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Nonalcoholic fatty liver disease is a rapidly rising problem in the 21st century and is a leading cause of chronic liver disease that can lead to end-stage liver diseases, including cirrhosis and hepatocellular cancer. Despite this rising epidemic, no pharmacological treatment has yet been established to treat this disease. The rapidly increasing prevalence of nonalcoholic fatty liver disease and its aggressive form, nonalcoholic steatohepatitis (NASH), requires novel therapeutic approaches to prevent disease progression. Alterations in microbiome dynamics and dysbiosis play an important role in liver disease and may represent targetable pathways to treat liver disorders. Improving microbiome properties or restoring normal bile acid metabolism may prevent or slow the progression of liver diseases such as NASH. Importantly, aberrant systemic circulation of bile acids can greatly disrupt metabolic homeostasis. Bile acid sequestrants are orally administered polymers that bind bile acids in the intestine, forming nonabsorbable complexes. Bile acid sequestrants interrupt intestinal reabsorption of bile acids, decreasing their circulating levels. We determined that treatment with the bile acid sequestrant sevelamer reversed the liver injury and prevented the progression of NASH, including steatosis, inflammation, and fibrosis in a Western diet-induced NASH mouse model. Metabolomics and microbiome analysis revealed that this beneficial effect is associated with changes in the microbiota population and bile acid composition, including reversing microbiota complexity in cecum by increasing Lactobacillus and decreased Desulfovibrio The net effect of these changes was improvement in liver function and markers of liver injury and the positive effects of reversal of insulin resistance.

BackgroundPhosphate binders are commonly used in the treatment of patients with hyperphosphatemia. While phosphate binders are used to lower phosphate, the effects of specific phosphate binder types on vitamin D metabolism are unknown.MethodsWe performed a secondary analysis of the Phosphate Normalization Trial in which patients with moderate to advanced chronic kidney disease were randomized to receive either placebo, sevelamer carbonate, lanthanum carbonate or calcium acetate for 9 months. We evaluated changes in serum concentrations of vitamin D metabolites including 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the ratio of 24,25(OH)2D3 to 25-hydroxyvitamin D [the vitamin D metabolite ratio (VMR)] and the ratio of serum 1,25(OH)2D to 25-hydroxyvitamin D.ResultsCompared with placebo, randomization to the calcium acetate arm was associated with a 0.6 ng/mL (95% CI 0.2, 1) and 13.5 pg/ng (95% CI 5.5, 21.5) increase in 24,25(OH)2D and VMR, respectively, and a 5.2 pg/mL (95% CI 1.1, 9.4) reduction in 1,25(OH)2D. Randomization to sevelamer carbonate was associated with a 0.5 ng/mL (95% CI -0.9, -0.1) and 11.8 pg/ng (95% CI -20, -3.5) reduction in 24,25(OH)2D3 and VMR, respectively. There was no association of the sevelamer arm with the change in 1,25(OH)2D3, and randomization to lanthanum carbonate was not associated with a change in any of the vitamin D metabolites.ConclusionAdministration of different phosphate binders to patients with moderate to severe CKD results in unique changes in vitamin D metabolism.

UnlabelledAbnormal 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 registrationNCT 01543958.

AimsIn individuals with chronic kidney disease (CKD), including those undergoing maintenance hemodialysis (MHD), coronary artery calcification (CAC) is common. We hypothesized that, in MHD patients, intake of the calcium-free phosphate binder sevelamer is associated with lower CAC compared to calcium-based phosphate binders (CBPB).Material and methodsThis is a cross-sectional study of MHD patients, who underwent computerized tomography to assess coronary artery calcium scores (CACS). Patients were stratified into two mutually exclusive groups based on taking only a CBPB vs. sevelamer. Logistic regression was used to calculate adjusted odds ratio (OR) of CACS > or = 400, CACS 100 < or =; CACS < 400, 10 < or =; CACS < 100 vs. CACS < 10.Results117 MHD patients were either on a CBPB alone (n = 60) or sevelamer alone (n = 57). Despite increased prevalence of DM in the sevelamer group (58%) as compared to the CBPB group (35%), CACS was significantly lower with sevelamer use (283 + or - 83 vs. 494 + or - 94, p = 0.02). The OR of significant CACS > or =; 400 vs. CAC < 10 was 4.35 (95% confidence interval: 1.5 - 9.9, p = 0.008) for CBPB compared with sevelamer, after controlling for case-mix, cholesterol-lowering medication, DM, and inflammatory markers.ConclusionIn our cohort, significant CAC was significantly more prevalent among MHD patients taking CBPB as compared to sevelamer monotherapy.

AimsIn individuals with chronic kidney disease (CKD), including those undergoing maintenance hemodialysis (MHD), coronary artery calcification (CAC) is common. We hypothesized that, in MHD patients, intake of the calcium-free phosphate binder sevelamer is associated with lower CAC compared to calcium-based phosphate binders (CBPB).Material and methodsThis is a cross-sectional study of MHD patients, who underwent computerized tomography to assess coronary artery calcium scores (CACS). Patients were stratified into two mutually exclusive groups based on taking only a CBPB vs. sevelamer. Logistic regression was used to calculate adjusted odds ratio (OR) of CACS > or = 400, CACS 100 < or =; CACS < 400, 10 < or =; CACS < 100 vs. CACS < 10.Results117 MHD patients were either on a CBPB alone (n = 60) or sevelamer alone (n = 57). Despite increased prevalence of DM in the sevelamer group (58%) as compared to the CBPB group (35%), CACS was significantly lower with sevelamer use (283 + or - 83 vs. 494 + or - 94, p = 0.02). The OR of significant CACS > or =; 400 vs. CAC < 10 was 4.35 (95% confidence interval: 1.5 - 9.9, p = 0.008) for CBPB compared with sevelamer, after controlling for case-mix, cholesterol-lowering medication, DM, and inflammatory markers.ConclusionIn our cohort, significant CAC was significantly more prevalent among MHD patients taking CBPB as compared to sevelamer monotherapy.

Many traditional and nontraditional risk factors contribute to vascular calcification among maintenance hemodialysis (MHD) patients. It is not clear whether coronary artery calcification (CAC) delineates a higher mortality risk independent of known risk factors. We examined 6-year (10/2001-9/2007) survival of 166 MHD patients, aged 53 +/- 13 years, with baseline CAC scores. Patients were grouped into four CAC groups: 0, 1-100, 101-400, and 400+. The 101-400 and 400+ groups were associated with a significantly higher adjusted risk of death than CAC 0 with hazard ratios (HR) 8.5 (95% CI: 1.1-48.1, p = 0.02) and 13.3 (95% CI: 1.3-65.1, p = 0.01), respectively, independent of demographics, comorbidity, lipids and other cardiovascular risks, surrogates of bone disease, nutritional and inflammatory markers and dialysis dose. Total CAC [HR 6.7 (1.1-21.5, p = 0.03)] followed by the presence of CAC in the left main [4.6 (2.2-9.8, p = 0.001)] and left anterior descending artery [4.3 (2.1-14.2, p = 0.001)] were strong independent predictors of mortality even after adjusting for above covariates. Total and vessel-specific CAC predict mortality in MHD patients independent of traditional and nontraditional risk factors.

Many traditional and nontraditional risk factors contribute to vascular calcification among maintenance hemodialysis (MHD) patients. It is not clear whether coronary artery calcification (CAC) delineates a higher mortality risk independent of known risk factors. We examined 6-year (10/2001-9/2007) survival of 166 MHD patients, aged 53 +/- 13 years, with baseline CAC scores. Patients were grouped into four CAC groups: 0, 1-100, 101-400, and 400+. The 101-400 and 400+ groups were associated with a significantly higher adjusted risk of death than CAC 0 with hazard ratios (HR) 8.5 (95% CI: 1.1-48.1, p = 0.02) and 13.3 (95% CI: 1.3-65.1, p = 0.01), respectively, independent of demographics, comorbidity, lipids and other cardiovascular risks, surrogates of bone disease, nutritional and inflammatory markers and dialysis dose. Total CAC [HR 6.7 (1.1-21.5, p = 0.03)] followed by the presence of CAC in the left main [4.6 (2.2-9.8, p = 0.001)] and left anterior descending artery [4.3 (2.1-14.2, p = 0.001)] were strong independent predictors of mortality even after adjusting for above covariates. Total and vessel-specific CAC predict mortality in MHD patients independent of traditional and nontraditional risk factors.

Amino-terminally truncated parathyroid hormone (PTH) fragments are detected to differing degrees by first- and second-generation immunometric PTH assays (PTH-IMAs), and acute changes in serum calcium affect the proportion of these fragments in circulation. However, the effect of chronic calcium changes and different vitamin D doses on these PTH measurements remains to be defined. In this study, 60 pediatric dialysis patients, aged 13.9 ± 0.7 years, with secondary hyperparathyroidism were randomized to 8 months of therapy with oral vitamin D combined with either calcium carbonate (CaCO3) or sevelamer. Serum phosphorus levels did not differ between groups. Serum calcium levels rose from 9.3 ± 0.1 to 9.7 ± 0.1 mg/dl during CaCO3 therapy (p

IntroductionCardiovascular disease accounts for almost half of all deaths in individuals with chronic kidney disease stage 5 despite advances in both dialysis treatment and cardiology. A combination of lipid-lowering and anti-inflammatory effects along with avoidance of hypercalcemia should be taken into account when choosing phosphorus binders for maintenance hemodialysis (MHD) patients.MethodsWe examined the association of sevelamer versus calcium-based phosphorus binders with lipid profile, inflammatory markers including C-reactive protein (CRP), and mineral metabolism in MHD patients who participated in the Nutritional and Inflammatory Evaluation of Dialysis Patients (NIED) study from October 2001 to July 2005.ResultsOf the 787 MHD patients in the NIED study, 697 were on either sevelamer, a calcium-based binder, or both and eligible for this study. We compared the groups based on taking sevelamer monotherapy (n = 283) or calcium binder monotherapy (n = 266) for serum phosphate control. There were no differences between the groups on dialysis vintage. There were significant differences in age, serum calcium and phosphorus levels, as well as intact parathyroid hormone levels. Using a logistic regression models, the sevelamer group had a higher odds of serum CRP

IntroductionCardiovascular disease accounts for almost half of all deaths in individuals with chronic kidney disease stage 5 despite advances in both dialysis treatment and cardiology. A combination of lipid-lowering and anti-inflammatory effects along with avoidance of hypercalcemia should be taken into account when choosing phosphorus binders for maintenance hemodialysis (MHD) patients.MethodsWe examined the association of sevelamer versus calcium-based phosphorus binders with lipid profile, inflammatory markers including C-reactive protein (CRP), and mineral metabolism in MHD patients who participated in the Nutritional and Inflammatory Evaluation of Dialysis Patients (NIED) study from October 2001 to July 2005.ResultsOf the 787 MHD patients in the NIED study, 697 were on either sevelamer, a calcium-based binder, or both and eligible for this study. We compared the groups based on taking sevelamer monotherapy (n = 283) or calcium binder monotherapy (n = 266) for serum phosphate control. There were no differences between the groups on dialysis vintage. There were significant differences in age, serum calcium and phosphorus levels, as well as intact parathyroid hormone levels. Using a logistic regression models, the sevelamer group had a higher odds of serum CRP

Metabolic acidosis, a common condition in patients with renal failure, may be linked to protein-energy malnutrition (PEM) and inflammation, together also known as malnutrition-inflammation complex syndrome (MICS). Methods of serum bicarbonate measurement may misrepresent the true bicarbonate level, since the total serum carbon dioxide measurement usually overestimates the serum bicarbonate concentration. Moreover, the air transportation of blood samples to distant laboratories may lead to erroneous readings. In patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD), a significant number of endocrine, musculoskeletal, and metabolic abnormalities are believed to result from acidemia. Metabolic acidosis may be related to PEM and MICS due to an increased protein catabolism, decreased protein synthesis, endocrine abnormalities including insulin resistance, decreased serum leptin level, and inflammation among individuals with renal failure. Evidence suggests that the catabolic effects of metabolic acidosis may result from an increased activity of the adenosine triphosphate (ATP)-dependent ubiquitin-proteasome and branched-chain keto acid dehydrogenase. In contrast to the metabolic studies, many epidemiologic studies in maintenance dialysis patients have indicated a paradoxically inverse association between mildly decreased serum bicarbonate and improved markers of protein-energy nutritional state. Hence metabolic acidosis may be considered as yet another element of the reverse epidemiology in ESRD patients. Interventional studies have yielded inconsistent results in CKD and ESRD patients, although in peritoneal dialysis patients, mitigating acidemia appears to more consistently improve nutritional status and reduce hospitalizations. Large-scale, prospective randomized interventional studies are needed to ascertain the potential benefits of correcting acidemia in malnourished and/or inflamed CKD and maintenance hemodialysis patients. Until then, all attempts should be made to adhere to the National Kidney Foundation Kidney Disease and Dialysis Outcome Quality Initiative guidelines to maintain a serum bicarbonate level in ESRD patients of at least 22 mEq/L.

Metabolic acidosis, a common condition in patients with renal failure, may be linked to protein-energy malnutrition (PEM) and inflammation, together also known as malnutrition-inflammation complex syndrome (MICS). Methods of serum bicarbonate measurement may misrepresent the true bicarbonate level, since the total serum carbon dioxide measurement usually overestimates the serum bicarbonate concentration. Moreover, the air transportation of blood samples to distant laboratories may lead to erroneous readings. In patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD), a significant number of endocrine, musculoskeletal, and metabolic abnormalities are believed to result from acidemia. Metabolic acidosis may be related to PEM and MICS due to an increased protein catabolism, decreased protein synthesis, endocrine abnormalities including insulin resistance, decreased serum leptin level, and inflammation among individuals with renal failure. Evidence suggests that the catabolic effects of metabolic acidosis may result from an increased activity of the adenosine triphosphate (ATP)-dependent ubiquitin-proteasome and branched-chain keto acid dehydrogenase. In contrast to the metabolic studies, many epidemiologic studies in maintenance dialysis patients have indicated a paradoxically inverse association between mildly decreased serum bicarbonate and improved markers of protein-energy nutritional state. Hence metabolic acidosis may be considered as yet another element of the reverse epidemiology in ESRD patients. Interventional studies have yielded inconsistent results in CKD and ESRD patients, although in peritoneal dialysis patients, mitigating acidemia appears to more consistently improve nutritional status and reduce hospitalizations. Large-scale, prospective randomized interventional studies are needed to ascertain the potential benefits of correcting acidemia in malnourished and/or inflamed CKD and maintenance hemodialysis patients. Until then, all attempts should be made to adhere to the National Kidney Foundation Kidney Disease and Dialysis Outcome Quality Initiative guidelines to maintain a serum bicarbonate level in ESRD patients of at least 22 mEq/L.