Oct 14, 2025
Novel Podocyte-Targeting Biomarkers in Membranous Nephropathy: Looking beyond PLA2R & THSD7A – A Systematic Review
- Zoi Kleinaki1
- 1General Hospital of Athens ''LAIKO''
- Zoi Kleinaki: Nephrology & Transplantation Department
Protocol Citation: Zoi Kleinaki 2025. Novel Podocyte-Targeting Biomarkers in Membranous Nephropathy: Looking beyond PLA2R & THSD7A – A Systematic Review. protocols.io https://dx.doi.org/10.17504/protocols.io.6qpvrw2n3lmk/v1
License: This is an open access protocol distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Protocol status: Working
We use this protocol and it's working
Created: October 13, 2025
Last Modified: October 14, 2025
Protocol Integer ID: 229710
Keywords: membranous nephropathy, biomarkers, membranous glomerulopathy, NELL-1, NCAM-1, EXT1/EXT2, PCDH7, TGFBR3, serum biomarkers, targeting biomarkers in membranous nephropathy, new biomarkers of membranous nephropathy, systematic review membranous nephropathy, membranous nephropathy, autoimmune glomerular disease, nephrotic syndrome, frequent cause of nephrotic syndrome, transforming growth factor beta receptor, novel podocyte, new biomarker, targeting biomarker, neural cell adhesion molecule, thrombospondin type, protocadherin7, thsd7a
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Abstract
Membranous Nephropathy is an autoimmune glomerular disease and is the most frequent cause of nephrotic syndrome among Caucasian adults. Following Anti-Phospholipase A2 Receptor (PLA2R) and Thrombospondin Type 1 Domain Containing 7A (THSD7A), new biomarkers of Membranous Nephropathy (MN) in adults, including Neural Epidermal growth factor-Like 1 (NELL-1), Exostosin 1/ Exostosin 2 (EXT1/ EXT2), Protocadherin7 (PCDH7), Transforming Growth Factor Beta Receptor 3 (TGFBR3) and Neural Cell Adhesion Molecule 1 (NCAM1), have been discovered. PubMed, Scopus, Web of Science and CENTRAL will be systematically searched until February 2025. Two reviewers will determine study eligibility according to the title and the abstract of the articles. The full-text publications of potentially relevant articles will be retrieved and rescreened by the same investigators. ROBINS-E tool will be used to evaluate quality of evidence and risk of bias in the included studies.
Guidelines
PRISMA Guidelines
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for
reporting systematic reviews. J Clin Epidemiol (2021);134:178-189.
Robins-E for bias assessement of non-ramdomised trials
Higgins JPT, Morgan RL, Rooney AA, et al. A tool to assess risk of bias in non-randomized follow-
up studies of exposure effects (ROBINS-E). Environ Int (2024);186:108602.
Materials
PubMed, Scopus, Web of Science and CENTRAL (Cochrane Central Register of
Controlled Trials) were systematically searched from inception until 17 TH of February 2025.
Troubleshooting
Before start
The aim of the present systematic review is to evaluate all available data of patients with
MN and positivity of at least one of the aforementioned biomarkers.
Novel Podocyte-Targeting Biomarkers in Membranous Nephropathy: Looking beyond PLA2R & THSD7A – A Systematic Review
The present systematic review will be conducted in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.
Eligibility Criteria
PECOS method (P=Population, E=Exposure, C=Control, O=Outcomes, S=Studies), as
per PRISMA guidelines, will be used to identify eligible studies. The population of the
study will include adult patients with primary or secondary, biopsy-proven MN. The
exposure of interest is positivity of either NELL-1 or EXT1/EXT2 or PCDH7 or
TGFBR3 or NCAM1 in serum or tissue. Control group included patients
tested showing no expression of the above-mentioned markers. The primary study
outcome is to assess all available evidence regarding the importance of patients with
biopsy proven MN and positivity of either NELL-1 or EXT1/EXT2 or PCDH7 or TGFBR3
or NCAM1. Secondary outcomes are recording of all their clinical, histological
and prognostic characteristics, along with possible treatment interventions. Primary
research papers including cohort studies, case control or case series will be included.
Descriptive, animal and in vivo studies as well as review articles, editorials, opinion
articles and case reports will be excluded.
Literature Search
PubMed, Scopus, Web of Science and CENTRAL (Cochrane Central Register of
Controlled Trials) will be systematically searched from inception until 17 TH of February 2025. Full reference lists of the studies included will also be systematically searched
for potential eligible articles. The following search algorithm will be applied:
("Glomerulonephritis, Membranous"[Mesh] OR “membranous nephropathy” OR
“membranous glomerulonephritis” OR “membranous nephritis” OR “membranous
glomerulopathy”) AND (NELL-1 OR “Neural epidermal growth factor-like 1” OR
EXT1/EXT2 OR exostosin 1 / exostosin 2 OR PCDH7 OR Protocadherin7 OR TGFBR3
OR Transforming Growth Factor Beta Receptor 3 OR NCAM1 OR Neural Cell
Adhesion Molecule 1), in order to assess patients with Membranous Nephropathy
and positivity for either NELL-1 or EXT1/EXT2 or PCDH7 or TGFBR3 or NCAM1,
among studies published in English.
Study selection & Quality assessment
Two reviewers (K.Z & B.I.) will determine study eligibility according to the title and the
abstract of the articles. The full-text publications of potentially relevant articles will be
retrieved and rescreened by the same investigators (K.Z. & B.I.). Disagreements will be
resolved by consensus following full text screening. ROBINS-E tool will be used to
evaluate quality of evidence and risk of bias in the included studies in terms of
confounding, selection of participants, classification of exposures, deviations from
intended exposures, missing data, measurement of outcomes and selection of
reported results.
Data Extraction & Synthesis
Data extraction will then be performed by K.Z., using an extraction form in an Excel‱
spreadsheet. Information extracted will include: author, country, study period, study
design, number of individuals with biopsy-proven MN, demographics, assessment of
one, or more, of the following NELL-1 or EXT/EXT2 or PCDH7 or TGFBR3 or NCAM1,
tissue biomarker diagnostic technique used, serum biomarker testing, when
available, and possible correlations including autoimmune diseases, malignancies,
medication or alternative medicine exposure. Qualitative synthesis of the data will
then be performed.
Protocol references
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J Clin Epidemiol (2021);134:178-189.
Higgins JPT, Morgan RL, Rooney AA, et al. A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E). Environ Int (2024);186:108602.
Couser WG. Primary Membranous Nephropathy. Clin J Am Soc Nephrol (2017); 12(6):983–997.
Francis JM, Beck LH Jr., Salant DJ. Membranous nephropathy: A journey from bench to bedside. Am J Kidney Dis (2016);68(1):138–147.
Membranous nephropathy. Nat Rev Dis Primers (2021);7(1):70.
Ronco P, Debiec H. Pathophysiological Advances in Membranous Nephropathy: Time for a Shift in Patient’s Care. Lancet (2015);385 (9981):1983–1992.
Beck LH Jr., Salant DJ. Membranous nephropathy: from models to man. J Clin Invest (2014);124(6):2307–2314.
Beck LH, Bonegio RGB, Lambeau Gr, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. (2009);361:11–21.
Sanjeev Sethi, Fernando C Fervenza, Membranous nephropathy—diagnosis and identification of target antigens, Nephrology Dialysis Transplantation (2024); 39:(4)600–606.
Liu Q, Liu J, Lin B, et al. Novel Biomarkers in Membranous Nephropathy. Front Immunol (2022);13:845767.