Clinical trial NCT02294032: The Role of B Cells in Kidney Allograft Dysfunction
Official title: The Role of B Cells in Kidney Allograft Dysfunction
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Kidney; Complications, Allograft
Transplantation Infection
Keywords: Bcells
kidney allograft dysfunction
antibody mediated rejection
Lead sponsor: Loma Linda University
Sponsor class: OTHER
First posted: 2014-11-19
Enrollment: 180
Sex: ALL
Minimum age (years): 2
Maximum age (years): 85
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Pediatric and Adult patients who are on the waitlist for a kidney or liver, or are about to undergo kidney or liver transplantation.

Brief summary: The purpose of this study is to understand the role of specific B cells in activating or repressing an anti-allograft immune response after kidney transplantation. In this study, blood will be collected from kidney transplant patients during different timepoints, prior to and after their transplant. Knowledge gained from study findings will be used to develop therapeutic strategies to prevent antibody-mediated rejection, which is a major cause of long-term graft loss in kidney transplant patients.

Detailed description: The purpose of this study is to understand the role of specific B cells in activating or repressing an anti-allograft immune responses after kidney transplantation. This study aims to address two major challenges in kidney transplantation: 1. to guide physicians when immunosuppressive drugs are weaned, and 2. to identify patients who are at risk or in the process of developing antibody-mediated rejection. In this study, blood will be collected from kidney transplant patients during different timepoints, prior to and after their transplant. Knowledge gained from study findings will be used to develop therapeutic strategies to prevent antibody-mediated rejection, which is a major cause of long-term graft loss in kidney transplant patients.

Eligibility criteria: Inclusion Criteria:

* Ability to understand and willingness to sign the written informed consent form (ICF). For pediatric patients, a parent or legal guardian must sign ICF
* Either a Kidney or Liver transplant patient: 1) on the waitlist or 2) transplanted
* Healthy volunteer samples collected to use as the control group for statistical validity

Exclusion Criteria:

* Inability to make all of the required long-term post-transplant visits.
* Females who are pregnant or nursing a child
* Liver patients with hepatitis C virus

Primary outcomes:
measure: Blood collection prior to and after kidney transplantation
timeFrame: 1,3,6,12,18,24,36,48, and 60 months
Secondary outcomes:
measure: B cell count
timeFrame: Up to 60 months
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center, Transplantation Institute
state: California
Study officials:
affiliation: Loma Linda University Medical Center
name: Michael de Vera, MD, FACS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Seron D, Moreso F, Arias M, Campistol JM, Curto J, Hernandez D, Morales JM, Sanchez-Fructuoso A, Abraira V; Spanish Late Allograft Dysfunction Study Group. Estimation of renal allograft half-life: fact or fiction? Nephrol Dial Transplant. 2011 Sep;26(9):3013-8. doi: 10.1093/ndt/gfq788. Epub 2011 Feb 3.
citation: Colvin RB, Hirohashi T, Farris AB, Minnei F, Collins AB, Smith RN. Emerging role of B cells in chronic allograft dysfunction. Kidney Int Suppl. 2010 Dec;(119):S13-7. doi: 10.1038/ki.2010.436.
citation: Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, Burlingham WJ, Marks WH, Sanz I, Lechler RI, Hernandez-Fuentes MP, Turka LA, Seyfert-Margolis VL; Immune Tolerance Network ST507 Study Group. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest. 2010 Jun;120(6):1836-47. doi: 10.1172/JCI39933. Epub 2010 May 24.
citation: Sagoo P, Perucha E, Sawitzki B, Tomiuk S, Stephens DA, Miqueu P, Chapman S, Craciun L, Sergeant R, Brouard S, Rovis F, Jimenez E, Ballow A, Giral M, Rebollo-Mesa I, Le Moine A, Braudeau C, Hilton R, Gerstmayer B, Bourcier K, Sharif A, Krajewska M, Lord GM, Roberts I, Goldman M, Wood KJ, Newell K, Seyfert-Margolis V, Warrens AN, Janssen U, Volk HD, Soulillou JP, Hernandez-Fuentes MP, Lechler RI. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest. 2010 Jun;120(6):1848-61. doi: 10.1172/JCI39922. Epub 2010 May 24.
citation: Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004 Dec 23;351(26):2715-29. doi: 10.1056/NEJMra033540. No abstract available.
citation: Barnett AN, Hadjianastassiou VG, Mamode N. Rituximab in renal transplantation. Transpl Int. 2013 Jun;26(6):563-75. doi: 10.1111/tri.12072. Epub 2013 Feb 18.
citation: Rehnberg M, Amu S, Tarkowski A, Bokarewa MI, Brisslert M. Short- and long-term effects of anti-CD20 treatment on B cell ontogeny in bone marrow of patients with rheumatoid arthritis. Arthritis Res Ther. 2009;11(4):R123. doi: 10.1186/ar2789. Epub 2009 Aug 17.
citation: Everly MJ. Understanding and addressing the humoral immune response in transplant recipients. Clin Transpl. 2012:225-7. No abstract available.
citation: Everly MJ. Immunosuppression regimens to address alloantibodies in transplant recipients. Clin Transpl. 2012:219-23.
citation: Kannabhiran D, Everly MJ, Walker-McDermott JK, Tiongko S, Friedlander R, Putheti P, Sharma V, Dadhania D. Changes in IgG subclasses of donor specific anti-HLA antibodies following bortezomib-based therapy for antibody mediated rejection. Clin Transpl. 2012:229-35.
citation: Thibault-Espitia A, Foucher Y, Danger R, Migone T, Pallier A, Castagnet S, G-Gueguen C, Devys A, C-Gautier A, Giral M, Soulillou JP, Brouard S. BAFF and BAFF-R levels are associated with risk of long-term kidney graft dysfunction and development of donor-specific antibodies. Am J Transplant. 2012 Oct;12(10):2754-62. doi: 10.1111/j.1600-6143.2012.04194.x. Epub 2012 Aug 6.
citation: Xu H, He X, Liu Q, Chen Y, Zhu Y, Shi D, Zhang X. The abnormal high expression of B cell activating factor belonging to TNF superfamily (BAFF) and its potential role in kidney transplant recipients. Cell Mol Immunol. 2008 Dec;5(6):465-70. doi: 10.1038/cmi.2008.58.
citation: Clatworthy MR, Espeli M, Torpey N, Smith KG. The generation and maintenance of serum alloantibody. Curr Opin Immunol. 2010 Oct;22(5):669-81. doi: 10.1016/j.coi.2010.08.018.
citation: Stegall MD, Raghavaiah S, Gloor JM. The (re)emergence of B cells in organ transplantation. Curr Opin Organ Transplant. 2010 Aug;15(4):451-5. doi: 10.1097/MOT.0b013e32833b9c11.
citation: Lynch RJ, Silva IA, Chen BJ, Punch JD, Cascalho M, Platt JL. Cryptic B cell response to renal transplantation. Am J Transplant. 2013 Jul;13(7):1713-23. doi: 10.1111/ajt.12308. Epub 2013 Jun 10.
citation: Anolik JH, Looney RJ, Lund FE, Randall TD, Sanz I. Insights into the heterogeneity of human B cells: diverse functions, roles in autoimmunity, and use as therapeutic targets. Immunol Res. 2009 Dec;45(2-3):144-58. doi: 10.1007/s12026-009-8096-7. Epub 2009 Apr 7.
citation: Kaminski DA, Wei C, Qian Y, Rosenberg AF, Sanz I. Advances in human B cell phenotypic profiling. Front Immunol. 2012 Oct 10;3:302. doi: 10.3389/fimmu.2012.00302. eCollection 2012.
citation: Anolik JH, Barnard J, Cappione A, Pugh-Bernard AE, Felgar RE, Looney RJ, Sanz I. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum. 2004 Nov;50(11):3580-90. doi: 10.1002/art.20592.
citation: Iwata S, Saito K, Tokunaga M, Yamaoka K, Nawata M, Yukawa S, Hanami K, Fukuyo S, Miyagawa I, Kubo S, Tanaka Y. Phenotypic changes of lymphocytes in patients with systemic lupus erythematosus who are in longterm remission after B cell depletion therapy with rituximab. J Rheumatol. 2011 Apr;38(4):633-41. doi: 10.3899/jrheum.100729. Epub 2010 Dec 15.
citation: Kinnunen T, Chamberlain N, Morbach H, Cantaert T, Lynch M, Preston-Hurlburt P, Herold KC, Hafler DA, O'Connor KC, Meffre E. Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest. 2013 Jun;123(6):2737-41. doi: 10.1172/JCI68775. Epub 2013 May 15.
citation: Sanz I, Wei C, Lee FE, Anolik J. Phenotypic and functional heterogeneity of human memory B cells. Semin Immunol. 2008 Feb;20(1):67-82. doi: 10.1016/j.smim.2007.12.006. Epub 2008 Feb 6.
citation: Moens L, Wuyts M, Meyts I, De Boeck K, Bossuyt X. Human memory B lymphocyte subsets fulfill distinct roles in the anti-polysaccharide and anti-protein immune response. J Immunol. 2008 Oct 15;181(8):5306-12. doi: 10.4049/jimmunol.181.8.5306.
citation: Gambichler T, Tigges C, Burkert B, Hoxtermann S, Altmeyer P, Kreuter A. Absolute count of T and B lymphocyte subsets is decreased in systemic sclerosis. Eur J Med Res. 2010 Jan 29;15(1):44-6. doi: 10.1186/2047-783x-15-1-44.
citation: Adams AB, Newell KA. B cells in clinical transplantation tolerance. Semin Immunol. 2012 Apr;24(2):92-5. doi: 10.1016/j.smim.2011.08.019. Epub 2011 Sep 29.
citation: Bloom D, Chang Z, Pauly K, Kwun J, Fechner J, Hayes C, Samaniego M, Knechtle S. BAFF is increased in renal transplant patients following treatment with alemtuzumab. Am J Transplant. 2009 Aug;9(8):1835-45. doi: 10.1111/j.1600-6143.2009.02710.x. Epub 2009 Jun 12.
citation: Shlipak MG, Matsushita K, Arnlov J, Inker LA, Katz R, Polkinghorne KR, Rothenbacher D, Sarnak MJ, Astor BC, Coresh J, Levey AS, Gansevoort RT; CKD Prognosis Consortium. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 2013 Sep 5;369(10):932-43. doi: 10.1056/NEJMoa1214234.
citation: Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, Szabolcs PM, Bernstein SH, Magro CM, Williams AD, Hall RP, St Clair EW, Tedder TF. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011 Jan 13;117(2):530-41. doi: 10.1182/blood-2010-07-294249. Epub 2010 Oct 20.
citation: Lehnhardt A, Dunst F, van Husen M, Loos S, Oh J, Eiermann T, Koch M, Kemper MJ. Elevated serum levels of B-cell activating factor in pediatric renal transplant patients. Pediatr Nephrol. 2012 Aug;27(8):1389-95. doi: 10.1007/s00467-012-2142-8. Epub 2012 Mar 28.
citation: Banham G, Prezzi D, Harford S, Taylor CJ, Hamer R, Higgins R, Bradley JA, Clatworthy MR. Elevated pretransplantation soluble BAFF is associated with an increased risk of acute antibody-mediated rejection. Transplantation. 2013 Aug 27;96(4):413-20. doi: 10.1097/TP.0b013e318298dd65.
citation: Thien M, Phan TG, Gardam S, Amesbury M, Basten A, Mackay F, Brink R. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity. 2004 Jun;20(6):785-98. doi: 10.1016/j.immuni.2004.05.010.
citation: Woodland RT, Schmidt MR. Homeostatic proliferation of B cells. Semin Immunol. 2005 Jun;17(3):209-17. doi: 10.1016/j.smim.2005.02.006.
citation: Smith SH, Cancro MP. Cutting edge: B cell receptor signals regulate BLyS receptor levels in mature B cells and their immediate progenitors. J Immunol. 2003 Jun 15;170(12):5820-3. doi: 10.4049/jimmunol.170.12.5820.
citation: Kandala NB, Connock M, Grove A, Sutcliffe P, Mohiuddin S, Hartley L, Court R, Cummins E, Gordon C, Clarke A. Belimumab: a technological advance for systemic lupus erythematosus patients? Report of a systematic review and meta-analysis. BMJ Open. 2013 Jul 19;3(7):e002852. doi: 10.1136/bmjopen-2013-002852. Print 2013.
citation: Vadasz Z, Toubi E. [Belimumab--the biological drug for systemic lupus erythematosus: as discussed during the American College of Rheumatology (ACR) conference - 2012]. Harefuah. 2013 May;152(5):304-6. No abstract available. Hebrew.