Pirfenidone for Diabetic Nephropathy

Abstract

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.

Mechanisms and Treatment of CKD

“…66 Other Pathways Drugs are also being developed that may reduce renal disease progression targeting mechanisms downstream of proteinuria. In this line, pirfenidone, a TGF-b inhibitor, reduced renal function loss in small studies with FSGS 108 or diabetes 109 patients, but the high rate of dropouts raised serious concerns about the safety of this compound in particular in patients with diabetes. Bardoxolone methyl is an antioxidant and anti-inflammatory molecule that in a large trial of 227 diabetic patients with GFR ,45 ml/min per 1.73 m 2 increased estimated GFR over placebo in a dosedependent fashion.…”

PGD2-CRTH2 Pathway Promotes Tubulointerstitial Fibrosis

“…[1][2][3] It is noteworthy that some clinical trials are proving that antifibrotic therapies, such as pirfenidone against diabetic nephropathy, 4 are also effective for CKD. Therefore, elucidating the etiological mechanism underlying renal fibrosis and developing novel therapeutic strategies remains a serious, unmet medical need.…”

Drugs for Diabetic Nephropathy- Full Review

“…Also additional renoprotection can be offered when combined with angiotensin II receptor antagonist losartan [130,140] www.wjpps.com 2) Several blocking Abs against TGFβ reduce mesangial matrix accumulation and glomerulosclerosis in diabetic mouse model [75,132] 3) TGF-AY1Ab is in clinical development for the treatment of chronic kidney diseases with focus on diabetic nephropathy. [90] DRUGS-Pirfenidone [133] , Tranilast [134,135] , fresolimumab. [136,137] TGFβ BLOCKERS-have been tested in animal models but human study yet to be tested [138,139] Fresolimumab, tranilast-reduces proteinuria.…”