Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-β levels

Agarwal, Rajiv; Senthuran, Siva; Dunn, Stephen; Sharma, Kumar

doi:10.1053/ajkd.2002.31392

Cited by 106 publications

(74 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…20 Similarly, in an animal model pirfenidone conferred a benefit to glomerular histology and reduced gene expression of matrix molecules in the diabetic db/db mouse without lowering albuminuria. 19 Urine levels of TGF-␤ have been found to be increased in patients with diabetic nephropathy 12,29,30 and may reflect ongoing renal production. 12 However, in the study presentedhereurinelevelsofTGF-␤werenotsignificantlyaffectedby pirfenidone; this may be due to the wide variability of urine levels in patients and/or the small sample size.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pirfenidone for Diabetic Nephropathy

Sharma¹,

Ix²,

Mathew³

et al. 2011

Journal of the American Society of Nephrology

Self Cite

271

148

View full text Add to dashboard Cite

Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebocontrolled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m 2 ). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (ϩ3.3 Ϯ 8.5 ml/min per 1.73 m 2 ) whereas the mean eGFR decreased in the placebo group (Ϫ2.2 Ϯ 4.8 ml/min per 1.73 m 2 ; P ϭ 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (Ϫ1.9 Ϯ 6.7 ml/min per 1.73 m 2 ). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P ϭ 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.

show abstract

Section: Discussionmentioning

confidence: 99%

“…FGF-23 was measured by a C-terminal ELISA assay (Immutopics, San Clemente, CA). Urine biomarkers included urine TGF-␤1 (measured by Quantikine, R&D Biosystems, as described previously 29 ). Urine albumin was measured by nephelometry and urine creatinine was measured by the Jaffe method.…”

Section: Biomarker Analysismentioning

confidence: 99%

Pirfenidone for Diabetic Nephropathy

Sharma¹,

Ix²,

Mathew³

et al. 2011

Journal of the American Society of Nephrology

Self Cite

271

148

View full text Add to dashboard Cite

show abstract

“…TGF-␤1 in urine was assayed by a method previously described and developed by Sharma and Dunn (www.jeffersonhospital.org/cdkd) (21). This assay uses a sandwich ELISA (Quantikine kit for Human TGF-␤1 Immunoassay; R&D Systems, Minneapolis, MN).…”

Section: Tgf-␤1 Measurementsmentioning

confidence: 99%

Stimulation of Urinary TGF-β and Isoprostanes in Response to Hyperglycemia in Humans

McGowan

Dunn

Falkner

et al. 2006

Clinical Journal of the American Society of Nephrology

Self Cite

View full text Add to dashboard Cite

TGF-␤ and oxidant stress have been considered to play key roles in the pathogenesis of diabetic vascular complications; however, the stimulus for these factors in humans is not clear. The purpose of this in vivo study was to determine whether transient hyperglycemia in humans is sufficient to increase renal production of TGF-␤1 and urinary isoprostanes in normal humans. A hyperglycemic clamp procedure was performed on 13 healthy volunteers. An infusion of glucose was delivered to maintain the plasma glucose between 200 and 250 mg/dl for 120 min. Timed urine samples, collected on an overnight period before the study, at each void on completion of the procedure, and the following overnight, were assayed for TGF-␤1, F2-isoprostanes, and creatinine. Plasma samples were assayed for TGF-␤1 before and at timed intervals throughout hyperglycemia. Mean baseline TGF-␤1 in plasma was 4.57 ؎ 0.22 ng/ml, and no change in plasma TGF-␤1 levels was detected throughout the hyperglycemia period. Baseline urine TGF-␤1 was 4.14 ؎ 1.16 pg/mg creatinine. The fractional urine samples showed a sharp increase in TGF-␤1 excretion in the 12-h period after exposure to hyperglycemia, with a mean peak TGF-␤1 of 30.43 ؎ 8.05 pg/mg (P ‫؍‬ 0.002). TGF-␤1 excretion in the subsequent overnight urine sample was not different from baseline (4.62 ؎ 1.21 pg/mg). Urinary isoprostanes increased from a baseline of 4.92 ؎ 0.74 to 13.8 ؎ 3.37 ng/mg creatinine. It is concluded that 120 min of hyperglycemia in normal humans is sufficient to induce an increase in renal TGF-␤1 and isoprostane production.

show abstract

“…In a heterogeneous group of 16 severely obese, hypertensive, proteinuric diabetic African Americans with advanced renal failure, addition of losartan 50 mg daily to lisinopril 40 mg daily had no short-term effect on blood pressure and proteinuria (38). However, subsequent analysis in the same patients of urinary excretion of the profibrotic growth factor transforming growth factor-␤ (TGF-␤) showed elevated urinary TGF-␤ during monoblockade with maximal doses of ACEI and a 38% reduction during addition of losartan that was independent of changes in blood pressure or albuminuria (39). The lack of antiproteinuric effects of dual blockade in this study may be due to underdosing of the ARB, because 100 mg losartan is more effective than 50 mg in reducing both albuminuria and blood pressure in patients with diabetic and nondiabetic nephropathy (40,41).…”

Section: Dual Ras Blockade Versus Maximal Ace Inhibitionmentioning

confidence: 99%

Renoprotective Effects of Adding Angiotensin II Receptor Blocker to Maximal Recommended Doses of ACE Inhibitor in Diabetic Nephropathy

et al. 2003

View full text Add to dashboard Cite

OBJECTIVE -We evaluated the renoprotective effects as reflected by short-term changes in albuminuria of dual blockade of the renin-angiotensin system (RAS) by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an ACE inhibitor (ACEI) in patients with type 2 diabetes and nephropathy. RESEARCH DESIGN AND METHODS -A total of 20 patients (17 men and 3 women)with type 2 diabetes along with hypertension and nephropathy were enrolled in this doubleblind, randomized, two-period, crossover trial of 8 weeks of treatment with the ARB candesartan 16 mg daily and placebo added in random order to existing treatment with lisinopril/enalapril 40 mg daily or captopril 150 mg daily. At the end of each treatment period, we evaluated albuminuria in three 24-h urinary collections by turbidimetry, 24-h ambulatory blood pressure (ABP) using the Takeda-TM2420, and glomerular filtration rate (GFR) by the 51 Cr-EDTA plasmaclearance technique.RESULTS -During monoblockade of the RAS by ACEI treatment, albuminuria was 706 (349Ϫ1,219) mg/24 h [geometric mean (IQR)]; 24-h ABP was 138 Ϯ 3/72 Ϯ 2 mmHg (mean Ϯ SE); and GFR was 77 Ϯ 6 ml ⅐ min Ϫ1 ⅐ 1.73 m Ϫ2 (mean Ϯ SE). During dual blockade of the RAS by addition of candesartan 16 mg daily, there was a mean (95% CI) reduction in albuminuria of 28 (17Ϫ38) compared with ACEI alone (P Ͻ 0.001). There was a modest reduction in systolic/ diastolic 24-h ABP of 3/2 mmHg (Ϫ2 to 8 systolic, Ϫ2 to 5 diastolic; NS). Changes in albuminuria did not correlate to changes in ABP. Addition of candesartan 16 mg daily induced a small, insignificant decrease in GFR of 4 (Ϫ1 to 9) ml ⅐ min -1 ⅐ 1.73 m -2 .CONCLUSIONS -Dual blockade of the RAS provides superior short-term renoprotection independent of systemic blood pressure changes in comparison with maximally recommended doses of ACEI in patients with type 2 diabetes as well as nephropathy. Diabetes Care 26:2268 -2274, 2003D iabetic nephropathy occurs in 30 -40% of all diabetic patients and has become the leading cause of endstage renal disease in the western world (1). In diabetic patients, albuminuria independently predicts poor renal and cardiovascular outcome (1). Several clinical studies have clearly demonstrated that blockade of the renin-angiotensin system (RAS), either by an ACE inhibitor (ACEI) or an angiotensin II receptor blocker (ARB), reduces albuminuria, retards the progressive loss in renal function, and improves survival (2-7). The antiproteinuric response upon blockade of the RAS has been demonstrated to predict the subsequent long-term rate of decrease in glomerular filtration rate (GFR), i.e., the greater the initial decrease in albuminuria, the less the long-term decrease in kidney function (8,9). Consequently, the short-term reduction in albuminuria may serve to monitor treatment efficacy and long-term prognosis in diabetic nephropathy, and it has previously been advocated that albuminuria should be reduced as far as possible to obtain maximal renoprotective effects (10).Despite the proven benefit of ...

show abstract

Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-β levels

Cited by 106 publications

References 30 publications

Pirfenidone for Diabetic Nephropathy

Pirfenidone for Diabetic Nephropathy

Stimulation of Urinary TGF-β and Isoprostanes in Response to Hyperglycemia in Humans

Renoprotective Effects of Adding Angiotensin II Receptor Blocker to Maximal Recommended Doses of ACE Inhibitor in Diabetic Nephropathy

Contact Info

Product

Resources

About