Pirfenidone Slows Renal Function Decline in Patients with Focal Segmental Glomerulosclerosis

Abstract

Background and Objectives: Pirfenidone is an orally available antifibrotic agent that has shown benefit in animal models of pulmonary and renal fibrosis and in clinical trials of pulmonary fibrosis, multiple sclerosis, and hepatic cirrhosis. Our objective was to determine whether pirfenidone slows the loss of renal function in focal segmental glomerulosclerosis.Design, Setting, Participants, & Measurements: An open-label trial was performed to evaluate the safety and efficacy of pirfenidone in patients with idiopathic and postadaptive focal segmental glomerulosclerosis. The monthly change in estimated GFR, expressed as ml/min per 1.73 m 2 , was compared between the baseline period and the treatment period. During both periods, patients received angiotensin antagonist therapy if tolerated. Twenty-one patients were enrolled, and 18 patients completed a median of 13 mo of pirfenidone treatment.Results: The monthly change in GFR improved from a median of ؊0.61 ml/min per 1.73 m 2 (interquartile range ؊1.31 to ؊0.41) during the baseline period to ؊0.45 ml/min per 1.73 m 2 (interquartile range ؊0.78 to ؊0.16) with pirfenidone therapy. This change represents a median of 25% improvement in the rate of decline (P < 0.01). Pirfenidone had no effect on BP or proteinuria. Adverse events attributed to therapy included dyspepsia, sedation, and photosensitive dermatitis.Conclusions: It is concluded that pirfenidone is an attractive candidate for placebo-controlled trials in patients with progressive chronic kidney disease.

Focal Segmental Glomerulosclerosis

“…Many other agents have been tested in small trials or reported as case series, and they have been the subject of recent reviews (13,(108)(109)(110)(111). These agents include the following: adalimumab, an anti-TNF mAb (112); pirfenidone, an antifibrotic agent that suppresses TGF-b signaling (113); fresolimumab, an anti-TGF-b mAb (114); pulse steroids plus cyclophosphamide (115); and saquinivir (116). Achtar gel is unusual in that it was approved in the 1950s by the US Food and Drug Administration for nephrotic syndrome under criteria that were less stringent than required today.…”

“…Some of these therapies have some promise, including pirfenidone (113) and saquinivir (116). Other therapies that have been shown to be ineffective or even harmful include sirolimus (93), galactose (139), and adalimumab (mAb directed against TNF) (139).…”

Renal fibrosis is attenuated by targeted disruption of K Ca 3.1 potassium channels

“…In recent years, great efforts have been made to gain further insight into the mechanisms of fibrogenesis and several molecules with antifibrotic properties, such as bone morphogenic protein 7 (9), hepatocyte growth factor (10), and pirfenidone (11), have been proposed. According to current understanding, resident fibroblast activation and proliferation in the kidney is triggered by locally secreted fibrogenic chemokines including TGF␤ 1 , PDGF, CTGF, and bFGF.…”

Pathophysiology of the aging kidney and therapeutic interventions

“…97 Pirfenidone has been shown to exhibit anti-R-smad effects, 107 as well as beneficial effects on experimental renal disease 108,109 diabetic kidney disease 110 and focal segmental glomerulosclerosis. 111 (2) Counteract the TGF-b signaling pathway Counteracting the profibrotic TGF-b-smad signaling pathway by targeting other pathways is another anti-fibrosis strategy. The bone morphogenetic protein-7 (BMP7) and its associated molecules are well-established anti-fibrotic molecules.…”