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Cell-free donor-derived DNA – an outstanding tool for early detection of graft injury after kidney transplantation

Post-transplantation

Post-transplantation | December 7, 2022

Written by Dan Hauzenberg

Kidney transplantation is the best form of renal replacement therapy for patients with end-stage renal disease. Compared to dialysis, renal transplantation is associated with higher patient survival as well as superior quality of life (Vathsala 2005). However, one major clinical problem associated with kidney transplantation is the risk of allograft failure.

The major causes of allograft failure include acute and chronic rejection as well as non-immunological causes of graft loss such as surgical problems, renal vascular thrombosis, nephron injury due to various causes including ischemia-reperfusion and nephrotoxicity from calcineurin inhibitors (Vathsala 2005).

Matching patients and donors in solid organ transplantation to prevent graft rejections is an excellent example of the clinical implementation of precision medicine. Several immunological techniques have been developed to define the humoral (antibody-based) immunological status of the recipient prior to transplantation. These methods include cytotoxic crossmatch, flow cytometric crossmatch as well as detection of panel-reactive antibodies using solid-phase assays. Although many efforts are made to match patients and kidneys prior to transplantation to minimize the risk of immunological complications, early rejections may still occur even in the presence of negative lymphocyte cross-matches.

Acute rejection episodes are most prevalent in the first weeks after transplantation and can be categorized into T-cell-mediated rejection and antibody-mediated (ABMR) rejection. In TCMR, lymphocytes infiltrate and proliferate within the interstitial space. These lymphocytes may induce cytotoxic effects on the capillaries and renal tubular epithelial cells causing inflammation of the tubuli (tubulitis). Antibody-mediated rejection often presents as severe, refractory allograft dysfunction, which may be resistant to high doses of steroids and to anti-lymphocyte antibody therapy. Therefore, a prompt diagnosis of the presence and type of rejection is important for optimal treatment. Unfortunately, diagnostic assays for monitoring graft integrity after transplantation are still lacking, leaving laboratories and clinicians without sensitive tools for early detection of graft injury.

The current paradigm of detection of kidney transplant pathology, including graft rejection, depends upon repeated measurements of serum creatinine and complementary histologic assessment of kidney transplant biopsies. Serum creatinine is, however, a poor marker for the detection of rejection as it lags behind tissue injury thus leaving clinicians with fewer treatment options.

It has previously been shown in several studies, that donor-derived cell-free DNA (dd-cfDNA) can be detected in the urine and blood of kidney allograft recipients as a potential sign of allograft injury (Bloom et al 2017, Sigdel et al 2013 and Bromberg et al 2017). Studies also showed that dd-cfDNA concentrations increased markedly during acute rejection episodes, often before clinical diagnosis, and returned to reference values after antirejection treatment (Garcia Moreira, Prieto Garcia et al. 2009).

Taken together, dd-cfDNA has been suggested to be a surrogate marker for tissue damage in relation to graft rejection. Therefore, monitoring for increasing amounts of dd-cfDNA post-transplantation may serve as an important biomarker for follow-up of graft integrity after transplantation.

Since the process of immune activation, consecutive graft injury, and increase of currently used biomarkers, such as creatinine, remains unclear we were interested in performing a study that closely monitored kidney transplanted patients for the presence of dd-cDNA as a graft injury marker. We here present data that show that increase of dd-cfDNA may precede the increase of creatinine, caused by acute rejection, with as much as 5-7 days. This finding opens up the possibility of using the present novel diagnostic assay as a sensitive monitoring tool for graft injury. Since frequent monitoring appears to detect graft injury well before creatinine increases, this assay may prove to be an important new tool for the early detection of graft injury after kidney transplantation.

Vathsala, A. (2005). "Preventing renal transplant failure." Annals of the Academy of Medicine, Singapore 34(1): 36-43.

Bloom RD, Bromberg JS, Poggio ED, et al. Cell-free DNA and active rejection in kidney allografts. J Am Soc Nephrol. 2017;28:2221–2232.

Sigdel TK, Vitalone MJ, Tran TQ, et al. A rapid noninvasive assay for the detection of renal transplant injury. Transplantation. 2013;96:97–101.

Bromberg JS, Brennan DC, Poggio E, et al. Biological variation of donor- derived cell-free DNA in renal transplant recipients: clinical implications. J Appl Lab Med. 2017;2:309–321.

Garcia Moreira, V., B. Prieto Garcia, J. M. Baltar Martin, F. Ortega Suarez and F. V. Alvarez (2009). "Cell-free DNA as a noninvasive acute rejection marker in renal transplantation." Clinical Chemistry 55(11): 1958-1966.

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