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Food-Related Carbonyl Stress in Cardiometabolic and Cancer Risk Linked to Unhealthy Modern Diet. Nutrients 2022; 14:nu14051061. [PMID: 35268036 PMCID: PMC8912422 DOI: 10.3390/nu14051061] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 02/28/2022] [Accepted: 03/01/2022] [Indexed: 02/01/2023] Open
Abstract
Carbonyl stress is a condition characterized by an increase in the steady-state levels of reactive carbonyl species (RCS) that leads to accumulation of their irreversible covalent adducts with biological molecules. RCS are generated by the oxidative cleavage and cellular metabolism of lipids and sugars. In addition to causing damage directly, the RCS adducts, advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs), cause additional harm by eliciting chronic inflammation through receptor-mediated mechanisms. Hyperglycemia- and dyslipidemia-induced carbonyl stress plays a role in diabetic cardiovascular complications and diabetes-related cancer risk. Moreover, the increased dietary exposure to AGEs/ALEs could mediate the impact of the modern, highly processed diet on cardiometabolic and cancer risk. Finally, the transient carbonyl stress resulting from supraphysiological postprandial spikes in blood glucose and lipid levels may play a role in acute proinflammatory and proatherogenic changes occurring after a calorie dense meal. These findings underline the potential importance of carbonyl stress as a mediator of the cardiometabolic and cancer risk linked to today’s unhealthy diet. In this review, current knowledge in this field is discussed along with future research courses to offer new insights and open new avenues for therapeutic interventions to prevent diet-associated cardiometabolic disorders and cancer.
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Xu C, Smith ER, Tiong MK, Ruderman I, Toussaint ND. Interventions to Attenuate Vascular Calcification Progression in Chronic Kidney Disease: A Systematic Review of Clinical Trials. J Am Soc Nephrol 2022; 33:1011-1032. [PMID: 35232774 PMCID: PMC9063901 DOI: 10.1681/asn.2021101327] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 02/16/2022] [Indexed: 11/03/2022] Open
Abstract
Background Vascular calcification is associated with cardiovascular morbidity and mortality in people with chronic kidney disease (CKD). Evidence-based interventions that may attenuate its progression in CKD remain uncertain.
Methods We conducted a systematic review of prospective clinical trials of interventions to attenuate vascular calcification in people with CKD, compare with placebo, another comparator, or standard of care. We included prospective clinical trials (randomized and nonrandomized) involving participants with stage 3-5D CKD or kidney transplant recipients; the outcome was vascular calcification measured using radiological methods. Quality of evidence was determined by the Cochrane risk of bias assessment tool and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method.
Results There were 77 trials (63 randomized) involving 6898 participants eligible for inclusion (median sample size, 50; median duration, 12 months); 58 involved participants on dialysis, 15 involved individuals with nondialysis CKD, and 4 involved kidney transplant recipients. Risk of bias was moderate over all. Trials involving magnesium and sodium thiosulfate consistently showed attenuation of vascular calcification. Trials involving intestinal phosphate binders, alterations in dialysate calcium concentration, vitamin K therapy, calcimimetics, and antiresorptive agents had conflicting or inconclusive outcomes. Trials involving vitamin D therapy and HMG-CoA reductase inhibitors did not demonstrate attenuation of vascular calcification. Mixed results were reported for single studies of exercise, vitamin E-coated or high-flux hemodialysis membranes, interdialytic sodium bicarbonate, SNF472, spironolactone, sotatercept, nicotinamide, and oral activated charcoal.
Conclusions Currently, there are insufficient or conflicting data regarding interventions evaluated in clinical trials for mitigation of vascular calcification in people with CKD. Therapy involving magnesium or sodium thiosulfate appears most promising, but evaluable studies were small and of short duration.
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Affiliation(s)
- Chelsea Xu
- Department of Medicine, University of Melbourne, Parkville, Australia
| | - Edward R Smith
- Department of Medicine, University of Melbourne, Parkville, Australia
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia
| | - Mark K Tiong
- Department of Medicine, University of Melbourne, Parkville, Australia
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia
| | - Irene Ruderman
- Department of Medicine, University of Melbourne, Parkville, Australia
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia
| | - Nigel D Toussaint
- Department of Medicine, University of Melbourne, Parkville, Australia
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia
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Basutkar RS, Varghese R, Mathew NK, Sankar Indira P, Viswanathan B, Sivasankaran P. Systematic review and meta-analysis of potential pleiotropic effects of sevelamer in chronic kidney disease: Beyond phosphate control. Nephrology (Carlton) 2021; 27:337-354. [PMID: 34882904 DOI: 10.1111/nep.14011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/01/2021] [Accepted: 12/05/2021] [Indexed: 11/26/2022]
Abstract
Sevelamer, has been shown to have many pleiotropic actions on lipid panel, various inflammatory markers, and blood glucose levels in chronic kidney disease patients. We conducted a systematic review and meta-analysis to compare these pleiotropic effects of sevelamer to other phosphate binders used in chronic kidney disease patients. The relevant randomized controlled trials published from 1 January 2001 to 31 November 2019 on the following databases: Cochrane Central Register of Controlled Trials published in The Cochrane Library, PubMed, Scopus and Google Scholar were identified. All the included studies were independently assessed for eligibility and risk of bias. The modified data extraction form of Cochrane was used. This review included 44 studies for qualitative analysis and 28 reports for quantitative analysis. A meta-analysis of three studies (n = 180) showed that glycated haemoglobin had significantly decreased in sevelamer-treated patients (MD: 0.5%; p = <.001). Compared with calcium-based phosphate binders, sevelamer showed a significant reduction in low-density lipoprotein (MD: -19.43 mg/dL; p = <.001) and total cholesterol (MD: -19.98 mg/dL; p < .001). A significant increase in high-density lipoprotein (MD: 1.29 mg/dL; p = .05) was also prominent in sevelamer treated patients. However, we were not able to observe a significant change in other biochemical parameters such as TG, CRP, hs-CRP, FGF-23, IL-6 and albumin as, no statistically significant difference was observed.
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Affiliation(s)
- Roopa Satyanarayan Basutkar
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Tamil Nadu, India
| | - Resia Varghese
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Tamil Nadu, India
| | - Nina Kallanthanath Mathew
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Tamil Nadu, India
| | - Prithika Sankar Indira
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Tamil Nadu, India
| | | | - Ponnusankar Sivasankaran
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Tamil Nadu, India
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4
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Stompór T. An Overview of the Pathophysiology of Vascular Calcification in Chronic Kidney Disease. Perit Dial Int 2020. [DOI: 10.1177/089686080702702s37] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Abnormalities of calcium–phosphate balance, with subsequent bone metabolism disorders, are among the key and earliest features of chronic kidney disease (CKD). Recently, another consequence of these abnormalities was brought to light—namely, vascular calcification. Most studies performed in patients on dialysis suggest that their vascular calcification is more advanced than that seen in the general population. Furthermore, the progression of vessel wall mineralization is much more dynamic in patients with CKD. Apart from the commonly assessed factors that promote vascular calcification, such as age, duration of dialysis, or poor control of calcium–phosphate status, several other factors have recently been identified. In the spectrum of substances involved in the regulation of the process of soft-tissue calcification, the most extensively studied in the nephrology literature are bone morphogenetic protein 7, osteoprotegerin, matrix Gla protein, fetuin-A, and the phosphatonins. Better understanding of the mechanisms underlying excess vascular mineralization have led to the development of promising new therapies.
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Affiliation(s)
- Tomasz Stompór
- Chair and Department of Nephrology, Medical Faculty, Jagiellonian University, Cracow, Poland
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Effect of Sevelamer on Calciprotein Particles in Hemodialysis Patients: The Sevelamer Versus Calcium to Reduce Fetuin-A-Containing Calciprotein Particles in Dialysis (SCaRF) Randomized Controlled Trial. Kidney Int Rep 2020; 5:1432-1447. [PMID: 32954068 PMCID: PMC7486191 DOI: 10.1016/j.ekir.2020.06.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 06/10/2020] [Accepted: 06/17/2020] [Indexed: 01/03/2023] Open
Abstract
Introduction Calciprotein particles (CPPs) are potentially modifiable mediators of phosphate toxicity in patients with kidney disease. We compared the effects of calcium carbonate (CC) and the non–calcium-based phosphate binder sevelamer on CPP levels in patients undergoing hemodialysis (HD). We hypothesized that treatment with sevelamer would achieve greater reductions in amorphous calcium phosphate–containing CPP (CPP-1) and hydroxyapatite-containing CPP (CPP-2) owing to reduced calcium loading and anti-inflammatory pleiotropic effects. Methods We conducted an open-label, randomized controlled trial (RCT) in which 31 stable prevalent HD patients were allocated to receive either sevelamer hydrochloride (SH), sevelamer carbonate (SC), or CC for 24 weeks. Dual primary endpoints were the between groups differences in serum CPP-1 and CPP-2 levels at 24 weeks in SH + SC–treated versus CC-treated patients. Effects on aortic pulse wave velocity (aPWV), inflammatory cytokines (interleukin-6 and -8), and effects across individual treatment arms were also assessed. Results Serum CPP-1, but not CPP-2, levels were lower in those randomly assigned to the sevelamer (SH + SC) group compared with the CC group at 24 weeks (–70%, 95% confidence interval [CI] –90% to –15%, P = 0.02). In subgroup analysis, this effect was confined to those receiving SC (–83.4%, 95% CI –95.7% to –36.8%, P = 0.01). aPWV and interleukin-8 levels were also lower in those who received sevelamer compared with CC at 24 weeks (–2.0 m/s, 95% CI –2.9 to –1.1; –57%, 95% CI –73% to –30%, respectively, both P = 0.01). Conventional markers of mineral metabolism remained stable across all treatment groups. Discussion Compared with treatment with CC, use of sevelamer for 24 weeks was associated with lower serum CPP-1 levels and a reduction in aPWV and systemic inflammation.
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Katopodis KP, Andrikos EK, Gouva CD, Bairaktari ET, Nikolopoulos PM, Takouli LK, Tzallas CS, Elisaf MS, Pappas MV, Siamopoulos KC. Sevelamer Hydrochloride versus Aluminum Hydroxide: Effect on Serum Phosphorus and Lipids in CAPD Patients. Perit Dial Int 2020. [DOI: 10.1177/089686080602600308] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background Dietary phosphorus restriction, oral administration of phosphorus binders, and dialysis are the main strategies to control hyperphosphatemia in patients with stage 5 chronic kidney disease. Aluminum hydroxide (AH) and calcium carbonate, the most commonly used phosphorus binders, have serious disadvantages, such as aluminum toxicity and hypercalcemia. Sevelamer hydrochloride (SH) is a relatively new nonabsorbed calcium- and aluminum-free phosphorus binder. The present study was designed to evaluate the efficacy of SH in the control of hyperphosphatemia and its effect, compared to AH, on serum lipid parameters in patients on continuous ambulatory peritoneal dialysis (CAPD). Methods 30 stable patients on CAPD were included in an open-label, randomized crossover study. After a 2-week phosphorus binder washout period, 15 patients (group I) were administered SH for 8 weeks and in the remaining patients (group II), AH was introduced (phase A). After a new 2-week washout period, patients crossed over to the alternate agent for another 8 weeks (phase B). Results There were similar reductions in serum phosphorus levels over the course of the study with both agents: by 1.18 ± 0.07 mg/dL (0.38 ± 0.03 mmol/L) with SH and by 1.25 ± 0.15 mg/dL (0.40 ± 0.05 mmol/L) with AH in phase A ( p = NS), and by 1.35 ± 0.25 mg/dL (0.43 ± 0.08 mmol/L) with AH and by 1.23 ± 0.80 mg/dL (0.39 ± 0.25 mmol/L) with SH in phase B ( p = NS). Moreover, SH administration was associated with a 10.5% ± 9.4% and a 20.1% ± 6.8% fall in total cholesterol ( p < 0.05) and low-density lipoprotein cholesterol ( p < 0.001) in phase A, and 11.9% ± 7.2% ( p < 0.05) and 21.5% ± 2.4% ( p < 0.001), respectively, in phase B. In both phases of the study, AH administration was not followed by a significant change in serum lipid parameters. Conclusion Sevelamer hydrochloride is a well-tolerated alternative to calcium- or aluminum-containing phosphorus binder in the control of serum phosphorus in CAPD patients. Furthermore, SH improves the lipid profile in these patients.
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Affiliation(s)
| | - Emilios K. Andrikos
- Department of Nephrology, General Hospital “G. Hatzikosta” of Ioannina, Ioannina, Greece
| | | | | | | | | | | | - Moses S. Elisaf
- Department of Nephrology, University Hospital, Ioannina, Greece
| | - Michael V. Pappas
- Department of Nephrology, General Hospital “G. Hatzikosta” of Ioannina, Ioannina, Greece
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Brønden A, Larsen EL, Karstoft K, Henriksen T, Vilsbøll T, Poulsen HE, Knop FK. Changes in oxidative nucleic acid modifications and inflammation following one-week treatment with the bile acid sequestrant sevelamer: Two randomised, placebo-controlled trials. J Diabetes Complications 2020; 34:107446. [PMID: 31672458 DOI: 10.1016/j.jdiacomp.2019.107446] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 08/09/2019] [Accepted: 09/07/2019] [Indexed: 12/13/2022]
Abstract
AIMS Sevelamer has been reported to have anti-oxidative and anti-inflammatory effects as well as effects on glycaemic control and plasma lipids. The aim of this study was to determine the effects of one-week treatment with sevelamer on oxidative nucleic acid modifications and inflammation markers. METHODS Two double-blinded studies including 30 patients with type 2 diabetes (T2D) and 20 healthy individuals were conducted. Participants were randomised to one week of treatment with sevelamer (1600 mg three times daily) or placebo. RNA and DNA oxidation, measured by urinary excretion of 8-oxo-7,8-dihydroguanosine(8-oxoGuo) and (8-oxo-7,8-dihydro-2'-deoxyguanosine(8-oxodG), and markers of inflammation were determined before and after the intervention. RESULTS In patients with T2D there was no significant placebo-corrected reduction in 8-oxoGuo or 8-oxodG. However, a reduction in 8-oxoGuo was observed within the group treated with sevelamer (∆8-oxoGuo/creatinine (median[IQR]): -0.04 [-0.24; 0.01] nmol/mmol, p = 0.02). A sevelamer-mediated reduction in interleukin-2 (p = 0.04) and a trend towards reduction in interleukin-6 (p = 0.053) were found in patients with T2D. CONCLUSIONS This study reveals a potential effect of sevelamer treatment on inflammation and possible oxidative RNA modifications. The potential protective effects of sevelamer in terms of cardiovascular disease in patients with T2D need further investigation.
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Affiliation(s)
- Andreas Brønden
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Emil List Larsen
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Pharmacology, Bispebjerg-Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark.
| | - Kristian Karstoft
- Department of Clinical Pharmacology, Bispebjerg-Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Trine Henriksen
- Department of Clinical Pharmacology, Bispebjerg-Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Henrik Enghusen Poulsen
- Department of Clinical Pharmacology, Bispebjerg-Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Filip Krag Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark
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Rahbar Saadat Y, Niknafs B, Hosseiniyan Khatibi SM, Ardalan M, Majdi H, Bahmanpoor Z, Abediazar S, Zununi Vahed S. Gut microbiota; an overlooked effect of phosphate binders. Eur J Pharmacol 2019; 868:172892. [PMID: 31870830 DOI: 10.1016/j.ejphar.2019.172892] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 12/06/2019] [Accepted: 12/19/2019] [Indexed: 12/18/2022]
Abstract
Hyperphosphatemia is a mineral bone-disease that increases cardiovascular complications and all-cause mortality in chronic kidney disease (CKD) patients. Oral phosphate binders absorb the dietary phosphate to prevent its high plasma levels. Moreover, they can adsorb some uremic toxins and decrease inflammation. A few recent studies highlight an ignored effect of phosphate binders on gut microbiota. Phosphorous is a major nutrient for survival and reproduction of bacteria and its intestinal concentration may impact the activity and composition of the gut microbiota. CKD is a state of an altered gut microbiome and bacterial-derived uremic toxins stimulate cardiovascular disease and systemic inflammation. The identification of the impact of phosphate binders on gut opens a new era in nephrology and fill the existing gap in interpretation of beneficial effects of phosphate binders. This review aims to highlight the impact of oral phosphate binders on the gut microbiome in CKD.
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Affiliation(s)
- Yalda Rahbar Saadat
- Nutrition Research Center, Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahram Niknafs
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Hasan Majdi
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zahra Bahmanpoor
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sima Abediazar
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Does the Administration of Sevelamer or Nicotinamide Modify Uremic Toxins or Endotoxemia in Chronic Hemodialysis Patients? Drugs 2019; 79:855-862. [PMID: 31062264 DOI: 10.1007/s40265-019-01118-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Hyperphosphatemia control is a major issue in hemodialysis patients. Both sevelamer and nicotinamide are prescribed for this purpose. In addition, they exert pleiotropic effects such as an improvement of inflammatory status and potentially enhanced clearance of uremic toxins. In the present secondary analysis of the NICOREN trial, we investigated the impact of sevelamer and nicotinamide on uremic toxins, toxin precursors, and endotoxemia in chronic hemodialysis patients. METHODS Circulating uremic toxins (including phenylacetylglutamine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, kynurenine, hippuric acid, indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, kynurenic acid, and p-cresyl glucuronide) and precursors were measured by ultra-performance liquid chromatography-tandem mass spectrometry, and urea, uric acid, phosphate, C-reactive protein, and intact parathyroid hormone by routine biochemistry methods. Serum endotoxin (evaluated by lipopolysaccharide levels) and C-terminal fibroblast growth factor-23 levels were measured using enzyme-linked immunosorbent assay kits. RESULTS One hundred hemodialysis patients were randomized to receive either nicotinamide or sevelamer treatment. Among them, 63% were male, mean (± standard deviation) age was 65 ± 14 years, 47% had diabetes mellitus, and 51% had a history of cardiovascular disease. In the sevelamer group, but not the nicotinamide group, serum levels of urea, uric acid, and fibroblast growth factor-23 were significantly reduced after 6 months of treatment. The other circulating uremic toxins and toxin precursors remained unchanged in response to either phosphate-lowering agent. Sevelamer treatment led to a marked decrease in serum lipopolysaccharide (p < 0.001) whereas nicotinamide treatment induced an only modest decrease of borderline significance (p = 0.057). There was no change in C-reactive protein levels. CONCLUSION In contrast to sevelamer, nicotinamide did not reduce circulating levels of low-molecular-weight uremic toxins other than phosphate, and neither agent reduced circulating uremic toxins of high-molecular-weight or protein-bound toxins. Sevelamer, but not nicotinamide, reduced serum endotoxin levels. Despite no change in serum C-reactive protein, the endotoxin-lowering effect of sevelamer may help to attenuate the inflammatory status of patients with chronic kidney disease.
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Ruggiero B, Trillini M, Tartaglione L, Rotondi S, Perticucci E, Tripepi R, Aparicio C, Lecchi V, Perna A, Peraro F, Villa D, Ferrari S, Cannata A, Mazzaferro S, Mallamaci F, Zoccali C, Bellasi A, Cozzolino M, Remuzzi G, Ruggenenti P, Kohan DE. Effects of Sevelamer Carbonate in Patients With CKD and Proteinuria: The ANSWER Randomized Trial. Am J Kidney Dis 2019; 74:338-350. [PMID: 31027883 DOI: 10.1053/j.ajkd.2019.01.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 01/29/2019] [Indexed: 11/11/2022]
Abstract
RATIONALE & OBJECTIVE Hyperphosphatemia is associated with increased risk for chronic kidney disease (CKD) progression and reduced antiproteinuric effects of renin-angiotensin system (RAS) blockers. We investigated whether the phosphate binder sevelamer carbonate may enhance the antiproteinuric effect of RAS inhibitors in patients with CKD. STUDY DESIGN Phase 2, randomized, controlled, open-label, crossover trial. SETTING & PARTICIPANTS Between November 2013 and December 2014, we enrolled 53 patients with CKD with estimated glomerular filtration rates (eGFRs)>15mL/min/1.73m2 and residual proteinuria with protein excretion≥0.5g/24h despite maximal tolerated ramipril and/or irbesartan therapy from 2 nephrology units in Italy. INTERVENTION After stratification by serum phosphate level, ≤4 or>4mg/dL, patients were randomly assigned to 3 months of sevelamer (1,600mg thrice daily) treatment followed by 3 months without sevelamer separated by a 1-month washout period or 3 months without sevelamer followed by 3 months with sevelamer, also separated by a 1-month washout period. OUTCOMES The primary outcome was 24-hour proteinuria (n=49patients). Secondary outcomes included measured GFR (using iohexol plasma clearance), office blood pressure (BP), serum lipid levels, levels of inflammation and bone metabolism biomarkers, urinary electrolyte levels, and arterial stiffness. RESULTS Changes in proteinuria during the 3-month treatment with (from 1.36 [IQR, 0.77-2.51] to 1.36 [IQR, 0.77-2.60] g/24h) or without (from 1.36 [IQR, 0.99-2.38] to 1.48 [IQR, 0.81-2.77] g/24h) sevelamer were similar (P=0.1). Sevelamer reduced urinary phosphate excretion without affecting serum phosphate levels. Sevelamer reduced C-reactive protein (CRP), glycated hemoglobin, and total and low-density lipoprotein cholesterol levels and increased high-density lipoprotein cholesterol levels without affecting levels of office BP, measured GFR, fibroblast growth factor 23, klotho, intact parathyroid hormone, serum vitamin D, or other urinary electrolytes. Results were similar in the low- and high-phosphate groups. Sevelamer was well tolerated. Adverse events were comparable between treatment periods. One case of transient hypophosphatemia was observed during treatment with sevelamer. LIMITATIONS Short treatment duration, lower pretreatment proteinuria than expected. CONCLUSIONS 3-month sevelamer treatment did not reduce proteinuria in patients with CKD on maximal RAS blockade. Amelioration of inflammation and dyslipidemia with sevelamer treatment raises the possibility that it may confer benefit in patients with CKD beyond reduction of proteinuria. FUNDING Sanofi (Milan, Italy). TRIAL REGISTRATION Registered at ClinicalTrials.gov with study number NCT01968759.
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Affiliation(s)
- Barbara Ruggiero
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Matias Trillini
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Lida Tartaglione
- Department of Cardiovascular, Respiratory, Nephrologic, Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | - Silverio Rotondi
- Department of Cardiovascular, Respiratory, Nephrologic, Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | - Elena Perticucci
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Rocco Tripepi
- Bianchi-Melacrino-Morelli Hospital, Nephrology Unit, Reggio Calabria, Italy
| | - Carolina Aparicio
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Veruska Lecchi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Annalisa Perna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Francesco Peraro
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Davide Villa
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Silvia Ferrari
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Antonio Cannata
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Sandro Mazzaferro
- Department of Cardiovascular, Respiratory, Nephrologic, Anesthetic and Geriatric Sciences, Sapienza University of Rome, Rome, Italy
| | | | - Carmine Zoccali
- Bianchi-Melacrino-Morelli Hospital, Nephrology Unit, Reggio Calabria, Italy
| | - Antonio Bellasi
- Department of Nephrology and Dialysis, Sant'Anna Hospital, ASST-Lariana, Como, Italy
| | | | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; L. Sacco Department of Biomedical and Clinical Sciences, University of Milan, Italy.
| | - Piero Ruggenenti
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Donald E Kohan
- Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT
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Shirazian S, Smaldone A, Rao MK, Silberzweig J, Jacobson AM, Fazzari M, Weinger K. A protocol for a pilot randomized controlled trial to assess the feasibility and effect of a cognitive behavioral intervention on quality of life for patients on hemodialysis. Contemp Clin Trials 2018; 73:51-60. [PMID: 30172036 DOI: 10.1016/j.cct.2018.08.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 08/23/2018] [Accepted: 08/28/2018] [Indexed: 10/28/2022]
Abstract
INTRODUCTION Poor health-related quality of life (HrQOL) is highly prevalent in patients on hemodialysis (HD), and is associated with increased hospitalizations and mortality. Cognitive behavioral (CB) techniques have improved HrQOL in HD patients but have not been routinely translated into clinical practice. The investigators present the rationale, study design and protocol of a randomized controlled trial to pilot the feasibility and effect of a translatable, behavioral-education intervention using CB techniques to improve poor HrQOL and self-management in hemodialysis patients. METHODS Forty-eight HD patients will be randomly assigned to either the study intervention which includes 8-12 behavioral-education sessions with incorporated CB techniques delivered over 12 weeks or a control group of dialysis education without incorporated CB techniques. Subjects will be followed for 16 weeks and the primary outcome, change in kidney disease quality of life (KDQOL)-36 scores, will be measured at 0, 8, and 16 weeks. The study will have 85% power to detect an 8-point change in KDQOL-36 scores. At the end of the study, qualitative data will be gathered through end-of-study focus groups, and semi-structured interviews. These data will be used to refine the intervention and help translate it into clinical practice. DISCUSSION There is promising evidence in support of CB-based interventions to improve HrQOL for patients on HD. Despite this, these interventions have not been routinely incorporated into clinical practice. The proposed intervention has the potential to improve both HrQOL and self-management, while also being easily translatable to other HD units.
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Affiliation(s)
- Shayan Shirazian
- Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
| | - Arlene Smaldone
- School of Nursing and College of Dental Medicine, Columbia University Medical Center, New York, NY, USA
| | - Maya K Rao
- Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | | | - Alan M Jacobson
- Winthrop Research Institute, NYU Winthrop University Hospital, Mineola, NY, USA
| | - Melissa Fazzari
- Winthrop Research Institute, NYU Winthrop University Hospital, Mineola, NY, USA
| | - Katie Weinger
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
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12
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Ruospo M, Palmer SC, Natale P, Craig JC, Vecchio M, Elder GJ, Strippoli GFM. Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD). Cochrane Database Syst Rev 2018; 8:CD006023. [PMID: 30132304 PMCID: PMC6513594 DOI: 10.1002/14651858.cd006023.pub3] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Phosphate binders are used to reduce positive phosphate balance and to lower serum phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of chronic kidney disease-mineral and bone disorder (CKD-MBD). This is an update of a review first published in 2011. OBJECTIVES The aim of this review was to assess the benefits and harms of phosphate binders for people with CKD with particular reference to relevant biochemical end-points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD of any GFR category comparing a phosphate binder to another phosphate binder, placebo or usual care to lower serum phosphate. Outcomes included all-cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum phosphate, parathyroid hormone (PTH), and FGF23. DATA COLLECTION AND ANALYSIS Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random-effects meta-analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes. MAIN RESULTS We included 104 studies involving 13,744 adults. Sixty-nine new studies were added to this 2018 update.Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron-based binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)-oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow-up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty-seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty-one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium-based phosphate binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron-based binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron-based binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all binders were uncertain.In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium-based binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow-up of up to 36 months, compared to calcium-based binders. Compared with calcium-based binders, lanthanum had uncertain effects with respect to all-cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment-related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head-to-head studies of iron-based binders compared with calcium. The paucity of placebo-controlled studies in CKD G5D has led to uncertainty about the effects of phosphate binders on patient-important outcomes compared with placebo.It is uncertain whether the effects of binders on clinically-relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses. AUTHORS' CONCLUSIONS In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium-based binders and incur less treatment-related hypercalcaemia, while we found no clinically important benefits of any phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of binders on patient-important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron-based phosphate binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron-based binders may lead to diarrhoea.
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Affiliation(s)
| | - Suetonia C Palmer
- University of Otago ChristchurchDepartment of Medicine2 Riccarton AvePO Box 4345ChristchurchNew Zealand8140
| | - Patrizia Natale
- DiaverumMedical Scientific OfficeLundSweden
- University of BariDepartment of Emergency and Organ TransplantationBariItaly
| | - Jonathan C Craig
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchWestmeadNSWAustralia2145
- Flinders UniversityCollege of Medicine and Public HealthAdelaideSAAustralia5001
| | | | - Grahame J Elder
- Westmead HospitalDepartment of Renal MedicineWestmeadNSWAustralia2145
- Garvan Institute of Medical ResearchOsteoporosis and Bone Biology DivisionDarlinghurstNSWAustralia2010
| | - Giovanni FM Strippoli
- DiaverumMedical Scientific OfficeLundSweden
- University of BariDepartment of Emergency and Organ TransplantationBariItaly
- The Children's Hospital at WestmeadCochrane Kidney and Transplant, Centre for Kidney ResearchWestmeadNSWAustralia2145
- Diaverum AcademyBariItaly
- The University of SydneySydney School of Public HealthSydneyAustralia
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Ketteler M. The Control of Hyperphosphatemia in Chronic Kidney Disease: Which Phosphate Binder? Int J Artif Organs 2018; 32:95-100. [DOI: 10.1177/039139880903200206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Hyperphosphatemia is currently regarded as a key mortality risk predictor in late CKD stages and especially in patients on dialysis. Fortunately, the armatorium to effectively treat hyperphosphatemia in end-stage renal disease has grown in recent years, and we gained an improved understanding of potential benefits and harms of specific compounds. Most interestingly, novel insights into the pathophysiology of calcium and phosphate handling, especially, the discovery of the phosphatonin FGF23, suggest a more complex assessment of phosphate balance especially in predialysis stages is warranted. This assessment should probably include measurements of fractional phosphate excretion and phosphatonin levels to objectively judge and effectively correct phosphate overload, however, clinical data on calcium and phosphate metabolism in CKD stages 3 – 4 are still scarce. This overview will both discuss aspects of pathophysiology of phosphate regulation and current and future clinical treatement approaches.
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Riccio E, Sabbatini M, Bruzzese D, Grumetto L, Marchetiello C, Amicone M, Andreucci M, Guida B, Passaretti D, Russo G, Pisani A. Plasma p-cresol lowering effect of sevelamer in non-dialysis CKD patients: evidence from a randomized controlled trial. Clin Exp Nephrol 2017; 22:529-538. [PMID: 29159529 DOI: 10.1007/s10157-017-1504-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 10/31/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND The accumulation of p-cresol, a metabolic product of aromatic amino acids generated by intestinal microbiome, increases the cardiovascular risk in chronic kidney disease (CKD) patients. Therefore, therapeutic strategies to reduce plasma p-cresol levels are highly demanded. It has been reported that the phosphate binder sevelamer (SEV) sequesters p-cresol in vitro, while in vivo studies on dialysis patients showed controversial results. Aim of our study was to evaluate the effect of SEV on p-cresol levels in non-dialysis CKD patients. METHODS This was a single-blind, randomized placebo-controlled trial (Registration number NCT02199444) carried on 69 CKD patients (stage 3-5, not on dialysis), randomly assigned (1:1) to receive either SEV or placebo for 3 months. Total p-cresol serum levels were evaluated at baseline (T0), and 1 (T1) and 3 months (T3) after treatment start. The primary end-point was to evaluate the effect of SEV on p-cresol levels. RESULTS Compared to baseline (T0, 7.4 ± 2.7 mg/mL), p-cresol mean concentration was significantly reduced in SEV patients after one (- 2.06 mg/mL, 95% CI - 2.62 to - 1.50 mg/mL; p < 0.001) and 3 months of treatment (- 3.97 mg/mL, 95% CI - 4.53 to - 3.41 mg/mL; p < 0.001); no change of plasma p-cresol concentration was recorded in placebo-treated patients. Moreover, P and LDL values were reduced after 3 months of treatment by SEV but not placebo. CONCLUSIONS In conclusion, our study represents the first evidence that SEV is effective in reducing p-cresol levels in CKD patients in conservative treatment, and confirms its beneficial effects on inflammation and lipid pattern.
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Affiliation(s)
- Eleonora Riccio
- Department of Nephrology, Second University of Naples, Naples, Italy.
| | - Massimo Sabbatini
- Chair of Nephrology, Department of Public Health, Federico II University of Naples, Naples, Italy
| | - Dario Bruzzese
- Chair of Statistics, Department of Public Health, Federico II University of Naples, Naples, Italy
| | - Lucia Grumetto
- Department of Pharmacy, School of Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Cristina Marchetiello
- Chair of Nephrology, Department of Public Health, Federico II University of Naples, Naples, Italy
| | - Maria Amicone
- Chair of Nephrology, Department of Public Health, Federico II University of Naples, Naples, Italy
| | - Michele Andreucci
- Unit of Nephrology, Department of Health Sciences, "Magna Graecia" University, Catanzaro, Italy
| | - Bruna Guida
- Division of Physiology, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Davide Passaretti
- Department of Economics and Law, University of Cassino and Southern Lazio, Cassino, Italy
| | - Giacomo Russo
- Department of Pharmacy, School of Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Antonio Pisani
- Chair of Nephrology, Department of Public Health, Federico II University of Naples, Naples, Italy
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15
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Lin CJ, Pan CF, Chuang CK, Liu HL, Huang SF, Chen HH, Wu CJ. Effects of Sevelamer Hydrochloride on Uremic Toxins Serum Indoxyl Sulfate and P-Cresyl Sulfate in Hemodialysis Patients. J Clin Med Res 2017; 9:765-770. [PMID: 28811853 PMCID: PMC5544481 DOI: 10.14740/jocmr1803e] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Accepted: 03/13/2014] [Indexed: 12/19/2022] Open
Abstract
Background Beside the phosphate binding effect, non-calcium non-aluminum phosphate binder, namely sevelamer hydrochloride (SH), has many other effects in dialysis patients. It can absorb many other compounds, decrease low-density lipoprotein cholesterol (LDL-C) level, and attenuate the progression of vascular calcification; it has been reported to have anti-inflammatory effect. However, it is not clear whether it has any effect on uremic toxins, i.e. serum indoxyl sulfate (IS) and p-cresyl sulfate, (PCS) in hemodialysis (HD) patients. This study was carried out to appraise the effect of sevelamer on serum IS and PCS in HD patients. Methods Five adult HD patients from a single medical center were enrolled in this study; these patients were treated with 800 mg of sevelamer thrice per day for 3 months; a series of biochemical parameters, serum IS and PCS were monitored concurrently. Results There was a significant reduction in the mean level of phosphate from 7.20 ± 0.70 mg/dL (mean ± SD) before treatment to 5.40 ± 0.50 mg/dL (mean ± SD) after treatment, total cholesterol from 151.00 ± 37.40 mg/dL (mean ± SD) before treatment to 119.20 ± 29.40 mg/dL (mean ± SD) after treatment, and PCS from 31.30 ± 10.60 mg/L (mean ± SD) before treatment to 19.70 ± 10.50 mg/L (mean ± SD) after treatment. On the contrary, this treatment had no effect on IS. Conclusion A statistically significant reduction of serum phosphate and PCS in HD patients treated with SH suggests that beside the action of lowering serum phosphate, sevelamer may have an important role in the treatment of uremic syndrome by decreasing the uremic toxin.
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Affiliation(s)
- Cheng-Jui Lin
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China.,Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan, Republic of China.,Institute of Biotechnology, National Taipei University of Technology, Taipei, Taiwan, Republic of China
| | - Chi-Feng Pan
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China.,Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan, Republic of China
| | - Chih-Kuang Chuang
- Institute of Biotechnology, National Taipei University of Technology, Taipei, Taiwan, Republic of China.,Division of Genetics and Metabolism, Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China.,College of Medicine, Fu-Jen Catholic University, Taipei County, Taiwan, Republic of China
| | - Hsuan-Liang Liu
- Institute of Biotechnology, National Taipei University of Technology, Taipei, Taiwan, Republic of China
| | - Sung-Fa Huang
- Department of Laboratory Medicine, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China
| | - Han-Hsiang Chen
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China.,Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan, Republic of China
| | - Chih-Jen Wu
- Division of Nephrology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China.,Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan, Republic of China.,Graduate Institute of Medical Science, Taipei Medical University, Taipei, Taiwan, Republic of China
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Bandera A, Colella E, Rizzardini G, Gori A, Clerici M. Strategies to limit immune-activation in HIV patients. Expert Rev Anti Infect Ther 2016; 15:43-54. [PMID: 27762148 DOI: 10.1080/14787210.2017.1250624] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Antiretroviral treatment of HIV infection reduces, but does not eliminate, viral replication and down modulates immune activation. The persistence of low level HIV replication in the host, nevertheless, drives a smouldering degree of immune activation that is observed throughout the natural history of disease and is the main driving force sustaining morbidity and mortality. Areas covered: Early start of antiretroviral therapy (ART) and intensive management of behavioural risk factors are possible but, at best, marginally successful ways to manage immune activation. We review alternative, possible strategies to reduce immune activation in HIV infection including timing of ART initiation and ART intensification to reduce HIV residual viremia; switch of ART to newer molecules with reduced toxicity; use of anti inflammatory/immunomodulatory agents and, finally, interventions aimed at modifying the composition of the microbiota. Expert commentary: Current therapeutic strategies to limit immune activation are only marginally successful. Because HIV eradication is currently impossible, intensive studies are needed to determine if and how immune activation can be silenced in HIV infection.
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Affiliation(s)
- Alessandra Bandera
- a Clinic of Infectious Diseases, 'San Gerardo' Hospital - ASST Monza, School of Medicine and Surgery , University Milano-Bicocca , Monza , Italy
| | - Elisa Colella
- a Clinic of Infectious Diseases, 'San Gerardo' Hospital - ASST Monza, School of Medicine and Surgery , University Milano-Bicocca , Monza , Italy
| | - Giuliano Rizzardini
- b Department of Infectious Diseases , ASST Fatebenefratelli Sacco , Milano , Italy.,c School of Clinical Medicine, Faculty of Health Science , University of the Witwatersrand , Johannesburg , South Africa
| | - Andrea Gori
- a Clinic of Infectious Diseases, 'San Gerardo' Hospital - ASST Monza, School of Medicine and Surgery , University Milano-Bicocca , Monza , Italy
| | - Mario Clerici
- d Department of Physiopathology and Transplants , University of Milano , Milano , Italy.,e Don C. Gnocchi Foundation , Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] , Milano , Italy
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17
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Sharaf El Din UAA, Salem MM, Abdulazim DO. Vascular calcification: When should we interfere in chronic kidney disease patients and how? World J Nephrol 2016; 5:398-417. [PMID: 27648404 PMCID: PMC5011247 DOI: 10.5527/wjn.v5.i5.398] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 04/20/2016] [Accepted: 06/27/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) patients are endangered with the highest mortality rate compared to other chronic diseases. Cardiovascular events account for up to 60% of the fatalities. Cardiovascular calcifications affect most of the CKD patients. Most of this calcification is related to disturbed renal phosphate handling. Fibroblast growth factor 23 and klotho deficiency were incriminated in the pathogenesis of vascular calcification through different mechanisms including their effects on endothelium and arterial wall smooth muscle cells. In addition, deficient klotho gene expression, a constant feature of CKD, promotes vascular pathology and shares in progression of the CKD. The role of gut in the etio-pathogenesis of systemic inflammation and vascular calcification is a newly discovered mechanism. This review will cover the medical history, prevalence, pathogenesis, clinical relevance, different tools used to diagnose, the ideal timing to prevent or to withhold the progression of vascular calcification and the different medications and medical procedures that can help to prolong the survival of CKD patients.
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18
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Epicardial adipose tissue volume increase in hemodialysis patients treated with sevelamer or calcium-based phosphate binders: a substudy of the Renagel in new dialysis trial. J Nephrol 2016; 29:683-90. [PMID: 27102490 DOI: 10.1007/s40620-016-0310-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 04/09/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND In the general population and in hemodialysis patients epicardial adipose tissue (EAT) has been associated with increased mortality and cardiovascular events. Weight loss and lipid lowering therapies reduced EAT in the general population. It is unknown whether sevelamer, a phosphate (Pi) binder that lowers cholesterol and reduces inflammation in dialysis patients also affects EAT progression. METHODS Post-hoc analysis of a randomized trial of sevelamer (SVL) versus calcium-based Pi binders (CPiB) in incident hemodialysis patients. EAT was measured on cardiac computed tomography scans performed at enrollment, 6, 12 and 18 months from baseline. RESULTS Of 109 patients, 54 received SVL and 55 CPiB; the median LDL change was -16.4 % (IQR: -67.5, 142.3 %) and 12.1 % (IQR: -51.9, 193.8 %) with SVL and CPiB respectively (p < 0.001). At baseline EAT correlated significantly with gender, body mass index and total coronary artery calcium score (all p < 0.02). At the end of follow-up, EAT progressed significantly from baseline in the CPiB treated patients but not in the SVL treated patients [median increase 9.1 % (p = 0.005) vs 3.9 % (p = 0.25)]. However, there was no significant difference in the degree of progression between treatment groups (p = 0.34). There was no correlation between LDL or CRP change and EAT change. There were insufficient events in either arm to assess the impact of EAT change on mortality. CONCLUSION EAT progression from baseline was significantly smaller with SVL than with CPiB, although the difference between treatments was not statistically significant, probably due to the small sample size. Change in serum lipids and markers of inflammation did not predict EAT progression.
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Patel L, Bernard LM, Elder GJ. Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-Analysis of Randomized Controlled Trials. Clin J Am Soc Nephrol 2015; 11:232-44. [PMID: 26668024 DOI: 10.2215/cjn.06800615] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 10/19/2015] [Indexed: 01/24/2023]
Abstract
BACKGROUND AND OBJECTIVES People with CKD stages 3-5 and on dialysis (5D) have dramatically increased mortality, which has been associated with hyperphosphatemia in many studies. Oral phosphate binders are commonly prescribed to lower serum phosphate. We conducted an updated meta-analysis of the noncalcium-based binder (non-CBB) sevelamer versus CBBs in CKD stages 3-5D. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Randomized, controlled trials comparing sevelamer with CBBs were identified through MEDLINE and the Cochrane Central Register of Controlled Trials. Patient-level outcomes included all-cause mortality, cardiovascular events and mortality, hospitalization, and adverse effects. Intermediate outcomes included vascular calcification and bone changes. Biochemical outcomes included serum phosphate, calcium, parathyroid hormone, lipids, and hypercalcemia. We conducted and reported this review according to Cochrane guidelines. RESULTS We included 25 studies to March 31, 2015 with 4770 participants (88% on hemodialysis). Patients receiving sevelamer had lower all-cause mortality (risk ratio [RR], 0.54; 95% confidence interval [95% CI], 0.32 to 0.93), no statistically significant difference in cardiovascular mortality (n=2712; RR, 0.33; 95% CI, 0.07 to 1.64), and an increase in combined gastrointestinal events of borderline statistical significance (n=384; RR, 1.42; 95% CI, 0.97 to 2.08). For biochemical outcomes, patients receiving sevelamer had lower total serum cholesterol (mean difference [MD], -20.2 mg/dl; 95% CI, -25.9 to -14.5 mg/dl), LDL-cholesterol (MD, -21.6 mg/dl; 95% CI, -27.9 to -15.4 mg/dl), and calcium (MD, -0.4 mg/dl; 95% CI, -0.6 to -0.2 mg/dl) and a reduced risk of hypercalcemia (RR, 0.30; 95% CI, 0.19 to 0.48). End of treatment intact parathyroid hormone was significantly higher for sevelamer (MD, 32.9 pg/ml; 95% CI, 0.1 to 65.7 pg/ml). Serum phosphate values showed no significant differences. CONCLUSIONS Patients with CKD stages 3-5D using sevelamer have lower all-cause mortality compared with those using CBBs. Because of a lack of placebo-controlled studies, questions remain regarding phosphate binder benefits for patients with CKD stages 3-5 and not on dialysis.
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Affiliation(s)
- Leena Patel
- Cornerstone Research Group, Burlington, Ontario, Canada
| | | | - Grahame J Elder
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia; and Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia
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20
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Stinghen AEM, Massy ZA, Vlassara H, Striker GE, Boullier A. Uremic Toxicity of Advanced Glycation End Products in CKD. J Am Soc Nephrol 2015; 27:354-70. [PMID: 26311460 DOI: 10.1681/asn.2014101047] [Citation(s) in RCA: 160] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Advanced glycation end products (AGEs), a heterogeneous group of compounds formed by nonenzymatic glycation reactions between reducing sugars and amino acids, lipids, or DNA, are formed not only in the presence of hyperglycemia, but also in diseases associated with high levels of oxidative stress, such as CKD. In chronic renal failure, higher circulating AGE levels result from increased formation and decreased renal clearance. Interactions between AGEs and their receptors, including advanced glycation end product-specific receptor (RAGE), trigger various intracellular events, such as oxidative stress and inflammation, leading to cardiovascular complications. Although patients with CKD have a higher burden of cardiovascular disease, the relationship between AGEs and cardiovascular disease in patients with CKD is not fully characterized. In this paper, we review the various deleterious effects of AGEs in CKD that lead to cardiovascular complications and the role of these AGEs in diabetic nephropathy. We also discuss potential pharmacologic approaches to circumvent these deleterious effects by reducing exogenous and endogenous sources of AGEs, increasing the breakdown of existing AGEs, or inhibiting AGE-induced inflammation. Finally, we speculate on preventive and therapeutic strategies that focus on the AGE-RAGE axis to prevent vascular complications in patients with CKD.
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Affiliation(s)
- Andréa E M Stinghen
- Institut National de la Santé et de la Recherche Médicale (INSERM) U-1088, Jules Verne University of Picardie, Amiens, France
| | - Ziad A Massy
- Institut National de la Santé et de la Recherche Médicale (INSERM) U-1088, Jules Verne University of Picardie, Amiens, France; Division of Nephrology, Ambroise Paré University Medical Center, Assistance Publique-Hôpitaux de Paris (APHP), University of Paris Ouest, University Versailles-Saint Quentin, Boulogne Billancourt/Paris, France
| | - Helen Vlassara
- Division of Experimental Diabetes and Aging, Departments of Geriatrics and Palliative Care and Medicine and Division of Experimental Diabetes and Aging, Department of Geriatrics and Aging and Division of Nephrology, Department of Medicine, Icahn School of Medicine, New York, New York; and
| | - Gary E Striker
- Division of Experimental Diabetes and Aging, Departments of Geriatrics and Palliative Care and Medicine and Division of Experimental Diabetes and Aging, Department of Geriatrics and Aging and Division of Nephrology, Department of Medicine, Icahn School of Medicine, New York, New York; and
| | - Agnès Boullier
- Institut National de la Santé et de la Recherche Médicale (INSERM) U-1088, Jules Verne University of Picardie, Amiens, France; Biochemistry Laboratory, Amiens University Medical Center, Amiens, France
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Wang C, Liu X, Zhou Y, Li S, Chen Y, Wang Y, Lou T. New Conclusions Regarding Comparison of Sevelamer and Calcium-Based Phosphate Binders in Coronary-Artery Calcification for Dialysis Patients: A Meta-Analysis of Randomized Controlled Trials. PLoS One 2015; 10:e0133938. [PMID: 26230677 PMCID: PMC4521824 DOI: 10.1371/journal.pone.0133938] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Accepted: 07/02/2015] [Indexed: 01/31/2023] Open
Abstract
Background Sevelamer hydrochloride is used widely, but its impact upon cardiovascular calcification, cardiovascular mortality, all-cause mortality and hospitalization is not known. Outcomes Primary outcome was cardiovascular calcification (coronary artery calcification scores (CACS) and aortic calcification scores (ACS)). Secondary outcomes were serum characteristics, hospitalization, cardiovascular mortality and all-cause mortality. Risk ratio (RR), mean differences and standard mean difference with 95% confidence intervals (CIs) were pooled using random- or fixed-effects models. Results We identified 31 studies (on 23 randomized controlled trials with 4395 participants). An analysis pooling showed a significant decrease in serum levels of phosphate with calcium-based phosphate binders (CBPBs) by 0.17 mg/dL [mean difference (MD), 95% CI, 0.03, 0.31] than sevelamer. A significant difference in the change of CACS by –102.66 [MD: 95% CI, –159.51, –45.80] and ACS by –1008.73 [MD, 95% CI, –1664.75, –352.72] between sevelamer and CBPBs was observed. Prevalence of hypercalcemia (serum levels of calcium >10.2–10.5 mg/dL and >11.0 mg/dL) was significantly smaller for sevelamer (RR = 0.44, 95% CI, 0.33, 0.58; RR = 0.24, 95% CI, 0.14, 0.40). No significant difference was found in hospitalization, all-cause mortality or cardiovascular mortality. Conclusions This meta-analysis suggests that sevelamer benefits dialysis patients in terms of CACS, ACS and hypercalcemia.
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Affiliation(s)
- Caixia Wang
- Department of Nephrology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xun Liu
- Department of Nephrology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- * E-mail: (XL); (TQL)
| | - Yongming Zhou
- Department of Nephrology, The Affiliated Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Shaomin Li
- Department of Nephrology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanbing Chen
- Medical Genetics Center, Guangdong Women and Children Hospital, Guangzhou, China
| | - Yanni Wang
- Department of Nephrology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tanqi Lou
- Department of Nephrology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- * E-mail: (XL); (TQL)
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Mallipattu SK, Uribarri J. Advanced glycation end product accumulation: a new enemy to target in chronic kidney disease? Curr Opin Nephrol Hypertens 2015; 23:547-54. [PMID: 25160075 DOI: 10.1097/mnh.0000000000000062] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE OF REVIEW The critical role of advanced glycation end products (AGEs) in the progression of chronic diseases and their complications has recently become more apparent. This review summarizes the recent contributions to the field of AGEs in chronic kidney disease (CKD). RECENT FINDINGS Over the past 3 decades, AGEs have been implicated in the progression of CKD, and specifically diabetic nephropathy. Although numerous in-vitro and in-vivo studies highlight the detrimental role of AGEs accumulation in tissue injury, few prospective human studies or clinical trials show that inhibiting this process ameliorates disease. Nonetheless, recent studies have focused on the novel mechanisms that contribute to end-organ injury as a result of AGEs accumulation, as well as novel targets of therapy in kidney disease. SUMMARY As the prevalence and the incidence of CKD rises in the United States, it is essential to identify therapeutic strategies that either delay the progression of CKD or improve mortality in this population. The focus of this review is on highlighting the recent studies that advance our current understanding of the mechanisms mediating AGEs-induced CKD progression, as well as novel treatment strategies that have the potential to abrogate this disease process. VIDEO ABSTRACT http://links.lww.com/CONH/A12.
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Affiliation(s)
- Sandeep K Mallipattu
- aDivision of Nephrology, Department of Medicine, Stony Brook University bDivision of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA
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Abstract
Sevelamer carbonate (Renvela(®)), a buffered form of sevelamer hydrochloride (Renagel(®)), is an orally administered non-absorbed phosphate-binding anion exchange resin used in the treatment of hyperphosphataemia in chronic kidney disease (CKD). In the EU, sevelamer carbonate is approved in adult CKD patients who require dialysis and in those who do not require dialysis with serum phosphate levels ≥ 1.78 mmol/L, whereas in the USA sevelamer carbonate is approved in adult CKD patients who require dialysis. Sevelamer carbonate and sevelamer hydrochloride achieved similar reductions in serum phosphate levels in randomized comparative trials in patients with CKD receiving haemodialysis; sevelamer carbonate also reduced serum phosphate levels in noncomparative studies in CKD patients not requiring dialysis. The most common adverse events with sevelamer carbonate are gastrointestinal in nature. Sevelamer has pleiotropic effects, such as improving the serum lipid profile and attenuating endothelial and cardiovascular risk factors in CKD. All formulations of sevelamer have markedly higher acquisition costs than calcium-based phosphate binders. Cost-effectiveness analyses focusing specifically on sevelamer carbonate have not been conducted, and those based on clinical trial data with sevelamer hydrochloride have provided both favourable and unfavourable results compared with calcium-based phosphate binders, reflecting heterogeneity between modelled analyses in terms of data sources, assumptions, comparators, geographical regions, type of costs included and other factors. Although well-designed studies evaluating the impact of phosphate binders on hard clinical endpoints appear to be warranted, sevelamer carbonate may be particularly useful for the treatment of patients at risk of metabolic acidosis (offering advantages over sevelamer hydrochloride in this regard) and for individuals requiring treatment with a phosphate binding agent that does not contain aluminium or calcium.
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24
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Shaman AM, Kowalski SR. Hyperphosphatemia Management in Patients with Chronic Kidney Disease. Saudi Pharm J 2015; 24:494-505. [PMID: 27330380 PMCID: PMC4908098 DOI: 10.1016/j.jsps.2015.01.009] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 01/01/2015] [Indexed: 01/07/2023] Open
Abstract
Hyperphosphatemia in chronic kidney disease (CKD) patients is a potentially life altering condition that can lead to cardiovascular calcification, metabolic bone disease (renal osteodystrophy) and the development of secondary hyperparathyroidism (SHPT). It is also associated with increased prevalence of cardiovascular diseases and mortality rates. To effectively manage hyperphosphatemia in CKD patients it is important to not only consider pharmacological and nonpharmacological treatment options but also to understand the underlying physiologic pathways involved in phosphorus homoeostasis. This review will therefore provide both a background into phosphorus homoeostasis and the management of hyperphosphatemia in CKD patients. In addition, it will cover some of the most important reasons for failure to control hyperphosphatemia with emphasis on the effect of the gastric pH on phosphate binders efficiency.
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Affiliation(s)
- Ahmed M Shaman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Stefan R Kowalski
- School of Pharmacy and Medical Sciences, University of South Australia, South Australia, Australia
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25
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Raggi P. Inflammation and calcification: the chicken or the hen? Atherosclerosis 2014; 238:173-4. [PMID: 25525745 DOI: 10.1016/j.atherosclerosis.2014.10.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 10/17/2014] [Indexed: 12/18/2022]
Affiliation(s)
- Paolo Raggi
- Mazankowski Alberta Heart Institute, Division of Cardiology and Department of Medicine, University of Alberta, Edmonton, AB, Canada.
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26
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Kinetic and thermodynamic evaluation of phosphate ions binding onto sevelamer hydrochloride. Int J Pharm 2014; 474:25-32. [DOI: 10.1016/j.ijpharm.2014.08.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 08/03/2014] [Indexed: 11/29/2022]
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Rastogi A. Sevelamer revisited: pleiotropic effects on endothelial and cardiovascular risk factors in chronic kidney disease and end-stage renal disease. Ther Adv Cardiovasc Dis 2014; 7:322-42. [PMID: 24327730 PMCID: PMC3917706 DOI: 10.1177/1753944713513061] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Endothelial dysfunction underlies multiple cardiovascular consequences of chronic kidney disease (CKD) and antecedent diabetes or hypertension. Endothelial insults in CKD or end-stage renal disease (ESRD) patients include uremic toxins, serum uric acid, hyperphosphatemia, reactive oxygen species, and advanced glycation endproducts (AGEs). Sevelamer carbonate, a calcium-free intestinally nonabsorbed polymer, is approved for hyperphosphatemic dialysis patients in the US and hyperphosphatemic stage 3-5 CKD patients in many other countries. Sevelamer has been observed investigationally to reduce absorption of AGEs, bacterial toxins, and bile acids, suggesting that it may reduce inflammatory, oxidative, and atherogenic stimuli in addition to its on-label action of lowering serum phosphate. Some studies also suggest that noncalcium binders may contribute less to vascular calcification than calcium-based binders. Exploratory sevelamer carbonate use in patients with stages 2-4 diabetic CKD significantly reduced HbA1c, AGEs, fibroblast growth factor (FGF)-23, and total and low-density lipoprotein (LDL) cholesterol versus calcium carbonate; inflammatory markers decreased and defenses against AGEs increased. Sevelamer has also been observed to reduce circulating FGF-23, potentially reducing risk of left ventricular hypertrophy. Sevelamer but not calcium-based binders in exploratory studies increases flow-mediated vasodilation, a marker of improved endothelial function, in patients with CKD. In contrast, lanthanum carbonate and calcium carbonate effects on FMV did not differ in hemodialysis recipients. The recent independent-CKD randomized trial compared sevelamer versus calcium carbonate in predialysis CKD patients (investigational in the US, on-label in European participants); sevelamer reduced 36-month mortality and the composite endpoint of mortality or dialysis inception. Similarly, independent-HD in incident dialysis patients showed improved survival with 24 months of sevelamer versus calcium-based binders. This review discusses recent exploratory evidence for pleiotropic effects of sevelamer on endothelial function in CKD or ESRD. Endothelial effects of sevelamer may contribute mechanistically to the improved survival observed in some studies of CKD and ESRD patients.
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Affiliation(s)
- Anjay Rastogi
- Division of Nephrology, Department of Medicine, 10630 Santa Monica Boulevard, Los Angeles, CA 90025, USA
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Massy ZA, Maizel J. [Pleiotropic effects of sevelamer: a model of intestinal tract chelating agent]. Nephrol Ther 2014; 10:441-50. [PMID: 25070605 DOI: 10.1016/j.nephro.2014.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 03/29/2014] [Accepted: 04/15/2014] [Indexed: 12/25/2022]
Abstract
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.
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Affiliation(s)
- Ziad A Massy
- Inserm U-1088, UFR de médecine et de pharmacie, université de Picardie-Jules-Verne, 1, rue des Louvels, 80037 Amiens cedex, France; Service de néphrologie, université Paris Île-de-France ouest (UVSQ), hôpital Ambroise-Paré, 9, avenue Charles-de-Gaulle, 92104 Boulogne-Billancourt cedex, France.
| | - Julien Maizel
- Inserm U-1088, UFR de médecine et de pharmacie, université de Picardie-Jules-Verne, 1, rue des Louvels, 80037 Amiens cedex, France; Unité de réanimation médicale, service de néphrologie, CHU d'Amiens, place Victor-Pauchet, 80054 Amiens cedex, France
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Sandler NG, Zhang X, Bosch RJ, Funderburg NT, Choi AI, Robinson JK, Fine DM, Coombs RW, Jacobson JM, Landay AL, Douek DC, Tressler R, Read SW, Wilson CC, Deeks SG, Lederman MM, Gandhi RT. 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. J Infect Dis 2014; 210:1549-54. [PMID: 24864123 DOI: 10.1093/infdis/jiu305] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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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Tzanno-Martins C, Biavo BMM, Ferreira-Filho O, Ribeiro-Junior E, João-Luiz MVS, Degaspari S, Scavone C, Kawamoto E. Clinical efficacy, safety and anti-inflammatory activity of two sevelamer tablet forms in patients on low-flux hemodialysis. Int J Immunopathol Pharmacol 2014; 27:25-35. [PMID: 24674676 DOI: 10.1177/039463201402700105] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Sevelamer hydrochloride is an ionic exchange resin with high affinity for phosphate. This phosphate-binding agent has few serious adverse reactions with the advantage of reducing total and low density lipoprotein (LDL) cholesterol levels. However, it is controversial as to whether sevelamer hydrochloride can modulate the inflammatory response via endotoxin reduction. Therefore, a single-center, open-label, prospective and randomized study was performed to compare the clinical efficacy, safety and anti-inflammatory activity of two sevelamer hydrochloride tablet forms a branded tablet form, Renagel (Genzyme manufacturer) and its generic equivalent (EMS manufacturer). Twenty-eight chronic kidney disease volunteer patients at stage 5 (CDK 5D), on chronic low-flux hemodialysis carried out in 4-hour sessions, three times a week, were studied. The serum phosphorus, ionic calcium, total cholesterol and fractions, bicarbonate, blood pH, interleukin (IL)-6, IL-10, IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels were collected prior to dialysis at mid-week. The incidence of gastrointestinal adverse effects were determined at the end of the phosphate-binder washout period as well as at the end of the fourth and eighth weeks of use of both tablet forms. The same magnitude of reduction in serum phosphorus was observed with both sevelamer tablet forms. Only the Renagel group showed lower total cholesterol and lower LDL cholesterol levels at the fourth and eighth week versus baseline. No significant differences in serum cytokine levels were identified in either drug group. However, the incidence of intestinal obstipation was higher among patients who used the generic equivalent form. In conclusion, Renagel and its EMS generic equivalent tablet forms have a similar clinical efficacy in reducing phosphorus in CKD 5D patients on low-flux hemodialysis and a similar safety profile.
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Affiliation(s)
- C Tzanno-Martins
- Home Dialysis Center (HDC), Center of Study for Social and Health Humaniztion (CEHUS), São Paulo, Brazil
| | - B M M Biavo
- Home Dialysis Center (HDC), Center of Study for Social and Health Humaniztion (CEHUS), São Paulo, Brazil
| | - O Ferreira-Filho
- Home Dialysis Center (HDC), Center of Study for Social and Health Humaniztion (CEHUS), São Paulo, Brazil
| | - E Ribeiro-Junior
- Home Dialysis Center (HDC), Center of Study for Social and Health Humaniztion (CEHUS), São Paulo, Brazil
| | - M V S João-Luiz
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil
| | - S Degaspari
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil
| | - C Scavone
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil
| | - E Kawamoto
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil
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Nonextracorporeal Methods for Decreasing Uremic Solute Concentration: A Future Way To Go? Semin Nephrol 2014; 34:228-43. [DOI: 10.1016/j.semnephrol.2014.02.012] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Alam S, Hussain A, Daiwajna R, Tan J. Clinical efficacy of sevelamer hydrochloride in patients with end-stage renal disease: a retrospective study. Singapore Med J 2013; 54:263-6. [PMID: 23716151 DOI: 10.11622/smedj.2013105] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Sevelamer hydrochloride (Renagel) is frequently used as a second-line phosphate binder in patients on renal replacement therapy. Many studies have shown that sevelamer can improve vascular calcification, serum uric acid and low-density lipoprotein (LDL) cholesterol levels. The main objectives of this study were to assess the efficacy of sevelamer against calcium-based phosphate binders, as well as its tolerability and side-effect profile. METHODS This was a retrospective study that included all patients on renal replacement therapy (between 2008 and 2011) who had previously received calcium-based binders for ≥ 6 months and were subsequently switched to sevelamer. Data collected from the patients' medical records included demographics, as well as renal parameters three months prior to sevelamer treatment, and at three and six months post treatment. The study excluded patients on multiple, concomitant phosphate binders or with functioning renal transplants, and those who were noncompliant or had inadequate follow-up blood investigations. RESULTS A total of 39 patients were included in the study. No major side effects were reported by any of the patients. There were improvements in calcium, phosphate, uric acid and LDL cholesterol levels at three and six months post-sevelamer treatment. CONCLUSION We found sevelamer to be superior to calcium-based phosphate binders in reducing serum calcium, phosphate, uric acid and LDL cholesterol levels in our patient population with advanced renal bone disease. Sevelamer also appears to be well tolerated with no significant side effects.
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Affiliation(s)
- Sartaj Alam
- Renal Unit, Suri Seri Begawan Hospital, Kuala Belait Dialysis Center, Kuala Belait, Brunei Darussalam.
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Sonikian M, Papachristou E, Goumenos DS. Optimal use of phosphate binders in chronic kidney disease. Expert Opin Pharmacother 2013; 14:2521-32. [PMID: 24215605 DOI: 10.1517/14656566.2013.852183] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Hyperphosphatemia is one of the major factors associated with the development of vascular calcification in patients with chronic kidney disease (CKD). Since phosphate is retained in such patients, pharmacological treatment and other measures are necessary to control hyperphosphatemia. Several phosphate binders (calcium salts, magnesium salts, non-calcium-based binders and aluminium) are available for the treatment of hyperphosphatemia. Nevertheless, none of the above mentioned agents has shown an overall superiority over others, while potency and side effects are quite variable among them creating difficulties in choosing the optimal drug for each patient. AREAS COVERED The authors discuss the disturbed phosphate metabolism, the available phosphate binders, as well as the general therapeutic principles of treating hyperphosphatemia in CKD patients. The literature used for this review had been retrieved from PubMed and covers a large number of original and retrospective studies as well as prospective cohort studies, meta-analyses and international clinical guidelines. EXPERT OPINION Lowering serum phosphate levels in CKD patients may potentially have a positive impact on cardiovascular morbidity and mortality. Factors that should be taken into consideration when selecting a specific drug include CKD stage, cardiovascular disease, severity of secondary hyperparathyroidism, concomitant medications, life expectancy and patient compliance. Therefore, when selecting a specific phosphate binder, individualisation is mandatory.
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Affiliation(s)
- Makrouhi Sonikian
- Sismanoglion - A. Fleming General Hospital, Department of Nephrology , 15232 Athens , Greece +0030 210 6859562 ; +0030 2610 994424 ;
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Phosphate restriction significantly reduces mortality in uremic rats with established vascular calcification. Kidney Int 2013; 84:1145-53. [PMID: 24107846 DOI: 10.1038/ki.2013.213] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 03/28/2013] [Accepted: 04/04/2013] [Indexed: 01/25/2023]
Abstract
The role of hyperphosphatemia in the pathogenesis of secondary hyperparathyroidism, cardiovascular disease, and progression of renal failure is widely known. Here we studied effects of dietary phosphate restriction on mortality and vascular calcification in uremic rats. Control and uremic rats were fed a high-phosphate diet and at 3 months a portion of rats of each group were killed. Serum phosphate and the calcium phosphate product increased in uremic rats, as did aortic calcium. Of the rats, 56% had positive aortic staining for calcium (von Kossa), RUNX2, and osteopontin. The remaining uremic rats were continued on diets containing high phosphate without and with sevelamer, or low phosphate, and after 3 more months they were killed. Serum phosphate was highest in uremic rats on high phosphate. Serum PTH and FGF-23 were markedly lower in rats on low phosphate. Mortality on high phosphate was 71.4%, with sevelamer reducing this to 37.5% and phosphate restriction to 5.9%. Positive aortic staining for von Kossa, RUNX2, and osteopontin was increased, but phosphate restriction inhibited this. Kidneys from low-phosphate and sevelamer-treated uremic rats had less interstitial fibrosis, glomerulosclerosis, and inflammation than those of uremic rats on high phosphate. Importantly, kidneys from rats on low phosphate showed improvement over kidneys from high-phosphate rats at 3 months. Left ventricles from rats on low phosphate had less perivascular fibrosis and smaller cardiomyocyte size compared to rats on high phosphate. Thus, intensive phosphate restriction significantly reduces mortality in uremic rats with severe vascular calcification.
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Cupisti A, Gallieni M, Rizzo MA, Caria S, Meola M, Bolasco P. Phosphate control in dialysis. Int J Nephrol Renovasc Dis 2013; 6:193-205. [PMID: 24133374 PMCID: PMC3797240 DOI: 10.2147/ijnrd.s35632] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Prevention and correction of hyperphosphatemia is a major goal of chronic kidney disease–mineral and bone disorder (CKD–MBD) management, achievable through avoidance of a positive phosphate balance. To this aim, optimal dialysis removal, careful use of phosphate binders, and dietary phosphate control are needed to optimize the control of phosphate balance in well-nourished patients on a standard three-times-a-week hemodialysis schedule. Using a mixed diffusive–convective hemodialysis tecniques, and increasing the number and/or the duration of dialysis tecniques are all measures able to enhance phosphorus (P) mass removal through dialysis. However, dialytic removal does not equal the high P intake linked to the high dietary protein requirement of dialysis patients; hence, the use of intestinal P binders is mandatory to reduce P net intestinal absorption. Unfortunately, even a large dose of P binders is able to bind approximately 200–300 mg of P on a daily basis, so it is evident that their efficacy is limited in the case of an uncontrolled dietary P load. Hence, limitation of dietary P intake is needed to reach the goal of neutral phosphate balance in dialysis, coupled to an adequate protein intake. To this aim, patients should be informed and educated to avoid foods that are naturally rich in phosphate and also processed food with P-containing preservatives. In addition, patients should preferentially choose food with a low P-to-protein ratio. For example, patients could choose egg white or protein from a vegetable source. Finally, boiling should be the preferred cooking procedure, because it induces food demineralization, including phosphate loss. The integrated approach outlined in this article should be actively adapted as a therapeutic alliance by clinicians, dieticians, and patients for an effective control of phosphate balance in dialysis patients.
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Affiliation(s)
- Adamasco Cupisti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Guida B, Cataldi M, Riccio E, Grumetto L, Pota A, Borrelli S, Memoli A, Barbato F, Argentino G, Salerno G, Memoli B. Plasma p-cresol lowering effect of sevelamer in peritoneal dialysis patients: evidence from a Cross-Sectional Observational Study. PLoS One 2013; 8:e73558. [PMID: 24015307 PMCID: PMC3756054 DOI: 10.1371/journal.pone.0073558] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Accepted: 07/29/2013] [Indexed: 12/13/2022] Open
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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Affiliation(s)
- Bruna Guida
- Division of Physiology, Dept. of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Mauro Cataldi
- Division of Pharmacology, Dept. of Neuroscience, Reproductive and Odontostomatologic Sciences, Federico II University of Naples, Naples, Italy
| | - Eleonora Riccio
- Dept. of Nephrology, Federico II University of Naples, Naples, Italy
| | - Lucia Grumetto
- Dept. of Pharmaceutical and Toxicological Chemistry, Federico II University of Naples, Naples, Italy
| | - Andrea Pota
- Dept. of Nephrology, Federico II University of Naples, Naples, Italy
| | - Silvio Borrelli
- Nephrology Division, Second University of Naples, Naples, Italy
| | - Andrea Memoli
- Dept. of Nephrology, Federico II University of Naples, Naples, Italy
| | - Francesco Barbato
- Dept. of Pharmaceutical and Toxicological Chemistry, Federico II University of Naples, Naples, Italy
| | - Gennaro Argentino
- Dept. of Nephrology, Federico II University of Naples, Naples, Italy
| | - Giuliana Salerno
- Dept. of Biochemistry and Medical Biotechnology, Federico II University of Naples, Naples, Italy
| | - Bruno Memoli
- Dept. of Nephrology, Federico II University of Naples, Naples, Italy
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Thomsen S. Delayed progression to dialysis with early and intensive management of predialysis chronic kidney disease: a case-based approach. CASE REPORTS IN NEPHROLOGY AND UROLOGY 2013; 3:74-86. [PMID: 24167516 PMCID: PMC3808807 DOI: 10.1159/000353265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
In addition to hypertension and diabetes, disorders in mineral metabolism and bone disease (e.g. affecting phosphorus, calcium, parathyroid hormone, and vitamin D) are common complications of chronic kidney disease (CKD) and contribute to morbidity and mortality. Consequently, CKD requires multifactorial treatment to slow CKD progression and avoid end-stage renal disease. CKD progression and treatment outcomes are monitored by measuring the estimated glomerular filtration rate (eGFR), which decreases by 2–12 ml/min/1.73 m2 per year depending on the stage of CKD and comorbidities, such as diabetes. This paper presents representative case studies illustrating the delay and reversal of CKD progression with comprehensive, individualized treatment regimens, including non-calcium phosphate binders, antihypertensives, lipid-lowering drugs, calcimimetics, and other drugs as required, to treat each component of CKD including CKD-mineral and bone disorder. Four patients are included, with an average age of 70–81 years and CKD stage 3 or 4 accompanied by various comorbidities, most notably diabetes and hypertension. The range of treatment and follow-up durations was 6–7 years. In each case, there was evidence of slowing or prevention of CKD progression, according to eGFR and serum creatinine, regardless of the patient's age or CKD stage. Despite a baseline eGFR of <20 ml/min/1.73 m2 in 1 female patient, after 6 years of follow-up, her eGFR had stabilized and was maintained at >15 ml/min/1.73 m2. These observations reinforce the value of early nephrology referral and comprehensive management of CKD and underlying conditions (hypertension and diabetes) beginning at eGFR <60 ml/min/1.73 m2.
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Ikee R, Tsunoda M, Sasaki N, Sato N, Hashimoto N. Emerging effects of sevelamer in chronic kidney disease. Kidney Blood Press Res 2013; 37:24-32. [PMID: 23486088 DOI: 10.1159/000343397] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2013] [Indexed: 11/19/2022] Open
Abstract
Sevelamer, a non-absorbable anion exchange resin, is used to control hyperphosphatemia in chronic kidney disease (CKD) by binding to dietary phosphate in the gastrointestinal tract. Lipid-lowering effect is a widely recognized pleiotropic effect of sevelamer. In addition, many studies have reported that sevelamer leads to reduced vascular calcification compared with calcium-containing phosphate binders, which is attributed to the improved lipid profiles and decreased calcium load. In addition, recent studies have suggested novel pleiotropic effects on bone structure, inflammation, oxidative stress, anemia, fetuin-A, and trace element metabolism in CKD patients. All of these effects have the potential to suppress the development/progression of cardiovascular lesions and reduce mortality. This review summarizes novel findings from recent studies and discusses the potential pleiotropic effects of sevelamer on non-traditional cardiovascular risk factors in CKD patients.
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Affiliation(s)
- Ryota Ikee
- Department of Nephrology and Dialysis, H. N. Medic Kitahiroshima, Japan
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Potential beneficial role of sevelamer hydrochloride in diabetic retinopathy. Med Hypotheses 2013; 80:431-5. [PMID: 23357670 DOI: 10.1016/j.mehy.2012.12.035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2012] [Accepted: 12/29/2012] [Indexed: 11/23/2022]
Abstract
Patients with chronic kidney disease (CKD) experience co-morbid illnesses, including cardiovascular disease and retinopathy. Sevelamer hydrochloride (Renagel®); a non-calcium phosphate binder reduces coronary artery and aortic calcification as compared to calcium containing phosphate binders and additionally effects inflammatory biomarkers such as C-reactive protein (CRP), and lowers LDL cholesterol in patients with CKD. Since retinopathy is proven to be associated with increased coronary calcification, shared pathophysiological processes may contribute to both microvascular and macrovascular disease. We here suggest three different mechanisms of possible sevelamer's influence on the retinopathy: (1) by direct effect on the microvasculature through lowering CRP and LDL, involved in endothelial dysfunction and atherogenesis, (2) indirectly by attenuation of vascular calcification of aorta and carotid internal artery, it reduces ischaemia and improves circulation in the opthalmic artery and hence postponing retinopathy, (3) through hypertension by reducing atherosclerosis and calcification of carotid arteries, sevelamer decreases stiffness and intima-media wall thickness, therefore lowering blood pressure, which is well known to increase progression of diabetic retinopathy. So far no studies have yet been published on the direct influence of sevelamer on the retinopathy which we believe has good theoretical background. With its combined macrovascular and microvascular effect, sevelamer could potentially postpone and/or decrease retinopathy in diabetic patients with hypertension, and that are on hemodialysis or even predialysis patients.
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Cozzolino M, Rizzo MA, Stucchi A, Cusi D, Gallieni M. Sevelamer for hyperphosphataemia in kidney failure: controversy and perspective. Ther Adv Chronic Dis 2012; 3:59-68. [PMID: 23251769 DOI: 10.1177/2040622311433771] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The term 'chronic kidney disease-mineral and bone disorder' (CKD-MBD), coined in 2006, was introduced in a position statement by the Kidney Disease: Improving Global Outcomes (KDIGO) organization. According to the KDIGO guidelines, CKD-MBD is a systemic disorder and patients with vascular or valvular calcifications should be included in the group with the greatest cardiovascular risk. Therefore, the presence or absence of calcification is a key factor in strategy decisions for such patients. In particular, it is recommended that the use of calcium-based phosphate binders should be restricted in patients with hypercalcaemia, vascular calcification, low levels of parathyroid hormone (PTH) or adynamic bone disease. In this respect, it should be underscored that treatment with phosphate-binding agents can normalise the levels of phosphate and PTH, but the use of calcium carbonate can favour the progression of vascular calcifications. There is evidence of reduced progression of vascular calcification in patients treated with sevelamer compared with high doses of calcium-based binders, but there is as yet no strong evidence regarding hard outcomes, such as mortality or hospitalization, to support the use of one treatment over another. Nevertheless, a number of experimental and observational findings seem to suggest that sevelamer should be preferred over calcium-based binders, in as much as these can increase cardiovascular mortality when used in high doses. A threshold dose below which calcium-based binders can be used safely in CKD patients with hyperphosphatemia has yet to be established.
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Vlassara H, Uribarri J, Cai W, Goodman S, Pyzik R, Post J, Grosjean F, Woodward M, Striker GE. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol 2012; 7:934-42. [PMID: 22461535 PMCID: PMC3362316 DOI: 10.2215/cjn.12891211] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Accepted: 03/03/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND OBJECTIVES Increased inflammation and oxidative stress may be caused by proteins and lipids modified by cytotoxic advanced glycation end products (AGEs) in food. Restricting food containing elevated AGEs improves these risk factors in diabetic CKD. Because diet adherence can be problematic, this study aimed to remove cytotoxic AGEs from food already ingested and to determine whether sevelamer carbonate sequesters cytotoxic AGEs in the gut, preventing their uptake and thereby reducing AGE-induced abnormalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This single-center, randomized, 2-month, open-label, intention-to-treat, crossover study compared sevelamer carbonate with calcium carbonate treatment in stage 2-4 diabetic CKD. Participants received 2 months of treatment with one drug, had a 1-week washout, and then received the opposite drug for 2 months. RESULTS Sevelamer carbonate reduced HbA1c, serum methylglyoxal, serum (ε)N-carboxymethyl-lysine, triglycerides, and 8-isoprostanes. Total cholesterol and fibroblast growth factor 23 were reduced by sevelamer carbonate, relative to calcium carbonate. AGE receptor 1 and sirtuin 1 mRNA were increased and PMNC TNFα levels were decreased by sevelamer carbonate, but not calcium carbonate. Medications and caloric and AGE intake remained unchanged. Sevelamer carbonate reversibly bound AGE-BSA at intestinal, but not stomach, pH. CONCLUSIONS Sevelamer carbonate significantly reduces HbA1c, fibroblast growth factor 23, lipids, and markers of inflammation and oxidative stress, and markedly increases antioxidant markers, independently of phosphorus in patients with diabetes and early kidney disease. These novel actions of sevelamer carbonate on metabolic and inflammatory abnormalities in type 2 diabetes mellitus may affect progression of early diabetic CKD.
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Affiliation(s)
- Helen Vlassara
- Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York
| | - Jaime Uribarri
- Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
| | - Weijing Cai
- Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York
| | - Susan Goodman
- Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York
| | - Renata Pyzik
- Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York
| | - James Post
- Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
- Bronx Veterans Administration Hospital, Bronx, New York
| | - Fabrizio Grosjean
- Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York
- Division of Nephrology, Department of Medicine, Pavia, Italy; and
| | - Mark Woodward
- George Institute, University of Sydney, Sydney, Australia
| | - Gary E. Striker
- Division of Experimental Diabetes and Aging, Department of Geriatrics, Mount Sinai School of Medicine, New York, New York
- Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York
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Mallipattu SK, He JC, Uribarri J. Role of advanced glycation endproducts and potential therapeutic interventions in dialysis patients. Semin Dial 2012; 25:529-38. [PMID: 22548330 DOI: 10.1111/j.1525-139x.2012.01081.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
It has been nearly 100 years since the first published report of advanced glycation end products (AGEs) by the French chemist Maillard. Since then, our understanding of AGEs in diseased states has dramatically changed. Especially in the last 25 years, AGEs have been implicated in complications related to aging, neurodegenerative diseases, diabetes, and chronic kidney disease. Although AGE formation has been well characterized by both in vitro and in vivo studies, few prospective human studies exist demonstrating the role of AGEs in patients on chronic renal replacement therapy. As the prevalence of end-stage renal disease (ESRD) in the United States rises, it is essential to identify therapeutic strategies that either delay progression to ESRD or improve morbidity and mortality in this population. This article reviews the role of AGEs, especially those of dietary origin, in ESRD patients as well as potential therapeutic anti-AGE strategies in this population.
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Affiliation(s)
- Sandeep K Mallipattu
- Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA
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43
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Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, Donate-Correa J, Cazaña-Pérez V, García-Pérez J. Effect of phosphate binders on serum inflammatory profile, soluble CD14, and endotoxin levels in hemodialysis patients. Clin J Am Soc Nephrol 2011; 6:2272-9. [PMID: 21784820 DOI: 10.2215/cjn.01650211] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND OBJECTIVES Hyperphosphatemia and subclinical endotoxemia are important sources of inflammation in HD. Proinflammatory cytokines are strong correlates of soluble CD14 (sCD14) concentrations, an independent predictor of mortality in this population. We evaluated the effects of calcium acetate and sevelamer hydrochloride on serum inflammatory profile, endotoxin concentrations, and sCD14 levels in HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Prospective, randomized, open-label, parallel design trial. Fifty-nine stable HD patients, 30 receiving sevelamer, and 29 receiving calcium acetate were evaluated. Serum levels of inflammatory parameters (high-sensitivity C-reactive protein [hs-CRP], TNF-α, interleukin (IL)-1, -6, -10, and -18), as well as endotoxin and sCD14 concentrations, were measured at baseline and after 3 months of therapy. RESULTS Serum IL-6 increased in patients receiving calcium acetate, whereas hs-CRP and IL-6 significantly decreased in subjects treated with sevelamer, with IL-10 experiencing a trend to increase (P = 0.052). Serum endotoxin and sCD14 levels did not change after treatment with calcium acetate. However, these parameters decreased by 22.6% and 15.2%, respectively (P < 0.01), in patients receiving sevelamer. Multiple regression analysis showed that variation in serum endotoxin concentrations was the strongest factor associated with IL-6 change, whereas the only variables independently associated with changes in sCD14 levels were the variations in serum IL-6 and endotoxin concentrations. CONCLUSIONS Administration of the noncalcium phosphate binder sevelamer to maintenance HD patients is associated with a significant decrease in hs-CRP, IL-6, serum endotoxin levels and sCD14 concentrations.
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Affiliation(s)
- Juan F Navarro-González
- Research Unit, University Hospital Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain.
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Abstract
Uremic toxins are associated with various disorders in patients with end-stage renal disease and it is difficult to remove some of these toxins by dialysis. Since some uremic toxins are generated by bacterial metabolites in the colon, oral adsorbents that interfere with the absorption of uremic toxins or their precursors are believed to prevent their accumulation in the body. AST-120 adsorbs various uremic retention solutes in the gastrointestinal system and has potential for providing clinical benefit. Sevelamer hydrochloride binds some harmful compounds in addition to phosphate and seems to have pleiotropic effects that include lowering serum LDL cholesterol levels and reduction of inflammation. The effect of sevelamer hydrochloride on indoxyl sulfate and p-cresol has been shown in an in vitro study; however, in vivo studies in mice or humans did not demonstrate this effect on protein-binding uremic toxins. Oral adsorbents are thus one of the important modalities in the treatment of uremic syndrome.
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Affiliation(s)
- Shunsuke Goto
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, Kobe, Japan.
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45
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Navaneethan SD, Palmer SC, Vecchio M, Craig JC, Elder GJ, Strippoli GF. Phosphate binders for preventing and treating bone disease in chronic kidney disease patients. Cochrane Database Syst Rev 2011:CD006023. [PMID: 21328279 DOI: 10.1002/14651858.cd006023.pub2] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Phosphate binders are widely used to lower serum phosphorus levels in people with chronic kidney disease (CKD) but their impact in CKD remains controversial. OBJECTIVES To review the effects of various phosphate binders on biochemical and patient-level end-points in CKD stages 3 to 5D. SEARCH STRATEGY In March 2010 we searched MEDLINE, EMBASE, the Cochrane Renal Group's Specialised Register and CENTRAL for relevant studies. SELECTION CRITERIA Randomised controlled trials (RCTs) or quasi-RCTs that assessed the effects of various phosphate binders in adults with CKD. DATA COLLECTION AND ANALYSIS Two authors independently reviewed search results and extracted data. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model. MAIN RESULTS Sixty studies (7631 participants) were included. There was no significant reduction in all-cause mortality (10 studies, 3079 participants: RR 0.73, 95% CI 0.46 to 1.16), or serum calcium by phosphorus (Ca x P) product with sevelamer hydrochloride compared to calcium-based agents. There was a significant reduction in serum phosphorus (16 studies, 3126 participants: MD 0.23 mg/dL, 95% CI 0.04 to 0.42) and parathyroid hormone (PTH) (12 studies, 2551 participants; MD 56 pg/mL, 95% CI 26 to 84) but a significant increase in the risk of hypercalcaemia (12 studies, 1144 participants: RR 0.45, 95% CI 0.35 to 0.59) with calcium-based agents compared to sevelamer hydrochloride. There was a significant increase in the risk of adverse gastrointestinal events with sevelamer hydrochloride in comparison to calcium salts (5 studies, 498 participants: RR 1.58, 95% CI 1.11 to 2.25). Compared with calcium-based agents, lanthanum significantly reduced serum calcium (2 studies, 122 participants: MD -0.30 mg/dL, 95% CI -0.64 to -0.25) and the Ca x P product, but not serum phosphorus levels. The effects of calcium acetate on biochemical end-points were similar to those of calcium carbonate. The phosphorus lowering effects of novel agents such as ferric citrate, colestilan and niacinamide were only reported in a few studies. AUTHORS' CONCLUSIONS Available phosphate-binding agents have been shown to reduce phosphorus levels in comparison to placebo. However, there are insufficient data to establish the comparative superiority of novel non-calcium binding agents over calcium-containing phosphate binders for patient-level outcomes such as all-cause mortality and cardiovascular end-points in CKD.
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Affiliation(s)
- Sankar D Navaneethan
- Department of Nephrology and Hypertension, Glickman Urological and Kidney institute, Cleveland Clinic, Cleveland, OH, USA, 44195
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Biggar P, Ketteler M. Sevelamer carbonate for the treatment of hyperphosphatemia in patients with kidney failure (CKD III - V). Expert Opin Pharmacother 2011; 11:2739-50. [PMID: 20977406 DOI: 10.1517/14656566.2010.526107] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
IMPORTANCE OF THE FIELD Altered mineral metabolism in chronic kidney disease (CKD) is associated with increased morbidity, mortality, hospitalization, cost of care and reduced quality of life. Phosphorus control, one component of CKD metabolic derangements, is potentially related to impaired outcomes and has significant room for improvement. AREAS COVERED IN THIS REVIEW Historical, present and future aspects of treatment of hyperphosphatemia focusing on sevelamer hydrochloride and sevelamer carbonate. WHAT THE READER WILL GAIN Comprehensive insight into the background and controversies regarding phosphate binders. TAKE HOME MESSAGE While calcium-free phosphate binders with a sevelamer backbone may offer therapeutic advantages for CKD patients at risk, more studies comprising significant patient numbers are warranted to answer compelling clinical questions.
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Affiliation(s)
- Patrick Biggar
- Klinikum Coburg, Nephrological Department, Ketschendorferstrasse 33, 96450 Coburg, Germany.
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47
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Boaz M, Katzir Z, Schwartz D, Gafter U, Biro A, Shtendik L, Kon V, Chernin G, Weinstein T. Effect of Sevelamer Hydrochloride Exposure on Carotid Intima Media Thickness in Hemodialysis Patients. ACTA ACUST UNITED AC 2011; 117:c83-8. [DOI: 10.1159/000319654] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Accepted: 04/08/2010] [Indexed: 11/19/2022]
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Abstract
Control of serum phosphorus remains a vexing problem in chronic kidney disease. Although novel dialysis regimens may provide excellent phosphorus control, phosphate binders remain necessary for most dialysis patients. Block et al. present a phase I clinical trial examining the safety and efficacy of SBR759, a novel non-calcium, iron-based phosphate binder. Although the risks of iron accumulation and hypocalcemia must be addressed, this phosphate binder appears to be well tolerated and effective and offers a powder-based formulation.
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Affiliation(s)
- Joshua J Zaritsky
- Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
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Resić H, Kukavica N, Sahović V, Masnić F. Different effects of low weight molecular heparin and unfractioned heparin on lipid profile and coagulation at haemodialysis patients. Bosn J Basic Med Sci 2010; 10 Suppl 1:S56-62. [PMID: 20433433 DOI: 10.17305/bjbms.2010.2650] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Each haemodialysis treatment requires the application of anticoagulation medicines, which will prevent coagulation in extracorporal blood circulation. In this study we try to determine the quality of admitted anticoagulant and his effect on lipid profile on hemodialysis patients after twelve months. We were applying standard heparin and low weight molecular heparin (LWMH). During our study we was analyzed effect of anticoagulant therapy on lipid profile of hemodialysis patients. In that parameters was included triglycerides, cholesterol, lipoprotein fractions, complete blood count, Hgb, HCT; All of these parameters was analyzed in correlation with duration of hemodialysis treatment, sex and age of the patients. Our research was carried out as a prospective study, for the period of 12 months. In the study were included 60 patients (34M/26F), who were on chronic hemodialysis program. All patients were divided into two groups. The first group of patients was included 27 patients (15M/12F) who were treated with standard heparin. The second group was included 33 patients (19M/14F) treated with LWMH (enoxaparin). The average length of hemodialysis was 4.15 +/- 0.52 years. Each patient had a protocol in which is marked parameters such as flushing dialysator, creating fibrin-ring in vein and arterial dropper and the time it takes to stop the bleeding. In the results the average age amounted to 58.54 +/- 2.24 years. The average value of cholesterol in the blood was 5.38 +/- 2.26. Values of HDL-cholesterol in patients treated with LWMH were significantly lower (P<or=0.05) in the treated group compared to standard heparin. There were no significant statistical differences between both groups in relation to the level of LDL cholesterol in the blood. (p ns). LWMH had a better effect on the irrigation system and dialysator on both sex equally, compared with standard heparin. LWMH is in the female dialysis population has led to improvements in lipid profile. After the first six months of study in male patients treated with standard heparin in relation to the female part of the observed patients was significantly better anticoagulation effect in the first half of the study (1.85 +/- 0.05 compared to 2.09 +/- 0.10) (P<or=0.001). Average rating blood clots were statistically significant for standard heparin (p<or=0,001) with 1,86 at the beginning the value is fell to 1.41, while for LWMH with 1.85 at the beginning of the study amounted to 1.52 grade average. (P<or=0.05). The results of our study show that LWMH had a better rinsing effect of dialysis systems and dialysator in both sex equally, compared to standard unfractioned heparin. When the male part of the respondents in the first six months of standard heparin had a better evaluation of blood clots than women in the same group, and also better than the group on enoxaparin for both gender. LWMH in female dialysis population has led to improved lipid profiles. Patients treated with standard heparin had a statistically significant reduction in the rate of blood clots than patients who received enoxaparin (LWMH). Such differences were minimal, which can be interpreted by the fact that LWMH still derivative of the standard heparin.
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Affiliation(s)
- Halima Resić
- Clinic for Hemodialysis, University of Sarajevo Clinics Centre, Bolnicka 25, Sarajevo, Bosnia and Herzegovina
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50
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Raggi P, Vukicevic S, Moysés RM, Wesseling K, Spiegel DM. Ten-year experience with sevelamer and calcium salts as phosphate binders. Clin J Am Soc Nephrol 2010; 5 Suppl 1:S31-40. [PMID: 20089501 DOI: 10.2215/cjn.05880809] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Most patients with chronic kidney disease experience abnormalities in serum calcium, phosphorus, parathyroid hormone, and vitamin D metabolism. These can lead to vascular calcification (VC), which has been associated with increased risk for cardiovascular disease and mortality. Although hyperphosphatemia is believed to be a risk factor for mortality and VC, no randomized trial was ever designed to demonstrate that lowering phosphate reduces mortality. Nonetheless, binders have been used extensively, and the preponderance of evidence shows that sevelamer slows the development of VC whereas calcium salts do not. Four studies have demonstrated a slower progression of VC with sevelamer than with calcium-containing binders, although a fifth study showed nonsuperiority. Conversely, the results on mortality with sevelamer have been variable, and data on calcium-based binders are nonexistent. Improved survival with sevelamer was demonstrated in a small randomized clinical trial, whereas a larger randomized trial failed to show a benefit. In addition, preclinical models of renal failure and preliminary clinical data on hemodialysis patients suggest a potential benefit for bone with sevelamer. Meanwhile, several randomized and observational studies suggested no improvement in bone density and fracture rate, and a few noted an increase in total and cardiovascular mortality in the general population given calcium supplements. Although additional studies are needed, there are at least indications that sevelamer may improve vascular and bone health and, perhaps, mortality in hemodialysis patients, whereas data on calcium-based binders are lacking.
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Affiliation(s)
- Paolo Raggi
- Department of Medicine and Radiology, Emory University School of Medicine, 1365 Clifton Road NE, Atlanta, GA 30322, USA.
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