Looking for the needle in the kidney transplantation haystack

The diagnosis of acute rejection still relies on renal allograft biopsy. In fact, histological features including C4d staining can be useful to differentiate cellular and antibody-mediated acute rejection. However, the pathogenic mechanism to define the type of rejection is usually assessed by anti-HLA donor specific antibodies (DSA) monitoring. Suspicion of acute rejection is usually based on renal function deterioration. This method has low sensitivity. Moreover, creatinine increase follows graft injury and therefore the diagnosis is performed when there is an ongoing acute rejection. One strategy to overcome the limitation of serum creatinine as predictor of acute rejection is to perform surveillance protocol biopsies. However, the low incidence of subclinical acute rejection among patients treated with tacrolimus-based immunosuppression makes this procedure questionable in terms of cost-effectiveness. In this scenario new biomarkers predicting acute rejection are urgently needed. Ideally, such biomarkers should anticipate acute rejection, thus allowing preventive actions such as maintenance immunosupression intensification and/or modification. Alternatively, these new biomarkers should at least improve the predictive value of serum creatinine monitoring. Although many of the new biomarkers are promising, none have been translated to the clinic to date because of a lack of validation studies and the existence of major methodological concerns.