Table 1.
Antifibrotic strategies for treating CKD
| Agent | Setting | Primary outcome and/or results |
|---|---|---|
| Preclinical studies | ||
| Anti-TGF-β antibody | Leprdb/db diabetic mice3,4 | Reduction in plasma TGF-β1 levels, prevention of increases in plasma creatinine levels and glomerular mesangial matrix expansion, associated with decreased renal mRNAs encoding collagen IV and fbronectin |
| Anti-TGF-β antibody | Rats with chronic allograft rejection nephropathy5 | Reduction of proteinuria, attenuation of mononuclear cell infltration and interstitial fbrosis along with downregulation of mRNA levels of TGF-β1, TGF-β2, and proinfammatory cytokines, or with upregulation of mRNA levels of HGF, BMP-5, and BMP-7 |
| Anti-TGF-β antibody | Mice with STZ-induced diabetes12 | Prevention of glomerular hypertrophy, attenuated gain in kidney weight, and attenuation of increased mRNA levels of TGF-β1, type II TGF-β receptor, collagen I V, and fbronectin |
| Anti-TGF-β antibody | Rats with puromycin aminonucleoside nephropathy13 | Reduction of TGF-β isoform mRNA expression and collagen III production, and amelioration of histological sclerosis with low dose of antibody |
| Soluble β-glycan | Leprdb/db diabetic mice14 | Reduction in serum creatinine, albuminuria, and structural renal damage |
| siRNA for TGF-β type II receptor | Mice with UUO15 | Decreased TGF-β receptor and α-SMA overexpression at the mRNA level, collagen deposition, and fbrotic area |
| Tranilast | Rats with remnant kidney,28 rats with chronic cyclosporin-induced nephrotoxicity,29 hypertensive Ren-2 rats with STZ-induced diabetes,30 and rats with UUO31 | Inhibition of TGF-β-induced glomerulosclerosis and tubulointerstitial fbrosis, reduction in albuminuria and plasma creatinine, attenuation of macrophage accumulation, and decreased oxidative stress |
| Analogue of tranilast (FT061) | Rats with progressive diabetic nephropathy6 | Reduction of albuminuria |
| Analogue of tranilast (FT011) | 5/6 nephrectomized rats and rats with STZ-induced diabetic nephropathy35 | Reduction in proteinuria, infammation, and glomerulosclerosis |
| Pirfenidone | Leprdb/db diabetic mice25 and 5/6 nephrectomized rats26 | Reduction in ECM accumulation and infammatory cell infltration |
| CTGF antisense oligonucleotide | Mice with STZ-induced diabetes19 and Leprdb/db diabetic mice19 | Reduction in CTGF mRNA expression, decreased proteinuria and albuminuria, attenuation in mRNA expression of fbronectin, and collagens I and IV |
| CTGF siRNA | Rats with chronic allograft rejection nephropathy20 | Reduction in mRNA CTGF expression, amelioration of serum creatinine level, reduction in mRNA expression of α-SMA and collagens I and IV |
| miR-21 | Leprdb/db diabetic mice39 | Amelioration of albuminuria, renal fbrosis, and infammation |
| Recombinant human BMP-7 | Mouse model of CKD44 | Decreased damage to renal tubular epithelial cells, in association with reversal of chronic renal injury |
| Exogenous HGF | Rats with remnant kidney,46,48,50 5/6 nephrectomized rats,52 and mice with STZ-induced diabetic nephropathy53 | Amelioration of renal fbrosis and tubulointerstitial collagen deposition; decreased renal infammation, glomerular hypertrophy, and sclerosis |
| Hgf gene transfection | Mouse model of chronic graft-versus-host disease49 | Prevention of proteinuria and histopathological changes associated with glomerulonephritis |
| Genetic deletion of CDA1 | Diabetic mice with CDA1 knockout55 | Reduction in ECM accumulation, decreased mRNA levels of TGF-β, TGF-β receptor, and Smad3 |
| Clinical studies | ||
| Anti-TGF-β antibody (fresolimumab) | Phase I Patients with primary steroid-resistant FSGS17 | Single dose was well tolerated |
| Anti-TGF-β antibody (LY2382770) | Phase II (ongoing) Patients with type 1 or type 2 diabetes mellitus and diabetic nephropathy16 | Change in serum creatinine levels from baseline to 12 months, results not yet reported |
| Tranilast | Phase I Patients with diabetic nephropathy32 | Amelioration of urinary excretion of type IV collagen and albumin |
| Analogue of tranilast (FT061) | Phase I Patients with type 2 diabetes mellitus and diabetic nephropathy36 | Reduction in proteinuria, infammation, and glomerulosclerosis |
| Pirfenidone | Phase I Patients with diabetic nephropathy27 | Encouraging results for increased mean eGFR but without improvement in proteinuria |
| Anti-CTGF monoclonal antibody (FG-3019) | Phase I Patients with diabetic nephropathy21 | FG-3019 was well tolerated and associated with decreased albuminuria |
| Anti-CTGF monoclonal antibody (FG-3019) and ACE inhibitors or ARBs | Phase I Patients with type 1 or type 2 diabetes mellitus and diabetic nephropathy22 | Safety and tolerability of two doses of FG-3019 administered for 12 weeks; results not yet reported |
| Anti-CTGF monoclonal antibody (FG-3019) | Phase II Patients with type 2 diabetes mellitus and diabetic nephropathy23 | To assess the effect of FG-3019 on proteinuria as assessed by urinary ACR, trial terminated |
| Anti-CTGF monoclonal antibody (FG-3019) | Phase I Patients with steroid-resistant FSGS24 | To assess safety and tolerability of FG3019; trial terminated |
Abbreviations: α-SMA, α smooth muscle actin; ACE, angiotensin-converting enzyme; ACR, albumin:creatinine ratio; ARB, angiotensin receptor blocker; BMP, bone morphogenetic protein; CDA1, cell division autoantigen 1; CKD, chronic kidney disease; CTGF, connective tissue growth factor; ECM, extracellular matrix; eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; HGF, hepatocyte growth factor; siRNA, small interfering RNA; Smad3, mothers against decapentaplegic homologue 3; STZ, streptozotocin; TGF-β, transforming growth factor β; UUO, unilateral ureteral obstruction.