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.
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.
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.
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.
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Torres VE, Harris PC, Pirson Y (2007) Autosomal dominant polycystic kidney disease. Lancet 369(9569):1287–1301
Ecder T, Schrier RW (2001) Hypertension in autosomal-dominant polycystic kidney disease: early occurrence and unique aspects. J Am Soc Nephrol 12:1 94–200
Gabow PA (1993) Autosomal dominant polycystic kidney disease. N Engl J Med 329:3 32–342
Torres VE, Harris PC (2009) Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int 76:149–168
Chang M-Y, Ong ACM (2011) Endothelin in renal physiology and disease. Contrib Nephrol 172:200–209
Yanagisawa M, Kurihara H, Kimura S et al (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332(6163):411–415
Kohan DE (2010) Endothelin, hypertension and chronic kidney disease: new insights. Curr Opin Nephrol Hypertens 19(2):134–139
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 99:1380–1389
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), 1140–1152
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:e80
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 4:1064–1072
Hocher B, Zart R, Schwarz A et al (1998) Renal endothelin system in polycystic kidney disease. J Am Soc Nephrol 9:1169–1177
Sakurai T, Yanagisawa M, Takuwa Y et al (1990) Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor. Nature 348:732–735
Arai H, Hori S, Aramori I, Ohkubo H, Nakanishi S (1990) Cloning and expression of a cDNA encoding an endothelin receptor. Nature 348:730–732
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):560–569
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):713–735
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):604–612
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):499–502
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):1111–1115
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):257–265
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):333–341
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):405–423
Ong ACM, Harris PC (2005) Molecular pathogenesis of ADPKD: the polycystin complex gets complex. Kidney Int 67:1234–1247
Schrier RW, Brosnahan G, Cadnapaphornchai MA et al (2014) Predictors of autosomal dominant polycystic kidney disease progression. J Am Soc Nephrol 25(11):2399–2418
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)
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):87–94
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):218–225
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):181–186
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):11–18
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):269–279
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 24:561–568
Giusti R, Neri M, Angelini D et al (1995) Plasma concentration of endothelin and arterial pressure in patients with ADPKD. Contrib Nephrol 115:118–121
Chang MY, Ong AC (2011) Endothelin in polycystic kidney disease. Contrib Nephrol 172:200–209
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 20:1888–1893
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 14:367–376
Grantham JJ, Mulamalla S, Swenson-Fields KI (2011) Why kidneys fail in autosomal dominant polycystic kidney disease. Nat Rev Nephrol 7(10):556–566
Chang M-Y, Ong ACM (2013) New treatments for autosomal dominant polycystic kidney disease. Br J Clin Pharm 76:524–535
We thank to the all study participants who enrolled to the study.
There is no funding of the study.
Conflict of interest
All authors declare that there is no conflict of interest.
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 was obtained from all individual participants included in the study.
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Kocyigit, I., Eroglu, E., Kaynar, A.S. et al. The association of endothelin-1 levels with renal survival in polycystic kidney disease patients. J Nephrol 32, 83–91 (2019). https://doi.org/10.1007/s40620-018-0514-2
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