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Complement Profiling in Glomerular Disease: Insights from Laser Microdissection and Mass Spectrometry
1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Insights
Laser microdissection and mass spectrometry (LMD/MS) offers detailed complement analysis in kidney biopsies. This advanced method aids in understanding glomerular diseases and personalizing anticomplement therapy.
Area of Science:
- Nephrology
- Immunology
- Proteomics
Background:
- Complement activation is common in glomerular diseases, indicated by C3c and C1q deposition on biopsies.
- Kidney biopsies offer limited insights, failing to identify all complement proteins or distinguish active from inactive forms.
Purpose of the Study:
- To evaluate the utility of laser microdissection and mass spectrometry (LMD/MS) for comprehensive complement profiling in glomerular diseases.
- To analyze the proteomic complement profile in various glomerular diseases using LMD/MS.
Main Methods:
- Utilized laser microdissection and mass spectrometry (LMD/MS) for in-depth proteomic evaluation of kidney biopsy samples.
- Applied principal component analysis, volcano plots, and heatmaps for protein analysis.
Main Results:
- LMD/MS identified distinct complement profiles and pathways across different glomerular diseases, including membranous nephropathy, Ig-associated GN, C3 glomerulopathy, and IgA nephropathy.
- Demonstrated variations in complement burden and profile even within specific diseases, such as different antigens in membranous nephropathy.
- Showcased LMD/MS's ability to determine the presence of active complement fragments and quantify complement burden.
Conclusions:
- LMD/MS is a valuable tool for detailed analysis of complement proteins, regulatory proteins, and pathways in glomerular diseases.
- Accurate complement profiling using LMD/MS is crucial for personalized treatment strategies, especially with the advent of new anticomplement drugs.
Abstract:
Complement activation occurs in most glomerular diseases. Complement activation on the kidney biopsy is evidenced by deposition of C3c and C1q on the kidney biopsy. The kidney biopsy provides only limited information as other complement proteins and complement-regulating proteins are not typically studied. Furthermore, kidney biopsy does not distinguish between activated versus inactive complement proteins. Laser microdissection and mass spectrometry (LMD/MS) is a relatively new methodology that can provide an in-depth evaluation of the proteomic profile of complement proteins, complement regulating proteins, complement pathways, and can also determine whether active complement fragments are present in the kidney biopsy sample. A semiquantitative burden of complement can be determined. Furthermore, proteins of a disease can be analyzed using principal component analysis, volcano plots, and heatmaps. In this review, the complement proteomic profile of diseases representing the spectrum of glomerular diseases are shown. The proteomic complement profile of membranous nephropathy associated with various antigens, Ig-associated GN, such as proliferative GN with monoclonal Ig deposits and fibrillary GN, C3 glomerulopathy, and IgA nephropathy, are shown. The findings show important differences in the complement profile including pathways of complement in each disease, and even within the disease, such as altered complement burden and profile between different antigens associated with membranous nephropathy. In conclusion, LMD/MS is a valuable tool for determining the complement proteins, complement-regulating proteins, complement pathways, and determining the burden of complement in each individual case of glomerular disease. In the era of new anticomplement drugs, it will become essential to accurately determine the complement profile in each kidney biopsy for a personalized approach to treating the glomerular disease. LMD/MS is a methodology that can help provide such answers.
