Clinical Chemistry
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Clinical Chemistry 55: 1958-1966, 2009. First published September 3, 2009; 10.1373/clinchem.2009.129072
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(Clinical Chemistry. 2009;55:1958-1966.)
© 2009 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Cell-Free DNA as a Noninvasive Acute Rejection Marker in Renal Transplantation

Vanessa García Moreira1, Belen Prieto García1, Jose M. Baltar Martín2, Francisco Ortega Suárez2 and Francisco V. Alvarez1,3,a

1 Biochemistry Laboratory and 2 Nephrology and Bone Metabolism Unit, Hospital Universitario Central de Asturias, Asturias, Spain; 3 Department of Biochemistry and Molecular Biology, Universidad de Oviedo, Asturias, Spain.

aAddress correspondence to this author at: Servicio de Bioquímica Clínica, Hospital Universitario Central de Asturias, 33006 Oviedo, Asturias, Spain. Fax 34-985108073; e-mail falvarezmen{at}gmail.com.

Background: Acute rejection (AR) is a key conditioning factor for long-term graft function and survival in renal transplantation patients. The standard care with creatinine measurements and biopsy upon allograft dysfunction implies that AR is usually detected at advanced stages. Rapid noninvasive biomarkers of rejection are needed to improve the management of these patients. We assessed whether total cell-free DNA (tCF-DNA) and donor-derived cell-free DNA (ddCF-DNA) were useful markers for this purpose, both in plasma and in urine.

Methods: Plasma and urine samples from 100 renal transplant recipients were obtained during the first 3 months after transplantation. tCF-DNA and ddCF-DNA were analyzed by quantitative PCR for the HBB (hemoglobin, beta) and the TSPY1 (testis specific protein, Y-linked 1) genes, respectively. We observed 19 episodes of AR, as well as other complications, such as acute tubular necrosis, nephrotoxicity, and infections.

Results: Plasma tCF-DNA concentrations increased markedly during AR episodes, often before clinical diagnosis, and returned to reference values after antirejection treatment. A cutoff plasma tCF-DNA concentration of 12 000 genome equivalents/mL correctly classified AR and non-AR episodes in 86% of posttransplantation complications (diagnostic sensitivity, 89%; specificity, 85%). Although similar increases were observed during severe posttransplantation infections, use of the combination of plasma tCF-DNA and procalcitonin (PCT), a specific marker of sepsis, significantly improved the diagnostic specificity (to 98%; 95% CI, 92%–100%), with 97% of the episodes being correctly classified. Use of transrenal DNA and ddCF-DNA concentrations did not add relevant information.

Conclusions: Given that renal biopsy is the gold standard for detecting AR, analysis of both plasma tCF-DNA and PCT could permit a more selective use of this invasive procedure.






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Copyright © 2009 by the American Association for Clinical Chemistry.