Oral Phosphate Binders Research Articles

Oral phosphate binders and incident osteoporotic fracture in patients on dialysis.

End-stage kidney disease (ESKD) has an elevated risk of osteoporotic fractures in relation to mineral and bone disorder (MBD) as well as conventional risks of osteoporosis. We investigated the association between oral phosphate binders, the mainstay of MBD treatment, and osteoporotic fracture in dialysis patients. We obtained data from the National Health Insurance database for incident dialysis patients without a history of osteoporotic fractures. Participants were categorized into four groups based on their initial 1-year prescription profiles: calcium-based phosphate binder (CBPB), non-calcium-based phosphate binder (NCBPB), both calcium and non-calcium-based binders (Mixed), and non-phosphate binder (non-user) groups. The primary outcome was the occurrence of new-onset osteoporotic fractures after 1 year of dialysis. Secondary outcomes included cardiovascular events and mortality. Out of 69368 incident dialysis patients, 22326, 5020, 2853, and 39169 were included in the CBPB, NCBPB, mixed, and non-user groups, respectively. The overall risk of osteoporotic fractures was lower in patients taking any phosphate binders compared to non-users. Specifically, only the CBPB group showed a reduced risk of vertebral (adjusted hazard ratio (aHR) 0.83 [0.76-0.92]), hip (aHR 0.81 [0.74-0.89]), and distal radius (aHR 0.88 [0.78-0.99]) fractures compared to non-users. This relationship was represented by a time-dependent manner with fracture risk reduction in patients taking CBPB for 3-6 months (aHR 0.9 [0.83-0.99]) and≥6 months (aHR 0.83 [0.78-0.89]), compared to those using CBPB for less than 3 months. Additionally, only the CBPB group had a lower risk of MACE, cardiac arrest, and ventricular arrhythmia than non-users. All phosphorus binder groups showed a reduced mortality risk compared to non-users. Our findings indicate that the using phosphate binders in ESKD patients is lowers the risk of osteoporotic fractures. Notably, those taking CBPB had a reduced risk without increasing cardiovascular events or mortality compared to non-users.

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 .

Risk factors for arteriovenous fistula dysfunction in hemodialysis patients: a retrospective study

Arteriovenous fistula (AVF) is the first choice of vascular access in hemodialysis (HD) patients. However, the correlations between patient factors and the arteriovenous fistula patency remain unclear. Therefore, our study investigates the risk factors associated with AVF dysfunction in HD patients. A total of 233 end-stage renal disease (ESDR) patients who met the study inclusion criteria in the Nephrology Department of Hunan Provincial People’s Hospital between December 2020 and June 2022 were included in this study. The baseline demographic, clinical and laboratory parameters were collected at the time of AVF creation and analyzed. Of the 233 ESRD patients, 146 (62.7%) were male and the mean age was 56.11 ± 12.14 (21–82) years. The patients were followed for a median time of 14 months. Kaplan–Meier analysis showed a 6-, 12- and 24-month post-placement survival of 87.1%, 82.8% and 80.7%, respectively. Univariate Cox regression analysis revealed weight (HR, 1.03; P = 0.03) as a predictor for the loss of vascular access functionality. In addition, multivariate Cox regression analysis further demonstrated that sex (HR, 3.41; P = 0.03), weight (HR 1.08; P < 0.01) and phosphorus level (HR: 3.03; P = 0.01) are independent risk factors for AVF dysfunction. AVF dysfunction is highly associated with several risk factors including weight, phosphorus level, and sex. Positive intervention strategies targeting these potential factors, such as weight loss or oral phosphate binders could improve the long-term success of AVF.

Can Oral Phosphate Binders Be Added to Dialysate to Improve the Efficacy of Hemodialysis?

Can Oral Phosphate Binders Be Added to Dialysate to Improve the Efficacy of Hemodialysis?

#4296 EFFECTS OF FERRIC CITRATE HYDRATE ON FIBROBLAST GROWTH FACTOR 23 AND PLATELET COUNT IN CKD AND NON-CKD PATIENTS WITH IRON DEFICIENCY ANAEMIA

Abstract Background and Aims Iron deficiency increases the transcription and cleavage of the peptide hormone, fibroblast growth factor 23(FGF23). Elevated FGF23 has been associated with increased risk of cardiovascular events and mortality. Iron deficiency also increases platelet count (PLT) in part, and higher levels PLT are associated with arterial thrombosis in the brain. Ferric citrate hydrate (FC, Riona®, Torii Pharmaceutical Co., Ltd. Tokyo, Japan) is an oral iron-based phosphate binder for patients with chronic kidney disease (CKD) and also an iron preparation approved for treatment of iron deficiency anaemia (IDA) in Japan. A phase 3 study was conducted to investigate the efficacy and safety of FC in CKD and non-CKD patients with IDA. This study aimed to evaluate the effects of FC on intact FGF23 and c-terminal FGF23 levels, and the proportion of patients with high PLT (exceeding upper limit: &amp;gt;35.2 × 104/µL). Method A randomized, open-label, multicentre, uncontrolled, 24-week study was conducted at 31 centres in Japan from July 2018 to December 2019 (JapicCTI-184000) in CKD and non-CKD patients with IDA (Hb: ≥8.0 g/dL and &amp;lt;11.0 g/dL, serum ferritin &amp;lt;50 ng/mL in CKD (eGFRcre &amp;lt;60 mL/min/1.73 m2) and &amp;lt;12 ng/mL in non-CKD). CKD patients scheduled to initiate maintenance dialysis were excluded. Dynamic allocation was used to randomise subjects (CKD and non-CKD with Hb at baseline) to the FC-low group (500 mg [approximately 120 mg elemental iron]/day) or FC-high group (1000 mg [approximately 240 mg elemental iron]/day) (1:1). Notably, if investigators determined that sufficient iron replacement had been achieved from week 8 onwards, the study treatment was completed. For this reason, changes from baseline to week 8 were evaluated. Results Of 73 patients (CKD n = 42, non-CKD n = 31), 36 were allocated to the FC-low group (CKD n = 21, non-CKD n = 15) and 37 to the FC-high group (CKD n = 21, non-CKD n = 16). Baseline levels of serum ferritin, transferrin saturation (TSAT), c-terminal FGF23, intact FGF23, and PLT are shown in Table 1. Regardless of CKD status, serum ferritin and TSAT increased. After FC-low treatment, mean changes from baseline to week 8 (95% CI) in serum ferritin and TSAT were 18.8 (13.3, 24.2) ng/mL and 8.1 (4.4, 11.8) % in CKD, 17.5 (13.8, 21.3) ng/mL and 13.8 (8.7, 18.9) % in non-CKD;, they were 28.1 (13.4, 42.7) ng/mL and 8.8 (5.4, 12.1) % in CKD, 15.9 (12.1, 19.8) ng/mL and 19.9 (9.8, 30.1) % in non-CKD. After administration of FC, in both groups, intact FGF23 levels did not change, whereas c-terminal FGF23 levels decreased. Median changes (interquartile range) from baseline to week 8 of c-terminal FGF23 were -58.00 (-227.50, -12.25) RU/mL in CKD and -725.00 (-1124.00, -168.50) RU/mL in non-CKD, and -66.00 (-265.70, -27.00) RU/mL in CKD and -649.50 (-1127.00, -326.65) RU/mL in non-CKD. Serum phosphate did not change regardless of CKD status. At baseline, high PLT was observed in the FC-low group in 1 CKD case (5.0%) and 8 non-CKD cases (53.3%), and in the FC-high group in 3 CKD cases (15.8%) and 8 non-CKD cases (50.0%). In all these patients, PLT reduction to below 35.2 × 104/µL was observed until week 8. Conclusion In patients with IDA, administration of FC increased serum ferritin and TSAT, decreased c-terminal FGF23, and normalized PLT in patients with high PLT at baseline regardless of CKD status. FC may decrease the potential risk of cardiovascular events in CKD or non-CKD patients with IDA.

Efficacy of Lanthanum Carbonate and Sevelamer Carbonate as Phosphate Binders in Chronic Kidney Disease—A Comparative Clinical Study

(1) Background: Hyperphosphatemia is correlated with an increased rate of mortality and morbidity due to cardiovascular diseases in chronic kidney disease (CKD) patients. It can be improved by restricting dietary intake of phosphate and oral phosphate binders, such as lanthanum carbonate and sevelamer carbonate. (2) Objective: To evaluate the clinical efficacy of sevelamer carbonate in comparison to lanthanum carbonate as phosphate binders for the treatment of hyperphosphatemia in CKD patients. (3) Methods: A randomized control comparative clinical study was conducted for one year on 150 CKD patients associated with hyperphosphatemia, divided into two groups, i.e., Group 1 (n = 75) treated with sevelamer carbonate 800 mg thrice daily and Group 2 (n = 75) treated with lanthanum carbonate 500 mg thrice daily. The patients were assessed at the time of enrollment in the study, after three months and after six months from baseline for different parameters, i.e., complete blood count, liver function tests, renal function tests, electrolytes, and serum phosphate level. (4) Results: 150 CKD patients aged 51-60 participated in the study. The mean age of patients was 54 ± 4.6 years, and males (55.71%) were more common than females (44.29%). Hypertension was the common comorbidity in both groups with chronic kidney disease. After six months of treatment, the mean serum phosphate level was significantly decreased from 8.31 ± 0.09 mg/dL to 5.11 ± 0.18 (38%) in Group 1 and from 8.79 ± 0.28 mg/dl to 4.02 ± 0.12 (54%; p < 0.05) in Group 2, respectively. In both groups, no significant difference was found in other parameters such as parathyroid hormone, calcium, uric acid, LFT, RFT, CBC, etc. (5) Conclusion: Lanthanum carbonate is more efficacious in lowering serum phosphate concentrations and effectively managing hyperphosphatemia as compared to sevelamer carbonate.

Health Economic Benefits of Introducing Sucroferric Oxyhydroxide in the Treatment of Patients with Chronic Kidney Disease under Dialysis in the Kingdom of Saudi Arabia.

Hyperphosphatemia is an electrolyte disorder highly prevalent in patients with chronic kidney disease undergoing hemodialysis (HD) that usually requires treatment with oral phosphate binders (PBs). Sucroferric oxyhydroxide (SO) is a calcium-free, iron-based PB indicated for the control of serum phosphorus. In the real-world setting, SO has shown clinical effectiveness with a lower pill burden and has also been associated with reduced hospital admission rates. This study aims to assess the potential economic benefits resulting from the introduction of SO to the health-care setting of the Kingdom of Saudi Arabia (KSA). An economic analysis using data from a retrospective real-world study that compared HD patients with uninterrupted SO prescriptions with patients who discontinued SO and switched to other PBs (oPBs). Annual drug costs for the estimated PB-eligible population in KSA were quantified. Costs per responder were estimated for all treatments. Hospital admissions' incidence rates were converted into annual inpatient cost savings and were deducted from drug costs to estimate the annual economic effect of SO versus oPBs. Sensitivity and breakeven analyses were also conducted. The eligible population for PB therapy in KSA was estimated at n = 14,748. Treating therapy-eligible populations exclusively with SO was estimated to generate annual inpatient cost-savings of SAR 107.4-119.4 million compared to treating the population with oPBs. The estimated economic effect signified overall annual savings ranging from SAR 82.8 to SAR 94.8 million when the population is treated with SO. Sensitivity analyses showed persistent cost savings. The estimated benefit-cost ratios showed that for every SAR 1 spent on SO, the expected return on investment was SAR 4.4-4.9. SO is an effective therapy that may result in substantial cost savings from reducing hospital admission costs that are attributable to hyperphosphatemia among HD patients.

Effects of ferric citrate hydrate in patients with chronic kidney disease and heart failure: subgroup analysis of a long-term, real-world, post-marketing surveillance study

BackgroundIron deficiency is widely present in patients with heart failure (HF) and is associated with an increased risk of mortality and poor clinical outcomes regardless of anemia. HF is highly prevalent in patients with chronic kidney disease (CKD). However, existing oral iron preparations have failed to improve iron-related parameters in patients with HF, and intravenous iron preparations are recommended. Ferric citrate hydrate (FC) is an oral iron-based phosphate binder for CKD that is also approved for the treatment of patients with iron-deficiency anemia in Japan. In this subgroup analysis, we evaluated the effect of oral FC on iron-related parameters in CKD patients with and without HF.MethodsWe examined iron- and phosphate-related parameters and adverse drug reactions in subpopulations of CKD patients with and without HF enrolled in a previously reported 104-week, real-world, post-marketing surveillance study of FC in Japan.ResultsAmong 2811 enrolled CKD patients, 348 patients had HF and 2352 did not have HF, including 166 and 1401 undergoing hemodialysis (HD), 36 and 173 undergoing peritoneal dialysis (PD), and 146 and 778 non-dialysis-dependent (ND) patients, respectively. The mean changes (95% confidence interval (CI)) in serum ferritin from baseline to week 36 were 90.98 (62.99–118.97) and 81.86 (72.68–91.03) ng/mL in HD, 158.64 (108.91–208.36) and 132.91 (98.59–167.23) ng/mL in PD, and 68.06 (40.40–95.73) and 99.75 (81.10–118.40) ng/mL in ND group, respectively. The mean changes (95% CI) in transferrin saturation (TSAT) (%) from baseline to week 12 in patients with and without HF were 12.79 (9.15–16.44) % and 9.57 (8.46–10.68) % in HD, 9.55 (1.31–17.78) % and 4.96 (1.44–8.48) % in PD, and 5.85 (2.02–9.69) % and 5.21 (3.34–7.09) in ND patients, respectively. Levels of these parameters were well maintained thereafter. Mean serum phosphate levels decreased after FC treatment initiation and were well maintained in all groups.ConclusionsThis study demonstrated that oral FC had a tendency to increase serum ferritin and TSAT, and controlled serum phosphate in CKD patients regardless of the presence of HF.Trial registration This surveillance was conducted in accordance with the Good Post-marketing Study Practice of Ministry of Health, Labour, and Welfare in Japan.

Phosphate-Trapping Liposomes for Long-Term Management of Hyperphosphatemia.

Hyperphosphatemia is a typical complication of end-stage renal disease, characterized by elevated and life-threatening serum phosphate levels. Hemodialysis does not enable sufficient clearance of phosphate, due to slow cell-to-plasma kinetics of phosphate ions; moreover, dietary restrictions and conventional treatment with oral phosphate binders have low success rates, together with adverse effects. Here, we developed a new concept of phosphate-trapping liposomes, to improve and prolong the control over serum phosphate levels. We designed liposomes modified with polyethylene glycol and encapsulated with the phosphate binder ferric citrate (FC liposomes). These liposomes were found to trap phosphate ions in their inner core, and thereby lower free phosphate ion concentrations in solution and in serum. The FC liposomes showed higher phosphate binding ability as phosphate concentrations increased. Moreover, these liposomes showed a time-dependent increase in uptake of phosphate, up to 25 h in serum. Thus, our findings demonstrate effective long-term phosphate trapping by FC liposomes, indicating their potential to reduce serum phosphate toxicity and improve current management of hyperphosphatemia.

S2126 Sevelamer-Induced Colitis

Introduction: Drug-induced Gastrointestinal (GI) injury has been well established throughout the literature and continues to prevail with the ever-growing expansion of pharmaceutical drug development. Mucosal injuries due to medications ranging from common over-the-counter drugs to novel chemotherapeutics, have been one of the more common findings seen both endoscopically and histologically in drug-induced GI injury. Though frequently seen with NSAIDs, iron pills, and bisphosphonates, lately, resin-based binders like Sevelamer have shown an increased incidence of GI mucosal injuries. Sevelamer is an oral phosphate binder widely used to treat hyperphosphatemia in patients with chronic kidney disease. Here we present a case of Sevelamer induced colitis in a patient on Sevelamer Carbonate therapy for hyperphosphatemia secondary to acute kidney injury. Case Description/Methods: 34 year old male with history of hypertension, obesity class III status post sleeve gastrectomy, OSA, congestive heart failure, and a recent diagnosis of COVID-19 was admitted to the MICU for acute hypoxemic respiratory failure requiring intubation. His hospital course was complicated by worsening renal function and oliguria with creatinine 8.9 and phosphorus 6.4. He was started on hemodialysis (HD), followed by Sevelamer Carbonate 0.8 g TID then increased to 1.6 g TID. Weeks after initiating HD, he developed bright red blood per rectum requiring intermittent transfusions. CT abdomen pelvis and mesenteric angiogram were unremarkable. Upper GI endoscopy showed a Forest Class III duodenal ulcer. Colonoscopy showed localized severe friable ulcerated mucosa with loss of vascular pattern in the cecum and ascending colon. Biopsy at these sites revealed mucosal ulcerations with granulation tissue with Sevelamer crystal deposits. Hematochezia improved on discontinuing Sevelamer (Figure). Discussion: Sevelamer is a calcium-free oral phosphate binder that has replaced calcium-based binders to treat hyperphosphatemia. Common side effects include nausea, vomiting, and diarrhea. GI mucosal injury from resin-based binders has been reported, although colitis induced by Sevelamer crystal deposition is rare. Previous literature shows a wide range of presentations, including ulcerations, GI bleeding, and colonic strictures. As with prior reports, we show similar endoscopic and histological findings from our patient consistent with this rare entity.Figure 1.: A, Colonoscopic finding showing erythematous ulcerated mucosa in the proximal ascending colon. B, Biopsy from proximal ascending colon site showing granulation tissue with ulceration. The black arrow indicates the Sevelamer Crystal deposition, showing the characteristic “Fish Scale” pattern.

Binding and inhibitory activities: A novel oral therapeutic agent for the treatment of hyperphosphataemia rats

Novel oral therapeutic agents based on inhibition or binding activity without adverse events in CKD patients are urgently needed. Here, 5/6 nephrectomy (NX) rats were used to construct a CKD model. Aminated cellulose (AC711), which is metal-free, non-absorbable, and low-volume expansive, was used as a novel oral therapeutic agent for hyperphosphataemia treatment in rats. The efficacy of AC711 on serum and urinary phosphate levels, the expression of type II sodium-dependent phosphate cotransporter (NPT2b), and type III Na-dependent phosphate cotransporter (PiT-1/2) was examined. Serum fibroblast growth factor-23 (FGF-23) levels, parathyroid hormone (PTH) levels, and the phenotypic transformation of vascular smooth muscle cell markers (smooth muscle 22 (SM22) and Runx2) are considered an adaptive response to elevated serum phosphate levels. A similar efficacy of AC711 was observed on serum and urinary phosphate levels when the same dose of AC711 and sevelamer was administered to 5/6 NX rats. The decreasing expression of NPT2b, PiT-1, and PiT-2 was examined in the AC711 groups in a dose-dependent manner. The sevelamer and AC711-MD groups for FGF-23 and PTH indicated no significant difference. The down-regulation of Runx2 expression and up-regulation of SM22 expression were seen in the AC711 groups in a dose-dependent manner. Two suppression mechanisms (binding and inhibiting activities) were observed in the gastrointestinal (GI) tract in the AC711 groups. A novel oral phosphate binder, AC711, showed both binding and inhibition characteristics. The low-volume expansion of AC711 following exposure to simulated intestinal fluid provides the potential therapeutic benefits with the advantage of moderate GI side effects.

Sevelamer arsenite nanoparticle as a Pi-responsive drug carrier and embolic agent for chemoembolization

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50–300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO’s anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δψm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy.

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: &amp;lt;150 pg/mL, 150–300 pg/mL, 301–600 pg/mL and &amp;gt;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 &amp;lt; 150 pg/mL, 44 (29.5%) 150–300 pg/mL, 35 (23.5%) 301–600 pg/mL and 13 (8.7%) &amp;gt; 600 pg/mL. There were no age, gender, comorbidity or HD modality differences among groups. Patients with iPTH &amp;lt; 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 &amp;lt; 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 &amp;gt; 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 &amp;lt; 150 pg/mL and iPTH 150–300 pg/mL groups. When the reference was changed to iPTH &amp;gt; 600 pg/mL, patients in this group had a decreased mortality risk when compared with those with iPTH &amp;lt; 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 &amp;gt; 300 pg/mL in this group of patients.

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 &amp;lt;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 &amp;lt;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 &amp;lt;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.

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.

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.

A safety evaluation of sucroferric oxyhydroxide for the treatment of hyperphosphatemia

ABSTRACT Introduction Hyperphosphatemia is a common complication as chronic kidney disease (CKD) progresses and most patients undergoing dialysis are prescribed oral phosphate binder therapy to control serum phosphate concentrations. Sucroferric oxyhydroxide is an iron-based phosphate binder approved for the treatment of hyperphosphatemia in CKD patients on dialysis. Areas covered This article reviews key safety and effectiveness data for sucroferric oxyhydroxide from both prospective clinical trials and real-world observational studies. Expert opinion Sucroferric oxyhydroxide potently binds dietary phosphate in the gastrointestinal (GI) tract, resulting in effective reduction of serum phosphate concentrations with a relatively low daily pill burden. Data from clinical trials and real-world observational studies show sucroferric oxyhydroxide has a favorable safety and tolerability profile. The most frequent side effects observed with sucroferric oxyhydroxide are GI-related, mainly discolored (black) stools and mild or moderate transient diarrhea, both of which are manageable. There is minimal systemic iron absorption from sucroferric oxyhydroxide, and therefore the drug is associated with a low risk of iron accumulation. Sucroferric oxyhydroxide also displays low potential for drug–drug interactions with other commonly prescribed oral medications. Overall, sucroferric oxyhydroxide offers an effective and well-tolerated treatment option for the management of hyperphosphatemia.

The Effect of Baru (Dypterix alata Vog.) Almond Oil on Markers of Bowel Habits in Hemodialysis Patients.

Gastrointestinal symptoms are common in patients in hemodialysis treatment and were frequently associated with low intake of dietary fibers and liquids, oral iron supplementation, phosphate binders, and low level of physical activity. Thus, the aim of this study was to evaluate the effect of baru almond oil in comparison with mineral oil supplementation on bowel habits of hemodialysis patients. Thirty-five patients on hemodialysis (57% men, 49.9 ± 12.4 years) were enrolled in a 12-week single-blind clinical trial. Patients were allocated (1 : 2) by sex and age into (1) the mineral group: 10 capsules per day of mineral oil (500 mg each) or (2) the baru almond oil group: 10 capsules per day of baru almond oil (500 mg each). Bowel habits were assessed by the Rome IV criteria, Bristol scale, and self-perception of constipation. Food consumption, physical activity level, and time spent sitting were also evaluated at the baseline and at the end of the study. After 12 weeks of supplementation, the baru almond oil group showed reduced Rome IV score (6.1 ± 5.5 vs 2.8 ± 4.3, p=0.04) and the straining on the evacuation score (1.2 ± 1.4 vs 0.4 ± 0.7; p=0.04), while the mineral group did not show any change in the parameters. The frequency of self-perception of constipation was lower in the baru almond oil group after intervention (45.0% vs 15.0%, p=0.04). Baru almond oil improved bowel habit and the straining on evacuation in hemodialysis patients.

Phase I result of ICP-192 (gunagratinib), a highly selective irreversible FGFR inhibitor, in patients with advanced solid tumors harboring FGFR pathway alterations.

4092 Background: ICP-192 (gunagratinib), developed by InnoCare Pharma, is a novel pan-FGFR (fibroblast growth factor receptors) inhibitor that potently and selectively inhibits FGFR activities irreversibly by covalent binding. Preclinical data showed that gunagratinib overcomes the acquired resistance to the first-generation reversible FGFR inhibitors, e.g., infigratinib. ICP-CL-00301 is a phase I, first-in-human, clinical study which includes a dose escalation followed by dose expansion. The safety and tolerability as well as pharmacokinetics/pharmacodynamics (PK/PD) of gunagratinib were evaluated in patients with advanced solid tumors, and the preliminary anti-tumor activity was evaluated by RECIST1.1 in patients with FGF/FGFR gene aberrations. Methods: In the dose-escalation stage, patients with advanced solid tumors with or without FGF/FGFR alterations were treated with escalating doses (2, 4, 8, 10, 12, 14, 16 mg etc.) of gunagratinib once daily in 21-day cycles until disease progression or unacceptable toxicity. During the dose-expansion stage, patients with cholangiocarcinoma harboring FGFR2 gene fusion/translocation received the treatment of gunagratinib daily at 12 mg continuously. Results: As of February 2021, a total of 30 patients had received the treatment of gunagratinib. The median age of the treated patients was 55.0 (range: 28 to 75 years) with 56.7% male and ECOG performance status between 0-1. The maximum tolerated dose (MTD) had not been reached. The most common treatment-related adverse events (TRAEs) ( &gt; 20%) included hyperphosphatemia, hypercalcemia, increased ALT or AST, diarrhea and hypertriglyceridemia. Hyperphosphatemia is a commonly reported AE from other trials targeting FGFR and here serves as a PD biomarker of FGFR inhibition. This PD biomarker was observed in 73.3% of the patients treated with gunagratinib at all dose levels and was consistently observed at doses of 8 mg QD and above. Hyperphosphatemia was well managed with oral phosphate binders when necessary. The plasma exposure increased proportionally to the oral dosage levels of gunagratinib. Among the 12 patients with FGF/FGFR gene aberrations who have completed at least one tumor assessment, the overall response rate (ORR) was 33.3%, including 1 patient (8.3%) of cholangiocarcinoma with complete response (CR) and 3 patients (25%) with partial response (PR). The disease control rate (DCR) was 91.7% (11 of 12 patients). Conclusions: Gunagratinib is safe and well-tolerated in patients with advanced solid tumors. Anti-tumor activity was demonstrated in patients with FGF/FGFR gene aberrations in multiple tumor types, including cholangiocarcinoma (NCT03758664). Better response is expected with the increase of treatment durations. Clinical trial information: NCT03758664.