Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria.
OBJECTIVE
Soluble Klotho is an anti-aging phosphaturic protein associated with vascular-renal protection. In vitro and in vivo studies have demonstrated that renin-angiotensin system (RAS) blockade increases soluble Klotho levels. The effect of RAS blockers on soluble Klotho in patients with diabetic kidney disease (DKD) is unknown.


METHODS
Plasma-soluble Klotho was measured in a secondary analysis of a randomized controlled clinical trial performed at a single university hospital center (ClinicalTrials.gov number NCT001715, from March 2003 to September 2006). Seventy-six patients with type 2 diabetes and DKD (all with albuminuria and serum creatinine <1.7 mg/dl) were studied at baseline and at 24 weeks (study end) after randomization to valsartan/hydrochlorothiazide (n=37) or amlodipine (n=39) treatment. Aortic-pulse wave velocity by applanation tonometry and albuminuria (from three timed urine collections) were also measured at baseline and 24 weeks.


RESULTS
Valsartan/hydrochlorothiazide treatment significantly increased mean (± SD) soluble Klotho (from 432.7 ± 179 to 506.4 ± 226.8 pg/ml; P=0.01) and reduced serum phosphate (from 3.25 ± 1.18 to 2.60 ± 0.96 mg/dl; P=0.04) compared with amlodipine (from 430.1 ± 145.8 to 411.9 ± 157.6 pg/ml and from 2.94 ± 0.56 to 2.69 ± 1.52 mg/dl, respectively). There was a significant difference between treatment groups in soluble Klotho (mean 91.9 pg/ml; 95% confidence interval, 19.9 to 162) and serum phosphate levels (mean -0.68 mg/dl; 95% confidence interval, -0.15 to -1.33) with valsartan/hydrochlorothiazide treatment (P=0.03 and P=0.04, respectively). Attained BP was similar in the two groups and levels of soluble Klotho were not associated with aortic-pulse wave velocity and albuminuria, variables that fell significantly only with valsartan/hydrochlorothiazide.


CONCLUSIONS
Treatment with a RAS blocker, valsartan, is associated with an increase in soluble Klotho, which may contribute to the BP-independent cardiorenal benefits of these drugs in DKD.
Cardiovascular Division, King's College London, London, United Kingdom.
Janaka
J
Karalliedde
Giuseppe
G
Maltese
Benjamin
B
Hill
Giancarlo
G
Viberti
Luigi
L
Gnudi
D000368:Aged; D000419:Albuminuria / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D017311:Amlodipine / Q000627:therapeutic use; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000175:diagnosis / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D004232:Diuretics / Q000627:therapeutic use; D005260:Female; D005966:Glucuronidase / Q000097:blood*; D006785:Hospitals, University; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006973:Hypertension / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D000090265:Klotho Proteins; D008131:London; D008297:Male; D008875:Middle Aged; D010710:Phosphates / Q000097:blood; D063177:Pulse Wave Analysis; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013599:Systole; D013777:Tetrazoles / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan
D047228:Angiotensin II Type 1 Receptor Blockers; D015415:Biomarkers; D002121:Calcium Channel Blockers; D004232:Diuretics; D010710:Phosphates; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D017311:Amlodipine; D000068756:Valsartan; D005966:Glucuronidase; D000090265:Klotho Proteins; D014633:Valine