Urinary cell levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts

Cheguevara Afaneh, Thangamani Muthukumar, Michelle Lubetzky, Ruchuang Ding, Catherine Snopkowski, Vijay K. Sharma, Surya Seshan, Darshana Dadhania, Joseph E. Schwartz, Manikkam Suthanthiran

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Background. The positive costimulatory proteins OX40 and OX40L and negative regulatory proteins programmed death (PD)-1, PD ligand 1, and PD ligand 2 have emerged as significant regulators of acute rejection in experimental transplantation models. Methods. We obtained 21 urine specimens from 21 renal allograft recipients with graft dysfunction and biopsy-confirmed acute rejection and 25 specimens from 25 recipients with stable graft function and normal biopsy results (stable). Urinary cell levels of mRNAs were measured using real-time quantitative polymerase chain reaction assays, and the levels were correlated with allograft status and outcomes. Results. Levels of OX40 mRNA (P<0.0001, Mann-Whitney test), OX40L mRNA (P=0.0004), and PD-1 mRNA (P=0.004), but not the mRNA levels of PD ligand 1 (P=0.08) or PD ligand 2 (P=0.20), were significantly higher in the urinary cells from the acute rejection group than the stable group. Receiver operating characteristic curve analysis demonstrated that acute rejection is predicted with a sensitivity of 95% and a specificity of 92% (area under the curve=0.98, 95% confidence interval 0.96-1.0, P<0.0001) using a combination of levels of mRNA for OX40, OX40L, PD-1, and levels of mRNA for the previously identified biomarker Foxp3. Within the acute rejection group, levels of mRNA for OX40 (P=0.0002), OX40L (P=0.0004), and Foxp3 (P=0.04) predicted acute rejection reversal, whereas only OX40 mRNA levels (P=0.04) predicted graft loss after acute rejection. Conclusion. A linear combination of urinary cell levels of mRNA for OX40, OX40L, PD-1, and Foxp3 was a strong predictor of acute rejection in human renal allograft biopsies. This prediction model should be validated using an independent cohort of renal allograft recipients.

Original languageEnglish
Pages (from-to)1381-1387
Number of pages7
JournalTransplantation
Volume90
Issue number12
DOIs
Publication statusPublished - 27 Dec 2010
Externally publishedYes

Fingerprint

Allografts
Kidney
Messenger RNA
Ligands
Transplants
Biopsy
OX40 Ligand
ROC Curve
Area Under Curve
Real-Time Polymerase Chain Reaction
Theoretical Models
Transplantation
Biomarkers
Urine
Confidence Intervals

Keywords

  • Acute rejection
  • Costimulation
  • OX40
  • Urinary biomarkers

ASJC Scopus subject areas

  • Transplantation

Cite this

Urinary cell levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts. / Afaneh, Cheguevara; Muthukumar, Thangamani; Lubetzky, Michelle; Ding, Ruchuang; Snopkowski, Catherine; Sharma, Vijay K.; Seshan, Surya; Dadhania, Darshana; Schwartz, Joseph E.; Suthanthiran, Manikkam.

In: Transplantation, Vol. 90, No. 12, 27.12.2010, p. 1381-1387.

Research output: Contribution to journalArticle

Afaneh, C, Muthukumar, T, Lubetzky, M, Ding, R, Snopkowski, C, Sharma, VK, Seshan, S, Dadhania, D, Schwartz, JE & Suthanthiran, M 2010, 'Urinary cell levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts', Transplantation, vol. 90, no. 12, pp. 1381-1387. https://doi.org/10.1097/TP.0b013e3181ffbadd
Afaneh, Cheguevara ; Muthukumar, Thangamani ; Lubetzky, Michelle ; Ding, Ruchuang ; Snopkowski, Catherine ; Sharma, Vijay K. ; Seshan, Surya ; Dadhania, Darshana ; Schwartz, Joseph E. ; Suthanthiran, Manikkam. / Urinary cell levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts. In: Transplantation. 2010 ; Vol. 90, No. 12. pp. 1381-1387.
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abstract = "Background. The positive costimulatory proteins OX40 and OX40L and negative regulatory proteins programmed death (PD)-1, PD ligand 1, and PD ligand 2 have emerged as significant regulators of acute rejection in experimental transplantation models. Methods. We obtained 21 urine specimens from 21 renal allograft recipients with graft dysfunction and biopsy-confirmed acute rejection and 25 specimens from 25 recipients with stable graft function and normal biopsy results (stable). Urinary cell levels of mRNAs were measured using real-time quantitative polymerase chain reaction assays, and the levels were correlated with allograft status and outcomes. Results. Levels of OX40 mRNA (P<0.0001, Mann-Whitney test), OX40L mRNA (P=0.0004), and PD-1 mRNA (P=0.004), but not the mRNA levels of PD ligand 1 (P=0.08) or PD ligand 2 (P=0.20), were significantly higher in the urinary cells from the acute rejection group than the stable group. Receiver operating characteristic curve analysis demonstrated that acute rejection is predicted with a sensitivity of 95{\%} and a specificity of 92{\%} (area under the curve=0.98, 95{\%} confidence interval 0.96-1.0, P<0.0001) using a combination of levels of mRNA for OX40, OX40L, PD-1, and levels of mRNA for the previously identified biomarker Foxp3. Within the acute rejection group, levels of mRNA for OX40 (P=0.0002), OX40L (P=0.0004), and Foxp3 (P=0.04) predicted acute rejection reversal, whereas only OX40 mRNA levels (P=0.04) predicted graft loss after acute rejection. Conclusion. A linear combination of urinary cell levels of mRNA for OX40, OX40L, PD-1, and Foxp3 was a strong predictor of acute rejection in human renal allograft biopsies. This prediction model should be validated using an independent cohort of renal allograft recipients.",
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T1 - Urinary cell levels of mRNA for OX40, OX40L, PD-1, PD-L1, or PD-L2 and acute rejection of human renal allografts

AU - Afaneh, Cheguevara

AU - Muthukumar, Thangamani

AU - Lubetzky, Michelle

AU - Ding, Ruchuang

AU - Snopkowski, Catherine

AU - Sharma, Vijay K.

AU - Seshan, Surya

AU - Dadhania, Darshana

AU - Schwartz, Joseph E.

AU - Suthanthiran, Manikkam

PY - 2010/12/27

Y1 - 2010/12/27

N2 - Background. The positive costimulatory proteins OX40 and OX40L and negative regulatory proteins programmed death (PD)-1, PD ligand 1, and PD ligand 2 have emerged as significant regulators of acute rejection in experimental transplantation models. Methods. We obtained 21 urine specimens from 21 renal allograft recipients with graft dysfunction and biopsy-confirmed acute rejection and 25 specimens from 25 recipients with stable graft function and normal biopsy results (stable). Urinary cell levels of mRNAs were measured using real-time quantitative polymerase chain reaction assays, and the levels were correlated with allograft status and outcomes. Results. Levels of OX40 mRNA (P<0.0001, Mann-Whitney test), OX40L mRNA (P=0.0004), and PD-1 mRNA (P=0.004), but not the mRNA levels of PD ligand 1 (P=0.08) or PD ligand 2 (P=0.20), were significantly higher in the urinary cells from the acute rejection group than the stable group. Receiver operating characteristic curve analysis demonstrated that acute rejection is predicted with a sensitivity of 95% and a specificity of 92% (area under the curve=0.98, 95% confidence interval 0.96-1.0, P<0.0001) using a combination of levels of mRNA for OX40, OX40L, PD-1, and levels of mRNA for the previously identified biomarker Foxp3. Within the acute rejection group, levels of mRNA for OX40 (P=0.0002), OX40L (P=0.0004), and Foxp3 (P=0.04) predicted acute rejection reversal, whereas only OX40 mRNA levels (P=0.04) predicted graft loss after acute rejection. Conclusion. A linear combination of urinary cell levels of mRNA for OX40, OX40L, PD-1, and Foxp3 was a strong predictor of acute rejection in human renal allograft biopsies. This prediction model should be validated using an independent cohort of renal allograft recipients.

AB - Background. The positive costimulatory proteins OX40 and OX40L and negative regulatory proteins programmed death (PD)-1, PD ligand 1, and PD ligand 2 have emerged as significant regulators of acute rejection in experimental transplantation models. Methods. We obtained 21 urine specimens from 21 renal allograft recipients with graft dysfunction and biopsy-confirmed acute rejection and 25 specimens from 25 recipients with stable graft function and normal biopsy results (stable). Urinary cell levels of mRNAs were measured using real-time quantitative polymerase chain reaction assays, and the levels were correlated with allograft status and outcomes. Results. Levels of OX40 mRNA (P<0.0001, Mann-Whitney test), OX40L mRNA (P=0.0004), and PD-1 mRNA (P=0.004), but not the mRNA levels of PD ligand 1 (P=0.08) or PD ligand 2 (P=0.20), were significantly higher in the urinary cells from the acute rejection group than the stable group. Receiver operating characteristic curve analysis demonstrated that acute rejection is predicted with a sensitivity of 95% and a specificity of 92% (area under the curve=0.98, 95% confidence interval 0.96-1.0, P<0.0001) using a combination of levels of mRNA for OX40, OX40L, PD-1, and levels of mRNA for the previously identified biomarker Foxp3. Within the acute rejection group, levels of mRNA for OX40 (P=0.0002), OX40L (P=0.0004), and Foxp3 (P=0.04) predicted acute rejection reversal, whereas only OX40 mRNA levels (P=0.04) predicted graft loss after acute rejection. Conclusion. A linear combination of urinary cell levels of mRNA for OX40, OX40L, PD-1, and Foxp3 was a strong predictor of acute rejection in human renal allograft biopsies. This prediction model should be validated using an independent cohort of renal allograft recipients.

KW - Acute rejection

KW - Costimulation

KW - OX40

KW - Urinary biomarkers

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