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Fibroblast growth factor-23 but not sKlotho levels are related to diastolic dysfunction in type 1 diabetic patients with early diabetic nephropathy

Abstract

Purpose

To investigate the soluble Klotho (sKlotho) and fibroblast growth factor-23 (FGF-23) levels and echocardiographic findings in type 1 diabetic patients with no or early diabetic nephropathy.

Methods

A total of 147 subjects (mean age 34.1 ± 9.2 years, 55.8 % were females) including type 1 diabetic patients with glomerular filtration rate (GFR) >60 ml/min (n = 71, mean age 34.3 ± 9.5 years, 54.9 % were females) and healthy controls (n = 76, mean age 33.9 ± 9.1 years, 56.6 % were females) were included in this study. Data on demographic characteristics, blood biochemistry, urinalysis, diabetes-related complications and echocardiography were recorded. Serum levels for sKlotho and FGF-23 were determined by ELISA method.

Results

Patient and control groups were similar in terms of mean sKlotho (509.2 ± 183.5 and 547.6 ± 424.0 pg/ml, respectively) and FGF-23 (76.2 ± 15.6 and 77.2 ± 15.1 pg/ml, respectively) levels as well as echocardiographic findings. No significant correlation of sKlotho (pg/ml) and FGF-23 (pg/ml) levels with cardiac parameters was noted among diabetic patients. In subgroup analysis, the correlations between FGF-23 levels and isovolumic relaxation time (ms) and early diastolic velocity at medial/septal annulus (E’med) (m/s) were significant only in patients with early diabetic nephropathy (DN) but not in non-DN patients. No significant association of sKlotho levels with echocardiographic findings was noted.

Conclusions

Our findings in young adult type 1 diabetic patients with GFR >60 ml/min versus healthy controls revealed no difference between groups in terms of sKlotho and FGF-23 levels and echocardiographic findings, while a significant correlation of FGF-23 (pg/ml) levels and diastolic dysfunction was noted only in patients with DN.

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References

  1. Koivisto VA, Stevens LK, Mattock M, Ebeling P, Muggeo M, Stephenson J, Idzior-Walus B (1996) EURODIAB IDDM Complications Study Group. Cardiovascular disease and its risk factors in IDDM in Europe. Diabetes Care 19:689–697

    Article  CAS  PubMed  Google Scholar 

  2. Brindisi MC, Bouillet B, Vergès B, Halimi S (2010) Cardiovascular complications in type 1 diabetes mellitus. Diabetes Metab 36:341–344 (Review)

    Article  PubMed  Google Scholar 

  3. Shivalkar B, Dhondt D, Goovaerts I, Van Gaal L, Bartunek J, Van Crombrugge P, Vrints C (2006) Flow mediated dilatation and cardiac function in type 1 diabetes mellitus. Am J Cardiol 97:77–82

    Article  PubMed  Google Scholar 

  4. Kacso IM, Bondor CI, Kacso G (2012) Soluble serum Klotho in diabetic nephropathy: relationship to VEGF-A. Clin Biochem 45:1415–1420

    Article  CAS  PubMed  Google Scholar 

  5. Nakano C, Hamano T, Fujii N, Obi Y, Matsui I, Tomida K, Mikami S, Inoue K, Shimomura A, Nagasawa Y, Okada N, Tsubakihara Y, Rakugi H, Isaka Y (2012) Intact fibroblast growth factor 23 levels predict incident cardiovascular event before but not after the start of dialysis. Bone 50:1266–1274

    Article  CAS  PubMed  Google Scholar 

  6. Donate-Correa J, Muros-de-Fuentes M, Mora-Fernández C, Navarro-González JF (2012) FGF23/Klotho axis: phosphorus, mineral metabolism and beyond. Cytokine Growth Factor Rev 23:37–46

    Article  CAS  PubMed  Google Scholar 

  7. Long YC, Kharitonenkov A (2011) Hormone-like fibroblast growth factors and metabolic regulation. Biochim Biophys Acta 1812:791–795

    Article  CAS  PubMed  Google Scholar 

  8. Kurosu H, Kuro-O M (2009) The Klotho gene family as a regulator of endocrine fibroblast growth factors. Mol Cell Endocrinol 299:72–78

    Article  CAS  PubMed  Google Scholar 

  9. Wang Y, Sun Z (2009) Current understanding of klotho. Ageing Res Rev. 8:43–51 (Review)

    PubMed Central  Article  PubMed  Google Scholar 

  10. Hu MC, Kuro-o M, Moe OW (2013) Renal and extrarenal actions of Klotho. Semin Nephrol. 33:118–129 (Review)

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  11. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T (2004) FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 19:429–435

    Article  CAS  PubMed  Google Scholar 

  12. Isakova T, Xie H, Yang W, Xie D, Anderson AH, Scialla J, Wahl P, Gutiérrez OM, Steigerwalt S, He J, Schwartz S, Lo J, Ojo A, Sondheimer J, Hsu CY, Lash J, Leonard M, Kusek JW, Feldman HI, Wolf M (2011) Chronic Renal Insufficiency Cohort (CRIC) Study Group. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 305:2432–2439

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  13. Ix JH, Shlipak MG, Wassel CL, Whooley MA (2010) Fibroblast growth factor-23 and early decrements in kidney function: the Heart and Soul Study. Nephrol Dial Transplant 25:993–997

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  14. Ix JH, Katz R, Kestenbaum BR, de Boer IH, Chonchol M, Mukamal KJ, Rifkin D, Siscovick DS, Sarnak MJ, Shlipak MG (2012) Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol 60:200–207

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  15. Jovanovich A, Ix JH, Gottdiener J, McFann K, Katz R, Kestenbaum B, de Boer IH, Sarnak M, Shlipak MG, Mukamal KJ, Siscovick D, Chonchol M (2013) Fibroblast growth factor 23, left ventricular mass, and left ventricular hypertrophy in community-dwelling older adults. Atherosclerosis 231:114–119

    Article  CAS  PubMed  Google Scholar 

  16. Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, Gutiérrez OM, Aguillon-Prada R, Lincoln J, Hare JM, Mundel P, Morales A, Scialla J, Fischer M, Soliman EZ, Chen J, Go AS, Rosas SE, Nessel L, Townsend RR, Feldman HI, St John Sutton M, Ojo A, Gadegbeku C, Di Marco GS, Reuter S, Kentrup D, Tiemann K, Brand M, Hill JA, Moe OW, Kuro-O M, Kusek JW, Keane MG, Wolf M (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121:4393–4408

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  17. Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE (2009) Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 207:546–551

    Article  CAS  PubMed  Google Scholar 

  18. Mirza MA, Larsson A, Lind L, Larsson TE (2009) Circulating fibroblast growth factor- 23 is associated with vascular dysfunction in the community. Atherosclerosis 205:385–390

    Article  CAS  PubMed  Google Scholar 

  19. Pedersen L, Pedersen SM, Brasen CL, Rasmussen LM (2013) Soluble serum Klotho levels in healthy subjects. Comparison of two different immunoassays. Clin Biochem 46:1079–1083

    Article  CAS  PubMed  Google Scholar 

  20. Smith ER, McMahon LP, Holt SG (2013) Method-specific differences in plasma fibroblast growth factor 23 measurement using four commercial ELISAs. Clin Chem Lab Med 51:1971–1981

    Article  CAS  PubMed  Google Scholar 

  21. Lacombe F, Dart A, Dewar E, Jennings G, Cameron J, Laufer E (1992) Arterial elastic properties in man: a comparison of echo-Doppler indices of aortic stiffness. Eur Heart J 13:1040–1045

    CAS  PubMed  Google Scholar 

  22. Hu MC, Shi M, Zhang J, Quiñones H, Griffith C, Kuro-o M, Moe OW (2011) Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 22:124–136

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  23. Devaraj S, Syed B, Chien A, Jialal I (2012) Validation of an immunoassay for soluble Klotho protein: decreased levels in diabetes and increased levels in chronic kidney disease. Am J Clin Pathol 137:479–485

    Article  CAS  PubMed  Google Scholar 

  24. Zhao Y, Banerjee S, Dey N, LeJeune WS, Sarkar PS, Brobey R, Rosenblatt KP, Tilton RG, Choudhary S (2011) Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine) 536 phosphorylation. Diabetes 60:1907–1916

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  25. Cheng MF, Chen LJ, Cheng JY (2010) Decrease of Klotho in the kidney of streptozotocin induced diabetic rats. J Biomed Biotechnol 2010:513853

    PubMed Central  Article  PubMed  Google Scholar 

  26. Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, Guralnik JM, Ferrucci L (2011) Plasma Klotho and cardiovascular disease in adults. J Am Geriatr Soc 59:1596–1601

    PubMed Central  Article  PubMed  Google Scholar 

  27. Gutierrez O, Isakova T, Rhee E, Shah A, Holmes J, Collerone G, Jüppner H, Wolf M (2005) Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol 16:2205–2215

    Article  CAS  PubMed  Google Scholar 

  28. Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB (2003) Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64:2272–2279

    Article  CAS  PubMed  Google Scholar 

  29. Koh N, Fujimori T, Nishiguchi S, Tamori A, Shiomi S, Nakatani T, Sugimura K, Kishimoto T, Kinoshita S, Kuroki T, Nabeshima Y (2001) Severely reduced production of klotho in human chronic renal failure kidney. Biochem Biophys Res Commun 280:1015–1020

    Article  CAS  PubMed  Google Scholar 

  30. Yamazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, Hasegawa H, Yamashita T, Nakatani K, Saito Y, Okamoto N, Kurumatani N, Namba N, Kitaoka T, Ozono K, Sakai T, Hataya H, Ichikawa S, Imel EA, Econs MJ, Nabeshima Y (2010) Establishment of sandwich ELISA for soluble alpha-Klotho measurement: age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun 398:513–518

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  31. Yilmaz MI, Sonmez A, Saglam M, Yaman H, Kilic S, Demirkaya E, Eyileten T, Caglar K, Oguz Y, Vural A, Yenicesu M, Zoccali C (2010) FGF-23 and vascular dysfunction in patients with stage 3 and 4 chronic kidney disease. Kidney Int 78:679–685

    Article  CAS  PubMed  Google Scholar 

  32. Gutierrez OM, Januzzi JL, Isakova T, Laliberte K, Smith K, Collerone G, Sarwar A, Hoffmann U, Coglianese E, Christenson R, Wang TJ, deFilippi C, Wolf M (2009) Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119:2545–2552

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  33. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT (2010) Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative metaanalysis. Lancet 375:2073–2081

    PubMed Central  Article  PubMed  Google Scholar 

  34. Wolf M, Shah A, Gutierrez O, Ankers E, Monroy M, Tamez H, Steele D, Chang Y, Camargo CA Jr, Tonelli M, Thadhani R (2007) Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 72:1004–1013

    Article  CAS  PubMed  Google Scholar 

  35. Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS (2006) Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 21:1187–1196

    Article  CAS  PubMed  Google Scholar 

  36. Kazik A, Wilczek K, Polonski L (2010) Management of diastolic heart failure. Cardiol J 17:558–565

    PubMed  Google Scholar 

  37. Patil VC, Patil HV, Shah KB, Vasani JD, Shetty P (2011) Diastolic dysfunction in asymptomatic type 2 diabetes mellitus with normal systolic function. J Cardiovasc Dis Res 2:213–222

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  38. Yancy CW, Lopatin M, Stevenson LW, DeMarco T, Fonarow GC (2006) ADHERE Scientific Advisory Committee and Investigators. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Hearth Failure National Registry (ADHERE) Database. J Am Coll Cardiol 47:76–84

    Article  PubMed  Google Scholar 

  39. Kardami E, Jiang ZS, Jimenez SK, Hirst CJ, Sheikh F, Zahradka P, Cattini PA (2004) Fibroblast growth factor 2 isoforms and cardiac hypertrophy. Cardiovasc Res 63:458–466

    Article  CAS  PubMed  Google Scholar 

  40. van Ark J, Hammes HP, van Dijk MC, Vervloet MG, Wolffenbuttel BH, van Goor H, Hillebrands JL (2013) Circulating alpha-klotho levels are not disturbed in patients with type 2 diabetes with and without macrovascular disease in the absence of nephropathy. Cardiovasc Diabetol 12:116

    PubMed Central  Article  PubMed  Google Scholar 

  41. Smith ER, Cai MM, McMahon LP, Holt SG (2012) Biological variability of plasma intact and C-terminal FGF23 measurements. J Clin Endocrinol Metab 97:3357–3365

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The study is granted by Sanofi-Aventis, Turkey. We thank Cagla Ayhan, MD, and Prof. Sule Oktay, MD, Ph.D., from KAPPA Consultancy Training Research Ltd., Istanbul, who provided editorial support funded by Sanofi-Aventis, Turkey.

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Correspondence to Burcu Dogan.

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Dogan, B., Arikan, I.H., Guler, D. et al. Fibroblast growth factor-23 but not sKlotho levels are related to diastolic dysfunction in type 1 diabetic patients with early diabetic nephropathy. Int Urol Nephrol 48, 399–407 (2016). https://doi.org/10.1007/s11255-015-1190-y

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  • DOI: https://doi.org/10.1007/s11255-015-1190-y

Keywords

  • Type 1 diabetes mellitus
  • sKlotho
  • FGF-23
  • Cardiac function
  • Diabetic nephropathy