Biomarkers for early and late stage chronic allograft nephropathy by proteogenomic profiling of peripheral blood
Sunil M Kurian, Raymond Heilman, Tony S Mondala, Aleksey Nakorchevsky, Johannes A Hewel, Daniel Campbell, Elizabeth H Robison, Lin Wang, Wen Lin, Lillian Gaber, Kim Solez, Hamid Shidban, Robert Mendez, Randolph L Schaffer, Jonathan S Fisher, Stuart M Flechner, Steve R Head, Steve Horvath, John R Yates, Christopher L Marsh, Daniel R Salomon, Sunil M Kurian, Raymond Heilman, Tony S Mondala, Aleksey Nakorchevsky, Johannes A Hewel, Daniel Campbell, Elizabeth H Robison, Lin Wang, Wen Lin, Lillian Gaber, Kim Solez, Hamid Shidban, Robert Mendez, Randolph L Schaffer, Jonathan S Fisher, Stuart M Flechner, Steve R Head, Steve Horvath, John R Yates, Christopher L Marsh, Daniel R Salomon
Abstract
Background: Despite significant improvements in life expectancy of kidney transplant patients due to advances in surgery and immunosuppression, Chronic Allograft Nephropathy (CAN) remains a daunting problem. A complex network of cellular mechanisms in both graft and peripheral immune compartments complicates the non-invasive diagnosis of CAN, which still requires biopsy histology. This is compounded by non-immunological factors contributing to graft injury. There is a pressing need to identify and validate minimally invasive biomarkers for CAN to serve as early predictors of graft loss and as metrics for managing long-term immunosuppression.
Methods: We used DNA microarrays, tandem mass spectroscopy proteomics and bioinformatics to identify genomic and proteomic markers of mild and moderate/severe CAN in peripheral blood of two distinct cohorts (n = 77 total) of kidney transplant patients with biopsy-documented histology.
Findings: Gene expression profiles reveal over 2400 genes for mild CAN, and over 700 for moderate/severe CAN. A consensus analysis reveals 393 (mild) and 63 (moderate/severe) final candidates as CAN markers with predictive accuracy of 80% (mild) and 92% (moderate/severe). Proteomic profiles show over 500 candidates each, for both stages of CAN including 302 proteins unique to mild and 509 unique to moderate/severe CAN.
Conclusions: This study identifies several unique signatures of transcript and protein biomarkers with high predictive accuracies for mild and moderate/severe CAN, the most common cause of late allograft failure. These biomarkers are the necessary first step to a proteogenomic classification of CAN based on peripheral blood profiling and will be the targets of a prospective clinical validation study.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
References
- Meier-Kriesche HU, Ojo AO, Port FK, Arndorfer JA, Cibrik DM, et al. Survival improvement among patients with end-stage renal disease: trends over time for transplant recipients and wait-listed patients. J Am Soc Nephrol. 2001;12:1293–1296.
- Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349:2326–2333.
- Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med. 2002;346:580–590.
- Solez K, Colvin RB, Racusen LC, Haas M, Sis B, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8:753–760.
- Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int. 1999;55:713–723.
- Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, et al. Banff' 05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant. 2007;7:518–526.
- Banasik M, Klinger M. Chronic allograft nephropathy–immunologic and nonimmunologic factors. Ann Transplant. 2006;11:7–10.
- Yates PJ, Nicholson ML. The aetiology and pathogenesis of chronic allograft nephropathy. Transpl Immunol. 2006;16:148–157.
- Calne RY, White DJ, Thiru S, Evans DB, McMaster P, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet. 1978;2:1323–1327.
- de Mattos AM, Olyaei AJ, Bennett WM. Nephrotoxicity of immunosuppressive drugs: long-term consequences and challenges for the future. Am J Kidney Dis. 2000;35:333–346.
- Jevnikar AM, Mannon RB. Late kidney allograft loss: what we know about it, and what we can do about it. Clin J Am Soc Nephrol. 2008;3(Suppl 2):S56–67.
- Pascual M, Swinford RD, Ingelfinger JR, Williams WW, Cosimi AB, et al. Chronic rejection and chronic cyclosporin toxicity in renal allografts. Immunol Today. 1998;19:514–519.
- Nankivell BJ, Chapman JR. Chronic allograft nephropathy: current concepts and future directions. Transplantation. 2006;81:643–654.
- Colvin RB. Chronic allograft nephropathy. N Engl J Med. 2003;349:2288–2290.
- Flechner SM, Goldfarb D, Solez K, Modlin CS, Mastroianni B, et al. Kidney transplantation with sirolimus and mycophenolate mofetil-based immunosuppression: 5-year results of a randomized prospective trial compared to calcineurin inhibitor drugs. Transplantation. 2007;83:883–892.
- Flechner SM, Kurian SM, Solez K, Cook DJ, Burke JT, et al. De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years. Am J Transplant. 2004;4:1776–1785.
- Yilmaz S, Isik I, Afrouzian M, Monroy M, Sar A, et al. Evaluating the accuracy of functional biomarkers for detecting histological changes in chronic allograft nephropathy. Transpl Int. 2007;20:608–615.
- Lachenbruch PA, Rosenberg AS, Bonvini E, Cavaille-Coll MW, Colvin RB. Biomarkers and surrogate endpoints in renal transplantation: present status and considerations for clinical trial design. Am J Transplant. 2004;4:451–457.
- Pascual M, Vallhonrat H, Cosimi AB, Tolkoff-Rubin N, Colvin RB, et al. The clinical usefulness of the renal allograft biopsy in the cyclosporine era: a prospective study. Transplantation. 1999;67:737–741.
- Kurian S, Flechner SM, Salomon DR. Genomics and proteomics in transplantation. Current Opinion in Organ Transplantation. 2005;10:193–197.
- Kurian S, Grigoryev Y, Head S, Campbell D, Mondala T, et al. Applying genomics to organ transplantation medicine in both discovery and validation of biomarkers. Int Immunopharmacol. 2007;7:1948–1960.
- Oetting WS, Rogers TB, Krick TP, Matas AJ, Ibrahim HN. Urinary beta2-microglobulin is associated with acute renal allograft rejection. Am J Kidney Dis. 2006;47:898–904.
- Schaub S, Wilkins JA, Antonovici M, Krokhin O, Weiler T, et al. Proteomic-based identification of cleaved urinary beta2-microglobulin as a potential marker for acute tubular injury in renal allografts. Am J Transplant. 2005;5:729–738.
- Flechner SM, Kurian SM, Head SR, Sharp SM, Whisenant TC, et al. Kidney transplant rejection and tissue injury by gene profiling of biopsies and peripheral blood lymphocytes. Am J Transplant. 2004;4:1475–1489.
- Bolstad BM, Irizarry RA, Astrand M, Speed TP. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics. 2003;19:185–193.
- Dudoit S, Fridlyand J, Speed TP. Comparison of discrimination methods for the classification of tumors using gene expression data. Journal of the American Statistical Association. 2002;97:77–87.
- Eisen MB, Spellman PT, Brown PO, Botstein D. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A. 1998;95:14863–14868.
- Washburn MP, Wolters D, Yates JR., 3rd Large-scale analysis of the yeast proteome by multidimensional protein identification technology. Nat Biotechnol. 2001;19:242–247.
- Sadygov RG, Eng J, Durr E, Saraf A, McDonald H, et al. Code developments to improve the efficiency of automated MS/MS spectra interpretation. J Proteome Res. 2002;1:211–215.
- Tabb DL, McDonald WH, Yates JR., 3rd DTASelect and Contrast: tools for assembling and comparing protein identifications from shotgun proteomics. J Proteome Res. 2002;1:21–26.
- Liu H, Sadygov RG, Yates JR., 3rd A model for random sampling and estimation of relative protein abundance in shotgun proteomics. Anal Chem. 2004;76:4193–4201.
- Guo Y, Hastie T, Tibshirani R. Regularized linear discriminant analysis and its application in microarrays. Biostatistics. 2007;8:86–100.
- Huang CC, Cutcliffe C, Coffin C, Sorensen PH, Beckwith JB, et al. Classification of malignant pediatric renal tumors by gene expression. Pediatr Blood Cancer. 2006;46:728–738.
- Woolf SH. Screening for prostate cancer with prostate-specific antigen. An examination of the evidence. N Engl J Med. 1995;333:1401–1405.
- Deng MC, Eisen HJ, Mehra MR, Billingham M, Marboe CC, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant. 2006;6:150–160.
- Horwitz PA, Tsai EJ, Putt ME, Gilmore JM, Lepore JJ, et al. Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression. Circulation. 2004;110:3815–3821.
- Brouard S, Mansfield E, Braud C, Li L, Giral M, et al. Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A. 2007;104:15448–15453.
- Mas V, Maluf D, Archer K, Yanek K, Mas L, et al. Establishing the molecular pathways involved in chronic allograft nephropathy for testing new noninvasive diagnostic markers. Transplantation. 2007;83:448–457.
- Clarke W, Silverman BC, Zhang Z, Chan DW, Klein AS, et al. Characterization of renal allograft rejection by urinary proteomic analysis. Ann Surg. 2003;237:660–664. discussion 664–665.
Source: PubMed