Antifibrotic Therapy (2013)

CKD is a major burden for the individual patient as well as for society in general. Whereas only 2% of all patients with CKD eventually reach the stage of dialysis dependency, cardiovascular risk rises steadily with the decline in kidney function, resulting in a robust increase in morbidity and mortality. Morphologically, chronic renal failure is most often characterized by glomerulosclerosis, tubular atrophy, and tubulointerstitial fibrosis, the latter often being the most prominent feature.1 Tubulointerstitial fibrosis consists of proliferation and activation of various cells to so-called myofibroblasts and synthesis of extracellular matrix by these cells. A long-standing controversy surrounds which cell type is the main precursor of these matrix-producing cells, including resident fibroblasts, fibrocytes, pericytes, endothelial cells, and epithelial cells. However, the individual contribution of these various cell types to myofibroblast formation may vary according to the method and model examined, pointing to a certain heterogeneity of these cells.2 However, once matrix-synthesizing myofibroblasts have been formed, renal interstitial fibrosis represents a final common pathway for a plethora of CKDs. Thus, renal interstitial fibrosis is a worthwhile target because antifibrotic therapy would make almost all patients with CKD suitable candidates for therapy. Moreover, antifibrotic therapy may also be of clinical importance in other organs, such as the lung and the liver. Initial antifibrotic strategies focused mainly on the neutralization of profibrotic cytokines or the application of antifibrotic cytokines.3 However, in recent years the focus of antifibrotic therapy has shifted to antioxidant therapy. Although oxidation was thought to be of primary importance for inflammatory processes, recent evidence has shown that it is also critical for organ fibrosis in general and the liver and the kidney in particular.4 Many of these potential therapeutical agents have been tested experimentally and clinically in diabetic kidney disease.5 One of the more interesting substances in this regard is pirfenidone, which has antifibrotic, anti-inflammatory, and antioxidant properties. The drug was used successfully to treat many fibrotic disorders, not only in the kidney but also in the lung and the liver. Furthermore, the drug has already been approved for use in patients with idiopathic pulmonary fibrosis; it is in clinical use in Europe but not the United States (the Food and Drug Administration has withdrawn approval in the United States). However, one clinical trial in patients with diabetic nephropathy gave only mixed results,6 whereas a second trial in patients with FSGS is still ongoing.7 Another interesting antioxidant and again antifibrotic agent is tranilast. This synthetic compound attenuates the induction of thioredoxin-interacting protein and oxidative stress. It is used as an antifibrotic agent in Southeast Asia for the treatment of keloid formation. In addition, the drug has been evaluated experimentally8 as well as clinically in diabetic nephropathy,9 although clinical use was confined to only a few patients. Pentoxifylline is a methylxanthine phosphodiesterase inhibitor that has been evaluated in more than 20 studies, mostly in patients with diabetic nephropathy. Unfortunately, most of these studies included only a handful of individuals and were of short duration.10 There was a tendency toward decreased serum creatinine values but no significant effects on proteinuria, and the current evidence does not support the use of the drug in patients with diabetic kidney disease.5 Another antioxidative and antifibrotic therapeutic agent is bardoxolone methyl. This synthetic compound is an antioxidant that mediates at least part of its effects by induction of nuclear factor erythroid 2–related factor 2, a transcription factor that downregulates NF-κB signaling, resulting in a robust decrease in inflammatory response. The drug was very effective in the initial BEAM (Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes) phase 2b trial during 24 weeks in patients with diabetic nephropathy.11 However, the large subsequent phase 3 BEACON (Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events) trial had to be terminated because of an increase in serious adverse effects, including an increased mortality rate.12 The premature termination of this trial raised many questions, including the design of experimental studies before embarking on a clinical trial and advocation of a more careful approach in clinical studies with novel compounds.13 Despite the failure of bardoxolone, the potential of antioxidative therapy in CKD in animal models is evident; however, the definite clinical efficacy of any of these antioxidant therapies has yet to be demonstrated. Now comes another antioxidant therapy. In this issue of JASN, Okamura and colleagues describe the effects of the antioxidant cysteamine bitartrate as a potential antifibrotic agent.14 Cysteamine bitartrate is an established agent for patients with nephropathic cystinosis, a rare autosomal recessive lysosomal storage disease, but it may have potential in other diseases, such as chronic liver disease, neurodegenerative disease, and even cancer. The authors tested the drug in two established models of chronic progressive renal disease: the model of unilateral ureteral obstruction and the renal ischemia reperfusion model. Animals treated with cysteamine bitartrate did have considerably less renal interstitial fibrosis compared with sham-treated animals, although matrix accumulation could not be inhibited completely. The authors carefully analyzed the dosing but were able to achieve drug levels considered therapeutic in patients only at night. Thus, a higher dose associated with higher levels of the drug could be even more effective as an antifibrotic agent. In this regard, it is also noteworthy that a new enteric-coated form of cysteamine may decrease the dosing frequency in patients. A second set of experiments tested the effects of cysteamine in an ischemia reperfusion injury model. The antifibrotic effects were even more robust despite a delay in therapy of 10 days after ischemia-inducing injury. This experimental delay is very important because it better mimics the clinical situation, in which the patient is usually identified only after fibrosis is already present. Still, it would have been even more convincing had the delay in therapy been tested in the more chronic model of unilateral ureteral obstruction. What is the mechanism of action of cysteamine bitartrate? Being an antioxidative agent suggests that this mechanism is the most important. Accordingly, the potential antioxidant thiol was increased by more than 50%, but only on day 7—not at the later time points. Similarly, carbonylated protein levels were decreased in cysteamine bitartrate–treated animals; however, this decrease, despite being robust at 48%, was not significant at the 14-day time point. Conversely, inhibition of the enzyme tissue transglutaminase 2 could not explain the antifibrotic effects of the drug because there was no difference between treated and control animals. The main therapeutic effect of cysteamine seems to be the inhibition of fibroblast proliferation and activation. This was shown very nicely in in vivo and in vitro studies using NRK 49F fibroblasts. The effects were cell type–specific for myofibroblast precursors because they could be reproduced in pericyte-derived fibroblasts but not in tubular epithelial cells. In addition, some inhibition of macrophage accumulation was observed, although treatment did not affect the synthesis of cytokines. There was, however, a reduced generation of reactive oxygen species. Clearly, more studies are needed to confirm the status of cysteamine as a novel antifibrotic agent. In addition, the recent experience with bardoxolone should caution against a premature clinical trial. Still, cysteamine is one of the better hopes for an effective antifibrotic therapy in the relatively near future, and the authors should be applauded for bringing us this hope. Disclosures None.