Reduction of urinary connective tissue growth factor by Losartan in type 1 patients with diabetic nephropathy.
BACKGROUND
Connective tissue growth factor (CTGF) is an important profibrotic cytokine implicated in development of diabetic glomerulosclerosis. Urinary CTGF is reported to be significantly increased in patients with diabetic nephropathy. The present study aimed to investigate the short- and long term effects of angiotensin II receptor blockade by Losartan on urinary CTGF levels in hypertensive type 1 diabetic patients with diabetic nephropathy.


METHODS
Seventy-one hypertensive type 1 diabetic patients with diabetic nephropathy were included in the study. After a washout period of 4 weeks, the patients received Losartan 50 mg, 100 mg, and 150 mg once daily in treatment periods each lasting 2 months. Thereafter, patients were followed prospectively during treatment with Losartan 100 mg o.d. with a total mean follow-up time of 36 months. At baseline, after 2, 4, and 6 months and then biannually, urinary and plasma CTGF levels [enzyme linked immunosorbent assay (ELISA) fibroGen], albuminuria (Turbidimetry), glomerular filtration rate (GFR) [51-creatinine ethylenediaminetetraacetic acid ((51)Cr-EDTA plasma clearance)] and 24 hours blood pressure (TM2420)) were determined.


RESULTS
Baseline levels of urinary and plasma CTGF were 7076 (5708 to 8770) ng/24 hours [geometric mean (95% CI)] and 12.7 (7.3) ng/mL [mean (SD)], respectively. Albuminuria, GFR, and arterial blood pressure at baseline were 1152 (937 to 1416) mg/24 hours, 88 (24) mL/min/1.73 m(2), and 153/80 (17/9) mm Hg, respectively. Losartan significantly reduced urinary CTGF by 21% (9 to 31) (95% CI) initially (P < 0.05 vs. baseline), with no further reduction after increasing dose. The sustained reduction in urinary CTGF was 22% (12 to 32) (P < 0.05 vs. baseline). Rate of decline in GFR during the study was 3.2 (-1.6 to 15.9) mL/min/year [median (range)]. Reduction in urinary CTGF was correlated with a lower rate of decline in GFR (r= 0.23, P= 0.05). Plasma CTGF remained unchanged throughout the study.


CONCLUSIONS
Our 3-year study demonstrates that Losartan persistently reduces urinary CTGF excretion, which is associated with a slower rate of decline in GFR.
Andersen
Steen
S
Steno Diabetes Center, Gentofte, Denmark. stan@steno.dk
van Nieuwenhoven
Frans A
FA
Tarnow
Lise
L
Rossing
Peter
P
Rossing
Kasper
K
Wieten
Lotte
L
Goldschmeding
Roel
R
Parving
Hans-Henrik
HH
D000328:Adult; D055513:Connective Tissue Growth Factor; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000652:urine*; D003928:Diabetic Nephropathies / Q000652:urine*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D017874:Immediate-Early Proteins / Q000097:blood / Q000652:urine*; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000652:urine*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
C526317:CCN2 protein, human; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055513:Connective Tissue Growth Factor; D019808:Losartan