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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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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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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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Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).
Qunibi, WY, Hootkins, RE, McDowell, LL, Meyer, MS, Simon, M, Garza, RO, Pelham, RW, Cleveland, MV, Muenz, LR, He, DY, et al
Kidney international. 2004;(5):1914-26
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Abstract
BACKGROUND Hyperphosphatemia underlies development of hyperparathyroidism, osteodystrophy, extraosseous calcification, and is associated with increased mortality in hemodialysis patients. METHODS To determine whether calcium acetate or sevelamer hydrochloride best achieves recently recommended treatment goals of phosphorus ≤5.5 mg/dL and Ca x P product ≤55 mg(2)/dL(2), we conducted an 8-week randomized, double-blind study in 100 hemodialysis patients. RESULTS Comparisons of time-averaged concentrations (weeks 1 to 8) demonstrated that calcium acetate recipients had lower serum phosphorus (1.08 mg/dL difference, P= 0.0006), higher serum calcium (0.63 mg/dL difference, P < 0.0001), and lower Ca x P (6.1 mg(2)/dL(2) difference, P= 0.022) than sevelamer recipients. At each week, calcium acetate recipients were 20% to 24% more likely to attain goal phosphorus [odds ratio (OR) 2.37, 95% CI 1.28-4.37, P= 0.0058], and 15% to 20% more likely to attain goal Ca x P (OR 2.16, 95% CI 1.20-3.86, P= 0.0097). Transient hypercalcemia occurred in 8 of 48 (16.7%) calcium acetate recipients, all of whom received concomitant intravenous vitamin D. By regression analysis hypercalcemia was more likely with calcium acetate (OR 6.1, 95% CI 2.8-13.3, P < 0.0001). Week 8 intact PTH levels were not significantly different. Serum bicarbonate levels were significantly lower with sevelamer hydrochloride treatment (P < 0.0001). CONCLUSION Calcium acetate controls serum phosphorus and calcium-phosphate product more effectively than sevelamer hydrochloride. Cost-benefit analysis indicates that in the absence of hypercalcemia, calcium acetate should remain the treatment of choice for hyperphosphatemia in hemodialysis patients.
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Impact of LKM512 yogurt on improvement of intestinal environment of the elderly.
Matsumoto, M, Ohishi, H, Benno, Y
FEMS immunology and medical microbiology. 2001;(3):181-6
Abstract
Improvement of the intestinal environment by administration of LKM512 yogurt was examined using polyamine, haptoglobin and mutagenicity as indexes which directly reflect the health condition of the host. The concentration of spermine in feces increased significantly by 3-fold (P<0.05) at week 2 of administration of LKM512 yogurt compared with before administration, and that of putrescine, spermidine, and cadaverine also tended to increase with administration of LKM512 yogurt. The haptoglobin content in feces decreased significantly (P<0.05) at week 2 of administration of LKM512 yogurt, and it showed a negative correlation with the polyamine content, indicating that acute intestinal inflammation was suppressed. Fecal mutagenicity was measured using fecal extract and fecal precipitate. Both preparations showed similar significant decreases (P<0.05) by the administration of LKM512 yogurt, as well as a negative correlation with polyamine content. This result indicated that antimutagenicity due to administration of LKM512 yogurt was not based on binding of the mutagen to the bacterial cell wall. Many reports have suggested that polyamines increased by the administration of LKM512 yogurt led to inhibition of inflammation and antimutagenicity in the intestinal tract.