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Renal Transplant Monitoring

Renal Transplant Monitoring

Test Summary

Renal Transplant Monitoring (FOXP3, Granzyme B,
Perforin, IP10)

  

Clinical Use

  • Assess risk of acute cellular rejection in renal transplant patients

Clinical Background

Acute cellular rejection (ACR) is an important risk factor for renal graft failure.1 ACR affects 10% to 12% of transplant recipients, making it the most common serious complication of renal transplants.2,3 In ACR, activated cytotoxic T lymphocytes from the host infiltrate the transplanted kidney and cause tissue damage and dysfunction.4,5 Prompt diagnosis could direct appropriate changes in immunosuppressant therapy before significant damage has occurred, which can improve graft outcomes.

ACR diagnosis is currently based on histologic examination of biopsy specimens, which is usually performed when creatinine levels rise above the reference range. However, by this point graft damage has already occurred.6 Studies have shown that graft outcomes can be improved through use of frequent scheduled biopsies that detect ACR before clinical signs appear.6,7 However, biopsy is invasive and not ideal for routine monitoring because of the potential for complications such as bleeding, arteriovenous fistula, and graft loss.8 Accurate noninvasive tests for ACR are thus needed.

Promising noninvasive markers include mRNA transcripts of genes that code for granzyme B and perforin, which are found in activated cytotoxic T lymphocytes, and the T-cell regulatory protein FOXP3.5,8-11 Elevated blood mRNA levels have been used to detect ACR in patients with delayed graft function. Sensitivity ranges from 88% to 100% and specificity ranges from 75% to 95%, depending on the marker.10 Elevated blood mRNA levels of CXCL10, the gene that encodes interferon-gamma-inducible protein 10 (IP10), have also been associated with ACR.12 The Renal Transplant Monitoring test measures blood concentrations of mRNA transcripts of the genes coding for FOXP3, granzyme B, perforin, and IP10.

Individuals Suitable for Testing

  • Those who received a renal transplant in the last 6 months.13

Method

  • Quantitative real-time reverse-transcription PCR amplification of the following:

–  Marker gene mRNA (FOXP3 [FOXP3], GZMB [granzyme B], PRF1 [perforin], and CXCL10 [IP10])

–  Normalizer gene mRNA (CD3e, a T-cell marker; and ABL1, a pan-cell marker)

  • Results reported: relative quantity (RQ) of each marker gene mRNA to each normalizer gene mRNA

Reference Ranges
Marker (Protein) Marker (Gene) Reference Range (RQ) with CD3e Normalizer Reference Range (RQ) with ABL1 Normalizer
FOXP3 FOXP3 0.5-1.8 0.5-1.7
Granzyme B GZMB 0.3-2.4 0.3-2.0
Perforin PRF1 0.4-2.2 0.4-1.9
IP10 CXCL10 0.1-1.1 0.1-1.2


Reference ranges are defined as RQ values within the 95% confidence intervals established in apparently healthy adults.

Interpretive Information

Markers with RQ values above the reference range, using either normalizer gene, are considered elevated. Increased blood mRNA levels of individual marker genes have been associated with biopsy-confirmed ACR.9,10,12

Based on a small study of 21 patients undergoing biopsy for possible ACR, elevation in ≥2 markers may be associated with ACR (Quest Diagnostics data on file). The clinical relevance of RQ values below the reference range has not been established.

References

  1. Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000;342:605-612.

  2. Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients
    (SRTR). OPTN/SRTR 2010 Annual Data Report. Department of Health and Human Services; 2011:9-32. http://www.srtr.org/annual_reports/2010/flash/00_full/index.html#/8/. Published December 19, 2011.
    Accessed March 21, 2012.

  3. Cecka JM, Terasaki PI. The UNOS Scientific Renal Transplant Registry. In: Terasaki PI, Cecka JM, eds. Clinical Transplants 1992. Los Angeles, CA: UCLA Tissue Typing Laboratory; 1992:1-16.

  4. Avihingsanon Y, Ma N, Pavlakis M, et al. On the intraoperative molecular status of renal allografts after vascular reperfusion and clinical outcomes. J Am Soc Nephrol. 2005;16:1542-1548.

  5. Hartono C, Muthukumar T, Suthanthiran M. Noninvasive diagnosis of acute rejection of renal allografts. Curr Opin Organ Transplant. 2010;15:35-41.

  6. Strom TB. Rejection—more than the eye can see. N Engl J Med. 2005;353:2394-2396.

  7. Rush D, Nickerson P, Gough J, et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol. 1998;9:2129-2134.

  8. Muthukumar T, Dadhania D, Ding R, et al. Messenger RNA for FOXP3 in the urine of renal-allograft recipients. N Engl J Med. 2005;353:2342-2351.

  9. Simon T, Opelz G, Wiesel M, et al. Expression measurements for prediction of acute rejection in kidney graft recipients. Am J Transplant. 2003;3:1121-1127.

  10. Aquino-Dias EC, Joelsons G, da Silva DM, et al. Non-invasive diagnosis of acute rejection in kidney transplants with delayed graft function. Int Soc Nephrol. 2008;73:877-884.

  11. Anglicheau D, Suthanthiran D. Noninvasive prediction of organ graft rejection and outcome using gene expression patterns. Transplantation. 2008;86:192-199.

  12. Mao Y, Wang M, Zhou Q, et al. CXCL10 and CXCL13 expression were highly up-regulated in peripheral blood mononuclear cells in acute rejection and poor response to anti-rejection therapy. J Clin Immunol. 2011;31:414-418.

  13. Baker R, Jardine A, Andrews P. UK Renal Association clinical practice guidelines for post-operative care of the kidney transplant recipient. http://www.renal.org/clinical/guidelinessection/Post-operative-Care-Kidney-Transplant-Recipient.aspx. Published February 5, 2011. Accessed March 21, 2012.
     
This test was developed and its performance characteristics have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

Polymerase chain reaction (PCR) is performed pursuant to a license agreement with Roche Molecular Systems, Inc.
 Content reviewed 03/2012
 

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