Complement Profiling in Glomerular Disease: Insights from Laser Microdissection and Mass Spectrometry

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, immunoglobulin-associated glomerulonephritis such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits and fibrillary glomerulonephritis, 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 anti-complement 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.