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.
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.
Yilmaz
Mahmut Ilker
MI
Department of Nephrology, Gülhane School of Medicine, Ankara, Turkey.
Carrero
Juan Jesús
JJ
Martín-Ventura
Jose Luis
JL
Sonmez
Alper
A
Saglam
Mutlu
M
Celik
Turgay
T
Yaman
Halil
H
Yenicesu
Mujdat
M
Eyileten
Tayfun
T
Moreno
Juan Antonio
JA
Egido
Jesús
J
Blanco-Colio
Luis Miguel
LM
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
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