Glomerulonephritis: immunopathogenesis and immunotherapy

Abstract

'Glomerulonephritis' (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney (the glomeruli). These disorders are currently classified largely on the basis of histopathological lesion patterns, but these patterns do not align well with their diverse pathological mechanisms and hence do not inform optimal therapy. Instead, we propose grouping GN disorders into five categories according to their immunopathogenesis: infection-related GN, autoimmune GN, alloimmune GN, autoinflammatory GN and monoclonal gammopathy-related GN. This categorization can inform the appropriate treatment; for example, infection control for infection-related GN, suppression of adaptive immunity for autoimmune GN and alloimmune GN, inhibition of single cytokines or complement factors for autoinflammatory GN arising from inborn errors in innate immunity, and plasma cell clone-directed or B cell clone-directed therapy for monoclonal gammopathies. Here we present the immunopathogenesis of GN and immunotherapies in use and in development and discuss how an immunopathogenesis-based GN classification can focus research, and improve patient management and teaching.

Fig. 1. Anatomy of the glomerulus.

The glomerulus is the blood-filtering unit of the kidney. Each glomerulus drains the filtrate into its own tubule, and the glomerulus and its tubules together constitute the functional unit of the kidney, the nephron. The vascular part of each glomerulus includes an afferent arteriole, an efferent arteriole and a capillary network inside the glomerulus, where the filtration occurs under conditions of high perfusion pressure and shear stress. The capillary network is held together by mesenchymal cells, known as mesangial cells, and a matrix, which regulate capillary tension. Parts of the glomerular filtrate pass through the mesangium; hence, circulating antigens and immunoglobulins can get trapped there. Glomerular capillaries are characterized by a fenestrated endothelium covered with glycocalyx and attached to the glomerular basement membrane. At the outer aspect of the glomerular capillaries, podocytes attach to the glomerular basement membrane. Podocytes are specialized epithelial cells with neuron-like primary and secondary foot processes interdigitated with the respective secondary foot processes of neighbouring podocytes. Between podocyte foot processes is the slit diaphragm, which covers a large area of the filtration barrier and is essential for preventing the passage of serum proteins such as albumin into the filtrate. Water, ions and other small solutes cross the filtration barrier through pores in the slit diaphragm. Inflammatory processes in the glomerulus typically alter the barrier function and cause leakage of serum proteins and frequently also of intact blood cells into the urine.

Fig. 2. Histopathological lesion patterns common in glomerulonephritis.

Common histopathological lesion patterns characteristic of glomerulonephritis (GN) are shown; for example, endocapillary lesions (part a), mesangioproliferative lesions (part b) and membranoproliferative lesions (part c). Immunostaining is routinely performed as one element of immunophenotyping and shows, for example, granular IgG4 positivity along the filtration barrier in a membranous GN (part d), diffuse fibrinogen positivity in necrotizing and crescentic GN (part e) and a relative lack of immunoglobulins and complement deposition in pauci-immune GN (part f). Mesangial IgA positivity is typical of IgA nephropathy (part g) and complement factor C3 positivity in absence of IgG deposits defines complement factor C3 GN (C3GN) (part h). Staining for κ and λ immunoglobulin chains (part i) helps to distinguish monotypic and polytypic immune deposits. For example, monotypic λ deposits occur in proliferative GN with monoclonal immunoglobulin deposits. HE, hematoxylin–eosin.

Fig. 3. Simplified schematic of the pathogenesis of the five categories of glomerulonephritis.

Glomerulonephritis (GN) comprises a group of immune-mediated disorders with the involvement of different innate and adaptive immune pathways in glomerular injury. a, Infection-related GN is triggered by pathogens or pathogen-associated molecular patterns (PAMPs) that elicit host defence mechanisms, which may affect the kidney in various ways as indicated. Circulating immune complexes (ICs) can become trapped in the mesangium or they can form in situ in the subendothelial space, where they can trigger complement activation. In addition, some pathogens have direct cytopathic effects, precipitating glomerular filtration barrier impairments. b, Autoimmune GN involves loss of tolerance to self-antigens in glomerular cells but frequently also to extrarenal antigens, which localize to the kidney or affect the kidney in other ways. Memory T cells in lymphoid tissues and long-lived plasma cells in the bone marrow maintain chronic autoimmunity. Infections can trigger flares of autoimmune GN via a nonspecific activation of autoreactive lymphocyte clones. c, Alloimmune GN can occur following transplantation and is associated with the development of donor-specific antibodies to HLA and non-HLA antigens of the graft and can lead to thrombotic microangiopathy and endothelial damage. d, Genetic variants in genes encoding cytokine pathways or regulatory elements of the complement cascade cause autoinflammatory disorders, some of which cause GN. Mechanisms of kidney pathology include spontaneous complement activation in complementopathies and AA amyloid deposits in periodic fever syndromes. e, Monoclonal gammopathy-related GN develops from somatic mutations in B cell clones or plasma cell clones that produce immunoglobulins or immunoglobulin components with nephrotoxic properties. These reach the glomerulus via the circulation. ANCA, antineutrophil cytoplasmic antibody; GBM, glomerular basement membrane; NET, neutrophil extracellular trap.

Fig. 4. Primary site of action for drugs in use or in the pipeline for glomerulonephritis.

Most immunosuppressive drugs primarily act inside lymphoid organs, whereas complement inhibitors and calcineurin inhibitors directly act at the site of glomerular injury. Steroids (glucocorticoids) suppress local inflammation in the kidney as well as adaptive immunity in lymphoid organs. Imlifidase degrades IgG in the circulatory system but possibly also IgG deposits inside the kidney. Drugs in use are shown in bold. APOL1, apolipoprotein L1; APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; BTK, Bruton’s tyrosine kinase; C5aR, C5a receptor; CAR, chimeric antigen receptor; CTLA4, cytotoxic T lymphocyte-associated protein 4; DC, dendritic cell; FB, factor B; FcR, Fc receptor; FD, factor D; IFNAR1, type I interferon receptor; JAK, Janus kinase; MASP2, mannan-binding lectin serine protease 2; MC1R, melanocortin 1 receptor; MC3R, melanocortin 3 receptor; siRNA, small interfering RNA; SLIT2, Slit homologue 2 protein; STAT, signal transducer and activator of transcription; TACI, transmembrane activator and CAML interactor; TRPC5, transient receptor potential cation channel subfamily C member 5.