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Lower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis

  • Nephrology - Original Paper
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Abstract

Purpose

This study aimed to investigate the association between circulating soluble Klotho level and risk of all-cause mortality in chronic kidney disease (CKD) patients using systematic review and meta-analysis technique.

Methods

Potentially eligible studies were identified from Medline and EMBASE databases from inception to March 2020 using a search strategy that consisted of terms for “Klotho” and “Mortality”. Eligible study must be a cohort study that consists of one cohort of CKD patients with higher circulating soluble Klotho level and another cohort of CKD patients with lower circulating soluble Klotho level. The study must also report relative risk (RR), incidence rate ratio, hazard risk ratio or standardized incidence ratio with 95% confidence intervals (95% CIs) comparing all-cause mortality between CKD patients with lower circulating soluble Klotho level versus CKD patients with higher circulating soluble Klotho level. If the study divides patients (per circulating soluble Klotho level) into more than two groups, a comparison between the highest and the lowest group would be extracted. Point estimates with standard errors were retrieved from each study and were combined together using the generic inverse variance method.

Results

A total of 2964 articles were retrieved. After two rounds of an independent review by two investigators, six prospective cohort studies met the eligibility criteria and were included into the meta-analysis. CKD patients with lower circulating soluble Klotho level had a significantly increased risk of all-cause mortality with the pooled risk ratio of 1.88 (95% CI 1.29–2.74; I2 0%). The funnel plot was fairly symmetric and did not reveal any suggestive evidence of publication bias.

Conclusion

The current study found a significant association between lower circulating soluble Klotho level and increased risk of all-cause mortality in CKD patients. However, this meta-analysis carries some limitations, including relatively small sample size, lack of adjustment for potential confounders and between-study heterogeneity in baseline characteristics of the patients and cut-off values used to categorize patients into higher and lower circulating serum Klotho level group.

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References

  1. Xu Y, Sun Z (2015) Molecular basis of Klotho: from gene to function in aging. Endocr Rev 36(2):174–193. https://doi.org/10.1210/er.2013-1079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hu MC, Shi M, Zhang J, Addo T, Cho HJ, Barker SL, Ravikumar P, Gillings N, Bian A, Sidhu SS, Kuro-o M, Moe OW (2016) Renal production, uptake, and handling of circulating α Klotho. J Am Soc Nephrol 27(1):79–90. https://doi.org/10.1681/ASN.2014101030

    Article  CAS  PubMed  Google Scholar 

  3. Kim J-H, Hwang K-H, Park K-S, Kong ID, Cha S-K (2015) Biological role of anti-aging protein Klotho. J Lifestyle Med 5(1):1–6. https://doi.org/10.15280/jlm.2015.5.1.1

    Article  PubMed  PubMed Central  Google Scholar 

  4. Dalton GD, Xie J, An S-W, Huang C-L (2017) New insights into the mechanism of action of soluble Klotho. Front Endocrinol 8:323

    Article  Google Scholar 

  5. Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, Kuro-o M (2005) Suppression of aging in mice by the hormone Klotho. Science 309(5742):1829–1833. https://doi.org/10.1126/science.1112766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, Ho K, Yu G-Q, Kim D, Betourne A, Kuro-o M, Masliah E, Abraham CR, Mucke L (2015) Life extension factor Klotho prevents mortality and enhances cognition in hAPP transgenic mice. J Neurosci 35(6):2358. https://doi.org/10.1523/JNEUROSCI.5791-12.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY-M, Yang C-W (2013) Chronic kidney disease: global dimension and perspectives. Lancet 382(9888):260–272. https://doi.org/10.1016/S0140-6736(13)60687-X

    Article  PubMed  Google Scholar 

  8. Manjunath G, Tighiouart H, Ibrahim H, MacLeod B, Salem DN, Griffith JL, Coresh J, Levey AS, Sarnak MJ (2003) Level of kidney function as a risk factor for atherosclerotic cardiovascular outcomes in the community. J Am Coll Cardiol 41(1):47–55. https://doi.org/10.1016/S0735-1097(02)02663-3

    Article  PubMed  Google Scholar 

  9. Thompson S, James M, Wiebe N, Hemmelgarn B, Manns B, Klarenbach S, Tonelli M (2015) Cause of death in patients with reduced kidney function. J Am Soc Nephrol 26(10):2504. https://doi.org/10.1681/ASN.2014070714

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hu MC, Kuro-o M, Moe OW (2013) Klotho and chronic kidney disease. Contrib Nephrol 180:47–63. https://doi.org/10.1159/000346778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kuro-o M (2018) Klotho and endocrine fibroblast growth factors: markers of chronic kidney disease progression and cardiovascular complications? Nephrol Dial Transplant 34(1):15–21. https://doi.org/10.1093/ndt/gfy126

    Article  CAS  Google Scholar 

  12. Otani-Takei N, Masuda T, Akimoto T, Honma S, Watanabe Y, Shiizaki K, Miki T, Kusano E, Asano Y, Kuro OM, Nagata D (2015) Association between serum soluble Klotho levels and mortality in chronic hemodialysis patients. Int J Endocrinol. https://doi.org/10.1155/2015/406269

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zheng S, Zheng Y, Jin L, Zhou Z, Li Z (2018) Relationship between serum soluble Klotho protein and coronary artery calcification and prognosis in patients on maintenance hemodialysis. Iran J Public Health 47(4):510–518

    PubMed  PubMed Central  Google Scholar 

  14. Kim HR, Nam BY, Kim DW, Kang MW, Han JH, Lee MJ, Shin DH, Doh FM, Koo HM, Ko KI, Kim CH, Oh HJ, Yoo TH, Kang SW, Han DS, Han SH (2013) Circulating α-klotho levels in CKD and relationship to progression. Am J Kidney Dis 61(6):899–909. https://doi.org/10.1053/j.ajkd.2013.01.024

    Article  CAS  PubMed  Google Scholar 

  15. Liu QF, Ye JM, Yu LX, He AL, Sun Q, He DW, Li SS (2018) Plasma s-Klotho is related to kidney function and predicts adverse renal outcomes in patients with advanced chronic kidney disease. J Investig Med 66(3):669–675. https://doi.org/10.1136/jim-2017-000560

    Article  PubMed  Google Scholar 

  16. Valenzuela PL, Cobo F, Diez-Vega I, Sanchez-Hernandez R, Pedrero-Chamizo R, Verde-Rello Z, Gonzalez-Gross M, Santiago C, Perez Ruiz M (2019) Physical performance, plasma S-klotho, and all-cause mortality in elderly dialysis patients: a prospective cohort study. Exp Gerontol 122:123–128. https://doi.org/10.1016/j.exger.2019.05.003

    Article  CAS  PubMed  Google Scholar 

  17. Memmos E, Sarafidis P, Pateinakis P, Tsiantoulas A, Faitatzidou D, Giamalis P, Vasilikos V, Papagianni A (2019) Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis. BMC Nephrol 20(1):217. https://doi.org/10.1186/s12882-019-1391-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605

    Article  PubMed  Google Scholar 

  19. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  CAS  PubMed  Google Scholar 

  20. Higgins JPT, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557. https://doi.org/10.1136/bmj.327.7414.557

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ding H-Y, Ma H-X (2015) Significant roles of anti-aging protein klotho and fibroblast growth factor 23 in cardiovascular disease. J Geriatr Cardiol 12(4):439–447. https://doi.org/10.11909/j.issn.1671-5411.2015.04.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kitagawa M, Sugiyama H, Nakamura K, Ito H, Makino H (2015) Soluble Klotho as biomarker of vascular dysfunction in chronic kidney disease. In: Preedy VR, Patel VB (eds) General methods in biomarker research and their applications. Springer, Netherlands, Dordrecht, pp 891–917. https://doi.org/10.1007/978-94-007-7696-8_44

    Chapter  Google Scholar 

  23. Kusaba T, Okigaki M, Matui A, Murakami M, Ishikawa K, Kimura T, Sonomura K, Adachi Y, Shibuya M, Shirayama T, Tanda S, Hatta T, Sasaki S, Mori Y, Matsubara H (2010) Klotho is associated with VEGF receptor-2 and the transient receptor potential canonical-1 Ca2 + channel to maintain endothelial integrity. Proc Natl Acad Sci U S A 107(45):19308–19313. https://doi.org/10.1073/pnas.1008544107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Martin A, David V, Quarles LD (2012) Regulation and function of the FGF23/klotho endocrine pathways. Physiol Rev 92(1):131–155. https://doi.org/10.1152/physrev.00002.2011

    Article  CAS  PubMed  Google Scholar 

  25. Hu MC, Kuro-o M, Moe OW (2012) Secreted klotho and chronic kidney disease. Adv Exp Med Biol 728:126–157. https://doi.org/10.1007/978-1-4614-0887-1_9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang Q, Su W, Shen Z, Wang R (2018) Correlation between soluble α-Klotho and renal function in patients with chronic kidney disease: a review and meta-Analysis. Biomed Res Int 2018:9481475. https://doi.org/10.1155/2018/9481475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Amaro-Gahete FJ, de-la-O A, Jurado-Fasoli L, Gutiérrez Á, Ruiz JR, Castillo MJ (2019) Association of physical activity and fitness with S-Klotho plasma levels in middle-aged sedentary adults: the FIT-AGEING study. Maturitas 123:25–31. https://doi.org/10.1016/j.maturitas.2019.02.001

    Article  CAS  PubMed  Google Scholar 

  28. Kim HJ, Kang E, Oh YK, Kim YH, Han SH, Yoo TH, Chae D-W, Lee J, Ahn C, Oh K-H (2018) The association between soluble klotho and cardiovascular parameters in chronic kidney disease: results from the KNOW-CKD study. BMC Nephrol 19(1):51. https://doi.org/10.1186/s12882-018-0851-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Patel MS, Donaldson AV, Lewis A, Natanek SA, Lee JY, Andersson YM, Haji G, Jackson SG, Bolognese BJ, Foley JP, Podolin PL, Bruijnzeel PLB, Hart N, Hopkinson NS, Man WDC, Kemp PR, Polkey MI (2016) Klotho and smoking—an interplay influencing the skeletal muscle function deficits that occur in COPD. Respir Med 113:50–56. https://doi.org/10.1016/j.rmed.2016.02.004

    Article  CAS  PubMed  Google Scholar 

  30. Su X-M, Yang W (2014) Klotho protein lowered in elderly hypertension. Int J Clin Exp Med 7(8):2347–2350

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Prannok Road, Bangkoknoi, Bangkok, 10700, Thailand

    Nipith Charoenngam

  2. Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Ben Ponvilawan

  3. Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland, OH, USA

    Patompong Ungprasert

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  1. Nipith Charoenngam
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  3. Patompong Ungprasert
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Charoenngam, N., Ponvilawan, B. & Ungprasert, P. Lower circulating soluble Klotho level is associated with increased risk of all-cause mortality in chronic kidney disease patients: a systematic review and meta-analysis. Int Urol Nephrol 52, 1543–1550 (2020). https://doi.org/10.1007/s11255-020-02510-1

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  • DOI: https://doi.org/10.1007/s11255-020-02510-1

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