Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Abstract

New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a “molecular” diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of “immunoquiescent” or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.

BK Polyomavirus Nephropathy in Kidney Transplantation: Balancing Rejection and Infection

“…The challenge faced during biomarker development of BKVN is the overlapping pathogenetic mechanisms of BKVN with other allograft injuries, such as rejection and tubular interstitial fibrosis. There are still no mature biomarkers yet and need future research for clinical monitoring and guiding optimal IS adjustment [ 141 ].…”

A novel genomic model for predicting the likelihood of delayed graft function in DCD kidney transplantation

“…This may attribute to the following reasons. First, the optimal sample types (kidney tissue, serum, urine, perfusate or preservation fluid) and sampling timepoint (before organ retrieval, pretransplant or postreperfusion) for DGF prediction are currently disputable (24). Given that DGF occurs in the context of IRI, the biomarkers or models identified based on the samples taken from donors or allografts before organ retrieval or pretransplant might not fully reflect the actual renal damage caused by ischemia or reperfusion (25,26).…”

Acute Kidney Injury (AKI) before and after Kidney Transplantation: Causes, Medical Approach, and Implications for the Long-Term Outcomes

“…Complement modulation of klotho was found to contribute to DGF-associated chronic allograft disfunction. On the other hand, more recently, several studies showed that complement factors might directly trigger fibrogenesis, by inducing tubular apoptosis, endothelial-to-mesenchymal transition, pericytes-to-mesenchymal transition, and accelerated senescence [ 35 , 36 , 37 , 38 ].…”

“…Monitoring of DGF in transplanted kidneys has been traditionally based on a combination of clinical (e.g., serum creatinine, urinary output), immunological (e.g., donor-specific antibodies, DSA), instrumental (e.g., resistive index at Doppler ultrasound), and histological parameters. Because of the limits and the complexity of the “traditional biomarkers”, over the last decade, new biomarkers have been introduced that can be easily measured in biological fluids, such as perfusion solution, patient’s serum, plasma, or urine [ 37 ]. Among them, those that can be measured in graft preservation fluid or in the perfusate of machine-perfused kidneys, have been proposed for organ allocation [ 39 ], and those that are measured in the recipient at the time of transplantation have been proposed to predict the occurrence of DGF and graft function recovery.…”