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Inflammation Research

, Volume 66, Issue 5, pp 425–432 | Cite as

The association of urinary interferon-gamma inducible protein-10 (IP10/CXCL10) levels with kidney allograft rejection

  • Ali Raza
  • Sadaf Firasat
  • Shagufta Khaliq
  • Tahir Aziz
  • Muhammed Mubarak
  • Syed Ali Anwar Naqvi
  • Syed Qasim Mehdi
  • Syed Adib-ul-Hasan Rizvi
  • Aiysha AbidEmail author
Original Research Paper

Abstract

Background

Interferon-gamma inducible protein-10 (IP-10/CXCL10) is a chemokine involved in the alloimmune response against kidney allograft. We aimed to investigate the association of urinary CXCL10 protein levels with rejection in renal transplant patients.

Methods

A total of 273 urine samples from (biopsy-proven) rejection and non-rejection patients and controls were included in this study. CXCL10 levels were analyzed for association with rejection.

Results

The data showed statistically significant differences in the CXCL10 levels between rejection vs. non-rejection (p < 0.001). Among the rejection groups, statistically significant differences for CXCL10 levels were found between ACR vs. NAD (p < 0.001), ACR vs. BLR (p = 0.019) and AVR vs. NAD (p = 0.009). Receiver Operating Characteristic (ROC) curve analysis of CXCL10 showed an area under the curve (AUC) of 0.74 with 72% sensitivity and 71% specificity at 27.5 pg/ml between rejection and non-rejection group. Kaplan–Meier curve analysis among different levels of CXCL10 showed a better rejection-free graft survival in patients with <100 pg/ml when compared to >200 pg/ml (38 ± 6 vs. 12 ± 1.0 weeks; log-rank p < 0.001) and 100–200 pg/ml (38 ± 6 vs. 22 ± 9 weeks; log-rank p = 0.442) concentration.

Conclusion

The results indicate significantly increased levels of CXCL10 protein in the urine at the time of allograft rejection. This association of urinary CXCL10 protein levels with rejection could provide an additional tool for the non-invasive monitoring of allograft rejection.

Keywords

Kidney transplantation Allograft rejection Acute rejection Chemokines 

Notes

Acknowledgements

We are grateful to the patients and their donors who participated in the study and the technical staff of SIUT operation and intensive care unit (ICU) and transplant outpatient department (OPD). This study was supported by a core grant to SIUT.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest to disclose.

References

  1. 1.
    Roedder S, Vitalone M, Khatri P, Sarwal MM. Biomarkers in solid organ transplantation: establishing personalized transplantation medicine. Genome Med. 2011;3:37.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Pereira AB, Teixeira AL, Rezende NA, et al. Urinary chemokines and anti-inflammatory molecules in renal transplanted patients as potential biomarkers of graft function: a prospective study. Int Urol Nephrol. 2012;44(5):1539–48.CrossRefPubMedGoogle Scholar
  3. 3.
    Loetscher M, Gerber B, Loetscher P, et al. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T lymphocytes. J Exp Med. 1996;184:963–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Bonecchi R, Bianchi G, Bordignon PP, et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med. 1998;187:129–34.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Romagnani P, Annunziato F, Lazzeri E, et al. Interferon-inducible protein 10, monokine induced by interferon gamma, and interferon-inducible T cell alpha chemoattractant are produced by thymic epithelial cells and attract T cell receptor (TCR) alphabeta + CD8 + single-positive T cells, TCRgammadelta + T cells, and natural killer-type cells in human thymus. Blood. 2001;97:601–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Panzer U, Reinking RR, Steinmetz OM, et al. CXCR3 and CCR5 positive T cell recruitment in acute human renal allograft rejection. Transplantation. 2004;78:1341–50.CrossRefPubMedGoogle Scholar
  7. 7.
    Romagnani P, Crescioli C. CXCL10: a candidate biomarker in transplantation. Clin Chim Acta. 2012;413:1364–73.CrossRefPubMedGoogle Scholar
  8. 8.
    Rotondi M, Rosati A, Buonamano A, et al. High pretransplant serum levels of CXCL10/IP-10 are related to increased risk of renal allograft failure. Am J Transplant. 2004;4:1466–74.CrossRefPubMedGoogle Scholar
  9. 9.
    Lazzeri E, Rotondi M, Mazzinghi B, et al. High CXCL10 expression in rejected kidneys and predictive role of pretransplant serum CXCL10 for acute rejection and chronic allograft nephropathy. Transplantation. 2005;79:1215–20.CrossRefPubMedGoogle Scholar
  10. 10.
    Matl I, Hribova P, Honsova E, Brabcova I, Viklicky O. Potential predictive markers in protocol biopsies for premature renal graft loss. Kidney Blood Press Res. 2010;33:7–14.CrossRefPubMedGoogle Scholar
  11. 11.
    Lo DJ, Weaver TA, Kleiner DE, et al. Chemokines and their receptors in human renal allotransplantation. Transplantation. 2011;91:70–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 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;31:414–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Blydt-Hansen TD, Gibson IW, Gao A, Dufault B, Ho J. Elevated urinary CXCL10-to-creatinine ratio is associated with subclinical and clinical rejection in pediatric renal transplantation. Transplantation. 2015;99:797–804.CrossRefPubMedGoogle Scholar
  14. 14.
    Hirt-Minkowski P, Ho J, Gao A, Amico P, Koller MT, Hopfer H, Rush DN, Nickerson PW, Schaub S. Prediction of long-term renal allograft outcome by early urinary CXCL10 chemokine levels. Transplant Direct. 2015;1:e31.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hirt-Minkowski P, Rush DN, Gao A, Hopfer H, Wiebe C, Nickerson PW, Schaub S, Ho J. Six-month urinary CCL2 and CXCL10 levels predict long-term renal allograft outcome. Transplantation. 2016;100:1988–96.CrossRefPubMedGoogle Scholar
  16. 16.
    Ho J, Sharma A, Mandal R, Wishart DS, Wiebe C, Storsley L, Karpinski M, Gibson IW, Nickerson PW, Rush DN. Detecting renal allograft inflammation using quantitative urine metabolomics and CXCL10. Transplant Direct. 2016;2:e78.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rabant M, Amrouche L, Lebreton X, Aulagnon F, Benon A, Sauvaget V, Bonifay R, Morin L, Scemla A, Delville M, Martinez F, Timsit MO, Duong Van Huyen JP, Legendre C, Terzi F, Anglicheau D. Urinary C-X-C motif chemokine 10 independently improves the noninvasive diagnosis of antibody-mediated kidney allograft rejection. J Am Soc Nephrol. 2015;26:2840–51.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Rabant M, Amrouche L, Morin L, Bonifay R, Lebreton X, Aouni L, Benon A, Sauvaget V, Le Vaillant L, Aulagnon F, Sberro R, Snanoudj R, Mejean A, Legendre C, Terzi F, Anglicheau D. Early low urinary CXCL9 and CXCL10 might predict immunological quiescence in clinically and histologically stable kidney recipients. Am J Transplant. 2016;16:1868–81.CrossRefPubMedGoogle Scholar
  19. 19.
    Hirt-Minkowski P, Amico P, Ho J, et al. Detection of clinical and subclinical tubulo-interstitial inflammation by the urinary CXCL10 chemokine in a real-life setting. Am J Transplant. 2012;12:1811–23.CrossRefPubMedGoogle Scholar
  20. 20.
    Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int. 1999;55:713–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Varma PP, Hooda AK, Sinha T, Chopra GS, Karan SC, Sethi GS, Badwal S, Kotwal A. Renal transplantation: an experience of 500 patients. MJAFI. 2007;63:107–11.Google Scholar
  22. 22.
    Rizvi SA, Naqvi SA, Zafar MN, Akhtar SF. A kidney transplantation model in a low-resource country: an experience from Pakistan. Kidney Int Suppl (2011). 2013;2:236–40.CrossRefGoogle Scholar
  23. 23.
    Hu H, Aizenstein BD, Puchalski A, Burmania JA, Hamawy MM, Knechtle SJ. Elevation of CXCR3-binding chemokines in urine indicates acute renal-allograft dysfunction. Am J Transplant. 2004;4:432–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Khan A. Detection and quantitation of forty eight cytokines, chemokines, growth factors and nine acute phase proteins in healthy human plasma, saliva and urine. Proteomics. 2012;75:4802–19.CrossRefPubMedGoogle Scholar
  25. 25.
    Lo DJ, Kaplan B, Kirk AD. Biomarkers for kidney transplant rejection. Nat Rev Nephrol. 2014;10:215–25.CrossRefPubMedGoogle Scholar
  26. 26.
    Kanmaz T, Feng P, Torrealba J, Kwun J, Fechner JH, Schultz JM, Dong Y, Kim HT, Dar W, Hamawy MM, Knechtle SJ, Hu H. Surveillance of acute rejection in baboon renal transplantation by elevation of interferon-gamma inducible protein-10 and monokine induced by interferon-gamma in urine. Transplantation. 2004;78:1002–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Hauser IA, Spiegler S, Kiss E, Gauer, Sichler O, Scheuermann EH, Ackermann H, Pfeilschifter JM, Geiger H, Grone HJ, Radeke HH. Prediction of acute renal allograft rejection by urinary monokine induced by IFN-Y (MIG). J Am Soc Nephrol. 2005;16:1849–58.CrossRefPubMedGoogle Scholar
  28. 28.
    Jackson JA, Kim EJ, Begley B, et al. Urinary chemokines CXCL9 and CXCL10 are noninvasive markers of renal allograft rejection and BK viral infection. Am J Transplant. 2011;11:2228–34.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Schaub S, Nickerson P, Rush D, et al. Urinary CXCL9 and CXCL10 levels correlate with the extent of subclinical tubulitis. Am J Transplant. 2009;9:1347–53.CrossRefPubMedGoogle Scholar
  30. 30.
    Matz M, Beyer J, Wunsch D, et al. Early post-transplant urinary IP-10 expression after kidney transplantation is predictive of short- and long-term graft function. Kidney Int. 2006;69:1683–90.CrossRefPubMedGoogle Scholar
  31. 31.
    Tatapudi RR, Muthukumar T, Dadhania D, Ding R, Li B, Sharma VK, Lozada-Pastorio E, Seetharamu N, Hartono C, Serur D, Seshan SV, Kapur S, Hancock WW, Suthanthiran M. Noninvasive detection of renal allograft inflammation by measurements of mRNA for IP-10 and CXCR3 in urine. Kidney Int. 2004;65:2390–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Suthanthiran M, Schwartz JE, Ding R, Clinical Trials in Organ Transplantation 04 (CTOT-04) Study Investigators, et al. Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. N Engl J Med. 2013;369:20–31.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  • Ali Raza
    • 1
  • Sadaf Firasat
    • 1
  • Shagufta Khaliq
    • 1
    • 2
  • Tahir Aziz
    • 3
  • Muhammed Mubarak
    • 4
  • Syed Ali Anwar Naqvi
    • 3
  • Syed Qasim Mehdi
    • 1
  • Syed Adib-ul-Hasan Rizvi
    • 3
  • Aiysha Abid
    • 1
    Email author
  1. 1.Centre for Human Genetics and Molecular MedicineSindh Institute of Urology and Transplantation (SIUT)KarachiPakistan
  2. 2.Department of Human GeneticsUniversity of Health Sciences (UHS)LahorePakistan
  3. 3.Department of UrologySindh Institute of Urology and Transplantation (SIUT)KarachiPakistan
  4. 4.Department of HistopathologySindh Institute of Urology and Transplantation (SIUT)KarachiPakistan

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