Combination treatment with tenapanor and sevelamer synergistically reduces urinary phosphorus excretion in rats.

The majority of patients with chronic kidney disease (CKD) receiving dialysis do not achieve target serum phosphorus concentrations, despite treatment with phosphate binders. Tenapanor is a nonbinder, sodium/hydrogen exchanger isoform 3 (NHE3) inhibitor that reduces paracellular intestinal phosphate absorption. This preclinical study evaluated the effect of tenapanor and varying doses of sevelamer carbonate on urinary phosphorus excretion, a direct reflection of intestinal phosphate absorption. We measured 24-h urinary phosphorus excretion in male rats assigned to groups dosed orally with vehicle or tenapanor (0.3 mg/kg/day) and provided a diet containing varying amounts of sevelamer [0-3% (wt/wt)]. We also evaluated the effect of the addition of tenapanor or vehicle on 24-h urinary phosphorus excretion to rats on a stable dose of sevelamer [1.5% (wt/wt)]. When administered together, tenapanor and sevelamer decreased urinary phosphorus excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels. The Bliss statistical model of independence indicated that the combination was synergistic. A stable sevelamer dose [1.5% (wt/wt)] reduced mean ± SE urinary phosphorus excretion by 42 ± 3% compared with vehicle; together, tenapanor and sevelamer reduced residual urinary phosphorus excretion by an additional 37 ± 6% (P < 0.05). Although both tenapanor and sevelamer reduce intestinal phosphate absorption individually, administration of tenapanor and sevelamer together results in more pronounced reductions in intestinal phosphate absorption than if either agent is administered alone. Further evaluation of combination tenapanor plus phosphate binder treatment in patients receiving dialysis with hyperphosphatemia is warranted.

The Role of Extracellular Phosphate Levels on Kidney Disease Progression in a Podocyte Injury Mouse Model.

BACKGROUND: Hyperphosphatemia is a major accelerator of complications in chronic kidney disease and dialysis, and phosphate (Pi) binders have been shown to regulate extracellular Pi levels. Research on hyperphosphatemia in mouse models is scarce, and few models display hyperphosphatemia induced by glomerular injury, despite its relevance to human glomerular disease conditions. In this study, we investigated the involvement of hyperphosphatemia in kidney disease progression using a mouse model in which hyperphosphatemia is induced by focal segmental glomerulosclerosis (FSGS). METHODS: We established the NEP25 mouse model in which FSGS-hyperphosphatemia is induced by podocyte injury and evaluated the effect of a Pi binder, sevelamer. RESULTS: After disease induction, we confirmed a gradual increase in serum Pi accompanied by reduced renal function and observed increases in serum FGF23 and PTH. Treatment with sevelamer significantly reduced serum Pi and urinary Pi fractional excretion and suppressed increases in serum FGF23 and PTH. A high dose improved serum creatinine and tubular injury markers, and pathological analysis confirmed amelioration of glomerular and tubular damage. Gene expression and marker analysis suggested protective effects on tubular epithelial cells in the diseased kidney. Compared to disease control, NEP25 mice treated with sevelamer retained their mRNA expression of Klotho, a known FGF23 co-receptor and renoprotective factor. CONCLUSIONS: Hyperphosphatemia caused by renal function decline was observed in a FSGS-induced NEP25 mouse model. Studies using this model showed that Pi regulation had a positive impact on kidney disease progression, and notably on tubular epithelial cell injury, which indicates the importance of Pi regulation in the treatment of kidney disease progression.

Sevelamer hydrochloride suppresses proliferation of parathyroid cells during the early phase of chronic renal failure in rats.

AIM: We examined the effects of sevelamer on parathyroid cell proliferation and secondary hyperparathyroidism in rats following induction of early-phase of chronic renal failure (CRF) by unilateral ureteral obstruction (UUO). METHODS: For 5 days, rats in the control group received normal food, rats in the sevelamer group (SH) received control food plus 5% sevelamer, and rats in the low protein group (LP) received low protein food. Five rats of each group were killed at baseline (day 0). All other rats were given UUO, and five rats per group were killed on days 3, 7, 14, and 28 after UUO. Changes in body weight, serum phosphorus, calcium, intact-parathyroid hormone (i-PTH), creatinine (SCr), creatinine clearance rate (CCR), blood urea nitrogen (BUN), and 24-h urinary phosphorus were determined. Parathyroid tissues were removed for histological examination of proliferating cell nuclear antigen-positive (PCNA+) cells. RESULTS: Measurement of body weight, BUN, and SCr in the controls indicated successful establishment of this model of early-phase CRF. The controls also had remarkable proliferation of PCNA+ cells beginning on day 3, but this did not occur in the SH or LP groups. After 28 days, serum phosphorus had decreased more in the SH and LP groups than in the control group, and phosphorus excretion was much greater in the control group than in the SH and LP groups. The three groups had similar increases in serum i-PTH. CONCLUSION: Sevelamer rapidly lowered the serum phosphorus and inhibited the proliferation of PCNA+ cells in this experimental model of early-phase CRF.

Influence of Carnicor, Venofer, and Sevelamer on the levels of genotoxic damage in end-stage renal disease patients.

End-stage renal disease (ESRD) patients present high levels of phosphorus and calcium products in serum, which contribute to the development of vascular calcification and cardiovascular disease, and to low iron stores and carnitine deficiency. For these reasons, ESRD patients are generally supplemented with different medicines. Some of the most common treatments include the use of Carnicor, Venofer, and Sevelamer drugs. Carnicor is used as a source of L-carnitine, acting as antioxidant and neuroprotector. Venofer is used to reduce the deficit of iron. Sevelamer is used to treat hyperphosphatemia. To determine the potential harmful genotoxic effects of these drugs, a group of 214 patients included in a hemodialysis program with different intakes of Carnicor, Venofer, and Sevelamer were evaluated. The levels of basal and oxidative DNA damage, as well as chromosomal damage, were measured in all individuals using the comet and the micronucleus assays, respectively. Our results indicate that Carnicor administration was associated with low but significant increases in the frequency of basal DNA damage and micronuclei. Environ. Mol. Mutagen. 59:302-311, 2018. © 2018 Wiley Periodicals, Inc.

Randomized Clinical Trial of Sevelamer Carbonate on Serum Klotho and Fibroblast Growth Factor 23 in CKD.

BACKGROUND AND OBJECTIVES: Epidemiologic studies suggest that higher serum phosphaturic hormone fibroblast growth factor 23 levels are associated with increase morbidity and mortality. The aim of the FGF23 Reduction Efficacy of a New Phosphate Binder in CKD Trial was to evaluate the effect of sevelamer carbonate on serum C-terminal fibroblast growth factor 23 levels in normophosphatemic patients with CKD stage 3b/4. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with CKD, eGFR between 45 and 15 ml/min per 1.73 m2, fasting serum phosphate concentration >3.1 mg/dl, and serum C-terminal fibroblast growth factor 23 >80 relative units/ml were included in our double-blind, placebo-controlled, randomized multicenter study. All patients received 100,000 IU cholecalciferol at time of randomization. Participants received either placebo or sevelamer carbonate 4.8 g daily during a 12-week period. Biologic parameters, including serum C-terminal fibroblast growth factor 23, intact fibroblast growth factor 23, and α-klotho, were evaluated at baseline and 12 weeks after inclusion. RESULTS: Of 96 screened patients, 78 (mean±SD age: 63±13 years old; 70% men; mean eGFR: 27±9 ml/min per 1.73 m2) met the inclusion criteria. At baseline, mean eGFR was 27±9 ml/min per 1.73 m2, mean serum phosphate level was 3.8±0.5 mg/dl, and median (interquartile range) serum C-terminal fibroblast growth factor 23 level was 157 (120-241) relative units/ml. After 12 weeks of treatment, urinary phosphate-to-creatinine ratio fell significantly in the sevelamer group. The sevelamer and placebo groups did not differ significantly in terms of median change in serum C-terminal fibroblast growth factor 23 levels: the median (interquartile range) change was 38 (-13-114) relative units/ml in the placebo group and 37 (-1-101) relative units/ml in the sevelamer group (P=0.77). There was no significant difference in serum intact fibroblast growth factor 23, α-klotho, or phosphate levels changes between the two groups. Serum total and LDL cholesterol levels fell significantly in the sevelamer group. CONCLUSIONS: In our double-blind, placebo-controlled, randomized study performed in normophosphatemic patients with CKD, a 12-week course of sevelamer carbonate significantly reduced phosphaturia without changing serum phosphorus but did not significantly modify serum C-terminal fibroblast growth factor 23 and intact fibroblast growth factor 23 or α-klotho levels.

PA21, a novel phosphate binder, improves renal osteodystrophy in rats with chronic renal failure.

The effects of PA21, a novel iron-based and non-calcium-based phosphate binder, on hyperphosphatemia and its accompanying bone abnormality in chronic kidney disease-mineral and bone disorder (CKD-MBD) were evaluated. Rats with adenine-induced chronic renal failure (CRF) were prepared by feeding them an adenine-containing diet for four weeks. They were also freely fed a diet that contained PA21 (0.5, 1.5, and 5%), sevelamer hydrochloride (0.6 and 2%) or lanthanum carbonate hydrate (0.6 and 2%) for four weeks. Blood biochemical parameters were measured and bone histomorphometry was performed for femurs, which were isolated after drug treatment. Serum phosphorus and parathyroid hormone (PTH) levels were higher in the CRF rats. Administration of phosphate binders for four weeks decreased serum phosphorus and PTH levels in a dose-dependent manner and there were significant decreases in the AUC0-28 day of these parameters in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups compared with that in the CRF control group. Moreover, osteoid volume improved significantly in 5% of the PA21 group, and fibrosis volume and cortical porosity were ameliorated in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups. These results suggest that PA21 is effective against hyperphosphatemia, secondary hyperparathyroidism, and bone abnormalities in CKD-MBD as sevelamer hydrochloride and lanthanum carbonate hydrate are, and that PA21 is a new potential alternative to phosphate binders.

Preclinical and Healthy Volunteer Studies of Potential Drug-Drug Interactions Between Tenapanor and Phosphate Binders.

Tenapanor (RDX5791, AZD1722), a first-in-class small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3. Tenapanor acts locally in the gut, where it reduces absorption of sodium and phosphate. It is being studied in patients with chronic kidney disease requiring dialysis, who are often administered phosphate binders such as sevelamer to help control hyperphosphatemia. We investigated whether coadministration of tenapanor with phosphate binders (sevelamer or calcium-based binders) impacts the pharmacodynamic effects of tenapanor. In vitro studies suggested a binding interaction between tenapanor and sevelamer, but this did not translate into altered pharmacodynamic effects in rats. An open-label, 2-way crossover study was then conducted in healthy volunteers (NCT02346890). This showed that 4 days' treatment with tenapanor hydrochloride (15 mg twice daily) with or without sevelamer carbonate (800 mg 3 times daily) resulted in comparable 24-hour stool and urinary sodium and phosphorus levels. Stool frequency, consistency, and weight were also comparable between the treatments. These results suggest that the binding between sevelamer and tenapanor observed in vitro does not translate into altered pharmacodynamic effects in humans.

Use of sevelamer in chronic kidney disease: beyond phosphorus control.

Sevelamer is a non-calcium phosphate binder used in advanced chronic kidney disease (CKD) and in dialysis for hyperphosphataemia control. Several experimental, observational studies and clinical trials have shown that sevelamer has pleiotropic effects, beyond hyperphosphataemia control, including actions on inflammation, oxidative stress, lipid profile and atherogenesis, vascular calcification, endothelial dysfunction and the reduction of several uremic toxins. This is the biological basis for its global effect on cardiovascular morbidity and mortality in patients with chronic kidney disease. This review focuses on these pleiotropic actions of sevelamer and their impact on cardiovascular health, with the experience published after more than ten years of clinical expertise.

Renal formulas pretreated with medications alters the nutrient profile.

BACKGROUND: Pretreating renal formulas with medications to lower the potassium and phosphorus content is common in clinical practice; however, the effect of this treatment on other nutrients is relatively unstudied. We examine whether nutrient composition is affected by pretreating renal formulas with sodium polystyrene sulfonate (SPS) suspension and sevelamer carbonate. METHODS: Fixed medication doses and treatment times were utilized to determine changes in the nutrient composition of Suplena® and Similac® PM 60/40. The effect of simultaneously adding both medications (co-administration) to the formula on the nutrient composition of Suplena® was also evaluated. RESULTS: Pretreatment of Suplena® with SPS reduced the concentrations of calcium (11-38 %), copper (3-11 %), manganese (3-16 %), phosphorus (0-7 %), potassium (6-34 %), and zinc (5-20 %) and increased those of iron (9-34 %), sodium (89-260 %), and sulfur (19-45 %) and the pH (0.20-0.50 units). Pretreatment of Similac® PM 60/40 with SPS reduced the concentrations of calcium (8-29 %), copper (5-19 %), magnesium (3-26 %), and potassium (33-63 %) and increased those of iron (13-87 %) and sodium (86-247 %) and the pH (0.40-0.81 units). Pretreatment of both formulas with the SPS suspension led to significant increases in the aluminum concentration in both formulas (507-3957 %). No differences in potassium concentration were observed between treatment times. Unexpectedly, the levels of neither phosphorus nor potassium were effectively reduced in Suplena® pretreated with sevelamer carbonate alone or when co-administered with SPS. CONCLUSIONS: Pretreating formula with medications alters nutrients other than the intended target(s). Future studies should be aimed at predicting the loss of these nutrients or identifying alternative methods for managing serum potassium and phosphorus levels in formula-fed infants. The safety of pretreating formula with SPS suspension should also be examined.

Sevalamer Hydrochloride, Sevelamer Carbonate and Lanthanum Carbonate: In Vitro and In Vivo Effects on Gastric Environment.

Hyperphosphatemia is common in patients with chronic renal failure. Phosphate binders are associated with gastric intolerance, representing the main reason of drug discontinuation. The aim of this study was to compare the effects in vitro and in vivo of sevelamer hydrochloride (SH), sevelamer carbonate (SC) and lanthanum carbonate (LC) on gastric microenvironment. We have also evaluated the efficacy and tolerability of these drugs in hemodialysis (HD) patients. In vitro analysis: Dissolution time, ability to uptake phosphorus, changes in pH starting from gastric milieu and the amount of carbon dioxide (CO(2)) produced were the variables analyzed. In vivo analysis: 24-h esophago-gastric pH measurement was evaluated in 24 HD patients treated with phosphate binders and proton pump inhibitor (PPI). In vitro: LC dissolved over a longer time compared with SC (58 ± 2.4 vs. 12 ± 0.6 min; P < 0.001) and SH (58 ± 2.4 vs. 10.3 ± 0.8 min; P < 0.001), determining the most alkaline pH. SC had the highest chelation power, binding 4.00 × 10(-9) mol/L of phosphoric acid. CO2 volume released was increased in LC solution (53.2 ± 7.8) compared to SC (33.9 ± 6.2; P < 0.001) and SH (2.3 ± 1.8; P < 0.001). In vivo: gastric pH increased after administration of phosphate binder. The most alkaline pH was recorded in patients treated with SC. The alkalinization of the gastric environment was not prevented by PPI therapy. 424 episodes of esophageal reflux were registered, 74% of them were alkaline. The LC group was characterized by the highest number of episodes. Sevelamer carbonate had a greater capacity and rapidity to chelate phosphorus, with a mild tolerability, due to its low CO(2) production. Sevelamer HCl was the most tolerated chelator because it did not produce CO(2), while lanthanum carbonate was the least soluble.

[Pleiotropic effects of sevelamer: a model of intestinal tract chelating agent]. / Effets pléïotropes du sévélamer, précurseur d'agent chélateur de la voie intestinale.

The number of patients with chronic kidney disease (CKD) with its associated complications has increased dramatically worldwide in recent years. Therefore, many experimental and clinical studies have examined over the last decade the mechanisms involved, in order to explain the sharp increase in cardiovascular mortality. Hyperphosphatemia is a major problem in these patients especially at advanced stages of CKD, and it is associated with cardiovascular and mineral complications in these patients. Sevelamer is a phosphate binder that allows a better control of hyperphosphatemia, like other phosphate binder agents, but it has additional pleiotropic effects such as correcting certain abnormalities of lipid metabolism and clearance of several uremic toxins. These effects of sevelamer, restricted to the intestinal lumen, underline the importance of intestinal pathway in CKD and open the way to new therapeutic strategies for the management of the CKD and its complications.