Sevelamer reverses liver fibrosis by deactivation of hepatic stellate cells.

Liver fibrosis is a chronic liver disease characterized by a progressive wound healing response caused by chronic liver injury. Currently, there are no approved clinical treatments for liver fibrosis. Sevelamer is used clinically to treat hyperphosphatemia and has shown potential therapeutic effects on liver diseases. However, there have been few studies evaluating the therapeutic effects of sevelamer on liver fibrosis, and the specific mechanisms are still unclear. In this study, we investigated the antifibrotic effects of sevelamer-induced low inorganic phosphate (Pi) stress in vitro and in vivo and analyzed the detailed mechanisms. We found that low Pi stress could inhibit the proliferation of activated hepatic stellate cells (HSCs) by promoting apoptosis, effectively suppressing the migration and epithelial-mesenchymal transition (EMT) of hepatic stellate cells. Additionally, low Pi stress significantly increased the antioxidant stress response. It is worth noting that low Pi stress indirectly inhibited the activation and migration of HSCs by suppressing transforming growth factor ß (TGF-ß) expression in macrophages. In a rat model of liver fibrosis, oral administration of sevelamer significantly decreased blood phosphorus levels, improved liver function, reduced liver inflammation, and increased the antioxidant stress response in the liver. Our study revealed that the key mechanism by which sevelamer inhibited liver fibrosis involved binding to gastrointestinal phosphate, resulting in a decrease in blood phosphorus levels, the downregulation of TGF-ß expression in macrophages, and the inhibition of HSC migration and fibrosis-related protein expression. Therefore, our results suggest that sevelamer-induced low Pi stress can attenuate hepatic stellate cell activation and inhibit the progression of liver fibrosis, making it a potential option for the treatment of liver fibrosis and other refractory chronic liver diseases.

Sevelamer-Induced Gastrointestinal Disease in 12 Patients with End-Stage Renal Disease: A Case Series.

INTRODUCTION: Isolated case reports and case series have linked the use of sevelamer to severe gastrointestinal (GI) inflammation and perforation among patients with end-stage renal disease. METHODS: In this study, we identified 12 cases of biopsy-proven sevelamer-induced gastrointestinal disease from a large urban community hospital over the course of 5 years. We described baseline characteristics, sites and types of injury, histological findings, timing and dosing of sevelamer initiation compared with symptom onset, and in a smaller subset, endoscopic resolution post drug cessation. We also reviewed preexisting conditions to identify trends in populations at risk. RESULTS: Several of the patients reviewed had preexisting conditions of decreased motility and/or impaired mucosal integrity. The presentation of disease was broad and included both upper-GI and lower-GI pathologies and in varying severity. DISCUSSION: There is a broad phenotypic range of sevelamer-induced gastrointestinal disease. As this becomes a more frequently recognized pathology, clinicians should be aware of how it may present and which populations may be more susceptible.

Patterns of gastrointestinal injury in patients with chronic kidney disease: Comparison of cases with and without sevelamer crystals.

AIMS: Sevelamer is a phosphate-binding resin implicated in gastrointestinal (GI) injury. This study aimed to investigate the role of sevelamer in GI injury among chronic kidney disease (CKD) patients. METHODS AND RESULTS: The study included 17 CKD patients (cases) with and 18 CKD patients (comparisons) without sevelamer crystals in specimens. All cases were on sevelamer. Six comparison patients were also taking sevelamer, but crystals were absent in tissue sections. The comparison group was thus subclassified into patients who were and were not taking sevelamer. The frequency of underlying disorders was similar between two groups, including hypertension (cases = 82%; comparisons = 78%) and diabetes mellitus (cases = 53%, comparisons = 50%). The most common presentation was GI bleeding (cases = 41%, comparisons = 33%). Predominant histological patterns were also similar, with ulcers (cases = 42%; comparisons = 39%) and acute ischaemia (cases = 35%; comparisons = 28%) being predominant in both cohorts. Of note, sevelamer was present with amyloidosis and cytomegalovirus in one study case each. Two study patients who continued sevelamer had follow-up biopsies; one showed persistent ulceration and the other appeared normal. Crystals were absent in both. CONCLUSIONS: GI injury in CKD patients in both groups had similar features regardless of presence of sevelamer, suggesting that it adheres to tissue rather than causes injury. The study highlights other histologically identifiable causes of intestinal injury, as well as injuries unassociated with sevelamer in patients undergoing therapy. Therefore, physicians should be cautious in attributing GI injuries to sevelamer to avoid overlooking other causes and unnecessary treatment discontinuation.

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 (2400 mg) on the bioavailability of enarodustat (25 mg) when the 2 drugs were administered together (Treatment B) or when enarodustat was administered 3 hours after (Treatment C) or 1 hour 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 25 mg, with or without sevelamer carbonate, were safe and well tolerated in this study.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Elucidating the glucose-lowering effect of the bile acid sequestrant sevelamer.

AIM: Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycaemic control in people with type 2 diabetes. The mechanism behind the glucose-lowering effect is unknown but has been proposed to be mediated by increased glucagon-like peptide-1 (GLP-1) secretion. Here, we investigated the glucose-lowering effects of sevelamer including any contribution from GLP-1 in people with type 2 diabetes. MATERIALS AND METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 15 people with type 2 diabetes on metformin monotherapy underwent two 17-day treatment periods with the bile acid sequestrant sevelamer and placebo, respectively, in a randomized order and with an interposed wash-out period of minimum 6 weeks. On days 15 and 17 of each treatment period, participants underwent experimental days with 4-h liquid meal tests and application of concomitant infusion of exendin(9-39)NH2 or saline. RESULTS: Compared with placebo, sevelamer improved insulin sensitivity (assessed by homeostatic model assessment of insulin resistance) and beta-cell sensitivity to glucose and lowered fasting and postprandial plasma glucose concentrations. In both treatment periods, exendin(9-39)NH2 increased postprandial glucose excursions compared with saline but without absolute or relative difference between the two treatment periods. In contrast, exendin(9-39)NH2 abolished the sevelamer-induced improvement in beta-cell glucose sensitivity. CONCLUSIONS: The bile acid sequestrant sevelamer improved insulin sensitivity and beta-cell sensitivity to glucose, but using the GLP-1 receptor antagonist exendin(9-39)NH2 we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer in individuals with type 2 diabetes. Nevertheless, the sevelamer-induced improvement of beta-cell sensitivity to glucose was shown to be GLP-1-dependent.

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.

Comparison of homocitrulline and carbamylated albumin as biomarkers of carbamylation reactions in hemodialyzed patients.

To describe the association between levels of homocitrulline (HCit) and the degree of albumin carbamylation in a cohort of hemodialyzed patients. Plasma total and protein-bound HCit concentrations in samples from hemodialyzed patients included in NICOREN trial were determined by LC-MS/MS at baseline and after 24 weeks of treatment with either sevelamer or nicotinamide. HCit concentrations at all timepoints and in both groups were positively and significantly correlated with the degree of albumin carbamylation. Plasma concentrations of total HCit, protein-bound HCit and carbamylated albumin did not decrease after 24 weeks of treatment with either sevelamer or nicotinamide. The present results demonstrate that plasma total and protein-bound HCit concentrations were closely associated with albumin carbamylation in hemodialyzed patients. Therefore, total and protein-bound HCit concentrations might be valuable biomarkers of the overall intensity of protein carbamylation in this context. Given the less complex and time-consuming analytical methods required, these markers should be favored in future clinical studies of carbamylation reaction.

Progress in pharmacotherapy for the treatment of hyperphosphatemia in renal failure.

INTRODUCTION: Among the clinical and metabolic complications of progressive chronic kidney disease (CKD), CKD-mineral bone disorder (CKD-MBD) significantly contributes to morbidity and mortality. While overt and persistent hyperphosphatemia is typical of advanced CKD and requires treatment, other abnormalities of calcium/phosphate metabolism begin to occur since the early stages of the disease. AREAS COVERED: We searched on the PubMed database, without restrictions for language or time range, for randomized clinical trials and meta-analyses investigating phosphate-lowering therapies. The various phosphate binders show different safety profiles and diverse effects on calcium/phosphate metabolism and vascular calcification. The in-depth knowledge of the characteristics of these drugs is crucial to ensure adequate treatment to CKD patients. EXPERT OPINION: A proper control of serum phosphate can be achieved using phosphate binders. These medications may induce side effects. Moreover, data on their impact on clinical outcomes are partly controversial or scarce, especially for the new generation drugs. Hyperphosphatemia favors cardiovascular disease and increases the risk for CKD progression. These effects are partially mediated by fibroblast growth factor 23 (FGF23), a phosphaturic hormone that raises to maintain normal serum phosphate. Since there are no data supporting the use of phosphate-lowering agents when phosphataemia is normal, a key role is played by reducing dietary phosphate intake with the aim to control serum phosphate and the compensatory FGF23 and parathyroid hormone (PTH) increase.

PLAIN LANGUAGE SUMMARY: The progressive reduction in renal function, a condition known as chronic kidney disease (CKD), is characterized by several clinical and metabolic complications. Among them are the alterations of calcium and phosphorous metabolism that are part of the so-called CKD-MBD (chronic kidney disease-mineral bone disorder) and contribute to increase morbidity and mortality, especially due to vascular calcification. Persistent hyperphosphatemia is typical of advanced CKD but other abnormalities occur earlier to maintain normal serum calcium and phosphorus levels. These compensatory mechanisms are also involved in the pathophysiology of CKD-MBD and should be counteracted to improve clinical outcomes of CKD patients. Given the crucial role of hyperphosphatemia, numerous therapeutic strategies have been developed over time to help maintain phosphate serum levels within the normal range and prevent or treat CKD-MBD and its consequences. Phosphate binders act by binding dietary phosphate in the gastrointestinal lumen to prevent its absorption. According to their molecular structure, these drugs can be classified into calcium-based (calcium carbonate, calcium acetate), non-calcium-containing (sevelamer carbonate, sevelamer hydrochloride, lanthanum carbonate), aluminum-containing (aluminum hydroxide), and iron-based (sucroferric oxyhydroxide, ferric citrate) compounds. The various phosphate binders show different safety profiles and diverse effects on calcium/phosphate metabolism and vascular calcification. Despite the ability of hyperphosphatemia to favor CKD-MBD development and cardiovascular risk, there are no data supporting the use of phosphate-lowering agents when serum phosphate is normal also due to the potential adverse effects of long-term therapies. Accordingly, a key role is played by reducing dietary phosphate overload since the first stages of CKD.

Meta-analysis of the efficacy and safety of sevelamer as hyperphosphatemia therapy for hemodialysis patients.

This study was designed to examine the relative safety and efficacy of sevelamer in the treatment of chronic kidney disease (CKD) patients in comparison to placebo, calcium carbonate (CC), or lanthanum carbonate (LC). The PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were searched for articles published through 18 June 2022. The quality of relevant studies was independently analyzed by two investigators who also extracted data from these manuscripts as per Cochrane Collaboration Handbook 5.3. The safety and efficacy of sevelamer as a treatment for hyperphosphatemia in CKD patients were then examined through a meta-analysis, with the primary patient-level outcomes of interest in this analysis being all-cause mortality and the incidence of gastrointestinal adverse effects. Vascular calcification score was also examined as an intermediate outcome, while serum biochemical parameters including levels of phosphate (P), calcium (Ca), intact parathyroid hormone (iPTH), lipids, C-reactive protein (CRP), or fibroblast growth factor-23 (FGF-23) were additionally assessed. In total, this meta-analysis incorporated data from 34 randomized controlled trials (RCTs) enrolling 2802 patients. Sevelamer was associated with reduced all-cause mortality (RR 0.28, CI 0.19 - 0.41, very low certainty) and Vessel calcification score (RR -0.58, CI -1.11 to -0.04, low certainty) and induced less hypercalcemia (MD -0.28, CI 0.40 to -0.16, low certainty) and hyperphosphatemia (MD -0.22, CI -0.32 to -0.13, low certainty) when compared with Ca-based binders in CKD5D individuals. No significant differences in gastrointestinal adverse events (GAEs) incidence were observed. These data suggest that sevelamer may represent a beneficial means of protecting CKD patients against death and vessel calcification when used to treat hyperphosphatemia, while we found no clinically important benefits in decreasing gastrointestinal adverse effects.

Regulatory considerations for generic products of non-biological complex drugs.

The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means". There are concerns about the potential clinical differences between the follow-on versions and the originator products and within the individual follow-on versions. In the present study, we compare the regulatory requirements for developing generic products of NBCDs in the European Union (EU) and the United States (US). The NBCDs investigated included nanoparticle albumin-bound paclitaxel (nab-paclitaxel) injections, liposomal injections, glatiramer acetate injections, iron carbohydrate complexes, and sevelamer oral dosage forms. The demonstration of pharmaceutical comparability between the generic products and the reference products through comprehensive characterization is emphasized for all product categories investigated. However, the approval pathways and detailed requirements in terms of non-clinical and clinical aspects may differ. The general guidelines in combination with product-specific guidelines are considered effective in conveying regulatory considerations. While regulatory uncertainties still prevail, it is anticipated that through the pilot program established by the European Medicines Agency (EMA) and the FDA, harmonization of the regulatory requirements will be achieved, thereby facilitating the development of follow-on versions of NBCDs.

The Role of Iron-Based Phosphate Binder in the Treatment of Hyperphosphatemia.

Hyperphosphatemia is a well-known complication of kidney disease. Phosphate binders are a mainstay treatment, but despite the existence of several phosphate binders, there is no one best approach to manage hyperphosphatemia. Phosphate binders are calcium-based, non-calcium- based, and others. While calcium-based phosphate binders are used frequently, they may cause hypercalcemia. Conversely, lanthanum carbonate and sevelamer were not linked to hypercalcemia but are costlier. The most recently developed class of phosphate binders is the ironbased ferric citrate and sucroferric oxyhydroxide. These have an important role in controlling phosphate levels due to their ability to lower the phosphate while concurrently providing iron sources. This review provides pharmacological profiles of different phosphate binders and their clinical usages, and further elaborates on their place in hyperphosphatemia management.

Real-World Phosphate Binder Use among Dialysis-Dependent Patients with CKD.

INTRODUCTION: For patients with chronic kidney disease (CKD), the need for phosphate binder (PB) treatment peaks at onset of dialysis. This real-world study assessed rates of PB utilization and switching in patients with dialysis-dependent CKD (DD-CKD). METHODS: We identified patients with PB utilization among those with prevalent DD-CKD using 2018-2019 Medicare Parts A/B/D data. Patients were assigned to cohorts based on primary (most frequently used) PB among calcium acetate, ferric citrate, lanthanum carbonate, sevelamer (hydrochloride and carbonate), sucroferric oxyhydroxide. We measured proportion of patients who were adherent (proportion of days covered >80%) and persistent (patients whose last 90 days of outpatient dialysis reported PB use). Net switching rates were calculated as the difference between switches to and from the primary agent. RESULTS: We identified 136,912 patients with PB use. Proportion of patients adherent ranged from 63.8% (lanthanum carbonate) to 67.7% (sevelamer) and persistent from 85.1% (calcium acetate) to 89.5% (ferric citrate). Most patients (73%) used the same PB throughout the study. Overall, 20.5% of patients experienced one switch and 2.3% two or more. Positive net switching rates were observed for ferric citrate, sucroferric oxyhydroxide, and lanthanum carbonate (2-10%) but negative for sevelamer and calcium acetate (-2% to -7%). CONCLUSION: Adherence and persistence rates were low with slight variation across PBs. Net positive switching occurred for ferric citrate, sucroferric oxyhydroxide, and lanthanum carbonate. Further studies are needed to determine the reasons for these findings and could identify opportunities for better control of phosphate levels among patients with CKD.

In vitro cytogenetic analysis of two different anti-phosphates (sevelamer hydrochloride and calcium carbonate) agents used by patients with hyperphosphatemia.

Sevelamer hydrochloride (SH) and calcium carbonate (CaCO3) are two agents included in the phosphate-binding group which are frequently prescribed in the treatment of patients with hyperphosphatemia. However, there are no satisfactory studies on the genotoxic effects of SH in vitro. This study was conducted to reveal the genotoxic and/or cytotoxic potential of these two drugs in cultured human peripheral lymphocytes. Human peripheral lymphocytes were treated with SH and CaCO3 at sublethal concentrations for 24 or 48 h for micronucleus assay and 1 h in the comet assay. CaCO3 and SH stimulated a slight increase in micronucleus formation however this increase was not significant compared to the control group. According to the findings of the comet test, only one concentration of the SH caused significant DNA damage (2 mg/ml, 48 h) whereas CaCO3 did not cause important DNA breakage. No significant oxidative damage or anti-radical effect caused by test substances was observed on the pure pBR322 plasmid DNA in a cell-free medium. Also, it was found that the drugs were devoid of mutagenic activity in the Ames test, but had a weak cytotoxic effect. Both test substances, particularly SH, significantly reduced the nuclear division index compared to the control group. In conclusion, the cytotoxic effect of SH was evident on the basis of in vitro tests and slightly higher than CaCO3.

Characterization of Risk Factors for Calciphylaxis in Hemodialysis Patients in the Fraser Health Renal Program - A Matched Case-Control Retrospective Review.

Introduction: Calciphylaxis is a lethal and rare disease characterized by ischemic and necrotic skin lesions caused by vascular calcification of adipose tissue. There have been many risk factors analyzed in the literature; however, the pathogenesis of calciphylaxis is still not well understood and treatment options are limited due to the lack of interventional studies. Our objectives were to describe risk factors, prevalence, incidence, and outcomes for calciphylaxis in hemodialysis patients within the Fraser Health Renal Program. Methods: This was a retrospective matched case-control study of hemodialysis patients within the Fraser Health Renal Program. Hemodialysis patients with calciphylaxis were matched to hemodialysis patients without calciphylaxis in a 1:2 ratio for age and sex from September 2, 2017 to July 3, 2020. Findings: There was a total of 40 calciphylaxis cases matched to 80 controls. In the univariate analysis, peritoneal dialysis, higher body mass index, lower serum iron, lower transferrin saturation, sevelamer, cinacalcet, warfarin, iron (PO), and insulin were associated with increased risk of calciphylaxis. In the multivariate analysis, only peritoneal dialysis, serum iron, sevelamer, and warfarin were identified as significant and strong risk factors associated with calciphylaxis. A low prevalence of 1.9% and high mortality rate of 57.5% at 12 months was found for calciphylaxis cases. Discussion: Significant risk factors associated with calciphylaxis were peritoneal dialysis, serum iron, sevelamer, and warfarin. Future studies should further investigate the impact of minimizing exposure to these risk factors to reduce calciphylaxis development.

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.

Pharmacokinetic/pharmacodynamic modeling of roxadustat's effect on LDL cholesterol in patients in Japan with dialysis-dependent chronic kidney disease and anemia.

AIMS: The objective of this analysis was to develop and evaluate a pharmacokinetic/pharmacodynamic (PK/PD) model of the effect of roxadustat on low-density lipoprotein cholesterol (LDL-C) in Japanese patients with anemia of dialysis-dependent chronic kidney disease while considering the impact of covariates on model parameters. METHODS: A total of 2330 LDL-C measurements from 275 patients in 3 clinical studies were analyzed using a nonlinear-mixed effects modeling approach in NONMEM software. RESULTS: The PK/PD relationship between roxadustat exposure and LDL-C was well described by a kinetic-pharmacodynamic model with a physiological indirect response model as the PD component. Co-administered statin usage, sevelamer usage, type of dialysis (hemodialysis or peritoneal dialysis), and sex were selected as covariates for LDLbaseline. Weight was selected as a covariate for ID50. Imax and ID50 were estimated as 0.661 and 1.51 mg/h, respectively. CONCLUSION: Roxadustat can decrease LDL-C independent of statins and sevelamer. Further study of the ability of roxadustat to lower LDL-C and any potential effects on outcomes is needed.

Effect of Calcium-based Phosphate Binders Versus Sevelamer on Mortality of Patients with Hemodialysis: A Meta-analysis.

Chronic kidney disease is a public health problem. The purpose of this study was to compare the effects of sevelamer and calciumbased binders on mortality of hemodialysis patients. PubMed, EMBASE and Web of Science were searched for related articles published before May 14, 2020. We included six studies with 43330 participants, of which 21147 and 22183 received calciumbased phosphate binders and sevelamer, respectively. In the analysis of unadjusted data, sevelamer could lower cardiovascular mortality. When adjusted HRs was pooled, the cardiovascular mortality did not differ significantly in the sevelamer and calcium-based phosphate binders groups. Additionally, the all-cause mortality rate in sevelamer group was different from that in calcium-based phosphate binders group. However, sevelamer could not lower all-cause mortality in terms of the adjusted data. No significant difference was found in calcium and phosphorus between calcium-based phosphate binders and sevalmer. Sensitivity analysis showed that partial results of the study were inconsistent. There was no difference in the effect of sevelamer and calciumbased phosphate binders on the risk of all-cause mortality in patients with hemodialysis, after adjusting confounders. However, given the instability of the results, the results need to be further confirmed by a large sample and high quality RCTs.  DOI: 10.52547/ijkd.6814.