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1
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Zheng C, Liu J, Wang T, Hu H, Chen Y. A network meta-analysis of therapies for hyperphosphatemia in CKD based on randomized trials. Sci Rep 2025; 15:2012. [PMID: 39814766 PMCID: PMC11736078 DOI: 10.1038/s41598-024-84942-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 12/30/2024] [Indexed: 01/18/2025] Open
Abstract
To update the efficacy and safety of different drugs for the treatment of patients with hyperphosphatemia in chronic kidney disease, we conducted a network meta-analysis of 22 therapies for the treatment of uncontrolled hyperphosphatemia in patients with chronic kidney disease (CKD). All randomized controlled trials on hyperphosphatemia published from January 2013 to November 2023 were searched from CNKI, VIP database, Wanfang database, PubMed, Scopus, and Cochrane databases. Meta-analysis was used to evaluate the serum phosphorus, calcium levels, total effective rate and adverse events of patients with chronic kidney disease (CKD). Data collection and quality evaluation were carried out by three evaluators, RevMan (5.5.3) and Stata (1.3.0). A total of 71 RCTs, and 22 treatment strategies were included in this NMA. The results showed that all treatment strategies were effective in improving patients' blood phosphorus levels. Among them, SL + CT, CA + CC, SL and TCM had higher overall efficacy, RT, TCM and SL + CT had lower blood phosphorus levels, SL + CT, SL and NAM had lower blood calcium levels, and OAC, CC, NAM and SL had higher safety. Among them, SL + CT seems to be the most recommended treatment strategy. In addition, multidrug combination strategies usually have a higher efficacy and safety profile.
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Affiliation(s)
- Congyang Zheng
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
- Medical School of Chinese PLA, Beijing, China
| | - Jia Liu
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tao Wang
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Haiyang Hu
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanyuan Chen
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China.
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2
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Najafgholian S, Soltani M, Amirian S, Pourahmadian N. A Rare Presentation of Fahr's Syndrome Associated With Secondary Hyperparathyroidism. Clin Case Rep 2025; 13:e70134. [PMID: 39835167 PMCID: PMC11742964 DOI: 10.1002/ccr3.70134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/31/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025] Open
Abstract
Fahr's syndrome (FS) is a rare disorder characterized by intracerebral calcification, presenting with various neuropsychiatric symptoms. This case highlights a rare presentation of FS with secondary hyperparathyroidism. It underscores the importance of comprehensive evaluation of early symptoms, effective use of diagnostic procedures, and proper management of symptoms.
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Affiliation(s)
- Simin Najafgholian
- Department of Clinical Research DevelopmentArak University of Medical SciencesArakIran
| | - Mahbod Soltani
- Department of Clinical Research DevelopmentArak University of Medical SciencesArakIran
| | - Sanaz Amirian
- Department of Clinical Research DevelopmentArak University of Medical SciencesArakIran
| | - Negar Pourahmadian
- Department of Clinical Research DevelopmentArak University of Medical SciencesArakIran
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3
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Marando M, Tamburello A, Salera D, Di Lullo L, Bellasi A. Phosphorous metabolism and manipulation in chronic kidney disease. Nephrology (Carlton) 2024; 29:791-800. [PMID: 39433296 PMCID: PMC11579558 DOI: 10.1111/nep.14407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 09/13/2024] [Accepted: 10/05/2024] [Indexed: 10/23/2024]
Abstract
Chronic kidney disease-mineral bone disorder (CKD-MBD) is a syndrome commonly observed in subjects with impaired renal function. Phosphate metabolism has been implicated in the pathogenesis of CKD-MBD and according to the phosphorocentric hypothesis may be the key player in the pathogenesis of these abnormalities. As phosphorous is an essential component for life, absorption from the bowel, accumulation and release from the bones, and elimination through the kidneys are all homeostatic mechanisms that maintain phosphate balance through very sophisticated feedback mechanisms, which comprise as main actors: vitamin D (VD), parathyroid hormone (PTH), calciproteins particles (CPPs), fibroblast growth factor-23 (FGF-23) and other phosphatonins and klotho. Indeed, as the renal function declines, factors such as FGF-23 and PTH prevent phosphate accumulation and hyperphosphatemia. However, these factors per se may be responsible for the organ damages associated with CKD-MBD, such as bone osteodystrophy and vascular calcification. We herein review the current understanding of the CKD-MBD focusing on phosphorous metabolism and the impact of phosphate manipulation on surrogate and hard outcomes.
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Affiliation(s)
- Marco Marando
- Service of PneumologyHôpitaux Universitaires de GenèveGenevaSwitzerland
| | | | - Davide Salera
- Department of Internal MedicineOspedale Regionale di Lugano, Ospedale Civico, Ente Ospedaliero CantonaleLuganoSwitzerland
| | - Luca Di Lullo
- UOC Nephrology and Dialysis UnitAzienda USL Roma 6Albano LazialeItaly
| | - Antonio Bellasi
- Service of NephrologyOspedale Regionale di Lugano, Ospedale Civico, Ente Ospedaliero CantonaleLuganoSwitzerland
- Faculty of Biomedical SciencesUniversità della Svizzera italianaLuganoSwitzerland
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Via Reque Cortes DDP, Drueke TB, Moysés RMA. Persistent uncertainties in optimal treatment approaches of secondary hyperparathyroidism and hyperphosphatemia in patients with chronic kidney disease. Curr Osteoporos Rep 2024; 22:441-457. [PMID: 39158828 DOI: 10.1007/s11914-024-00881-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/09/2024] [Indexed: 08/20/2024]
Abstract
PURPOSE OF REVIEW This review is a critical analysis of treatment results obtained in clinical trials conducted in patients with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT), hyperphosphatemia, or both. RECENT FINDINGS Patients with CKD have a high mortality rate. The disorder of mineral and bone metabolism (CKD-MBD), which is commonly present in these patients, is associated with adverse outcomes, including cardiovascular events and mortality. Clinical trials aimed at improving these outcomes by modifying CKD-MBD associated factors have most often resulted in disappointing results. The complexity of CKD-MBD, where many players are closely interconnected, might explain these negative findings. We first present an historical perspective of current knowledge in the field of CKD-MBD and then examine potential flaws of past and ongoing clinical trials targeting SHPT and hyperphosphatemia respectively in patients with CKD.
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Affiliation(s)
| | - Tilman B Drueke
- Inserm Unit 1018, CESP, Hôpital Paul Brousse, Paris-Sud University (UPS) and Versailles Saint-Quentin-en-Yvelines University (Paris-Ile-de-France-Ouest University, UVSQ), Team 5, Villejuif, France
| | - Rosa Maria Affonso Moysés
- Laboratório de Fisiopatologia Renal, Faculdade de Medicina da USP, Nephrology Division, LIM 16, São Paulo, Brazil.
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5
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Karaca MO, Özyıldıran M, Savran MD, Başarır K, Yıldız HY. Brown tumors: Retrospective analysis of 26 cases. Arch Orthop Trauma Surg 2024; 144:2927-2934. [PMID: 38795187 PMCID: PMC11319420 DOI: 10.1007/s00402-024-05372-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 05/07/2024] [Indexed: 05/27/2024]
Abstract
INTRODUCTION Brown tumors are reactive osteolytic lesions caused by hyperparathyroidism. These rare lesions are non-neoplastic processes that result from bone resorption. The purpose of this study was to retrospectively review a 34-year experience with brown tumors in our institution. MATERIALS AND METHODS We retrospectively analyzed the records of 26 consecutive patients with brown tumor who were treated in our institution between May 1988 and October 2020, with a mean follow-up of 36,1 months. RESULTS 17 male (65,4%) and 9 female (34,6%) patients with a mean age of 41,6 were included in the study. Localized bone pain was present in 13 cases (50,0%) as the first presenting symptom. 3 patients (11,5%) presented with diffuse bone pain. 7 patients (26,9%) were diagnosed with brown tumor while being investigated for pathological fractures. The other 3 patients (11,5%) were diagnosed while being evaluated for hypercalcemia symptoms. 7 patients (26,9%) had solitary lesions, while 19 patients (73,1%) had multiple lesions. Pelvis, femur, ribs, tibia, proximal humerus and mandible were the most common sites of localization. 23 patients (88,5%) were diagnosed with primary hyperparathyroidism, while the other 3 patients (11,5%) had secondary hyperparathyroidism. A total of the 65 lesions, 23 (35.4%) underwent orthopedic surgery, and 42 (64.6%) were followed up conservatively after parathyroidectomy. Orthopedic surgery was performed in 21 of 26 patients, the other 5 cases were followed up conservatively. Intralesional curettage was performed in 19 cases (82,6%). The resulting cavity was filled with bone cement in 11 cases (47,8%). Bone grafting was applied in 8 cases (34,8%). No recurrence was observed in any of the patients. CONCLUSION The diagnosis of brown tumor begins with clinical suspicion. Endocrinology and general surgery consultation is important before surgery. Treatment of brown tumors requires a multidisciplinary approach.
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Affiliation(s)
- Mustafa Onur Karaca
- Department of Orthopedics and Traumatology, Ankara University, Ankara, Turkey
| | - Mustafa Özyıldıran
- Department of Orthopedics and Traumatology, Sandıklı State Hospital, Afyonkarahisar, Turkey.
| | - Merve Dursun Savran
- Department of Orthopedics and Traumatology, Ankara University, Ankara, Turkey
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Cernaro V, Longhitano E, Casuscelli C, Peritore L, Santoro D. Hyperphosphatemia in Chronic Kidney Disease: The Search for New Treatment Paradigms and the Role of Tenapanor. Int J Nephrol Renovasc Dis 2024; 17:151-161. [PMID: 38831770 PMCID: PMC11144652 DOI: 10.2147/ijnrd.s385826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 05/14/2024] [Indexed: 06/05/2024] Open
Abstract
Hyperphosphataemia represents a significant challenge in the management of chronic kidney disease, exerting a pronounced influence on the pathogenesis of cardiovascular complications and mineral bone disorders. Traditional approaches to address hyperphosphataemia involve implementing dietary phosphate restrictions, administering phosphate binders, and, in cases of end-stage renal disease, resorting to dialysis. Unfortunately, these interventions frequently prove inadequate in maintaining phosphate levels within recommended ranges. Additionally, commonly employed pharmacological agents are not immune to eliciting adverse events, thereby limiting their prescription and therapeutic adherence. There is a growing focus on exploring novel therapeutic strategies in this context. The current discussion centres on tenapanor, a pharmacological agent predominantly acting as a selective inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3). Its mechanism of action involves modulating tight junctions, resulting in reduced sodium absorption and intestinal paracellular permeability to phosphate. Furthermore, tenapanor downregulates sodium-dependent phosphate 2b transport protein (NaPi2b) expression, thereby impeding active transcellular phosphate transport. Clinical trials have elucidated the efficacy and safety profile of tenapanor. This evidence hints at a potential paradigm shift in the management of hyperphosphataemia. However, the burgeoning optimism surrounding tenapanor warrants tempered enthusiasm, as further research remains indispensable. The imperative lies in meticulously delineating its efficacy and safety contours within the crucible of clinical practice. In this review, we synthesize the intricate interplay between hyperphosphataemia and Chronic Kidney Disease-Mineral Bone Disorder, and we discuss the existing pharmacological interventions for hyperphosphataemia and explore emerging treatment paradigms that offer novel perspectives in managing elevated phosphate levels in CKD patients.
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Affiliation(s)
- Valeria Cernaro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Elisa Longhitano
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Chiara Casuscelli
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Luigi Peritore
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
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Evenepoel P, Jørgensen HS, Bover J, Davenport A, Bacchetta J, Haarhaus M, Hansen D, Gracia-Iguacel C, Ketteler M, McAlister L, White E, Mazzaferro S, Vervloet M, Shroff R. Recommended calcium intake in adults and children with chronic kidney disease-a European consensus statement. Nephrol Dial Transplant 2024; 39:341-366. [PMID: 37697718 DOI: 10.1093/ndt/gfad185] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Indexed: 09/13/2023] Open
Abstract
Mineral and bone disorders (MBD) are common in patients with chronic kidney disease (CKD), contributing to significant morbidity and mortality. For several decades, the first-line approach to controlling hyperparathyroidism in CKD was by exogenous calcium loading. Since the turn of the millennium, however, a growing awareness of vascular calcification risk has led to a paradigm shift in management and a move away from calcium-based phosphate binders. As a consequence, contemporary CKD patients may be at risk of a negative calcium balance, which, in turn, may compromise bone health, contributing to renal bone disease and increased fracture risk. A calcium intake below a certain threshold may be as problematic as a high intake, worsening the MBD syndrome of CKD, but is not addressed in current clinical practice guidelines. The CKD-MBD and European Renal Nutrition working groups of the European Renal Association (ERA), together with the CKD-MBD and Dialysis working groups of the European Society for Pediatric Nephrology (ESPN), developed key evidence points and clinical practice points on calcium management in children and adults with CKD across stages of disease. These were reviewed by a Delphi panel consisting of ERA and ESPN working groups members. The main clinical practice points include a suggested total calcium intake from diet and medications of 800-1000 mg/day and not exceeding 1500 mg/day to maintain a neutral calcium balance in adults with CKD. In children with CKD, total calcium intake should be kept within the age-appropriate normal range. These statements provide information and may assist in decision-making, but in the absence of high-level evidence must be carefully considered and adapted to individual patient needs.
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Affiliation(s)
- Pieter Evenepoel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Medicine, Division of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Hanne Skou Jørgensen
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
- Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Nephrology, Aalborg University Hospital, Aalborg, Denmark
| | - Jordi Bover
- Department of Nephrology, University Hospital Germans Trias i Pujol, Barcelona, Catalonia, Spain
- REMAR-IGTP Group, Germans Trias i Pujol Research Institute, Can Ruti Campus, Barcelona, Catalonia, Spain
| | - Andrew Davenport
- Department of Renal Medicine, Royal Free Hospital, University College London, London, UK
| | - Justine Bacchetta
- Pediatric Nephrology Rheumatology and Dermatology Unit, Reference Center for Rare Renal Diseases, ORKID and ERK-Net networks, Lyon University Hospital, Bron, France
- Lyon Est Medical School, INSERM1033 Research Unit, Claude Bernard Lyon 1 University, Lyon, France
| | - Mathias Haarhaus
- Division of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Diaverum Sweden, Malmö, Sweden
| | - Ditte Hansen
- Department of Nephrology, Copenhagen University Hospital-Herlev, Copenhagen
- Institute of Clinical Medicine, University of Copenhagen, Denmark
| | - Carolina Gracia-Iguacel
- Department of Renal Medicine, IIS-Fundación Jiménez Díaz UAM University Hospital, Madrid, Spain
| | - Markus Ketteler
- Department of General Internal Medicine and Nephrology, Robert-Bosch Hospital, Stuttgart, Germany
| | - Louise McAlister
- Dietetic Team, UCL Great Ormond Street Hospital for Children and University College London, London, UK
| | - Emily White
- Dietetic Team, Royal Free Hospital, University College London, London, UK
| | - Sandro Mazzaferro
- Department of Translation and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Marc Vervloet
- Amsterdam Cardiovascular Sciences, Amsterdam UMC, The Netherlands
- Department of Nephrology, Amsterdam UMC, The Netherlands
| | - Rukshana Shroff
- Renal Unit, UCL Great Ormond Street Hospital for Children, London, UK
- Institute of Child Health, University College London, London, UK
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Molina P, Molina MD, Carrero JJ, Escudero V, Torralba J, Castro-Alonso C, Beltrán S, Vizcaíno B, González-Moya M, Kanter J, Sancho-Calabuig A, Bover J, Górriz JL. Sevelamer Use and Mortality in People with Chronic Kidney Disease Stages 4 and 5 Not on Dialysis. J Clin Med 2023; 12:7631. [PMID: 38137700 PMCID: PMC10743559 DOI: 10.3390/jcm12247631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 11/27/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Rationale and objective: Data suggest that non-calcium-based binders, and specifically sevelamer, may lead to lower rates of death when compared with calcium-based binders in end-stage renal disease (ESRD) patients. However, the association between sevelamer use and mortality for those with non-dialysis-dependent chronic kidney disease (NDD-CKD) patients has been uncertain. Study design: Our research is presented in a prospective cohort study. Setting and participants: A total of 966 participants with NDD-CKD stages 4-5 were enrolled in the PECERA study from 12 centers in Spain. Exposure: The participants were treated with sevelamer. Outcome: This study yielded all-cause and cardiovascular mortality outcomes. Analytical approach: We conducted an association analysis between mortality and sevelamer use with time-dependent Cox proportional hazards models. Results: After a median follow-up of 29 months (IQR: 13-36 months), death occurred in 181 participants (19%), with cardiovascular (n = 95, 53%) being the leading cause of death. In a multivariable model, the adjusted hazard ratios (HRs) for patients under sevelamer treatment were 0.44 (95% CI, 0.22 to 0.88) and 0.37 (95% CI, 0.18 to 0.75) for all-cause and cardiovascular mortality, respectively, compared with those of untreated patients. Limitations: Some limitations include potential confusion via indication bias; causal statements about these associations cannot be made due to the observational nature of this study. Conclusions: In this prospective NDD-CKD cohort study, the administration of sevelamer was independently associated with lower all-cause and cardiovascular mortality, suggesting that non-calcium-based phosphate binders might be the first-line therapy for phosphate lowering in this population. Further interventional studies clarifying the risks and benefits of phosphate binders in NDD-CKD are warranted.
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Affiliation(s)
- Pablo Molina
- Department of Nephrology, Hospital Universitari Dr. Peset, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, 46017 Valencia, Spain; (V.E.); (C.C.-A.); (S.B.); (B.V.); (M.G.-M.); (J.K.); (A.S.-C.)
- Department of Medicine, Universitat de València, 46010 Valencia, Spain;
| | - Mariola D. Molina
- Department of Mathematics, Universidad de Alicante, 03690 Sant Vicent del Raspeig, Spain;
| | - Juan J. Carrero
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
| | - Verónica Escudero
- Department of Nephrology, Hospital Universitari Dr. Peset, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, 46017 Valencia, Spain; (V.E.); (C.C.-A.); (S.B.); (B.V.); (M.G.-M.); (J.K.); (A.S.-C.)
| | - Javier Torralba
- Department of Nephrology, Hospital General Universitario, 03010 Alicante, Spain;
| | - Cristina Castro-Alonso
- Department of Nephrology, Hospital Universitari Dr. Peset, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, 46017 Valencia, Spain; (V.E.); (C.C.-A.); (S.B.); (B.V.); (M.G.-M.); (J.K.); (A.S.-C.)
| | - Sandra Beltrán
- Department of Nephrology, Hospital Universitari Dr. Peset, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, 46017 Valencia, Spain; (V.E.); (C.C.-A.); (S.B.); (B.V.); (M.G.-M.); (J.K.); (A.S.-C.)
| | - Belén Vizcaíno
- Department of Nephrology, Hospital Universitari Dr. Peset, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, 46017 Valencia, Spain; (V.E.); (C.C.-A.); (S.B.); (B.V.); (M.G.-M.); (J.K.); (A.S.-C.)
- Department of Medicine, Universitat de València, 46010 Valencia, Spain;
| | - Mercedes González-Moya
- Department of Nephrology, Hospital Universitari Dr. Peset, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, 46017 Valencia, Spain; (V.E.); (C.C.-A.); (S.B.); (B.V.); (M.G.-M.); (J.K.); (A.S.-C.)
- Department of Medicine, Universitat de València, 46010 Valencia, Spain;
| | - Julia Kanter
- Department of Nephrology, Hospital Universitari Dr. Peset, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, 46017 Valencia, Spain; (V.E.); (C.C.-A.); (S.B.); (B.V.); (M.G.-M.); (J.K.); (A.S.-C.)
| | - Asunción Sancho-Calabuig
- Department of Nephrology, Hospital Universitari Dr. Peset, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana, 46017 Valencia, Spain; (V.E.); (C.C.-A.); (S.B.); (B.V.); (M.G.-M.); (J.K.); (A.S.-C.)
- Department of Medicine, Universitat de València, 46010 Valencia, Spain;
| | - Jordi Bover
- Nephrology Department, University Hospital Germans Trias i Pujol, 08916 Badalona, Spain;
| | - José L. Górriz
- Department of Medicine, Universitat de València, 46010 Valencia, Spain;
- Department of Nephrology, Hospital Clínico Universitario, Fundación para la Investigación del Hospital Clínico de la Comunidad Valenciana, 46010 Valencia, Spain
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9
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Cernaro V, Longhitano E, Calabrese V, Casuscelli C, Di Carlo S, Spinella C, Gembillo G, Santoro D. Progress in pharmacotherapy for the treatment of hyperphosphatemia in renal failure. Expert Opin Pharmacother 2023; 24:1737-1746. [PMID: 37527180 DOI: 10.1080/14656566.2023.2243817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/03/2023]
Abstract
INTRODUCTION Among the clinical and metabolic complications of progressive chronic kidney disease (CKD), CKD-mineral bone disorder (CKD-MBD) significantly contributes to morbidity and mortality. While overt and persistent hyperphosphatemia is typical of advanced CKD and requires treatment, other abnormalities of calcium/phosphate metabolism begin to occur since the early stages of the disease. AREAS COVERED We searched on the PubMed database, without restrictions for language or time range, for randomized clinical trials and meta-analyses investigating phosphate-lowering therapies. The various phosphate binders show different safety profiles and diverse effects on calcium/phosphate metabolism and vascular calcification. The in-depth knowledge of the characteristics of these drugs is crucial to ensure adequate treatment to CKD patients. EXPERT OPINION A proper control of serum phosphate can be achieved using phosphate binders. These medications may induce side effects. Moreover, data on their impact on clinical outcomes are partly controversial or scarce, especially for the new generation drugs. Hyperphosphatemia favors cardiovascular disease and increases the risk for CKD progression. These effects are partially mediated by fibroblast growth factor 23 (FGF23), a phosphaturic hormone that raises to maintain normal serum phosphate. Since there are no data supporting the use of phosphate-lowering agents when phosphataemia is normal, a key role is played by reducing dietary phosphate intake with the aim to control serum phosphate and the compensatory FGF23 and parathyroid hormone (PTH) increase.
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Affiliation(s)
- Valeria Cernaro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Elisa Longhitano
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Vincenzo Calabrese
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Chiara Casuscelli
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Silvia Di Carlo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Claudia Spinella
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
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10
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Yamada S, Nakano T. Role of Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (MBD) in the Pathogenesis of Cardiovascular Disease in CKD. J Atheroscler Thromb 2023; 30:835-850. [PMID: 37258233 PMCID: PMC10406631 DOI: 10.5551/jat.rv22006] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 05/18/2023] [Indexed: 06/02/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Multiple factors account for the increased incidence of cardiovascular morbidity and mortality in patients with CKD. Traditional risk factors for atherosclerosis and arteriosclerosis, including age, hypertension, dyslipidemia, diabetes mellitus, and smoking, are also risk factors for CKD. Non-traditional risk factors specific for CKD are also involved in CVD pathogenesis in patients with CKD. Recently, CKD-mineral and bone disorder (CKD-MBD) has emerged as a key player in CVD pathogenesis in the context of CKD. CKD-MBD manifests as hypocalcemia and hyperphosphatemia in the later stages of CKD; however, it initially develops much earlier in disease course. The initial step in CKD-MBD involves decreased phosphate excretion in the urine, followed by increased circulating concentrations of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH), which increase urinary phosphate excretion. Simultaneously, the serum calcitriol concentration decreases as a result of FGF23 elevation. Importantly, FGF23 and PTH cause left ventricular hypertrophy, arrhythmia, and cardiovascular calcification. More recently, calciprotein particles, which are nanoparticles composed of calcium, phosphate, and fetuin-A, among other components, have been reported to cause inflammation, cardiovascular calcification, and other clinically relevant outcomes. CKD-MBD has become one of the critical therapeutic targets for the prevention of cardiovascular events and is another link between cardiology and nephrology. In this review, we describe the role of CKD-MBD in the pathogenesis of cardiovascular disorders and present the current treatment strategies for CKD-MBD.
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Affiliation(s)
- Shunsuke Yamada
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshiaki Nakano
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Centers for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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11
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Cernaro V, Calderone M, Gembillo G, Calabrese V, Casuscelli C, Lo Re C, Longhitano E, Santoro D. Phosphate Control in Peritoneal Dialysis Patients: Issues, Solutions, and Open Questions. Nutrients 2023; 15:3161. [PMID: 37513579 PMCID: PMC10386128 DOI: 10.3390/nu15143161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 07/14/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Hyperphosphatemia is a common complication in advanced chronic kidney disease and contributes to cardiovascular morbidity and mortality. The present narrative review focuses on the management of phosphatemia in uremic patients receiving peritoneal dialysis. These patients frequently develop hyperphosphatemia since phosphate anion behaves as a middle-size molecule despite its low molecular weight. Accordingly, patient transporter characteristics and peritoneal dialysis modalities and prescriptions remarkably influence serum phosphate control. Given that phosphate peritoneal removal is often insufficient, especially in lower transporters, patients are often prescribed phosphate binders whose use in peritoneal dialysis is primarily based on clinical trials conducted in hemodialysis because very few studies have been performed solely in peritoneal dialysis populations. A crucial role in phosphate control among peritoneal dialysis patients is played by diet, which must help in reducing phosphorous intake while preventing malnutrition. Moreover, residual renal function, which is preserved in most peritoneal dialysis patients, significantly contributes to maintaining phosphate balance. The inadequate serum phosphate control observed in many patients on peritoneal dialysis highlights the need for large and well-designed clinical trials including exclusively peritoneal dialysis patients to evaluate the effects of a multiple therapeutic approach on serum phosphate control and on hard clinical outcomes in this high-risk population.
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Affiliation(s)
- Valeria Cernaro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Michela Calderone
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Guido Gembillo
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Vincenzo Calabrese
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Chiara Casuscelli
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Claudia Lo Re
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Elisa Longhitano
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
| | - Domenico Santoro
- Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy
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12
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Besseling PJ, Krebber MM, Fledderus JO, Teraa M, den Ouden K, van de Kaa M, de Bree PM, Serrero A, Bouten CVC, Dankers PYW, Cox MAJ, Verhaar MC. The effect of chronic kidney disease on tissue formation of in situ tissue-engineered vascular grafts. APL Bioeng 2023; 7:026107. [PMID: 37234843 PMCID: PMC10208679 DOI: 10.1063/5.0138808] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Vascular in situ tissue engineering encompasses a single-step approach with a wide adaptive potential and true off-the-shelf availability for vascular grafts. However, a synchronized balance between breakdown of the scaffold material and neo-tissue formation is essential. Chronic kidney disease (CKD) may influence this balance, lowering the usability of these grafts for vascular access in end-stage CKD patients on dialysis. We aimed to investigate the effects of CKD on in vivo scaffold breakdown and tissue formation in grafts made of electrospun, modular, supramolecular polycarbonate with ureido-pyrimidinone moieties (PC-UPy). We implanted PC-UPy aortic interposition grafts (n = 40) in a rat 5/6th nephrectomy model that mimics systemic conditions in human CKD patients. We studied patency, mechanical stability, extracellular matrix (ECM) components, total cellularity, vascular tissue formation, and vascular calcification in CKD and healthy rats at 2, 4, 8, and 12 weeks post-implantation. Our study shows successful in vivo application of a slow-degrading small-diameter vascular graft that supports adequate in situ vascular tissue formation. Despite systemic inflammation associated with CKD, no influence of CKD on patency (Sham: 95% vs CKD: 100%), mechanical stability, ECM formation (Sirius red+, Sham 16.5% vs CKD 25.0%-p:0.83), tissue composition, and immune cell infiltration was found. We did find a limited increase in vascular calcification at 12 weeks (Sham 0.08% vs CKD 0.80%-p:0.02) in grafts implanted in CKD animals. However, this was not associated with increased stiffness in the explants. Our findings suggest that disease-specific graft design may not be necessary for use in CKD patients on dialysis.
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Affiliation(s)
| | - Merle M. Krebber
- Department of Nephrology and Hypertension, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Joost O. Fledderus
- Department of Nephrology and Hypertension, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Krista den Ouden
- Department of Nephrology and Hypertension, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Melanie van de Kaa
- Department of Nephrology and Hypertension, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Petra M. de Bree
- Department of Nephrology and Hypertension, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Carlijn V. C. Bouten
- Department of Biomedical Engineering and Institute for Complex Molecular Systems, TU/e, Eindhoven, The Netherlands
| | - Patricia Y. W. Dankers
- Department of Biomedical Engineering and Institute for Complex Molecular Systems, TU/e, Eindhoven, The Netherlands
| | | | - Marianne C. Verhaar
- Department of Nephrology and Hypertension, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands
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13
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Williams MJ, White SC, Joseph Z, Hruska KA. Updates in the chronic kidney disease-mineral bone disorder show the role of osteocytic proteins, a potential mechanism of the bone-Vascular paradox, a therapeutic target, and a biomarker. Front Physiol 2023; 14:1120308. [PMID: 36776982 PMCID: PMC9909112 DOI: 10.3389/fphys.2023.1120308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 01/17/2023] [Indexed: 01/27/2023] Open
Abstract
The chronic kidney disease-mineral bone disorder (CKD-MBD) is a complex multi-component syndrome occurring during kidney disease and its progression. Here, we update progress in the components of the syndrome, and synthesize recent investigations, which suggest a potential mechanism of the bone-vascular paradox. The discovery that calcified arteries in chronic kidney disease inhibit bone remodeling lead to the identification of factors produced by the vasculature that inhibit the skeleton, thus providing a potential explanation for the bone-vascular paradox. Among the factors produced by calcifying arteries, sclerostin secretion is especially enlightening. Sclerostin is a potent inhibitor of bone remodeling and an osteocyte specific protein. Its production by the vasculature in chronic kidney disease identifies the key role of vascular cell osteoblastic/osteocytic transdifferentiation in vascular calcification and renal osteodystrophy. Subsequent studies showing that inhibition of sclerostin activity by a monoclonal antibody improved bone remodeling as expected, but stimulated vascular calcification, demonstrate that vascular sclerostin functions to brake the Wnt stimulation of the calcification milieu. Thus, the target of therapy in the chronic kidney disease-mineral bone disorder is not inhibition of sclerostin function, which would intensify vascular calcification. Rather, decreasing sclerostin production by decreasing the vascular osteoblastic/osteocytic transdifferentiation is the goal. This might decrease vascular calcification, decrease vascular stiffness, decrease cardiac hypertrophy, decrease sclerostin production, reduce serum sclerostin and improve skeletal remodeling. Thus, the therapeutic target of the chronic kidney disease-mineral bone disorder may be vascular osteoblastic transdifferentiation, and sclerostin levels may be a useful biomarker for the diagnosis of the chronic kidney disease-mineral bone disorder and the progress of its therapy.
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Affiliation(s)
- Matthew J. Williams
- Division of Pediatric Nephrology, Department of Pediatrics, Washington University, Saint Louis, MO, United States
| | - Sarah C. White
- Division of Pediatric Nephrology, Department of Pediatrics, Washington University, Saint Louis, MO, United States
| | - Zachary Joseph
- Division of Pediatric Nephrology, Department of Pediatrics, Washington University, Saint Louis, MO, United States
| | - Keith A. Hruska
- Division of Pediatric Nephrology, Department of Pediatrics, Washington University, Saint Louis, MO, United States
- Departments of Medicine and Cell Biology, Washington University, Saint Louis, MO, United States
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14
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Ren SC, Mao N, Yi S, Ma X, Zou JQ, Tang X, Fan JM. Vascular Calcification in Chronic Kidney Disease: An Update and Perspective. Aging Dis 2022; 13:673-697. [PMID: 35656113 PMCID: PMC9116919 DOI: 10.14336/ad.2021.1024] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/24/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic kidney disease is a devastating condition resulting from irreversible loss of nephron numbers and function and leading to end-stage renal disease and mineral disorders. Vascular calcification, an ectopic deposition of calcium-phosphate salts in blood vessel walls and heart valves, is an independent risk factor of cardiovascular morbidity and mortality in chronic kidney disease. Moreover, aging and related metabolic disorders are essential risk factors for chronic kidney disease and vascular calcification. Marked progress has been recently made in understanding and treating vascular calcification in chronic kidney disease. However, there is a paucity of systematic reviews summarizing this progress, and investigating unresolved issues is warranted. In this systematic review, we aimed to overview the underlying mechanisms of vascular calcification in chronic kidney diseases and discuss the impact of chronic kidney disease on the pathophysiology of vascular calcification. Additionally, we summarized potential clinical diagnostic biomarkers and therapeutic applications for vascular calcification with chronic kidney disease. This review may offer new insights into the pathogenesis, diagnosis, and therapeutic intervention of vascular calcification.
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Affiliation(s)
- Si-Chong Ren
- Chengdu Medical College, Chengdu, China.
- Department of Nephrology, First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
- Center for Translational Medicine, Sichuan Academy of Traditional Chinese Medicine, Chengdu, China.
| | - Nan Mao
- Chengdu Medical College, Chengdu, China.
- Department of Nephrology, First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
| | - Si Yi
- Chengdu Medical College, Chengdu, China.
- Clinical Research Center for Geriatrics of Sichuan Province, Chengdu, China.
| | - Xin Ma
- Chengdu Medical College, Chengdu, China.
- Department of Nephrology, First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
| | - Jia-Qiong Zou
- Chengdu Medical College, Chengdu, China.
- Department of Nephrology, First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
| | - Xiaoqiang Tang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Jun-Ming Fan
- Chengdu Medical College, Chengdu, China.
- Clinical Research Center for Geriatrics of Sichuan Province, Chengdu, China.
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15
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Jadav PR, Husain SA, Mohan S, Crew R. Non calcium phosphate binders - Is there any evidence of benefit. Curr Opin Nephrol Hypertens 2022; 31:288-296. [PMID: 35266882 DOI: 10.1097/mnh.0000000000000796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Low-level evidence and opinion-based clinical practice guidelines highlight the substantial uncertainty in the practice patterns of hyperphosphatemia management in patients with chronic kidney disease (CKD). This manuscript reviews the evidence for the choice of phosphate binders and its impact on clinical outcomes. RECENT FINDINGS Phosphate binders are among the most common medications prescribed for patients on dialysis. Clinical practice guidelines recommend lowering phosphate levels toward normal range and restricting calcium-based binders in all CKD patients. There is substantial gap in the evidence underlying these recommendations with lack of any placebo-controlled, randomized trials showing survival benefits for any class of phosphate-binders. Despite the lack of evidence for specific phosphate target or if lowering phosphate improves survival, use of phosphate binders has remained central strategy in approach to hyperphosphatemia. Use of binders has added to the cost and contributed significant pill burden. Restriction of calcium-based binders to avoid positive calcium balance and consequent vascular calcification risk has a physiological rationale and weight of observational studies. SUMMARY There is currently no conclusive evidence that definitively guides the choice of any specific binders for management of hyperphosphatemia in patients with CKD. Use of noncalcium-based binders has a theoretical advantage in restricting total calcium intake to decrease the risk of vascular calcification but no proven benefits for mortality.
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Affiliation(s)
- Paresh R Jadav
- Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, NY
| | - S Ali Husain
- Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, NY
- The Columbia University Renal Epidemiology (CURE) Group
| | - Sumit Mohan
- Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, NY
- The Columbia University Renal Epidemiology (CURE) Group
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
| | - Russell Crew
- Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, NY
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16
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Cardiac Calcifications: Phenotypes, Mechanisms, Clinical and Prognostic Implications. BIOLOGY 2022; 11:biology11030414. [PMID: 35336788 PMCID: PMC8945469 DOI: 10.3390/biology11030414] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/21/2022] [Accepted: 03/07/2022] [Indexed: 12/20/2022]
Abstract
There is a growing interest in arterial and heart valve calcifications, as these contribute to cardiovascular outcome, and are leading predictors of cardiovascular and kidney diseases. Cardiovascular calcifications are often considered as one disease, but, in effect, they represent multifaced disorders, occurring in different milieus and biological phenotypes, following different pathways. Herein, we explore each different molecular process, its relative link with the specific clinical condition, and the current therapeutic approaches to counteract calcifications. Thus, first, we explore the peculiarities between vascular and valvular calcium deposition, as this occurs in different tissues, responds differently to shear stress, has specific etiology and time courses to calcification. Then, we differentiate the mechanisms and pathways leading to hyperphosphatemic calcification, typical of the media layer of the vessel and mainly related to chronic kidney diseases, to those of inflammation, typical of the intima vascular calcification, which predominantly occur in atherosclerotic vascular diseases. Finally, we examine calcifications secondary to rheumatic valve disease or other bacterial lesions and those occurring in autoimmune diseases. The underlying clinical conditions of each of the biological calcification phenotypes and the specific opportunities of therapeutic intervention are also considered and discussed.
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17
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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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18
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Lavainne F, Guillot P, Figueres L. Troubles minéraux et osseux dans la maladie rénale chronique : physiopathologie, conséquences et prise en charge. Rev Med Interne 2022; 43:225-232. [DOI: 10.1016/j.revmed.2022.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 01/26/2022] [Accepted: 01/29/2022] [Indexed: 02/07/2023]
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19
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Lioufas NM, Pascoe EM, Hawley CM, Elder GJ, Badve SV, Block GA, Johnson DW, Toussaint ND. Systematic Review and Meta-Analyses of the Effects of Phosphate-Lowering Agents in Nondialysis CKD. J Am Soc Nephrol 2022; 33:59-76. [PMID: 34645696 PMCID: PMC8763193 DOI: 10.1681/asn.2021040554] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 09/22/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Benefits of phosphate-lowering interventions on clinical outcomes in patients with CKD are unclear; systematic reviews have predominantly involved patients on dialysis. This study aimed to summarize evidence from randomized controlled trials (RCTs) concerning benefits and risks of noncalcium-based phosphate-lowering treatment in nondialysis CKD. METHODS We conducted a systematic review and meta-analyses of RCTs involving noncalcium-based phosphate-lowering therapy compared with placebo, calcium-based binders, or no study medication, in adults with CKD not on dialysis or post-transplant. RCTs had ≥3 months follow-up and outcomes included biomarkers of mineral metabolism, cardiovascular parameters, and adverse events. Outcomes were meta-analyzed using the Sidik-Jonkman method for random effects. Unstandardized mean differences were used as effect sizes for continuous outcomes with common measurement units and Hedge's g standardized mean differences (SMD) otherwise. Odds ratios were used for binary outcomes. Cochrane risk of bias and GRADE assessment determined the certainty of evidence. RESULTS In total, 20 trials involving 2498 participants (median sample size 120, median follow-up 9 months) were eligible for inclusion. Overall, risk of bias was low. Compared with placebo, noncalcium-based phosphate binders reduced serum phosphate (12 trials, weighted mean difference -0.37; 95% CI, -0.58 to -0.15 mg/dl, low certainty evidence) and urinary phosphate excretion (eight trials, SMD -0.61; 95% CI, -0.90 to -0.31, low certainty evidence), but resulted in increased constipation (nine trials, log odds ratio [OR] 0.93; 95% CI, 0.02 to 1.83, low certainty evidence) and greater vascular calcification score (three trials, SMD, 0.47; 95% CI, 0.17 to 0.77, very low certainty evidence). Data for effects of phosphate-lowering therapy on cardiovascular events (log OR, 0.51; 95% CI, -0.51 to 1.17) and death were scant. CONCLUSIONS Noncalcium-based phosphate-lowering therapy reduced serum phosphate and urinary phosphate excretion, but there was an unclear effect on clinical outcomes and intermediate cardiovascular end points. Adequately powered RCTs are required to evaluate benefits and risks of phosphate-lowering therapy on patient-centered outcomes.
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Affiliation(s)
- Nicole M. Lioufas
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia,Department of Medicine, University of Melbourne, Parkville, Australia,Department of Nephrology, Western Health, Melbourne, Australia
| | | | - Carmel M. Hawley
- Australasian Kidney Trials Network, Brisbane, Australia,Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia,Translational Research Institute, Brisbane, Australia
| | - Grahame J. Elder
- School of Medicine, University of Notre Dame, Sydney, Australia,Department of Medicine, University of Sydney, Sydney, Australia,Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, Australia,Department of Nephrology, Westmead Hospital, Sydney, Australia
| | - Sunil V. Badve
- Australasian Kidney Trials Network, Brisbane, Australia,Department of Nephrology, St. George Hospital, Sydney, Australia,Renal and Metabolic Division, the George Institute for Global Health, University of New South Wales, Sydney, Australia
| | | | - David W. Johnson
- Australasian Kidney Trials Network, Brisbane, Australia,Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia,Translational Research Institute, Brisbane, Australia
| | - Nigel D. Toussaint
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia,Department of Medicine, University of Melbourne, Parkville, Australia
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20
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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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21
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Characterization of Medication Trends for Chronic Kidney Disease: Mineral and Bone Disorder Treatment Using Electronic Health Record-Based Common Data Model. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5504873. [PMID: 34853790 PMCID: PMC8629641 DOI: 10.1155/2021/5504873] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 10/26/2021] [Accepted: 10/29/2021] [Indexed: 11/25/2022]
Abstract
Chronic kidney disease–mineral bone disorder (CKD-MBD) is the most common complication in CKD patients. Although there is a consensus on treatment guidelines for CKD-MBD, it remains uncertain whether these treatment recommendations reflect actual practice. Therefore, the aim of this study was to investigate the CKD-MBD medication trend in real-world practice. This was a retrospective and observational study using a 12-year period database transformed into a common data model from three tertiary university hospitals. Study populations were subjects initially diagnosed as CKD. The date of diagnosis was designated as the index date. New patients were categorized year to year from 2008 to 2019 with a fixed observation period of 365 days to check the prescription of CKD-MBD medications including calcium-containing phosphate binder, noncalcium-containing phosphate binder, aluminium hydroxide, vitamin D receptor activator (VDRA), and cinacalcet. The numbers of CKD patients in the three hospitals were 7555, 2424, and 5351, respectively. The proportion for patients with CKD-MBD medication prescription decreased yearly regardless of hospital and CKD stage (p for trend < 0.05). The use of aluminium hydroxide disappeared steadily while the use of VDRA increased annually in all settings. Despite these changes in prescription patterns, the mean value for CKD-MBD-related serologic markers was almost within target range. The proportion of the population within the target value was not significantly changed. Irrespective of hospital and CKD stage, similar trends of prescription for CKD-MBD medications were observed in real-world practice. Further research with a distributed network study may be helpful to understand medication trends in CKD-MBD treatment.
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22
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Xu H, Lindholm B, Lundström UH, Heimbürger O, Stendahl M, Rydell H, Segelmark M, Carrero JJ, Evans M. Treatment practices and outcomes in incident peritoneal dialysis patients: the Swedish Renal Registry 2006-2015. Clin Kidney J 2021; 14:2539-2547. [PMID: 34950465 PMCID: PMC8690080 DOI: 10.1093/ckj/sfab130] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Therapeutic developments have contributed to markedly improved clinical outcomes in peritoneal dialysis (PD) during the 1990s and 2000s. We investigated whether recent advances in PD treatment are implemented in routine Swedish care and whether their implementation parallels improved patient outcomes. METHODS We conducted an observational study of 3122 patients initiating PD in Sweden from 2006 to 2015. We evaluated trends of treatment practices (medications, PD-related procedures) and outcomes [patient survival, major adverse cardiovascular events (MACEs), peritonitis, transfer to haemodialysis (HD) and kidney transplantation] and analysed associations of changes of treatment practices with changes in outcomes. RESULTS Over the 10-year period, demographics (mean age 63 years, 33% women) and comorbidities remained essentially stable. There were changes in clinical characteristics (body mass index and diastolic blood pressure increased), prescribed drugs (calcium channel blockers, non-calcium phosphate binders and cinacalcet increased and the use of renin-angiotensin system inhibitors, erythropoietin and iron decreased) and dialysis treatment (increased use of automated PD, icodextrin and assisted PD). The standardized 1- and 2-year mortality and MACE risk did not change over the period. Compared with the general population, the risk of 1-year mortality was 4.1 times higher in 2006-2007 and remained stable throughout follow-up. However, the standardized 1- and 2-year peritonitis rate decreased and the incidence of kidney transplantation increased while transfers to HD did not change. CONCLUSIONS Over the last decade, treatment advances in PD patients were accompanied by a substantial decline in peritonitis frequency and an increased rate of kidney transplantations, while 1- and 2-year survival and MACE risk did not change.
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Affiliation(s)
- Hong Xu
- Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
| | - Bengt Lindholm
- Division of Renal Medicine and Baxter Novum, Department of Clinical Sciences Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Ulrika Hahn Lundström
- Division of Renal Medicine and Baxter Novum, Department of Clinical Sciences Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Olof Heimbürger
- Division of Renal Medicine and Baxter Novum, Department of Clinical Sciences Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Maria Stendahl
- Swedish Renal Registry, Department of Internal Medicine, Ryhov Regional Hospital, Jönköping, Sweden
| | - Helena Rydell
- Division of Renal Medicine and Baxter Novum, Department of Clinical Sciences Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Mårten Segelmark
- Division of Nephrology, Department of Clinical Sciences, Lund University and Skane University Hospital, Lund, Sweden
| | - Juan-Jesus Carrero
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Marie Evans
- Division of Renal Medicine and Baxter Novum, Department of Clinical Sciences Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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Wang AYM, Pasch A, Wong CK, Chu IMT, Tang TK, Chu J, Cheuk-Ying Fong C, Yau YY, Lo WK. Long-Term Effects of Sevelamer on Vascular Calcification, Arterial Stiffness, and Calcification Propensity in Patients Receiving Peritoneal Dialysis: The Randomized Pilot SERENE (Sevelamer on Vascular Calcification, Arterial Stiffness) Trial. Kidney Med 2021; 4:100384. [PMID: 35243302 PMCID: PMC8861951 DOI: 10.1016/j.xkme.2021.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Rationale & Objective There is a concern regarding increased risk of vascular calcification with the use of calcium-based phosphorus binders. This study aimed to compare the effects of sevelamer used as a second-line, low-dose therapy with calcium-based phosphorus binders with those of sevelamer used as a first-line, high-dose therapy on coronary artery and heart valve calcification, aortic pulse wave velocity (PWV), and calcification propensity over 2 years in patients with hyperphosphatemia receiving peritoneal dialysis (PD). Study Design A 2-year-long prospective, multicenter, open-label, randomized pilot study. Setting & Participants Prevalent patients with hyperphosphatemia receiving PD from 2 university-affiliated hospitals in Hong Kong. Interventions The patients were randomized to receive sevelamer either as a first-line therapy at a high dose of 800 mg thrice daily (can titrate up to 1,200 mg thrice daily as required) or a second-line therapy at a low dose of 400 mg thrice daily with calcium carbonate to achieve a serum phosphorus target of ≤5.5 mg/dL. Outcomes The primary endpoints were changes in coronary artery calcium score and aortic PWV over 104 weeks. The secondary endpoints were changes in heart valve calcium scores, calcification propensity measure, and biochemical parameters of chronic kidney disease–mineral bone disease over 104 weeks. Results Among 60 prevalent patients receiving PD, with a mean age of 53 ± 10 years and with 57% men, changes in the coronary artery calcium score (median [interquartile range], 225 [79-525] vs 223 [56-1,212], respectively; P = 0.21), aortic PWV (mean ± standard error, 0.3 ± 0.1 vs 0.8 ± 0.2 m/s, respectively; P = 0.31), heart valve calcium score, maturation or transformation time, serum calcium levels, and phosphorus levels over 104 weeks were similar for the second-line, low-dose and first-line, high-dose sevelamer groups. Alkaline phosphatase and intact parathyroid hormone levels increased and low-density lipoprotein cholesterol decreased in both the groups, with no significant between-group differences. Limitations The sample size was small, and the dropout rates were relatively high. Conclusions Low-dose sevelamer used as a second-line therapy for hyperphosphatemia in combination with a calcium-based phosphorus binder had similar effects on vascular calcification, valvular calcification, and arterial stiffness compared with high-dose sevelamer used as a first-line therapy. This approach may be considered in resource-constrained countries to minimize calcium loading. Funding The study was supported by a competitive grant from SK Yee Medical Foundation. T50 assays and other biochemical assays were funded by a research grant from Sanofi Renal Corporation. Trial Registration NCT00745589.
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The Role of Diet in Bone and Mineral Metabolism and Secondary Hyperparathyroidism. Nutrients 2021; 13:nu13072328. [PMID: 34371838 PMCID: PMC8308808 DOI: 10.3390/nu13072328] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 12/13/2022] Open
Abstract
Bone disorders are a common complication of chronic kidney disease (CKD), obesity and gut malabsorption. Secondary hyperparathyroidism (SHPT) is defined as an appropriate increase in parathyroid hormone (PTH) secretion, driven by either reduced serum calcium or increased phosphate concentrations, due to an underlying condition. The available evidence on the effects of dietary advice on secondary hyperparathyroidism confirms the benefit of a diet characterized by decreased phosphate intake, avoiding low calcium and vitamin D consumption (recommended intakes 1000-1200 mg/day and 400-800 UI/day, respectively). In addition, low protein intake in CKD patients is associated with a better control of SHPT risk factors, although its strength in avoiding hyperphosphatemia and the resulting outcomes are debated, mostly for dialyzed patients. Ultimately, a consensus on the effect of dietary acid loads in the prevention of SHPT is still lacking. In conclusion, a reasonable approach for reducing the risk for secondary hyperparathyroidism is to individualize dietary manipulation based on existing risk factors and concomitant medical conditions. More studies are needed to evaluate long-term outcomes of a balanced diet on the management and prevention of secondary hyperparathyroidism in at-risk patients at.
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Phannajit J, Wonghakaeo N, Takkavatakarn K, Asawavichienjinda T, Praditpornsilpa K, Eiam-Ong S, Susantitaphong P. The impact of phosphate lowering agents on clinical and laboratory outcomes in chronic kidney disease patients: a systematic review and meta-analysis of randomized controlled trials. J Nephrol 2021; 35:473-491. [PMID: 34061337 DOI: 10.1007/s40620-021-01065-3] [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: 01/27/2021] [Accepted: 05/09/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Besides reducing hyperphosphatemia in chronic kidney disease (CKD) patients, phosphate lowering agents might provide beneficial effects on clinical and laboratory parameters. This meta-analysis was conducted to comprehensively examine the impact of all phosphate lowering agents on various aspects of clinical and laboratory outcomes in CKD patients. METHOD A systematic literature search was performed in MEDLINE, Scopus, and the Cochrane Register of Controlled Trials until July 2020 to identify randomized controlled trials (RCTs) which compared the effects of each phosphate lowering agent with controls, comprising placebo and all other phosphate lowering agents. Various clinical and laboratory outcomes were analyzed. Random effects model was used to compute the standardized mean difference for continuous variables and the risk ratio (RR) for binary variables. RESULTS This meta-analysis included 127 RCTs with 20,215 patients. Sevelamer and lanthanum significantly reduced all-cause mortality (RR 0.610, 95% CI 0.401-0.929 and 0.467, 95% CI 0.337-0.647, respectively) but not cardiovascular (CV) mortality or CV events. Hospitalization rates were significantly diminished by sevelamer (RR 0.527; 95% CI 0.308-0.902). Certain phosphate lowering agents improved biochemical parameters including serum phosphate, calcium, coronary artery calcium scores, fibroblast growth factor-23, bone biomarkers, and lipid profiles. Intact parathyroid hormone and bone mineral density were not significantly changed. CONCLUSIONS In addition to decreasing serum phosphate levels, various beneficial effects on clinical and laboratory parameters of phosphate lowering agents might play potential roles in diminishing morbidity and mortality in CKD patients.
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Affiliation(s)
- Jeerath Phannajit
- Division of Nephrology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, 1873 RAMA IV, Bangkok, 10330, Thailand.,Division of Clinical Epidemiology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.,Research Unit for Metabolic Bone Disease in CKD Patients, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natthaphon Wonghakaeo
- Division of Nephrology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, 1873 RAMA IV, Bangkok, 10330, Thailand
| | - Kullaya Takkavatakarn
- Division of Nephrology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, 1873 RAMA IV, Bangkok, 10330, Thailand
| | - Thanin Asawavichienjinda
- Division of Clinical Epidemiology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kearkiat Praditpornsilpa
- Division of Nephrology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, 1873 RAMA IV, Bangkok, 10330, Thailand
| | - Somchai Eiam-Ong
- Division of Nephrology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, 1873 RAMA IV, Bangkok, 10330, Thailand
| | - Paweena Susantitaphong
- Division of Nephrology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, 1873 RAMA IV, Bangkok, 10330, Thailand. .,Research Unit for Metabolic Bone Disease in CKD Patients, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
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Bover J, Aguilar A, Arana C, Molina P, Lloret MJ, Ochoa J, Berná G, Gutiérrez-Maza YG, Rodrigues N, D'Marco L, Górriz JL. Clinical Approach to Vascular Calcification in Patients With Non-dialysis Dependent Chronic Kidney Disease: Mineral-Bone Disorder-Related Aspects. Front Med (Lausanne) 2021; 8:642718. [PMID: 34095165 PMCID: PMC8171667 DOI: 10.3389/fmed.2021.642718] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 04/12/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic kidney disease (CKD) is associated with a very high morbimortality, mainly from cardiovascular origin, and CKD is currently considered in the high- or very high risk- cardiovascular risk category. CKD-mineral and bone disorders (CKD-MBDs), including vascular and/or valvular calcifications, are also associated with these poor outcomes. Vascular calcification (VC) is very prevalent (both intimal and medial), even in non-dialysis dependent patients, with a greater severity and more rapid progression. Simple X-ray based-scores such as Adragão's (AS) are useful prognostic tools and AS (even AS based on hand-X-ray only) may be superior to the classic Kauppila's score when evaluating non-dialysis CKD patients. Thus, in this mini-review, we briefly review CKD-MBD-related aspects of VC and its complex pathophysiology including the vast array of contributors and inhibitors. Furthermore, although VC is a surrogate marker and is not yet considered a treatment target, we consider that the presence of VC may be relevant in guiding therapeutic interventions, unless all patients are treated with the mindset of reducing the incidence or progression of VC with the currently available armamentarium. Avoiding phosphate loading, restricting calcium-based phosphate binders and high doses of vitamin D, and avoiding normalizing (within the normal limits for the assay) parathyroid hormone levels seem logical approaches. The availability of new drugs and future studies, including patients in early stages of CKD, may lead to significant improvements not only in patient risk stratification but also in attenuating the accelerated progression of VC in CKD.
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Affiliation(s)
- Jordi Bover
- Department of Nephrology, Fundació Puigvert, IIB Sant Pau, Universitat Autònoma, REDinREN, Barcelona, Spain
| | - Armando Aguilar
- Department of Nephrology, Instituto Mexicano del Seguro Social, Hospital General de Zona No. 2, Tuxtla Gutiérrez, Mexico
| | - Carolt Arana
- Department of Nephrology, Fundació Puigvert, IIB Sant Pau, Universitat Autònoma, REDinREN, Barcelona, Spain
| | - Pablo Molina
- Department of Nephrology, Hospital Universitario Dr Peset, Universidad de Valencia, REDinREN, Valencia, Spain
| | - María Jesús Lloret
- Department of Nephrology, Fundació Puigvert, IIB Sant Pau, Universitat Autònoma, REDinREN, Barcelona, Spain
| | - Jackson Ochoa
- Department of Nephrology, Fundació Puigvert, IIB Sant Pau, Universitat Autònoma, REDinREN, Barcelona, Spain
| | - Gerson Berná
- Department of Nephrology, Fundació Puigvert, IIB Sant Pau, Universitat Autònoma, REDinREN, Barcelona, Spain
| | - Yessica G. Gutiérrez-Maza
- Department of Nephrology, Instituto Mexicano del Seguro Social, Hospital General de Zona No. 2, Tuxtla Gutiérrez, Mexico
| | - Natacha Rodrigues
- Division of Nephrology and Renal Transplantation, Department of Medicine, Centro Hospitalar Universitário Lisboa Norte, EPE, Lisboa, Portugal
| | - Luis D'Marco
- Servicio de Nefrología, Hospital Clínico Universitario, INCLIVA, Universidad de Valencia, Valencia, Spain
| | - José L. Górriz
- Servicio de Nefrología, Hospital Clínico Universitario, INCLIVA, Universidad de Valencia, Valencia, Spain
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Ogata H, Fukagawa M, Hirakata H, Kagimura T, Fukushima M, Akizawa T. Effect of Treating Hyperphosphatemia With Lanthanum Carbonate vs Calcium Carbonate on Cardiovascular Events in Patients With Chronic Kidney Disease Undergoing Hemodialysis: The LANDMARK Randomized Clinical Trial. JAMA 2021; 325:1946-1954. [PMID: 34003226 PMCID: PMC8132143 DOI: 10.1001/jama.2021.4807] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 03/12/2021] [Indexed: 11/14/2022]
Abstract
Importance Among patients with hyperphosphatemia undergoing dialysis, it is unclear whether non-calcium-based phosphate binders are more effective than calcium-based binders for reducing cardiovascular events. Objective To determine whether lanthanum carbonate reduces cardiovascular events compared with calcium carbonate in patients with hyperphosphatemia at risk of vascular calcification undergoing hemodialysis. Design, Setting, and Participants Open-label, randomized, parallel-group clinical trial with blinded end point adjudication performed in 2374 patients with chronic kidney disease from 273 hemodialysis facilities in Japan. Eligible patients had hyperphosphatemia and 1 or more risk factors for vascular calcification (ie, ≥65 years, postmenopausal, diabetes). Enrollment occurred from November 2011 to July 2014; follow-up ended June 2018. Interventions Patients were randomized to receive either lanthanum carbonate (n = 1154) or calcium carbonate (n = 1155) and titrated to achieve serum phosphate levels of between 3.5 mg/dL and 6.0 mg/dL. Main Outcomes and Measures The primary outcome was a composite cardiovascular event (cardiovascular death, nonfatal myocardial infarction or stroke, unstable angina, transient ischemic attack, or hospitalization for heart failure or ventricular arrhythmia). Secondary outcomes included overall survival, secondary hyperparathyroidism-free survival, hip fracture-free survival, and adverse events. Results Among 2309 randomized patients (median age, 69 years; 40.5% women), 1851 (80.2%) completed the trial. After a median follow-up of 3.16 years, cardiovascular events occurred in 147 of 1063 patients in the lanthanum calcium group and 134 of 1072 patients in the calcium carbonate group (incidence rate, 4.80 vs 4.30 per 100 person-years; difference 0.50 per 100 person-years [95% CI, -0.57 to 1.56]; hazard ratio [HR], 1.11 [95%, CI, 0.88 to 1.41], P = .37). There were no significant differences in all-cause death (difference, 0.43 per 100 person-years [95% CI, -0.63 to 1.49]; HR, 1.10 [95% CI, 0.88 to 1.37]; P = .42) or hip fracture (difference, 0.10 per 100 person-years [95% CI, -0.26 to 0.47]; HR, 1.21 [95% CI, 0.62 to 2.35]; P = .58). The lanthanum carbonate group had an increased risk of cardiovascular death (difference, 0.61 per 100 person-years [95% CI, 0.02 to 1.21]; HR, 1.51 [95% CI, 1.01 to 2.27]; P = .045) and secondary hyperparathyroidism (difference, 1.34 [95% CI, 0.49 to 2.19]; HR, 1.62 [95% CI, 1.19 to 2.20]; P = .002). Adverse events occurred in 282 (25.7%) in the lanthanum carbonate group and 259 (23.4%) in the calcium carbonate groups. Conclusions and Relevance Among patients undergoing hemodialysis with hyperphosphatemia and at least 1 vascular calcification risk factor, treatment of hyperphosphatemia with lanthanum carbonate compared with calcium carbonate did not result in a significant difference in composite cardiovascular events. However, the event rate was low, and the findings may not apply to patients at higher risk. Trial Registration ClinicalTrials.gov Identifier: NCT01578200; UMIN Clinical Trial Registry Identifier: UMIN000006815.
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Affiliation(s)
- Hiroaki Ogata
- Division of Nephrology, Department of Internal Medicine, Showa University Northern Yokohama Hospital, Tsuzuki, Yokohama, Kanagawa, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | | | - Tatsuo Kagimura
- The Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Chuo-ku, Kobe, Hyogo, Japan
| | - Masanori Fukushima
- The Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Chuo-ku, Kobe, Hyogo, Japan
| | - Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan
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Tsuchiya K, Akihisa T. The Importance of Phosphate Control in Chronic Kidney Disease. Nutrients 2021; 13:nu13051670. [PMID: 34069053 PMCID: PMC8156430 DOI: 10.3390/nu13051670] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/06/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
A series of problems including osteopathy, abnormal serum data, and vascular calcification associated with chronic kidney disease (CKD) are now collectively called CKD-mineral bone disease (CKD-MBD). The pathophysiology of CKD-MBD is becoming clear with the emerging of αKlotho, originally identified as a progeria-causing protein, and bone-derived phosphaturic fibroblast growth factor 23 (FGF23) as associated factors. Meanwhile, compared with calcium and parathyroid hormone, which have long been linked with CKD-MBD, phosphate is now attracting more attention because of its association with complications and outcomes. Incidentally, as the pivotal roles of FGF23 and αKlotho in phosphate metabolism have been unveiled, how phosphate metabolism and hyperphosphatemia are involved in CKD-MBD and how they can be clinically treated have become of great interest. Thus, the aim of this review is reconsider CKD-MBD from the viewpoint of phosphorus, its involvement in the pathophysiology, causing complications, therapeutic approach based on the clinical evidence, and clarifying the importance of phosphorus management.
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Affiliation(s)
- Ken Tsuchiya
- Department of Blood Purification, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
- Correspondence:
| | - Taro Akihisa
- Department of Nephrology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan;
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Bielach-Bazyluk A, Zbroch E, Czajkowska K, Koc-Zorawska E, Kakareko K, Rydzewska-Rosolowska A, Hryszko T. Serum sirtuin 1 is independently associated with intact PTH among patients with chronic kidney disease. Clin Interv Aging 2021; 16:525-536. [PMID: 33790547 PMCID: PMC8007476 DOI: 10.2147/cia.s293665] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/26/2021] [Indexed: 11/23/2022] Open
Abstract
Background Sirtuin 1 is involved in the pathogenesis of age-related diseases. Purpose The aim of the study was to assess the clinical and diagnostic value of serum sirtuin 1 concentration in patients with CKD. Patients and Methods The serum sirtuin 1 level was evaluated using ELISA kit in 100 CKD patients stratified for five stages and in a control group of 24 healthy volunteers. Results Serum sirtuin 1 concentration was higher in the CKD group compared with the control group (p<0.05). Sirtuin 1 correlated with conventional CKD biomarkers and eGFR equations, intact parathyroid hormone (iPTH) and age (all p<0.05). Statins, AT1 receptor antagonists and β-blockers use were associated with decreased sirtuin concentration (p<0.05). Sirtuin 1 was able to distinguish CKD from control group with high sensitivity and specificity (93% and 87%, respectively; AUC=0.954). Surprisingly, after adjustment only iPTH concentration was an independent predictor of sirtuin 1 level. Conclusion The association between sirtuin 1, eGFR equations and iPTH indicates its possible usefulness as a kidney function marker. In terms of iPTH being the only independent predictor of circulating sirtuin 1 it can be considered as an indirect cardiovascular risk biomarker regardless of renal function and provide additional information for patient management. Alternatively, sirtuin 1 is recognized as protective against vascular disease, and we demonstrated a positive correlation with iPTH, which may be related to accumulation of (7-84)-PTH having opposite biological effects to full-length PTH. Further studies are needed to explore the interplay between sirtuin 1, PTH and CKD-related vascular calcification as well as to assess its prognostic value in observational studies.
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Affiliation(s)
- Angelika Bielach-Bazyluk
- 2nd Department of Nephrology and Hypertension with Dialysis Centre, Medical University, Bialystok, Poland
| | - Edyta Zbroch
- Department of Internal Medicine and Hypertension, Medical University, Bialystok, Poland
| | - Katarzyna Czajkowska
- 2nd Department of Nephrology and Hypertension with Dialysis Centre, Medical University, Bialystok, Poland
| | - Ewa Koc-Zorawska
- 2nd Department of Nephrology and Hypertension with Dialysis Centre, Medical University, Bialystok, Poland
| | - Katarzyna Kakareko
- 2nd Department of Nephrology and Hypertension with Dialysis Centre, Medical University, Bialystok, Poland
| | | | - Tomasz Hryszko
- 2nd Department of Nephrology and Hypertension with Dialysis Centre, Medical University, Bialystok, Poland
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Winiarska A, Filipska I, Knysak M, Stompór T. Dietary Phosphorus as a Marker of Mineral Metabolism and Progression of Diabetic Kidney Disease. Nutrients 2021; 13:789. [PMID: 33673618 PMCID: PMC7997399 DOI: 10.3390/nu13030789] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 12/31/2022] Open
Abstract
Phosphorus is an essential nutrient that is critically important in the control of cell and tissue function and body homeostasis. Phosphorus excess may result in severe adverse medical consequences. The most apparent is an impact on cardiovascular (CV) disease, mainly through the ability of phosphate to change the phenotype of vascular smooth muscle cells and its contribution to pathologic vascular, valvular and other soft tissue calcification. Chronic kidney disease (CKD) is the most prevalent chronic disease manifesting with the persistent derangement of phosphate homeostasis. Diabetes and resulting diabetic kidney disease (DKD) remain the leading causes of CKD and end-stage kidney disease (ESRD) worldwide. Mineral and bone disorders of CKD (CKD-MBD), profound derangement of mineral metabolism, develop in the course of the disease and adversely impact on bone health and the CV system. In this review we aimed to discuss the data concerning CKD-MBD in patients with diabetes and to analyze the possible link between hyperphosphatemia, certain biomarkers of CKD-MBD and high dietary phosphate intake on prognosis in patients with diabetes and DKD. We also attempted to clarify if hyperphosphatemia and high phosphorus intake may impact the onset and progression of DKD. Careful analysis of the available literature brings us to the conclusion that, as for today, no clear recommendations based on the firm clinical data can be provided in terms of phosphorus intake aiming to prevent the incidence or progression of diabetic kidney disease.
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Affiliation(s)
| | | | | | - Tomasz Stompór
- Department of Nephrology, Hypertension and Internal Medicine, University of Warmia and Mazury in Olsztyn, 10561 Olsztyn, Poland; (A.W.); (I.F.); (M.K.)
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Cozzolino M, Galassi A, Ciceri P. Do we need new phosphate binders in dialysis? Clin Kidney J 2021; 14:474-475. [PMID: 33626110 PMCID: PMC7886565 DOI: 10.1093/ckj/sfaa246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 10/19/2020] [Indexed: 11/28/2022] Open
Abstract
Patients affected by chronic kidney disease (CKD) have a greater risk of mortality than the general population. Fatal cardiovascular events are the most frequent cause of death in CKD patients, especially in the late stages of disease. Derangement of mineral metabolism and hyperphosphataemia are currently accepted as pivotal triggers of these vascular complications. Phosphate binders represent the common strategy to counteract hyperphosphataemia in dialysis patients. Several studies have reported a reduction in mortality risk in dialysis patients receiving phosphate binders compared with untreated patients, independent of the class of binder prescribed.
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Affiliation(s)
- Mario Cozzolino
- Renal Division, ASST Santi Paolo e Carlo, Depart. of Health Sciences, University of Milan, Milan, Italy
| | - Andrea Galassi
- Renal Division, ASST Santi Paolo e Carlo, Depart. of Health Sciences, University of Milan, Milan, Italy
| | - Paola Ciceri
- Renal Research Laboratory, Department of Nephrology, Dialysis and Renal Transplant, Fondazione Ca' Granda IRCCS, Ospedale Maggiore Policlinico, Milan, Italy
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Scialla JJ, Kendrick J, Uribarri J, Kovesdy CP, Gutiérrez OM, Jimenez EY, Kramer HJ. State-of-the-Art Management of Hyperphosphatemia in Patients With CKD: An NKF-KDOQI Controversies Perspective. Am J Kidney Dis 2021; 77:132-141. [PMID: 32771650 PMCID: PMC8109252 DOI: 10.1053/j.ajkd.2020.05.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 05/16/2020] [Indexed: 02/07/2023]
Abstract
Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney disease (CKD). In patients with CKD glomerular filtration rate category 3a (G3a) or worse, including those with kidney failure who are receiving dialysis, clinical practice guidelines suggest "lowering elevated phosphate levels towards the normal range" with possible strategies including dietary phosphate restriction or use of binders. Additionally, guidelines suggest restricting the use of oral elemental calcium often contained in phosphate binders. Nutrition guidelines in CKD suggest<800-1,000mg of calcium daily, whereas CKD bone and mineral disorder guidelines do not provide clear targets, but<1,500mg in maintenance dialysis patients has been previously recommended. Many different classes of phosphate binders are now available and clinical trials have not definitively demonstrated the superiority of any class of phosphate binders over another with regard to clinical outcomes. Use of phosphate binders contributes substantially to patients' pill burden and out-of-pocket costs, and many have side effects. This has led to uncertainty regarding the use and best choice of phosphate binders for patients with CKD or kidney failure. In this controversies perspective, we discuss the evidence base around binder use in CKD and kidney failure with a focus on comparisons of available binders.
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Affiliation(s)
- Julia J Scialla
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA; Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA.
| | - Jessica Kendrick
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Jaime Uribarri
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Csaba P Kovesdy
- Department of Medicine, University of Tennessee Health Science Center and Memphis Veterans Affairs Medical Center, Memphis, TN
| | - Orlando M Gutiérrez
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
| | - Elizabeth Yakes Jimenez
- Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico; Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico; Nutrition Research Network, Academy of Nutrition and Dietetics, Chicago, IL
| | - Holly J Kramer
- Department of Medicine, Loyola University Chicago, Maywood, IL; Department of Public Health Sciences, Loyola University Chicago, Maywood, IL
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Chao CT, Lin SH. Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins. Toxins (Basel) 2020; 12:toxins12120812. [PMID: 33371477 PMCID: PMC7767516 DOI: 10.3390/toxins12120812] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/11/2020] [Accepted: 12/11/2020] [Indexed: 12/16/2022] Open
Abstract
Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC.
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Affiliation(s)
- Chia-Ter Chao
- Nephrology Division, Department of Medicine, National Taiwan University Hospital BeiHu Branch, Taipei 10845, Taiwan;
- Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei 100233, Taiwan
- Nephrology Division, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan
| | - Shih-Hua Lin
- Department of Internal Medicine, Tri-Service General Hospital and National Defense Medical Center, Taipei 11490, Taiwan
- Correspondence:
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Targeting Uremic Toxins to Prevent Peripheral Vascular Complications in Chronic Kidney Disease. Toxins (Basel) 2020; 12:toxins12120808. [PMID: 33419312 PMCID: PMC7765928 DOI: 10.3390/toxins12120808] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 12/24/2022] Open
Abstract
Chronic kidney disease (CKD) exhibits progressive kidney dysfunction and leads to disturbed homeostasis, including accumulation of uremic toxins, activated renin-angiotensin system, and increased oxidative stress and proinflammatory cytokines. Patients with CKD are prone to developing the peripheral vascular disease (PVD), leading to poorer outcomes than those without CKD. Cumulative evidence has showed that the synergy of uremic milieu and PVD could exaggerate vascular complications such as limb ischemia, amputation, stenosis, or thrombosis of a dialysis vascular access, and increase mortality risk. The role of uremic toxins in the pathogenesis of vascular dysfunction in CKD has been investigated. Moreover, growing evidence has shown the promising role of uremic toxins as a therapeutic target for PVD in CKD. This review focused on uremic toxins in the pathophysiology, in vitro and animal models, and current novel clinical approaches in reducing the uremic toxin to prevent peripheral vascular complications in CKD patients.
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Castañeda TR, Méndez M, Davison I, Elvert R, Schwahn U, Boldina G, Rocher C, Scherer P, Singh K, Bangari DS, Falkenhahn M, Kannt A, Konkar A, Larsen PJ, Arbeeny C, Dhal PK, Hübschle T. The Novel Phosphate and Bile Acid Sequestrant Polymer SAR442357 Delays Disease Progression in a Rat Model of Diabetic Nephropathy. J Pharmacol Exp Ther 2020; 376:190-203. [PMID: 33203659 DOI: 10.1124/jpet.120.000285] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 11/10/2020] [Indexed: 12/11/2022] Open
Abstract
As a gut-restricted, nonabsorbed therapy, polymeric bile acid sequestrants (BAS) play an important role in managing hyperlipidemia and hyperglycemia. Similarly, nonabsorbable sequestrants of dietary phosphate have been used for the management of hyperphosphatemia in end-stage renal disease. To evaluate the potential utility of such polymer sequestrants to treat type 2 diabetes (T2D) and its associated renal and cardiovascular complications, we synthesized a novel polymeric sequestrant, SAR442357, possessing optimized bile acid (BA) and phosphate sequestration characteristics. Long-term treatment of T2D obese cZucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) with SAR442357 resulted in enhanced sequestration of BAs and phosphate in the gut, improved glycemic control, lowering of serum cholesterol, and attenuation of diabetic kidney disease (DKD) progression. In comparison, colesevelam, a BAS with poor phosphate binding properties, did not prevent DKD progression, whereas losartan, an angiotensin II receptor blocker that is widely used to treat DKD, showed no effect on hyperglycemia. Analysis of hepatic gene expression levels of the animals treated with SAR442357 revealed upregulation of genes responsible for the biosynthesis of cholesterol and BAs, providing clear evidence of target engagement and mode of action of the new sequestrant. Additional hepatic gene expression pathway changes were indicative of an interruption of the enterohepatic BA cycle. Histopathological analysis of ZSF1 rat kidneys treated with SAR442357 further supported its nephroprotective properties. Collectively, these findings reveal the pharmacological benefit of simultaneous sequestration of BAs and phosphate in treating T2D and its associated comorbidities and cardiovascular complications. SIGNIFICANCE STATEMENT: A new nonabsorbed polymeric sequestrant with optimum phosphate and bile salt sequestration properties was developed as a treatment option for DKD. The new polymeric sequestrant offered combined pharmacological benefits including glucose regulation, lipid lowering, and attenuation of DKD progression in a single therapeutic agent.
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Affiliation(s)
- Tamara R Castañeda
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - María Méndez
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Ian Davison
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Ralf Elvert
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Uwe Schwahn
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Galina Boldina
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Corinne Rocher
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Petra Scherer
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Kuldeep Singh
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Dinesh S Bangari
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Mechthilde Falkenhahn
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Aimo Kannt
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Anish Konkar
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Philip J Larsen
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Cynthia Arbeeny
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Pradeep K Dhal
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
| | - Thomas Hübschle
- R&D Diabetes (T.R.C., R.E., A.Ka., A.Ko., P.J.L., C.A., T.H.), Integrated Drug Discovery (M.M.), Biomarkers and Clinical Bioanalysis (U.S.), Translational In Vivo Models, Global Discovery Pathology (P.S.), and Global Research Project Management (M.F.), Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, Frankfurt, Germany; C&BD Haverhill Operations, Sanofi GB Genzyme Limited, Haverhill, Suffolk, United Kingdom (I.D.); R&D Translational Sciences France, Bioinformatics, Sanofi, Chilly-Mazarin Cedex, France (C.R.); Translational In Vivo Models, Global Discovery Pathology, Framingham, Massachusetts (K.S., D.S.B.); and Pharmaceutical Development Platform, Sanofi Global R&D, Waltham, Massachusetts (P.K.D.)
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Tsai PH, Chung CH, Chien WC, Chu P. Effects of calcium-containing phosphate binders on cardiovascular events and mortality in predialysis CKD stage 5 patients. PLoS One 2020; 15:e0241435. [PMID: 33125428 PMCID: PMC7598463 DOI: 10.1371/journal.pone.0241435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 10/15/2020] [Indexed: 01/25/2023] Open
Abstract
Background Hyperphosphatemia and calcium load were associated with vascular calcification. The role of calcium-containing phosphate binders (CCPBs) use as important determinants of death and cardiovascular events in predialysis hyperphosphatemic chronic kidney disease (CKD) patients remain unclear due to the absence of evidence for reduced mortality with CCPB use compared with placebo. We aimed to investigate the effect of using CCPBs or nonuse in all-cause mortality rates and cardiovascular events in CKD stage 5 patients between 2000 and 2005 in the Taiwanese National Health Insurance Research Database. Methods Patients with known coronary heart disease and those who had undergone dialysis or renal transplantation were excluded. The CCPB users were matched with nonusers by the propensity score model. Multivariable Cox proportional hazards model was used to estimate hazard ratios (HRs) of all-cause mortality and cardiovascular events. Results During a mean follow-up of 4.58 years, 879 CCPB users were matched with 3516 nonusers. CCPB use was an independent risk factor for cardiovascular events [adjusted hazard ratio (HR) 1.583, 95% confidence interval (CI) 1.393–1.799]. The increased cardiovascular risk was dose-dependent and consistent across all subgroup analyses. Compared with no use, CCPB use was associated with no significant all-cause mortality risk (1.74 vs. 1.75 events per 100 person-years, adjusted HR 0.964, 95% CI 0.692–1.310). Conclusions CCPB use in CKD stage 5 patients was associated with a significantly increased cardiovascular event risk compared with the nonusers, whereas the all-cause mortality risk was similar between the two groups. Whether these relationships are causal require further randomized controlled trials.
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Affiliation(s)
- Ping-Huang Tsai
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
- Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical Center, Taipei, Taiwan
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
- Department of Medical Research, Tri-Service General Hospital, Taipei, Taiwan
| | - Pauling Chu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- * E-mail:
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Kuzmina AV. Nutritional support for patients with chronic kidney disease at pre-dialysis stages. TERAPEVT ARKH 2020; 92:117-123. [DOI: 10.26442/00403660.2020.06.000353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Indexed: 11/22/2022]
Abstract
Chronic kidney disease (CKD) is characterized by poor outcomes, an increasing frequency of new cases, the need for expensive method of renal replacement therapy at the terminal stage. The main task facing the doctor is slowing the progression of CKD and delay the start of dialysis by applying the nephroprotective strategy, of which diet therapy is an essential part. The key components of the diet for CKD patients are reducing sodium intake to 2.3 g per day in order to improve control of blood pressure (BP), dietary protein restriction adequate to renal function from 0.8 to 0.3 g/kg of body weight per day combined with the prescribing of ketoanalogues of essential amino acids, hyperglycemia control. With the progression of CKD, the main objectives of the diet therapy are the prevention/correction of complications: protein-energy waisting, metabolic acidosis, ensuring sufficient calories, corresponding to the bodys energy expenditures (3035 kcal/kg of body weight per day), limiting phosphate intake to 0.81 g a day, restriction of food potassium. Low-protein diet in combination with ketoanalogues of amino acids, regular monitoring and correction of the nutritional status of patients at the pre-dialysis stages of CKD is an effective and safe method of nephroprotection, which allows delaying the start of dialysis.
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Cozzolino M, Cianciolo G, Podestà MA, Ciceri P, Galassi A, Gasperoni L, La Manna G. Current Therapy in CKD Patients Can Affect Vitamin K Status. Nutrients 2020; 12:nu12061609. [PMID: 32486167 PMCID: PMC7352600 DOI: 10.3390/nu12061609] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/27/2020] [Accepted: 05/28/2020] [Indexed: 12/15/2022] Open
Abstract
Chronic kidney disease (CKD) patients have a higher risk of cardiovascular (CVD) morbidity and mortality compared to the general population. The links between CKD and CVD are not fully elucidated but encompass both traditional and uremic-related risk factors. The term CKD-mineral and bone disorder (CKD-MBD) indicates a systemic disorder characterized by abnormal levels of calcium, phosphate, PTH and FGF-23, along with vitamin D deficiency, decreased bone mineral density or altered bone turnover and vascular calcification. A growing body of evidence shows that CKD patients can be affected by subclinical vitamin K deficiency; this has led to identifying such a condition as a potential therapeutic target given the specific role of Vitamin K in metabolism of several proteins involved in bone and vascular health. In other words, we can hypothesize that vitamin K deficiency is the common pathogenetic link between impaired bone mineralization and vascular calcification. However, some of the most common approaches to CKD, such as (1) low vitamin K intake due to nutritional restrictions, (2) warfarin treatment, (3) VDRA and calcimimetics, and (4) phosphate binders, may instead have the opposite effects on vitamin K metabolism and storage in CKD patients.
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Affiliation(s)
- Mario Cozzolino
- Renal Division, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy; (M.C.); (M.A.P.); (A.G.)
| | - Giuseppe Cianciolo
- Nephrology, Dialysis and Renal Transplant Unit, Department of Experimental Diagnostic and Specialty Medicine (DIMES), S. Orsola Hospital, University of Bologna, 40126 Bologna, Italy; (G.C.); (L.G.)
| | - Manuel Alfredo Podestà
- Renal Division, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy; (M.C.); (M.A.P.); (A.G.)
| | - Paola Ciceri
- Renal Research Laboratory, Department of Nephrology, Dialysis and Renal Transplant, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy;
| | - Andrea Galassi
- Renal Division, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, 20142 Milan, Italy; (M.C.); (M.A.P.); (A.G.)
| | - Lorenzo Gasperoni
- Nephrology, Dialysis and Renal Transplant Unit, Department of Experimental Diagnostic and Specialty Medicine (DIMES), S. Orsola Hospital, University of Bologna, 40126 Bologna, Italy; (G.C.); (L.G.)
| | - Gaetano La Manna
- Nephrology, Dialysis and Renal Transplant Unit, Department of Experimental Diagnostic and Specialty Medicine (DIMES), S. Orsola Hospital, University of Bologna, 40126 Bologna, Italy; (G.C.); (L.G.)
- Correspondence: ; Tel.: +39-051214-3255
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Nelson AJ, Raggi P, Wolf M, Gold AM, Chertow GM, Roe MT. Targeting Vascular Calcification in Chronic Kidney Disease. JACC Basic Transl Sci 2020; 5:398-412. [PMID: 32368697 PMCID: PMC7188874 DOI: 10.1016/j.jacbts.2020.02.002] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/24/2020] [Accepted: 02/03/2020] [Indexed: 12/22/2022]
Abstract
Cardiovascular (CV) disease remains an important cause of morbidity and mortality for patients with chronic kidney disease (CKD). Although clustering of traditional risk factors with CKD is well recognized, kidney-specific mechanisms are believed to drive the disproportionate burden of CV disease. One perturbation that is frequently observed at high rates in patients with CKD is vascular calcification, which may be a central mediator for an array of CV sequelae. This review summarizes the pathophysiological bases of intimal and medial vascular calcification in CKD, current strategies for diagnosis and management, and posits vascular calcification as a risk marker and therapeutic target.
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Key Words
- CAC, coronary artery calcification
- CI, confidence interval
- CKD, chronic kidney disease
- CT, computed tomography
- CV, cardiovascular
- CVD, cardiovascular disease
- ESKD, end-stage kidney disease
- FGF, fibroblast growth factor
- HR, hazard ratio
- LDL-C, low-density lipoprotein cholesterol
- MGP, matrix Gla protein
- PTH, parathyroid hormone
- VSMC, vascular smooth muscle cell
- chronic kidney disease
- dialysis
- eGFR, estimated glomerular filtration rate
- medial calcification
- vascular calcification
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Affiliation(s)
- Adam J. Nelson
- Division of Cardiology, Duke Clinical Research Institute, Durham, North Carolina
| | - Paolo Raggi
- Division of Cardiology, Department of Medicine, University of Alberta and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada
| | - Myles Wolf
- Division of Nephrology, Department of Medicine, and Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
| | - Alexander M. Gold
- Research and Development, Sanifit Therapeutics, San Diego, California
- Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Glenn M. Chertow
- Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Matthew T. Roe
- Division of Cardiology, Duke Clinical Research Institute, Durham, North Carolina
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Hedayati SS. A Novel Treatment for Vascular Calcification in Patients With Dialysis-Dependent Chronic Kidney Disease: Are We There Yet? Circulation 2020; 141:740-742. [PMID: 32119585 DOI: 10.1161/circulationaha.119.044801] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Affiliation(s)
- S Susan Hedayati
- Division of Nephrology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas
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Bover J, Cozzolino M. Small steps towards the potential of 'preventive' treatment of early phosphate loading in chronic kidney disease patients. Clin Kidney J 2019; 12:673-677. [PMID: 31584564 PMCID: PMC6768463 DOI: 10.1093/ckj/sfz082] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Indexed: 12/31/2022] Open
Abstract
Few clinical studies have investigated the value of phosphate (P)-lowering therapies in early chronic kidney disease (CKD) patients in whom hyperphosphataemia has not yet clearly developed and they report conflicting and even unexpected results. In this issue of Clinical Kidney Journal, de Krijger et al. found that sevelamer carbonate (4.8 g/day for 8 weeks) did not induce a significant reduction of pulse wave velocity (PWV) and that fibroblast growth factor 23 (FGF23) did not decrease despite a decline in 24-h urine P excretion. To some extent these findings challenge the concept that 'preventive' P binder therapy to lower FGF23 is a useful approach, at least over this short period of time. Interestingly, in a subgroup of patients with absent or limited abdominal vascular calcification, treatment did result in a statistically significant reduction in adjusted PWV, suggesting that PWV is amenable to improvement in this subset. Interpretation of the scarce and heterogeneous observations described in early CKD remains difficult and causality and/or the possibility of 'preventive' treatment may not yet be completely disregarded. Moreover, de Krijger et al. contribute to the identification of new sources of bias and methodological issues that may lead to more personalized treatments, always bearing in mind that not all patients and not all P binders are equal.
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Affiliation(s)
- Jordi Bover
- Fundació Puigvert, Department of Nephrology and Cardiology, IIB Sant Pau, RedinRen, Barcelona, Catalonia, Spain
| | - Mario Cozzolino
- Renal Unit, San Paolo Hospital and San Carlo Hospital, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
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Cano-Megías M, Guisado-Vasco P, Bouarich H, de Arriba-de la Fuente G, de Sequera-Ortiz P, Álvarez-Sanz C, Rodríguez-Puyol D. Coronary calcification as a predictor of cardiovascular mortality in advanced chronic kidney disease: a prospective long-term follow-up study. BMC Nephrol 2019; 20:188. [PMID: 31138150 PMCID: PMC6537175 DOI: 10.1186/s12882-019-1367-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 04/30/2019] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Patients with advanced chronic kidney disease (CKD) exhibit higher prevalence of coronary artery calcification (CaC) than general population. CaC has been proposed as a risk factor for mortality in end-stage CKD, but most studies in the field are based on short-term follow-up. METHODS We conducted a cohort, 10-year prospective longitudinal study of consecutive cases referred to the renal unit. A non-enhanced multislice coronary computed tomography was performed at baseline. CaC was assessed by Agatston method. Patients were stratified according to their CaC score: severe calcification group (CaCs< 400 HU) and mild-moderate calcification group (CaCs≥400 HU). The overall and cardiovascular (CV) mortality, CV events, and factors potentially associated with CaC development were recorded. RESULTS 137 patients with advanced CKD were enrolled and provided consent. Overall mortality rate was 58%; 40% due to CV events. The rate of overall mortality in the severe calcification group was 75%, and 30% in the low calcification group, whereas the rate of CV mortality was 35% vs. 6%, respectively (p < 0.001). The severe calcification group was older, had higher prevalence of type 2 diabetes mellitus, former cardiologic events, and lower albumin serum levels than the mild-moderate calcification group. In a multivariate Cox model, severe CaC was a significant predictor of CV mortality (HR 5.01; 95%CI 1.28 to 19.6, p = 0.02). CONCLUSIONS Among advanced CKD, there was a significantly increase of CV mortality in patients with severe CaCs during a 10-year follow-up period. CaCs could be a useful prognostic tool to predict CV mortality risk in CKD patients.
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Affiliation(s)
- Marta Cano-Megías
- 'Principe de Asturias' University Hospital, Ctra Alcalá-Meco s/n. Alcalá de Henares, 28805, Madrid, Spain.
| | - Pablo Guisado-Vasco
- European University, Internal Medicine, Ruber Juan Bravo Hospital, Juan Bravo St 39-49, ZP 28006, Madrid, Spain
| | - Hanane Bouarich
- 'Principe de Asturias' University Hospital, Ctra Alcalá-Meco s/n. Alcalá de Henares, 28805, Madrid, Spain
| | | | | | - Concepción Álvarez-Sanz
- 'Principe de Asturias' University Hospital, Ctra Alcalá-Meco s/n. Alcalá de Henares, 28805, Madrid, Spain
| | - Diego Rodríguez-Puyol
- Research Foundation of 'Principe de Asturias' University Hospital, Ctra Alcalá-Meco s/n, Alcalá de Henares, 28805, Madrid, Spain
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Di Micco L, Di Lullo L, Bellasi A, Di Iorio BR. Very Low Protein Diet for Patients with Chronic Kidney Disease: Recent Insights. J Clin Med 2019; 8:jcm8050718. [PMID: 31137545 PMCID: PMC6572310 DOI: 10.3390/jcm8050718] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 05/17/2019] [Accepted: 05/17/2019] [Indexed: 12/30/2022] Open
Abstract
Use of nutritional therapy (NT) in chronic kidney disease (CKD) patients is still debated among nephrologists, but it represents a fundamental point in the conservative treatment of CKD. It has been used for years and it has new goals today, such as (1) the reduction of edema, diuretics, and blood pressure values with a low sodium-content diet; (2) the dose reduction of phosphate levels and phosphate binders; (3) the administration of bicarbonate with vegetables in order to correct metabolic acidosis and delay CKD progression; (4) the reduction of the number and the doses of drugs and chemical substances; and (5) the lowering of urea levels, the cure of intestinal microbioma, and the reduction of cyanates levels (such as indoxyl-sulphate and p-cresol sulphate), which are the most recent known advantages achievable with NT. In conclusion, NT and especially very low protein diet (VLPD) have several beneficial effects in CKD patients and slows the progression of CKD.
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Affiliation(s)
- Lucia Di Micco
- Nefrology and Dialysis, AORN "San Giuseppe Moscati, 83100 Avellino AV, Italy.
| | - Luca Di Lullo
- Department of Nephrology and Dialysis, Parodi-Delfino Hospital, 00034 Colleferro, Rome, Italy.
| | - Antonio Bellasi
- Department of Research, Innovation and Brand Reputation, ASST Papa Giovanni XXIII, 24127 Bergamo BG, Italy.
| | - Biagio R Di Iorio
- Nephrology and Dialysis, AORN "Antonio Cardarelli", 80131 Napoli, Italy.
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44
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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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Ferreira A, Pinto B, Navarro D, Aniceto J, Neves PL, Ponce P. Effectiveness of sucroferric oxyhydroxide in patients on on-line hemodiafiltration in real-world clinical practice: A retrospective study. J Bras Nefrol 2019; 41:224-230. [PMID: 30742699 PMCID: PMC6699437 DOI: 10.1590/2175-8239-jbn-2018-0142] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 10/14/2018] [Indexed: 01/25/2023] Open
Abstract
INTRODUCTION Hyperphosphatemia is a serious consequence of chronic kidney disease and has been associated with an increased risk for cardiovascular disease. Controlling serum phosphorus levels in patients on dialysis is a challenge for the clinicians and implies, in most cases, the use of phosphate binders (PB). Part of the reason for this challenge is poor adherence to treatment because of the high pill burden in this patient group. OBJECTIVE To assess the real-world effectiveness of sucroferric oxyhydroxide (SO) in controlling serum phosphorus levels and determine the associated pill burden. METHODS A multicenter, quantitative, retrospective, before-after study was conducted with patients receiving online hemodiafiltration. Patients who switched to SO as a part of routine care were included in the study. PB treatment, number of pills, serum phosphorus levels, and intravenous iron medication and dosage were collected monthly during the six months of treatment with either PB or SO. RESULTS A total of 42 patients were included in the study. After switching from a PB to SO, the prescribed pills/day was reduced 67% from 6 pills/day to 2 pills/day (p < 0.001) and the frequency of pill intake was lowered from 3 times/day to 2 times/day (p < 0.001). During the treatment with SO, the proportion of patients with serum phosphorus ≤ 5.5 mg/dL increased from 33.3% at baseline to 45% after six months of treatment. CONCLUSION During the six-month follow-up with SO, serum phosphorus levels were controlled with one third of the pills/day compared to other PB.
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Affiliation(s)
- Aníbal Ferreira
- Universidade Nova de LisboaNova Medical SchoolLisboaPortugalUniversidade Nova de Lisboa, Nova Medical
School, Lisboa, Portugal.
- NephroCare Vila Franca de XiraVila Franca de XiraPortugalNephroCare Vila Franca de Xira, Vila Franca de
Xira, Portugal.
| | - Bruno Pinto
- NephroCare PortugalFresenius Medical Care PortugalLisboaPortugalNephroCare Portugal, Fresenius Medical Care
Portugal, Lisboa, Portugal.
| | - David Navarro
- NephroCare Vila Franca de XiraVila Franca de XiraPortugalNephroCare Vila Franca de Xira, Vila Franca de
Xira, Portugal.
| | - João Aniceto
- NephroCare ÉvoraÉvoraPortugalNephroCare Évora, Évora,
Portugal.
| | - Pedro L Neves
- Centro Hospitalar Universitário do
AlgarveFaroPortugalCentro Hospitalar Universitário do Algarve,
Faro, Portugal
| | - Pedro Ponce
- NephroCare LumiarLisboaPortugalNephroCare Lumiar, Lisboa,
Portugal.
- NephroCare PortugalLisboaPortugalNephroCare Portugal, Lisboa,
Portugal.
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Yaseen M, Hassan W, Awad R, Ashqar B, Neyra J, Heister T, Malik O, El-Husseini A. Impact of Recent Clinical Trials on Nephrology Practice: Are We in a Stagnant Era? KIDNEY DISEASES (BASEL, SWITZERLAND) 2019; 5:69-80. [PMID: 31019921 PMCID: PMC6465696 DOI: 10.1159/000495139] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 10/31/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although renal replacement therapy prevents death from uremia, survival among patients with acute and chronic kidney diseases (CKD) remains an imperative concern. The expected life span of US dialysis patients 60-64 years of age is approximately 4.5 years; this is similar to that of patients with lung cancer. Despite substantial progress in many medical specialties over the past decades (e.g., notable reductions in myocardial infarction, stroke, and mortality rates in the general population), survival among dialysis patients has not improved significantly over the same period. A few decades ago, HIV infection and AIDS were pretty much a death sentence. Because of progress in HIV treatment, now it can be controlled with a daily pill, and ongoing research is pushing treatment even further and controls the virus with longer-acting treatment. A cure is no longer impossible for HIV and other viral infections such as hepatitis B and C and many malignancies, but so far there is no cure for CKD. SUMMARY Billions of dollars have been spent on kidney disease research in the past decades, with no tangible progress in clinical practice. The challenges of improving the quantity and quality of trials in nephrology are enormous. The number of randomized controlled trials (RCTs) published in nephrology is lower than that in other medical subspecialties, and most of the big RCTs in nephrology yield negative results. Nephrology studies evaluating hard clinical endpoints or surrogate endpoints are scarce. KEY MESSAGE Herein we discuss the slow progress in nephrology research that has impacted clinical practice over the last couple of decades and highlight the major obstacles, challenges, and potential solutions.
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Affiliation(s)
- Maria Yaseen
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky, USA
| | - Waleed Hassan
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky, USA
| | - Radwa Awad
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky, USA
| | - Bilal Ashqar
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky, USA
| | - Javier Neyra
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky, USA
| | - Tagalie Heister
- Medical Center Library, University of Kentucky, Lexington, Kentucky, USA
| | - Omar Malik
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky, USA
| | - Amr El-Husseini
- Division of Nephrology, Bone and Mineral Metabolism, University of Kentucky, Lexington, Kentucky, USA
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47
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CKD, arterial calcification, atherosclerosis and bone health: Inter-relationships and controversies. Atherosclerosis 2018; 278:49-59. [DOI: 10.1016/j.atherosclerosis.2018.08.046] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 07/12/2018] [Accepted: 08/29/2018] [Indexed: 01/14/2023]
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Cost-Effectiveness Analysis for the Treatment of Hyperphosphatemia in Predialysis Patients: Calcium-Based versus Noncalcium-Based Phosphate Binders. Int J Nephrol 2018; 2018:2138528. [PMID: 30327732 PMCID: PMC6169205 DOI: 10.1155/2018/2138528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 09/02/2018] [Indexed: 11/18/2022] Open
Abstract
Background Hyperphosphatemia in chronic kidney disease (CKD) patients is often treated with calcium carbonate (CaCO3) despite the fact that CaCO3 is associated with increased calcium load and potentially increased cardiovascular risk. Alternative treatments with noncalcium-based phosphate binders do not increase the calcium load but are more costly. This study analyzes the cost-effectiveness of sevelamer versus CaCO3 for the treatment of hyperphosphatemia in stage III-V predialysis CKD patients in Malaysia. Methods A Markov decision model was adapted to simulate a hypothetical cohort of CKD patients requiring treatment for hyperphosphatemia. Survival was estimated by using efficacy data from the INDEPENDENT-CKD clinical trial. Cost data was obtained from Malaysian studies while health state utilities were derived from literature. Analysis was performed over lifetime duration from the perspective of the Ministry of Health Malaysia with 2013 as reference year. Results In the base case analysis, sevelamer treatment gained 6.37 life years (5.27 QALY) compared to 4.25 life years (3.54 QALY) with CaCO3. At 3% discount, lifetime costs were RM159,901 ($48,750) and RM77,139 ($23,518) on sevelamer and CaCO3, respectively. Incremental cost-effectiveness (ICER) of sevelamer versus CaCO3 was RM47,679 ($14,536) per QALY, which is less than the WHO threshold of three times GDP per capita (RM99,395) per QALY. Sensitivity analyses, both using scenario sensitivity analysis and probabilistic sensitivity analysis, showed the result to be robust. Conclusions Our study finds that sevelamer is potentially cost-effective compared to CaCO3, for the treatment of hyperphosphatemia in predialysis CKD III-V. We propose that sevelamer should be an option in the treatment of Malaysian predialysis patients with hyperphosphatemia, particularly those with high calcium load.
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Burton JO, Goldsmith DJ, Ruddock N, Shroff R, Wan M. Renal association commentary on the KDIGO (2017) clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of CKD-MBD. BMC Nephrol 2018; 19:240. [PMID: 30236082 PMCID: PMC6149202 DOI: 10.1186/s12882-018-1037-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 09/04/2018] [Indexed: 11/24/2022] Open
Abstract
This report comments on the relevance and utility of the recently published (2017) KDIGO Clinical Practice Guideline Update for the diagnosis, evaluation, prevention and treatment of mineral bone disease in patients with chronic kidney disease (CKD-MBD) with respect to UK clinical practice. This document replaces all previously published Renal Association guidelines on the topic.
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Affiliation(s)
- James O. Burton
- College of Life Sciences, University of Leicester, Leicester, UK
- University Hospitals of Leicester NHS Trust, Leicester, UK
| | | | - Nicki Ruddock
- University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Rukshana Shroff
- Great Ormond Street Hospital for Children and University College London, London, UK
| | - Mandy Wan
- Institute of Pharmaceutical Science, King’s College, London, UK
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50
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Beto J, Bhatt N, Gerbeling T, Patel C, Drayer D. Overview of the 2017 KDIGO CKD-MBD Update: Practice Implications for Adult Hemodialysis Patients. J Ren Nutr 2018; 29:2-15. [PMID: 30150095 DOI: 10.1053/j.jrn.2018.05.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 04/06/2018] [Accepted: 05/25/2018] [Indexed: 01/10/2023] Open
Abstract
Renal dietitians play a pivotal role in the ongoing management of chronic kidney disease in patients on hemodialysis. Awareness of changes to clinical practice guidelines that may impact laboratory parameters associated with chronic kidney disease-mineral and bone disorder is important for optimal patient care. In this article, the Kidney Disease: Improving Global Outcomes 2017 Clinical Practice Guideline Update recommendations related to the treatment of secondary hyperparathyroidism in adults on hemodialysis are reviewed and treatment implications for renal dietitians discussed. Specific attention is given to the integration of updated recommendations such as the use of calcimimetics as part of a combination approach to the existing treatment paradigm. Renal dietitians can directly apply the updated clinical recommendations in the evaluation of diet composition; food additives; medication adherence challenges with phosphate binder type and use and serial monitoring of phosphorus, calcium, and parathyroid hormone levels to inform clinical decisions on treatment options for patients.
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Affiliation(s)
- Judith Beto
- Research Associate, Division of Nephrology and Hypertension, Loyola University of Chicago, Maywood, Illinois.
| | - Nisha Bhatt
- US Medical Leader Nephrology, Medical Affairs, Amgen Inc., Thousand Oaks, California
| | - Teresa Gerbeling
- Renal Dietitian Coordinator, Dialysis Center of Lincoln, Lincoln, Nebraska
| | - Chhaya Patel
- Nutrition Program Manager, Divisional Lead RD, ORCA Division, DaVita Inc., Denver, Colorado
| | - Debra Drayer
- Senior Regional Medical Liaison Nephrology, Amgen Inc., Thousand Oaks, California
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