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Steven K Burke - One of the best experts on this subject based on the ideXlab platform.
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sevelamer hydrochloride a Phosphate Binder protects against deterioration of renal function in rats with progressive chronic renal insufficiency
Nephrology Dialysis Transplantation, 2003Co-Authors: Nobuo Nagano, Steven K Burke, Sonoe Miyata, Nami Kobayashi, Sachiko Obana, Naoshi Fukushima, Michihito WadaAbstract:BACKGROUND: Dietary Phosphate restriction prevents renal function deterioration in animal models. This study examined whether sevelamer hydrochloride (Renagel(R); 'sevelamer' hereafter), a non-calcaemic Phosphate Binder could slow deterioration of renal function in rats with progressive renal insufficiency. METHODS: Wistar Kyoto male rats were singly injected with normal rabbit serum or rabbit anti-rat glomerular basement membrane serum. Three days later, rats were fed a powder diet containing 0, 1 or 3% sevelamer for 58 days. Time course changes of serum levels of blood urea nitrogen (BUN), creatinine, calcium, phosphorus and parathyroid hormone (PTH) were measured throughout, and creatinine clearance (CCr), kidney calcium content and renal histology examined at the end of the study. RESULTS: Sevelamer partially inhibited elevation of BUN and serum creatinine, and completely inhibited increases in serum phosphorus, PTH and calcium xphosphorus product. Sevelamer significantly prevented the decrease in CCr and kidney calcium content elevation. Kidney calcium content and BUN and serum creatinine were strongly positively correlated, and kidney calcium content and CCr strongly negatively correlated. Kidney calcium content correlated well with serum phosphorus, serum calcium x phosphorus product and PTH, but not serum calcium. Sevelamer treatment partly prevented histological deterioration of both glomerular and tubulointerstitial lesions of the kidney. CONCLUSIONS: The results suggest that sevelamer protects against renal function deterioration by maintaining kidney calcium at a low level as a result of reducing serum phosphorus and PTH.
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sevelamer hydrochloride renagel a non calcaemic Phosphate Binder arrests parathyroid gland hyperplasia in rats with progressive chronic renal insufficiency
Nephrology Dialysis Transplantation, 2001Co-Authors: Nobuo Nagano, Steven K Burke, Sonoe Miyata, Nami Kobayashi, Sachiko Obana, Naoshi Fukushima, Masako Ozai, Michihito WadaAbstract:BACKGROUND: It has been demonstrated that dietary Phosphate restriction suppresses parathyroid hormone (PTH) secretion and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI) independently of serum calcium and 1,25(OH)(2)D3 levels. This study was conducted to examine whether sevelamer hydrochloride (Renagel); hereafter referred to as sevelamer), a non-calcaemic Phosphate Binder could inhibit the parathyroid gland (PTG) hyperplasia in rats with progressive CRI. METHODS: Male Sprague-Dawley rats were injected twice with low doses of adriamycin (ADR). Two weeks after the last injection of ADR, rats were fed a diet containing 1 or 3% sevelamer for 84 days. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of study, serum 1,25(OH)(2)D3 levels were measured and the maximal two-dimension area of the PTG in paraffin section was calculated using an imaging analyser. RESULTS: Dietary sevelamer treatment inhibited the elevations of serum phosphorus, calciumxphosphorus product, and PTH levels that occurred as the study progressed. Sevelamer also suppressed maximal PTG area and there existed positive strong correlation between maximal PTG area and serum PTH levels at the end of the study. Serum phosphorus levels positively correlated well with serum PTH levels and maximal PTG area. In contrast, serum calcium or 1,25(OH)(2)D3 levels did not show any correlation with serum PTH levels and maximal PTG area. CONCLUSIONS: Sevelamer treatment arrested hyperphosphataemia and PTG hyperplasia accompanied by the elevation of serum PTH levels. The correlation analysis suggests that reduced serum phosphorus levels contributed to the suppression of PTG hyperplasia and resulted in the reduction of PTH levels in this animal model after the sevelamer treatment. The management of phosphorus control started from early stage of CRI could prevent PTG hyperplasia and facilitate later management of secondary hyperparathyroidism.
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a comparison of the calcium free Phosphate Binder sevelamer hydrochloride with calcium acetate in the treatment of hyperPhosphatemia in hemodialysis patients
American Journal of Kidney Diseases, 1999Co-Authors: Anthony J. Bleyer, Steven K Burke, Maureen A Dillon, Bruce Garrett, Shashi K Kant, David Lynch, Noor S Rahman, Patricia Y Schoenfeld, Isaac Teitelbaum, Steven ZeigAbstract:Abstract Current Phosphate Binders used in hemodialysis patients include calcium-based Binders that result in frequent hypercalcemia and aluminum-based Binders that result in total body aluminum accumulation over time. This investigation describes the use of a calcium- and aluminum-free Phosphate-binding polymer in hemodialysis patients and compares it with a standard calcium-based Phosphate Binder. An open-label, randomized, crossover study was performed to evaluate the safety and effectiveness of sevelamer hydrochloride in controlling hyperPhosphatemia in hemodialysis patients. After a 2-week Phosphate Binder washout period, stable hemodialysis patients were administered either sevelamer or calcium acetate, and the dosages were titrated upward to achieve improved Phosphate control over an 8-week period. After a 2-week washout period, patients crossed over to the alternate agent for 8 weeks. Eighty-four patients from eight centers participated in the study. There was a similar decrease in serum Phosphate values over the course of the study with both sevelamer (−2.0 ± 2.3 mg/dL) and calcium acetate (−2.1 ± 1.9 mg/dL). Twenty-two percent of patients developed a serum calcium greater than 11.0 mg/dL while receiving calcium acetate, versus 5% of patients receiving sevelamer ( P
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renagel a nonabsorbed calcium and aluminum free Phosphate Binder lowers serum phosphorus and parathyroid hormone
Kidney International, 1999Co-Authors: Eduardo Slatopolsky, Steven K Burke, Maureen A DillonAbstract:Background This multicenter, open-label, dose-titration study assessed the safety and efficacy of RenaGel(R), a nonabsorbed calcium- and aluminum-free Phosphate Binder, in lowering serum phosphorus. Secondary outcomes were its effects on serum intact parathyroid hormone (iPTH) and serum lipids. Methods Phosphate Binders were discontinued during a two-week washout period. Patients whose serum phosphorus was more than 6.0 mg/dl during washout were eligible for treatment. RenaGel(R), at starting doses of two, three, or four 440 mg capsules three times per day with meals, was administered to 172 hemodialysis patients for eight weeks. RenaGel(R) could be increased by one capsule per meal every two weeks as necessary to achieve serum phosphorus control. A second two-week washout period followed. Results Mean serum phosphorus rose from 6.8 +/- 2.0 mg/dl at prewashout to 9.1 +/- 2.4 mg/dl at the end of the washout period. It then declined to 6.6 +/- 1.9 mg/dl by the end of the eight-week RenaGel(R) treatment period (P Conclusions RenaGel(R), a novel and calcium- plus aluminum-free effective Phosphate Binder, can control serum phosphorus and reduce the levels of PTH and cholesterol without inducing hypercalcemia or other side effects. Thus, this new Phosphate Binder may be effective in the treatment of renal osteodystrophy in uremic patients.
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effect of renagel a non absorbed calcium and aluminium free Phosphate Binder on serum phosphorus calcium and intact parathyroid hormone in end stage renal disease patients
Nephrology Dialysis Transplantation, 1998Co-Authors: Dennis I Goldberg, Eduardo Slatopolsky, Maureen A Dillon, Duane Wombolt, Bruce Garrett, John R Gray, Thomas C Marbury, Marc Weinberg, Steven K BurkeAbstract: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 pre-washout 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.
Dennis I Goldberg - One of the best experts on this subject based on the ideXlab platform.
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effect of renagel a non absorbed calcium and aluminium free Phosphate Binder on serum phosphorus calcium and intact parathyroid hormone in end stage renal disease patients
Nephrology Dialysis Transplantation, 1998Co-Authors: Dennis I Goldberg, Eduardo Slatopolsky, Maureen A Dillon, Duane Wombolt, Bruce Garrett, John R Gray, Thomas C Marbury, Marc Weinberg, Steven K BurkeAbstract: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 pre-washout 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.
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renagel a novel calcium and aluminium free Phosphate Binder inhibits Phosphate absorption in normal volunteers
Nephrology Dialysis Transplantation, 1997Co-Authors: Steven K Burke, Eduardo Slatopolsky, Dennis I GoldbergAbstract:Background. Available Phosphate Binders contain aluminium or calcium which can be associated with undesirable effects. RenaGel®, cross-linked poly(allylamine hydrochloride), is a non-absorbed Phosphate-binding polymer, free of calcium and aluminium. We conducted this study to examine the safety and Phosphate binding efficacy of RenaGel in volunteers. Methods. During 18 days (days 0-17) at the clinical study unit, 24 subjects consumed a Phosphate-controlled diet designed to provide 37.5 mmol (1200 mg) elemental phosphorus per day. From the morning of day 5 to the morning of day 9, urine and faeces were collected. Average baseline urine and faecal phosphorus contents were determined. On days 9-16, the subjects received either RenaGel I g, 2.5 g, or 5 g or placebo three times per day immediately prior to the meals. From the morning of day 13 to the morning of day 17, urine and faeces were again collected and phosphorus contents on treatment were determined. Results. RenaGel inhibited dietary Phosphate absorption as measured by a decline in average daily urinary phosphorus excretion and an increase in average daily fecal phosphorus excretion. Average urine phosphorus contents on treatment were 27.2 mmol (870mg) per day in the placebo group vs 23.8 mmol (762mg), 19.5 mmol (625 mg), and 16.6 mmol (530 mg) per day in the RenaGel 1-g, 2.5-g, and 5-g groups. Average daily faecal phosphorus content on treatment was markedly higher in the RenaGel 5-g group, 19.1 mmol (611 mg) per day vs 10.7 mmol (342 mg) per day for the placebo group. RenaGel also decreased total serum cholesterol by 0.71 mmol/L (27.5 mg/dl), 0.55 mmol/l (21.3mg/dl), and 1.08 mmol/1 (41.8 mg/dl) for the RenaGel 1-g, 2.5-g, and 5-g groups. RenaGel was well tolerated with adverse events similar to placebo. Conclusions. RenaGel is a safe, effective, and well tolerated Phosphate Binder in normal volunteers. The degree of Phosphate binding is consistent with its potential use as a Phosphate Binder in renal failure patients.
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effect of renagel a non absorbable cross linked polymeric Phosphate Binder on urinary phosphorus excretion in rats
Nephrology Dialysis Transplantation, 1997Co-Authors: D P Rosenbaum, S R Holmesfarley, W Mandeville, M Pitruzzello, Dennis I GoldbergAbstract: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 analysed 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 decreased urinary phosphorus excretion in a dose dependent manner. RenaGel particles with a 23 microns 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.
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poly allylamine hydrochloride renagel a noncalcemic Phosphate Binder for the treatment of hyperPhosphatemia in chronic renal failure
American Journal of Kidney Diseases, 1997Co-Authors: Glenn M Chertow, Dennis I Goldberg, Steven K Burke, Michael J Lazarus, Kurt H Stenzel, Duane Wombolt, Joseph V Bonventre, Eduardo SlatopolskyAbstract:Abstract Dietary Phosphate restriction and the oral administration of calcium and aluminum salts have been the principal means of controlling hyperPhosphatemia in individuals with end-stage renal disease over the past decade. Although relatively well-tolerated, a large fraction of patients treated with calcium develop hypercalcemia, particularly when administered concurrently with calcitriol, despite a lowering of the dialysate calcium concentration. We evaluated the efficacy of cross-linked poly[allylamine hydrochloride] (RenaGel; Geltex Pharmaceuticals, Waltham, MA), a nonabsorbable calcium- and aluminum-free Phosphate Binder, in a randomized, placebo-controlled, double-blind trial of 36 maintenance hemodialysis patients followed over an 8-week period. RenaGel was found to be as effective as calcium carbonate or acetate as a Phosphate Binder. The reduction in serum phosphorus was significantly greater after 2 weeks of treatment with RenaGel (6.6 ± 2.1 mg/dL to 5.4 ± 1.5 mg/dL) compared with placebo (7.0 ± 2.1 mg/dL to 7.2 ± 2.4 mg/dL; P = 0.037). There was no significant change in serum calcium concentration in either treatment group. The total serum cholesterol and low-density lipoprotein cholesterol fraction were significantly reduced in RenaGel-treated patients compared with placebo-treated patients ( P = 0.013 and P = 0.003, respectively) without a concomitant reduction in high-density lipoprotein cholesterol ( P = 0.93). There was no difference among recipients of RenaGel and placebo in terms of adverse events. RenaGel is a safe and effective alternative to oral calcium for the management of hyperPhosphatemia in end-stage renal disease.
Stuart M Sprague - One of the best experts on this subject based on the ideXlab platform.
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one year efficacy and safety of the iron based Phosphate Binder sucroferric oxyhydroxide in patients on peritoneal dialysis
Nephrology Dialysis Transplantation, 2017Co-Authors: Jurgen Floege, Adrian Covic, Viatcheslav Rakov, Markus Ketteler, Johannes F E Mann, Anjay Rastogi, Bruce Spinowitz, Laura J Lisk, Stuart M SpragueAbstract:Background: Sucroferric oxyhydroxide is a noncalcium, iron-based Phosphate Binder that demonstrated sustained serum phosphorus control, good tolerability and lower pill burden compared with sevelamer carbonate (sevelamer) in a Phase 3 study conducted in dialysis patients. This subanalysis examines the efficacy and tolerability of sucroferric oxyhydroxide and sevelamer in the peritoneal dialysis (PD) patient population. Methods: The initial study (NCT01324128) and its extension (NCT01464190) were multicenter, Phase 3, open-label, randomized (2:1), active-controlled trials comparing sucroferric oxyhydroxide (1.0-3.0 g/day) with sevelamer (2.4-14.4 g/day) in dialysis patients over 52 weeks in total. Results: In the overall study, 84/1055 (8.1%) patients received PD and were eligible for efficacy analysis (sucroferric oxyhydroxide, n = 56; sevelamer, n = 28). The two groups were broadly comparable to each other and to the overall study population. Serum phosphorus concentrations decreased comparably with both Phosphate Binders by week 12 (mean change from baseline - 0.6 mmol/L). Over 52 weeks, sucroferric oxyhydroxide effectively reduced serum phosphorus concentrations to a similar extent as sevelamer; 62.5% and 64.3% of patients, respectively, were below the Kidney Disease Outcomes Quality Initiative target range (≤1.78 mmol/L). This was achieved with a lower pill burden (3.4 ± 1.3 versus 8.1 ± 3.7 tablets/day) with sucroferric oxyhydroxide compared with sevelamer. Treatment adherence rates were 91.2% with sucroferric oxyhydroxide and 79.3% with sevelamer. The proportion of patients reporting at least one treatment-emergent adverse event was 86.0% with sucroferric oxyhydroxide and 93.1% with sevelamer. The most common adverse events with both treatments were gastrointestinal: diarrhea and discolored feces with sucroferric oxyhydroxide and nausea, vomiting and constipation with sevelamer. Conclusions: Sucroferric oxyhydroxide is noninferior to sevelamer for controlling serum phosphorus in patients undergoing PD, while providing a relatively low pill burden and a high rate of adherence.
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long term effects of the iron based Phosphate Binder sucroferric oxyhydroxide in dialysis patients
Nephrology Dialysis Transplantation, 2015Co-Authors: Jurgen Floege, Adrian Covic, Sylvain Gaillard, Markus Ketteler, Johannes F E Mann, Anjay Rastogi, Bruce Spinowitz, Edward M F Chong, Laura J Lisk, Stuart M SpragueAbstract:Background. HyperPhosphatemia necessitates the use of Phosphate Binders in most dialysis patients. Long-term efficacy and tolerability of the iron-based Phosphate Binder, sucroferric oxyhydroxide (previously known as PA21), was compared with that of sevelamer carbonate (sevelamer) in an open-label Phase III extension study. Methods. In the initial Phase III study, hemo- or peritoneal dialysis patients with hyperPhosphatemia were randomized 2:1 to receive sucroferric oxyhydroxide 1.0−3.0 g/day (2−6 tablets/day; n = 710) or sevelamer 2.4−14.4 g/day (3−18 tablets/day; n = 349) for 24 weeks. Eligible patients could enter the 28-week extension study, continuing the same treatment and dose they were receiving at the end of the initial study. Results. Overall, 644 patients were available for efficacy analysis (n = 384 sucroferric oxyhydroxide; n= 260 sevelamer). Serum phosphorus concentrations were maintained during the extension study. Mean ± standard deviation (SD) change in serum phosphorus concentrations from extension study baseline to Week 52 end point was 0.02±0.52 mmol/L with sucroferric oxyhydroxide and 0.09±0.58 mmol/L with sevelamer. Mean serum phosphorus concentrations remained within Kidney Disease Outcomes Quality Initiative target range (1.13– 1.78 mmol/L) for both treatment groups. Mean (SD) daily tablet number over the 28-week extension study was lower for
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a phase iii study of the efficacy and safety of a novel iron based Phosphate Binder in dialysis patients
Kidney International, 2014Co-Authors: Jurgen Floege, Adrian Covic, Sylvain Gaillard, Markus Ketteler, Anjay Rastogi, Edward M F Chong, Laura J Lisk, Stuart M SpragueAbstract:Efficacy of PA21 (sucroferric oxyhydroxide), a novel calcium-free polynuclear iron(III)-oxyhydroxide Phosphate Binder, was compared with that of sevelamer carbonate in an open-label, randomized, active-controlled phase III study. Seven hundred and seven hemo- and peritoneal dialysis patients with hyperPhosphatemia received PA21 1.0–3.0g per day and 348 received sevelamer 4.8–14.4g per day for an 8-week dose titration, followed by 4 weeks without dose change, and then 12 weeks maintenance. Serum phosphorus reductions at week 12 were -0.71mmol/l (PA21) and -0.79mmol/l (sevelamer), demonstrating non-inferiority of, on average, three tablets of PA21 vs. eight of sevelamer. Efficacy was maintained to week 24. Non-adherence was 15.1% (PA21) vs. 21.3% (sevelamer). The percentage of patients that reported at least one treatment-emergent adverse event was 83.2% with PA21 and 76.1% with sevelamer. A higher proportion of patients withdrew owing to treatment-emergent adverse events with PA21 (15.7%) vs. sevelamer (6.6%). Mild, transient diarrhea, discolored feces, and hyperPhosphatemia were more frequent with PA21; nausea and constipation were more frequent with sevelamer. After 24 weeks, 99 hemodialysis patients on PA21 were re-randomized into a 3-week superiority analysis of PA21 maintenance dose in 50 patients vs. low dose (250mg per day (ineffective control)) in 49 patients. The PA21 maintenance dose was superior to the low dose in maintaining serum phosphorus control. Thus, PA21 was effective in lowering serum phosphorus in dialysis patients, with similar efficacy to sevelamer carbonate, a lower pill burden, and better adherence.
Geert J Behets - One of the best experts on this subject based on the ideXlab platform.
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a magnesium based Phosphate Binder reduces vascular calcification without affecting bone in chronic renal failure rats
PLOS ONE, 2014Co-Authors: Ellen Neven, Geert Dams, Patrick C Dhaese, Tineke M De Schutter, Sonja Steppan, Kristina Gundlach, Jutta Passlickdeetjen, Janine Buchel, Geert J BehetsAbstract:The alternative Phosphate Binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperPhosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced Phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to Phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the Phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover.
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effect of a magnesium based Phosphate Binder on medial calcification in a rat model of uremia
Kidney International, 2013Co-Authors: Tineke M De Schutter, Geert J Behets, Patrick C Dhaese, Hilde Geryl, Mirjam Peter, Sonja Steppan, Kristina Gundlach, Jutta Passlickdeetjen, Ellen NevenAbstract:Calcium-based Phosphate Binders are used to control hyperPhosphatemia; however, they promote hypercalcemia and may accelerate aortic calcification. Here we compared the effect of a Phosphate Binder containing calcium acetate and magnesium carbonate (CaMg) to that of sevelamer carbonate on the development of medial calcification in rats with chronic renal failure induced by an adenine diet for 4 weeks. After 1 week, rats with chronic renal failure were treated with vehicle, 375 or 750mg/kg CaMg, or 750mg/kg sevelamer by daily gavage for 5 weeks. Renal function was significantly impaired in all groups. Vehicle-treated rats with chronic renal failure developed severe hyperPhosphatemia, but this was controlled in treated groups, particularly by CaMg. Neither CaMg nor sevelamer increased serum calcium ion levels. Induction of chronic renal failure significantly increased serum PTH, dose-dependently prevented by CaMg but not sevelamer. The aortic calcium content was significantly reduced by CaMg but not by sevelamer. The percent calcified area of the aorta was significantly lower than vehicle-treated animals for all three groups. The presence of aortic calcification was associated with increased sox9 , bmp-2 , and matrix gla protein expression, but this did not differ in the treatment groups. Calcium content in the carotid artery was lower with sevelamer than with CaMg but that in the femoral artery did not differ between groups. Thus, treatment with either CaMg or sevelamer effectively controlled serum Phosphate levels in CRF rats and reduced aortic calcification.
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lanthanum a safe Phosphate Binder
Seminars in Dialysis, 2006Co-Authors: Veerle P Persy, Geert J Behets, Marc E De Broe, An R Bervoets, Patrick C DhaeseAbstract:: Accumulation of inorganic Phosphate due to renal functional impairment contributes to the increased cardiovascular mortality observed in dialysis patients. Phosphate plays a causative role in the development of vascular calcification in renal failure; treatment with calcium-based Phosphate Binders and vitamin D can further increase the Ca x PO(4) product and add to the risk of ectopic mineralization. The new generation of calcium-free Phosphate Binders, sevelamer and lanthanum, can control hyperPhosphatemia without adding to the patients calcium load. In this article, the metabolism of lanthanum carbonate and its effects in bone, liver and brain are discussed. Although lanthanum is a metal cation its effects are not comparable to those of aluminum. Indeed, in clinical studies no toxic effects of lanthanum have been reported after up to four years of follow-up. The bioavailability of lanthanum is extremely low. The effects observed in bone are due to Phosphate depletion, with no signs of direct bone toxicity yet observed in rats or humans. The liver is the main route of excretion for lanthanum carbonate, which can be localized in the lysosomes of hepatocytes. No lanthanum could be detected in brain tissue.
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does the Phosphate Binder lanthanum carbonate affect bone in rats with chronic renal failure
Journal of The American Society of Nephrology, 2004Co-Authors: Geert J Behets, Stephen J P Damment, Geert Dams, Sven R Vercauteren, Roger Bouillon, Marc E De Broe, Patrick C DhaeseAbstract:ABSTRACT. Adequate control of Phosphate levels remains an important issue in patients with chronic renal failure (CRF). Lanthanum carbonate has been proposed as a new Phosphate Binder. Previous studies have shown a high Phosphate binding capacity (>97%) and low gastrointestinal absorption of lanthanum, without serious toxic side effects in the presence of a normal renal function (NRF). Because of lanthanum’s physicochemical resemblance to calcium, the possible effects of it on bone have to be considered. The aim of this study was to investigate the effects of lanthanum carbonate on bone histology in NRF and CRF rats after oral administration of the compound with doses of 100, 500, or 1000 mg/kg per d for 12 wk. Bone histomorphometry showed that CRF animals that received vehicle developed secondary hyperparathyroidism. Urinalysis of lanthanum-loaded CRF animals showed a dose-dependent decrease in urinary phosphorus excretion, which was clearly more pronounced in the CRF groups compared with NRF animals. Phosphatemia, however, remained normal. Lanthanum carbonate administration induced a dose-dependent decrease in bone formation rate and increase in osteoid area in CRF animals. Three of seven animals in the CRF-1000 group and one of eight animals in the NRF-100 group were classified as having a mineralization defect. The number of cuboidal osteoblasts, however, was not affected, indicating that bone changes were not due to a toxic effect of lanthanum on the osteoblast. Furthermore, lanthanum concentrations in the femur remained low and did not correlate with histomorphometric parameters. These findings suggest that the administration of high doses of Phosphate Binder (1000 mg/kg per d lanthanum carbonate), in combination with decreased 25-(OH) vitamin D 3 in the uremic state, resulted in Phosphate depletion and followed by an increased mobilization of phosphorus out of bone and/or reduced incorporation into bone. There was no evidence that lanthanum had a direct toxic effect on osteoblasts.
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lanthanum carbonate a new Phosphate Binder
Current Opinion in Nephrology and Hypertension, 2004Co-Authors: Geert J Behets, Patrick C Dhaese, Steven C Verberckmoes, Marc E De BroeAbstract:Purpose of reviewHyperPhosphatemia remains an important aspect in the management of end-stage renal disease patients. Consequently, there is a need for new, efficient and well-tolerated Phosphate Binders. In this review, a new Phosphate-binding drug, lanthanum carbonate, with an attractive preclinic
Michihito Wada - One of the best experts on this subject based on the ideXlab platform.
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effect of manipulating serum phosphorus with Phosphate Binder on circulating pth and fgf23 in renal failure rats
Kidney International, 2006Co-Authors: Nobuo Nagano, Sonoe Miyata, Nami Kobayashi, Sachiko Wakita, T Yamashita, Michihito WadaAbstract:Phosphorus directly controls parathyroid hormone (PTH) synthesis and secretion. Serum levels of the novel Phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), are positively correlated with hyperPhosphatemia in patients with chronic renal insufficiency (CRI). We proposed that changes in serum PTH and FGF23 levels might be associated with changes in serum phosphorus levels caused by the Phosphate Binder sevelamer hydrochloride (sevelamer, i.e. crosslinked poly[allylamine hydrochloride]). Rats were fed a diet containing adenine for 4 weeks to establish CRI. Animals were then offered either a normal diet or a diet containing 1 or 3% sevelamer for 8 weeks continuously, or intermittently with sevelamer diet or a normal diet offered for alternating 2-week periods. Changes in the serum levels of phosphorus, calcium, PTH, FGF23, and 1 α ,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) were monitored over time. Adenine-treated rats developed severe CRI, with markedly elevated serum levels of phosphorus, PTH and FGF23, and reduced levels of serum 1,25(OH) 2 D 3 . Continuous treatment with sevelamer suppressed these increases throughout the study period. Serum phosphorus, PTH, and FGF23 levels decreased rapidly when sevelamer treatments commenced and recovered rapidly once they were discontinued. However, the changes in serum FGF23 levels began after the onset of changes in serum phosphorus and PTH levels. In conclusion, circulating PTH, and FGF23 levels can be promptly manipulated through the control of serum phosphorus levels. Moreover, Phosphate-Binder treatment can effectively inhibit the elevation of serum FGF23 levels, as well as PTH levels, under conditions of CRI.
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sevelamer hydrochloride a Phosphate Binder protects against deterioration of renal function in rats with progressive chronic renal insufficiency
Nephrology Dialysis Transplantation, 2003Co-Authors: Nobuo Nagano, Steven K Burke, Sonoe Miyata, Nami Kobayashi, Sachiko Obana, Naoshi Fukushima, Michihito WadaAbstract:BACKGROUND: Dietary Phosphate restriction prevents renal function deterioration in animal models. This study examined whether sevelamer hydrochloride (Renagel(R); 'sevelamer' hereafter), a non-calcaemic Phosphate Binder could slow deterioration of renal function in rats with progressive renal insufficiency. METHODS: Wistar Kyoto male rats were singly injected with normal rabbit serum or rabbit anti-rat glomerular basement membrane serum. Three days later, rats were fed a powder diet containing 0, 1 or 3% sevelamer for 58 days. Time course changes of serum levels of blood urea nitrogen (BUN), creatinine, calcium, phosphorus and parathyroid hormone (PTH) were measured throughout, and creatinine clearance (CCr), kidney calcium content and renal histology examined at the end of the study. RESULTS: Sevelamer partially inhibited elevation of BUN and serum creatinine, and completely inhibited increases in serum phosphorus, PTH and calcium xphosphorus product. Sevelamer significantly prevented the decrease in CCr and kidney calcium content elevation. Kidney calcium content and BUN and serum creatinine were strongly positively correlated, and kidney calcium content and CCr strongly negatively correlated. Kidney calcium content correlated well with serum phosphorus, serum calcium x phosphorus product and PTH, but not serum calcium. Sevelamer treatment partly prevented histological deterioration of both glomerular and tubulointerstitial lesions of the kidney. CONCLUSIONS: The results suggest that sevelamer protects against renal function deterioration by maintaining kidney calcium at a low level as a result of reducing serum phosphorus and PTH.
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sevelamer hydrochloride renagel a non calcaemic Phosphate Binder arrests parathyroid gland hyperplasia in rats with progressive chronic renal insufficiency
Nephrology Dialysis Transplantation, 2001Co-Authors: Nobuo Nagano, Steven K Burke, Sonoe Miyata, Nami Kobayashi, Sachiko Obana, Naoshi Fukushima, Masako Ozai, Michihito WadaAbstract:BACKGROUND: It has been demonstrated that dietary Phosphate restriction suppresses parathyroid hormone (PTH) secretion and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI) independently of serum calcium and 1,25(OH)(2)D3 levels. This study was conducted to examine whether sevelamer hydrochloride (Renagel); hereafter referred to as sevelamer), a non-calcaemic Phosphate Binder could inhibit the parathyroid gland (PTG) hyperplasia in rats with progressive CRI. METHODS: Male Sprague-Dawley rats were injected twice with low doses of adriamycin (ADR). Two weeks after the last injection of ADR, rats were fed a diet containing 1 or 3% sevelamer for 84 days. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of study, serum 1,25(OH)(2)D3 levels were measured and the maximal two-dimension area of the PTG in paraffin section was calculated using an imaging analyser. RESULTS: Dietary sevelamer treatment inhibited the elevations of serum phosphorus, calciumxphosphorus product, and PTH levels that occurred as the study progressed. Sevelamer also suppressed maximal PTG area and there existed positive strong correlation between maximal PTG area and serum PTH levels at the end of the study. Serum phosphorus levels positively correlated well with serum PTH levels and maximal PTG area. In contrast, serum calcium or 1,25(OH)(2)D3 levels did not show any correlation with serum PTH levels and maximal PTG area. CONCLUSIONS: Sevelamer treatment arrested hyperphosphataemia and PTG hyperplasia accompanied by the elevation of serum PTH levels. The correlation analysis suggests that reduced serum phosphorus levels contributed to the suppression of PTG hyperplasia and resulted in the reduction of PTH levels in this animal model after the sevelamer treatment. The management of phosphorus control started from early stage of CRI could prevent PTG hyperplasia and facilitate later management of secondary hyperparathyroidism.