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Proteomic profiling of kidney biopsies in nephrotic syndrome

ABSTRACT: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are patterns of kidney injury observed in the filtering units of the kidney known as glomeruli. From the NURTuRE cohort of individuals with nephrotic syndrome (NS), we performed laser microdissection and mass spectrometry analysis of kidney biopsy samples to identify proteomic patterns of disease. 56 individuals with idiopathic NS segregated by histological pattern (37 MCD and 19 FSGS) across three age groups: early childhood (0-6 years), late childhood (6-18 years) and adult (>18 years). We identified global differences in glomerular cell and extracellular matrix composition related to both histological pattern and age.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

SUBMITTER: Anna S Li

LAB HEAD: Rachel Lennon

PROVIDER: PXD053362 | Pride | 2024-07-15

REPOSITORIES: Pride

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			Action	DRS
	20211027_LennonR_WilliamsE_01.raw	Raw
	20211027_LennonR_WilliamsE_02.raw	Raw
	20211027_LennonR_WilliamsE_03.raw	Raw
	20211027_LennonR_WilliamsE_04.raw	Raw
	20211027_LennonR_WilliamsE_05.raw	Raw

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Project description:Recurrence of focal segmental glomerulosclerosis (rFSGS) after kidney transplantation is a cause of early and accelerated graft loss. Immuneadsorption can alleviate renal dysfunction and suggests that circulating antibodies (Ab) are likely implicated in disease pathogenesis. To evaluate pathogenic Ab in rFSGS, we processed 141 unique serum samples from patients with and without primary rFSGS (n=64) and 34 non-FSGS control, transplanted at five (US and EU) hospitals. 9000 antigens were screened in pre-transplant sera by protein arrays and 10 Ab targeting glomerular antigens were selected for ELISA validation. A panel of 7 Ab (CD40, PTPRO, CGB-5, FAS, P2RY11, SNRPB2 and APOL2) could predict post-transplant FSGS recurrence with 92% accuracy. Pre-transplant elevation of anti-CD40 Ab levels alone had a substantial impact (78% accuracy) on the identification of 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 of these antigens in FSGS compared to non-FSGS. Anti-CD40 Ab purified from rFSGS patients were uniquely pathogenic in human podocyte cultures; injection of these Ab resulted in heightened proteinuria, independently and in combination with suPAR in a rodent model, abrogated by injection of monoclonal Ab to CD40. In conclusion, a panel of 7 Ab can identify primary FSGS patients at high risk of recurrence prior to transplantation, allowing for customized therapies and improved patient selection for transplant. Intra-renal CD40 is an important axis of disease pathogenesis, and human trials of anti-CD40 therapies are warranted to evaluate their efficacy in preventing rFSGS and improving graft survival. The purpose of the study was to identify potential auto-Abs associated with rFSGS. We used a discovery set of pre-transplant sera from 20 unique patients with biopsy confirmed diagnosis of primary FSGS as their cause of ESRD, of which 10 had progressed to rFSGS within the first post-transplant year and 10 did not have recurrence of proteinuria or histological disease after transplantation (nrFSGS).

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Proteomic profiling of kidney biopsies in nephrotic syndrome

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