Modulation of advanced glycation end products by candesartan in patients with diabetic kidney disease--a dose-response relationship study.
Advanced glycation end products (AGEs) are proinflammatory mediators implicated in the pathogenesis of diabetic kidney disease (DKD). In this study, dose-dependent effects of angiotensin receptor blockade on urinary AGEs were evaluated in patients with DKD. Patients with type 2 diabetes and proteinuria ≥500 mg/d (n = 11) were compared with diabetic controls without DKD (n = 10) and normal controls (n = 11). After a 2-week washout period, DKD participants were treated with candesartan doses progressively increasing from 8, 16, 32, to 64 mg/d every 3 weeks for a total of 12 weeks. Other antihypertensive agents were adjusted to maintain stable blood pressure. At baseline and after each dosing period, blood pressure measurements and 24-hour urine collections were obtained. Urinary carboxymethyl lysine, an AGE biomarker, was reduced over the 12-week dose escalation protocol (r = 0.38, P = 0.01) in DKD participants. Creatinine clearance increased slightly, but albuminuria was unaffected by candesartan administration. Baseline urinary transforming growth factor-β₁ excretion was lower in DKD participants than in controls and did not change during the study period. Reducing kidney exposure to AGEs may be a mechanism of protection by angiotensin receptor blockade in DKD. AGEs may also impact the diabetic kidney through mechanisms independent of transforming growth factor-β₁.
Saha
Sandeep A
SA
Providence Medical Research Center, Sacred Heart Medical Center, Spokane, WA 99204, USA. sahas@u.washington.edu
LaSalle
Brian K
BK
Clifton
G Dennis
GD
Short
Robert A
RA
Tuttle
Katherine R
KR
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000652:urine
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D017127:Glycation End Products, Advanced; D013777:Tetrazoles; D053773:Transforming Growth Factor beta1; D003404:Creatinine; C081643:candesartan