BACKGROUND: T cell-mediated rejection (TCMR) is the most frequent type of acute rejection and is associated with kidney allograft failure. Almost 40% of TCMR episodes are nonresponsive to therapy, and molecular mechanisms for the nonresponsiveness are unknown. Our single-center study identified that urinary cell FOXP3 mRNA abundance predicts TCMR reversibility and allograft survival. METHODS: We developed PCR assays and measured absolute copy numbers of transcripts for FOXP3, CD25, CD3E, perforin, and 18S rRNA in 3559 urines from 480 kidney allograft recipients prospectively enrolled in the multicenter Clinical Trials in Organ Transplantation-04. In this replication study, we investigated the association between mRNA profile and TCMR diagnosis, TCMR reversibility, and allograft survival. RESULTS: 18S rRNA normalized levels of mRNA for FOXP3 (P = 0.01, Kruskal-Wallis test), CD25 (P = 0.01), CD3E (P < 0.0001), and perforin (P < 0.0001) were diagnostic of TCMR, but only FOXP3 mRNA level predicted TCMR reversibility (ROC AUC = 0.764; 95% confidence interval, 0.611-0.917; P = 0.008). Multivariable logistic regression analyses showed that urinary cell FOXP3 mRNA level predicted reversal, independent of clinical variables. A composite model of clinical variables and FOXP3 mRNA (AUC = 0.889; 95% CI, 0.781-0.997; P < 0.001) outperformed FOXP3 mRNA or clinical variables in predicting TCMR reversibility (P = 0.01, likelihood ratio test). Multivariable Cox proportional hazards regression analyses showed that FOXP3 mRNA level predicts kidney allograft survival (P = 0.047) but not after controlling for TCMR reversal (P = 0.477). CONCLUSIONS: Urinary cell level of FOXP3 mRNA is diagnostic of TCMR, predicts TCMR reversibility, and is prognostic of kidney allograft survival via a mechanism involving TCMR reversal.
BACKGROUND: T cell-mediated rejection (TCMR) is the most frequent type of acute rejection and is associated with kidney allograft failure. Almost 40% of TCMR episodes are nonresponsive to therapy, and molecular mechanisms for the nonresponsiveness are unknown. Our single-center study identified that urinary cell FOXP3 mRNA abundance predicts TCMR reversibility and allograft survival. METHODS: We developed PCR assays and measured absolute copy numbers of transcripts for FOXP3, CD25, CD3E, perforin, and 18S rRNA in 3559 urines from 480 kidney allograft recipients prospectively enrolled in the multicenter Clinical Trials in Organ Transplantation-04. In this replication study, we investigated the association between mRNA profile and TCMR diagnosis, TCMR reversibility, and allograft survival. RESULTS: 18S rRNA normalized levels of mRNA for FOXP3 (P = 0.01, Kruskal-Wallis test), CD25 (P = 0.01), CD3E (P < 0.0001), and perforin (P < 0.0001) were diagnostic of TCMR, but only FOXP3 mRNA level predicted TCMR reversibility (ROC AUC = 0.764; 95% confidence interval, 0.611-0.917; P = 0.008). Multivariable logistic regression analyses showed that urinary cell FOXP3 mRNA level predicted reversal, independent of clinical variables. A composite model of clinical variables and FOXP3 mRNA (AUC = 0.889; 95% CI, 0.781-0.997; P < 0.001) outperformed FOXP3 mRNA or clinical variables in predicting TCMR reversibility (P = 0.01, likelihood ratio test). Multivariable Cox proportional hazards regression analyses showed that FOXP3 mRNA level predicts kidney allograft survival (P = 0.047) but not after controlling for TCMR reversal (P = 0.477). CONCLUSIONS: Urinary cell level of FOXP3 mRNA is diagnostic of TCMR, predicts TCMR reversibility, and is prognostic of kidney allograft survival via a mechanism involving TCMR reversal.
Authors: Peter N Furness; Carl M Philpott; Mary T Chorbadjian; Michael L Nicholson; Jean-Louis Bosmans; Bob L Corthouts; Johannes J P M Bogers; Anke Schwarz; Wilfried Gwinner; Hermann Haller; Michael Mengel; Daniel Seron; Francesc Moreso; Conception Cañas Journal: Transplantation Date: 2003-09-27 Impact factor: 4.939
Authors: Brian J Nankivell; Nidhi Agrawal; Ankit Sharma; Anne Taverniti; Chow H P'Ng; Meena Shingde; Germaine Wong; Jeremy R Chapman Journal: Am J Transplant Date: 2019-01-22 Impact factor: 8.086
Authors: Wenjun Li; Jason M Gauthier; Ryuji Higashikubo; Hsi-Min Hsiao; Satona Tanaka; Linh Vuong; Jon H Ritter; Alice Y Tong; Brian W Wong; Ramsey R Hachem; Varun Puri; Ankit Bharat; Alexander S Krupnick; Chyi S Hsieh; William M Baldwin; Francine L Kelly; Scott M Palmer; Andrew E Gelman; Daniel Kreisel Journal: J Clin Invest Date: 2018-12-18 Impact factor: 14.808
Authors: Akanksha Verma; Thangamani Muthukumar; Hua Yang; Michelle Lubetzky; Michael F Cassidy; John R Lee; Darshana M Dadhania; Catherine Snopkowski; Divya Shankaranarayanan; Steven P Salvatore; Vijay K Sharma; Jenny Z Xiang; Iwijn De Vlaminck; Surya V Seshan; Franco B Mueller; Karsten Suhre; Olivier Elemento; Manikkam Suthanthiran Journal: JCI Insight Date: 2020-02-27
Authors: Lorraine C Racusen; Robert B Colvin; Kim Solez; Michael J Mihatsch; Philip F Halloran; Patricia M Campbell; Michael J Cecka; Jean-Pierre Cosyns; Anthony J Demetris; Michael C Fishbein; Agnes Fogo; Peter Furness; Ian W Gibson; Denis Glotz; Pekka Hayry; Lawrence Hunsickern; Michael Kashgarian; Ronald Kerman; Alex J Magil; Robert Montgomery; Kunio Morozumi; Volker Nickeleit; Parmjeet Randhawa; Heinz Regele; Daniel Seron; Surya Seshan; Stale Sund; Kiril Trpkov Journal: Am J Transplant Date: 2003-06 Impact factor: 8.086
Authors: Unsal Yapici; Fréderike J Bemelman; Cornelis G Scheepstra; Joris J T H Roelofs; Nike Claessen; Chris van der Loos; Karlijn van Donselaar-van der Pant; Antonia H M Bouts; Mirza M Idu; Ajda T Rowshani; Ineke J M ten Berge; Sandrine Florquin Journal: Transplantation Date: 2009-05-15 Impact factor: 4.939