**4. Chronic Allograft Dysfunction (CAD)**

Chronic allograft dysfunction is the main cause of long-term graft loss [147].

Different entities can be accounted for this picture, with chronic ABMR (cABMR) playing a predominant role in most cases [148].

However, other components can be represented by CNI nephrotoxicity, PVAN, de novo or relapsing glomerulonephritis. Many studies have focused on biomarkers for late graft dysfunction as a global entity, while others have tried to identify specific biomarkers to dissect each of these components.

In general, defining specific biomarkers for CAD is difficult, because molecular fingerprints of acute and chronic rejection are overlapping, partly reflecting similar mechanisms. Some authors propose a "threshold effect", with AR developing when intensity of alterations is high and chronic rejection expressing a less important degree of alterations [2]. For example, Complement is not only involved in ABMR, as described in a previous paragraph, but also plays a pivotal role as mediator of tubular senescence [28,30,149] and interstitial fibrosis, premature aging phenomena that characterize progression to chronic damage [150]. C3a, C5a, and the terminal C5b-9 complex can each amplify damage during CKD progression. Anaphylatoxins bind to their specific receptors inducing pro-inflammatory and fibrogenic activity on tubular and endothelial cells [151,152], pericytes [153], and resident fibroblasts, whereas C5b-9 complex can regulate production of pro-fibrotic and pro-inflammatory cytokines [97]. Collectively, these data indicate that uncontrolled Complement activation may result in maladaptive tissue repair with irreversible development of renal fibrosis and aging. Identification of biomarkers of CAD is therefore challenging due to coexistence of acute and chronic processes, but it would be extremely useful for a differential diagnosis [154].
