Advertisement

Journal of Nephrology

, Volume 32, Issue 1, pp 83–91 | Cite as

The association of endothelin-1 levels with renal survival in polycystic kidney disease patients

  • Ismail Kocyigit
  • Eray ErogluEmail author
  • Ahmet Safa Kaynar
  • Derya Kocer
  • Seval Kargi
  • Gokmen Zararsiz
  • Ruslan Bayramov
  • Hakan Imamoglu
  • Murat Hayri Sipahioglu
  • Bulent Tokgoz
  • Munis Dundar
  • Oktay Oymak
Original Article

Abstract

Background

The prominent features of autosomal dominant polycystic kidney disease (ADPKD) are early development of hypertension, chronic kidney disease and cardiovascular problems. Thus, we aimed to investigate the role of endothelin, a vascular biomarker, in the clinical course of ADPKD, including renal and cardiovascular survival.

Methods

In 138 patients with ADPKD and 28 healthy controls, we measured serum endothelin-1 (ET-1) levels by enzyme-linked immunosorbent assay (ELISA). Endothelium-dependent vasodilatation (flow-mediated dilatation, FMD) and endothelium-independent vasodilatation (nitroglycerin-mediated dilatation, NMD) of the brachial artery were assessed non-invasively with high-resolution ultrasound. Magnetic resonance imaging (MRI) was performed with a 1.5-T system, and total kidney volumes were calculated using mid-slice technique. To determine PKD1 and PKD2 genotype, we performed molecular and genetic tests involving the following steps: DNA isolation, next-generation sequencing (NGS) and data analysis.

Results

Endothelin levels and height-adjusted total kidney volumes (hTKV) significantly increased while the estimated glomerular filtration rate (eGFR) decreased across CKD stages 1–4. Hypertension was more frequent in ADPKD patients with high serum endothelin. At multivariate Cox analysis, endothelin level, PKD1 truncating mutation, hTKV, high-sensitive C reactive protein (hs-CRP) level and the presence of diabetes mellitus were associated with the risk of overall survival. Moreover, endothelin level, PKD1 truncating mutation, hTKV, age and presence of hypertension were associated with the risk of renal survival. Additionally, body mass index (BMI), FMD, PKD1 truncating mutation, endothelin and triglyceride levels were independently associated with hypertension.

Conclusions

Increased serum endothelin levels independently predict hypertension in ADPKD. Serum endothelin levels are also associated with both renal and overall survival in patients with ADPKD.

Keywords

Endothelin Biomarkers CKD Endothelial dysfunction ADPKD 

Notes

Acknowledgements

We thank to the all study participants who enrolled to the study.

Author contributions

IK, EE, ASK and GZ conceived of the study and designed the protocol which was implemented by IK, EE, MHS and BT. These authors also recruited the participants. MD, OO helped with the study design. HI performed the assessments of total kidney volume. DK and RB set up and validated the endothelin assay and helped to interpret the results. IK and EE coordinated the study. All authors participated in data analysis and interpretation, and also read and approved the final manuscript.

Funding

There is no funding of the study.

Compliance with ethical standards

Conflict of interest

All authors declare that there is no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Torres VE, Harris PC, Pirson Y (2007) Autosomal dominant polycystic kidney disease. Lancet 369(9569):1287–1301CrossRefGoogle Scholar
  2. 2.
    Ecder T, Schrier RW (2001) Hypertension in autosomal-dominant polycystic kidney disease: early occurrence and unique aspects. J Am Soc Nephrol 12:1 94–200Google Scholar
  3. 3.
    Gabow PA (1993) Autosomal dominant polycystic kidney disease. N Engl J Med 329:3 32–342CrossRefGoogle Scholar
  4. 4.
    Torres VE, Harris PC (2009) Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int 76:149–168CrossRefGoogle Scholar
  5. 5.
    Chang M-Y, Ong ACM (2011) Endothelin in renal physiology and disease. Contrib Nephrol 172:200–209CrossRefGoogle Scholar
  6. 6.
    Yanagisawa M, Kurihara H, Kimura S et al (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332(6163):411–415CrossRefGoogle Scholar
  7. 7.
    Kohan DE (2010) Endothelin, hypertension and chronic kidney disease: new insights. Curr Opin Nephrol Hypertens 19(2):134–139CrossRefGoogle Scholar
  8. 8.
    Hocher B, Thdne-Reineke C, Rohmeiss P et al (1997) Endothelin-l transgenic mice develop renal cysts, interstitial fibrosis and glomerulosclerosis but not hypertension. J Clin Invest 99:1380–1389CrossRefGoogle Scholar
  9. 9.
    Lai X, Bacallao RL, Blazer-Yost BL, Hong D, Mason SB, Witzmann FA (2008) Characterization of the renal cyst fluid proteome in autosomal dominant polycystic kidney disease (ADPKD) patients. Proteomics 2(7–8), 1140–1152Google Scholar
  10. 10.
    Ong AC, Newby LJ, Dashwood MR (2003) Expression and cellular localisation of renal endothelin-1 and endothelin receptor subtypes in autosomal-dominant polycystic kidney disease. Nephron Exp Nephrol 93:e80CrossRefGoogle Scholar
  11. 11.
    Nakamura T, Ebihara I, Fukui M et al (1993) Increased endothelin and endothelin receptor mRNA expression in polycystic kidneys of cpk mice. J Am Soc Nephrol 4:1064–1072Google Scholar
  12. 12.
    Hocher B, Zart R, Schwarz A et al (1998) Renal endothelin system in polycystic kidney disease. J Am Soc Nephrol 9:1169–1177Google Scholar
  13. 13.
    Sakurai T, Yanagisawa M, Takuwa Y et al (1990) Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 348:732–735CrossRefGoogle Scholar
  14. 14.
    Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S (1990) Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348:730–732CrossRefGoogle Scholar
  15. 15.
    Chang MY, Parker E, El Nahas M, Haylor JL, Ong AC (2007) Endothelin B receptor blockade accelerates disease progression in a murine model of autosomal dominant polycystic kidney disease. J Am Soc Nephrol 18(2):560–569CrossRefGoogle Scholar
  16. 16.
    Inker LA, Astor BC, Fox CH et al (2014) KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 63(5):713–735CrossRefGoogle Scholar
  17. 17.
    Levey AS, Stevens LA, Schmid CH, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612CrossRefGoogle Scholar
  18. 18.
    Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18(6):499–502Google Scholar
  19. 19.
    Celermajer DS, Sorensen KE, Gooch VM et al (1992) Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340(8828):1111–1115CrossRefGoogle Scholar
  20. 20.
    Corretti MC, Anderson TJ, Benjamin EJ, International Brachial Artery Reactivity Task Force et al (2002) Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 39(2):257–265CrossRefGoogle Scholar
  21. 21.
    Bae KT, Tao C, Wang J, Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) et al (2013) Novel approach to estimate kidney and cyst volumes using mid-slice magnetic resonance images in polycystic kidney disease. Am J Nephrol 38(4):333–341CrossRefGoogle Scholar
  22. 22.
    Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–423CrossRefGoogle Scholar
  23. 23.
    Ong ACM, Harris PC (2005) Molecular pathogenesis of ADPKD: the polycystin complex gets complex. Kidney Int 67:1234–1247CrossRefGoogle Scholar
  24. 24.
    Schrier RW, Brosnahan G, Cadnapaphornchai MA et al (2014) Predictors of autosomal dominant polycystic kidney disease progression. J Am Soc Nephrol 25(11):2399–2418CrossRefGoogle Scholar
  25. 25.
    Di Iorio BR, Cupisti A, D’Alessandro C, Bellasi A, Barbera V, Di Lullo L (2018) Nutritional therapy in autosomal dominant polycystic kidney disease. J Nephrol.  https://doi.org/10.1007/s40620-018-0470-x (Epub ahead of print) Google Scholar
  26. 26.
    Girardat-Rotar L, Puhan MA, Braun J, Serra AL (2018) Long-term effect of coffee consumption on autosomal dominant polycystic kidneys disease progression: results from the Suisse ADPKD, a Prospective Longitudinal Cohort Study. J Nephrol 31(1):87–94CrossRefGoogle Scholar
  27. 27.
    Kocyigit I, Yilmaz MI, Unal A et al (2013) A link between the intrarenal renin angiotensinsystem and hypertension in autosomal dominant polycystic kidney disease. Am J Nephrol 38(3):218–225CrossRefGoogle Scholar
  28. 28.
    Kocyigit I, Eroglu E, Orscelik O et al (2014) Pentraxin 3 as a novel bio-marker of inflammation and endothelial dysfunction in autosomal dominant polycystic kidney disease. J Nephrol 27(2):181–186CrossRefGoogle Scholar
  29. 29.
    Kocyigit I, Kaya MG, Orscelik O et al (2012) Early arterial stiffness and inflammatory bio-markers in normotensive polycystic kidney disease patients. Am J Nephrol 36(1):11–18CrossRefGoogle Scholar
  30. 30.
    Kocyigit I, Taheri S, Sener EF et al (2014) Endothelial nitric oxide synthase gene expression is associated with hypertension in autosomal dominant polycystic kidney disease. Cardiorenal Med 4(3–4):269–279CrossRefGoogle Scholar
  31. 31.
    Munemura C, Uemasu J, Kawasaki H (1994) Epidermal growth factor and endothelin in cyst fluid from autosomal dominant polycystic kidney disease cases: possible evidence of heterogeneity in cystogenesis. Am J Kidney Dis 24:561–568CrossRefGoogle Scholar
  32. 32.
    Giusti R, Neri M, Angelini D et al (1995) Plasma concentration of endothelin and arterial pressure in patients with ADPKD. Contrib Nephrol 115:118–121CrossRefGoogle Scholar
  33. 33.
    Chang MY, Ong AC (2011) Endothelin in polycystic kidney disease. Contrib Nephrol 172:200–209CrossRefGoogle Scholar
  34. 34.
    Schrier RW (2009) Renal volume, renin-angiotensin-aldosterone system, hypertension, and left ventricular hypertrophy in patients with autosomal dominant polycystic kidney disease. J Am Soc Nephrol 20:1888–1893CrossRefGoogle Scholar
  35. 35.
    Hocher B, Kalk P, Slowinski T et al (2003) ETA receptor blockade induces tubular cell proliferation and cyst growth in rats with polycystic kidney disease. J Am Soc Nephrol 14:367–376CrossRefGoogle Scholar
  36. 36.
    Grantham JJ, Mulamalla S, Swenson-Fields KI (2011) Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol 7(10):556–566CrossRefGoogle Scholar
  37. 37.
    Chang M-Y, Ong ACM (2013) New treatments for autosomal dominant polycystic kidney disease. Br J Clin Pharm 76:524–535Google Scholar

Copyright information

© Italian Society of Nephrology 2018

Authors and Affiliations

  • Ismail Kocyigit
    • 1
  • Eray Eroglu
    • 1
    Email author
  • Ahmet Safa Kaynar
    • 2
  • Derya Kocer
    • 3
  • Seval Kargi
    • 2
  • Gokmen Zararsiz
    • 4
  • Ruslan Bayramov
    • 5
  • Hakan Imamoglu
    • 6
  • Murat Hayri Sipahioglu
    • 1
  • Bulent Tokgoz
    • 1
  • Munis Dundar
    • 5
  • Oktay Oymak
    • 1
  1. 1.Department of NephrologyErciyes University Medical FacultyKayseriTurkey
  2. 2.Department of Internal MedicineErciyes University Medical FacultyKayseriTurkey
  3. 3.Department of BiochemistryTraining and Research HospitalKayseriTurkey
  4. 4.Department of BiostatisticsErciyes University Medical FacultyKayseriTurkey
  5. 5.Department of GeneticErciyes University Medical FacultyKayseriTurkey
  6. 6.Department of RadiologyErciyes University Medical FacultyKayseriTurkey

Personalised recommendations