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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.

Background Adherence to phosphate binder treatment is important to prevent high serum phosphate level in chronic dialysis patients. We therefore wanted to investigate patient knowledge, beliefs about and adherence to phosphate binders among these patients and assess whether one-to-one pharmacist-led education and counselling enhance adherence and lead to changes in serum phosphate levels. Methods A descriptive, interventional, single arm, pre-post study was performed at a hospital in Norway, including chronic dialysis patients aged 18 years or more using phosphate binders. The primary end-point was change in the proportion of patients with serum phosphate below 1.80 mmol/L and the secondary end-points included change in the patient’s knowledge, beliefs and adherence after the intervention measured by completion of questionnaires ‘Patient Knowledge’, Medication Adherence Report Scale (MARS− 5) and Beliefs about Medicines Questionnaire (BMQ). Data was collected both prior to and after one-to-one pharmacist-led education and counselling about their phosphate binders. Other medicines used by the patient was also registered. Results A total of 69 patients were enrolled in the study. After intervention, the probability of serum phosphate being below the target threshold 1.80 mmol/L (5.58 mg/dL) increased, although no significant change in mean serum phosphate levels was seen. On the other hand, the knowledge regarding phosphate binder treatment and the patients’ beliefs about the necessity of the treatment increased, while the concerns decreased (BMQ). This effect did not lead to increase in self-reported adherence measured by MARS-5. However the scores were high before the intervention. Conclusions Short term one-to-one individualized pharmacist-led education and counselling about phosphate binders increased the probability of serum phosphate concentrations being below the target threshold level 1.80 mmol/L (5.58 mg/dL), although not statistically significant. However, it did not decrease the mean serum phosphate level or increase the patients’ self-reported adherence. The patients increased their knowledge about the phosphate binder and their understanding of adherence, and were less concerned about the side effects of the medication. Trial registration ISRCTN52852596 , registered 11 April 2019. The trial was registered retrospectively.

Background Hyperphosphataemia in dialysis subjects is associated with increased mortality. However cause and effect has not been proven, and the ideal phosphate target range is unknown despite KDOQI’s call for studies over 12 years ago. The design and conduct of a randomized controlled trial is challenging because maintaining two groups within differing target ranges of serum phosphate has not been achieved over a long follow-up of 1 year, in a trial setting, before. The SPIRiT study examines the subject acceptance, recruitment and retention rates for such a study in which subjects were randomised to two distinct serum phosphate concentrations, then titrated and maintained over 12 months. Methods A two center trial of 104 hemodialysis subjects randomized to lower range LRG 0.8–1.4 mmol/L or 2.5–4.3 mg/dL) and higher range (HRG 1.8–2.4 mmol/L or 5.6–7.4 mg/dL) serum phosphate groups. Two months’ titration and ten months’ maintenance phase. Interventions were non-calcium phosphate binders, self-help questionnaires, with blood tests at specified time intervals. Results Thirteen percent of the eligible dialysis population were successfully recruited. A mean separation by serum phosphate of 1.1 mg/dL was achieved and maintained between the groups over 10 months. Drop-out rate was 27% with mortality 10%. Nine subjects in the HRG (17.6%) and two subjects in the LRG (3.8%) died during the study, however the study was not powered to detect significant differences in outcomes. Conclusion Randomizing dialysis subjects to separate treatment targets for serum phosphate can achieve a clinically significant sustained separation over 12 months. A large scale longer term study is required to examine outcomes including mortality. Trial registration The trial registration number is ISRCTN24741445 – Date of registration 16th January, retrospectively registered.

Background Elevated serum phosphorus concentrations are common among maintenance hemodialysis patients. Protein is a major source of dietary phosphate, but restriction of protein intake can result in hypoalbuminemia and protein-energy wasting. We hypothesized that sucroferric oxyhydroxide (SO), a potent phosphate binder with a low pill burden, may reduce serum phosphorus levels in hemodialysis patients with hypoalbuminemia without adversely impacting albumin levels or dietary intake of protein. Methods We retrospectively examined de-identified data from 79 adult, in-center hemodialysis patients with baseline hypoalbuminemia (≤ 3.5 g/dL) switched to SO as part of routine clinical care for at least 1 year. Temporal changes (3-month intervals from baseline through Q4) in phosphate binder pill burden, serum phosphorous levels, nutritional markers, and equilibrated Kt/V were analyzed. Data from a matched reference group of non-hypoalbuminemic patients ( N  = 79) switched to SO were also examined. Results SO therapy was associated with a mean reduction of 45.7 and 45.1% in daily phosphate binder pill burden, and a mean reduction of 0.4 mg/dL and 0.51 mg/dL in serum phosphorus levels for the hypoalbuminemic and non-hypoalbuminemic patients, respectively. Hypoalbuminemic patients demonstrated significant increases in mean serum albumin levels from 3.50 mg/dL at baseline to 3.69, 3.74, 3.70, and 3.69 mg/dL during Q1 through Q4, respectively ( P  < 0.0001), whereas serum albumin levels remained unchanged in the non-hypoalbuminemic group. Conclusions Both hypoalbuminemic and non-hypoalbuminemic patients switching to SO exhibited significant reductions in serum phosphorus concentrations and daily phosphate binder pill burden. Among hypoalbuminemic patients, the initiation of SO therapy was also associated with increases in serum albumin, suggesting therapy may have allowed patients to increase their dietary intake of protein.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been linked to poor health outcomes, including diminished quality and length of life. This condition is characterized by high phosphate levels and requires phosphate-lowering agents-phosphate binders. The objective of this systematic review is to compare the effects of available phosphate binders on patient-important outcomes in patients with CKD-MBD. Data sources included MEDLINE and EMBASE Trials from 1996 to February 2016. We also searched the Cochrane Register of Controlled Trials up to April 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility, and subsequently abstracted data and assessed risk of bias in eligible randomized controlled trials (RCTs). Eligible trials enrolled patients with CKD-MBD, randomized them to receive calcium (delivered as calcium acetate, calcium citrate or calcium carbonate), non-calcium-based phosphate binders (NCBPB) (sevelamer hydrochloride, sevelamer carbonate, lanthanum carbonate, sucroferric oxyhydroxide and ferric citrate), phosphorus restricted diet, placebo or no treatment, and reported effects on all-cause mortality, cardiovascular mortality or hospitalization at ≥4 weeks follow-up. We performed network meta-analyses (NMA) for all cause-mortality for individual agents (seven-node analysis) and conventional meta-analysis of calcium vs. NCBPBs for all-cause mortality, cardiovascular mortality and hospitalization. In the NMAs, we calculated the effect estimates for direct, indirect and network meta-analysis estimates; for both NMA and conventional meta-analysis, we pooled treatment effects as risk ratios (RR) and calculated 95% confidence intervals (CIs) using random effect models. We used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to rate the quality of evidence for each paired comparison. Our search yielded 1190 citations, of which 71 RCTs were retrieved for full review and 15 proved eligible. With 13 eligible studies from a prior review, we included 28 studies with 8335 participants; 25 trials provided data for our quantitative synthesis. Results suggest higher mortality with calcium than either sevelamer (NMA RR, 1.89 [95% CI, 1.02 to 3.50], moderate quality evidence) or NCBPBs (conventional meta-analysis RR, 1.76 [95% CI, 1.21 to 2.56, moderate quality evidence). Conventional meta-analysis suggested no difference in cardiovascular mortality between calcium and NCBPBs (RR, 2.54 [95% CI, 0.67 to 9.62 low quality evidence). Our results suggest higher hospitalization, although non-significant, with calcium than NCBPBs (RR, 1.293 [95% CI, 0.94 to 1.74, moderate quality evidence). Use of calcium results in higher mortality than either sevelamer in particular and NCBPBs in general (moderate quality evidence). Our results raise questions about whether administration of calcium as an intervention for CKD- MBD remains ethical. Further research is needed to explore the effects of different types of phosphate binders, including novel agents such as iron, on quality and quantity of life. PROSPERO CRD-42016032945.

Vascular calcification (VC) is common in dialysis and non-dialysis chronic kidney disease (CKD) patients, even in the early stage of the disease. For this reason, it can be considered a CKD hallmark. VC contributes to cardiovascular disease (CVD) and increased mortality among CKD patients, although it has not been proven. There are more than one type of VC and every form represents a marker of systemic vascular disease and is associated with a higher prevalence of CVD in CKD patients, as shown by several clinical studies. Major risk factors for VC in CKD include: Increasing age, dialysis vintage, hyperphosphatemia (particularly in the setting of intermittent or persistent hypercalcemia), and a positive net calcium and phosphate balance. Excessive oral calcium intake, including calcium-containing phosphate binders, increases the risk for VC. Moreover, it has been demonstrated that there is less VC progression with non-calcium-containing phosphate binders. Unfortunately, until now, a specific therapy to prevent progression or to facilitate regression of VC has been found, beyond careful attention to calcium and phosphate balance.

Despite the availability of global and regional guidelines to curtail the adverse clinical outcomes associated with chronic kidney disease-mineral and bone disorder (CKD-MBD), most CKD patients are still affected by the consequences of abnormalities of CKD-MBD. This important clinical complication of CKD continues to be studied, in order to improve the understanding and management of CKD-MBD. Some notable discoveries include the role of fibroblast growth factor 23 (FGF23) in the pathogenesis of CKD-MBD, leading to a shift from the previous well-established classic trade-off hypothesis to the updated trade-off hypothesis. More recently, there has been a shift from the treatment of CKD-MBD based on a single level of biomarkers to serial measurements of calcium, phosphate and parathyroid hormone (PTH). Furthermore, some clinical trials have emerged after the 2009 Kidney Disease-Improving Global Outcomes (KDIGO) Guidelines, leading to the 2017 KDIGO updated recommendations. Hence, this review gives an overview of the rapidly evolving trends in CKD-MBD, linking the past and current concepts of CKD-MBD.

The risk of death in hemodialysis patients treated with calcium-containing phosphate binders or sevelamer is not known. We assessed all-cause mortality in 127 patients new to hemodialysis assigned to calcium-containing binders or sevelamer after a median follow-up of 44 months from randomization. This was a predetermined secondary end point of a randomized clinical trial designed to assess progression of coronary artery calcium (CAC) scores in the two treatment arms. Thirty-four deaths occurred during the follow-up period: 23 in subjects randomized to calcium-containing phosphate binders and 11 in subjects randomized to sevelamer. Baseline CAC score was a significant predictor of mortality after adjustment for age, race, gender, and diabetes with increased mortality proportional to baseline score (P=0.002). Mortality was borderline significantly lower in subjects randomized to sevelamer (5.3/100 patient years, confidence interval (CI) (2.2–8.5) compared to those randomized to calcium-containing binders (10.6/100 patient years, CI 6.3–14.9) (P=0.05). The greater risk of death for patients treated with calcium-containing phosphate binders persisted after full multivariable adjustment (P=0.016, hazard ratio 3.1, CI 1.23–7.61). In subjects new to hemodialysis baseline CAC score was a significant predictor of all-cause mortality. Treatment with sevelamer was associated with a significant survival benefit as compared to the use of calcium-containing phosphate binders.

Patients with chronic kidney disease (CKD) are given calcium carbonate to bind dietary phosphorus, reduce phosphorus retention, and prevent negative calcium balance; however, data are limited on calcium and phosphorus balance during CKD to support this. Here, we studied eight patients with stage 3 or 4 CKD (mean estimated glomerular filtration rate 36ml/min) who received a controlled diet with or without a calcium carbonate supplement (1500mg/day calcium) during two 3-week balance periods in a randomized placebo-controlled cross-over design. All feces and urine were collected during weeks 2 and 3 of each balance period and fasting blood, and urine was collected at baseline and at the end of each week. Calcium kinetics were determined using oral and intravenous 45calcium. Patients were found to be in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation 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 soft-tissue deposition. Fasting blood and urine biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate. Thus, the positive calcium balance produced by calcium carbonate treatment within 3 weeks cautions against its use as a phosphate binder in patients with stage 3 or 4 CKD, if these findings can be extrapolated to long-term therapy.

Hyperphosphatemia is a common complication in advanced chronic kidney disease and contributes to cardiovascular morbidity and mortality. The present narrative review focuses on the management of phosphatemia in uremic patients receiving peritoneal dialysis. These patients frequently develop hyperphosphatemia since phosphate anion behaves as a middle-size molecule despite its low molecular weight. Accordingly, patient transporter characteristics and peritoneal dialysis modalities and prescriptions remarkably influence serum phosphate control. Given that phosphate peritoneal removal is often insufficient, especially in lower transporters, patients are often prescribed phosphate binders whose use in peritoneal dialysis is primarily based on clinical trials conducted in hemodialysis because very few studies have been performed solely in peritoneal dialysis populations. A crucial role in phosphate control among peritoneal dialysis patients is played by diet, which must help in reducing phosphorous intake while preventing malnutrition. Moreover, residual renal function, which is preserved in most peritoneal dialysis patients, significantly contributes to maintaining phosphate balance. The inadequate serum phosphate control observed in many patients on peritoneal dialysis highlights the need for large and well-designed clinical trials including exclusively peritoneal dialysis patients to evaluate the effects of a multiple therapeutic approach on serum phosphate control and on hard clinical outcomes in this high-risk population.