Pathogenesis and Preventive Strategies of Chronic Dysfunction of Renal Allograft

Novel immunosuppressants have decreased the incidence rate of acute rejection significantly, but fail to prevent chronic allograft dysfunction (CAD). Around 40% patients develop CAD gradually in several months or several years after renal transplantation. They present with progressive deterioration of long-term allograft function and allograft failure, and end up with resuming dialysis. It has also been demonstrated that CAD may increase the cardiovascular mortality after renal transplantation. Therefore, it is crucial for promoting long-term allograft survival to investigate the pathogenesis and preventive and therapeutic strategies of CAD. CAD, formerly termed chronic rejection (CR), is also known as late graft loss (LGI) or chronic allograft nephropathy (CAN), since it involves both immune factors (transplantation antigen dependent) and non-immune factors (transplantation antigen independent). CAD refers to progressive functional impairment of allograft, with pathologic changes including tubular atrophy, interstitial fibrosis, progressive glomerulosclerosis, and arterial fibrous intimal thickening and arteriole hyalinosis. These pathologic changes include immune and non-immune injury to allograft. Chronic rejection is usually associated with acute rejection or subclinical rejection, HLA mismatch, panel reactive antibodies (PRA), and donor specific antibodies (DSA). In contrast, non-immune allograft injury is usually associated with calcineurin inhibitors (CNI), preexisting delayed graft function (DGF), hypertension, hyperlipidemia, proteinuria, viral infection, chronic obstruction and chronic pyelonephritis. In addition, CAD includes recurrent kidney disease, de novo nephritis, posttransplantation lymphoproliferative diseases (PTLD). Many of the above-mentioned factors that lead to CAD usually exist simultaneously; thus, the pathologic manifestations of CAD are complex and not specific, making the treatment of CAD difficult. In short, there are many factors influencing the incidence and development of CAD, and the pathogenesis of CAD remains largely unclear. Microcirculation injury mediated by donor specific antibodies is thought to be the major cause for long-term allograft dysfunction.