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

Paola Romagnani1, A. Richard Kitching2, Nelson Leung3, and Hans-Joachim Anders4

1 Department of Experimental and Biomedical Sciences "Mario Serio" and Nephrology and
Dialysis Unit, Meyer Children's University Hospital, Florence, Italy
2 Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash

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Medical Centre, Clayton, Victoria, Australia. Departments of Nephrology and Paediatric
Nephrology, Monash Health, Clayton, Victoria, Australia
3 Divisions of Nephrology and Hypertension and of Hematology, Mayo Clinic, Rochester, MN, US
4 Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-

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Maximilians-University Munich, Munich, Germany

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Correspondence to: Hans-Joachim Anders; E-mail: hjanders@med.uni-muenchen.de or Paola

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Romagnani; E-mail: paola.romagnani@unifi.it

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© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA. This is an Open Access article
distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/
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 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: 1) Infection-related GN require pathogen identification and control, 2)

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Autoimmunity-related GN, defined by presence of autoantibodies, and 3) Alloimmunity-related
GN in transplant recipients both require the suppression of adaptive immunity in lymphoid
organs and bone marrow, 4) Autoinflammation-related GN, e.g., inborn errors of immunity

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diagnosed by genetic testing, requires suppression of single cytokine or complement pathways,
and 5) Monoclonal gammopathy-related GN requires B or plasma cell clone-directed therapy. A

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new GN classification should include a) disease category, b) immunological activity to tailor the
use of the increasing number of immunomodulatory drugs, and c) chronicity to trigger standard

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CKD care including the evolving spectrum of cardio-renoprotective drugs. Certain biomarkers
allow diagnosis and the assessment of immunological activity and disease chronicity without

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kidney biopsy. These five GN categories and a therapy-focused GN classification is likely to

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overcome some of the existing hurdles in GN research, management, and teaching by reflecting
disease pathogenesis and guiding the therapeutic approach.
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Keywords: complement, hyperfiltration, mesangial cell, podocyte, proteinuria
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 INTRODUCTION
As glomeruli function as high flow filters that produce a substantial ultrafiltrate, they are
vulnerable to inflammatory injury from a variety of causes, resulting in a diverse range of causes
of GN. Understanding, treating, studying, and teaching glomerulonephritis (GN) is difficult, not
only due to the diversity of diseases themselves, but also because there is no simple logical
classification to underpin the long list of disease entities that comprise the GNs.
Currently, GN is categorized based largely on histopathological lesion patterns, with primary

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and secondary forms and a myriad of differential diagnoses for each entity 1. There are historical
reasons why we group GN in this manner, specifically the development of kidney biopsy and the
capacity of light microscopy to describe patterns of glomerular injury, based largely on changes in

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cell number, deposits and matrix proteins in different parts of the glomerulus. The introduction of
immunohistochemistry for immunoglobulins and complement, and electron microscopy

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extended this paradigm 2. However, the evolution of immunophenotyping and the advent of
genetics demonstrated that the same histological lesions can develop from different disorders

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that require completely different treatments. Terms such as membranoproliferative GN (MPGN),
focal segmental glomerulosclerosis (FSGS), and complement factor 3 GN (C3GN) are examples of

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the focus on lesional patterns that remain in use in describing and defining glomerular diseases,

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despite their diverse origins and need for different treatments3. Classifying diseases caused by
different processes primarily according to pathology was useful when using generic therapies
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such as glucocorticoids, which although effective in some conditions, in other diseases either
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need to be combined with additional immunomodulatory therapies or are not indicated. In
addition, nomenclature and classification systems tend to drive kidney-focused research, e.g.,
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using each emerging -omic technology to repeatedly characterize kidney injury, inflammation,
fibrosis, and atrophy at an increasingly granular level within the kidney itself 4, while answers to
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the origin and persistence of immune-mediated GN can only be found outside the kidney.
Kidney biopsy confirms the GN diagnosis, helps to define immunological activity, and
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informs the degree of irreversible damage 5. However, a kidney-focused approach has impeded
conceptual advances regarding disease categories. In addition, this approach has had limited
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impact on understanding how to control the aberrant immune mechanisms that induce and
maintain GN by producing nephritogenic humoral and cellular immune effectors from outside the
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kidney.
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To overcome some of these hurdles, we propose first to acknowledge that as GN are

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primarily immune-mediated disorders and to categorize GN accordingly. In addition, we propose

to classify them by immunological activity (A) and chronicity (C) in a simple “GN-AC” matrix
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(Table 1). We discuss how approaching GN from an immunological perspective and positioning
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immunophenotyping at the center of the diagnostic approach has multiple important

implications for GN management, treatment, education, and research.
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 GN-AC MATRIX STEP 1: THE TYPE OF GN
Defining GN by general categories of immune-mediated disorders
Immune-mediated disorders can be dissected into five categories defined by the key
underlying immune-mechanisms, i.e., infection, autoimmunity, alloimmunity, autoinflammation
or monoclonal gammopathy.
Infection-related GNs arise from host defense against an acute, subacute of persistent

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infection somewhere in the body with three main immunologic mechanisms (Figure 1). 1.
Post-streptococcal GN arises for the capacity of group A β-haemolytic streptococci antigens to
activate complement directly or by inducing production of anti-factor B antibodies, mimicking a

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transient complementopathy. 2. Other infection-related GN are caused by deposition of
circulating immune complexes in the glomerulus related to : (i) primary or secondary (acquired or

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iatrogenic) immunodeficiencies that predispose to the severity or persistence of infection 6; (ii)
colonization of implanted device such as catheters; (iii) host defense-escape mechanisms proper

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of certain pathogens, such as Schistosoma. Host defense against pathogens involves innate and
adaptive immunity and can mimic an autoimmune disease, including transient positivity to

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anti-nuclear antibodies, cryoglobulines and other autoimmunity markers7. 3. Cytotoxic effects of

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pathogens that can infect podocytes such as HIV, EBV, arbovirus, parvovirus B19 or SARS-CoV-2
causing a podocytopathy, particularly in carriers of high-risk APOL1 genotype. In rare cases,
persistent infections can also cause AA amyloidosis. A
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Therapeutic approach. Even if the immune response contributes locally to glomerular injury,
the primary therapeutic target in infection-related GNs is the infection itself 8,9. Infection-related
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GN may spontaneously resume once host defense is able to eliminate the pathogen , while it
persists when pathogen keeps releasing antigens that maintain the respective immune response 7.
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Without controlling the infection, the use of immunosuppressants is questionable and may even
be counterproductive via their capacity to impair host defense against the infectious agent 11. For
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example, a diagnosis of endocarditis-related GN mandates the cure of endocarditis and not the
use of glucocorticoids to control glomerular inflammation. Improvements in socioeconomic
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conditions at a population level has reduced the incidence and impact of these diseases.
Autoimmunity-related GNs arise from adaptive immunity against a single or several of a
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wide spectrum of self-antigens (Figure 2). Even if the clinical presentations and histological
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lesions patterns differ depending on the localization of the self-antigens, the mechanisms of the
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underlying adaptive immune response share some common features . Autoimmunity arises
from a loss of tolerance to which genetic and environmental factors contribute. Once tolerance is
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lost, cellular and humoral autoimmunity develops so that multiple adaptive and innate
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components may mediate injury . Sometimes autoimmunity is transient, explaining

spontaneous remissions of some cases of anti-PLA2R autoimmune GN 14. Once long-term immune
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memory has formed, it manifests as clones of autoreactive memory T and B cells in the lymphoid
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organs and as long-lived plasma cells in their bone marrow niches that is similar to immune
 memory after infection or vaccination 15. Tissue-resident T memory cells have been described in
many autoimmune diseases including the kidney and intrarenal tertiary lymphoid organs with T
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and B cells may be present . Re-exposure or persistent exposure to antigen in an
immunologically “dangerous” context triggers antigen-specific immunological activity, which
either presents as persistent or relapsing disease activity, depending on many levels of regulation
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. Autoimmunity is always oligo- or polyclonal but can center on one or only a few antigenic
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epitopes . Measurement of serum autoantibodies to some nephritogenic autoantigens

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predict immunological disease activity well, e.g., in anti-GBM disease or in anti-PLA2R
autoimmune GN. However, in other conditions, while autoantibodies are relevant to disease,
serum titers do not predict activity well enough to predict outcome or meaningfully guide

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therapy. This may at least in part be due to the multiple autoantigens involved in lupus nephritis,
the multiple B cells epitopes detected in anti-MPO antibody assays in people with

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MPO-ANCA-associated GN 22, or antibodies targeting different forms of IgA in IgA nephropathy 23
Therapeutic approach. Treatments that restore tolerance by selectively eliminating the

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causative autoreactive lymphocyte clones or by selectively modulating their activity are not yet
available. Therefore, we remain with therapies targeting the various elements of adaptive

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immunity that are common to many autoimmune GNs. Drugs used in this context include

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azathioprine, mycophenolate mofetil, calcineurin inhibitors, B cell-depleting agents, and
belimumab. More recently, plasma cells have become a therapeutic target, with trials using
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proteasome inhibitors or anti-CD38 IgG 15. In addition, glucocorticoids are effective in this regard
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and suppress inflammation in the kidney. This dual effect of glucocorticoids is not shared by the
newer immune modulators, which may explain why steroids are still in use despite their
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significant metabolic toxicities. Complement C5aR inhibition can at least partially replace
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glucocorticoids in active ANCA-associated vasculitis (with rituximab) and may have a role in
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other highly active autoimmune GNs. An ultimate cure for autoimmune-GNs would selectively
eliminate or silence all T and B cell clones responding to the antigenic epitope. Therefore, a
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“clone-directed therapy”, is a conceptually promising approach also for autoimmune GNs, as is

the use of tolerogenic platforms that aim to selectively modulate the activity of these clones 25
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Alloimmunity-related GNs develop in patients that received an allograft of a solid organ,

bone marrow or cells (Figure 1). The adaptive immune response is in some ways conceptually like
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that of autoimmunity, although in classical alloimmunity there is no response against the self, and
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there is also more evidence in alloimmunity for a key role for CD8+ T cells via donor-specific
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alloantigenic peptides being presented in the context of MHC class I molecules. While alloreactive
CD8+ T effector cells are important, donor-specific antibodies are also crucial, especially in
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glomerular lesions . Immunity is directed against numerous HLA and non-HLA antigens . As
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the spectrum of donor antigens is wide, alloimmunity is polyclonal and biomarkers that would
allow a precise monitoring of the activity of alloimmunity are difficult to define.
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Therapeutic approach. Allo- and autoimmunity involve similar elements of the adaptive
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immune system, therefore, similar drugs are currently used to control alloimmunity in general
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and alloimmunity-related GNs . The precise alloantigens or their epitopes triggering GN are
difficult to define, a hurdle for the development of any antigen-specific therapy. Whether
complement inhibitors could improve the outcome of alloimmunity-related GNs is currently
unknown.
Autoinflammation-related GNs develop from inborn errors of immunity and therefore
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require genetic testing to establish the diagnosis (Figure 1) . For example, genetic variants
leading to overactivation of IL-1, TNF or type I interferon signaling pathways can be sufficient to

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cause systemic and tissue inflammation causing organ damage 30,31. Genetic complementopathies
leading to C3GN belong to this category and environmental co-factors may impose a second hit to
trigger kidney injury 32. Combinations with autoimmune forms of C3GN occur 33.

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Therapeutic approach. Inborn errors of innate immunity leading to GN do not require the
use of unspecific immunosuppressants because the adaptive immune system is not involved and

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there is often a single dysregulated pathway mediating disease. Innate glomerular inflammation
should be controllable by selective blockade of the affected cytokine pathway, e.g., anti-IL-1,

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anti-TNF, or anti-type I interferon, respectively . Inborn errors of the alternative complement
pathway belong to this category and such forms of e.g., C3GN should be treatable with a specific

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complement inhibitor, unless a mutated protein favors secondary autoimmunity 33. Such a C3GN

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would be categorized with and managed within the autoimmune GN framework and benefit from
immunosuppressants to suppress adaptive immunity.
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Monoclonal gammopathy-related GNs arise from a single B cell or plasma cell clone that
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produces a nephrotoxic immunoglobulin or immunoglobulin component (Figure 1)35. Such
monoclonal gammopathies of renal significance (MGRS) exemplify the management principle
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that targeting the primary problem, in this case the pathogenic clone in the bone marrow, is
essential. Targeting the kidney with anti-inflammatory or anti-fibrotic drugs is of little use without
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targeting the disease-inducing clone in the bone marrow . In an analogous manner, auto- and
alloimmunity-related GNs involve autoreactive clones that as well as infiltrating the kidney,
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themselves, produce nephritogenic antibodies in secondary lymphoid organs and bone marrow,
arguing against a solely kidney-focused approach to immunotherapy of the GNs 36.
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Therapeutic approach. ”Clone-directed therapy” with drugs targeting B cells or plasma cells
producing the nephrotoxic immunoglobulin or immunoglobulin component following the
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treatment algorithms for multiple myeloma is the standard approach for MGRS including GN 37.
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Diagnostic categorization of a GN requires multidimensional immunophenotyping

The pathogenesis-based GN categories require thorough immunophenotyping to accurately
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allocate patients to the correct disease category (Figure 3). Kidney biopsy can contribute
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significantly to immunophenotyping. For example, immune complex GN with either IgA, IgM, or
even full house Ig deposits in presence of C4d and in absence of a serum autoantibody (or even
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in presence of transient positivity to autoantibodies) strongly support an infection-related GN 7.

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Also, the presence of certain podocyte antigens in the presence of a respective autoantibody in
 the serum implies autoimmune membranous GN, a more suitable term than “primary
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membranous GN” . Monotypic immunoglobulin deposits in the glomerulus identify a
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monoclonal gammopathy-related GN . However, kidney biopsy is unable to dissect an
autoimmune, autoinflammatory or monoclonal cause of C3GN hence these different entities are
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still often managed erroneously as a single entity . In general, kidney biopsy cannot identify
autoinflammatory GNs, thus immunophenotyping may extend to genetic testing whenever
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infections, autoantibodies, a transplant or a monoclonal gammopathy are absent .

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Immunophenotyping may also include microbiology and serological studies to diagnose or
exclude infections, an extended search for autoantibodies, serum complement studies, a bone
marrow aspirate and flow cytometry studies of blood, bone marrow and urine. For example,

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ANCA-associated vasculitis can be diagnosed without a kidney biopsy in the presence of serum
ANCA, haematuria and proteinuria, and impaired kidney function 38. A similar concept applies to

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anti-GBM disease and has been proposed for anti-PLA2R-associated nephrotic syndrome .A
similar paradigm may apply to the podocytopathies that are not always considered GNs, as they

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lack proliferative lesions . However, patients with “minimal change disease” or “FSGS” need
work-up for adaptive, infectious, or genetic causes, as well as search for anti-nephrin antibodies

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to identify cases of autoimmune podocytopathies 41.

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The lesion-based diagnostic approach as a barrier to understanding and management of GN
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Some examples may illustrate better the limitations of the current approach.
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Membranoproliferative GN is perhaps the best example of how using descriptive terms can
hamper progress by causing confusion. The broad differential diagnosis of MPGN encompassing
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completely different disorders with different therapies disqualifies the use of this term to define a
disease entity. The lesion pattern of “membranoproliferative GN” can be replaced easily by more
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specific histopathological descriptions such as immune complex GN (infection or autoimmune),

MGRS (monotypic deposits) or C3GN (absence or low Ig levels in presence of C3) 2.
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C3GN is another descriptive term that may encompass a genetic disease, autoimmunity or a
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monoclonal gammopathy as the underlying disease requiring different treatments . Even
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though the upcoming complement inhibitors that will show effects on all forms of C3GN, a
detailed diagnostic work-up of the C3GNs for the sake of correct categorization may still be
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needed to define adjunct and duration of treatment, e.g., monoclonal gammopathy-related C3GN
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may require additional therapeutics.

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Lupus nephritis remains categorized by WHO or ISN/RPS classes that do not accurately
reflect the extent of the disease, do not clearly predict long-term outcomes, and do not define
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clinical management 42. Re-biopsy studies comparing classes in first and second biopsies are often
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distracting, while activity and chronicity indices are likely to guide lupus nephritis management
more reliably. In this context, class VI lupus nephritis is redundant as it implies a high chronicity
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index and does not address the question as to whether immunosuppressive therapy is still useful.
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IgA nephropathy is classified by the Oxford/MEST-C classification that is validated to predict

 outcomes 43, from the time of biopsy but which does not inform the use of immunotherapy. Until
reliable serum markers of immunological activity become broadly available, the NIH activity and
chronicity indices used in lupus nephritis could be applied to IgAN, as both proliferative
autoimmune GNs share many of their effector immune mechanisms of kidney injury.
Membranous nephropathy. The discovery of the many different autoantigens in
membranous GN has revolutionized our understanding of the diseases that cause this histological
pattern of injury and is making “primary” and “secondary” labels redundant 44. What is needed is

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a concerted effort to develop a panel of immunoassays for serum autoantibodies directed against
these autoantigens. 44.

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GN-AC MATRIX STEP 2: ACTIVITY AND CHRONICITY
Immunological disease activity determines immunosuppressive immunotherapy in

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autoimmune GNs
We have learned from AL amyloidosis how important it is to base treatment decisions on

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reliable biomarkers of immunological activity. In this condition, free-light chain assays have
entirely replaced the unreliable proteinuria or M-spike in electrophoresis measurements for

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tailoring therapy 45. In some autoimmune GNs with proven nephritogenic autoantibodies, serum

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titers provide highly relevant information about the immunological activity of the disease process
within lymphoid organs. For example, anti-GBM IgG and anti-PLA2R IgG levels can be used as
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biomarkers just as light chain levels in a monoclonal gammopathy-related GN 36,39
. Data from
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anti-PLA2R autoimmune GN has alerted us to the fact that proteinuria levels do not adequately
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reflect immunological disease activity, especially upon significant podocyte injury . The same
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principle applies to other forms of GN, including lupus nephritis, indicating the potential value of
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re-biopsy , e.g., protocol biopsy to assess immunological response to treatment whenever
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autoantibody tests are either not yet commercially available or are unreliable in predicting
immunological GN activity.
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However, lupus nephritis trials continue to enrol patients based on histopathological classes
and proteinuria levels rather than based eligibility on the NIH index of immunological disease
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activity, which would enrich an active LN population to enable testing of the efficacy of add-on
immunomodulatory agents. Similarly, IgA nephropathy trials testing immunotherapies are
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recruiting patients based on historical diagnostic biopsies and certain levels of proteinuria,
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assuming proteinuria represents immunological disease activity, which is frequently not the case.
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Obesity, a high salt or high-protein diet, low nephron number, glomerular scarring, diabetes
mellitus, and vasodilator therapy are common causes of proteinuria in patients with inactive GN
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. All these further factors always need to be first controlled before interpreting proteinuria as a
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marker of immunological activity.

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Non-immune drivers of kidney injury and CKD progression in GN as therapeutic opportunity

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All five forms of GNs can cause irreversible kidney damage via nephron loss. Nephron loss
 implies an increased workload for the remaining nephrons, which can be compensated to some
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extend by the so-called renal reserve . Compensation means increased shear stress for the
single podocyte at the filtration barrier and increased metabolic workload for the single epithelial
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cell in the proximal tubule . The more nephrons that are lost due to immunologically active
persistent or relapsing GN, the greater workload for the remaining glomeruli, leading, for
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example to the detachment and death of increasing numbers of podocytes and tubular cells .
Numerous cofactors enhance the workload of remnant nephrons and accelerate this process such

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as poor nephron endowment at birth or a reduced number of nephrons due to previous kidney
injury, obesity, high salt or protein diets, diabetes mellitus, and pregnancy 47,48. The consequence
is an increasingly hypocellular kidney, glomerulosclerosis, tubular atrophy, and interstitial fibrosis,

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clinically presenting as a progressive loss of GFR, often with proteinuria. Reducing the workload
of the remaining nephrons, e.g., with inhibitors of the renin-angiotensin system and the

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sodium-glucose transporter-2, is the main therapeutic strategy to prevent CKD progression
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beyond immunotherapy in all forms of GN . While this strategy is now established in the

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chronic phase of GN, it might well also apply to the acute phase, because reducing filtration
pressure should help to limit glomerular barotrauma in a moment when the injured glomerular

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filtration barrier is particularly sensitive to an increased filtration pressure.

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PRACTICAL IMPLICATIONS OF THE GN-AC MATRIX AND RESEARCH PERSPECTIVES
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The proposed GN-AC matrix has several practical implications. First: Non-invasive diagnostic
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tools become equally important to kidney biopsy to define the type of GN. Thus, we need
research efforts into biomarkers that dissect pathogenesis-based GN categories in a sensitive and
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specific manner, e.g., such as free light chain assays for the monoclonal gammopathies. This
could be novel diagnostic tests for pathogen detection, serum autoantibodies, and gene panels to
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identify causative inborn errors of immunity. Second: The increasing numbers of (costly)
immunomodulatory drugs require disease categories that align with their potential use not
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provided by disease categories-defined by unspecific lesion patterns. Third: Unspecific histological

lesion patterns become less relevant in guiding GN management and overemphasizing them in
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this context is confusing. Fourth: Determining immunological disease activity is key in guiding the
intensity of immunotherapy and may replace proteinuria-based treatment indications and
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inclusion criteria of clinical trials. Fifth: Patients with GN benefit from CKD care, especially when
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signs of chronicity and CKD progression in absence of immunological disease activity is present.
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Dissecting GN activity from chronicity with non-invasive biomarkers to monitor GN will be an

important step forward in GN management. Finally: A simple and intuitive GN classification
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matrix will reduce confusion in and outside nephrology, improve teaching, and advocacy.
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SUMMARY
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The last decade has witnessed unprecedented progress in the treatment of GNs because of
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an increasing understanding of the causative mechanism and the interacting innate and adaptive
 immune system. The latter implies a full pipeline of novel (and costly) immunomodulatory drugs
that warrant careful use where effective and no use where not. The GN-AC classification system
overcomes some of these hurdles. Where non-invasive biomarkers of the GN-AC criteria become
available, kidney biopsy may become dispensable, e.g., in autoimmune GN of the PLA2R type or
in multiple myeloma-related GN. Research on the immunopathogenesis of the GN may benefit
from a less kidney-focused perspective because pathogenesis and therapeutic targets localize
outside the kidney. As an exception, the upcoming complement inhibitors are an exciting tool to

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control glomerular injury locally. Furthermore, an increasing number of drugs targeting
non-immune mechanisms of GN chronicity will improve patient outcomes across all GN disease
entities. Therefore, the GN-AC matrix proposed here may help focusing on clinically relevant

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aspects and bypassing some of the existing hurdles in GN teaching, research, and management.

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DATA AVAILABILITY STATEMENT

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No new data were generated or analysed in support of this research.

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FUNDING

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HJA received funding from the Deutsche Forschungsgemeinschaft (AN372/27-1, 30-1 and TRR332:
INST211/1067-1/A07) and the Volkswagen Foundation (97-744). HJA and PR received support
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from the EU ERA-PerMed programm (Per-NEPH, 01KU2204). PR is supported by the European
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Research Council (ERC) under the European Union’s Horizon 2020 research and innovation
programme (grant agreement N° 101019891, SIMPOSION). ARK is funded by Australian National
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Health and Medical Research Council (NHMRC) Investigator and Grant (2008921).
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CONFLICT OF INTEREST STATEMENT

HJA received consultancy or lecture fees from Boehringer, Bayer, GSK, AstraZeneca, Novartis,
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Otsuka, Janssen, Kezar, Lilly, and PreviPharma. ARK has received lecture fees from Vifor Pharma
and research funding via consultancy and grants from Vifor, Visterra, Toleranzia, Variant Bio and
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CSL Limited. NL has received research funding from Omeros and has stocks in AbbVie and
Checkpoint Therapeutics. PR has nothing to disclose.
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AUTHORS’ CONTRIBUTIONS
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RP and HJA drafted the first version of the manuscript and all authors edited the text and
approved the final version.
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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.
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It is the underlying pathogenesis that determines the most appropriate type of (immuno-)therapy.
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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.

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Figure 2. Autoantigens in autoimmune glomerulonephritis. Autoimmune GN can involve

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different classes of autoantigens, which make them look differently under the microscope and

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present different clinically. However, the involved innate and adaptive immunity is similar.
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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,
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GBM=glomerular basement membrane, IC-GN=immune complex GN, TMA=thrombotic

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microangiopathy, C3GN=C3 glomerulonephritis

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Figure 3. Multilevel diagnostic algorithm of glomerulonephritis. The accurate diagnosis and

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stratification of GN requires multilevel immunophenotyping to allow classification and staging
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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,
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immunological activity and disease chronicity are available, kidney biopsy may become

dispensable. MGUS=monoclonal gammopathy of renal significance, PCD=polymerase chain

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reaction, PLA2R=phospholipaseA2 receptor, MPO=myeloperoxidase, PR3=proteinase 3,

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SLE=systemic lupus erythematosus, CKD=chronic kidney disease

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Table 1: Proposed GN-AC classification and reporting system for glomerulonephritis.

Classification criteria Reporting Therapy

GN GN defined by Infection: specify type of infection Infection control

immunophenotyping Autoimmunity: specify autoantigen (e.g., PLA2R, MPO, PR3, …) or systemic disorder (e.g., SLE) Immunotherapy (activity)

PT
Alloimmunity: specify type of graft Immunosuppression

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Autoinflammation: specify inborn error of immunity Specific pathway blockade

SC
Monoclonal gammopathy: specify type of paraprotein and either B or plasma cell clone Clone-directed

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A Activity (immunological) 0 Absent Observation

N
A
1 Low (serum biomarkers and/or no nephrotic syndrome and/or little active injury on biopsy) Observation/specific therapy

M
2 Moderate (serum biomarkers and/or moderate active injury on biopsy) Specific therapy

ED
3 High (serum biomarkers and/or nephrotic syndrome and/or high active injury on biopsy) Intense specific therapy

C Chronicity 0 Absent (less than 3 months) Observation

IT
1 Early CKD (G1/A1-2) and/or few fibrosis on biopsy Observation/CKD therapy
ED
2 Advanced CKD (G2-4/A1-3) and/or significant fibrosis on kidney biopsy CKD therapy
N

3 Kidney failure (G5, G5-D), kidney atrophy

U

GN=glomerulonephritis, PLA2R=phospholipaseA2 receptor, MPO=myeloperoxidase, PR3=proteinase 3, SLE=systemic lupus erythematosus, CKD=chronic kidney
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A

disease
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