Anti-fibrotic treatments: A review of clinical evidence

Highlights

• We review emerging anti-fibrotic drugs that demonstrated efficacy in experimental models and proceeded to clinical trials

• We discuss possible explanations that may potentially account for clinical trial failures

• We propose alternative therapeutic options by coupling anti-fibrotic treatments with drugs to enhance tissue regeneration

Abstract

Renal fibrosis is a condition characterized by excessive extracellular matrix accumulation in the kidney. Representing the final common result of a variety of injuries, it can lead to chronic kidney disease and end-stage renal disease. Although major efforts have been made in understanding the process of renal fibrosis, attempts to halt its progression have been successful only in a laboratory setting with limited success in clinical practice. Here, we review the current knowledge on the process of renal fibrogenesis and the emerging anti-fibrotic drugs that have shown encouraging results in experimental models and were subsequently tested in clinical trials. We also propose possible explanations that may account for clinical trial failures and poor translation outcomes. Finally, we discuss alternative therapeutic options and future directions in which anti-fibrotic treatments may be coupled with drugs that can enhance endogenous tissue regeneration.

Introduction

Renal fibrosis is a dynamic and converging process that consists of different overlapping phases of the essential process of wound healing and that leads to the formation of excessive fibrous connective tissue in the kidney during a reparative or reactive process [1]. Indeed, following an initial insult, the affected kidney undergoes a series of events in an attempt to repair and recover from the damage. Initially, fibrosis maintains the three dimensional stability and functionality of the remnant nephrons, but in severe and/or chronic renal injury, fibrosis has been recognized to sustain pathological responses in the functioning units of the kidney. Major cellular events in renal fibrosis include infiltration of inflammatory cells; fibroblast activation and expansion; production and deposition of extracellular matrix (ECM) components; tubular atrophy and microvascular rarefaction (Fig. 1). Fibrosis can occur in the tubular interstitium, and is then referred as “tubulointerstitial fibrosis” or in the glomerulus, where it is defined as “glomerulosclerosis”. In many aspects, major fibrogenic mechanisms are shared by different tissue compartments in the kidney. The established lesions of renal fibrosis have been considered to be permanent, but a reversal of glomerulosclerosis in patients with diabetic nephropathy has been previously reported [2], showing that human kidney has the potential to obtain a substantial architectural remodeling of the glomerular and tubular structures toward healing. Based on these observations, many efforts have been made to definitely understand the underlying pathways responsible for fibrogenesis [3], thus achieving remarkable insights in the identification of critical players and of molecular mechanisms that lead to the transcriptional activation of genes involved in the fibrotic process. Renal fibrosis is consistently associated with chronic kidney disease (CKD) which, with a very high prevalence among the population, poses one of the most serious health problems in current medicine as well as a serious economic burden to society [4]. Therefore, blocking fibrosis and its progression appears as an attractive possibility to delay CKD progression.

Here, we review ongoing and concluded clinical trials focusing particularly on compounds with either a direct or an indirect anti-fibrotic effect (Table 1). We also review prematurely terminated clinical trials highlighting the adverse effects or the reasons for discontinuation (Table 2). Finally, we discuss the potential pitfalls and shortcomings in translational research and propose some potential solutions for future research and development.