A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation

Marianne Delville, Tara K. Sigdel, Changli Wei, Jing Li, Szu Chuan Hsieh, Alessia Fornoni, George W Burke, Patrick Bruneval, Maarten Naesens, Annette Jackson, Nada Alachkar, Guillaume Canaud, Christophe Legendre, Dany Anglicheau, Jochen Reiser, Minnie M. Sarwal

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Abstract

Recurrence of focal segmental glomerulosclerosis (rFSGS) after kidney transplantation is a cause of accelerated graft loss. To evaluate pathogenic antibodies (Abs) in rFSGS, we processed 141 serum samples from 64 patients with and without primary rFSGS and 34 non-FSGS control patients transplanted at four hospitals. We screened about 9000 antigens in pretransplant sera and selected 10 Abs targeting glomerular antigens for enzyme-linked immunosorbent assay (ELISA) validation. A panel of seven Abs (CD40, PTPRO, CGB5, FAS, P2RY11, SNRPB2, and APOL2) could predict posttransplant FSGS recurrence with 92% accuracy. Pretransplant elevation of anti-CD40 Ab alone had the best correlation (78% accuracy) with rFSGS risk after transplantation. Epitope mapping of CD40 with customized peptide arrays and rFSGS sera demonstrated altered immunogenicity of the extracellular CD40 domain in rFSGS. Immunohistochemistry of CD40 demonstrated a differential expression in FSGS compared to non-FSGS controls. Anti-CD40 Abs purified from rFSGS patients were particularly pathogenic in human podocyte cultures. Injection of anti-CD40/rFSGS Ab enhanced suPAR (soluble urokinase receptor)-mediated proteinuria in wild-type mice, yet no sensitizing effect was noted in mice deficient in CD40 or in wild-type mice that received blocking Ab to CD40. In conclusion, a panel of seven Abs can help identify primary FSGS patients at high risk of recurrence before transplantation. Intrarenal CD40 (and possibly other specific glomerular antigens) is an important contributor to FSGS disease pathogenesis. Human trials of anti-CD40 therapies are warranted to evaluate their efficacy for preventing rFSGS and improving graft survival.

Original languageEnglish
Article number256ra136
JournalScience Translational Medicine
Volume6
Issue number256
DOIs
StatePublished - Jan 1 2014

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Focal Segmental Glomerulosclerosis
Kidney Transplantation
Recurrence
Antibodies
Antigens
Transplantation
Serum
Epitope Mapping
Podocytes
Urokinase-Type Plasminogen Activator
Graft Survival
Proteinuria
Anti-Idiotypic Antibodies
Enzyme-Linked Immunosorbent Assay
Immunohistochemistry
Transplants
Peptides
Injections

ASJC Scopus subject areas

  • Medicine(all)

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A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. / Delville, Marianne; Sigdel, Tara K.; Wei, Changli; Li, Jing; Hsieh, Szu Chuan; Fornoni, Alessia; Burke, George W; Bruneval, Patrick; Naesens, Maarten; Jackson, Annette; Alachkar, Nada; Canaud, Guillaume; Legendre, Christophe; Anglicheau, Dany; Reiser, Jochen; Sarwal, Minnie M.

In: Science Translational Medicine, Vol. 6, No. 256, 256ra136, 01.01.2014.

Research output: Contribution to journalArticle

Delville, M, Sigdel, TK, Wei, C, Li, J, Hsieh, SC, Fornoni, A, Burke, GW, Bruneval, P, Naesens, M, Jackson, A, Alachkar, N, Canaud, G, Legendre, C, Anglicheau, D, Reiser, J & Sarwal, MM 2014, 'A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation', Science Translational Medicine, vol. 6, no. 256, 256ra136. https://doi.org/10.1126/scitranslmed.3008538
Delville, Marianne ; Sigdel, Tara K. ; Wei, Changli ; Li, Jing ; Hsieh, Szu Chuan ; Fornoni, Alessia ; Burke, George W ; Bruneval, Patrick ; Naesens, Maarten ; Jackson, Annette ; Alachkar, Nada ; Canaud, Guillaume ; Legendre, Christophe ; Anglicheau, Dany ; Reiser, Jochen ; Sarwal, Minnie M. / A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. In: Science Translational Medicine. 2014 ; Vol. 6, No. 256.
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AU - Delville, Marianne

AU - Sigdel, Tara K.

AU - Wei, Changli

AU - Li, Jing

AU - Hsieh, Szu Chuan

AU - Fornoni, Alessia

AU - Burke, George W

AU - Bruneval, Patrick

AU - Naesens, Maarten

AU - Jackson, Annette

AU - Alachkar, Nada

AU - Canaud, Guillaume

AU - Legendre, Christophe

AU - Anglicheau, Dany

AU - Reiser, Jochen

AU - Sarwal, Minnie M.

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N2 - Recurrence of focal segmental glomerulosclerosis (rFSGS) after kidney transplantation is a cause of accelerated graft loss. To evaluate pathogenic antibodies (Abs) in rFSGS, we processed 141 serum samples from 64 patients with and without primary rFSGS and 34 non-FSGS control patients transplanted at four hospitals. We screened about 9000 antigens in pretransplant sera and selected 10 Abs targeting glomerular antigens for enzyme-linked immunosorbent assay (ELISA) validation. A panel of seven Abs (CD40, PTPRO, CGB5, FAS, P2RY11, SNRPB2, and APOL2) could predict posttransplant FSGS recurrence with 92% accuracy. Pretransplant elevation of anti-CD40 Ab alone had the best correlation (78% accuracy) with rFSGS risk after transplantation. Epitope mapping of CD40 with customized peptide arrays and rFSGS sera demonstrated altered immunogenicity of the extracellular CD40 domain in rFSGS. Immunohistochemistry of CD40 demonstrated a differential expression in FSGS compared to non-FSGS controls. Anti-CD40 Abs purified from rFSGS patients were particularly pathogenic in human podocyte cultures. Injection of anti-CD40/rFSGS Ab enhanced suPAR (soluble urokinase receptor)-mediated proteinuria in wild-type mice, yet no sensitizing effect was noted in mice deficient in CD40 or in wild-type mice that received blocking Ab to CD40. In conclusion, a panel of seven Abs can help identify primary FSGS patients at high risk of recurrence before transplantation. Intrarenal CD40 (and possibly other specific glomerular antigens) is an important contributor to FSGS disease pathogenesis. Human trials of anti-CD40 therapies are warranted to evaluate their efficacy for preventing rFSGS and improving graft survival.

AB - Recurrence of focal segmental glomerulosclerosis (rFSGS) after kidney transplantation is a cause of accelerated graft loss. To evaluate pathogenic antibodies (Abs) in rFSGS, we processed 141 serum samples from 64 patients with and without primary rFSGS and 34 non-FSGS control patients transplanted at four hospitals. We screened about 9000 antigens in pretransplant sera and selected 10 Abs targeting glomerular antigens for enzyme-linked immunosorbent assay (ELISA) validation. A panel of seven Abs (CD40, PTPRO, CGB5, FAS, P2RY11, SNRPB2, and APOL2) could predict posttransplant FSGS recurrence with 92% accuracy. Pretransplant elevation of anti-CD40 Ab alone had the best correlation (78% accuracy) with rFSGS risk after transplantation. Epitope mapping of CD40 with customized peptide arrays and rFSGS sera demonstrated altered immunogenicity of the extracellular CD40 domain in rFSGS. Immunohistochemistry of CD40 demonstrated a differential expression in FSGS compared to non-FSGS controls. Anti-CD40 Abs purified from rFSGS patients were particularly pathogenic in human podocyte cultures. Injection of anti-CD40/rFSGS Ab enhanced suPAR (soluble urokinase receptor)-mediated proteinuria in wild-type mice, yet no sensitizing effect was noted in mice deficient in CD40 or in wild-type mice that received blocking Ab to CD40. In conclusion, a panel of seven Abs can help identify primary FSGS patients at high risk of recurrence before transplantation. Intrarenal CD40 (and possibly other specific glomerular antigens) is an important contributor to FSGS disease pathogenesis. Human trials of anti-CD40 therapies are warranted to evaluate their efficacy for preventing rFSGS and improving graft survival.

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