Combating Chronic Renal Allograft Dysfunction : Optimal Immunosuppressive Regimens

Kidney transplantation is the best treatment for patients with end-stage renal disease, both in terms of survival benefit and quality of life. The major limitation is the continuing shortage of kidneys suitable for transplantation, reinforcing the need to maximise graft survival. After the first year of transplantation, chronic renal allograft dysfunction (CRAD) is the first cause of late graft deterioration and failure. CRAD has been defined as a progressive renal dysfunction, independent of acute rejection, drug toxicity and recurrent or de novo nephropathy, with features on biopsy of chronic allograft nephropathy (CAN) characterised by vascular intimal hyperplasia, tubular atrophy, interstitial fibrosis and chronic transplant glomerulopathy. Protocol biopsy-based studies have demonstrated a high and early prevalence of CAN lesions during the first year in patients with normal and stable renal function. Beyond 1 year, the injuries associated with calcineurin inhibitors (CNIs) appear to be very common. The physiopathology of CRAD is complex and multifactorial. Both alloantigen-dependent factors (acute rejection, HLA matching, donor-specific antibodies, inadequate immunosuppression) and alloantigen-independent factors (donor age, brain death, ischaemia/reperfusion injuries, hypertension, hyperlipidaemia, cytomegalovirus, CNI-related nephrotoxicity) are involved. Consequently, CRAD appears as a dynamic process, evolving with time, and immunosuppressive regimens need to be modulated in order to provide the most suitable treatment at the different phases of its natural history. On the basis of this scheme, the new paradigm would be the use of a CNI-based regimen during the period of maximal risk of (subclinical) acute rejection, followed by a conversion to a CNI-free regimen in order to avoid the long-term consequences of nephrotoxicity. Fortunately, new agents are being introduced in clinical practice providing a large range of combinations and allowing individualisation of immunosuppressive regimens. Large, prospective, multicentre trials are warranted, and the challenge is to define new endpoints of CRAD and to determine the best therapeutic strategy.