Treatment targets in renal fibrosis

Abstract

Renal fibrosis is the principal process underlying the progression of chronic kidney disease (CKD) to endstage renal disease (ESRD). It is a relatively uniform response involving glomerulosclerosis, tubulointerstitial fibrosis and changes in renal vasculature (loss of glomerular and peritubular capillaries) (Figure 1). Of these, tubulointerstitial fibrosis has evolved as the most consistent predictor of an irreversible loss of renal function and progression to ESRD [1]. Mechanisms contributing to tubulointerstitial injury and tubular atrophy include glomerular proteinuria, chronic hypoxia, misdirected glomerular ultrafiltration, tubular protein leakage and direct toxic insults of e.g. drugs (reviewed in detail elsewhere [1–6]) . Direct or indirect tubulointerstitial injury via oxidative stress and various effector molecules trigger cellular responses like (i) tubular epithelial cell (TEC) apoptosis, (ii) activation of fibroblasts and their phenotypic switch to myofibroblasts, (iii) influx and/or proliferation of lymphocytes/macrophages, fibrocytes (the circulating fibroblast precursors), fibroblasts as well as (iv) epithelial-to-mesenchymal transition (EMT) of TECs. Renal fibrosis provides an excellent treatment target, since a large variety of pathophysiologically distinct diseases converge finally into this single process. However, we still do not have effective therapies, nor does such a therapy exist in most other types of organ fibrosis. Why? As part of the vital repair process, the regulation and redundancy in this system must be highly effective. The consequence is an amazingly complicated process that involves many cell types and mediators [1,2,4,5,7]. Not unexpectedly, monotherapeutic approaches, or even a combination of therapies, fail to completely stop the progression of renal fibrosis [8–10]. In addition, not all combination therapies can be additive [11]. When identifying new targets or validating potential therapeutic options, we are confronted with several problems: