Phosphate Binders In Patients Research Articles

Comparative Gut Microbiome Differences between Ferric Citrate and Calcium Carbonate Phosphate Binders in Patients with End-Stage Kidney Disease.

Gut dysbiosis in patients with chronic kidney disease (CKD) may induce chronic inflammation and increase morbidity. Phosphate-binding agents, generally used in patients with CKD, may potentially change the composition of the gut microbiota. This study aimed to compare the microbiota composition in hemodialysis patients treated with ferric citrate or calcium carbonate. The stool microbiota was investigated in hemodialysis patients treated with ferric citrate (n = 8) and calcium carbonate (n = 46) using 16S rRNA gene amplicon sequencing profiling using linear discriminant analysis of effect size. Further predictive functional profiling of microbial communities was obtained with Tax4Fun in R. Hemodialysis patients treated with calcium carbonate had a significantly reduced microbial species diversity (Shannon index and Simpson index) and an increased microbial alteration ratio compared with patients treated with ferric citrate. A distinct microbial community structure was found in patients treated with ferric citrate, with an increased abundance of the Bacteroidetes phylum and a decreased abundance of the phylum Firmicutes. Members of the order Lactobacillales were enriched in patients treated with calcium carbonate, whereas taxa of the genera Ruminococcaceae UCG-004, Flavonifractor, and Cronobacter were enriched in patients treated with ferric citrate phosphate binder. In conclusion, Ferric citrate therapy results in a more diverse microbiome community compared to calcium carbonate therapy in hemodialysis patients with phosphate binder treatment. The gut microbiome reflects the phosphate binder choice in hemodialysis patients, further affecting the physiological environment in the gastrointestinal tract.

Investigation of the clinical significance and pathological features of lanthanum deposition in the gastric mucosa

BackgroundThere are often specific endoscopic findings caused by deposition of lanthanum (La) in the gastric mucosa of patients taking lanthanum carbonate (LaC), a novel phosphate binder for patients on hemodialysis. We conducted a retrospective study to investigate the clinical significance of La deposition in the gastric mucosa, and the association between endoscopic features and histologic findings in the same population.MethodsWe compared background factors in patients taking LaC with and without La deposition in their gastroscopic biopsy specimen. We also investigated the relationship between gastric endoscopic biopsy specimens with La deposition and the concurrent endoscopic images.ResultsThere was a significant difference in the total dose of LaC between the La-positive and La-negative groups (990 g [180–3150 g] vs. 480 g [225–1328 g]; p = 0.013). In 27 biopsy specimens with specific whitish mucosa, 10 showed mild histiocytic infiltration and 17 showed severe infiltration. In contrast, among 24 specimens with non-whitish mucosa, 5 showed no histiocytic infiltration, 10 showed mild infiltration, and 9 showed severe infiltration. There was a significant relationship between endoscopic features and the degree of histiocytic infiltration (p = 0.026).ConclusionsWe demonstrated that La deposition in the gastric mucosa depended on the total dose of LaC and was not affected by background factors. The specific endoscopic features of La deposition are associated with the infiltration of histiocytes, which represents the body’s normal response to foreign bodies.Trial registry The protocol was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000038929, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000044393).

Sevelamer Use in End-Stage Kidney Disease (ESKD) Patients Associates with Poor Vitamin K Status and High Levels of Gut-Derived Uremic Toxins: A Drug-Bug Interaction?

Gut microbial metabolism is not only an important source of uremic toxins but may also help to maintain the vitamin K stores of the host. We hypothesized that sevelamer therapy, a commonly used phosphate binder in patients with end-stage kidney disease (ESKD), associates with a disturbed gut microbial metabolism. Important representatives of gut-derived uremic toxins, including indoxyl sulfate (IndS), p-Cresyl sulfate (pCS), trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAG) and non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP; a marker of vitamin K status), were analyzed in blood samples from 423 patients (65% males, median age 54 years) with ESKD. Demographics and laboratory data were extracted from electronic files. Sevelamer users (n = 172, 41%) were characterized by higher phosphate, IndS, TMAO, PAG and dp-ucMGP levels compared to non-users. Sevelamer was significantly associated with increased IndS, PAG and dp-ucMGP levels, independent of age, sex, calcium-containing phosphate binder, cohort, phosphate, creatinine and dialysis vintage. High dp-ucMGP levels, reflecting vitamin K deficiency, were independently and positively associated with PAG and TMAO levels. Sevelamer therapy associates with an unfavorable gut microbial metabolism pattern. Although the observational design precludes causal inference, present findings implicate a disturbed microbial metabolism and vitamin K deficiency as potential trade-offs of sevelamer therapy.

Phosphate binders in patients with chronic kidney disease: Between the new and the old.

Impaired phosphate excretion by the kidney leads to Hyperphosphatemia. It is an independent predictor of cardiovascular disease and mortality in patients with advanced chronic kidney disease (stage 4 and 5) particularly in case of dialysis. Phosphate retention develops early in chronic kidney disease (CKD) due to the reduction in the filtered phosphate load. Overt hyperphosphatemia develops when the estimated glomerular filtration rate (eGFR) falls below 25 to 40 mL/min/1.73 m2. Hyperphosphatemia is typically managed with oral phosphate binders in conjunction with dietary phosphate restriction. These drugs aim to decrease serum phosphate by binding ingested phosphorus in the gastrointestinal tract and its transformation to non-absorbable complexes [1].

Phosphate binder use in patients undergoing centre‐based haemodialysis within the Metro North Kidney Health Service

Reducing polypharmacy directly improves quality use of medicines, a key arm of the Australian National Medicines Policy. Numerous studies have illustrated that a reduction in pill burden improves patient compliance, reduces drug economics and minimizes therapy-related adverse effects. Phosphate binders are the single largest contributor to the daily pill burden in chronic kidney disease patients undergoing renal replacement therapy. The aim of this study was to examine the relationship between pill burden and cost of phosphate binders with biochemical parameters in patients undergoing centre-based haemodialysis within the Kidney Health Service of the Metro North Hospital and Health Service. Centre-based haemodialysis patients from three geographically different kidney units in Queensland, Australia, underwent a single, cross-sectional assessment of total daily pill burden from phosphate binders between May 2015 and August 2015. The total number of phosphate binder pills per week comprised of calcium carbonate, aluminium hydroxide, sevelamer hydrochloride, lanthanum and cinacalcet. The urea reduction ratio, serum albumin, serum calcium, serum phosphate and serum parathyroid hormone (PTH) were averaged across this period. Of the 138 patients in this study, 62 (44.9%) patients were from the Royal Brisbane and Women’s Hospital (RBWH), 40 (29.0%) patients were from Redcliffe Satellite Unit and 36 (26.1%) patients were from the Northlakes Satellite Unit. Eighty-two (59.4%) were male and the mean age was 66 (standard deviation 15) years. Between hospital comparisons of baseline co-morbidities revealed significant difference in hypertension (P = 0.014) only. Sevelamer hydrochloride was most commonly used at RBWH at 41%, followed by calcium carbonate (32%) and aluminium hydroxide (22%). In contrast, both Northlakes and Redcliffe had similar phosphate binder use with calcium carbonate being most popular (36% and 58% respectively), followed by sevelamer hydrochloride (33% and 15% respectively) and aluminium hydroxide (8% and 14% respectively). Forty-two percent of RBWH patients, 45% of Redcliffe patients and 58% of Northlakes patients were taking two or more classes of phosphate binders. There were no statistically significant differences across the three kidney health services in relation to total pill burden (P = 0.17), weekly phosphate binder cost (P = 0.13), or serum calcium (P = 0.35), serum phosphate (P = 0.61) and serum PTH (P = 1.00). Comparison of weekly phosphate binder cost between the three sites revealed no significant difference (P = 0.12) with RBWH $41.58 (1.89–84.58), Redcliffe $5.32 (1.89–46.52) and Northlakes $44.87 (5.20–87.52). No appreciable differences in the pill burden and phosphate binder cost per week were associated with biochemical outcomes between the RBWH, Northlakes and Redcliffe kidney health service. Several studies have recently emerged regarding the lack of efficacy and survival benefit of phosphate binders in patients undergoing centre-based haemodialysis. This study reinforces ongoing concerns regarding the minimal biochemical and economic improvement associated with phosphate binder use in this group of dialysis patients. Future studies should compare the cost and pill burden of phosphate binders in other Australian centres and ascertain whether any biochemical and economic changes occur in patients undergoing haemodialysis in the home environment.

Phosphate binders in patients with chronic kidney disease.

Hyperphosphataemia in patients with chronic kidney disease, particularly those on dialysis, can be ameliorated by oral phosphate binders in conjunction with dietary phosphate restriction. Although phosphate binders reduce serum phosphate in these patients, it remains uncertain whether they improve clinical outcomes. Calcium-based binders are frequently used, but their popularity is waning due to emerging evidence of accelerated vascular calcification. The use of aluminium-based binders has been limited by a perceived risk of aluminium accumulation. The non-calcium-based phosphate binders - sevelamer hydrochloride, lanthanum carbonate and sucroferric oxyhydroxide - have become available and subsidised by the Pharmaceutical Benefits Scheme for patients on dialysis. The pill burden and adverse effects (particularly gastrointestinal intolerance) associated with phosphate binders often contribute to poor medication adherence.

Managing phosphate and phosphate binders in patients with kidney disease

The variety, format and availability of phosphate binders has increased greatly over recent years. In this article, renal dietitian Nick McAleer discusses what phosphate is, what role it has within the body, and the implications of poor phosphate control—especially for renal patients. He also outlines key recommendations from national guidance on phosphate management.

Novel iron-based phosphate binders in patients with chronic kidney disease.

Management of hyperphosphatemia remains an integral component in the care of patients with chronic kidney disease on dialysis. In addition to dietary restriction and dialysis, oral phosphate binders remain a key strategy in the control of serum phosphorus levels in this population. We review two new oral phosphate binders that are currently marketed in the United States. Sucroferric oxyhydroxide was approved by the U.S. Food and Drug Administration (FDA) in November 2013. A recent international, multicenter study found the drug to be efficacious and noninferior to sevelamer carbonate in magnitude of serum phosphate control. This was achieved with a significantly reduced daily pill burden for sucroferric oxyhydroxide. A second novel agent, ferric citrate was approved by the FDA in September, 2014. The drug was found to have similar phosphate control efficacy to active comparators and was superior to placebo. In addition, the drug delivers a significant amount of iron, resulting in improved erythropoietic parameters. Both drugs had diarrhea as a fairly frequent side-effect. These new phosphate binders offer alternatives to currently available agents. Both have interesting properties that may make them particularly useful in clinical practice.

Determinants of phosphorus mobilization during hemodialysis

Our recent work proposed a pseudo one-compartment model for describing intradialysis and postdialysis rebound kinetics of phosphorus. In this model, phosphorus is removed directly from a central distribution volume with the rate of phosphorus mobilization from a second, very large compartment proportional to the phosphorus mobilization clearance. Here, we evaluated factors of phosphorus mobilization clearance and postdialysis central distribution volume from 774 patients in the HEMO Study. Phosphorus mobilization clearance and postdialysis central distribution volume were 87 (65, 116) ml/min, median (interquartile range), and 9.4 (7.2, 12.0) liter, respectively. The phosphorus mobilization clearance was significantly higher for male patients than for female patients. Both the phosphorus mobilization clearance and the postdialysis central distribution volume were significantly associated with postdialysis body weight but negatively with the predialysis serum phosphorus concentration. The postdialysis central distribution volume was also significantly associated with age. Overall, the postdialysis central distribution volume was 13.6% of the postdialysis body weight. Thus, the phosphorus mobilization clearance during hemodialysis is higher when predialysis serum phosphorus concentration is low and higher in male patients than in female patients. The central distribution volume of phosphorus is a space approximating the extracellular fluid volume.

Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis

Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease. We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model. Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0·78, 95% CI 0·61-0·98). Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder. None.

Hyperphosphatemia in patients with ESRD: assessing the current evidence linking outcomes with treatment adherence

In recent years, the imbalance in phosphate homeostasis in patients with end-stage renal disease (ESRD) has been the subject of much research. It appears that, while hyperphosphatemia may be a tangible indicator of deteriorating kidney function, lack of phosphate homeostasis may also be associated with the increased risk of cardiovascular events and mortality that has become a hallmark of ESRD. The need to maintain phosphorus concentrations within a recommended range is reflected in evidence-based guidelines. However, these do not reflect serum phosphorus concentrations achieved by most patients in clinical practice. Given this discrepancy, it is important to consider ways in which dietary restriction of phosphorus intake and, in particular, use of phosphate binders in patients with ESRD can be made more effective. Poor adherence is common in patients with ESRD and has been associated with inadequate control of serum phosphorus concentrations. Studies indicate that, among other factors, major reasons for poor adherence to phosphate binder therapy include high pill burden and patients’ lack of understanding of their condition and its treatment. This review examines available evidence, seeking to understand fully the reasons underlying poor adherence in patients with ESRD and consider possible strategies for improving adherence in clinical practice.

In vitro phosphate-binding ability of calcium-based agents is augmented by co-administration of activated charcoal

Calcium carbonate is widely used as a phosphate binder in patients on maintenance hemodialysis. An unwanted side effect of calcium carbonate is hypercalcemia and vascular calcification. Oral activated charcoal (AC) is a non-selective and highly effective adsorbent. We hypothesized that AC augments the phosphate binding capacity of calcium-based agents. We performed an in vitro study to test this hypothesis. Simulated gastric fluid and intestinal fluid were prepared with a phosphate concentration of 10 mmol/l. Different dosages of calcium chloride (0.083 g, 0.167 g, and 0.250 g), AC (0.15 g, 0.30 g, and 0.45 g) or a combination of both were added to either gastric or intestinal fluid for phosphate binding. After a reaction time of 2 hours, phosphate concentrations in the supernatant were measured, and absolute reduction and percent reduction of phosphate were calculated. The phosphate-binding abilities of calcium chloride, AC, and a combination of both were compared. In simulated intestinal fluid there was no significant difference in the percent reduction of phosphate concentrations among the different calcium chloride concentration groups (28.90 ± 2.04 vs. 33.33 ± 3.90 vs. 31.86 ± 5.23) and there was still no significant difference in phosphate concentrations among the different AC groups (3.33 ± 0.08 vs. 3.26 ± 0.01 vs. 3.36 ± 0.11). In simulated gastric fluid phosphate concentrations at each of the time points (before the reaction, 1 hour after calcium chloride was added, and 2 hours after AC was added) were not significantly different. In simulated intestinal fluid the percent decrease in phosphate concentration in the calcium chloride + AC group was significantly higher than that in the calcium chloride group (48.23 ± 5.55 vs. 30.72 ± 6.11). AC alone had no phosphate-binding ability in either gastric or intestinal fluid. The phosphate-binding ability of calcium chloride was improved by AC in intestinal fluid.

Clinical efficacy of sevelamer hydrochloride in patients with end-stage renal disease: a retrospective study

Sevelamer hydrochloride (Renagel) is frequently used as a second-line phosphate binder in patients on renal replacement therapy. Many studies have shown that sevelamer can improve vascular calcification, serum uric acid and low-density lipoprotein (LDL) cholesterol levels. The main objectives of this study were to assess the efficacy of sevelamer against calcium-based phosphate binders, as well as its tolerability and side-effect profile. This was a retrospective study that included all patients on renal replacement therapy (between 2008 and 2011) who had previously received calcium-based binders for ≥ 6 months and were subsequently switched to sevelamer. Data collected from the patients' medical records included demographics, as well as renal parameters three months prior to sevelamer treatment, and at three and six months post treatment. The study excluded patients on multiple, concomitant phosphate binders or with functioning renal transplants, and those who were noncompliant or had inadequate follow-up blood investigations. A total of 39 patients were included in the study. No major side effects were reported by any of the patients. There were improvements in calcium, phosphate, uric acid and LDL cholesterol levels at three and six months post-sevelamer treatment. We found sevelamer to be superior to calcium-based phosphate binders in reducing serum calcium, phosphate, uric acid and LDL cholesterol levels in our patient population with advanced renal bone disease. Sevelamer also appears to be well tolerated with no significant side effects.

Oral calcium carbonate affects calcium but not phosphorus balance in stage 3–4 chronic kidney disease

Chronic kidney disease (CKD) patients are given calcium carbonate to bind dietary phosphorus and reduce phosphorus retention, and to prevent negative calcium balance. Data are limited on calcium and phosphorus balance in CKD to support this. The aim of this study was to determine calcium and phosphorus balance and calcium kinetics with and without calcium carbonate in CKD patients. Eight stage 3/4 CKD patients, eGFR 36 mL/min, participated in two 3-week balances in a randomized placebo-controlled cross-over study of calcium carbonate (1500 mg/d calcium). Calcium and phosphorus balance were determined on a controlled diet. Oral and intravenous 45calcium with blood sampling and urine and fecal collections were used for calcium kinetics. Fasting blood and urine were collected at baseline and end of each week of each balance period for biochemical analyses. Results showed that patients were in neutral calcium and phosphorus balance while on placebo. Calcium carbonate produced positive calcium balance, did not affect phosphorus balance, and produced only a modest reduction in urine phosphorus excretion compared with placebo. Calcium kinetics demonstrated positive net bone balance but less than overall calcium balance suggesting tissue deposition. Fasting biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate. If they can be extrapolated to effects of chronic therapy, these data caution against the use of calcium carbonate as a phosphate binder.

Lanthanum Carbonate Delays Progression of Coronary Artery Calcification Compared With Calcium-Based Phosphate Binders in Patients on Hemodialysis

Coronary artery calcification (CAC) is associated with future cardiovascular events and/or death of patients on hemodialysis (HD). We investigated whether progression of CAC in patients on HD could be delayed by switching from a calcium (Ca)-based phosphate (Pi) binder to lanthanum carbonate. The CAC scores were evaluated at study enrollment and after 6 months in 52 patients on HD using calcium carbonate (CC) as a Pi binder. Patients were randomly divided into 2 groups assigned to receive either CC or lanthanum carbonate (LC), and the CAC scores were evaluated after a 6-month treatment period. Progression of CAC was assessed, as were serum levels of Ca, Pi, and intact parathyroid hormone (iPTH). Forty-two patients completed the study (23 receiving CC and 19 receiving LC). In the 6 months prior to randomization, all patients were treated with CC. During this 6-month period, the CAC scores increased significantly in all 42 patients. Once randomized, there was significantly less progression in the group treated with LC than with CC. Changes in CAC scores from 6 to 12 months were significantly smaller in the LC group than the CC group (-288.9 ± 1176.4 vs 107.1 ± 559.6, P = .036), and percentage changes were also significantly different (-6.4% vs 41.2%, P = .024). Serum Ca, Pi, and iPTH levels were similar in both groups during the study period. This pilot study suggested that LC delayed progression of CAC in patients on HD compared with CC.

Phosphate Binders in CKD

Hyperphosphatemia has long been considered an important contributor to the mineral and bone disorder associated with CKD (CKD-MBD).[1][1] Already 50 years ago, Slatopolsky et al. [2][2] showed that as GFR decreased, fractional phosphate excretion rose because of inhibition of tubular phosphate

Rationale and study design of a three‐period, 58‐week trial of ferric citrate as a phosphate binder in patients with ESRD on dialysis

Chronic kidney disease associated mineral and bone disorders arise as a result of aberrant bone mineral metabolism in patients with advancing levels of renal dysfunction and end-stage renal disease. One of the cornerstones of treatment is the use of phosphate-binding agents. We describe the rationale and study design for a clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder. This trial is a three-period, international, multicenter, randomized, controlled clinical trial to assess the safety and efficacy of ferric citrate as a phosphate binder, consisting of a 2-week washout period, a 52-week safety assessment period in which subjects are randomized to ferric citrate or active control, and a 4-week efficacy assessment period in which subjects randomized to ferric citrate in the safety assessment period are randomized to ferric citrate or placebo. Eligible subjects include end-stage renal disease patients who have been treated with thrice-weekly hemodialysis or peritoneal dialysis for at least 3 months in dialysis clinics in the United States and Israel. Primary outcome measure will be the effect of ferric citrate vs. placebo on the change in serum phosphorus. Safety assessments will be performed by monitoring adverse events, concomitant medication use, and sequential blood chemistries (including iron parameters, phosphorus, and calcium). This three-period trial will assess the efficacy of ferric citrate as a phosphate binder. If proven safe and efficacious, ferric citrate will likely provide an additional phosphate binder to treat chronic kidney disease associated mineral and bone disorders.

Measurement of serum lanthanum in patients treated with lanthanum carbonate by inductively coupled plasma-mass spectrometry

Lanthanum carbonate is used as a phosphate binder in patients with stage V chronic kidney disease (CKD). While well tolerated in clinical trials, with no toxicity reported as regards bone and liver metabolism, and cognitive function, concerns remain over possible toxicity. Published methods for the measurement of lanthanum ion in biological samples include aggressive and complicated sample preparation steps that are unsuitable for routine use. A simple method has been developed and validated for the measurement of serum lanthanum. A ThermoFisher Scientific XSERIES-II inductively coupled plasma-mass spectrometer was used to monitor ¹³⁹La. Validation was undertaken using internal quality control solutions containing lanthanum ion (0.20, 0.70 and 4.00 μg/L). Lanthanum was measured in patients (number = 20) with CKD prescribed lanthanum carbonate (500-1500 mg/d) and patients undergoing haemodialysis not prescribed lanthanum carbonate (number = 20). Accuracy and imprecision were >95% and <5%, respectively. Calibration was linear (range 0.1-5 μg/L, R² = 0.99). The lower limit of quantification (LLoQ) was 0.1 μg/L lanthanum ion. In patients with CKD not prescribed lanthanum carbonate, serum lanthanum was below the LLoQ. Out of 20 CKD patients prescribed lanthanum carbonate, serum lanthanum was measurable in only 12 (range 0.11-0.60 μg/L lanthanum ion). There was no apparent relationship between dose and serum lanthanum in these patients. A lack of relationship between the dose of lanthanum carbonate and the serum lanthanum concentration may have been due to poor adherence to the treatment regimen. However the concentrations measured were close to the LLoQ.

Oral Phosphate Binders in Patients with Kidney Failure

Oral Phosphate Binders in Patients with Kidney Failure

Oral Phosphate Binders in Patients with Kidney Failure

Hyperphosphatemia, which is nearly universal in kidney failure, is accompanied by low serum levels of vitamin D and hypocalcemia. Without treatment, severe secondary hyperparathyroidism occurs, which may result in painful fractures, brown tumors, and generalized osteopenia. This article reviews the rationale for treatment with oral phosphate binders, discusses evidence supporting the use of available agents, and suggests an approach for clinical practice.