Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1

Sanjeev Sethi; Benjamin Madden; Marta Casal Moura; Samih H. Nasr; Nattawat Klomjit; Lou Ann Gross; Vivian Negron; M. Cristine Charlesworth; Mariam P. Alexander; Nelson Leung; Ulrich Specks; Fernando C. Fervenza; Mark Haas

doi:10.1681/ASN.2021111488

Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1

Sanjeev Sethi
, Benjamin Madden
, Marta Casal Moura
, Samih H. Nasr
, Nattawat Klomjit
, Lou Ann Gross
, Vivian Negron
, M. Cristine Charlesworth
, Mariam P. Alexander
, Nelson Leung
, Ulrich Specks
, Fernando C. Fervenza
, Mark Haas

Medicine - Renal and Hypertension Division

Research output: Contribution to journal › Article › peer-review

86 Scopus citations

Abstract

BACKGROUND: Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown.

METHODS: We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'.

RESULTS: MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN.

CONCLUSIONS: FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.

Original language	English (US)
Pages (from-to)	1033-1044
Number of pages	12
Journal	Journal of the American Society of Nephrology
Volume	33
Issue number	5
DOIs	https://doi.org/10.1681/ASN.2021111488
State	Published - May 2022

Bibliographical note

Funding Information:
F.C. Fervenza reports having consultancy agreements with Alexion Pharmaceuticals, Alnylam, ByoCrystal, Novartis, and Takeda; receiving research funding from Chemocentryx, Genentech, Janssen Pharmaceutical, Questcor/Mallinckrodt, and Retrophin; serving in an advisory or leadership role for JASN, Kidney International, Nephrology, Nephrology Dialysis and Transplantation, and UpToDate; and receiving honoraria from UpTo-Date. M. Haas reports having consultancy agreements with Argenx, Astra-Zeneca, CareDx, Novartis, Retrophin, and Shire Viropharma Inc.; serving in an advisory or leadership role for Argenx, CareDx, Novartis, and Retro-phin; and receiving honoraria from, and serving on a speakers bureau for, CareDx. N. Leung reports having consultancy agreements with AbbVie, Lilly, and Omeros; receiving research funding from Alnylam and Omeros; having other interests in, or relationships with, Amyloidosis Research Consortium; having ownership interest in Checkpoint Therapeutics; and serving in an advisory or leadership role for Journal of Nephrology. S. Sethi reports receiving honoraria for teaching, conducting grand rounds, giving lectures, reviewing slides for a study for Novartis, and from UpToDate. U. Specks reports having ownership interest in AbbVie, Johnson & Johnson, Pfizer, and Viatris; receiving research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myer Squibb, Genentech, and GlaxoSmithKline; having consultancy agreements with AstraZeneca and ChemoCentryx; and having patents with, or receiving royalties from, Mayo Foundation for Education and Research and UpToDate. All remaining authors have nothing to disclose.

Publisher Copyright:
© 2022 by the American Society of Nephrology.

Keywords

Autoantibodies
Cadherins
Female
Glomerulonephritis, Membranous
Hematopoietic Stem Cell Transplantation/adverse effects
High-Temperature Requirement A Serine Peptidase 1
Humans
Immunoglobulin G
Male
Protocadherins
Receptors, Phospholipase A2
Tandem Mass Spectrometry

PubMed: MeSH publication types

Journal Article

Publisher link

10.1681/ASN.2021111488

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Sethi, S., Madden, B., Casal Moura, M., Nasr, S. H., Klomjit, N., Gross, L. A., Negron, V., Charlesworth, M. C., Alexander, M. P., Leung, N., Specks, U., Fervenza, F. C., & Haas, M. (2022). Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1. Journal of the American Society of Nephrology, 33(5), 1033-1044. https://doi.org/10.1681/ASN.2021111488

Sethi, S, Madden, B, Casal Moura, M, Nasr, SH, Klomjit, N, Gross, LA, Negron, V, Charlesworth, MC, Alexander, MP, Leung, N, Specks, U, Fervenza, FC & Haas, M 2022, 'Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1', Journal of the American Society of Nephrology, vol. 33, no. 5, pp. 1033-1044. https://doi.org/10.1681/ASN.2021111488

@article{fe5c8b8670294126805bd6f46d8b6548,

title = "Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1",

abstract = "BACKGROUND: Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown.METHODS: We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'.RESULTS: MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN.CONCLUSIONS: FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.",

keywords = "Autoantibodies, Cadherins, Female, Glomerulonephritis, Membranous, Hematopoietic Stem Cell Transplantation/adverse effects, High-Temperature Requirement A Serine Peptidase 1, Humans, Immunoglobulin G, Male, Protocadherins, Receptors, Phospholipase A2, Tandem Mass Spectrometry",

author = "Sanjeev Sethi and Benjamin Madden and \{Casal Moura\}, Marta and Nasr, \{Samih H.\} and Nattawat Klomjit and Gross, \{Lou Ann\} and Vivian Negron and Charlesworth, \{M. Cristine\} and Alexander, \{Mariam P.\} and Nelson Leung and Ulrich Specks and Fervenza, \{Fernando C.\} and Mark Haas",

note = "Funding Information: F.C. Fervenza reports having consultancy agreements with Alexion Pharmaceuticals, Alnylam, ByoCrystal, Novartis, and Takeda; receiving research funding from Chemocentryx, Genentech, Janssen Pharmaceutical, Questcor/Mallinckrodt, and Retrophin; serving in an advisory or leadership role for JASN, Kidney International, Nephrology, Nephrology Dialysis and Transplantation, and UpToDate; and receiving honoraria from UpTo-Date. M. Haas reports having consultancy agreements with Argenx, Astra-Zeneca, CareDx, Novartis, Retrophin, and Shire Viropharma Inc.; serving in an advisory or leadership role for Argenx, CareDx, Novartis, and Retro-phin; and receiving honoraria from, and serving on a speakers bureau for, CareDx. N. Leung reports having consultancy agreements with AbbVie, Lilly, and Omeros; receiving research funding from Alnylam and Omeros; having other interests in, or relationships with, Amyloidosis Research Consortium; having ownership interest in Checkpoint Therapeutics; and serving in an advisory or leadership role for Journal of Nephrology. S. Sethi reports receiving honoraria for teaching, conducting grand rounds, giving lectures, reviewing slides for a study for Novartis, and from UpToDate. U. Specks reports having ownership interest in AbbVie, Johnson \& Johnson, Pfizer, and Viatris; receiving research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myer Squibb, Genentech, and GlaxoSmithKline; having consultancy agreements with AstraZeneca and ChemoCentryx; and having patents with, or receiving royalties from, Mayo Foundation for Education and Research and UpToDate. All remaining authors have nothing to disclose. Publisher Copyright: {\textcopyright} 2022 by the American Society of Nephrology.",

year = "2022",

month = may,

doi = "10.1681/ASN.2021111488",

language = "English (US)",

volume = "33",

pages = "1033--1044",

journal = "Journal of the American Society of Nephrology",

issn = "1046-6673",

publisher = "Wolters Kluwer Health",

number = "5",

}

TY - JOUR

T1 - Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1

AU - Sethi, Sanjeev

AU - Madden, Benjamin

AU - Casal Moura, Marta

AU - Nasr, Samih H.

AU - Klomjit, Nattawat

AU - Gross, Lou Ann

AU - Negron, Vivian

AU - Charlesworth, M. Cristine

AU - Alexander, Mariam P.

AU - Leung, Nelson

AU - Specks, Ulrich

AU - Fervenza, Fernando C.

AU - Haas, Mark

N1 - Funding Information: F.C. Fervenza reports having consultancy agreements with Alexion Pharmaceuticals, Alnylam, ByoCrystal, Novartis, and Takeda; receiving research funding from Chemocentryx, Genentech, Janssen Pharmaceutical, Questcor/Mallinckrodt, and Retrophin; serving in an advisory or leadership role for JASN, Kidney International, Nephrology, Nephrology Dialysis and Transplantation, and UpToDate; and receiving honoraria from UpTo-Date. M. Haas reports having consultancy agreements with Argenx, Astra-Zeneca, CareDx, Novartis, Retrophin, and Shire Viropharma Inc.; serving in an advisory or leadership role for Argenx, CareDx, Novartis, and Retro-phin; and receiving honoraria from, and serving on a speakers bureau for, CareDx. N. Leung reports having consultancy agreements with AbbVie, Lilly, and Omeros; receiving research funding from Alnylam and Omeros; having other interests in, or relationships with, Amyloidosis Research Consortium; having ownership interest in Checkpoint Therapeutics; and serving in an advisory or leadership role for Journal of Nephrology. S. Sethi reports receiving honoraria for teaching, conducting grand rounds, giving lectures, reviewing slides for a study for Novartis, and from UpToDate. U. Specks reports having ownership interest in AbbVie, Johnson & Johnson, Pfizer, and Viatris; receiving research funding from AstraZeneca, Boehringer Ingelheim, Bristol Myer Squibb, Genentech, and GlaxoSmithKline; having consultancy agreements with AstraZeneca and ChemoCentryx; and having patents with, or receiving royalties from, Mayo Foundation for Education and Research and UpToDate. All remaining authors have nothing to disclose. Publisher Copyright: © 2022 by the American Society of Nephrology.

PY - 2022/5

Y1 - 2022/5

N2 - BACKGROUND: Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown.METHODS: We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'.RESULTS: MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN.CONCLUSIONS: FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.

AB - BACKGROUND: Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown.METHODS: We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'.RESULTS: MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN.CONCLUSIONS: FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.

KW - Autoantibodies

KW - Cadherins

KW - Female

KW - Glomerulonephritis, Membranous

KW - Hematopoietic Stem Cell Transplantation/adverse effects

KW - High-Temperature Requirement A Serine Peptidase 1

KW - Humans

KW - Immunoglobulin G

KW - Male

KW - Protocadherins

KW - Receptors, Phospholipase A2

KW - Tandem Mass Spectrometry

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UR - https://www.scopus.com/pages/publications/85129073061#tab=citedBy

U2 - 10.1681/ASN.2021111488

DO - 10.1681/ASN.2021111488

M3 - Article

C2 - 35321939

AN - SCOPUS:85129073061

SN - 1046-6673

VL - 33

SP - 1033

EP - 1044

JO - Journal of the American Society of Nephrology

JF - Journal of the American Society of Nephrology

IS - 5

ER -

Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1

Abstract

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