Skip to main content
Top
Published in: Pediatric Nephrology 8/2012

01-08-2012 | Original Article

Elevated serum levels of B-cell activating factor in pediatric renal transplant patients

Authors: Anja Lehnhardt, Franziska Dunst, Michael van Husen, Sebastian Loos, Jun Oh, Thomas Eiermann, Martina Koch, Markus J. Kemper

Published in: Pediatric Nephrology | Issue 8/2012

Login to get access

Abstract

Background

B-cells are increasingly recognized as important players in alloimmunity. B cell-activating factor (BAFF) and its receptor BAFF-R are essential for B-cell differentiation and survival. Data on BAFF levels in pediatric renal transplant (RT) patients are scarce.

Objective

It is known from adult data that elevated BAFF levels correlate with an unfavorable outcome in bone marrow and kidney recipients. To analyze this hypothesis in pediatric renal transplant patients we performed a cross-sectional analysis of serum BAFF levels, lymphocyte surface BAFF-R expression, and clinical variables in a cohort of 43 pediatric renal transplant patients.

Methods

We studied serum BAFF, CD19+ B-, and FoxP3+ regulatory T-cells (Tregs) and BAFF-R expression in 43 children 2.9 (0.1–12.4) years after RT on maintenance immunosuppression. Twenty-two healthy children and 19 children with chronic kidney disease stage 5 (CKD5) served as controls.

Results

BAFF levels were significantly higher in RT patients than in healthy children (1,435±574 vs 894±189 pg/mL; p<0.0001) whereas numbers of B-cells and Tregs were significantly lower. BAFF-R expression on B-cells was decreased after RT (531±334 vs 707±257 MFI; p<0.005), BAFF inversely correlated with BAFF-R (r=-0.5022, p<0.006), but not with B-cell count. BAFF was elevated in CKD5 patients (1,276±294 pg/mL). In RT patients BAFF was significantly higher in those with eGFR <60 ml/min/1.73m2 (1,553±447 vs 1,234±323 pg/mL; p=0.02). BAFF levels and BAFF-R expression did not correlate with HLA antibody status, time after transplantation, age or gender of the patients.

Conclusion

Serum BAFF concentrations were significantly elevated in pediatric RT patients. They correlated with decreased BAFF-R expression on CD19+ B-cells and impaired allograft function. Our findings of a dysregulated BAFF/BAFF-R axis may be of clinical relevance after renal transplantation and therefore underline the importance of further research into BAFF-dependent mechanisms.
Literature
1.
go back to reference Kirk AD, Turgeon NA, Iwakoshi NN (2010) B cells and transplantation tolerance. Nat Rev Nephrol 6:584–593PubMedCrossRef Kirk AD, Turgeon NA, Iwakoshi NN (2010) B cells and transplantation tolerance. Nat Rev Nephrol 6:584–593PubMedCrossRef
2.
go back to reference Muorah MR, Brogan PA, Sebire NJ, Trompeter RS, Marks SD (2009) Dense B cell infiltrates in paediatric renal transplant biopsies are predictive of allograft loss. Pediatr Transplant 13:217–222PubMedCrossRef Muorah MR, Brogan PA, Sebire NJ, Trompeter RS, Marks SD (2009) Dense B cell infiltrates in paediatric renal transplant biopsies are predictive of allograft loss. Pediatr Transplant 13:217–222PubMedCrossRef
3.
go back to reference Lehnhardt A, Mengel M, Pape L, Ehrich JH, Offner G, Strehlau J (2006) Nodular B-cell aggregates associated with treatment refractory renal transplant rejection resolved by rituximab. Am J Transplant 6:847–851PubMedCrossRef Lehnhardt A, Mengel M, Pape L, Ehrich JH, Offner G, Strehlau J (2006) Nodular B-cell aggregates associated with treatment refractory renal transplant rejection resolved by rituximab. Am J Transplant 6:847–851PubMedCrossRef
4.
go back to reference Zarkhin V, Li L, Kambham N, Sigdel T, Salvatierra O, Sarwal MM (2008) A randomized, prospective trial of rituximab for acute rejection in pediatric renal transplantation. Am J Transplant 8:2607–2617PubMedCrossRef Zarkhin V, Li L, Kambham N, Sigdel T, Salvatierra O, Sarwal MM (2008) A randomized, prospective trial of rituximab for acute rejection in pediatric renal transplantation. Am J Transplant 8:2607–2617PubMedCrossRef
5.
go back to reference Kohei N, Hirai T, Omoto K, Ishida H, Tanabe K (2012) Chronic antibody-mediated rejection is reduced by targeting B-cell immunity during an introductory period. Am J Transplant 12:469–476PubMedCrossRef Kohei N, Hirai T, Omoto K, Ishida H, Tanabe K (2012) Chronic antibody-mediated rejection is reduced by targeting B-cell immunity during an introductory period. Am J Transplant 12:469–476PubMedCrossRef
6.
go back to reference Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM (1999) BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285:260–263PubMedCrossRef Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM (1999) BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285:260–263PubMedCrossRef
7.
go back to reference Mackay F, Browning JL (2002) BAFF: a fundamental survival factor for B cells. Nat Rev Immunol 2:465–475PubMedCrossRef Mackay F, Browning JL (2002) BAFF: a fundamental survival factor for B cells. Nat Rev Immunol 2:465–475PubMedCrossRef
8.
go back to reference Rodig SJ, Shahsafaei A, Li B, Mackay CR, Dorfman DM (2005) BAFF-R, the major B cell-activating factor receptor, is expressed on most mature B cells and B-cell lymphoproliferative disorders. Hum Pathol 36:1113–1119PubMedCrossRef Rodig SJ, Shahsafaei A, Li B, Mackay CR, Dorfman DM (2005) BAFF-R, the major B cell-activating factor receptor, is expressed on most mature B cells and B-cell lymphoproliferative disorders. Hum Pathol 36:1113–1119PubMedCrossRef
9.
go back to reference Mackay F, Leung H (2006) The role of the BAFF/APRIL system on T cell function. Semin Immunol 18:284–289PubMedCrossRef Mackay F, Leung H (2006) The role of the BAFF/APRIL system on T cell function. Semin Immunol 18:284–289PubMedCrossRef
10.
go back to reference Cheema GS, Roschke V, Hilbert DM, Stohl W (2001) Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 44:1313–1319PubMedCrossRef Cheema GS, Roschke V, Hilbert DM, Stohl W (2001) Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 44:1313–1319PubMedCrossRef
12.
go back to reference Vallerskog T, Heimburger M, Gunnarsson I, Zhou W, Wahren-Herlenius M, Trollmo C, Malmstrom V (2006) Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther 8:R167PubMedCrossRef Vallerskog T, Heimburger M, Gunnarsson I, Zhou W, Wahren-Herlenius M, Trollmo C, Malmstrom V (2006) Differential effects on BAFF and APRIL levels in rituximab-treated patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Res Ther 8:R167PubMedCrossRef
13.
go back to reference Ansell SM, Novak AJ, Ziesmer S, Price-Troska T, LaPlant B, Dillon SR, Witzig TE (2009) Serum BLyS levels increase after rituximab as initial therapy in patients with follicular Grade 1 non-Hodgkin lymphoma. Am J Hematol 84:71–73PubMedCrossRef Ansell SM, Novak AJ, Ziesmer S, Price-Troska T, LaPlant B, Dillon SR, Witzig TE (2009) Serum BLyS levels increase after rituximab as initial therapy in patients with follicular Grade 1 non-Hodgkin lymphoma. Am J Hematol 84:71–73PubMedCrossRef
14.
go back to reference Zarkhin V, Li L, Sarwal MM (2009) BAFF may modulate the rate of B-cell repopulation after rituximab therapy for acute renal transplant rejection. Transplantation 88:1229–1230PubMedCrossRef Zarkhin V, Li L, Sarwal MM (2009) BAFF may modulate the rate of B-cell repopulation after rituximab therapy for acute renal transplant rejection. Transplantation 88:1229–1230PubMedCrossRef
15.
go back to reference Bloom D, Chang Z, Pauly K, Kwun J, Fechner J, Hayes C, Samaniego M, Knechtle S (2009) BAFF is increased in renal transplant patients following treatment with alemtuzumab. Am J Transplant 9:1835–1845PubMedCrossRef Bloom D, Chang Z, Pauly K, Kwun J, Fechner J, Hayes C, Samaniego M, Knechtle S (2009) BAFF is increased in renal transplant patients following treatment with alemtuzumab. Am J Transplant 9:1835–1845PubMedCrossRef
16.
go back to reference Dorner T, Radbruch A, Burmester GR (2009) B-cell-directed therapies for autoimmune disease. Nat Rev Rheumatol 5:433–441PubMedCrossRef Dorner T, Radbruch A, Burmester GR (2009) B-cell-directed therapies for autoimmune disease. Nat Rev Rheumatol 5:433–441PubMedCrossRef
17.
go back to reference Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M, Ho VT, Alyea EP, Koreth J, Blazar BR, Soiffer RJ, Antin JH, Ritz J (2009) Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 113:3865–3874PubMedCrossRef Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M, Ho VT, Alyea EP, Koreth J, Blazar BR, Soiffer RJ, Antin JH, Ritz J (2009) Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 113:3865–3874PubMedCrossRef
18.
go back to reference Xu H, He X, Liu Q, Shi D, Chen Y, Zhu Y, Zhang X (2009) Abnormal high expression of B-cell activating factor belonging to the TNF superfamily (BAFF) associated with long-term outcome in kidney transplant recipients. Transplant Proc 41:1552–1556PubMedCrossRef Xu H, He X, Liu Q, Shi D, Chen Y, Zhu Y, Zhang X (2009) Abnormal high expression of B-cell activating factor belonging to the TNF superfamily (BAFF) associated with long-term outcome in kidney transplant recipients. Transplant Proc 41:1552–1556PubMedCrossRef
19.
go back to reference Filler G, Lepage N (2003) Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol 18:981–985PubMedCrossRef Filler G, Lepage N (2003) Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol 18:981–985PubMedCrossRef
20.
go back to reference White C, Akbari A, Hussain N, Dinh L, Filler G, Lepage N, Knoll GA (2007) Chronic kidney disease stage in renal transplantation classification using cystatin C and creatinine-based equations. Nephrol Dial Transplant 22:3013–3020PubMedCrossRef White C, Akbari A, Hussain N, Dinh L, Filler G, Lepage N, Knoll GA (2007) Chronic kidney disease stage in renal transplantation classification using cystatin C and creatinine-based equations. Nephrol Dial Transplant 22:3013–3020PubMedCrossRef
21.
go back to reference Wolpl A, Halder T, Kalbacher H, Neumeyer H, Siemoneit K, Goldmann SF, Eiermann TH (1998) Human monoclonal antibody with T-cell-like specificity recognizes MHC class I self-peptide presented by HLA-DR1 on activated cells. Tissue Antigens 51:258–269PubMedCrossRef Wolpl A, Halder T, Kalbacher H, Neumeyer H, Siemoneit K, Goldmann SF, Eiermann TH (1998) Human monoclonal antibody with T-cell-like specificity recognizes MHC class I self-peptide presented by HLA-DR1 on activated cells. Tissue Antigens 51:258–269PubMedCrossRef
22.
go back to reference Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, Wara DW, Douglas SD, Luzuriaga K, McFarland EJ, Yogev R, Rathore MH, Levy W, Graham BL, Spector SA (2003) Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 112:973–980PubMedCrossRef Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER, Wara DW, Douglas SD, Luzuriaga K, McFarland EJ, Yogev R, Rathore MH, Levy W, Graham BL, Spector SA (2003) Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 112:973–980PubMedCrossRef
23.
go back to reference Pranzatelli MR, Tate ED, Hoefgen ER, Swan JA, Colliver JA (2008) Therapeutic down-regulation of central and peripheral B-cell-activating factor (BAFF) production in pediatric opsoclonus-myoclonus syndrome. Cytokine 44:26–32PubMedCrossRef Pranzatelli MR, Tate ED, Hoefgen ER, Swan JA, Colliver JA (2008) Therapeutic down-regulation of central and peripheral B-cell-activating factor (BAFF) production in pediatric opsoclonus-myoclonus syndrome. Cytokine 44:26–32PubMedCrossRef
24.
go back to reference Zarkhin V, Lovelace PA, Li L, Hsieh SC, Sarwal MM (2011) Phenotypic evaluation of B-cell subsets after rituximab for treatment of acute renal allograft rejection in pediatric recipients. Transplantation 91:1010–1018PubMedCrossRef Zarkhin V, Lovelace PA, Li L, Hsieh SC, Sarwal MM (2011) Phenotypic evaluation of B-cell subsets after rituximab for treatment of acute renal allograft rejection in pediatric recipients. Transplantation 91:1010–1018PubMedCrossRef
25.
go back to reference Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, Plebani A, Lougaris V, Quinti I, Thon V, Litzman J, Schlesier M, Warnatz K, Thiel J, Rolink AG, Eibel H (2012) Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J Immunol 188:497–503PubMedCrossRef Kreuzaler M, Rauch M, Salzer U, Birmelin J, Rizzi M, Grimbacher B, Plebani A, Lougaris V, Quinti I, Thon V, Litzman J, Schlesier M, Warnatz K, Thiel J, Rolink AG, Eibel H (2012) Soluble BAFF levels inversely correlate with peripheral B cell numbers and the expression of BAFF receptors. J Immunol 188:497–503PubMedCrossRef
26.
go back to reference Demirkiran A, Hendrikx TK, Baan CC, van der Laan LJ (2008) Impact of immunosuppressive drugs on CD4 + CD25 + FOXP3+ regulatory T cells: does in vitro evidence translate to the clinical setting? Transplantation 85:783–789PubMedCrossRef Demirkiran A, Hendrikx TK, Baan CC, van der Laan LJ (2008) Impact of immunosuppressive drugs on CD4 + CD25 + FOXP3+ regulatory T cells: does in vitro evidence translate to the clinical setting? Transplantation 85:783–789PubMedCrossRef
27.
go back to reference Ng LG, Sutherland AP, Newton R, Qian F, Cachero TG, Scott ML, Thompson JS, Wheway J, Chtanova T, Groom J, Sutton IJ, Xin C, Tangye SG, Kalled SL, Mackay F, Mackay CR (2004) B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol 173:807–817PubMed Ng LG, Sutherland AP, Newton R, Qian F, Cachero TG, Scott ML, Thompson JS, Wheway J, Chtanova T, Groom J, Sutton IJ, Xin C, Tangye SG, Kalled SL, Mackay F, Mackay CR (2004) B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol 173:807–817PubMed
28.
go back to reference Pahl MV, Gollapudi S, Sepassi L, Gollapudi P, Elahimehr R, Vaziri ND (2009) Effect of end-stage renal disease on B-lymphocyte subpopulations, IL-7, BAFF and BAFF receptor expression. Nephrol Dial Transplant 25:205–212PubMedCrossRef Pahl MV, Gollapudi S, Sepassi L, Gollapudi P, Elahimehr R, Vaziri ND (2009) Effect of end-stage renal disease on B-lymphocyte subpopulations, IL-7, BAFF and BAFF receptor expression. Nephrol Dial Transplant 25:205–212PubMedCrossRef
29.
go back to reference Riccobene TA, Miceli RC, Lincoln C, Knight Y, Meadows J, Stabin MG, Sung C (2003) Rapid and specific targeting of 125I-labeled B lymphocyte stimulator to lymphoid tissues and B cell tumors in mice. J Nucl Med 44:422–433PubMed Riccobene TA, Miceli RC, Lincoln C, Knight Y, Meadows J, Stabin MG, Sung C (2003) Rapid and specific targeting of 125I-labeled B lymphocyte stimulator to lymphoid tissues and B cell tumors in mice. J Nucl Med 44:422–433PubMed
30.
go back to reference Bouts AH, Out TA, Schroder CH, Monnens LA, Nauta J, Krediet RT, Davin JC (2000) Characteristics of peripheral and peritoneal white blood cells in children with chronic renal failure, dialyzed or not. Perit Dial Int 20:748–756PubMed Bouts AH, Out TA, Schroder CH, Monnens LA, Nauta J, Krediet RT, Davin JC (2000) Characteristics of peripheral and peritoneal white blood cells in children with chronic renal failure, dialyzed or not. Perit Dial Int 20:748–756PubMed
31.
go back to reference Thorn M, Lewis RH, Mumbey-Wafula A, Kantrowitz S, Spatz LA (2009) BAFF overexpression promotes anti-dsDNA B-cell maturation and antibody secretion. Cell Immunol 261:9–22PubMedCrossRef Thorn M, Lewis RH, Mumbey-Wafula A, Kantrowitz S, Spatz LA (2009) BAFF overexpression promotes anti-dsDNA B-cell maturation and antibody secretion. Cell Immunol 261:9–22PubMedCrossRef
32.
go back to reference Thaunat O, Patey N, Gautreau C, Lechaton S, Fremeaux-Bacchi V, Dieu-Nosjean MC, Cassuto-Viguier E, Legendre C, Delahousse M, Lang P, Michel JB, Nicoletti A (2008) B cell survival in intragraft tertiary lymphoid organs after rituximab therapy. Transplantation 85:1648–1653PubMedCrossRef Thaunat O, Patey N, Gautreau C, Lechaton S, Fremeaux-Bacchi V, Dieu-Nosjean MC, Cassuto-Viguier E, Legendre C, Delahousse M, Lang P, Michel JB, Nicoletti A (2008) B cell survival in intragraft tertiary lymphoid organs after rituximab therapy. Transplantation 85:1648–1653PubMedCrossRef
33.
go back to reference Stohl W, Hiepe F, Latinis KM, Thomas M, Scheinberg MA, Clarke A, Aranow C, Wellborne FR, Abud-Mendoza C, Hough DR, Pineda L, Migone TS, Zhong ZJ, Freimuth WW, Chatham WW (2012) Belimumab reduces autoantibodies, normalizes low complement, and reduces select B-cell populations in patients with systemic lupus erythematosus. Arthritis Rheum doi: 10.1002/art.34400 Stohl W, Hiepe F, Latinis KM, Thomas M, Scheinberg MA, Clarke A, Aranow C, Wellborne FR, Abud-Mendoza C, Hough DR, Pineda L, Migone TS, Zhong ZJ, Freimuth WW, Chatham WW (2012) Belimumab reduces autoantibodies, normalizes low complement, and reduces select B-cell populations in patients with systemic lupus erythematosus. Arthritis Rheum doi: 10.​1002/​art.​34400
Metadata
Title
Elevated serum levels of B-cell activating factor in pediatric renal transplant patients
Authors
Anja Lehnhardt
Franziska Dunst
Michael van Husen
Sebastian Loos
Jun Oh
Thomas Eiermann
Martina Koch
Markus J. Kemper
Publication date
01-08-2012
Publisher
Springer-Verlag
Published in
Pediatric Nephrology / Issue 8/2012
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-012-2142-8

Other articles of this Issue 8/2012

Pediatric Nephrology 8/2012 Go to the issue