Belumosudil for Abrogation of Interstitial Fibrosis and Tubular Atrophy Following Kidney Transplantation

Of the 16,521 adult kidney transplants in 2008, death-censored graft loss occurred in 16% of deceased donor kidneys and 7% of living donor kidneys in the ensuing 5 years and has not largely changed in a decade. A majority of this graft loss is presumed to be from IF/TA, previously termed chronic allograft nephropathy. Various causes of injury to the kidney stimulate inflammatory processes. When the inflammation continues (ie, becomes chronic), changes occur in the kidney structure, specifically in the glomerulus and tubular interstitium which leads to fibrosis and a progressive decline in kidney function. Interstitial fibrosis and tubular atrophy almost invariably occur together and are present in approximately 45% of early indication kidney biopsies by the first year posttransplant. No risk factors have been identified to predict who will experience IF/TA. Combined, IF/TA contributes to renal graft dysfunction or the decline in kidney function after transplantation and may be a factor in the 20.6% of total grafts lost (including death) by 5 years post-transplant. Expansion of the interstitial compartment is a major component of IF/TA. Protocol and for-cause biopsies have provided evidence of the worsening of IF/TA with time in kidney transplant recipients and demonstrated a direct relationship between interstitial expansion and renal allograft functional decline and graft failure. Interstitial expansion will be assessed as the overall proportion of cortical tissue area associated with IF/TA. Previous work has shown that chronic rejection depends on macrophage movement to the graft, which is regulated by actin cytoskeleton controlled by the small GTPase RhoA/Rock pathway. Pharmacologic inhibition or macrophage-specific deletion of RhoA prevents chronic rejection in the rodent cardiac transplantation model, and belumosudil was superior in preventing fibrosis. Controlling hypertension and prevention and treatment of acute rejection are standard approaches to kidney function preservation in kidney transplant recipients. Additionally, the use of CNI-sparing protocols has been reported with various approaches but data are insufficient to equivocally demonstrate consistently lower IF/TA in the approaches reported to date. Thus, it is important to examine additional approaches for prevention of IF/TA in this population. This study will test the hypothesis that abrogating the fibrogenic effects of the RhoA pathway with belumosudil would abbrograte IF/TA and that reducing this structural damage in transplanted kidneys would result in improved or preserved kidney function and reduced graft loss. The purpose of this study is to demonstrate that 200mg/day of belumosudil for 12 months administered to de novo kidney transplant recipients will be safe and to examine the course of IF/TA over a 1-year period by testing the ability of 200mg/day belumosudil for 12 months to abrograte the development of IF/TA in de novo kidney transplant recipients compared to placebo.