Treatment of Renal Fibrosis—Turning Challenges into Opportunities

Current treatment modalities are not effective in halting the progression of most CKD. Renal fibrosis is a pathological process common to all CKD and thereby represents an excellent treatment target. A large number of molecular pathways involved in renal fibrosis were identified in preclinical studies, some of them being similar among different organs and some with available drugs in various phases of clinical testing. Yet only few clinical trials with antifibrotic drugs are being conducted in CKD patients. Here we review those clinical trials, focusing on agents with direct antifibrotic effects, with particular focus on pirfenidone and neutralizing antibodies directed against profibrotic growth factors and cell connection proteins. We discuss the potential reasons for the poor translation in treatment of renal fibrosis and propose possible approaches and future developments to improve it, eg, patient selection and companion diagnostics, specific and sensitive biomarkers as novel end points for clinical trials, and drug-targeting and theranostics. Current treatment modalities are not effective in halting the progression of most CKD. Renal fibrosis is a pathological process common to all CKD and thereby represents an excellent treatment target. A large number of molecular pathways involved in renal fibrosis were identified in preclinical studies, some of them being similar among different organs and some with available drugs in various phases of clinical testing. Yet only few clinical trials with antifibrotic drugs are being conducted in CKD patients. Here we review those clinical trials, focusing on agents with direct antifibrotic effects, with particular focus on pirfenidone and neutralizing antibodies directed against profibrotic growth factors and cell connection proteins. We discuss the potential reasons for the poor translation in treatment of renal fibrosis and propose possible approaches and future developments to improve it, eg, patient selection and companion diagnostics, specific and sensitive biomarkers as novel end points for clinical trials, and drug-targeting and theranostics. Clinical Summary•There are currently no drugs for CKD and fibrosis in clinical use that would specifically target the kidney.•Despite a number of potential anti-fibrotic treatment targets identified in preclinical studies, translation to clinical trials has remained remarkably poor.•Poor translation is due to several challenges in performing clinical trials in CKD and renal fibrosis, particularly due to the lack of short-term fibrosis-specific surrogate end-points for clinical trials, insufficient patient selection or lack of companion diagnostics.•Given the world-wide burden of CKD, overcoming these translational challenges and improving drug development should be one of the research priorities for the future. •There are currently no drugs for CKD and fibrosis in clinical use that would specifically target the kidney.•Despite a number of potential anti-fibrotic treatment targets identified in preclinical studies, translation to clinical trials has remained remarkably poor.•Poor translation is due to several challenges in performing clinical trials in CKD and renal fibrosis, particularly due to the lack of short-term fibrosis-specific surrogate end-points for clinical trials, insufficient patient selection or lack of companion diagnostics.•Given the world-wide burden of CKD, overcoming these translational challenges and improving drug development should be one of the research priorities for the future.