Renal transplant recipients may suffer serious consequences from graft rejection. We sought to develop an accurate, noninvasive test that can detect and distinguish acute cellular rejection (ACR), acute tubular necrosis (ATN), and other processes to allow early intervention.
We investigated expression patterns of 6 candidate markers of renal graft failure in 40 transplant recipients undergoing biopsy for suspected rejection. Four of these markers have been associated with ACR: the cytotoxic T lymphocyte markers PRF1 and GZMB; the regulatory T lymphocyte transcription factor FOXP3; and CXCL10 (IP10), a chemokine expressed in T lymphocytes and monocytes. The other 2, NK1 and NK3, are natural killer (NK) cell markers. RNA extracted from blood was reverse-transcribed for real-time PCR. Cycle threshold values were compared to a pooled control sample to give a relative quantity (RQ) for each marker normalized to 2 internal controls (CD3e, ABL1). RQ values above reference ranges, established from 120 health adults, were considered elevated. Biopsy documented ACR in 5 patients, ATN in 8, other processes in 35, and normal results in 2.
Results: ACR and ATN patients exhibited differential expression of ACR (CXCL10, FOXP3, GZMB, PRF1) and NK markers. 4 of 5 ACR patients had ≥1 elevated ACR marker relative to ABL1 and CD3e; 1 also had elevated NK3. All 8 ATN patients had elevated ABL1, and 7 had elevated CXCL10 relative to ABL1. All ATN patients had elevations in 3 or 4 ACR markers relative to CD3e. NK1 was markedly elevated relative to CD3e in 7 ATN patients, and NK3 in 6; 1 patient had normal levels of both. Few transplant recipients with other causes of rejection had marker elevations, and most were mild. 2 patients with normal biopsies had no elevated markers.
Taken together, information from markers of ACR and NK cells may help distinguish between ACR and ATN: Both ATN and ACR may be associated with elevations of ≥1 ACR marker. However, ATN is characterized by marked elevation of ABL1, NK1 or NK3, and ≥1 ACR marker, while ACR is generally characterized by normal levels of ABL1, NK1, and NK3.
Mikula, M.: Employee, Quest Diagnostics. Zhukov, O.: Employee, Quest Diagnostics. Hantash, F.: Employee, Quest Diagnostics. Zhang, K.: Employee, Quest Diagnostics. Rion, J.: Employee, Quest Diagnostics. Buller-Burckle, A.: Employee, Quest Diagnostics. Popov, J.: Employee, Quest Diagnostics. Sun, W.: Employee, Quest Diagnostics. Crossley, B.: Employee, Quest Diagnostics. Strom, C.: Employee, Quest Diagnostics. Naides, S.: Employee, Quest Diagnostics.
To cite this abstract in AMA style:Mikula M, Livingston K, Zhukov O, Hantash F, Zhang K, Rion J, Putheti P, Snopkowski C, Buller-Burckle A, Popov J, Sun W, Crossley B, Hernandez-Fuentes M, Sacks S, Suthanthiran M, Strom T, Strom C, Naides S. Molecular Markers To Distinguish Modes of Renal Graft Rejection [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/molecular-markers-to-distinguish-modes-of-renal-graft-rejection/. Accessed October 23, 2020.
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