The five types of glomerulonephritis classified by pathogenesis, activity and chronicity (GN-AC)

Abstract

Glomerulonephritis (GN) is a diverse group of immune-mediated disorders. Currently, GN is classified largely by histological patterns that are difficult to understand and teach, and most importantly, do not indicate treatment choices. Indeed, altered systemic immunity is the primary pathogenic process and the key therapeutic target in GN. Here, we apply a conceptual framework of immune-mediated disorders to GN guided by immunopathogenesis and hence immunophenotyping: (i) infection-related GN require pathogen identification and control; (ii) autoimmunity-related GN, defined by presence of autoantibodies and (iii) alloimmunity-related GN in transplant recipients both require the suppression of adaptive immunity in lymphoid organs and bone marrow; (iv) autoinflammation-related GN, e.g. inborn errors of immunity diagnosed by genetic testing, requires suppression of single cytokine or complement pathways; and (v) Monoclonal gammopathy-related GN requires B or plasma cell clone-directed therapy. A new GN classification should include disease category, immunological activity to tailor the use of the increasing number of immunomodulatory drugs, and chronicity to trigger standard chronic kidney disease care including the evolving spectrum of cardio-renoprotective drugs. Certain biomarkers allow diagnosis and the assessment of immunological activity and disease chronicity without kidney biopsy. The use of these five GN categories and a therapy-focused GN classification is likely to overcome some of the existing hurdles in GN research, management and teaching by reflecting disease pathogenesis and guiding the therapeutic approach.

Keywords: complement; hyperfiltration; mesangial cell; podocyte; proteinuria.

Figure 1:

The major entities of glomerulonephritis. The GNs can be classified into five major groups according to the respective pathogenesis that leads to glomerular injury and inflammation. It is the underlying pathogenesis that determines the most appropriate type of (immuno-)therapy. Immunophenotyping is the diagnostic approach to dissect the GNs and includes many different types of exams. Kidney biopsy may be needed or not in this context.

Figure 2:

Autoantigens in autoimmune glomerulonephritis. Autoimmune GN can involve different classes of autoantigens, which make them look different under the microscope and present differently clinically. However, the involved innate and adaptive immunity is similar. Therefore, they share key elements of pathophysiology implying the same set of immunotherapies to control immunological activity, if present. DC: dendritic cell; Th: T helper cell; IC-GN: immune complex GN; TMA: thrombotic microangiopathy.

Figure 3:

Multilevel diagnostic algorithm of GN. The accurate diagnosis and stratification of GN requires multilevel immunophenotyping to allow classification and staging according to the GN-AC matrix. The GN-AC classification defines the type and intensity of immunotherapy. Where non-invasive diagnostic markers for defining the type of GN, immunological activity and disease chronicity are available, kidney biopsy may become dispensable. MGUS: monoclonal gammopathy of unknown significance; PCR: polymerase chain reaction; MPO: myeloperoxidase; PR3: proteinase 3; SLE: systemic lupus erythematosus.