Finding the etiology of membranoproliferative glomerulonephritis

Membranoproliferative glomerulonephritis (MPGN) has undergone a change in classification that is focused on the etiology of MPGN. Thus, MPGN is classified into immune-complex (IC)-mediated MPGN and complement-mediated MPGN (C3 glomerulopathy) based on immunofluorescence microscopy studies that show positive staining for Igs and/or C3. IC-MPGN typically results from an infection or an autoimmune disease. Deposition of monotypic/monoclonal Ig also results in an MPGN. On the other hand, MPGN with bright C3 and minimal/no Ig is classified as C3 glomerulopathy. On the basis of the absence of any clinical evidence of an infection, autoimmune disease, or monoclonal gammopathy, the IC-MPGN is often labeled as primary/idiopathic MPGN. As such, increasing numbers of primary/idiopathic IC-MPGN are being diagnosed. In my renal biopsy practice, I have rarely seen an MPGN in an adult kidney biopsy in which I could not find an underlying etiology after diligent and careful evaluation of the biopsy. Some of the primary/idiopathic IC-MPGN falls into the monotypic/monoclonal Ig-associated MPGN, some into uncommon diseases, such as fibrillary glomerulonephritis, whereas others represent C3 glomerulopathy to begin with where the Ig is often entrapped in areas of scarring and does not represent true IC-MPGN. On the other hand, infection-related glomerulonephritis may be misclassified into C3 glomerulonephritis when there is sparse IgG on immunofluorescence microscopy. Chronic thrombotic microangiopathies can present with an MPGN pattern of injury and may be mislabeled as IC-MPGN or C3 glomerulonephritis from entrapment of IgM and/or C3. It is thus critical that we perform a thorough clinical and pathologic evaluation before labeling a case as idiopathic/primary IC-MPGN. Kidney biopsy evaluation should include complete immunofluorescence microscopy, including light chains, and electron microscopy. Pronase immunofluorescence microscopy and IgG subclass staining should be available to rule out masked Ig deposits and monotypic/monoclonal Ig-associated MPGN. An accurate diagnosis with identification of the etiology of IC-MPGN will allow for targeted treatment of the MPGN.