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Increased serum levels of GDF-15 associated with mortality and subclinical atherosclerosis in patients on maintenance hemodialysis

Erhöhte Serum-GDF-15-Level sind assoziiert mit Mortalität und subklinische Atherosklerose bei Langzeit-Hämodialyse-Patienten

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Abstract

Background/aims

Increased carotid intima–media thickness (CIMT) was shown to be an independent predictor of cardiovascular (CV) mortality in dialysis patients and the general population. Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor superfamily, is produced by cardiomyocytes and atherosclerotic lesions under stress conditions such as inflammation. We assessed associations between serum concentrations of GDF-15, mortality, and CIMT for subclinical atherosclerosis in hemodialysis (HD) patients.

Methods

A total of 87 patients on maintenance hemodialysis and 45 sex- and age-matched healthy controls were included in this prospective study. Serum GDF-15 levels were measured by ELISA. CIMT was assessed by Doppler ultrasonography. The association between serum GDF-15 levels and mortality was assessed using Cox regression analysis with serum levels categorized into two groups according to the median value (328.18 pg/ml). Patients were followed for 2 years and cause-specific and all-cause mortality were determined.

Results

The median level of serum GDF-15 was significantly higher in HD patients than controls [328 (198–522) vs. 176 (101–289) pg/ml, p < 0.01, respectively]. Serum GDF-15 levels were correlated to CIMT (r = 0.607, p < 0.001), C-reactive protein (CRP; r = 0.250, p = 0.010), HD duration (r = 0.376, p = 0.004), and serum albumin (r = − 0.156, p = 0.030). The multivariate analysis revealed that GDF-15 was found to be an independent variable of CIMT in HD patients. In the study, the serum GDF-15 level was an independent marker of all-cause of mortality when adjusted for age, CRP, and history of diabetes mellitus.

Conclusion

The relationship between serum GDF-15, mortality, and carotid artery thickening suggests that GDF-15 may be a novel marker of atherosclerosis, inflammation, and malnutrition in HD patients.

Zusammenfassung

Hintergrund/Ziele

Eine erhöhte Intima-Media-Dicke der A. carotis (CIMT) ist nachgewiesen als unabhängiger Prädiktor der kardiovaskulären Mortalität, sowohl bei Hämodialyse(HD-)Patienten als auch der Allgemeinbevölkerung. Der Wachstumsdifferenzierungsfaktor 15 (GDF-15) aus der TGF(„transforming growth factors“)-Superfamilie wird von Kardiomyozyten und in atherosklerotischen Läsionen unter Stressbedingungen gebildet, z. B. bei Inflammation. Bestimmt wurden Assoziationen zwischen GDF-15-Serumkonzentrationen, Mortalität und CIMT für eine subklinische Atherosklerose bei Hämodialysepatienten.

Methoden

Insgesamt wurden 87 Dauer-HD-Patienten und 45 geschlechts- und altersgematchte Kontrollprobanden in die prospektive Studie aufgenommen. Die GDF-15-Serumkonzentrationen wurden per ELISA bestimmt, die CIMT mit Dopplersonographie. Assoziationen zwischen Serum-GDF-15-Konzentrationen und Mortalität wurden überprüft mittels Cox-Regressionsanalyse. Ausgehend vom Median (328,18 pg/ml) wurden 2 Gruppen gebildet. Die Follow-up-Phase war 2 Jahre lang, ermittelt wurden krankheitsspezifische wie generelle Mortalität.

Ergebnisse

Die mediane Konzentration von GDF-15 im Serum war bei HD-Patienten im Vergleich mit den Kontrollen signifikant höher [328 (198–522) vs. 176 (101–289) pg/ml, p < 0,01]. Korreliert mit Serum-GDF-15-Konzentrationen wurden C-reaktives Protein (CRP; r = 0,250, p = 0,010), Dauer der Dialyse (r = 0,376, p = 0,004) und Albuminkonzentration im Serum (r = − 0,156, p = 0,030). In der multivariaten Analyse erwies sich GDF-15 als eine unabhängige Variable für CIMT bei HD-Patienten. Ferner war die Serum-GDF-15-Konzentrationen nach Adjustierung für Alter, CRP und Diabetes-mellitus-Anamnese ein unabhängiger Marker für Mortalität allgemein.

Fazit

Die Beziehung zwischen GDF-15-Serumkonzentrationen, Mortalität und erhöhter CIMT weist darauf hin, dass GDF-15 ein innovativer Marker für Atherosklerose, Inflammation und Mangelernährung bei HD-Patienten sein könnte.

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Compliance with ethical guidelines

Conflict of interest. H. Yilmaz, H.T. Çelik, O.M. Gurel, M.A. Bilgic, M. Namuslu, H. Bozkurt, A. Ayyildiz, O. Inan, N. Bavbek, and A. Akcay state that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.

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Authors and Affiliations

  1. Department of Internal Medicine, Section of Nephrology, Turgut Ozal University School of Medicine, Alparslan Türkes Cad. No: 57, 06510, Emek/Ankara, Turkey

    H. Yilmaz, M.A. Bilgic, N. Bavbek & A. Akcay

  2. Department of Biochemistry, Turgut Ozal University School of Medicine, Ankara, Turkey

    H.T. Çelik & M. Namuslu

  3. Department of Cardiology, Turgut Ozal University School of Medicine, Ankara, Turkey

    O.M. Gurel

  4. Department of Clinical Microbiology, Anamur State Hospital, Anamur, Turkey

    H. Bozkurt

  5. Department of Biochemistry, Agrı State Hospital, Agrı, Turkey

    A. Ayyildiz

  6. Department of Internal Medicine, Turgut Ozal University School of Medicine, Ankara, Turkey

    O. Inan

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  1. H. Yilmaz
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  2. H.T. Çelik
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Correspondence to H. Yilmaz.

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Yilmaz, H., Çelik, H., Gurel, O. et al. Increased serum levels of GDF-15 associated with mortality and subclinical atherosclerosis in patients on maintenance hemodialysis. Herz 40 (Suppl 3), 305–312 (2015). https://doi.org/10.1007/s00059-014-4139-5

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  • DOI: https://doi.org/10.1007/s00059-014-4139-5

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