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Raju S, Saxena R. Hyperphosphatemia in Kidney Failure: Pathophysiology, Challenges, and Critical Role of Phosphorus Management. Nutrients 2025; 17:1587. [PMID: 40362897 PMCID: PMC12073322 DOI: 10.3390/nu17091587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 04/28/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
Phosphorus is one of the most abundant minerals in the body and plays a critical role in numerous cellular and metabolic processes. Most of the phosphate is deposited in bones, 14% is present in soft tissues as various organic phosphates, and only 1% is found in extracellular space, mainly as inorganic phosphate. The plasma inorganic phosphate concentration is closely maintained between 2.5 and 4.5 mg/dL by intertwined interactions between fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), and vitamin D, which tightly regulate the phosphate trafficking across the gastrointestinal tract, kidneys, and bones. Disruption of the strict hemostatic control of phosphate balance can lead to altered cellular and organ functions that are associated with high morbidity and mortality. In the past three decades, there has been a steady increase in the prevalence of kidney failure (KF) among populations. Individuals with KF have unacceptably high mortality, and well over half of deaths are related to cardiovascular disease. Abnormal phosphate metabolism is one of the major factors that is independently associated with vascular calcification and cardiovascular mortality in KF. In early stages of CKD, adaptive processes involving FGF-23, PTH, and vitamin D occur in response to dietary phosphate load to maintain plasma phosphate level in the normal range. However, as the CKD progresses, these adaptive events are unable to overcome phosphate retention from continued dietary phosphate intake and overt hyperphosphatemia ensues. As these hormonal imbalances and the associated adverse consequences are driven by the underlying hyperphosphatemic state in KF, it appears logical to strictly control serum phosphate. Conventional dialysis is inadequate in removing phosphate and most patients require dietary restrictions and pharmacologic interventions to manage hyperphosphatemia. However, diet control comes with many challenges with adherence and may place patients at risk for inadequate protein intake and malnutrition. Phosphate binders help to reduce phosphate levels but come with a sizable pill burden and high financial costs and are associated with poor adherence and psychosocial issues. Additionally, long-term use of binders may increase the risk of calcium, lanthanum, or iron overload or promote gastrointestinal side effects that exacerbate malnutrition and affect quality of life. Given the aforesaid challenges with phosphorus binders, novel therapies targeting small intestinal phosphate absorption pathways have been investigated. Recently, tenapanor, an agent that blocks paracellular absorption of phosphate via inhibition of enteric sodium-hydrogen exchanger-3 (NHE3) was approved for the treatment of hyperphosphatemia in KF. While various clinical tools are now available to manage hyperphosphatemia, there is a lack of convincing clinical data to demonstrate improvement in outcomes in KF with the lowering of phosphorus level. Conceivably, deleterious effects associated with hyperphosphatemia could be attributable to disruptions in phosphorus-sensing mechanisms and hormonal imbalance thereof. Further exploration of mechanisms that precisely control phosphorus sensing and regulation may facilitate development of strategies to diminish the deleterious effects of phosphorus load and improve overall outcomes in KF.
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Affiliation(s)
| | - Ramesh Saxena
- Division of Nephrology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
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Akizawa T, Urano N, Ikejiri K, Nakanishi K, Fukagawa M. Tenapanor: A novel therapeutic agent for dialysis patients with hyperphosphatemia. Ther Apher Dial 2025; 29:157-169. [PMID: 39829064 PMCID: PMC11879479 DOI: 10.1111/1744-9987.14241] [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: 09/24/2024] [Revised: 11/27/2024] [Accepted: 12/08/2024] [Indexed: 01/22/2025]
Abstract
Patients on dialysis often develop hyperphosphatemia, contributing to an increased risk of cardiovascular events and mortality. Currently, several types of phosphate binders (PBs) exist for the treatment of hyperphosphatemia, but they are sometimes associated with drug-specific side effects and high pill burden, making it difficult to control serum phosphorus appropriately. Tenapanor, which has a novel mechanism to reduce serum phosphorus via selective sodium/proton exchange transporter 3 inhibition, was approved for hyperphosphatemia in Japan in 2023. Four phase 3 studies of tenapanor have been performed in Japan and have demonstrated its efficacy and safety as a single-agent drug, add-on effects to PBs for patients with refractory hyperphosphatemia that cannot be improved with PBs alone, and reduction of the pill burden associated with PBs. This review provides an overview of the characteristics and previous clinical studies of tenapanor and describes the clinical benefits of tenapanor over current therapy in patients on dialysis.
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Affiliation(s)
- Tadao Akizawa
- Division of Nephrology, Department of MedicineShowa University School of MedicineTokyoJapan
| | | | | | | | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology, and Metabolism, Department of Internal MedicineTokai University School of MedicineIseharaKanagawaJapan
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Wang X, Wang Z, He J. Similarities and Differences of Vascular Calcification in Diabetes and Chronic Kidney Disease. Diabetes Metab Syndr Obes 2024; 17:165-192. [PMID: 38222032 PMCID: PMC10788067 DOI: 10.2147/dmso.s438618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 12/21/2023] [Indexed: 01/16/2024] Open
Abstract
Presently, the mechanism of occurrence and development of vascular calcification (VC) is not fully understood; a range of evidence suggests a positive association between diabetes mellitus (DM) and VC. Furthermore, the increasing burden of central vascular disease in patients with chronic kidney disease (CKD) may be due, at least in part, to VC. In this review, we will review recent advances in the mechanisms of VC in the context of CKD and diabetes. The study further unveiled that VC is induced through the stimulation of pro-inflammatory factors, which in turn impairs endothelial function and triggers similar mechanisms in both disease contexts. Notably, hyperglycemia was identified as the distinctive mechanism driving calcification in DM. Conversely, in CKD, calcification is facilitated by mechanisms including mineral metabolism imbalance and the presence of uremic toxins. Additionally, we underscore the significance of investigating vascular alterations and newly identified molecular pathways as potential avenues for therapeutic intervention.
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Affiliation(s)
- Xiabo Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People’s Republic of China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People’s Republic of China
| | - Jianqiang He
- Department of Nephrology, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, People’s Republic of China
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Suh SH, Oh TR, Choi HS, Kim CS, Bae EH, Ma SK, Oh KH, Hyun YY, Sung S, Kim SW. Urinary Phosphorus Excretion and Cardiovascular Outcomes in Patients with Pre-Dialysis Chronic Kidney Disease: The KNOW-CKD Study. Nutrients 2023; 15:nu15102267. [PMID: 37242150 DOI: 10.3390/nu15102267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/08/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
The relationship between 24-h urinary phosphorus excretion (24 h UPE) and cardiovascular disease in patients with pre-dialysis chronic kidney disease (CKD) has rarely been studied, despite the fact that the relationship between serum phosphorus level and the risk of a cardiovascular event is well established. A total of 1701 patients with pre-dialysis CKD were finally included for the analyses and were divided into tertiles by 24 h UPE (first tertile (T1, 349.557 (mean) ± 88.413 (standard deviation)), second tertile (T2, 557.530 ± 50.738), and third tertile (T3, 851.695 ± 171.593). The study outcome was a six-point major adverse cardiac event (MACE). The median follow-up duration was 7.992 years. Kaplan-Meier curve analysis visualized that the cumulative incidences of a six-point MACE (p = 0.029) significantly differed from 24 h UPE levels, as the incidence rate of the study outcomes was highest in T1 and lowest in T3. Cox proportional hazard models unveiled that, compared to T1, the risk of a six-point MACE was significantly decreased in T3 (adjusted hazard ratio (HR) 0.376, 95% confidence interval (CI) 0.207 to 0.683). The restricted cubic spline curve analysis visualized an inverted S-shaped association between 24 h UPE level and the risk of a six-point MACE, indicating a significantly increased risk of a six-point MACE in patients with a low 24 h UPE level. In conclusion, low 24 h UPE is associated with adverse cardiovascular outcomes in patients with CKD. Our finding emphasizes that low 24 h UPE should not be a reliable marker for dietary restriction of phosphorus that essentially leads to better outcomes in patients with CKD.
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Grants
- 2011E3300300, 2012E3301100, 2013E3301600, 2013E3301601, 2013E3301602, 2016E3300200, 2016E3300201, 2016E3300202, 2019E320100, 2019E320101, 2019E320102 and 2022-11-007 the Research Program funded by the Korea Disease Control and Prevention Agency
- NRF-2019R1A2C2086276 the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT)
- BCRI22079, BCRI22042 Chonnam National University Hospital Biomedical Research Institute
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Affiliation(s)
- Sang Heon Suh
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Department of Internal Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea
| | - Tae Ryom Oh
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Department of Internal Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea
| | - Hong Sang Choi
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Department of Internal Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea
| | - Chang Seong Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Department of Internal Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea
| | - Eun Hui Bae
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Department of Internal Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea
| | - Seong Kwon Ma
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Department of Internal Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea
| | - Kook-Hwan Oh
- Department of Internal Medicine, Seoul National University Hospital, Seoul 03080, Republic of Korea
| | - Young Youl Hyun
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, Republic of Korea
| | - Suah Sung
- Department of Internal Medicine, Eulji Medical Center, Eulji University, Seoul 01830, Republic of Korea
| | - Soo Wan Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Department of Internal Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea
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Riauka R, Ignatavicius P, Barauskas G. Hypophosphatemia as a prognostic tool for post-hepatectomy liver failure: A systematic review. World J Gastrointest Surg 2023; 15:249-257. [PMID: 36896296 PMCID: PMC9988637 DOI: 10.4240/wjgs.v15.i2.249] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/01/2022] [Accepted: 11/29/2022] [Indexed: 02/27/2023] Open
Abstract
BACKGROUND Post-hepatectomy liver failure (PHLF) is one of the main causes of postoperative mortality and is challenging to predict early in patients after liver resection. Some studies suggest that the postoperative serum phosphorus might predict outcomes in these patients.
AIM To perform a systematic literature review on hypophosphatemia and evaluate it as a prognostic factor for PHLF and overall morbidity.
METHODS This systematic review was performed according to preferred reporting items for systematic reviews and meta-analyses statement. A study protocol for the review was registered in the International Prospective Register of Systematic Reviews database. PubMed, Cochrane and Lippincott Williams & Wilkins databases were systematically searched up to March 31, 2022 for studies analyzing postoperative hypophosphatemia as a prognostic factor for PHLF, overall postoperative morbidity and liver regeneration. The quality assessment of the included cohort studies was performed according to the Newcastle-Ottawa Scale.
RESULTS After final assessment, nine studies (eight retrospective and one prospective cohort study) with 1677 patients were included in the systematic review. All selected studies scored ≥ 6 points according to the Newcastle-Ottawa Scale. Cutoff values of hypophosphatemia varied from < 1 mg/dL to ≤ 2.5 mg/dL in selected studies with ≤ 2.5 mg/dL being the most used defining value. Five studies analyzed PHLF, while the remaining four analyzed overall complications as a main outcome associated with hypophosphatemia. Only two of the selected studies analyzed postoperative liver regeneration, with reported better postoperative liver regeneration in cases of postoperative hypophosphatemia. In three studies hypophosphatemia was associated with better postoperative outcomes, while six studies revealed hypophosphatemia as a predictive factor for worse patient outcomes.
CONCLUSION Changes of the postoperative serum phosphorus level might be useful for predicting outcomes after liver resection. However, routine measurement of perioperative serum phosphorus levels remains questionable and should be evaluated individually.
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Affiliation(s)
- Romualdas Riauka
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Povilas Ignatavicius
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
| | - Giedrius Barauskas
- Department of Surgery, Lithuanian University of Health Sciences, Kaunas 50161, Lithuania
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Yan J, Pan C, Liu Y, Liao X, Chen J, Zhu Y, Huang X, Yang X, Ren Z. Dietary vitamin D3 deprivation suppresses fibroblast growth factor 23 signals by reducing serum phosphorus levels in laying hens. ANIMAL NUTRITION 2022; 9:23-30. [PMID: 35949979 PMCID: PMC9344313 DOI: 10.1016/j.aninu.2021.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/28/2021] [Accepted: 07/18/2021] [Indexed: 11/30/2022]
Abstract
The present study was carried out to evaluate the effect of dietary supplemental vitamin D3 on fibroblast growth factor 23 (FGF23) signals as well as phosphorus homeostasis and metabolism in laying hens. Fourteen 40-week-old Hy-Line Brown layers were randomly assigned into 2 treatments: 1) vitamin D3 restriction group (n = 7) fed 0 IU/kg vitamin D3 diet, and 2) regular vitamin D3 group (n = 7) fed 1,600 IU/kg vitamin D3 diet. The study lasted for 21 d. Serum parameters, phosphorus and calcium excretion status, and tissue expressions of type II sodium-phosphate co-transporters (NPt2), FGF23 signals and vitamin D3 metabolic regulators were determined. Hens fed the vitamin D3 restricted diet had decreased serum phosphorus levels (by 31.3%, P = 0.028) when compared to those fed regular vitamin D3 diet. In response to the decreased serum phosphorus, the vitamin D3 restricted laying hens exhibited: 1) suppressed kidney expressions of 25-hydroxyvitamin D 1-α-hydroxylase (CYP27B1, by 52.8%, P = 0.036) and 1,25-dihydroxyvitamin D 24-hydroxylase (CYP24A1, by 99.4%, P = 0.032); 2) suppressed serum levels of FGF23 (by 14.6%, P = 0.048) and increased serum alkaline phosphatase level (by 414.1%, P = 0.012); 3) decreased calvaria mRNA expressions of fibroblast growth factor receptors (FGFR1, by 85.2%, P = 0.003, FGFR2, by 89.4%, P = 0.014, FGFR3, by 88.8%, P = 0.017, FGFR4, by 89.6%, P = 0.030); 4) decreased kidney mRNA expressions of FGFR1 (by 65.5%, P = 0.021), FGFR4 (by 66.0%, P = 0.050) and KLOTHO (by 68.8%, P = 0.038); 5) decreased kidney protein expression of type 2a sodium-phosphorus co-transporters (by 54.3%, P = 0.039); and 6) increased percent excreta calcium (by 26.9%, P = 0.002). In conclusion, the deprivation of dietary vitamin D3 decreased FGF23 signals in laying hens by reducing serum FGF23 level and suppressing calvaria and kidney mRNA expressions of FGF23 receptors.
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Paul D, Komarova NL. Multi-scale network targeting: A holistic systems-biology approach to cancer treatment. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2021; 165:72-79. [PMID: 34428429 DOI: 10.1016/j.pbiomolbio.2021.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 08/05/2021] [Accepted: 08/10/2021] [Indexed: 11/15/2022]
Abstract
The vulnerabilities of cancer at the cellular and, recently, with the introduction of immunotherapy, at the tissue level, have been exploited with variable success. Evaluating the cancer system vulnerabilities at the organismic level through analysis of network topology and network dynamics can potentially predict novel anti-cancer drug targets directed at the macroscopic cancer networks. Theoretical work analyzing the properties and the vulnerabilities of the multi-scale network of cancer needs to go hand-in-hand with experimental research that uncovers the biological nature of the relevant networks and reveals new targetable vulnerabilities. It is our hope that attacking cancer on different spatial scales, in a concerted integrated approach, may present opportunities for novel ways to prevent treatment resistance.
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Affiliation(s)
- Doru Paul
- Medical Oncology, Weill Cornell Medicine, 1305 York Avenue 12th Floor, New York, NY, 10021, USA.
| | - Natalia L Komarova
- Department of Mathematics, University of California Irvine, Irvine, CA, 92697, USA.
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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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Bird RP, Eskin NAM. The emerging role of phosphorus in human health. ADVANCES IN FOOD AND NUTRITION RESEARCH 2021; 96:27-88. [PMID: 34112356 DOI: 10.1016/bs.afnr.2021.02.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Phosphorus, an essential nutrient, performs vital functions in skeletal and non-skeletal tissues and is pivotal for energy production. The last two decades of research on the physiological importance of phosphorus have provided several novel insights about its dynamic nature as a nutrient performing functions as a phosphate ion. Phosphorous also acts as a signaling molecule and induces complex physiological responses. It is recognized that phosphorus homeostasis is critical for health. The intake of phosphorus by the general population world-wide is almost double the amount required to maintain health. This increase is attributed to the incorporation of phosphate containing food additives in processed foods purchased by consumers. Research findings assessed the impact of excessive phosphorus intake on cells' and organs' responses, and highlighted the potential pathogenic consequences. Research also identified a new class of bioactive phosphates composed of polymers of phosphate molecules varying in chain length. These polymers are involved in metabolic responses including hemostasis, brain and bone health, via complex mechanism(s) with positive or negative health effects, depending on their chain length. It is amazing, that phosphorus, a simple element, is capable of exerting multiple and powerful effects. The role of phosphorus and its polymers in the renal and cardiovascular system as well as on brain health appear to be important and promising future research directions.
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Affiliation(s)
- Ranjana P Bird
- School of Health Sciences, University of Northern British Columbia, Prince George, BC, Canada.
| | - N A Michael Eskin
- Department of Food and Human Nutritional Sciences, Faculty of Agricultural and Food Sciences, University of Manitoba, Winnipeg, MB, Canada
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Zhao L, Wang S, Liu H, Du X, Bu R, Li B, Han R, Gao J, Liu Y, Hao J, Zhao J, Meng Y, Li G. The Pharmacological Effect and Mechanism of Lanthanum Hydroxide on Vascular Calcification Caused by Chronic Renal Failure Hyperphosphatemia. Front Cell Dev Biol 2021; 9:639127. [PMID: 33928079 PMCID: PMC8076751 DOI: 10.3389/fcell.2021.639127] [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: 12/08/2020] [Accepted: 03/24/2021] [Indexed: 12/03/2022] Open
Abstract
Objective The present work aimed to explore the efficacy of lanthanum hydroxide in managing the vascular calcification induced by hyperphosphate in chronic renal failure (CRF) as well as the underlying mechanism. Methods Rats were randomly allocated to five groups: normal diet control, CKD hyperphosphatemia model, CKD model treated with lanthanum hydroxide, CKD model receiving lanthanum carbonate treatment, together with CKD model receiving calcium carbonate treatment. The serum biochemical and kidney histopathological parameters were analyzed. The aortic vessels were subjected to Von Kossa staining, CT scan and proteomic analysis. In vitro, the calcium content and ALP activity were measured, and RT-PCR (SM22α, Runx2, BMP-2, and TRAF6) and Western blot (SM22α, Runx2, BMP-2, TRAF6, and NF-κB) were performed. Results In the lanthanum hydroxide group, serum biochemical and kidney histopathological parameters were significantly improved compared with the model group, indicating the efficacy of lanthanum hydroxide in postponing CRF progression and in protecting renal function. In addition, applying lanthanum hydroxide postponed hyperphosphatemia-mediated vascular calcification in CKD. Furthermore, lanthanum hydroxide was found to mitigate vascular calcification via the NF-κB signal transduction pathway. For the cultured VSMCs, lanthanum chloride (LaCl3) alleviated phosphate-mediated calcification and suppressed the activation of NF-κB as well as osteo-/chondrogenic signal transduction. Lanthanum hydroxide evidently downregulated NF-κB, BMP-2, Runx2, and TRAF6 expression. Conclusion Lanthanum hydroxide protects against renal failure and reduces the phosphorus level in serum to postpone vascular calcification progression.
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Affiliation(s)
- Lulu Zhao
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
| | - Shengnan Wang
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
| | - Hong Liu
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
| | - Xiaoli Du
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
| | - Ren Bu
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
| | - Bing Li
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
| | - Ruilan Han
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
| | - Jie Gao
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
| | - Yang Liu
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
| | - Jian Hao
- Department of Nephrology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Jianrong Zhao
- Department of Nephrology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Yan Meng
- Department of Nephrology, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Gang Li
- Department of Pharmacology, College of Pharmacy, Inner Mongolia Medical University, Jinshan Development, Hohhot, China
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Abstract
Inorganic phosphate is a vital constituent of cells and cell membranes, body fluids, and hard tissues. It is a major intracellular divalent anion, participates in many genetic, energy and intermediary metabolic pathways, and is important for bone health. Although we usually think of phosphate mostly in terms of its level in the serum, it is needed for many biological and structural functions of the body. Availability of adequate calcium and inorganic phosphate in the right proportions at the right place is essential for proper acquisition, biomineralization, and maintenance of mass and strength of the skeleton. The three specialized mineralized tissues, bones, teeth, and ossicles, differ from all other tissues in the human body because of their unique ability to mineralize, and the degree and process of mineralization in these tissues also differ to suit the specific functions: locomotion, chewing, and hearing, respectively. Biomineralization is a dynamic, complex, and lifelong process by which precipitations of inorganic calcium and inorganic phosphate divalent ions form biological hard tissues. Understanding the biomineralization process is important for the management of diseases caused by both defective and abnormal mineralization. Hypophosphatemia results in mineralization defects and osteomalacia, and hyperphosphatemia is implicated in abnormal excess calcification and/or ossification, but the exact mechanisms underlying these processes are not fully understood. In this review, we summarize available evidence on the role of phosphate in biomineralization. Other manuscripts in this issue of the journal deal with other relevant aspects of phosphate homeostasis, phosphate signaling and sensing, and disorders resulting from hypo- and hyperphosphatemic states.
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Affiliation(s)
| | - Sudhaker D Rao
- Division of Endocrinology, Diabetes, and Bone & Mineral Disorders, Henry Ford Hospital, New Center One; Suite # 800, Detroit, MI, 48202, USA.
- Bone & Mineral Research Laboratory, Henry Ford Hospital, Detroit, MI, USA.
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12
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Clerin V, Saito H, Filipski KJ, Nguyen AH, Garren J, Kisucka J, Reyes M, Jüppner H. Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion. J Clin Invest 2020; 130:6510-6522. [PMID: 32853180 PMCID: PMC7685737 DOI: 10.1172/jci135665] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 08/20/2020] [Indexed: 12/16/2022] Open
Abstract
The sodium-phosphate cotransporter NPT2a plays a key role in the reabsorption of filtered phosphate in proximal renal tubules, thereby critically contributing to phosphate homeostasis. Inadequate urinary phosphate excretion can lead to severe hyperphosphatemia as in tumoral calcinosis and chronic kidney disease (CKD). Pharmacological inhibition of NPT2a may therefore represent an attractive approach for treating hyperphosphatemic conditions. The NPT2a-selective small-molecule inhibitor PF-06869206 was previously shown to reduce phosphate uptake in human proximal tubular cells in vitro. Here, we investigated the acute and chronic effects of the inhibitor in rodents and report that administration of PF-06869206 was well tolerated and elicited a dose-dependent increase in fractional phosphate excretion. This phosphaturic effect lowered plasma phosphate levels in WT mice and in rats with CKD due to subtotal nephrectomy. PF-06869206 had no effect on Npt2a-null mice, but promoted phosphate excretion and reduced phosphate levels in normophophatemic mice lacking Npt2c and in hyperphosphatemic mice lacking Fgf23 or Galnt3. In CKD rats, once-daily administration of PF-06869206 for 8 weeks induced an unabated acute phosphaturic and hypophosphatemic effect, but had no statistically significant effect on FGF23 or PTH levels. Selective pharmacological inhibition of NPT2a thus holds promise as a therapeutic option for genetic and acquired hyperphosphatemic disorders.
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Affiliation(s)
- Valerie Clerin
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | | | - Kevin J. Filipski
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | - An Hai Nguyen
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | - Jeonifer Garren
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | - Janka Kisucka
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | | | - Harald Jüppner
- Endocrine Unit and
- Pediatric Nephrology Unit, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts, USA
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13
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Abstract
Phosphate is an essential nutrient for life and is a critical component of bone formation, a major signaling molecule, and structural component of cell walls. Phosphate is also a component of high-energy compounds (i.e., AMP, ADP, and ATP) and essential for nucleic acid helical structure (i.e., RNA and DNA). Phosphate plays a central role in the process of mineralization, normal serum levels being associated with appropriate bone mineralization, while high and low serum levels are associated with soft tissue calcification. The serum concentration of phosphate and the total body content of phosphate are highly regulated, a process that is accomplished by the coordinated effort of two families of sodium-dependent transporter proteins. The three isoforms of the SLC34 family (SLC34A1-A3) show very restricted tissue expression and regulate intestinal absorption and renal excretion of phosphate. SLC34A2 also regulates the phosphate concentration in multiple lumen fluids including milk, saliva, pancreatic fluid, and surfactant. Both isoforms of the SLC20 family exhibit ubiquitous expression (with some variation as to which one or both are expressed), are regulated by ambient phosphate, and likely serve the phosphate needs of the individual cell. These proteins exhibit similarities to phosphate transporters in nonmammalian organisms. The proteins are nonredundant as mutations in each yield unique clinical presentations. Further research is essential to understand the function, regulation, and coordination of the various phosphate transporters, both the ones described in this review and the phosphate transporters involved in intracellular transport.
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Affiliation(s)
- Nati Hernando
- University of Zurich-Irchel, Institute of Physiology, Zurich, Switzerland; Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; and Robley Rex VA Medical Center, Louisville, Kentucky
| | - Kenneth Gagnon
- University of Zurich-Irchel, Institute of Physiology, Zurich, Switzerland; Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; and Robley Rex VA Medical Center, Louisville, Kentucky
| | - Eleanor Lederer
- University of Zurich-Irchel, Institute of Physiology, Zurich, Switzerland; Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; and Robley Rex VA Medical Center, Louisville, Kentucky
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14
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Role of the putative PKC phosphorylation sites of the type IIc sodium-dependent phosphate transporter in parathyroid hormone regulation. Clin Exp Nephrol 2019; 23:898-907. [DOI: 10.1007/s10157-019-01725-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 03/01/2019] [Indexed: 11/26/2022]
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15
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Saurette M, Alexander RT. Intestinal phosphate absorption: The paracellular pathway predominates? Exp Biol Med (Maywood) 2019; 244:646-654. [PMID: 30764666 DOI: 10.1177/1535370219831220] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
IMPACT STATEMENT This review summarizes the work on transcellular intestinal phosphate absorption, arguing why this pathway is not the predominant pathway in humans consuming a "Western" diet. We then highlight the recent evidence which is strongly consistent with paracellular intestinal phosphate absorption mediating the bulk of intestinal phosphate absorption in humans.
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Affiliation(s)
- Matthew Saurette
- 1 Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2R7, Canada.,2 The Women's & Children's Health Research Institute, Edmonton, Alberta T6G 1C9, Canada
| | - R Todd Alexander
- 1 Department of Physiology, University of Alberta, Edmonton, Alberta T6G 2R7, Canada.,2 The Women's & Children's Health Research Institute, Edmonton, Alberta T6G 1C9, Canada.,3 Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2R7, Canada
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16
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Živanović J, Jarić I, Ajdžanović V, Mojić M, Miler M, Šošić-Jurjević B, Milošević V, Filipović B. Daidzein upregulates anti-aging protein Klotho and NaPi 2a cotransporter in a rat model of the andropause. Ann Anat 2018; 221:27-37. [PMID: 30240906 DOI: 10.1016/j.aanat.2018.08.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 08/21/2018] [Accepted: 08/30/2018] [Indexed: 11/25/2022]
Abstract
In a rat model of the andropause we aimed to examine the influence of daidzein, soy isoflavone, on the structure and function of parathyroid glands (PTG) and the expression levels of some of the crucial regulators of Ca2+ and Pi homeostasis in the kidney, and to compare these effects with the effects of estradiol, serving as a positive control. Middle-aged (16-month-old) male Wistar rats were divided into the following groups: sham-operated (SO), orchidectomized (Orx), orchidectomized and estradiol-treated (Orx+E; 0.625mg/kg b.w./day, s.c.) as well as orchidectomized and daidzein-treated (Orx+D; 30mg/kg b.w./day, s.c.) group. Every treated group had a corresponding control group. PTH serum concentration was decreased in Orx+E and Orx+D groups by 10% and 21% (p<0.05) respectively, in comparison with the Orx. PTG volume was decreased in Orx+E group by 16% (p<0.05), when compared to the Orx. In Orx+E group expression of NaPi 2a was lower (p<0.05), while NaPi 2a abundance in Orx+D animals was increased (p<0.05), when compared to Orx. Expression of PTH1R was increased (p<0.05) in Orx+E group, while in Orx+D animals the same parameter was decreased (p<0.05), in comparison with Orx. Klotho expression was elevated (p<0.05) in Orx+D rats, in regard to Orx. Orx+D induced reduction in Ca2+/creatinine and Pi/creatinine ratio in urine by 32% and 16% (p<0.05) respectively, in comparison with Orx. In conclusion, presented results indicate the more coherent beneficial effects of daidzein compared to estradiol, on disturbed Ca2+ and Pi homeostasis, and presumably on bone health, in the aging male rats.
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Affiliation(s)
- Jasmina Živanović
- Department of Cytology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia.
| | - Ivana Jarić
- Department of Cytology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia
| | - Vladimir Ajdžanović
- Department of Cytology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia
| | - Marija Mojić
- Department of Immunology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia
| | - Marko Miler
- Department of Cytology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia
| | - Branka Šošić-Jurjević
- Department of Cytology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia
| | - Verica Milošević
- Department of Cytology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia
| | - Branko Filipović
- Department of Cytology, Institute for Biological Research "Siniša Stanković", University of Belgrade, Belgrade, Serbia
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17
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Tatsumi S, Katai K, Kaneko I, Segawa H, Miyamoto KI. NAD metabolism and the SLC34 family: evidence for a liver-kidney axis regulating inorganic phosphate. Pflugers Arch 2018; 471:109-122. [PMID: 30218374 DOI: 10.1007/s00424-018-2204-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 08/29/2018] [Accepted: 09/06/2018] [Indexed: 12/18/2022]
Abstract
The solute carrier 34 (SLC34) family of membrane transporters is a major contributor to Pi homeostasis. Many factors are involved in regulating the SLC34 family. The roles of the bone mineral metabolism factors parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) in Pi homeostasis are well studied. Intracellular Pi is thought to be involved in energy metabolism, such as ATP production. Under certain conditions of altered energy metabolism, plasma Pi concentrations are affected by the regulation of a Pi shift into cells or release from the tissues. We recently investigated the mechanism of hepatectomy-related hypophosphatemia, which is thought to involve an unknown phosphaturic factor. Hepatectomy-related hypophosphatemia is due to impaired nicotinamide adenine dinucleotide (NAD) metabolism through its effects on the SLC34 family in the liver-kidney axis. The oxidized form of NAD, NAD+, is an essential cofactor in various cellular biochemical reactions. Levels of NAD+ and its reduced form NADH vary with the availability of dietary energy and nutrients. Nicotinamide phosphoribosyltransferase (Nampt) generates a key NAD+ intermediate, nicotinamide mononucleotide, from nicotinamide and 5-phosphoribosyl 1-pyrophosphate. The liver, an important organ of NAD metabolism, is thought to release metabolic products such as nicotinamide and may control NAD metabolism in other organs. Moreover, NAD is an important regulator of the circadian rhythm. Liver-specific Nampt-deficient mice and heterozygous Nampt mice have abnormal daily plasma Pi concentration oscillations. These data indicate that NAD metabolism in the intestine, liver, and kidney is closely related to Pi metabolism through the SLC34 family. Here, we review the relationship between the SLC34 family and NAD metabolism based on our recent studies.
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Affiliation(s)
- Sawako Tatsumi
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.,Department of Food Science and Nutrition, School of Human Cultures, The University of Shiga Prefecture, Hikone, Japan
| | - Kanako Katai
- Faculty of Human Life and Science, Department of Food Science and Nutrition, Doshisha Women's College of Liberal Arts, Kyoto, Japan
| | - Ichiro Kaneko
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Hiroko Segawa
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan
| | - Ken-Ichi Miyamoto
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan.
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18
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Watanabe MT, Barretti P, Caramori JC. Attention to Food Phosphate and Nutrition Labeling. J Ren Nutr 2018; 28:e29-e31. [DOI: 10.1053/j.jrn.2017.12.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Revised: 11/24/2017] [Accepted: 12/20/2017] [Indexed: 11/11/2022] Open
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19
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Khalil R, Kim NR, Jardi F, Vanderschueren D, Claessens F, Decallonne B. Sex steroids and the kidney: role in renal calcium and phosphate handling. Mol Cell Endocrinol 2018; 465:61-72. [PMID: 29155307 DOI: 10.1016/j.mce.2017.11.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 11/14/2017] [Accepted: 11/14/2017] [Indexed: 12/16/2022]
Abstract
Calcium and phosphate are vital for the organism and constitute essential components of the skeleton. Serum levels are tightly hormonally regulated and maintained by exchange with three major sources: the intestines, the kidney and the bone. The effects of sex steroids on the bone have been extensively studied and it is well known that sex steroid deficiency induces bone loss, indirectly influencing renal calcium and phosphate homeostasis. However, it is unknown whether sex steroids also directly regulate renal calcium and phosphate handling, hereby potentially indirectly impacting on bone. The presence of androgen receptors (AR) and estrogen receptors (ER) in both human and rodent kidney, although their exact localization within the kidney remains debated, supports direct effects. Estrogens stimulate renal calcium reabsorption as well as phosphate excretion, while the effects of androgens are less clear. Many of the studies performed with regard to renal calcium and/or phosphate homeostasis do not correct for the calcium and phosphate fluxes from the bone and intestines, which complicates the differentiation between the direct effects of sex steroids on renal calcium and phosphate handling and the indirect effects via the bone and intestines. The objective of this study is to review the literature and current insight of the role of sex steroids in calcium and phosphate handling in the kidney.
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Affiliation(s)
- Rougin Khalil
- Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 Box 902, Belgium.
| | - Na Ri Kim
- Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 Box 902, Belgium
| | - Ferran Jardi
- Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 Box 902, Belgium
| | - Dirk Vanderschueren
- Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 Box 902, Belgium
| | - Frank Claessens
- Molecular Endocrinology, KU Leuven, Herestraat 49 Box 901, Belgium
| | - Brigitte Decallonne
- Clinical and Experimental Endocrinology, KU Leuven, Herestraat 49 Box 902, Belgium
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20
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Kosk D, Kramer H, Luke A, Camacho P, Bovet P, Rhule JP, Forrester T, Wolf M, Sempos C, Melamed ML, Dugas LR, Cooper R, Durazo-Arvizu R. Dietary factors and fibroblast growth factor-23 levels in young adults with African ancestry. J Bone Miner Metab 2017; 35:666-674. [PMID: 27942978 PMCID: PMC5711483 DOI: 10.1007/s00774-016-0804-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 10/31/2016] [Indexed: 11/30/2022]
Abstract
Fibroblast growth factor-23 (FGF23), a phosphaturic hormone secreted mainly by osteocytes, maintains serum phosphate levels within a tight range by promoting phosphaturia. Previous studies have mainly focused on the link between FGF23 levels and dietary intake of phosphate, but other dietary factors may also influence FGF23 levels. This cross-sectional study pooled three populations of young adults with African ancestry (452 in Chicago, IL, USA; 477 in Victoria, Seychelles; and 482 in Kumasi, Ghana) with estimated glomerular filtration rate >80 ml/min/1.73 m2 to examine the association of dietary factors based on two 24-h recalls with FGF23 levels measured using a C-terminal assay. Linear regression was used to examine the association between log-transformed FGF23 levels and quartiles of calorie-adjusted dietary factors with adjustment for covariates. In the pooled sample of 1411 study participants, the mean age was 35.2 (6.2) years and 45.3% were male. Median plasma C-terminal FGF23 values in relative units (RU)/ml were 59.5 [interquartile range (IQR) 44.1, 85.3] in the USA, 43.2 (IQR 33.1, 57.9) in Seychelles, and 34.0 (IQR 25.2, 50.4) in Ghana. With adjustment for covariates, increasing quartiles of calcium and animal protein and decreasing quartiles of vegetable protein, fiber, and magnesium intake were associated with significantly higher FGF23 levels compared to the lowest quartile. After further adjustment for dietary factors, significant trends in FGF23 levels were noted only for quartiles of calcium, fiber, and magnesium intake (P < 0.001). Dietary factors other than phosphate are associated with FGF23 levels in young adults.
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Affiliation(s)
- Dominique Kosk
- Department of Public Health Sciences, Loyola University Chicago, 2160 First Avenue, Maywood, IL, 60153, USA
| | - Holly Kramer
- Department of Public Health Sciences, Loyola University Chicago, 2160 First Avenue, Maywood, IL, 60153, USA.
- Division of Nephrology and Hypertension, Department of Public Health Sciences and Medicine, Loyola University Chicago, Maywood, IL, USA.
| | - Amy Luke
- Department of Public Health Sciences, Loyola University Chicago, 2160 First Avenue, Maywood, IL, 60153, USA
| | - Pauline Camacho
- Division of Endocrinology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA
| | - Pascal Bovet
- Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland
- Ministry of Health, Victoria, Republic of Seychelles
| | - Jacob Plange Rhule
- Department of Physiology, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Terrence Forrester
- University of West Indies Solutions for Developing Countries, University of the West Indies Mona, Kingston, Jamaica
| | - Myles Wolf
- Division of Nephrology and Hypertension, Department of Medicine, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Chris Sempos
- National Institutes of Health Office of Dietary Supplements, Bethesda, MD, USA
| | - Michal L Melamed
- Department of Medicine and Epidemiology and Population Health, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA
| | - Lara R Dugas
- Department of Public Health Sciences, Loyola University Chicago, 2160 First Avenue, Maywood, IL, 60153, USA
| | - Richard Cooper
- Department of Public Health Sciences, Loyola University Chicago, 2160 First Avenue, Maywood, IL, 60153, USA
| | - Ramon Durazo-Arvizu
- Department of Public Health Sciences, Loyola University Chicago, 2160 First Avenue, Maywood, IL, 60153, USA
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21
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Zheng J, Glezerman IG, Sadot E, McNeil A, Zarama C, Gönen M, Creasy J, Pak LM, Balachandran VP, D'Angelica MI, Allen PJ, DeMatteo RP, Kingham PT, Jarnagin WR, Jaimes EA. Hypophosphatemia after Hepatectomy or Pancreatectomy: Role of the Nicotinamide Phosphoribosyltransferase. J Am Coll Surg 2017; 225:488-497e2. [PMID: 28690207 PMCID: PMC5614834 DOI: 10.1016/j.jamcollsurg.2017.06.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 06/20/2017] [Accepted: 06/20/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Postoperative hypophosphatemia is common and is associated with a lower risk of liver failure after hepatectomy, but higher morbidity after pancreatectomy. Whether different physiologic mechanisms underlie the hypophosphatemia associated with these very different clinical outcomes is unclear. This study aims to evaluate the underlying mechanism in postoperative hypophosphatemia. STUDY DESIGN We prospectively enrolled 120 patients who underwent major hepatectomy (n = 30), minor hepatectomy (n = 30), pancreatectomy (n = 30), and laparotomy without resection (control group, n = 30). Preoperative and postoperative serum and urinary phosphorus, calcium, and creatinine, as well as phosphaturic factors, including serum nicotinamide phosphoribosyltransferase (NAMPT), fibroblast growth factor-23, and parathyroid hormone were measured. In addition, we evaluated urinary levels of nicotinamide catabolites, N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide. RESULTS We found that significant hypophosphatemia occurred from postoperative day (POD) 1 to POD 2 in all 4 groups and was preceded by hyperphosphaturia from preoperative day to POD 1. Phosphate level alterations were associated with a significant increase in NAMPT levels from preoperative day to POD 2 in all 3 resected groups, but not in the control group. The fibroblast growth factor-23 levels were significantly decreased postoperatively in all 4 groups, and parathyroid hormone levels did not change in any of the 4 groups. Urine levels of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-3-carboxamide decreased significantly in all 4 groups postoperatively. CONCLUSIONS This study demonstrates that the mechanism of hypophosphatemia is the same for both liver and pancreas resections. Postoperative hypophosphatemia is associated with increased NAMPT. The mechanism that upregulates NAMPT and its role on disparate clinical outcomes in postoperative patients warrant additional investigation.
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Affiliation(s)
- Jian Zheng
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY Department of Medicine, Weill Cornell Medical College, New York, NY Department of Surgery, Rabin Medical Center, Petah Tikva, Israel Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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22
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Yamada S, Giachelli CM. Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone 2017; 100:87-93. [PMID: 27847254 PMCID: PMC5429216 DOI: 10.1016/j.bone.2016.11.012] [Citation(s) in RCA: 217] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 09/23/2016] [Accepted: 11/11/2016] [Indexed: 02/07/2023]
Abstract
Vascular calcification (VC) is highly prevalent in aging, diabetes mellitus, and chronic kidney disease (CKD). VC is a strong predictor of cardiovascular morbidity and mortality in the CKD population. Complex pathological mechanisms are involved in the development of VC, including osteochondrogenic differentiation and apoptosis of vascular smooth muscle cells, instability and release of extracellular vesicles loaded calcium and phosphate, and elastin degradation. Elevated serum phosphate is a late manifestation of CKD, and has been shown to accelerate mineral deposition in both the vessel wall and heart valves. α-Klotho and fibroblast growth factor 23 (FGF23) are emerging factors in CKD-mineral and bone disorder (CKD-MBD) and are thought to be involved in the pathogenesis of uremic VC. There are discordant reports regarding the biomedical effects of FGF23 on VC. In contrast, mounting evidence supports a well-supported protective role for α-Klotho on VC. Further studies are warranted to elucidate potential roles of FGF23 and α-Klotho in VC and to determine where and how they are synthesized in normal and disease conditions. A thorough systemic evaluation of the biomedical interplay of phosphate, FGF23, and α-Klotho may potentially lead to new therapeutic options for patients with CKD-MBD.
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Affiliation(s)
- Shunsuke Yamada
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Cecilia M Giachelli
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA.
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23
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Fujii O, Tatsumi S, Ogata M, Arakaki T, Sakaguchi H, Nomura K, Miyagawa A, Ikuta K, Hanazaki A, Kaneko I, Segawa H, Miyamoto KI. Effect of Osteocyte-Ablation on Inorganic Phosphate Metabolism: Analysis of Bone-Kidney-Gut Axis. Front Endocrinol (Lausanne) 2017; 8:359. [PMID: 29312149 PMCID: PMC5742590 DOI: 10.3389/fendo.2017.00359] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 12/11/2017] [Indexed: 01/24/2023] Open
Abstract
In response to kidney damage, osteocytes increase the production of several hormones critically involved in mineral metabolism. Recent studies suggest that osteocyte function is altered very early in the course of chronic kidney disease. In the present study, to clarify the role of osteocytes and the canalicular network in mineral homeostasis, we performed four experiments. In Experiment 1, we investigated renal and intestinal Pi handling in osteocyte-less (OCL) model mice [transgenic mice with the dentin matrix protein-1 promoter-driven diphtheria toxin (DT)-receptor that were injected with DT]. In Experiment 2, we administered granulocyte colony-stimulating factor to mice to disrupt the osteocyte canalicular network. In Experiment 3, we investigated the role of osteocytes in dietary Pi signaling. In Experiment 4, we analyzed gene expression level fluctuations in the intestine and liver by comparing mice fed a high Pi diet and OCL mice. Together, the findings of these experiments indicate that osteocyte ablation caused rapid renal Pi excretion (P < 0.01) before the plasma fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels increased. At the same time, we observed a rapid suppression of renal Klotho (P < 0.01), type II sodium phosphate transporters Npt2a (P < 0.01) and Npt2c (P < 0.05), and an increase in intestinal Npt2b (P < 0.01) protein. In OCL mice, Pi excretion in feces was markedly reduced (P < 0.01). Together, these effects of osteocyte ablation are predicted to markedly increase intestinal Pi absorption (P < 0.01), thus suggesting that increased intestinal Pi absorption stimulates renal Pi excretion in OCL mice. In addition, the ablation of osteocytes and feeding of a high Pi diet affected FGF15/bile acid metabolism and controlled Npt2b expression. In conclusion, OCL mice exhibited increased renal Pi excretion due to enhanced intestinal Pi absorption. We discuss the role of FGF23-Klotho on renal and intestinal Pi metabolism in OCL mice.
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Affiliation(s)
- Osamu Fujii
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Sawako Tatsumi
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
- *Correspondence: Sawako Tatsumi, ; Ken-ichi Miyamoto,
| | - Mao Ogata
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Tomohiro Arakaki
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Haruna Sakaguchi
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Kengo Nomura
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Atsumi Miyagawa
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Kayo Ikuta
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Ai Hanazaki
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Ichiro Kaneko
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Hiroko Segawa
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Ken-ichi Miyamoto
- Department of Molecular Nutrition, Institution of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
- *Correspondence: Sawako Tatsumi, ; Ken-ichi Miyamoto,
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24
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Kaneko I, Tatsumi S, Segawa H, Miyamoto KI. Control of phosphate balance by the kidney and intestine. Clin Exp Nephrol 2016; 21:21-26. [PMID: 27900568 DOI: 10.1007/s10157-016-1359-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 11/07/2016] [Indexed: 01/06/2023]
Abstract
The prevention and correction of hyperphosphatemia are major goals of the treatment of chronic kidney disease (CKD)-bone mineral disorders, and thus, Pi balance requires special attention. Pi balance is maintained by intestinal absorption, renal excretion, and bone accretion. The kidney is mainly responsible for the plasma Pi concentration. In CKD, reduced glomerular filtration rate leads to various Pi metabolism abnormalities, and Pi absorption in the small intestine also has an important role in Pi metabolism. Disturbances in Pi metabolism are mediated by a series of complex changes in regulatory hormones originating from the skeleton, intestine, parathyroid gland, and kidney. In this review, we describe the regulation of type II sodium-dependent Pi co-transporters by the kidney and intestine, including the regulation of Pi transport, circadian rhythm, and the vicious circle between salivary Pi secretion and intestinal Pi absorption in animals with and without CKD.
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Affiliation(s)
- Ichiro Kaneko
- Department of Molecular Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Sawako Tatsumi
- Department of Molecular Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Hiroko Segawa
- Department of Molecular Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503, Japan
| | - Ken-Ichi Miyamoto
- Department of Molecular Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-Cho, Tokushima, 770-8503, Japan.
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