Non-invasive Biomarkers of Acute Rejection in Kidney Transplantation: Novel Targets and Strategies

Abstract

Kidney transplantation is considered the favored treatment for patients suffering from end-stage renal disease, since successful transplantation is associated with longer survival and improved quality of life compared to dialysis. Alloreactive immune responses against the donor kidney may lead to acute rejection of the transplant. The current diagnosis of renal allograft rejection mainly relies on clinical monitoring, including serum creatinine, proteinuria, and confirmation by histopathologic assessment in the kidney transplant biopsy. These parameters have their limitations. Identification and validation of biomarkers, which correlate with or predict the presence of acute rejection, and which could improve therapeutic decision making, are priorities for the transplantation community. There is a need for alternative, less invasive but sensitive markers to diagnose acute graft rejection. Here, we provide an overview of the current status on research of biomarkers of acute kidney transplant rejection in blood and urine. We specifically discuss relatively novel research strategies in biomarker research, including transcriptomics and proteomics, and elaborate on donor-derived cell-free DNA as a potential biomarker.

Keywords: acute rejection; biomarker; cell-free DNA; kidney transplantation; non-invasive; proteomics; transcriptomics; transplant outcome.

Figure 1

Schematic overview of the timing of different graft-associated complications, starting from the time of transplantation to the moment of graft failure. M, month; DGF, delayed graft function, CNI, calcineurin inhibitor; BKVN, BK virus nephropathy.

Figure 2

Involvement of innate and adaptive immunity in development of damage to the transplant. Ischemia reperfusion injury (IRI) leads to induction of necrosis of tubular cells and release of damage associated molecular patterns (DAMPs), which are normally hidden within intact cells. DAMPs bind to Toll-like receptors (TLRs) on dendritic cells (DC) and induce their activation and maturation. The matured DC present donor-derived HLA antigens and co-stimulatory molecules to naïve T cells, which drives T cell differentiation into IFNγ producing TH1 cells. IFNγ can stimulate maturation of other DCs, induce macrophage activation and recruitment, and direct differentiation of CD8⁺ T cells. The recipient DCs are also able to capture and present donor HLA antigens, and thereby stimulate recipient CD8⁺ T cells. IRI can lead to induction of a local increase of complement component 3 (C3). Cleavage of C3 by the alterative pathway results in C3b deposition on the cell membrane and complement cascade activation. The small fragments C3a and C5a, released during complement activation, have pro-inflammatory effects. The formation of membrane attack complex (MAC) leads to target cell lysis and release of DAMPs.