Multi-Omics: Complement Deposits Flag Poor FSGS Remission
Primary focal segmental glomerulosclerosis (FSGS) is filed under non-immune kidney disease, yet biopsies often show C3 caught in sclerotic lesions. Does that complement signal matter for the patient? A September 2026 study in Frontiers in Immunology used multi-omics profiling of kidney tissue, pairing LC-MS/MS proteomics with public RNA-seq data, to map complement dysregulation and test whether glomerular deposits predict treatment response. In this single-center cohort, they did.
Key Takeaways
Multi-omics profiling of FSGS kidney tissue ranks the complement and coagulation cascade among the most disrupted pathways at both protein and transcript level.
Glomerular C3c deposition, visible on routine immunofluorescence, was linked to lower complete remission rates in primary FSGS.
Upstream complement proteins fell while their mRNAs rose, so transcript data alone can misread pathway activity in diseased tissue.
The results support testing C3 or C5 inhibitors in selected FSGS patients, but come from a small retrospective cohort that needs replication.
How the Multi-Omics Study Was Built
The Sichuan team ran mass spectrometry-based protein profiling (Q Exactive HF-X, MaxQuant) on renal cortex from 11 FSGS patients and 12 controls, quantifying 9,039 proteins. Transcripts came from five GEO datasets covering 100 FSGS and 30 normal samples, harmonized with ComBat. A separate set of 32 biopsies was stained for seven complement components, scored blind, and linked to follow-up outcomes.
Key Findings
One pathway near the top of both lists: of 1,349 differentially expressed proteins, complement and coagulation cascades ranked second by KEGG enrichment; among 210 differentially expressed genes, it ranked first.
Upstream factors diverged between layers. C1R, C1S, C2, and CFB proteins decreased while their mRNAs increased, whereas terminal components C5, C8B, and C8G, plus C4BPA and CFHR5, rose at the protein level.
C3c was the most frequent glomerular deposit: it appeared in 14 of 32 biopsies (43.75%), ahead of C5a (21.88%) and C1q (15.63%), while MBL appeared in one patient.
Where C3c was present, remission lagged: complete remission reached 21.4% in C3c-positive patients versus 66.7% in C3c-negative patients (p = 0.012), and the association held after adjustment (OR 0.061, 95% CI 0.004 to 0.980).
Figure 1. Multi-omics screening points to complement disruption in FSGS kidney tissue. Panel A shows a volcano plot of differentially expressed proteins in renal cortex from 11 FSGS patients and 12 controls, with complement proteins labeled. Panel B ranks the KEGG pathways enriched among those proteins. Panel C presents the matching volcano plot for transcripts from 100 FSGS and 30 control samples, and Panel D shows their pathway enrichment, in which complement and coagulation cascades rank first. Adapted from Xu et al. (2026), Frontiers in Immunology.
Reading the Protein-Transcript Mismatch
The most interesting table is the one where the two layers disagree. C1R, C1S, and CFB protein dropped by roughly 0.9 to 1.6 log2 units in the tissue proteome while their transcripts rose. The authors read this as consumption: proteins are cleaved and cleared in the glomerulus while cells push out more message to compensate. It's a plausible story, and work from Aebersold and colleagues (2016) on the loose coupling of mRNA and protein abundance makes it easy to accept. Still, proteins and transcripts came from different patients, so cohort differences could explain part of the gap.
Complement Deposits as a Pathology Readout
For nephrologists, the immunofluorescence arm is closest to practice. C3c presence did not track with baseline creatinine or proteinuria, which hints that it carries information routine labs miss. Relapse ran at 63.6% in C3c-positive versus 35.3% in C3c-negative patients (p = 0.149), and the adjusted odds ratio has a confidence interval wide enough to drive a truck through. What the data do support is a two-pathway picture: classical (C1q) and alternative (CFB, CFH) deposits coexist while the lectin pathway stays largely silent. Readers who followed our earlier summary of proteomic subtypes in lupus nephritis will recognize the same push toward tissue-defined patient groups.
From Split Cohorts to Paired Samples
The weakest link here is structural rather than biological: protein came from 11 local biopsies and transcripts from 130 archived GEO samples, so the mismatch can't be pinned on consumption with confidence. Paired measurement from one biopsy would settle it, which is why we set up integrated proteomics and transcriptomics projects at Dalton by splitting each sample so both layers share the same patient, block, and batch correction across plates. For teams scoping multi-omics biomarker discovery in kidney disease, that design choice often matters more than raw proteome depth.
Frequently Asked Questions
What is multi-omics analysis used for in kidney disease research?
Multi-omics analysis combines molecular layers, such as proteins measured by mass spectrometry and transcripts measured by RNA-seq, to find pathways that hold up across both. In kidney disease it separates genuine mechanisms from single-dataset noise and points to candidate biomarkers and drug targets.
Is complement activation involved in FSGS?
This study suggests it is. Both omics layers ranked the complement cascade among the top pathways, and glomerular C3c deposits, seen in about 44% of biopsies, were linked to lower complete remission. The cohort was small and retrospective, so confirmation is needed.
What samples do you need for a multi-omics biomarker study on kidney biopsies?
Renal cortex from biopsies or nephrectomy tissue works for LC-MS/MS proteomics, including FFPE blocks with suitable extraction. Ideally, protein and RNA come from the same patients, since separate cohorts muddy cross-layer comparisons. Budget for an independent validation cohort alongside the discovery set.
Conclusion
It's now reasonable to treat complement in FSGS as more than a bystander, at least in patients with glomerular C3c. Whether that deposition drives injury or simply marks sclerotic tissue that traps IgM isn't answered by this design. The practical next step is cheap: complement staining is already on most biopsy panels, so scoring C3c systematically in prospective FSGS cohorts, ideally alongside a complement-inhibitor trial, would test the idea quickly.
Related Reading
See how we run these analyses in one lab: Dalton's multi-omics CRO services.
Citation
Xu, Y., Chen, S., Zhang, Y., Li, Y., & Li, G. (2026). Multi-omics analyses demonstrate complement dysregulation is involved in focal segmental glomerulosclerosis. Frontiers in Immunology, 17, 1852918. https://doi.org/10.3389/fimmu.2026.1852918
Note
This blog post summarizes findings from the above-cited research. Figures are adapted from the original publication. For full details, please refer to the source article.
By Seungjun Yeo, CEO at Dalton Bioanalytics. Specializing in multi-omics mass spectrometry for drug discovery and biomarker research.