title: Combined therapy with renin-angiotensin system and calcium channel blockers in type 2 diabetic hypertensive patients with proteinuria: effects on soluble TWEAK, PTX3, and flow-mediated dilation.
abstract: OBJECTIVE
  Soluble TNF-like weak inducer of apoptosis (sTWEAK) and long pentraxin-3 (PTX3) concentrations have been associated with endothelial function in patients with chronic kidney disease (CKD). This study tested the hypothesis that the improvement in endothelial function after initiation of angiotensin II receptor blocker (valsartan), calcium channel blocker (amlodipine) therapy, or a combination of both is directly linked to the normalization of sTWEAK and PTX3.
  
  
  METHODS
  One-hundred-eight diabetic CKD stage I patients with hypertension (56% men, 46.7+/-5.3 years) were allocated to a 12-week intervention with amlodipine (10 mg/d), valsartan (160 mg/d), or their combination. Plasma levels of sTWEAK, PTX3, and flow-mediated dilation (FMD) were studied during the interventions.
  
  
  RESULTS
  All treatment strategies effectively increased FMD and reduced proteinuria, confirming a more prone reduction with the combined therapy. These improvements were followed by significant PTX3 reductions. Valsartan alone and in combination with amlodipine achieved significant incremental raises in sTWEAK plasma levels. More importantly, the changes observed in sTWEAK (beta=0.25, P=0.006) or PTX3 (beta=-0.24, P=0.007) plasma levels were independently associated with the improvement in ultrasonographically measured FMD.
  
  
  CONCLUSIONS
  This study shows that treatment with antihypertensive drugs improves FMD and normalizes proteinuria, PTX3, and sTWEAK in diabetic CKD stage I patients with hypertension. The improvement in FMD was independently associated with PTX3 and sTWEAK normalization. Two surrogate biomarkers of endothelial function are therefore identified with potential as therapeutic targets. The study was registered in clinicaltrials.gov as NCT00921570.
authors.affiliation: Department of Nephrology, Gülhane School of Medicine, Ankara, Turkey.
authors.forename: Mahmut Ilker
authors.initials: MI
authors.lastname: Yilmaz
authors.forename: Juan Jesús
authors.initials: JJ
authors.lastname: Carrero
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Martín-Ventura
authors.forename: Alper
authors.initials: A
authors.lastname: Sonmez
authors.forename: Mutlu
authors.initials: M
authors.lastname: Saglam
authors.forename: Turgay
authors.initials: T
authors.lastname: Celik
authors.forename: Halil
authors.initials: H
authors.lastname: Yaman
authors.forename: Mujdat
authors.initials: M
authors.lastname: Yenicesu
authors.forename: Tayfun
authors.initials: T
authors.lastname: Eyileten
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Moreno
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
mesh_terms: D000328:Adult; D017311:Amlodipine / Q000627:therapeutic use; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D000074049:Cytokine TWEAK; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000683:Serum Amyloid P-Component / Q000378:metabolism*; D013777:Tetrazoles / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D048069:Tumor Necrosis Factors / Q000097:blood*; D014421:Turkey; D014633:Valine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000068756:Valsartan; D014664:Vasodilation / Q000187:drug effects*; D000099153:Pentraxins
chemical_list: D017311:Amlodipine; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D002097:C-Reactive Protein; D002121:Calcium Channel Blockers; D000074049:Cytokine TWEAK; D000683:Serum Amyloid P-Component; D013777:Tetrazoles; D048069:Tumor Necrosis Factors; D014633:Valine; D000068756:Valsartan; D000099153:Pentraxins; C109743:TNFSF12 protein, human