Hyperphosphatemia In Chronic Kidney Disease Research Articles

#1825 Treating hyperphosphatemia in CKD via targeting Npt2a in the kidney

Abstract Background and Aims Targeting the renal sodium phosphate cotransporter 2a (Npt2a) offers a novel strategy for treating hyperphosphatemia in chronic kidney disease (CKD). In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications and currently treatment options are limited. Method To study the role of a novel Npt2a inhibitor (PF-06869206) we used in vitro (Opossum kidney [OK] cells) and in vivo approaches (C57Bl/6 and Npt2a knockout [Npt2a−/−] mice). As models of CKD, 5/6 nephrectomy (5/6 Nx) as well as novel Alport/Npt2a knockout mice (Alport/Npt2a−/−) were studied. Results OK cell experiments showed that the Npt2a inhibitor caused dose-dependent reductions of Na+-dependent Pi uptake (IC50: ∼1.4 μmol/L) and Michaelis-Menten kinetics identified a ∼2.4-fold higher Km for Pi in response to Npt2a inhibition with no significant change in apparent Vmax, indicating a competitive mode of action. In vivo, Npt2a inhibition enhanced urinary excretions of Pi, Ca2+, and Na+ dose-dependently, which is recapitulated in animal models with reduced kidney function (5/6 Nx and Alport mice). Reductions in plasma Pi occur within 30 minutes and reach a maximum (40-50%) after 2 hours, this coincided with ∼50% reductions in PTH levels. No effects on FGF23 were observed in this time frame. In C57Bl/6 mice qualitative immunohistochemistry after 24 hours showed reductions in Npt2a labelling in apical microvilli compared to vehicle treatment. Providing proof of concept, Npt2a−/− and Alport/Npt2a−/− mice confirmed specificity of the drug, effects on urinary and plasma Pi were absent. Further electrophysiological studies in acutely isolated connecting tubule/cortical collecting duct showed that open probability of the epithelial Na+ channel (ENaC) was reduced in response to Npt2a inhibition, suggesting that the natriuretic effect is mediated, at least in part, by inhibition of ENaC. Conclusion Npt2a inhibition offers a promising therapeutic approach for treating hyperphosphatemia and possibly offers the opportunity of reducing cardiovascular complications in CKD.

Hyperphosphatemia in Chronic Kidney Disease: The Search for New Treatment Paradigms and the Role of Tenapanor

Hyperphosphatemia in Chronic Kidney Disease: The Search for New Treatment Paradigms and the Role of Tenapanor

Efficacy, tolerability, and safety of the oral phosphate binder VS-505 (AP301).

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 2 weeks 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 6 weeks. 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 were 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 1 week of VS-505 initiation, returning to baseline within 2 weeks 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. Clinical Trial registration number: NCT04551300.

Tenapanor (Xphozah) for hyperphosphatemia in chronic kidney disease.

The FDA has approved the sodium/hydrogen exchanger 3 (NHE3) inhibitor tenapanor (Xphozah – Ardelyx) to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy when phosphate binders are ineffective or as monotherapy when phosphate binders cannot be tolerated. Tenapanor is the first NHE3 inhibitor to be approved in the US for hyperphosphatemia. It was previously approved as Ibsrela to treat irritable bowel syndrome with constipation (IBS-C).

Effects of the novel sodium-dependent phosphate cotransporter 2b inhibitor DZ1462 on hyperphosphatemia in chronic kidney disease.

Serum phosphate levels remain insufficiently controlled in chronic kidney disease (CKD) patients, and novel therapeutic strategies are needed. Blocking intestinal phosphate absorption mediated by sodium-dependent phosphate cotransporter type 2b (NPT2b) holds promise as one such strategy. The in vitro cellular potency of DZ1462 was evaluated using a radioactive Pi uptake assay on stable Chinese hamster ovary (CHO) cell clones transfected with human NPT2b (hNPT2b) or rat NPT2b (rNPT2b). The ability of DZ1462 to inhibit phosphate absorption was studied in vivo in an acute model after oral bolus challenge with 33PO4 and in an adenine-induced chronic hyperphosphatemia rat model. PK and minitox was also evaluated. The cellular assays with the hNPT2b-CHO and rNPT2b-CHO clones showed that DZ1462 significantly and potently inhibited phosphate uptake. In vivo, in a chronic Pi-fed rat model, DZ1462 effectively inhibited intestinal Pi uptake. In a hyperphosphatemia rat model, DZ1462 significantly inhibited Pi uptake, and DZ1462 in combination with sevelamer had a synergistic effect. The pharmacokinetics (PK) study confirmed that DZ1462 is a gastrointestinal (GI)-restricted compound that can remain in the intestine for a sufficient duration. In addition, DZ1462 also reduced cardiovascular events and ameliorated osteoporosis in a CKD animal model. This study revealed that a GI-restricted NPT2b inhibitor DZ1462 potently inhibits NPT2b in vitro and blocks intestinal phosphate uptake in multiple animal models with potential to reduce various cardiovascular events in CKD models. Therefore, DZ1462 may be useful to treat renal disease patients who have shown an unsatisfactory response to phosphate binders.

The correlation between serum fibroblast growth factor-23 levels and left ventricular hypertrophy in chronic kidney disease patients

Introduction: Hyperphosphatemia in chronic kidney disease (CKD) patients can stimulate the production of the fibroblast growth factor-23 (FGF-23) phosphatonin hormone, which is associated with cardiac remodeling resulting in left ventricular hypertrophy (LVH). Objectives: To determine the correlation between FGF-23 level and LVH incidence in CKD patients and establish the associated risk factors. Materials and Methods: This cross-sectional study involved 74 CKD patients who were classified as stage 3 (n=18), stage 4 (n=17), stage 3 (n=18), dialysis stage 5 (n=20), or non-dialysis stage 5 (n=19). The FGF-23 levels of the patients were measured using the ELISA (enzyme-linked immunosorbent assay) kit method, whereas a cardiologist verified LVH using an echocardiographic examination based on the LVH criteria of >95 g/m2 for females and >115 g/m2 for males. Results: A significant difference was observed in the mean FGF-23 values between the LVH and non-LVH patients (443.27±437.047 RU/mL and 172.68±185.56 RU/mL, respectively; P<0.05). The receiver operating characteristics revealed that patients with FGF-23 levels >123.95 RU/mL had a 3.6 times greater risk of LVH compared to those with values ≤123.95 RU/mL. The LVH risk factors of gender and age, as well as hypertension, diabetes mellitus, and obesity diagnoses were not associated with LVH incidence in CKD patients. Conclusion: A significant association was found between FGF-23 level and LVH incidence in CKD patients, in which an FGF-23 level >123.95 RU/mL corresponded to a 3.6 times greater risk of LVH than those with FGF-23 levels below this value.

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.

A Systematic Review on Hyperphosphatemia in Chronic Kidney Disease

A Systematic Review on Hyperphosphatemia in Chronic Kidney Disease

Effectiveness of iron-based phosphate binders in reduction of hyperphosphataemia in chronic kidney disease patients

Background: Ferric citrate is novel iron-based phosphate-binding drug for management of hyperphosphataemia and iron-deficiency anaemia in chronic kidney disease (CKD) patients. Objectives: To evaluate impact of ferric citrate therapy on reduction of phosphate levels and improvement in haematological parameters in CKD stages 3-5. Methods: This analytical, observational study was conducted at Kathmandu Medical College Teaching Hospital from 2020 July-December after ethical clearance using convenience sampling method. Non-dialysis dependent patients at CKD stages 3-5, having hyperphosphataemia (serum phosphate >=4.6mg/dL) and anaemia (serum haemoglobin <12 gm%, transferrin saturation <=30%, ferritin <=300ng/mL) were administered with 2gm twice daily dose of ferric citrate for 12 weeks and evaluated on outcomes in terms of reduction in serum phosphate levels and improvement in haematological parameters as study endpoints. Data were entered in Microsoft Excel and analysed in SPSS v.25. Significance level was set at p <0.05. Results: Of 84 study participants, majority had CKD stage 4 (46, 54.76%). A significant reduction (p <0.001) in mean serum phosphate levels of 6.21 ± 1.062 mg/dL from baseline to 4.89 ± 1.100 mg/dL in 12-weeks was observed. Patients with CKD stages 3, 4, and 5 had mean reduction of 1.67 (p = 0.005), 1.40 (p <0.001), and 1.04 mg/dL (p = 0.002) of serum Phosphate level respectively. Significant (p <0.001) improvements in hemoglobin level, serum iron, ferritin, total iron binding capacity, and transferrin saturation were reported. Conclusion: Ferric citrate is effective and well-tolerated phosphate-binder to improve hyperphosphataemia and iron deficiency anaemia in non-dialysis CKD stage 3, 4, and 5.

Hyperphosphatemia in Chronic Kidney Disease: Drug Treatment and Effects on Metabolic Acidosis. A Mini Review

Hyperphosphatemia is a highly prevalent component of CKD and chronic kidney disease mineral bone disease (CKD-MBD). Its association with metabolic acidosis, hypertension, cardiovascular disease and chronic inflammation is common. Treatment is commonly with calcium based phosphate binder (PB) as the high cost of sevelamer makes it readily unavailable particularly in low income settings. Sevelamer has several comparative advantage over calcium based PBs, many of which, in addition to its non-worsening of tissue calcification contributes significantly to positive treatment outcome. The ability of sevelamer to reduce many cytokines and inflammatory mediators such as TNF-α, IL-1, IL-6, FGF-23 and high sensitivity CRP among others, contributes significantly to its renoprotection prowess.

Sodium phosphate cotransporter 2a inhibitors: potential therapeutic uses.

Purpose of reviewTargeting sodium phosphate cotransporter 2a (Npt2a) offers a novel strategy for treating hyperphosphatemia in chronic kidney disease (CKD). Here we review recent studies on the efficacy of Npt2a inhibition, its plasma phosphate (Pi)-lowering effects, as well as potential “off-target” beneficial effects on cardiovascular consequences.Recent findingsTwo novel Npt2a-selective inhibitors (PF-06869206 and BAY-767) have been developed. Pharmacological Npt2a inhibition shows a significant phosphaturic effect and consequently lowers plasma Pi and parathyroid hormone (PTH) levels regardless of CKD. However, plasma fibroblast growth factor 23 (FGF23), a master regulator of Pi homeostasis, shows inconsistent responses between these two inhibitors (no effect by PF-06869206 vs. reduction by BAY-767). In addition to the effects on Pi homeostasis, Npt2a inhibition also enhances urinary excretions of Na+, Cl−, and Ca2+, which is recapitulated in animal models with reduced kidney function. The effect of Npt2a inhibition by BAY-767 on vascular calcification has been studied, with positive results showing that oral treatment with BAY-767 (10 mg kg−1) attenuated the increases in plasma Pi and Ca2+ content in the aorta under the setting of vascular calcification induced by a pan-FGF receptor inhibitor. Together, Npt2a inhibition offers a promising therapeutic approach for treating hyperphosphatemia and reducing cardiovascular complications in CKD.SummaryNpt2a inhibition significantly increases urinary Pi excretion and lowers plasma Pi and PTH levels; moreover, it exerts pleiotropic “off-target” effects, providing a novel treatment for hyperphosphatemia and exhibiting beneficial potential for cardiovascular complications in CKD.

Phosphate in the Context of Cognitive Impairment and Other Neurological Disorders Occurrence in Chronic Kidney Disease

The nervous system and the kidneys are linked under physiological states to maintain normal body homeostasis. In chronic kidney disease (CKD), damaged kidneys can impair the central nervous system, including cerebrovascular disease and cognitive impairment (CI). Recently, kidney disease has been proposed as a new modifiable risk factor for dementia. It is reported that uremic toxins may have direct neurotoxic (astrocyte activation and neuronal death) and/or indirect action through vascular effects (cerebral endothelial dysfunction, calcification, and inflammation). This review summarizes the evidence from research investigating the pathophysiological effects of phosphate toxicity in the nervous system, raising the question of whether the control of hyperphosphatemia in CKD would lower patients’ risk of developing cognitive impairment and dementia.

MO809: Sucroferric Oxyhydroxide for the Management of Hyperphosphataemia in Peritoneal Dialysis Patients

Abstract BACKGROUND AND AIMS Bone and mineral metabolism disorders are very common in chronic kidney disease (CKD) patients. The increase in phosphorus levels leads to bone disease, risk of calcification and higher mortality, so any strategy aimed at reducing it should be welcomed. The latest drug added to the therapeutic arsenal to treat hyperphosphataemia in CKD is sucroferric oxyhydroxide (SO). Our objective was to analyse the efficacy and safety of SO in patients with CKD on peritoneal dialysis (PD), followed for 6 months. METHOD Observational, multicentre, prospective, clinical practice study. Patients who had been on PD for >6 months and who had been prescribed SO as a treatment for hyperphosphataemia were included; they should also meet any of the following conditions: serum phosphate >4.5 mg/dL, serum phosphate ≤4.5 mg/dL but receiving a high number of tablets or using another phosphate binder with adverse effects or intolerance. Clinical and epidemiological variables were analysed; also parameters related to bone and mineral metabolism disorders and anaemia. Variations in stool consistency and the need for laxatives were also taken into account. RESULTS A total of 92 patients (62 ± 14 years, 66% male, 23% diabetic), from 11 centres, were included in the study. In 66 patients (72%), SO was the first phosphate binder; in the other 26, a previous binder was replaced by SO due to lack of tolerance or efficacy. The initial dose of SO was 942 ± 516 mg/day. Globally, serum phosphate levels decrease at 3 (10.7%, P < .001) and at 6 months of treatment (18.3%, P < .001). After 6 months of treatment, 63% of the patients achieved a phosphataemia of <5 mg/dL and 41% <4.5 mg/dL. The decrease in serum phosphate levels correlated with baseline phosphate level (r = 0.367; P = .039), age (r = .338; P = .033) and time on dialysis (r = 0.578; P = 0.001). There were no differences in the efficacy of the drug when comparing the different populations analysed. Serum levels of calcium, iPTH, ferritin, transferrin saturation index and haemoglobin did not change throughout the study. Stool consistency was reduced, and the need for laxatives decreased by 18%. The mean dose of SO increased over time to 1167 ± 381 mg/day. The drug was well tolerated. CONCLUSION SO is an effective option for the treatment of hyperphosphataemia in PD patients. Age, basal phosphate levels and time in the technique are factors associated with a greater decrease in serum phosphate levels. Stool consistency became softer (which may improve dialysis efficiency) with less need for laxatives.

Sevelamer Attenuates Bioprosthetic Heart Valve Calcification.

Objective: Sevelamer hydrochloride is a phosphate binder used to treat hyperphosphatemia in chronic kidney disease (CKD) patients that can reduce valvular and vascular calcification. The aim of this study was to examine the effects of sevelamer treatment on calcification in bioprosthetic heart valves (BHVs).Methods: Wister rats were randomly divided into three groups according to sevelamer intake and implantation (sham–sham operation; implant–implantation and normal diet, implant+S implantation, and sevelamer diet). Two kinds of BHVs—bovine pericardium treated with glutaraldehyde (GLUT) or non-GLUT techniques—were implanted in rat dorsal subcutis at 4 weeks. After implantation, sevelamer was administered to the implant+S group. The animals were executed at days 0 (immediately after implantation), 7, 14, 28, and 56. Calcium levels were determined by atomic absorption spectroscopy and von Kossa staining. Serum biochemistry analysis, Western blotting, real-time quantitative polymerase chain reaction, alkaline phosphatase activity measurement, histopathologic analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were conducted to identify the anti-calcification mechanism of sevelamer.Results: Non-GLUT crosslinking attenuates BHV calcification. Serum phosphate and calcium remained unreactive to sevelamer after a 14-day treatment. However, the mean calcium level in the implant+S group was significantly decreased after 56 days. In addition, the PTH level, inflammatory cell infiltration, system and local inflammation, and expression of Bmp2, Runx2, Alp, IL-1β, IL-6, and TNF-α were significantly reduced in the implant+S group.Conclusion: Sevelamer treatment significantly attenuated the calcification of BHVs and had anti-inflammation effects that were independent from serum calcium and phosphate regulation. Thus, sevelamer treatment might be helpful to improve the longevity of BHVs.

The impact of phosphate lowering agents on clinical and laboratory outcomes in chronic kidney disease patients: a systematic review and meta-analysis of randomized controlled trials.

Besides reducing hyperphosphatemia in chronic kidney disease (CKD) patients, phosphate lowering agents might provide beneficial effects on clinical and laboratory parameters. This meta-analysis was conducted to comprehensively examine the impact of all phosphate lowering agents on various aspects of clinical and laboratory outcomes in CKD patients. A systematic literature search was performed in MEDLINE, Scopus, and the Cochrane Register of Controlled Trials until July 2020 to identify randomized controlled trials (RCTs) which compared the effects of each phosphate lowering agent with controls, comprising placebo and all other phosphate lowering agents. Various clinical and laboratory outcomes were analyzed. Random effects model was used to compute the standardized mean difference for continuous variables and the risk ratio (RR) for binary variables. This meta-analysis included 127 RCTs with 20,215 patients. Sevelamer and lanthanum significantly reduced all-cause mortality (RR 0.610, 95% CI 0.401-0.929 and 0.467, 95% CI 0.337-0.647, respectively) but not cardiovascular (CV) mortality or CV events. Hospitalization rates were significantly diminished by sevelamer (RR 0.527; 95% CI 0.308-0.902). Certain phosphate lowering agents improved biochemical parameters including serum phosphate, calcium, coronary artery calcium scores, fibroblast growth factor-23, bone biomarkers, and lipid profiles. Intact parathyroid hormone and bone mineral density were not significantly changed. In addition to decreasing serum phosphate levels, various beneficial effects on clinical and laboratory parameters of phosphate lowering agents might play potential roles in diminishing morbidity and mortality in CKD patients.

Evaluation of the cost-utility of phosphate binders as a treatment option for hyperphosphatemia in chronic kidney disease patients: a systematic review and meta-analysis of the economic evaluations

BackgroundUncontrolled hyperphosphatemia in chronic kidney disease (CKD) patients commonly results in vascular calcification leading to increased risk of cardiovascular disease. Phosphate binders (PBs) are used for hyperphosphatemia and can be calcium-based (CBPBs) or non-calcium-based (NCBPBs), the latter being more expensive than CBPBs. In this study, we used meta-analysis approaches to assess the cost-utility of PBs for hyperphosphatemia in CKD patients.MethodsRelevant studies published prior to June 2019 were identified from PubMed, Scopus, the Cochrane Library, the National Health Service Economic Evaluation Database, and the Cost-Effectiveness Analysis Registry. Studies were eligible if they included CKD patients with hyperphosphatemia, compared any PBs and reported economic outcomes. Meta-analysis was applied to pool incremental net benefit (INB) across studies stratified by country income.ResultsA total of 25 studies encompassing 32 comparisons were eligible. Lanthanum carbonate, a NCBPB, was a more cost-effective option than CBPBs in high-income countries (HICs), with a pooled INB of $3984.4 (599.5–7369.4), especially in pre-dialysis patients and used as a second-line option with INBs of $4860.2 (641.5–9078.8), $4011.0 (533.7–7488.3), respectively. Sevelamer, also a NCBPB, was not more cost-effective as a first-line option compared to CBPBs with a pooled INB of $6045.8 (− 23,453.0 to 35,522.6) and $34,168.9 (− 638.0 to 68,975.7) in HICs and upper middle-income countries, respectively.ConclusionsLanthanum carbonate was significantly more cost-effective than CBPBs as a second-line option for hyperphosphatemia in pre-dialysis patients in HICs. However, the use of sevelamer is not more cost-effective as a first-line option compared to CBPBs.

Hyperphosphatemia in chronic kidney disease exacerbates atherosclerosis via a mannosidases-mediated complex-type conversion of SCAP N-glycans

Blood phosphate levels are linked to atherosclerotic cardiovascular disease in patients with chronic kidney disease (CKD), but the molecular mechanisms remain unclear. Emerging studies indicate an involvement of hyperphosphatemia in CKD accelerated atherogenesis through disturbed cholesterol homeostasis. Here, we investigated a potential atherogenic role of high phosphate concentrations acting through aberrant activation of sterol regulatory element-binding protein (SREBP) and cleavage-activating protein (SCAP)-SREBP2 signaling in patients with CKD, hyperphosphatemic apolipoprotein E (ApoE) knockout mice, and cultured vascular smooth muscle cells. Hyperphosphatemia correlated positively with increased atherosclerotic cardiovascular disease risk in Chinese patients with CKD and severe atheromatous lesions in the aortas of ApoE knockout mice. Mice arteries had elevated SCAP levels with aberrantly activated SCAP-SREBP2 signaling. Excess phosphate invitro raised the activity of α-mannosidase, resulting in delayed SCAP degradation through promoting complex-type conversion of SCAP N-glycans. The retention of SCAP enhanced transactivation of SREBP2 and expression of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, boosting intracellular cholesterol synthesis. Elevated α-mannosidase II activity was also observed in the aortas of ApoE knockout mice and the radial arteries of patients with uremia and hyperphosphatemia. High phosphate concentration invitro elevated α-mannosidase II activity in the Golgi, enhanced complex-type conversion of SCAP N-glycans, thereby upregulating intracellular cholesterol synthesis. Thus, our studies explain how hyperphosphatemia independently accelerates atherosclerosis in CKD.

Safety and effectiveness of lanthanum carbonate for hyperphosphatemia in chronic kidney disease (CKD) patients: a meta-analysis

Objective The aim of this study was to determine the efficacy and safety of lanthanum carbonate (LC) versus calcium salts, non-LC phosphate binders (PBs), sevelamer, or placebo in patients with chronic kidney disease (CKD). Materials and methods A literature search on PubMed, Embase, and Cochrane Library databases was conducted up to 18 June 2021. Data acquisition and quality assessment were performed by two reviewers. Meta-analysis was performed to evaluate the serum biochemical parameters, adverse events, and patient-level outcomes of LC, non-LC PBs, and sevelamer for hyperphosphatemia in patients with CKD. Heterogeneity across studies was assessed utilizing the I 2 statistic and Q-test, and a random effect model was selected to calculate the pooled effect size. Results A total of 26 randomized, controlled trials and 3 observational studies were included. Compared to the other groups, better control effect of serum phosphorus (RR = 2.68, p < 0.001), reduction in serum phosphorus (95%CI = −1.93, −0.99; p < 0.001), Ca × P (95%CI = −13.89, −2.99; p = 0.002), serum intact parathyroid hormone levels (95%CI = −181.17, −3.96, p = 0.041) were found in LC group. Besides, reduced risk of various adverse effects, such as hypotension, abdominal pain, diarrhea, dyspepsia, and a score of coronary artery calcification were identified with LC in comparison to calcium salt, non-LC PBs, or placebo group. Significantly lower risk in mortality with LC treatment vs. non-LC PBs was observed, while no significant difference was identified between LC and calcium salt groups. Conclusion LC might be an alternative treatment for hyperphosphatemia in patients with CKD considering its comprehensive curative effect.

Efficacy and safety of sucroferric oxyhydroxide in the treatment of hyperphosphataemia in chronic kidney disease in Asturias. FOSFASTUR study

Alterations in bone and mineral metabolism are very common in chronic kidney disease (CKD). The increase in phosphate levels leads to bone disease, risk of calcification and greater mortality, so any strategy aimed at reducing them should be welcomed. The latest drug incorporated into the therapeutic arsenal to treat hyperphosphataemia in CKD is Sucroferric Oxyhydroxide (SFO). ObjectiveTo analyse the efficacy and safety of OSF in three cohorts of patients, one with advanced chronic kidney disease not on dialysis (CKD-NoD), another on peritoneal dialysis (PD) and the last on haemodialysis (HD), followed for six months. MethodsA prospective, observational, multicentre study in clinical practice. Clinical and epidemiological variables were analysed. The evolution of parameters relating to alterations in bone and mineral metabolism and anaemia was analysed. ResultsEighty-five patients were included in the study (62 ± 12 years, 64% male, 34% diabetic), 25 with CKD-NoD, 25 on PD and lastly, 35 on HD. In 66 patients (78%), SFO was the first phosphate binder; in the other 19, SFO replaced a previous phosphate binder due to poor tolerance or efficacy. The initial dose of SFO was 964 ± 323 mg/day. Overall, serum phosphate levels saw a significant reduction at three months of treatment (19.6%, P < 0.001). There were no differences in the efficacy of the drug when the different populations analysed were compared. Over the course of the study, there were no changes to levels of calcium, PTHi, ferritin, or the transferrin and haemoglobin saturation indices, although there was a tendency for the last two to increase. Twelve patients (14%) withdrew from follow-up, ten due to gastrointestinal adverse effects (primarily diarrhoea) and two were lost to follow-up (kidney transplant). The mean dose of the drug that the patients received increased over time, up to 1147 ± 371 mg/day. ConclusionsSFO is an effective option for the treatment of hyperphosphataemia in patients with CKD both in the advanced phases of the disease and on dialysis. We found similar efficacy across the three groups analysed. The higher their baseline phosphate level, the greater the reduction in the serum levels. A notable reduction in phosphate levels can be achieved with doses of around 1000 mg/day. Diarrhoea was the most common side effect, although it generally was not significant.

Eficacia y seguridad de oxihidróxido sucroférrico en el tratamiento de la hiperfosforemia en la enfermedad renal crónica. Estudio FOSFASTUR

IntroductionAlterations in bone and mineral metabolism are very common in chronic kidney disease (CKD). The increase in phosphate levels leads to bone disease, risk of calcification and greater mortality, so any strategy aimed at reducing them should be welcomed. The latest drug incorporated into the therapeutic arsenal to treat hyperphosphataemia in CKD is sucroferric oxyhydroxide (SFO). ObjectiveTo analyse the efficacy and safety of SFO in 3 cohorts of patients, one with advanced CKD not on dialysis, another on peritoneal dialysis and the last on haemodialysis, followed for 6 months. MethodsA prospective, observational, multicentre study in clinical practice. Clinical and epidemiological variables were analysed. The evolution of parameters relating to alterations in bone and mineral metabolism and anaemia was analysed. ResultsEighty-five patients were included in the study (62±12 years, 64% male, 34% diabetic), 25 with advanced CKD not on dialysis, 25 on peritoneal dialysis and lastly, 35 on haemodialysis. In 66 patients (78%), SFO was the first phosphate binder; in the other 19, SFO replaced a previous phosphate binder due to poor tolerance or efficacy. The initial dose of SFO was 964±323mg/day. Overall, serum phosphate levels saw a significant reduction at 3 months of treatment (19.6%; P<.001). There were no differences in the efficacy of the drug when the different populations analysed were compared. Over the course of the study, there were no changes to levels of calcium, PTHi, ferritin, transferrin saturation index or haemoglobin, although there was a tendency for the last 2 to increase. Twelve patients (14%) withdrew from follow-up, 10 due to gastrointestinal adverse effects (primarily diarrhoea) and 2 were lost to follow-up (kidney transplant). The mean dose of the drug that the patients received increased over time, up to 1,147±371mg/day. ConclusionsSFO is an effective option for the treatment of hyperphosphataemia in patients with CKD both in the advanced phases of the disease and on dialysis. We found similar efficacy across the 3 groups analysed. The higher their baseline phosphate level, the greater the reduction in the serum levels. A notable reduction in phosphate levels can be achieved with doses of around 1,000mg/day. Diarrhoea was the most common side effect, although it generally was not significant.