Efficacy and safety of tenapanor in hemodialysis patients with hyperphosphatemia: A systematic review and meta-analysis of randomized placebo-controlled trials
Houli Luo
Department of Radiology, Cheng du First People's Hospital, Chengdu, Sichuan, China
Search for more papers by this authorJian Feng
Department of Critical Care Medicine, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorYanbiao Zhang
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorJie Wang
Department of Critical Care Medicine, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorGang Xue
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorXi Huang
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorShuang You
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorHongfei Dong
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorLingfan Li
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorJuncheng Li
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorHualin Xiao
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorXiang Ai
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorXianhui Li
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorCorresponding Author
Bo Huang
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Correspondence
Bo Huang, Department of Burn and Plastic, The General Hospital of Western Theater Command, No. 270 Tianhui Road, Chengdu 610083, China.
Email: [email protected]
Search for more papers by this authorHouli Luo
Department of Radiology, Cheng du First People's Hospital, Chengdu, Sichuan, China
Search for more papers by this authorJian Feng
Department of Critical Care Medicine, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorYanbiao Zhang
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorJie Wang
Department of Critical Care Medicine, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorGang Xue
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorXi Huang
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorShuang You
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorHongfei Dong
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorLingfan Li
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorJuncheng Li
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorHualin Xiao
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorXiang Ai
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorXianhui Li
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Search for more papers by this authorCorresponding Author
Bo Huang
Department of Burn and Plastic, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
Correspondence
Bo Huang, Department of Burn and Plastic, The General Hospital of Western Theater Command, No. 270 Tianhui Road, Chengdu 610083, China.
Email: [email protected]
Search for more papers by this authorHouli Luo, Jian Feng, Yanbiao Zhang, Bo Huang, & Xianhui Li equally contributed to this study.
Abstract
Background
The effects of tenapanor in reducing serum phosphorus in hemodialysis patients with hyperphosphatemia are uncertain and no relevant meta-analysis has been conducted. We performed a meta-analysis of randomized placebo-controlled trials to evaluate the efficacy and safety of tenapanor.
Methods
All randomized controlled trials of tenapanor were searched up to 1 August 2022. The primary endpoint was the change in serum phosphorus level from baseline with tenapanor and placebo. Data on drug-related adverse events (AEs), gastrointestinal AEs and diarrhea were collected to determine the safety of tenapanor.
Results
There were 533 patients throughout five trials that were eligible. Tenapanor significantly lowered blood phosphorus level by 1.79 mg/dl in the mean difference than the placebo. Diarrhea, gastrointestinal AEs, and drug-related AEs were more severe than placebo.
Conclusions
This meta-analysis showed that although drug side effects were common, tenapanor significantly reduced serum phosphorus level in hemodialysis patients.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Supporting Information
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REFERENCES
- 1Vervloet MG, Sezer S, Massy ZA, et al. The role of phosphate in kidney disease. Nat Rev Nephrol. 2017; 13: 27–38. https://doi.org/10.1038/nrneph.2016.164
- 2Reiss AB, Miyawaki N, Moon J, Kasselman LJ, Voloshyna I, D'Avino R Jr, et al. CKD, arterial calcification, atherosclerosis and bone health: inter-relationships and controversies. Atherosclerosis. 2018; 278: 49–59. https://doi.org/10.1016/j.atherosclerosis.2018.08.046
- 3Michishita R, Matsuda T, Kawakami S, Tanaka S, Kiyonaga A, Tanaka H, et al. Hypertension and hyperglycemia and the combination thereof enhances the incidence of chronic kidney disease (CKD) in middle-aged and older males. Clin Exp Hypertens. 2017; 39: 645–54. https://doi.org/10.1080/10641963.2017.1306541
- 4Sarnak MJ, Amann K, Bangalore S, Cavalcante JL, Charytan DM, Craig JC, et al. Chronic kidney disease and coronary artery disease: JACC state-of-the-art review. J Am Coll Cardiol. 2019; 74: 1823–38. https://doi.org/10.1016/j.jacc.2019.08.1017
- 5Kalantar-Zadeh K, Kuwae N, Regidor DL, Kovesdy CP, Kilpatrick RD, Shinaberger CS, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 2006; 70: 771–80. https://doi.org/10.1038/sj.ki.5001514
- 6Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005; 16: 520–8. https://doi.org/10.1681/ASN.2004070602
- 7Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the dialysis outcomes and practice patterns study (DOPPS). Am J Kidney Dis. 2008; 52: 519–30. https://doi.org/10.1053/j.ajkd.2008.03.020
- 8 Erratum: Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017;7:1-59. 2011; 7:e1. https://doi.org/10.1016/j.kisu.2017.10.001
10.1016/j.kisu.2017.10.001 Google Scholar
- 9Ikizler TA, Burrowes JD, Byham-Gray LD, Campbell KL, Carrero JJ, Chan W, et al. KDOQI clinical practice guideline for nutrition in CKD: 2020 update. Am J Kidney Dis. 2020; 76: S1–S107. https://doi.org/10.1053/j.ajkd.2020.05.006
- 10Bobeck EA, Meyer KM, Helvig C, Petkovich M, Cook ME. Sevelamer hydrochloride binds phosphate released from phytate in chicks fed 1alpha-hydroxy cholecalciferol. J Ren Nutr. 2013; 23: 21–7. https://doi.org/10.1053/j.jrn.2011.12.005
- 11Fissell RB, Karaboyas A, Bieber BA, Sen A, Li Y, Lopes AA, et al. Phosphate binder pill burden, patient-reported non-adherence, and mineral bone disorder markers: findings from the DOPPS. Hemodial Int. 2016; 20: 38–49. https://doi.org/10.1111/hdi.12315
- 12King AJ, Siegel M, He Y, Nie B, Wang J, Koo-McCoy S, et al. Inhibition of sodium/hydrogen exchanger 3 in the gastrointestinal tract by tenapanor reduces paracellular phosphate permeability. Sci Transl Med. 2018; 10: 10. https://doi.org/10.1126/scitranslmed.aam6474
- 13Johansson S, Rosenbaum DP, Palm J, Stefansson B, Knutsson M, Lisbon EA, et al. Tenapanor administration and the activity of the H(+)-coupled transporter PepT1 in healthy volunteers. Br J Clin Pharmacol. 2017; 83: 2008–14. https://doi.org/10.1111/bcp.13313
- 14Inaba M, Une Y, Ikejiri K, Kanda H, Fukagawa M, Akizawa T. Dose-response of Tenapanor in patients with hyperphosphatemia undergoing hemodialysis in Japan-a phase 2 randomized trial. Kidney Int Rep. 2022; 7: 177–88. https://doi.org/10.1016/j.ekir.2021.11.008
- 15Shigematsu T, Une Y, Ikejiri K, Kanda H, Fukagawa M, Akizawa T. Therapeutic effects of add-on Tenapanor for hemodialysis patients with refractory hyperphosphatemia. Am J Nephrol. 2021; 52: 496–506. https://doi.org/10.1159/000516156
- 16Pergola PE, Rosenbaum DP, Yang Y, Chertow GM. A randomized trial of Tenapanor and phosphate binders as a dual-mechanism treatment for hyperphosphatemia in patients on maintenance dialysis (AMPLIFY). J Am Soc Nephrol. 2021; 32: 1465–73. https://doi.org/10.1681/ASN.2020101398
- 17Block GA, Rosenbaum DP, Leonsson-Zachrisson M, Åstrand M, Johansson S, Knutsson M, et al. Effect of Tenapanor on serum phosphate in patients receiving hemodialysis. J Am Soc Nephrol. 2017; 28: 1933–42. https://doi.org/10.1681/ASN.2016080855
- 18Block GA, Rosenbaum DP, Yan A, Chertow GM. Efficacy and safety of Tenapanor in patients with hyperphosphatemia receiving maintenance hemodialysis: a randomized phase 3 trial. J Am Soc Nephrol. 2019; 30: 641–52. https://doi.org/10.1681/ASN.2018080832
- 19Medscape MN. FDA Rejects tenapanor for control of phosphorus in kidney disease. 2021 https://www.medscape.com/viewarticle/956066
- 20Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009; 339:b2700. https://doi.org/10.1136/bmj.b2700
- 21Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011; 343:d5928. https://doi.org/10.1136/bmj.d5928
- 22Slinin Y, Foley RN, Collins AJ. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol. 2005; 16: 1788–93. https://doi.org/10.1681/ASN.2004040275
- 23Shang D, Xie Q, Ge X, Yan H, Tian J, Kuang D, et al. Hyperphosphatemia as an independent risk factor for coronary artery calcification progression in peritoneal dialysis patients. BMC Nephrol. 2015; 16: 107. https://doi.org/10.1186/s12882-015-0103-8
- 24Airy M, Schold JD, Jolly SE, Arrigain S, Bansal N, Winkelmayer WC, et al. Cause-specific mortality in patients with chronic kidney disease and atrial fibrillation. Am J Nephrol. 2018; 48: 36–45. https://doi.org/10.1159/000491023
- 25Ix JH, Katz R, Kestenbaum BR, de Boer IH, Chonchol M, Mukamal KJ, et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (cardiovascular health study). J Am Coll Cardiol. 2012; 60: 200–7. https://doi.org/10.1016/j.jacc.2012.03.040
- 26Almqvist EG, Bondeson AG, Bondeson L, Nissborg A, Smedgard P, Svensson SE. Cardiac dysfunction in mild primary hyperparathyroidism assessed by radionuclide angiography and echocardiography before and after parathyroidectomy. Surgery. 2002; 132: 1126–32; discussion 32. https://doi.org/10.1067/msy.2002.128692
- 27 Kidney Disease: Improving Global Outcomes CKDMBDUWG. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl (2011). 2017; 7: 1–59. https://doi.org/10.1016/j.kisu.2017.04.001
- 28Shinaberger CS, Greenland S, Kopple JD, van Wyck D, Mehrotra R, Kovesdy CP, et al. Is controlling phosphorus by decreasing dietary protein intake beneficial or harmful in persons with chronic kidney disease? Am J Clin Nutr. 2008; 88: 1511–8. https://doi.org/10.3945/ajcn.2008.26665
- 29 Phosphate Binder Use, Last 3 Months: DOPPS Practice Monitor; 2020. https://www.dopps.org/DPM-HD/Files/maxPBINDER_use_c_overallTAB.htm.
- 30Navaneethan SD, Palmer SC, Craig JC, Elder GJ, Strippoli GF. Benefits and harms of phosphate binders in CKD: a systematic review of randomized controlled trials. Am J Kidney Dis. 2009; 54: 619–37. https://doi.org/10.1053/j.ajkd.2009.06.004
- 31Karamanidou C, Clatworthy J, Weinman J, Horne R. A systematic review of the prevalence and determinants of nonadherence to phosphate binding medication in patients with end-stage renal disease. BMC Nephrol. 2008; 9:2. https://doi.org/10.1186/1471-2369-9-2
- 32Johansson S, Leonsson-Zachrisson M, Knutsson M, Spencer AG, Labonté ED, Deshpande D, et al. Preclinical and healthy volunteer studies of potential drug-drug interactions between Tenapanor and phosphate binders. Clin Pharmacol Drug Dev. 2017; 6: 448–56. https://doi.org/10.1002/cpdd.307
- 33Johansson S, Rosenbaum DP, Knutsson M, Leonsson-Zachrisson M. A phase 1 study of the safety, tolerability, pharmacodynamics, and pharmacokinetics of tenapanor in healthy Japanese volunteers. Clin Exp Nephrol. 2017; 21: 407–16. https://doi.org/10.1007/s10157-016-1302-8
- 34Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. N Engl J Med. 2010; 362: 1312–24. https://doi.org/10.1056/NEJMra0912522
- 35Block GA, Bleyer AJ, Silva AL, Weiner DE, Lynn RI, Yang Y, et al. Safety and efficacy of Tenapanor for long-term serum phosphate control in maintenance dialysis: a 52-week randomized phase 3 trial (PHREEDOM). Kidney360. 2021; 2(10): 1600–10. https://doi.org/10.34067/KID.0002002021