Abstract Background and Aims Hyperphosphatemia is a common and clinically significant complication in severe chronic kidney disease (CKD), associated with higher cardiovascular adverse events and higher mortality rates. High serum phosphate is also associated with a heightened risk of cardiovascular issues such as hypertension, left ventricular hypertrophy, atherosclerosis, and vascular calcifications. Phosphate binders are commonly used in patients receiving renal replacement therapy (RRT), aiming to reduce and maintain serum phosphorus. This study aims to examine the efficacy and safety of sucroferric oxyhydroxide versus sevelamer carbonate in patients receiving RRT. Method Data sources included MEDLINE(PubMed), Scopus, and the Cochrane Central Register of Controlled Clinical Trials with the search cut-off in October 2023. We examined RCTs that comparing sucroferric oxyhydroxide versus sevelamer carbonate in the adult population receiving RRT. Data extraction followed the PICOS protocol and bias risk was assessed using the Rob-2 tool. We performed a meta-analysis combining the data from RCTs, using R-studio. The primary endpoint of this study is the change in the serum phosphorus levels from baseline to end of treatment. Secondary outcomes included changes in serum intact parathormone (i-PTH) levels from baseline to end of treatment as well as the adverse events ratio during the study period. Given the prevalence of gastrointestinal side effects for both drugs, which often leads to drug discontinuation or patient non-adherence, a separate analysis focused on gastrointestinal-related adverse events. Results Inclusion criteria were met by 5 RCTs. No statistically significant difference was found in serum phosphorus reduction between the two groups {MD: −0.07 mmol/l,95% CI-random effects: −0.15 to 0.02}. Similarly, serum i-PTH reduction showed no statistically significant difference between the two drugs {MD = −1.53 mg/dl, 95% CI = (−4.45, 1.4), p = 0.26, random effects model}. Adverse events were comparable between the groups (OR: 1.11, 95% CI: 0.65-1.88, random effects model). However, further analysis of gastrointestinal adverse evets indicated a 60% increase with sevelamer carbonate {OR: 1.60, 95% CI 1.31-1.97, common(fixed) effect model}. Funnel plot examination for both continuous and dichotomous outcomes revealed a high chance for small study effect and publication bias. Conclusion This meta-analysis found that sucroferric oxyhydroxide and sevelamer carbonate are equally effective in controlling serum phosphorus and i-PTH levels. Sucroferric oxyhydroxide, however, demonstrated a more favorable profile regarding gastrointestinal adverse events. Our findings suggest sucroferric oxyhydroxide as a valuable alternative for RRT patients who have difficulty tolerating sevelamer carbonate.

#2524 Impact of sevelamer hydrochloride on fibroblast growth factor-23 levels in patients undergoing hemodialysis

Abstract Background and Aims Serum intact fibroblast growth factor 23 (FGF23) levels are progressively increased in relation to the severity of kidney dysfunction. High serum intact FGF23 concentration is associated with the increased cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Clinically, phosphate binders are commonly used to reduce serum intact FGF23 levels in CKD patients by lowering serum phosphate levels. Reduction of high intact FGF23 concentration is a strategy, possibly improving the consequences of CKD. We aimed to Assessing the Impact of Sevelamer Carbonate on Fibroblast Growth Factor-23 Levels. Method This case-control study enrolled 100 pre-existing hemodialysis patients, evenly divided into two groups of 50. Group I received a specific sevelamer hydrochloride (Renagel)® dose (2 tablets every 8 hrs), while Group II served as the control group and did not receive (Renagel)®. All patients received the same modality of dialysis with a consistent dialysate calcium concentration. Additionally, they received comprehensive dietary phosphate counseling as part of the standard dietary education provided to our dialysis patients. The levels of phosphorus, calcium, alkaline phosphatase, and FGF23 were assessed in all individuals at the beginning of the study (baseline) and again following 3 months of sevelamer therapy. Results While baseline FGF-23 levels were not statistically different, a highly significant divergence emerged after 3 months of treatment. The sevelamer group experienced a remarkable 38.4% decrease in FGF-23, compared to a mere 0.5% change in the control group, highlighting the pronounced effect of sevelamer on this key protein. Analysis of PO4 levels revealed a remarkable difference between the groups following treatment. While initial PO4 measurements were statistically comparable, the sevelamer group experienced a significantly larger decrease compared to the control group (p < 0.001). Both baseline and follow-up FGF-23 levels displayed highly statistically significant positive correlations with PO4, PTH, alkaline phosphatase, and hsCRP. Conclusion This study found that non-calcium-based phosphate binders were associated with a substantial reduction in FGF-23 in hemodialysis patients. This finding suggests that utilizing such binders may offer protection against the adverse effects of high FGF-23 levels, which are prevalent in this population.

Tolerability, safety and efficacy of a novel phosphate binder VS-505 (AP301): a Phase 2 dose-escalation and dose-ranging study in patients undergoing maintenance hemodialysis.

VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part Phase 2 study evaluated the tolerability, safety and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50 and 9.00g/day for 2weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50 or 6.75g/day) or sevelamer carbonate 4.80g/day for 6weeks. The primary efficacy endpoint was the change in serum phosphorus. The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during Weeks 1-2 of treatment). Most gastrointestinal disorders resolved without intervention, and none was serious. In Part 1, serum phosphorus significantly improved (mean change -2.0mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75g/day, and sevelamer carbonate 4.80g/day [mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2) and -1.4 (-2.2, -0.5) mg/dL, respectively]. In both parts, serum phosphorus reductions occurred within 1week of VS-505 initiation, returning to baseline within 2weeks of VS-505 discontinuation. VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. NCT04551300 .

Deposition of Sevelamer crystals in gastrointestinal tract and lung parenchyma: A rare autopsy finding

Abstract Introduction/Objective Sevelamer carbonate is a non-calcium-based phosphate binder used for the management of hyperphosphatemia in patients with end stage renal disease. The well-known side effects of sevelamer include nausea, vomiting and abdominal pain. However, there are few case reports which described the deposition of sevelamer crystals in the gastrointestinal tract causing mucosal injury, pseudotumor or obstruction. Methods/Case Report We hereby present a case of a 43-year-old decedent female with past medical history of seizures, hypertension, cocaine use, type B aortic dissection status post thoracic endovascular aortic repair, total arch replacement, reconstruction of innominate, carotid, and subclavian artery who presented with hematochezia concerning for possible aorto-esophageal fistula on 10/06/2022 and acute kidney injury. Imaging showed a thrombus in mid-esophagus, blood in trachea and narrowing of the left main stem bronchus. Labs revealed worsening of BUN and creatinine and up trending hyperphosphatemia and therefore sevelamer carbonate via nasogastric route was started on 10/13/22. Unfortunately, the patient’s hospital course was complicated, and she passed away on 11/14/2022. At autopsy, the deceased had gross evidence of acute lung injury with diffuse alveolar hemorrhage, aorta-bronchial ruptured aneurysm defect and aorto-esophageal fistulas. On histopathological examination, the stomach, small and large bowel showed autolysis, necrosis, and numerous rectangular shaped, non-polarizable crystals. The crystals with characteristic morphology of “fish scale” with hues of pink in the center and yellow to orange in the periphery were identified as sevelamer crystals. Interestingly, crystal deposition was also identified in lung parenchyma and rarely in aortic wall and the fistula. Results (if a Case Study enter NA) NA Conclusion As one of the more commonly used resins in end stage kidney disease, gastrointestinal adverse effect of sevelamer carbonate is often underrecognized. Our case report heightens the awareness of the characteristic morphology of this biologically inert agent, sevelamer to those who are unaware of their morphology. This case also highlights the adverse effect of sevelamer in all patients presenting with gastrointestinal symptoms, such as gastrointestinal bleeding and abdominal pain with the use of sevelamer.

Effect of the Phosphate Binder Sevelamer Carbonate on the Bioavailability of Enarodustat, an Oral Erythropoiesis Stimulating Agent.

Enarodustat is an orally available hypoxia-inducible factor-prolyl hydroxylase inhibitor which can correct the erythropoietic capacity and improve anemia in chronic kidney disease. Sevelamer carbonate, a non-calcium-based polymeric resin, is one of the commonly prescribed agents for the management of hyperphosphatemia in patients undergoing hemodialysis. This was an open-label, crossover study in healthy male subjects (N=12) that evaluated the effect of sevelamer carbonate (2400mg) on the bioavailability of enarodustat (25mg) when the 2 drugs were administered together (Treatment B) or when enarodustat was administered 3hours after (Treatment C) or 1hour before (Treatment D) sevelamer carbonate compared to enarodustat alone (Treatment A). With coadministration of the 2 drugs (Treatment B), enarodustat Cmax and AUCinf reductions were 53% and 45%, respectively. For Treatment C, Cmax and AUCinf reductions were 11% and 6%, respectively, and for Treatment D the corresponding values were 8% and 20%. Thus, coadministration of enarodustat and sevelamer carbonate resulted in a substantial reduction (≈50%) in the oral bioavailability of enarodustat. However, the interaction was substantially mitigated by staggering the administration of enarodustat and sevelamer carbonate. Administration of 4 single oral doses of enarodustat 25mg, with or without sevelamer carbonate, were safe and well tolerated in this study.

Safety Analysis of Tenapanor Monotherapy vs. Sevelamer Carbonate in Patients on Maintenance Dialysis with Hyperphosphatemia

Safety Analysis of Tenapanor Monotherapy vs. Sevelamer Carbonate in Patients on Maintenance Dialysis with Hyperphosphatemia

Tenapanor Improves Long-Term Control of Hyperphosphatemia in Patients Receiving Maintenance Dialysis: the NORMALIZE Study.

Most patients with end-stage kidney disease and hyperphosphatemia have difficulty controlling serum phosphate concentrations (sP) despite maintenance dialysis, dietary restriction, and phosphate binder treatment. NORMALIZE evaluated the efficacy and safety of tenapanor 30 mg twice daily alone or in combination with phosphate binders to achieve sP within the adult population reference range (2.5-4.5 mg/dL). Patients who completed the phase 3 PHREEDOM study could enroll in NORMALIZE. Patients enrolled in NORMALIZE who had received tenapanor during the PHREEDOM study (n=111) added sevelamer carbonate if sP was >4.5 mg/dL. Patients who had received sevelamer carbonate during the PHREEDOM study (n=61) added tenapanor and decreased sevelamer carbonate if sP was ≤4.5 mg/dL, per protocol titration schedule. Patients were followed in NORMALIZE for up to 18 months. We assessed efficacy in the full analysis set (FAS), defined as patients who received ≥1 dose of study drug and had ≥1 posttreatment sP measurement (n=171). We assessed safety in all patients who received ≥1 dose of study drug (n=172). At the endpoint visit, 57 of 171 patients (33%) in the FAS achieved sP between 2.5 and 4.5 mg/dL. Eight of 23 patients (35%) who were on tenapanor alone at the endpoint visit achieved sP between 2.5 and 4.5 mg/dL. The mean reduction from PHREEDOM baseline to end of NORMALIZE in sP was 2.0 mg/dL. Serum iFGF23 was significantly reduced; serum iPTH was significantly reduced among patients with iPTH ≥300 pg/mL at PHREEDOM baseline. The most commonly reported treatment-emergent adverse event was diarrhea in 38 of 172 patients (22%), which led to tenapanor discontinuation in 4 patients (2%). Tenapanor alone or in combination with phosphate binders helped adult patients on maintenance dialysis achieve normal sP concentrations. Safety was consistent with previous studies of tenapanor. A Long-Term Study to Evaluate the Ability of Tenapanor Alone or in Combination With Sevelamer to Treat to Goal Serum Phosphorus in Patients With End-Stage Kidney Disease on Dialysis (NORMALIZE), NCT03988920.

Efficacy and Safety of Ferric Citrate on Hyperphosphatemia among Chinese Patients with Chronic Kidney Disease Undergoing Hemodialysis: A Phase III Multicenter Randomized Open-Label Active-Drug-Controlled Study

Introduction: Hyperphosphatemia in chronic kidney disease (CKD) patients is positively associated with mortality. Ferric citrate is a potent phosphorus binder that lowers serum phosphorus level and improves iron metabolism. We compared its efficacy and safety with active drugs in Chinese CKD patients with hemodialysis. Methods: Chinese patients undergoing hemodialysis were randomized into two treatment groups in a 1:1 ratio, receiving either ferric citrate or sevelamer carbonate, respectively, for 12 weeks. Serum phosphorus levels, calcium concentration, and iron metabolism parameters were evaluated every 2 weeks. Frequency and severity of adverse events were recorded. Results: 217 (90.4%) patients completed the study with balanced demographic and baseline characteristics between two groups. Ferric citrate decreased the serum phosphorus level to 0.59 ± 0.54 mmol/L, comparable to 0.56 ± 0.62 mmol/L by sevelamer carbonate. There was no significant difference between two groups (p > 0.05) in the proportion of patients with serum phosphorus levels reaching the target range, the response rate to the study drug, and the changes of corrected serum calcium concentrations, and intact-PTH levels at the end of treatment. The change of iron metabolism indicators in the ferric citrate group was significantly higher than those in the sevelamer carbonate group. There are 47 (40.5%) patients in the ferric citrate group, and 26 (21.3%) patients in the sevelamer carbonate group experienced drug-related treatment emergent adverse events (TEAEs); most were mild and tolerable. Common drug-related TEAEs were gastrointestinal disorders, including diarrhea (12.9 vs. 2.5%), fecal discoloration (14.7 vs. 0%), and constipation (1.7 vs. 7.4%) in ferric citrate and sevelamer carbonate group. Conclusion: Ferric citrate capsules have good efficacy and safety in the control of hyperphosphatemia in adult patients with CKD undergoing hemodialysis. Efficacy is not inferior to sevelamer carbonate. The TEAEs were mostly mild and tolerated by the patients.

Elderly-onset calcinosis of hyperphosphataemic familial tumoural calcinosis/hyperostosis-hyperphosphataemia syndrome: the role of comorbid scleroderma.

A 73-year-old woman with type 2 diabetes mellitus was referred to our department for glycaemic control. Physical examination revealed two subcutaneous hard masses around the left shoulder and the right hip joint. The patient could not fully extend her fingers because of skin sclerosis in both hands. Laboratory studies showed hyperphosphataemia and a high ratio of renal tubular maximum reabsorption of phosphate to glomerular filtration rate. There were no abnormalities in serum calcium, creatinine, alkaline phosphatase, and intact parathyroid hormone levels, whereas serum fibroblast growth factor 23 was low. Hyperphosphataemic familial tumoural calcinosis/hyperostosis-hyperphosphataemia syndrome (HFTC/HHS) was diagnosed using whole genome sequencing that revealed a novel frameshift beyond the 584th threonine located in the lectin domain of UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 associated with a duplication of the 1748th thymine in the coding region of the corresponding gene. Furthermore, anti-nuclear, anti-centromere, and anti-cardiolipin antibodies were positive, implying that comorbid limited type scleroderma might play a role in tumoural calcinosis (TC) development. A low phosphate diet was prescribed with phosphate-lowering medications, including aluminium hydroxide, acetazolamide, and sevelamer hydrochloride. The patient displayed a decrease in serum phosphate levels from 6.5 to 5.5 mg/dL 10 months after the initiation of treatment, but her TC had not improved during treatment for more than 1 year. This case was interesting because the patient with HFTC/HHS exhibited TC despite being over her 60s, and subsequent scleroderma might contribute to the specific clinical course. When HFTC/HHS presents with elderly-onset TC, the involvement of comorbidities in exacerbating TC should be considered. HFTC/HHS occurs on an autosomal recessive basis, but its clinical course and manifestations differ significantly throughout the cases. HFTC/HHS may be undiagnosed until later in life because of its rarity, unfamiliarity, and phenotype diversity; therefore, HFTC/HHS should be included in the differential diagnosis of elderly patients with unexplained hyperphosphataemia or ectopic calcinosis. Comorbidities, including rheumatologic disorders, may contribute to developing HFTC/HHS-associated calcinosis.

Biochemical markers of iron status and iron accumulation in peritoneal dialysis patients treated with ferric citrate.

Hyperphosphataemia is a common complication of kidney disease. Current dialysis techniques do not provide enough phosphorus clearance, hence the need to use phosphorus binders. Treatment options include calcium carbonate, calcium acetate, lanthanum carbonate, sevelamer hydrochloride and iron-based binders. Patients receiving peritoneal dialysis (PD) with sustained elevated ferritin levels exceeding 800 ng/mL are at a higher risk of death. We identify PD patients treated with iron-based binders and compare ferritin and risk of iron accumulation to patients treated with non-iron-based binders. All records of patients receiving PD at Emory dialysis centres until 30 October 2021 were reviewed for phosphorus binders. Basic demographics and laboratory data were time-referenced to the days on treatment with a particular binder. Patients were followed until discontinuation of the phosphorus binder, death, transplant, transfer to another dialysis provider or censoring at 36 months after medication was started. Compared to calcium acetate and sevelamer, ferric citrate utilisation in PD patients resulted in a sustained increase in ferritin. The proportion of patients with a ferritin equal to or greater than 800 ng/dL and transferrin saturation greater than 40% increased over time in patients treated with ferric citrate and was higher during the second and third year of follow-up compared to baseline values and to patients treated with calcium acetate or sevelamer. Two patients (7%) treated with ferric citrate developed clinically significant haemosiderosis. Use of ferric citrated in PD resulted in significant iron accumulation as judged by ferritin levels.

Efficacy and Safety of Sucroferric Oxyhydroxide Compared with Sevelamer Carbonate in Chinese Dialysis Patients with Hyperphosphataemia: A Randomised, Open-Label, Multicentre, 12-Week Phase III Study

Introduction: This study aimed to investigate the efficacy and safety of sucroferric oxyhydroxide (SFOH) versus sevelamer carbonate in controlling serum phosphorus (sP) in adult Chinese dialysis patients with hyperphosphataemia (sP >1.78 mmol/L). Methods: Open-label, randomised (1:1), active-controlled, parallel group, multicentre, phase III study of SFOH and sevelamer at starting doses corresponding to 1,500 mg iron/day and 2.4 g/day, respectively, with 8-week dose titration and 4-week maintenance (NCT03644264). Primary endpoint was non-inferiority analysis of change in sP from baseline to week 12. Secondary endpoints included sP over time and safety. Results: 415 patients were screened; 286 were enrolled and randomised (142 and 144 to SFOH and sevelamer, respectively). Mean (SD) baseline sP: 2.38 (0.57) and 2.38 (0.52) mmol/L, respectively. Mean (SD) change in sP from baseline to week 12: – 0.71 (0.60) versus −0.63 (0.52) mmol/L, respectively; difference (sevelamer minus SFOH) in least squares means (95% CI): 0.08 mmol/L (−0.02, 0.18) with the lower limit of 95% CI above the non-inferiority margin of −0.34 mmol/L. The SFOH group achieved target sP (1.13–1.78 mmol/L) earlier than the sevelamer group (56.5% vs. 32.8% at week 4) and with a lower pill burden (mean 3.7 vs. 9.1 tablets/day over 4 weeks of maintenance, respectively). Safety and tolerability of SFOH was consistent with previous studies, and no new safety signals were observed. Conclusion: SFOH effectively reduced sP from baseline and was non-inferior to sevelamer after 12 weeks of treatment but had a lower pill burden in Chinese dialysis patients with hyperphosphataemia; SFOH benefit-risk profile is favourable in Chinese patients.

High Phosphate-Binding Capacity of Oxylanthanum Carbonate with a Low Medication Volume: Comparison with Commercially Available Phosphate Binders

Background: A key focus for chronic kidney disease management is phosphate control, but currently available binders have suboptimal phosphate-binding capacity, and their characteristics result in low adherence and poor phosphate regulation. Oxylanthanum carbonate, a novel compound that uses proprietary nanoparticle technology to deliver lanthanum, has the potential to combine high phosphate-binding capacity with good intake convenience, thus improving adherence and patient quality of life. The goal of this study was to assess the volume of oxylanthanum Carbonate required to bind 1 g of phosphate and compare it with other currently available phosphate binders to determine which binder allows for the highest normalized potency with the lowest daily medication volume. Methods: Six phosphate binders were assessed: ferric citrate, calcium acetate, lanthanum carbonate, sevelamer carbonate, sucroferric oxyhydroxide, and oxylanthanum carbonate. Table volume measurements were taken using fluid displacement in corn oil or water. Mean daily dose volume to bind 1 g of phosphate was calculated as volume per tablet multiplied by the mean number of tablets taken per day. Volume to bind 1 g of phosphate was calculated by dividing the volume per tablet by its in vivo binding capacity. Results: Oxylanthanum carbonate had the lowest mean volume, daily phosphate binder dose volume, and equivalent phosphate-binding dose volume (volume to bind 1 g of phosphate for each binder). Conclusions: Oxylanthanum carbonate has the lowest daily phosphate binder dose volume and the smallest volume required to bind 1 g of phosphate compared to all other commercially available phosphate binders. A randomized trial that compares gastrointestinal tolerability across binders would be warranted to demonstrate acceptability and adherence in the target population.

#6606 MEDICATION VOLUME COMPARISON TO BIND PHOSPHATE

Abstract Background and Aims Elevated phosphate concentrations are associated with a significantly increased risk of cardiovascular disease and overall mortality in patients with chronic kidney disease. Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend lowering elevated serum phosphorus concentrations toward the normal range in patients with end-stage kidney disease on dialysis through restriction of dietary phosphorus intake, increase in clearance by dialysis, and the use of phosphate binders. However, ∼75% of dialysis patients are not achieving normal phosphate concentrations, potentially due to low adherence and/or binders’ insufficient phosphate binding capacity to match dietary intake. A phosphate binder with a higher phosphate binding capacity could improve phosphate control and potentially clinical outcomes. This study evaluated the medication volume of various phosphate binders to bind 1 gram of phosphorus. Methods Five phosphate binders were assessed: ferric citrate (210 mg ferric iron), calcium acetate (667 mg calcium acetate), lanthanum carbonate (500 and 1,000 mg lanthanum), sevelamer carbonate (800 mg sevelamer carbonate), and lanthanum dioxycarbonate (500 and 1,000 mg lanthanum). The mean daily dose volume to bind 1 g of phosphate was calculated as volume per tablet multiplied by the mean number of tablets taken per day. The volume to bind 1 g of phosphate was calculated by dividing the volume per tablet by its in vivo binding capacity, based on NIH DailyMed website. Results Binding to 1 g of phosphate required 5.6 cm3 of lanthanum dioxycarbonate compared with lanthanum carbonate (19.8 cm3), calcium acetate binders (25.0 cm3), ferric citrate (46.5 cm3), and sevelamer carbonate (73.4 cm3) (Figure 1). Conclusion The study found that lanthanum dioxycarbonate had the lowest volume to bind the same amount of phosphate compared to other binders. With a low medication volume and high phosphate binding capacity, lanthanum dioxycarbonate, a novel investigational nanotechnology product, can be a welcoming choice for patients to manage their hyperphosphatemia. The drug's decreased pill size (making it easy to swallow) and its tolerability have the potential to increase medication adherence and improve phosphate control.

#2887 ASSESSMENT OF EXTRA-BONE CALCIFICATION IN PATIENTS UNDERGOING PROGRAMMED HEMODIALYSIS

Abstract Background and Aims Chronic kidney disease is associated with the accumulation of so-called medium molecules in the blood, in particular parathyroid hormone, and the formation of secondary hyperparathyroidism with a tendency to extra-bone calcification. The most vulnerable organ in relation to calcification is the vascular wall. The ail of the study to study the features of vascular wall remodeling in patients with chronic kidney disease who are being treated with programmed hemodialysis. Method The study included 86 patients with CKD C5 (mean age 47.44±5.04 years) who had been on programmed hemodialysis for at least 6 months. All patients underwent examination, including multislice spiral computed tomography (MSCT) with an assessment of the calcium content in the coronary arteries (Agatston index), ultrasound examination of the carotid arteries with determination of the thickness of the intima-media complex, the degree of endothelium-dependent vasodilation in a sample with 5-minute compression of the brachial artery and determination of changes in the diameter of the brachial artery. The data obtained (presented in the form of an arithmetic mean and its standard error) were compared with normal values typical for a healthy population. Results There was an accumulation of calcium in the coronary vessels with an average Agatstone index of 146.83 ± 13.26 units. Also, during MSCT, calcifications were found in the aortic wall in 86 out of 57 patients. The intima-media complex in patients with CKD was significantly increased and averaged 1.21±0.06mm. The degree of endothelium-dependent vasodilation in patients with CKD was reduced and amounted to 5.48± 0.03% of the initial diameter of the brachial artery. Correlation analysis revealed significant positive associations of average strength between the value of the Agatson index, the thickness of the intima-media complex of the carotid arteries and the concentration of parathyroid hormone in peripheral blood (g = +0.58,P<0.05 with the Agatson index and P = 0.42, P<0.05 with the thickness of the intima-media complex), as well as a significant negative relationship between the product of the concentration of calcium and phosphorus in peripheral blood and the degree of endothelium-dependent vasodilation (g = -0.49, P<0.05). Conclusion In patients with CKD, against the background of programmed hemodialysis, there is a remodeling of the heart with an increase in the size of the heart cavities and LV myocardial mass, a violation of regional and general LV contractile function, LV diastolic dysfunction and an increase in pressure in the pulmonary artery system. The introduction of sevelamer hydrochloride into the therapy regimen is associated with the prevention of the progression of cardiac remodeling. Calcification of the aortic valve progresses, regardless of the therapy used. Vascular remodeling in patients with CKD on the background of programmed hemodialysis is manifested by an increase in the thickness of the intima-media complex of the carotid arteries and a violation of endothelium-dependent vasodilation in favor of paradoxical vasoconstriction. Against the background of calcium carbonate therapy, structural disorders of the vascular wall progress. The introduction of sevelamer phosphate binder into the therapy regimen allows to prevent the progression and improve the functional state of endothelial function.

#2886 THE COURSE OF OSTEODYSTROPHY IN PATIENTS WITH STAGE 5 CHRONIC KIDNEY DISEASE RECEIVING PROGRAMMED HEMODIALYSIS

Abstract Background and Aims In a normal physiological state, there are many regulatory molecules that act as inhibitors of mineral formation to prevent the spread of tissue hardening. In patients with CKD, the levels or functions of these inhibitors may be abnormal, which in turn may predispose to or enhance ectopic calcification. to increase the effectiveness of early diagnosis of demineralization of the bone skeleton in patients with stage V chronic kidney disease receiving hemodialysis. Method The study included 94 CKD patients receiving hemodialysis for 15 months. The average age of the patients was 42.13±12.16 years. Etiologically, the cohort of patients included in the study was diverse, with a significant predominance of chronic glomerulonephritis as the cause of CKD in 72 patients, chronic pyelonephritis in 22 patients occupied the second place among the causes of CKD, the remaining causes occurred with a single frequency. Anemia was diagnosed in 71 patients. The observation lasted 12 months. Pathological changes in phosphorus-calcium metabolism and secondary hyperparathyroidism in patients were associated with a significant decrease in bone mineral density, it was shown both for the bodies of the lumbar vertebrae and for the femoral neck, the significance of the difference from the control group for absolute values of mineral density and relative deviation. Results In dynamics for 6 months in the general cohort of patients, there was a significant increase in the absolute mineral density of the femoral neck by 11.38%, p<0.01 the reliability of the difference with the baseline data, and a decrease in the degree of deviation of the mineral density index from the age norm -3.13%, p<0.05 for the bodies of the lumbar vertebrae and -4.01%, p<0.01 for the femoral neck, which confirms the effectiveness of osteoporosis therapy. In the present study, in 45 patients 37.5% at the time of inclusion in the study in the bodies of the lumbar vertebrae, the T-index was higher than -2.5 SD, in respect of the femoral neck – in all patients, the T was lower than 2.5 ST. The study of bone mineral density in patients with HCBP, the decrease of which reflects the syndrome of renal osteodystrophy, developing in response to secondary hyperparathyroidism, against the background of osteoporosis therapy. Conclusion In patients with CKD, against the background of programmed hemodialysis, there is a decrease in bone mineral density (1.93 times the bodies of the lumbar vertebrae and 2.83 times the femoral neck). The use of calcium carbonate, biphosphonate and vitamin D3 contributes to an increase in the mineral density of the femoral neck by 8.64% (p<0.05). The introduction of sevelamer hydrochloride into the therapy regimen increases the effectiveness of therapy and increases the mineral density of the bodies of the lumbar vertebrae by 5.96% (p< 0.05) and the femoral neck by 14.04% (p<0.05).

A Comparative Study on Approval of Follow-on Version of Sevelamer Carbonate and Glatiramer Acetate (GA) in US, EU

Abstract: Many non-biological drugs, different in terms of their structure and mode of action, pharmacological classification, and therapeutic indication, have a common factor of structural complexity and are grouped as non-biological complex drugs (NBCDs). When an innovator drug nears the time of off-patent, different manufacturers attempt to produce its subsequent version, so the patients will have a cost-effective therapeutic equivalent. Since the innovator molecule is complex, its follow-on drug can be called its true generic version, if its bioavailability, bioequivalence and therapeutic equivalence to the innovator drug are demonstrated. However, it is observed that a case-to-case basis approach is implemented by European Medicines Agency (EMA) and Food and Drug Administration, US (USFDA) in the approval of such drugs and there is no uniformity observed between the two. : In this study, an attempt is made to study the complexity of molecules compare and understand the data requirements, and procedures adopted for the review and approval of such complex products. Therefore, drug sevelamer carbonate and glatiramer acetate are selected for the study. A methodical approach was followed. European assessment reports and drug approvals available in the orange book database of the former two regulatory agencies were studied. It is observed that the generic version of glatiramer acetate is approved as an abbreviated new drug application (ANDA) by Food and Drug Administration whereas the same was approved as the hybrid application by European Medicines Agency requiring the applicant to generate and submit more data. Thus, harmonization of the regulatory requirements for the approval of follow-on versions of such complex drugs is essential for better understanding, predictability of the regulatory process, and acceleration of the drug approval process, in the interest of patients. This will help the faster access of the drugs to the patients and allow interchangeability of the innovator drugs with its cost-effective generic version.