JOURNAL READING

• dr. Devi Albaiti Jannati

• dr. Yulita Galih Pangesti

PROGRAM PENDIDIKAN DOKTER SPESIALIS-1 ILMU KESEHATAN ANAK

FAKULTAS KEDOKTERAN UNIVERSITAS BRAWIJAYA
RSUD DR. SAIFUL ANWAR MALANG
01 Background

02 Methods

03 Outcome

04 Conclusion
 Nephrotic Syndrome

Presence of generalized edema, heavy proteinuria (urine protein >0,2 g/mmol, urinary total protein
excretion >3,5 g/day/1,73m2, hypoalbuminemia <25g/L, Hypercholesterolemia >5,2mmol/L.
Columbia Classification
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A comprehensive analysis of ECM composition and

differences among FSGS variants has not been
performed. Thus, the contribution of abnormal ECM
composition to development and progression of FSGS
remains unclear.
 METHODS

Glomerular ECM ECM proteins in glomeruli from biopsy specimens of

proteins were patients with FSGS not otherwise specified (FSGS-
identified from 38 to NOS) or cFSGS and from normal controls were
124 glomerular distinguished and quantified using mass
sections from each of spectrometry, verified and localized using
seven patients immunohistochemistry (IHC) and confocal
diagnosed with microscopy, and assessed for gene expression. The
cFSGS, six with analysis also quantified urinary excretion of ECM
FSGS-NOS, and two proteins and peptides.
NCs
 METHODS
1. Study Approval
2. Tissue Collection
3. Urine Collection
4. ECM Enrichment and Protein Extraction
5. Proteomic Liquid Chromatography Mass Spectrometry
6. Mass Spectrometry Data Analysis
7. Identification of Candidate Proteases
8. Immunohistochemistry
9. Matrisome Identification within Proteomic Data Sets
10. Confocal Microscopy
11. Glomerular Transcriptome
12. Statistical Analysis
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 OUTCOME
1. Proteomic analysis found 41 ECM proteins with increased abundance in
cFSGS and 17 with increased abundance in FSGS-NOS.
2. IHC and confocal microscopy confirmed the enhanced expression and
colocalization of three proteins—cathepsin B, cathepsin C, and annexin A3
— in cells lining Bowman’s capsule and infiltrating capillary tufts in cFSGS.
Those three proteins were not seen in normal glomerular tufts and were
uncommon in glomerular tufts from other FSGS variants, MCD, and MN.
3. A number of reports indicated a contribution of PECs to the development of
FSGS in humans and animal models, including their proliferation in cFSGS
and increased synthesis of ECM.
4. Colocalization of annexin A3, CD44, and pERK1/2 in this study is also
consistent with a PEC origin of cells infiltrating c FSGS glomeruli
 CONCLUSION
1. Proteomic analysis of glomerular ECM composition shows distinct differences
between c FSGS and FSGS-NOS, suggesting the mechanisms of abnormal
ECM remodeling differ.
2. Extensive glomerular tuft infiltration of cells with an activated PEC phenotype
differentiates c FSGS from other FSGS variants and other proteinuric glomerular
diseases. Those cells introduce a new set of proteases, cathepsins B and C, into
glomeruli.
3. Evidence from animal studies suggests those proteases contribute to
development of FSGS. Whereas podocyte injury likely initiates FSGS, the data
support the concept that PEC activation and migration determine disease
severity.
4. Targeting PECs for therapeutic intervention may alter disease progression,
particularly in c FSGS.
5. Multiple pathways leading to focal sclerotic lesions complicate identification of
therapeutic targets for disruption of ECM deposition in FSGS. In this study point
to cathepsin proteases as possible candidates for pharmacologic intervention
THANK YOU