Effect of RenaGel(R), a non-absorbed, calcium- and aluminium-free phosphate binder, on serum phosphorus, calcium, and intact parathyroid hormone in end-stage renal disease patients

Background: Control of dietary phosphate absorption in end-stage renal disease patients is essential to prevent the deleterious sequelae of phosphorus retention. Efficacy of currently available calcium- and aluminium-containing phosphate binders is constrained by the side-effects associated with the absorption of calcium and aluminium. The current study examined the efficacy of RenaGel, a calcium- and aluminium-free, polymeric phosphate binder, in end-stage renal disease patients. Methods: Administration of calcium- or aluminium-containing phosphate binders ceased during a 2-week washout period. RenaGel, at starting doses of one, two, or three 500-mg capsules three times per day with meals, was administered for 8 weeks. RenaGel dose was titrated up 1 capsule per meal at the end of each 2-week period if necessary to achieve phosphorus control. A second 2-week washout period followed the end of RenaGel treatment. Results: Mean serum phosphorus rose from a prewashout level of 6.9 mg/dl (2.23 mmol/l) to 8.1 mg/dl (2.62 mmol/l) at the end of the initial 2-week washout. With RenaGel treatment, serum phosphorus declined and returned to pre-washout levels after 4 weeks. Serum phosphorus reached a nadir of 6.5 mg/dl (2.10 mmol/l) after 7 weeks of RenaGel treatment. Serum phosphorus rose to 8.2 mg/dl (2.65 mmol/l) 2 weeks after cessation of RenaGel treatment. As anticipated, calcium declined during the initial washout period when calcium-based phosphate binders were stopped for the majority of patients. The rise in serum phosphorus and decline in serum calcium during washout resulted in an increase in median intact parathyroid hormone (iPTH) levels from 292 pg/ml to 395 pg/ml. iPTH fell to 283 pg/ml after 6 weeks of RenaGel treatment despite a persistently lower serum calcium. RenaGel treatment also reduced serum total and LDL cholesterol by 25 mg/dl (0.65 mmol/l) and 23 mg/dl 0.59 mmol/l) respectively. Conclusions: RenaGel appears to be an effective phosphate binder free of calcium and aluminium. Phosphorus control with two to four RenaGel capsules per meal appears to result in comparable phosphorus lowering seen with calcium- or aluminium-based phosphate binders. RenaGel may offer an alternative for the control of phosphorus retention in end-stage renal disease patients. Key words: hyperphosphataemia; hyperparathyroidism; chronic renal disease; randomized controlled trial; cholesterol      

Efficacy and safety of SBR759, a novel calcium-free,iron (III)-based phosphate binder,versus placebo in chronic kidney disease stage V Japanese patients on maintenance renal replacement therapy

Background

SBR759, an iron (III)-based oral phosphate binder, was developed for the treatment of hyperphosphataemia in chronic kidney disease stage V patients receiving maintenance renal replacement therapy (RRT). Serum phosphate-lowering efficacy and dose response of SBR759 (3-, 6-, 9- and 12-g/day doses) were compared with placebo.

Methods

Japanese patients with hyperphosphataemia (P ≥ 5.5 mg/dL [≥1.78 mmol/L]) receiving maintenance RRT (N = 63) were randomised to receive either SBR759 (3-, 6-, 9-, 12-g/day dose) or placebo (12-g/day dose) for 4 weeks. The primary endpoint was change from baseline in 72-h post-dialysis serum phosphate levels at week 4 for different doses of SBR759 versus placebo. Secondary endpoints were change from baseline in serum phosphate levels and dose-dependent efficacy of SBR759 during the 4-week treatment period.

Results

SBR759 showed significant reduction in serum phosphate levels compared with placebo at week 4, demonstrating a significant linear dose response (P < 0.001). Incidence of adverse events was comparable between the SBR759 treatment groups (7/13 and 5/12 in the 3- and 12-g/day groups, respectively, and 8/13 in the 6- and 9-g/day groups) and was 6/12 in the placebo group. Discoloured faeces and diarrhoea were the most frequently reported adverse events. Two serious adverse events were reported—one in the SBR759 3-g/day group (1/13, skin ulcer) and one in the SBR759 12-g/day group (1/12, arthralgia).

Conclusions

SBR759 showed significant phosphate-lowering efficacy and dose-dependent response compared with placebo in patients with chronic kidney disease receiving RRT.     

Efficacy and safety of lanthanum carbonate for reduction of serum phosphorus in patients with chronic renal failure receiving hemodialysis

BACKGROUND: Lanthanum carbonate is a highly effective phosphate binder with significant potential as a treatment for hyperphosphatemia in patients with end-stage renal disease (ESRD). Here, the results of a placebo-controlled, dose-ranging study are presented. METHODS: 196 patients (> or = 18 years) receiving hemodialysis for at least 6 months entered a 1- to 3-week, single-blind, placebo run-in phase. Of these, 145 patients were randomized to a double-blind phase in which they received placebo or lanthanum carbonate in daily lanthanum doses of 225, 675, 1,350 or 2,250 mg for 6 weeks. Serum levels of phosphorus, calcium and parathyroid hormone, and adverse events were monitored throughout the study. RESULTS: The intent-to-treat analysis (n = 144) showed significant dose-related reductions in serum phosphorus at lanthanum doses of 675, 1,350 and 2,250 mg. After 6 weeks of treatment, phosphorus levels were significantly lower in the lanthanum groups receiving 1,350 mg/day and 2,250 mg/day, compared with the placebo group (respective changes from randomization: -0.95 +/- 1.39 mg/dl (-0.31 +/- 0.45 mmol/l), -1.13 +/- 2.01 mg/dl (-0.36 +/- 0.65 mmol/l), 0.75 +/- 1.47 mg/dl (0.24 +/- 0.47 mmol/l), p < 0.001). Significant reductions in serum phosphorus, compared with placebo, occurred in the lanthanum 1,350 mg/day group from the second week of treatment and in the 2,250 mg/day group from the first week of treatment. Adverse events were mainly gastrointestinal (e.g. nausea and vomiting). Treatment-related adverse events occurred in 39% of patients treated with lanthanum carbonate and 44% of the placebo group. CONCLUSION: Lanthanum carbonate is an effective and well-tolerated agent for the short-term treatment of hyperphosphatemia in patients with ESRD.     

Stabilized polynuclear iron hydroxide is an efficient oral phosphate binder in uraemic patients.

BACKGROUND: There is a continuing need for non-aluminium and non-calcium-containing oral phosphate binders. A novel product, i.e. stabilized polynuclear iron hydroxide, has experimentally been shown to be an effective phosphate binder. The purpose of the study was to test the efficacy and tolerability of the compound in hyperphosphataemic patients with stable preterminal renal failure. METHODS: In an open uncontrolled study we examined a total of 13 patients with stable preterminal renal failure (median serum-creatinine 5.4 mg/dl, range 4.2-7.3 mg/dl) and hyperphosphataemia (median fasting plasma-Pi 2.2 mmol/l, range 1.95 3.0 mmol/l). Patients were given dietary advise to maintain a constant intake of phosphate and this was verified by measuring urinary Pi excretion. After 2 weeks on no oral phosphate binders, patients were given daily 3 x 2.5 g stabilized polynuclear iron hydroxide with meals for 4 weeks. In a blinded fashion plasma-Pi and urinary-Pi as well as 1,84 i-PTH, vitamin D metabolites, serum-iron and ferritin were measured in a central laboratory. RESULTS: Compared to baseline (no oral phosphate binders), the median per cent decrease of fasting plasma-Pi at day 14 was 20% (7.2-41%) (P<0.001 by Wilcoxon test) and the median per cent decrease of urinary P excretion was 37% (9.6-56.6%) (P<0.0003 by Wilcoxon test for paired differences). Ferritin levels did not differ significantly during the study. Apart from a certain laxative action and black discolouration of the faeces, no side effects were noted in this short-term study. CONCLUSION: Stabilized polynuclear iron hydroxide is a promising, efficaceous and well tolerated phosphate binder.     

Effect of RenaGel(R), a non-absorbable, cross-linked, polymeric phosphate binder, on urinary phosphorus excretion in rats

Background. Normalization of serum phosphorus is critical in the treatment of End Stage Renal Failure patients. Aluminum or calcium based phosphate binders, while efficacious, are associated with potential adverse side effects and toxicities. We have developed RenaGel®, a novel, non-absorbed hydrogel which binds dietary phosphate leading to increased fecal excretion, decreased absorption and decreased serum phosphorus levels. In this paper, we present results from both in vitro and in vivo studies in which we examined the efficacy of this novel phosphate binder. Methods. In vitro, RenaGel® was suspended in the test solution, and the mixture was stirred for 1 hour at room temperature. The solid was then filtered off, and the residual liquid analyzed for phosphate. In vivo, RenaGel was mixed in rodent feed at different concentrations and fed to normal rats for up to 4 days. Urine was collected and analyzed for phosphate content. Results and conclusions. In vitro binding studies demonstrate that RenaGel has an extremely high phosphate binding capacity. At an estimated physiological concentration of 5 mM phosphate, RenaGel binds 2.6 mmole phosphate/g of phosphate binder. The in vivo binding study shows that RenaGel mixed into the diet increased urinary phosphorus excretion in a dose dependent manner. RenaGel particles with a 23 &mgr;m mean diameter are more efficacious than the larger ones. In conclusion, the above studies indicate that RenaGel is a potent phosphate binder. RenaGel® contains no calcium or aluminum and offers an alternative to existing phosphate binder treatments.     

Sevelamer hydrochloride: an effective phosphate binder in dialyzed children

This pilot study was designed to evaluate the efficacy and acceptability of sevelamer hydrochloride as a phosphate binder in pediatric patients treated with dialysis. A 6-month open-label trial of sevelamer hydrochloride (Renagel) was initiated in 17 patients, aged 11.8±3.7 years, undergoing hemodialysis (n=3) or peritoneal dialysis (n=14). Following a 2-week washout period of the phosphate binders, serum phosphorus increased from 5.2±1.3 mg/dl to 7.5±2.2 mg/dl (P<0.0002). After initiation of therapy with sevelamer hydrochloride, serum phosphorus levels decreased to 6.2±1.2 mg/dl (P<0.01) during the first 8 weeks and final values were 6.3±1.5 mg/dl. Serum calcium concentration decreased during the washout period from 9.4±0.9 mg/dl to 8.9±1.5 mg/dl (P<0.01); values remained unchanged thereafter. The serum calcium-phosphorus ion product decreased during the first 8 weeks and values did not change subsequently. Serum bicarbonate, parathyroid hormone, total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol, and triglyceride levels did not change. The initial prescribed dose of sevelamer hydrochloride was 121±50 mg/kg (4.5±5 g/day) and the final prescribed dose was 163±46 mg/kg (6.7±2.4 g/day). Sevelamer hydrochloride was well tolerated and without adverse effects related to the drug.     

Effects of Phosphate Binders in Moderate CKD

Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m(2) to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.     

药用活性炭有效降低顽固性高磷血症透析患者血磷水平与钙磷乘积

目的 研究口服药用活性炭对未能控制的高磷血症透析患者血磷与钙磷乘积的作用.方法 采用单中心、前瞻性、自身前后对照研究.经含钙的磷结合剂治疗后仍存在高磷血症的血液透析或腹膜透析患者,餐中加服药用活性炭4.5～7.2 g/d治疗3个月.检测治疗前后血磷、钙、钙磷乘积、全段甲状旁腺激素( iPTH)、白蛋白、血红蛋白水平.用配对t检验进行统计学分析.结果 与治疗前比较,治疗3个月后患者血磷水平显著下降[(1.85±0.30)mmol/L比(2.16±0.34) mmol/L,P＜0.01];血钙磷乘积也相应显著下降[(54.12±8.37) mg2/dl2比(63.93±8.83) mg2/dl2,P＜0.01];有更多并发继发性甲状旁腺功能亢进症的患者可以接受维生素D治疗(83.3％比50％);血钙与iPTH水平无显著性变化(P=0.734,0.665).活性碳治疗期间血白蛋白水平较前下降[(40.1±2.2)g/L比(41.7±2.9) g/L,P=0.001].结论 顽固性高磷血症透析患者在继续原有磷结合剂治疗基础上,口服药用活性炭可以有效地降低血磷水平与钙磷乘积,对血钙及iPTH水平没有显著性影响.活性炭治疗可使患者血白蛋白水平轻度下降.     

The effect of oral phosphate administration on major indices of skeletal metabolism in normal subjects

The effect of brief periods of phosphate administration on indices of human skeletal metabolism was investigated. Thirteen subjects (8 women, 5 men; 19-36 years old) received 2 g of oral phosphate daily for 5 days. Serum phosphorus rose 26% (3.8 +/- 0.1 mg/dl to 4.8 +/- 0.1 mg/dl; p less than .01) while total calcium fell (9.3 +/- 0.1 mg/dl to 8.9 +/- 0.1 mg/dl; p less than .01). Parathyroid hormone levels increased by 50% (14.1 +/- 2.0 pg/ml to 21.5 +/- 1.7 pg/ml; p less than .05) although values remained within the normal range. A persistent phosphaturia (0.64 +/- 0.10 g/g Cr to 1.8 +/- 0.4 g/g Cr; p less than .05) and a 69% fall in urinary calcium (80.8 +/- 10.0 mg/g Cr to 24.6 +/- 6.0 mg/g Cr; p less than .001) were observed. 1,25-dihydroxyvitamin D3 and urinary hydroxyproline concentrations did not change significantly but the bone gamma-carboxyglutamic acid protein (BGP) concentration rose 41% by day 2 (9.6 +/- 1.3 mg/ml to 13.5 +/- 2.2 mg/ml; p less than .005) and remained elevated throughout the study period. These results support the possibility that brief periods of phosphate administration may be useful in the therapy of disorders associated with low bone turnover, such as osteoporosis.     

Effect of MCI-196 (colestilan) as a phosphate binder on hyperphosphataemia in aemodialysis patients: a double-blind, placebo-controlled, short-term trial.

BACKGROUND: MCI-196 (colestilan), an anion exchange resin, is widely used as an anti-hypercholesterolaemic drug in Japan. To evaluate the efficacy and safety of MCI-196 as a phosphate binder, a double-blind, randomized, placebo-controlled prospective trial was conducted in Japanese end-stage renal disease patients with hyperphosphataemia on intermittent haemodialysis treatment. METHODS: Phosphate binders were discontinued during a 2-week washout period. Subsequently, patients whose serum phosphorus levels were > or =6.5 mg/dl, but <10 mg/dl were eligible to enter the treatment protocol. Patients were randomized to either MCI-196 6 g/day or placebo for 2 weeks. The efficacy and safety of MCI-196 were assessed in 33 and 46 patients, respectively. RESULTS: Serum phosphorus in the placebo group increased by 0.84+/-0.95 mg/dl (mean+/-SD), while serum phosphorus in the MCI-196 group decreased by 0.55+/-1.23 mg/dl. The difference between the two groups was statistically significant (P = 0.002). A reduction of > or =1 mg/dl in serum phosphorus was observed in 43% in the MCI-196 group and 0% of patients in the placebo group (P = 0.0122). Calcium-phosphorus (Ca x P) product, intact parathyroid hormone (iPTH) and low-density lipoprotein (LDL)-cholesterol in the MCI-196 group also decreased significantly compared with the placebo group, while serum calcium was unchanged. Adverse reactions were observed in 51.7% of the MCI-196 group and 29.4% of the placebo group (P = 0.2186). The most frequent adverse reactions in the MCI-196 group were gastrointestinal symptoms and signs, including constipation. CONCLUSIONS: The present findings suggest that the short-term administration of MCI-196 is effective in decreasing serum phosphorus in haemodialysis patients. Its long-term efficacy needs to be evaluated.     

Perioperative hypophosphatemia in general surgery

Blood phosphorus was measured in consecutive 136 admitted patients in the department of general surgery between Oct. 1987 and Jan. 1988. It was found that 32 cases (23.5%) were with hypophosphatemia on perioperative period. Sixteen patients with normal preoperative blood phosphorus level undergoing digestive tract surgery were randomly divided into 3 groups, each was fasted for 7 days postoperation and given different kind of transfusions. Group 1, patients were given 250 g of glucose daily with no phosphorus, blood phosphorus level was significantly decreased. Group 2, 250 g of glucose with 7.5 mmol of phosphate daily, blood phosphorus level decreased slightly on the 2nd-4th day and returned back to normal on day 7. Group 3,500 g of glucose with 15 mmol of phosphate daily, blood phosphorus level decreased moderately on the 2nd-4th day, and returned to normal level on day 7. Perioperative hypophosphatemia was attributed to: (1) Poor absorption or massive loss of phosphorus through digestive tract. (2) Intracellular transferring of blood phosphorus accompanied by the phosphorylation of saccharide. (3) Excessive excretion of phosphorus through urine. The authors suggested that 7-9 mmol of phosphates per 100 kcal daily for the prevention and 7-15 mmol of phosphates per 1000 kcal daily for the treatment of hypophosphatemia.     

Lanthanum carbonate (Fosrenol) efficacy and tolerability in the treatment of hyperphosphatemic patients with end-stage renal disease

AIMS: High serum phosphorus levels are a common problem in patients receiving long-term dialysis treatment. Lanthanum carbonate (Fosrenol) is a new non-aluminum, non-calcium phosphate binder developed for the treatment of hyperphosphatemia in patients with end-stage renal disease (ESRD). We report data from a recent trial, which, for the first time, assessed the efficacy and tolerability of lanthanum carbonate treatment, compared with placebo, in Chinese patients with ESRD. PATIENTS AND METHODS: Following a one- to three-week washout phase and a four-week, open-label lanthanum carbonate dose-titration phase, male and female hemodialysis patients were randomized (1:1) to receive either lanthanum carbonate or placebo for four weeks. The primary efficacy parameter of the study was the control of serum phosphorus levels (< or =1.8 mmol/l [< or = 5.6 mg/dl]). Secondary endpoints included the profile of serum phosphorus during titration and parathyroid hormone, calcium, and calcium x phosphorus (Ca x P) product levels. The safety and tolerability of lanthanum carbonate were assessed by monitoring adverse events throughout the study. RESULTS: Mean serum phosphorus level at the end of washout was 2.5 +/- 0.5 mmol/l (7.7 +/- 1.5 mg/dl; n=73), and there was no evidence of a difference in levels between the treatment groups pre-randomization. At the end of the study, lanthanum carbonate-treated patients had significantly lower phosphorus levels (1.6 +/- 0.5 mmol/l [5.1 +/- 1.5 mg/dl]; n=30) than those receiving placebo (2.3 +/- 0.4 mmol/l [7.2 +/- 1.3 mg/dl]; n=31; p < 0.001). In addition, a significantly higher proportion of patients receiving lanthanum carbonate had controlled serum phosphorus levels (60%) compared with the placebo group (10%; p < 0.001). Ca x P product levels were also significantly lower in the lanthanum carbonate group at the end of randomized treatment (p < 0.001). Lanthanum carbonate was well tolerated; only one serious adverse event was reported, which was unrelated to treatment. CONCLUSIONS: Lanthanum carbonate was shown to be an effective and well-tolerated phosphate binder for the treatment of hyperphosphatemia in Chinese patients with ESRD. This finding supports the results of previous US and European studies, which have also shown that lanthanum carbonate treatment effectively controls serum phosphorus levels.     

Prevention of hypophosphatemia during postoperative routine glucose administration

The main study comprised 16 patients undergoing colon surgery. On the day of operation and the 3 following days 100 g of glucose was infused at the rate of 0.3 g/kg/h. Half the patients had 10 mmol of phosphorus added to each 1 000 ml 10% glucose solution. The investigation demonstrated that two different kinds of hypophosphatemia occur in the immediate postoperative period. A significant decrease in fasting plasma phosphate was found at the first, second and the third postoperative morning, most pronounced at the second day (1.20 +/- 0.05 to 0.78 +/- 0.07 mmol/l). A significant correlation between these changes and the corresponding 24-hour phosphorus balance was demonstrated (r = 0.61, p < 0.001). The falls in fasting phosphate could not be prevented by phosphorus addition because an amount of phosphorus corresponding to the amount added was excreted in excess in the urine. The plasma phosphate was decreased furthermore during and even 4 hours after the 5-hour glucose infusion (from 0.76 +/- 0.05 to 0.49 +/- 0.07 nmol/l at the end of the infusion at the second day). This hypophosphatemia was prevented by the phosphorus addition.--In average 3% of the infused sugar was lost in the urine. The solitary examples of higher losses (10-20%) were not followed by a higher urinary production. It is therefore concluded that 0.3 g glucose/kg/h is a suitable infusion rate in the immediate postoperative period.     

Control of serum phosphate by oral lanthanum carbonate in patients undergoing haemodialysis and continuous ambulatory peritoneal dialysis in a short-term, placebo-controlled study.

BACKGROUND: Hyperphosphataemia in dialysis patients is associated with significant morbidity. We assessed the ability of lanthanum carbonate to control phosphate levels in patients undergoing haemodialysis or continuous ambulatory peritoneal dialysis (CAPD) in a short-term, placebo-controlled study. METHODS: This was a double-blind, placebo-controlled, parallel-group study consisting of three phases: a 2 week washout period; a 4 week, open-label, dose-titration phase; and a 4 week, double-blind, placebo-controlled phase. After washout, patients (n = 59) received lanthanum (375 mg/day), titrated up to a maintenance dose (maximum: 2250 mg) that achieved control of serum phosphate levels between 1.3 and 1.8 mmol/l (4.03-5.58 mg/dl). After titration, patients were randomized to receive their maintenance dose of lanthanum (n = 17) or placebo (n = 19) for 4 weeks. Control of serum phosphate was the primary efficacy assessment. Levels of calcium, parathyroid hormone, calcium x phosphate product and lanthanum as well as adverse events were evaluated. RESULTS: By the end of titration, 70% of patients had serum phosphate levels < or =1.8 mmol/l. Lanthanum carbonate continued to control serum phosphate levels in the double-blind phase. At the end of the study, 64.7% of lanthanum carbonate-treated patients were controlled compared with 21.4% in the placebo group. Results in patients receiving CAPD were similar to those seen in the group as a whole. Mean parathyroid hormone levels (P = 0.41) and calcium x phosphate product (P<0.001) were both higher in the placebo than the lanthanum carbonate group. CONCLUSIONS: Lanthanum carbonate is an effective phosphate binder able to control serum phosphate and calcium x phosphate product.     

Efficacy and side-effect profile of sevelamer hydrochloride used in combination with conventional phosphate binders

BACKGROUND: Poor phosphate control is common among patients with end-stage renal disease. Sevelamer hydrochloride has been demonstrated to be a safe and effective phosphate binder when used as a monotherapy. However, cost limits its usefulness in many countries. Data assessing its effectiveness and safety in combination with conventional phosphate binders are lacking. METHODS: Dialysis patients meeting the following inclusion criteria participated in this study: (i) hyperphosphataemia >1.8 mmol/L (5.6 mg/dL); and (ii) an inability to tolerate currently available binders. The trial was conducted in three phases each lasting 3 months: (i) an observation phase (patients continued on their regular phosphate binders); (ii) a titration phase (sevelamer was added at a dose of 403 mg three times daily with meals, titrated to a maximum of 1209 mg three times daily); and (iii) a maintenance phase. RESULTS: Twenty-five patients were recruited into the study. Eighteen patients completed all three trial phases. Mean serum phosphate dropped from 2.11 +/- 0.06 mmol/L (6.6 +/- 0.2 mg/dL) during the observation period to 1.91 +/- 0.01 mmol/L (5.9 +/- 0.003 mg/dL) during the maintenance phase (P=0.02). Calcium x phosphate product fell from 5.49 +/- 0.17 mmol2/L2 (68.64 +/- 2.11 mg2 dL2) to 4.89 +/- 0.27 mmol2/L2 (61.36 +/- 3.35 mg2 dL2) (P=0.02). There was no significant change in serum calcium or parathyroid hormone. Total serum cholesterol fell from 3.8 mmol/L (3.4-4.37) 147 mg/dL (131-169) to 3.55 mmol/L (2.97-4.2) 137 mg/dL (115-162) (P=0.02). Serum low-density lipoprotein cholesterol also fell significantly from 1.67 +/- 0.10 mmol/L (65 +/- 4 mg/dL) to 1.52 +/- 0.11 mmol/L (59 +/- 4 mg/dL) (P=0.04). The average prescribed dose of sevelamer was 2.4 g/day. Elemental calcium dropped from 3.4 g/day (1.4 to 4.6) to 1.2 g/day (0.6-2.4) (P=0.04). Seventy-two per cent of patients reported mild flatulence, nausea and indigestion. Three patients discontinued treatment because of adverse effects. CONCLUSIONS: Sevelamer in combination with conventional phosphate binders is effective in lowering serum phosphate and calcium-phosphate product in patients with refractory hyperphosphataemia. Beneficial effects on lipid profile were also observed. Mild gastrointestinal upset is common.     

Renal phosphate leak in patients with idiopathic hypercalciuria and calcium nephrolithiasis

Although urine phosphate loss has been associated with hypercalciuria, it is debated how frequently renal phosphate leak is present in hypercalciuric patients. We reviewed the records of 100 consecutive adult patients who were diagnosed with idiopathic hypercalciuria and calcium urolithiasis, searching for the presence of renal phosphate leak. The renal phosphate threshold, normalized for the glomerular filtration rate (TmPO4/GFR), of the hypercalciuric patients followed a normal distribution and had a good correlation with serum phosphate (r=0.77; p<0.0001). There were no correlations between TmPO4/GFR and urinary calcium or between serum phosphorus and urinary calcium. We found only nine patients (9%) with renal phosphate leak. These patients had a mean TmPO4/GFR of 2.19 mg% (0.70 mmol/l) and serum phosphorus of 2.65 mg% (0.85 mmol/l). Nevertheless, urinary calcium was not significantly different between patients with or without low TmPO4/GFR. We conclude that renal phosphate leak is an infrequent finding in patients with idiopathic hypercalciuria and is not associated with a higher urinary calcium loss.     

Magnesium carbonate for phosphate control in patients on hemodialysis. A randomized controlled trial

Background Magnesium salts bind dietary phosphorus, but their use in renal patients is limited due to their potential for causing side effects. The aim of this study was to evaluate the efficacy and safety of magnesium carbonate (MgCO₃) as a phosphate-binder in hemodialysis patients. Methods Forty-six stable hemodialysis patients were randomly allocated to receive either MgCO₃ (n = 25) or calcium carbonate (CaCO₃), (n = 21) for 6 months. The concentration of Mg in the dialysate bath was 0.30 mmol/l in the MgCO₃ group and 0.48 mmol/l in the CaCO₃ group. Results Only two of 25 patients (8%) discontinued ingestion of MgCO₃ due to complications: one (4%) because of persistent diarrhea, and the other (4%) because of recurrent hypermagnesemia. In the MgCO₃ and CaCO₃ groups, respectively, time-averaged (months 1–6) serum concentrations were: phosphate (P), 5.47 vs. 5.29 mg/dl, P = ns; Ca, 9.13 vs. 9.60 mg/dl, P < 0.001; Ca × P product, 50.35 vs. 50.70 (mg/dl)², P = ns; Mg, 2.57 vs. 2.41 mg/dl, P = ns; intact parathyroid hormone (iPTH), 285 vs. 235 pg/ml, P < 0.01. At month 6, iPTH levels did not differ between groups: 251 vs. 212 pg/ml, P = ns. At month 6 the percentages of patients with serum levels of phosphate, Ca × P product and iPTH that fell within the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines were similar in both groups, whereas more patients in the MgCO₃ group (17/23; 73.91%) than in the CaCO₃ group (5/20, 25%) had serum Ca levels that fell within these guidelines, with the difference being significant at P < 0.01. Conclusion Our study shows that MgCO₃ administered for a period of 6 months is an effective and inexpensive agent to control serum phosphate levels in hemodialysis patients. The administration of MgCO₃ in combination with a low dialysate Mg concentration avoids the risk of severe hypermagnesemia.     

A phase 1 study of the safety,tolerability, pharmacodynamics,and pharmacokinetics of tenapanor in healthy Japanese volunteers

Background

Tenapanor (RDX5791, AZD1722), a small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3). Tenapanor acts locally in the gut to reduce absorption of sodium and phosphate. It is being developed for the treatment of patients with hyperphosphatemia in CKD requiring dialysis and patients with constipation-predominant irritable bowel syndrome. We report the safety, pharmacodynamics, and pharmacokinetics of tenapanor in Japanese volunteers.

Methods

In this phase 1, double-blind study (NCT02176252), healthy Japanese adults (aged 20–45 years) received single-dose tenapanor 180 mg (n = 6), repeated-dose tenapanor 15, 30, 60, or 90 mg twice daily (n = 12 each) for 7 days, or placebo (n = 14). All participants received a standardized diet.

Results

Single and repeated doses of tenapanor resulted in higher mean stool sodium content vs. placebo (single dose, 41.9 mmol/day; repeated dose, range of means 21.3–32.2 mmol/day; placebo, 4.1 mmol/day) accompanied by lower urinary sodium content (single dose, 110 mmol/day; repeated dose, 101–112 mmol/day; placebo, 143 mmol/day). Additionally, stool phosphorus content was increased (single dose, 31.0 mmol/day; repeated dose, 17.6–24.8 mmol/day; placebo, 16.8 mmol/day) and urinary phosphorus content decreased (single dose, 18.7 mmol/day; repeated dose, 15.3–19.4 mmol/day; placebo, 25.5 mmol/day). Tenapanor had minimal systemic exposure, provided a softer stool consistency, and was well tolerated.

Conclusions

Tenapanor treatment reduced absorption of intestinal sodium and phosphate from the gut in Japanese adults. Tenapanor had minimal systemic exposure and was well tolerated. Further research into the clinical benefits of tenapanor is warranted.

     

Phosphorus control in peritoneal dialysis patients

Hyperphosphatemia is independently associated with an increased risk of death among dialysis patients. In this study, we have assessed the status of phosphate control and its clinical and laboratory associations in a large international group of patients on chronic peritoneal dialysis (PD) treatment. This cross-sectional multicenter study was carried out in 24 centers in three different countries (Canada, Greece, and Turkey) among 530 PD patients (235 women, 295 men) with a mean+/-s.d. age of 55+/-16 years and mean duration of PD of 33+/-25 months. Serum calcium (Ca(2+)), ionized Ca(2+), phosphate, intact parathyroid hormone (iPTH), 25-hydroxy vitamin D(3), 1,25-dihydroxy vitamin D(3), total alkaline phosphatase, and bone alkaline phosphatase concentrations were investigated, along with adequacy parameters such as Kt/V, weekly creatinine clearance, and daily urine output. Mean Kt/V was 2.3+/-0.65, weekly creatinine clearance 78.5+/-76.6 l, and daily urine output 550+/-603 ml day(-1). Fifty-five percent of patients had a urine volume of <400 ml day(-1). Mean serum phosphorus level was 4.9+/-1.3 mg per 100 ml, serum Ca(2+) 9.4+/-1.07 mg per 100 ml, iPTH 267+/-356 pg ml(-1), ionized Ca(2+) 1.08+/-0.32 mg per 100 ml, calcium phosphorus (Ca x P) product 39+/-19 mg(2)dl(-2), 25(OH)D(3) 8.3+/-9.3 ng ml(-1), 1,25(OH)(2)D(3) 9.7+/-6.7 pg ml(-1), total alkaline phosphatase 170+/-178 U l(-1), and bone alkaline phosphatase 71+/-108 U l(-1). While 14% of patients were hypophosphatemic, with a serum phosphorus level lower than 3.5 mg per 100 ml, most patients (307 patients, 58%) had a serum phosphate level between 3.5 and 5.5 mg per 100 ml. Serum phosphorus level was 5.5 mg per 100 ml or greater in 28% (149) of patients. Serum Ca(2+) level was > or =9.5 mg per 100 ml in 250 patients (49%), between 8.5 and 9.5 mg per 100 ml in 214 patients (40%), and lower than 8.5 mg per 100 ml in 66 patients (12%). Ca x P product was >55 mg(2)dl(-2) in 136 patients (26%) and lower than 55 mg(2)dl(-2) in 394 patients (74%). Serum phosphorus levels were positively correlated with serum albumin (P<0.027) and iPTH (P=0.001), and negatively correlated with age (P<0.033). Serum phosphorus was also statistically different (P = 0.013) in the older age group (>65 years) compared to younger patients; mean levels were 5.1+/-1.4 and 4.5+/-1.1 mg per 100 ml, respectively, in the two groups. In our study, among 530 PD patients, accepted uremic-normal limits of serum phosphorus control was achieved in 58%, Ca x P in 73%, serum Ca(2+) in 53%, and iPTH levels in 24% of subjects. Our results show that chronic PD, when combined with dietary measures and use of phosphate binders, is associated with satisfactory serum phosphorus control in the majority of patients.