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Alterations in Polyamine Metabolism in Patients With Lymphangioleiomyomatosis and Tuberous Sclerosis Complex 2-Deficient Cells.
Tang, Y, El-Chemaly, S, Taveira-Dasilva, A, Goldberg, HJ, Bagwe, S, Rosas, IO, Moss, J, Priolo, C, Henske, EP
Chest. 2019;(6):1137-1148
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Abstract
BACKGROUND Lymphangioleiomyomatosis (LAM), a destructive lung disease that affects primarily women, is caused by loss-of-function mutations in TSC1 or TSC2, leading to hyperactivation of mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Rapamycin (sirolimus) treatment suppresses mTORC1 but also induces autophagy, which promotes the survival of TSC2-deficient cells. Based on the hypothesis that simultaneous inhibition of mTORC1 and autophagy would limit the availability of critical nutrients and inhibit LAM cells, we conducted a phase 1 clinical trial of sirolimus and hydroxychloroquine for LAM. Here, we report the analyses of plasma metabolomic profiles from the clinical trial. METHODS We analyzed the plasma metabolome in samples obtained before, during, and after 6 months of treatment with sirolimus and hydroxychloroquine, using univariate statistical models and machine learning approaches. Metabolites and metabolic pathways were validated in TSC2-deficient cells derived from patients with LAM. Single-cell RNA-Seq was employed to assess metabolic enzymes in an early-passage culture from an LAM lung. RESULTS Metabolomic profiling revealed changes in polyamine metabolism during treatment, with 5'-methylthioadenosine and arginine among the most highly upregulated metabolites. Similar findings were observed in TSC2-deficient cells derived from patients with LAM. Single-cell transcriptomic profiling of primary LAM cultured cells revealed that mTORC1 inhibition upregulated key enzymes in the polyamine metabolism pathway, including adenosylmethionine decarboxylase 1. CONCLUSIONS Our data demonstrate that polyamine metabolic pathways are targeted by the combination of rapamycin and hydroxychloroquine, leading to upregulation of 5'-methylthioadenosine and arginine in the plasma of patients with LAM and in TSC2-deficient cells derived from a patient with LAM upon treatment with this drug combination. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov. Partners Human Research Committee, protocol No. 2012P000669.
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Bixalomer in Hyperphosphatemic Patients With Chronic Kidney Disease Not on Dialysis: Phase 3 Randomized Trial.
Akizawa, T, Origasa, H, Kameoka, C, Tsukada, J, Kuroishi, K, Yamaguchi, Y
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2016;(6):588-597
Abstract
Currently, calcium- or metal-containing phosphate binders are available to treat hyperphosphatemia in predialysis patients with chronic kidney disease. Bixalomer, a non-calcium, metal-free phosphate binder, has not been studied in these patients. We evaluated the efficacy and safety of bixalomer versus placebo for treatment of hyperphosphatemia in Japanese predialysis patients with chronic kidney disease. This multicenter, randomized, double-blind, phase 3 trial, randomized eligible patients 1:1 to receive bixalomer or placebo for 12 weeks. Bixalomer was started at 1500 mg/day and adjusted up to 7500 mg/day depending on serum phosphorus concentrations. The primary endpoint was change in serum phosphorus concentration from baseline to end of treatment. After a 4-week pre-investigational period, 163 patients (bixalomer: N = 81; placebo: N = 82) were randomized. The adjusted mean change (95% confidence interval) from baseline to end of treatment in serum phosphorus was significantly greater with bixalomer (-0.78 [-0.98, -0.57] mg/dL) versus placebo (0.20 [-0.00, 0.41] mg/dL); mean difference: -0.98 (-1.27, -0.69), P < 0.001. At end of treatment, 57.5% of bixalomer-treated patients achieved target serum phosphorus concentrations, mean serum intact parathyroid hormone and fibroblast growth factor-23 decreased, and there were no significant changes in corrected serum calcium. The safety and tolerability of bixalomer was similar to placebo. The most common drug-related adverse events were gastrointestinal (>24% patients per group). There was a significant increase in bicarbonate concentrations with bixalomer versus placebo (P = 0.003). Bixalomer was superior to placebo for hyperphosphatemia in Japanese predialysis patients with chronic kidney disease and may constitute a new treatment option.
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A randomized trial of JTT-751 versus sevelamer hydrochloride in patients on hemodialysis.
Yokoyama, K, Akiba, T, Fukagawa, M, Nakayama, M, Sawada, K, Kumagai, Y, Chertow, GM, Hirakata, H
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2014;(5):1053-60
Abstract
BACKGROUND JTT-751 is a novel phosphate binder containing ferric citrate as the active ingredient. METHODS In this Phase 3, multicenter, randomized, open-label, parallel-group study, we compared the efficacy and safety of JTT-751 and sevelamer hydrochloride in patients undergoing hemodialysis. A total of 230 patients with a serum phosphate ≥1.97 and <3.23 mmol/L were randomized to JTT-751 (dose adjusted between 1.5 and 6.0 g/day) or sevelamer hydrochloride (dose adjusted between 3.0 and 9.0 g/day) for 12 weeks. The primary outcome was change in serum phosphate from baseline to end of treatment. Secondary outcomes included the changes in corrected serum calcium and intact parathyroid hormone (PTH). The changes in ferritin, transferrin saturation and erythropoiesis-stimulating agent dose were additional outcomes. RESULTS Changes in serum phosphate at the end of treatment were -0.82 mmol/L in the JTT-751 group and -0.78 mmol/L in the sevelamer group, establishing non-inferiority of JTT-751 compared with sevelamer (least squares mean, -0.03 mmol/L; 95% confidence interval, -0.13 to 0.07 mmol/L). Corrected serum calcium increased and PTH decreased from baseline within both groups; changes between groups were similar. Gastrointestinal disorders were the most common adverse events in both groups; the incidence of diarrhea was higher in the JTT-751 group, while constipation occurred frequently in the sevelamer group. Treatment with JTT-751 resulted in significant relative increases in serum ferritin and transferrin saturation. CONCLUSIONS Efficacy and safety of JTT-751 was comparable to sevelamer in patients on hemodialysis with hyperphosphatemia. Differential adverse effects were observed; biochemical markers of iron status increased in patients treated with JTT-751. TRIAL REGISTRATION NUMBER CTI-111433 (The Japan Pharmaceutical Information Center at: http//www.clinicaltrials.jp). Date of registration: 7 March 2011.
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Sevelamer does not decrease lipopolysaccharide or soluble CD14 levels but decreases soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol levels in individuals with untreated HIV infection.
Sandler, NG, Zhang, X, Bosch, RJ, Funderburg, NT, Choi, AI, Robinson, JK, Fine, DM, Coombs, RW, Jacobson, JM, Landay, AL, et al
The Journal of infectious diseases. 2014;(10):1549-54
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Abstract
UNLABELLED Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits. CLINICAL TRIALS REGISTRATION NCT 01543958.
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The real-world dose-relativity of sevelamer hydrochloride and lanthanum carbonate monotherapy in patients with end-stage renal disease.
Wilson, RJ, Keith, MS, Preston, P, Copley, JB
Advances in therapy. 2013;(12):1100-10
Abstract
INTRODUCTION Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used for the management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to evaluate the real-world dose-relativity between SH and LC monotherapy in US patients with ESRD. METHODS This was a post hoc analysis of a 16-week, real-world study (Vemuri et al. in BMC Nephrol 12:49, 2011) of the efficacy of conversion to LC monotherapy from other phosphate binders. The SH:LC dose-relativity ratio, based on the mean daily dose, was calculated in the subset of patients from the Vemuri study who converted from SH to LC monotherapy and had available SH and LC dose data. RESULTS A total of 950 patients converted from SH to LC monotherapy and had recorded dose data. The post hoc analysis population comprised 691 patients with available dose data for both SH at baseline and LC at week 16. The mean (SD) serum phosphate level at baseline was 5.91 (1.66) mg/dL. After conversion to LC monotherapy for 16 weeks, the mean (SD) serum phosphate level was 5.93 (1.85) mg/dL. The mean (SD) daily baseline SH dose was 7,703 (3,642) mg and the mean (SD) daily LC dose at week 16 was 2,800 (939) mg (9.6 versus 2.8 tablets, respectively; P < 0.0001), resulting in a SH:LC dose-relativity ratio of 2.8. The median individual patient SH:LC dose-relativity ratio was 2.6 (95% CI 2.6-2.8). Across baseline SH dose subgroups (2,400-4,800, >4,800-7,200, >7,200-9,600, and >9,600 mg/day), the mean daily SH dose was 4,051, 7,047, 9,253, and 13,150 mg, respectively. In comparison, the mean daily LC dose was 2,445-3,156 mg. Thus, patients requiring baseline SH doses >7,200 mg/day (41% of the analysis population) had higher SH:LC dose-relativity ratios of 3.1-4.2 (median individual patient ratios 3.1-4.0). CONCLUSION In this post hoc analysis of real-world dose-relativity, the overall SH:LC dose-relativity ratio was 2.8 (median individual patient ratio 2.6 (95% CI 2.6-2.8). These findings are consistent with the World Health Organization-defined daily dose and previous studies of the relative phosphate binding capacity of the two drugs. Patients requiring SH doses >7,200 mg/day had higher SH:LC dose-relativities of 3.1-4.2 (median individual patient ratios 3.1-4.0). These findings have implications for the tablet burden and cost-effectiveness of SH and LC in the treatment of hyperphosphatemia.
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Comparison of sevelamer and calcium carbonate on endothelial function and inflammation in patients on peritoneal dialysis.
Chennasamudram, SP, Noor, T, Vasylyeva, TL
Journal of renal care. 2013;(2):82-9
Abstract
BACKGROUND Hyperphosphataemia is a known independent risk factor for cardiovascular mortality. The objective of the study was to compare the effects of two phosphate binders, sevelamer carbonate and calcium carbonate on endothelial function (EF) and inflammation in patients on peritoneal dialysis (PD) with Type 2 diabetes mellitus (T2DM). METHODS Fifteen subjects with hyperphosphataemia discontinued all phosphate binders to undergo a two-week washout and were assigned to sevelamer carbonate or calcium carbonate treatments for eight weeks. After a second two-week washout period, subjects crossed over to either of the alternate treatments for another eight weeks. At the beginning and end of each treatment, biomarkers of EF, pro-inflammatory cytokines, serum albumin, calcium, phosphate and lipids were measured. RESULTS Sevelamer carbonate significantly improved lipid profile compared with calcium carbonate. Amongst the EF and pro-inflammatory biomarkers, sevelamer carbonate decreased serum endothelin-1, plasminogen activator inhibitor-1, C-reactive protein and interleukin-6. Both phosphate binders were effective in decreasing serum phosphate but sevelamer had a positive effect on EF. CONCLUSIONS Treatment with sevelamer carbonate has beneficial effects compared with calcium carbonate in decreasing inflammation and improving EF in patients with T2DM on PD.
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Effect of a non-calcium-based phosphate binder on fibroblast growth factor 23 in chronic kidney disease.
Spatz, C, Roe, K, Lehman, E, Verma, N
Nephron. Clinical practice. 2013;(1-2):61-6
Abstract
BACKGROUND Elevated fibroblast growth factor 23 (FGF23) levels are associated with progression of chronic kidney disease (CKD) and increased mortality. Studies in individuals without CKD suggest that FGF23 levels are regulated by dietary phosphorus; however, the effect of pharmacologic phosphorus restriction on FGF23 in CKD patients is uncertain. METHODS We performed a prospective cohort study examining the effect of phosphorus reduction with sevelamer carbonate on FGF23 levels in CKD patients. Adults with an estimated glomerular filtration rate <60 ml/min/1.73 m(2) according to MDRD (Modification of Diet in Renal Disease) and hyperphosphatemia were enrolled. Subjects were started on sevelamer carbonate 800 mg by mouth with meals and the dose was titrated to achieve a serum phosphorus between 2.7 and 4.6 mg/dl for those with CKD stages III and IV, and between 3.5 and 5.5 mg/dl for CKD stage V. FGF23 levels were measured at baseline and 3 months. Results were analyzed as percent change from baseline. RESULTS 40 patients completed the study. Mean estimated glomerular filtration rate by MDRD at entry was 21.2 ± 10.5, serum phosphorus 4.8 ± 0.8, and FGF23 level 602.3 ± 1,074.6. Mean serum phosphorus and FGF23 levels after 3 months were 4.4 ± 0.9 and 599.2 ± 720.9, respectively. No significant difference was seen in FGF23 (p = 0.76) despite a significant difference in phosphorus (p = 0.001). CONCLUSION The patients treated with sevelamer carbonate did not have a significant change in plasma FGF23 levels despite a significant reduction in phosphorus. It is possible that once overt hyperphosphatemia develops, FGF23 levels may not be reduced by phosphorus reduction alone in CKD patients.
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Plasma p-cresol lowering effect of sevelamer in peritoneal dialysis patients: evidence from a Cross-Sectional Observational Study.
Guida, B, Cataldi, M, Riccio, E, Grumetto, L, Pota, A, Borrelli, S, Memoli, A, Barbato, F, Argentino, G, Salerno, G, et al
PloS one. 2013;(8):e73558
Abstract
p-Cresol is a by-product of the metabolism of aromatic aminoacid operated by resident intestinal bacteria. In patients with chronic kidney disease, the accumulation of p-cresol and of its metabolite p-cresyl-sulphate causes endothelial dysfunction and ultimately increases the cardiovascular risk of these patients. Therapeutic strategies to reduce plasma p-cresol levels are highly demanded but not available yet. Because it has been reported that the phosphate binder sevelamer sequesters p-cresol in vitro we hypothesized that it could do so also in peritoneal dialysis patients. To explore this hypothesis we measured total cresol plasma concentrations in 57 patients with end-stage renal disease on peritoneal dialysis, 29 receiving sevelamer for the treatment of hyperphosphatemia and 28 patients not assuming this drug. Among the patients not assuming sevelamer, 16 were treated with lanthanum whereas the remaining 12 received no drug because they were not hyperphosphatemic. Patients receiving sevelamer had plasma p-cresol and serum high sensitivity C-reactive protein concentrations significantly lower than those receiving lanthanum or no drug. Conversely, no difference was observed among the different groups either in residual glomerular filtration rate, total weekly dialysis dose, total clearance, urine volume, protein catabolic rate, serum albumin or serum phosphate levels. Multiple linear regression analysis showed that none of these variables predicted plasma p-cresol concentrations that, instead, negatively correlated with the use of sevelamer. These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect cardiovascular risk because of its anti-inflammatory effect.
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[The use of sevelamer in the treatment of resistant hyperphosphataemia in children with chronic renal disease].
Runowski, D, Jachimiak, B, Cieślak-Puchalska, A, Pacanowska, B, Zimoń, T
Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego. 2009;(154):318-21
Abstract
UNLABELLED The aim of study was the estimation of efficacy and safety of sevelamer treatment in children with chronic kidney disease with resistant hyperphsphatemia. MATERIAL AND METHODS The study group was 7 patients (hemodialysed--2 boys, mean age 7, 7+/-0.1; peritoneal dialysis--5: 3 boys and 2 girls, mean age 5, 6+/-5.0). Sevelamer (Renagel, 800 mg, Genzyme) was used in all patients in mean dosis of 117 mg/kgm.c./d due to lack of effect of the typical treatment (vitamin D, diet, calcium carbonate). Results of treatment by sevelamer were estimated by measuring of calcium, phosphates, albumins, parathormone and alkalic phosphate concentration in the serum and blood gases after 6 and 12 month. RESULTS There were found that sevelamer treatment significantly decrease the phosphates concentration and CaxP product in the serum without influence on concentration of PTH or calcium. Any adverse events were observed during the study and any drug intolerance. CONCLUSION Sevelamer treatment may be usefulness in children with resistant hyperphosphatemia.
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Calcium load during administration of calcium carbonate or sevelamer in individuals with normal renal function.
Heinrich, T, Heidt, H, Hafner, V, Schmidt-Gayk, H, Jenetzky, E, Walter-Sack, I, Mikus, G, Bommer, J
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2008;(9):2861-7
Abstract
BACKGROUND Under steady-state conditions urinary calcium (Ca) excretion corresponds to the Ca load in healthy subjects. However, in chronic haemodialysis patients reliable data on Ca load are not available. In these patients Ca-containing phosphate binders are suspected to play a role in the progression of arteriosclerosis via increased but not quantified Ca load. The present study evaluated the effect of calcium carbonate (CC) and sevelamer hydrochloride (SEV), a calcium-free phosphate binder, on serum Ca and urinary Ca excretion in healthy individuals. METHODS Twelve healthy male individuals were included in a monocentre, randomized, single-blind, placebo-controlled, three-way crossover phase I study. Concurrently with their meals, participants received 4 x 2 tablets of SEV (800 mg), CC (500 mg) or placebo for 6 days with 1-week washout between the treatment periods. During the study, weekly blood samples were taken and 24-h urine was collected each day for measurement of calcium, magnesium, phosphorus, chloride and iPTH. RESULTS Mean daily urinary phosphorus excretion was significantly lower in subjects undergoing SEV treatment compared to those taking placebo (P < 0.001). Mean daily total urinary excretion of calcium was significantly higher in CC-treated participants compared to those receiving placebo (P < 0.001). Mean 24-h calcium excretion during the 6 treatment days was 6.60 +/- 2.62 mmol [265 +/- 105 mg] (CC) versus 5.15 +/- 2.16 mmol [206 +/- 87 mg] (SEV) versus 4.95 +/- 1.63 mmol [198 +/- 65 mg] (Placebo). Taking into account nutritional calcium intake estimated from dietary records fractional calcium absorption was 8.7% (CC), 13.3% (placebo) and 14.8% (sevelamer). CONCLUSION Intake of calcium carbonate compared to placebo in contrast to sevelamer in healthy individuals was associated with increased total urinary calcium excretion indicating an increased calcium load due to increased intestinal calcium absorption.