Do we have a pill for renal fibrosis?

R enal fibrosis, characterized by glomerulosclerosis and tubulointerstitial fibrosis, is the final common pathway of a wide variety of chronic kidney diseases (CKD). Regardless of the underlying disorder and whether the injury is sustained, the kidney will follow a doomsday path of fibrogenesis, a condition characterized by excessive extracellular matrix accumulation. Can we do anything to slow the rate of functional decline associated with fibrotic renal diseases? This major challenge requires an understanding of the mechanisms involved in the pathogenesis of renal fibrosis. Doing so may allow us to develop new therapeutic targets to ameliorate disease directly and to identify those who are at risk for future disease. It should be stressed that renal fibrosis is a dynamic process in which many cellular events occur simultaneously, often in a mutually stimulating manner. These events include increased matrix production, inhibition of matrix degradation, modulation of matrix receptors to facilitate cell–matrix interactions, mesangial and fibroblast activation, tubular epithelial-to-mesenchymal transition, monocytic and lymphocytic cell infiltration, and cell apoptosis. It is also widely accepted that TGFand its downstream Smad signaling play an essential role in tissue fibrosis in general and in renal fibrosis in particular. Therefore, therapeutic targeting of TGFis seemingly critical and attractive and holds much hope for slowing or halting fibrosis. Attempts to block renal fibrosis have been successful in laboratory settings but have fallen short of the goal in clinical practice. The approach of limiting fibrosis through angiotensin II inhibition or antagonism has been exploited clinically, but the success has been limited. In the laboratory setting, some of the TGF–targeted therapies have included neutralizing antibodies, antisense oligonucleotides, and natural inhibitors such as the hormone relaxin and the proteoglycan decorin. However, these experimental interventions proved to be difficult to carry to the real world. It is for this reason that a great deal of interest has emerged when a relatively novel antifibrotic molecule, pirfenidone, was introduced (1). To make things better, it is a pill! Pirfenidone (5-methyl-N-phenyl-2-(1H)-pyridone) is a small, nonpeptide, orally available molecule that has been shown to prevent or even reverse excess matrix accumulation in experimental models, including pulmonary fibrosis (2), peritoneal sclerosis (3), cardiac fibrosis (4), and progressive renal diseases (5–8). The antifibrotic properties of pirfenidone are poorly understood. Pirfenidone has been shown to decrease TGF1 production and actions on matrix synthesis, to antagonize TNF, and to be a scavenger of reactive oxygen species. Moreover, pirfenidone may reduce the availability of hydroxyproline required for collagen synthesis and was shown to reduce fibroblast proliferation and macrophage infiltration. In a rat model of chronic cyclosporine nephrotoxicity, pirfenidone ameliorated interstitial fibrosis by approximately 50% and reduced TGF1 mRNA and protein expression in addition to decreasing plasminogen activator inhibitor-1 and other extracellular matrix proteins (5). It also affected the balance of apoptotic genes in a manner that favored antiapoptosis, resulting in downregulation of caspase activity (6). Similar results were previously observed in other progressive renal disease models, including the remnant kidney model (7), and in unilateral ureteral obstruction (8), a well-characterized model of tubulointerstitial fibrosis. The first clinical use of pirfenidone was in the setting of idiopathic pulmonary fibrosis (IPF). Two uncontrolled, openlabel studies of oral pirfenidone have been published. Raghu et al. (9) studied the drug in 54 patients with IPF and suggested that it may help to stabilize lung function. Nagai et al. (10) studied eight patients with IPF and noticed no deterioration in the chest radiographic scores and arterial oxygen pressure. Pirfenidone was also shown to slow the progression of lung impairment in a small group of patients with pulmonary fibrosis as a result of Hermansky-Pudlak syndrome (11). A recent randomized phase II trial in IPF showed a significant improvement in exercise-induced hypoxemia in pirfenidone-treated patients, but the study was aborted early because of an increase in acute exacerbations in the placebo group (12). Conversely, the results were discouraging in pilot studies involving patients with myelofibrosis (13) and in primary sclerosing cholangitis (14), whereas they were inconclusive in familial adenomatous polyposis (15). More recently, pirfenidone proved to be useful in a small group of patients with advanced liver fibrosis (16), in patients with secondary progressive multiple sclerosis (17), and in patients with neurofibromatosis type 1 (18). In addition, pirfenidone ameliorated radiation-induced fibrosis in seven patients who had undergone regional radiation therapy (19). In all of those studies, adverse effects that were attributable to the drug were relatively minimal and were mostly gastrointestinal (e.g., dyspepsia, nausea), sedation or fatigue, and a photosensitivity dermatitis. This issue of CJASN offers the first glimpse on the clinical Published online ahead of print. Publication date available at www.cjasn.org.