Hans Joachim Anders Glomerulonephritis

nature reviews immunology https://doi.org/10.
1038/s41577-022-00816-y
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Glomerulonephritis:
immunopathogenesis
and immunotherapy
Hans-Joachim Anders 1
, A. Richard Kitching , Nelson Leung
2,3,4 5,6
& Paola Romagnani7,8
Abstract Sections
‘Glomerulonephritis’ (GN) is a term used to describe a group of Introduction
heterogeneous immune-mediated disorders characterized by Key features of glomerular

inflammation of the filtration units of the kidney (the glomeruli). anatomy and function
These disorders are currently classified largely on the basis of Clinical presentation and
diagnosis of GN
histopathological lesion patterns, but these patterns do not align well
with their diverse pathological mechanisms and hence do not inform Infection-related GN
optimal therapy. Instead, we propose grouping GN disorders into five Autoimmune GN

categories according to their immunopathogenesis: infection-related Alloimmune GN
GN, autoimmune GN, alloimmune GN, autoinflammatory GN and
Autoinflammatory GN
monoclonal gammopathy-related GN. This categorization can inform
Monoclonal gammopathy-
the appropriate treatment; for example, infection control for infection- related GN
related GN, suppression of adaptive immunity for autoimmune GN and
Concluding remarks
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.
1
Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig Maximilian University Munich,
Munich, Germany. 2Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash
Medical Centre, Clayton, VIC, Australia. 3Department of Nephrology, Monash Health, Clayton, VIC, Australia.
4
Department of Paediatric Nephrology, Monash Health, Clayton, VIC, Australia. 5Division of Nephrology and
Hypertension, Mayo Clinic, Rochester, MN, USA. 6Division of Hematology, Mayo Clinic, Rochester, MN, USA.
7
Department of Experimental and Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy.
8
Nephrology and Dialysis Unit, Meyer Children’s University Hospital, Florence, Italy. e-mail: hjanders@
med.uni-muenchen.de
Nature Reviews Immunology | Volume 23 | July 2023 | 453–471 453

Review article
Introduction pass through tight glomerular capillaries at a higher pressure and flow
Glomerulonephritis (GN) describes a variety of relatively rare immune- velocity compared with other capillary beds, which promotes the release
mediated diseases characterized by damage to the glomerular com- of NETs14 followed by focal capillary necrosis in the glomerulus10,14.
partment of the nephrons of the kidney1. If not properly treated, acute
GN can lead to chronic kidney disease and irreversible kidney failure2,3, Clinical presentation and diagnosis of GN
with patients requiring kidney replacement therapy (dialysis or kidney Acute GN most frequently presents with high blood pressure (hyper-
transplantation). Data from a US Medicare cohort (with average age of tension), proteinuria (excessive protein in the urine) and haematuria
75 years) indicated that up to 1.2% of individuals are affected by GN4. (blood in the urine), whereas GN with predominant podocyte injury
Moreover, GN accounts for 18.7% of Germans with chronic kidney dis- causes nephrotic syndrome presenting with a massive proteinuria caus-
ease and 30–36% of end-stage kidney disease in US children and ado- ing leg oedema (Box 1). In general, proteinuria with a predominant
lescents5,6. In addition, GN is more prevalent and may be more severe component of albumin indicates podocyte injury, whereas haema-
in certain ethnic groups, such as African American, Hispanic, Asian, turia implies ruptures of the GBM. As these unspecific clinical signs
and Australian and Canadian First Nations populations. rarely allow a precise diagnosis of the GN subtype, only kidney biopsy
Traditionally, GN has been classified by histopathological lesion can confirm GN, and histopathological lesion patterns visualized by
patterns. However, the growing understanding of immunopathogen- immunostaining for immunoglobulin and complement components
esis of the wide spectrum of GN and the increasing numbers of immuno are used to define GN subcategories15,16.
modulatory drugs require a categorization that better connects with
effective treatments. Here we propose a new classification for GN, Lesion patterns and histological signs
present the latest insights on their respective immunopathogenesis A diagnostic kidney biopsy can distinguish GN from other kidney dis-
and discuss how these imply specific immunotherapies. orders and define the injured glomerular compartment. This has led to
descriptive terms such as ‘mesangioproliferative glomerulonephritis’,
Key features of glomerular anatomy and function ‘membranoproliferative glomerulonephritis’, ‘membranous glomeru-
The glomerular filtration barrier is responsible for creating an ultrafiltrate lonephritis’, ‘crescentic glomerulonephritis’, ‘minimal change disease’
of water and low molecular weight solutes, while retaining most high and ‘focal segmental glomerulosclerosis’ (Table 1 and Fig. 2). Histologi-
molecular weight proteins and blood cells within the vasculature7. The cal signs of immunological activity, such as the presence of deposits of
glomerular microvasculature is particularly vulnerable to immune- complement factors and immune complexes, their isotypes and their
mediated injury because the filtration process involves delicate ana- clonality, as well as ultrastructural changes observed with electron
tomical structures that are exposed to substantial shear stress and microscopy, provide further clues to the underlying cause of GN. For
perfusion pressure. Highly specialized glomerular endothelial cells example, expansion of the cisternae of the endoplasmic reticulum,
build a size- and charge-dependent barrier to serum proteins, while in a named ‘tubuloreticular structures’, in glomerular cells is considered
similar manner the glomerular basement membrane (GBM) itself is also an ultrastructural hallmark of type I interferon signalling, although the
highly specialized. The outer aspect of the filter membrane harbours molecular mechanisms remain unknown17. However, lesion patterns
postmitotic epithelial cells with octopus-like primary, secondary and such as immune complex GN, complement factor C3 GN (C3GN) and
interdigitating tertiary foot processes, cells known as podocytes8 (Fig. 1). pauci-immune GN are nonspecific regarding the underlying patho-
A zipper-like slit membrane between these foot processes comprising physiology. Frequently, additional immunophenotyping is needed
nephrin and other podocyte proteins forms the ultimate barrier to small to precisely define the type of GN (Box 1).
serum proteins9. The glomerular tuft is surrounded by parietal epithelial Kidney biopsy also allows active and potentially reversible lesions to
cells along the Bowman capsule, which directs the ultrafiltrate towards be distinguished from inactive disease or chronic and irreversible lesions
the draining tubule. Immune-mediated injury to any of these structures (Table 1), and this informs immunotherapy. Active lesions include intra-
can cause loss of serum proteins into the urine or even stop filtration, the vascular neutrophil karyorrhexis or NETosis, immunothrombosis and
key function of the kidney needed to maintain internal homeostasis1,10. fibrin deposition, endothelial and mesangial cell proliferation, glomeru-
Infectious organisms, their immunostimulatory or toxic compo- lar leukocytic infiltrates, vascular loop necrosis, cellular crescents (that
nents, immunoglobulins activating complement, spontaneous activa- is, massive hyperplasia of parietal epithelial cells in the Bowman space
tion of the complement system, neutrophil extracellular traps (NETs), obstructing glomerular outflow)10 and periglomerular lymphocyte
infiltrating myeloid cells, helper or cytotoxic T cells and other innate and infiltrates18. Glomerular deposits of IgM, IgG, C1q, C3c and C4d or a com-
adaptive immune effectors can cause glomerular injury, detectable as bination of these support complement activation. Only GN with such
leakage of albumin or other serum proteins, erythrocytes and leukocytes evidence of immunological activity may benefit from immunotherapy.
into the urine1. Depending on the acuity of the immune process, GN pre- By contrast, any fibrous transformation of glomerular structures and
sents as a chronic, a subacute or even a peracute illness1. For example, atrophy of kidney tubules or fibrosis within the interstitium indicate irre-
certain infectious or autoimmune stimuli can lead to massive activation versible loss of kidney parenchyma. However, pathology lesion-based GN
of complement or NET release inside glomeruli, causing diffuse capillary categories often do not dissect the diversity of underlying immunologi-
loop necrosis and necroinflammation and impairing glomerular filtra- cal disorders, which require different treatments19–21; hence, treatment
tion, leading to a rapid decline in the excretory function of the kidneys11,12. of lesion-based GN categories results in many ‘non-responders’22.
Because the filtration process occurs under high perfusion pressure
across a delicate barrier, serum proteins can be easily trapped within Pathophysiology-based classification
the mesangium or along the GBM. Diabetes mellitus, obesity, a high-salt With use of modern immunophenotyping, it is possible to define five
diet and hypertension further increase filtration pressure and acceler- major GN categories that connect directly with their respective immuno
ate glomerular injury (glomerular barotrauma) and promote barrier therapies (Table 2). The first category is GN due to infection, which
dysfunction even in less severe inflammatory states13. Finally, leukocytes involves glomerular injury via humoral and cellular mechanisms of

Review article
Endothelial cell
Basement membrane
Afferent Glomerulus
arteriole Bowman
space Parietal
epithelial cell
Glomerular
capillary
Proximal tubule
Distal
tubule Mesangium
Proximal tubule
epithelial cell
Efferent
arteriole
Mesangial cell Slit diaphragm
(nephrin and other proteins)
Podocyte Podocyte
foot process
Fig. 1 | Anatomy of the glomerulus. The glomerulus is the blood-filtering and attached to the glomerular basement membrane. At the outer aspect
unit of the kidney. Each glomerulus drains the filtrate into its own tubule, and of the glomerular capillaries, podocytes attach to the glomerular basement
the glomerulus and its tubules together constitute the functional unit of the membrane. Podocytes are specialized epithelial cells with neuron-like primary
kidney, the nephron. The vascular part of each glomerulus includes an afferent and secondary foot processes interdigitated with the respective secondary foot
arteriole, an efferent arteriole and a capillary network inside the glomerulus, processes of neighbouring podocytes. Between podocyte foot processes is the
where the filtration occurs under conditions of high perfusion pressure and slit diaphragm, which covers a large area of the filtration barrier and is essential
shear stress. The capillary network is held together by mesenchymal cells, for preventing the passage of serum proteins such as albumin into the filtrate.
known as mesangial cells, and a matrix, which regulate capillary tension. Parts Water, ions and other small solutes cross the filtration barrier through pores in
of the glomerular filtrate pass through the mesangium; hence, circulating the slit diaphragm. Inflammatory processes in the glomerulus typically alter the
antigens and immunoglobulins can get trapped there. Glomerular capillaries barrier function and cause leakage of serum proteins and frequently also of intact
are characterized by a fenestrated endothelium covered with glycocalyx blood cells into the urine.
host defence. This category of GN responds to infection control with cases worldwide, mostly in low-income and middle-income countries
antibiotics or antivirals. The second category is autoimmune GN, owing to social factors and the absence of early antibiotic treatment23,24.
which involves adaptive immune responses directed against distinct GN affects 30% of patients with endocarditis (a rare and potentially fatal
autoantigens, and thus therapeutic targets involve suppression of infection of the inner lining of the heart)25 and 0.7–2% of patients with
autoantigen presentation and clones of autoreactive lymphocytes. infected ventriculoatrial shunts25,26. HIV-associated nephropathy is more
Third, alloimmune GN can occur in the context of kidney transplanta- common in individuals of sub-Saharan descent due in part to the high prev-
tion and requires suppression of donor-specific immunity. Fourth, alence of apolipoprotein L1 (APOL1) risk alleles in this population27,28. GN
autoinflammatory GN originates from inborn errors of innate immu- occurs in more than 50% of patients with hepatitis C virus (HCV) infection29.
nity and responds to inhibitors of single cytokines or complement GN due to hepatitis B virus (HBV) infection is common in HBV-endemic
factors. Finally, monoclonal gammopathy-related GN involves direct areas but has become rare in HBV-vaccinated populations30. Like other
glomerular deposition of monoclonal immunoglobulins and requires helminthic diseases, schistosomiasis can cause GN31,32. Limited data exist
therapies directed against the pathogenic plasma cell clone or B cell in developing countries, but in sub-Saharan Africa, eosinophil-mediated
clone. Here we discuss recent developments in immunophenotyping, glomerular injury is common in children, likely due to the infections preva-
immune mechanisms of glomerular injury, and recent and upcoming lent in this region33. Indeed, Epstein–Barr virus (EBV), parvovirus B19,
immunotherapies for each of these GN subtypes. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), syphilis,
tuberculosis and malaria have all been linked to the development of GN34.
Infection-related GN
Risk factors and epidemiology In situ immune complex formation
Infection-related GN is caused by an immune response to pathogens Poststreptococcal GN occurs after an acute infection with certain
(Table 3). For example, poststreptococcal GN, which occurs following nephrogenic strains of group A β-haemolytic streptococci, because
infection with group A streptococci, has an estimated 470,000 new annual their antigens can attach to glomerular endothelial cells24. IgG, IgM

Review article
antibodies or cryoglobulins24 as an additional autoimmune component

Box 1 to infection-related GN.
Deposition of circulating immune complexes

Immunophenotyping for the The most important mechanism precipitating kidney injury during
active infection involves the deposition of circulating immune com-
classification of patients with plexes, as observed in endocarditis, skin ulcers and cellulitis, osteo-
glomerulonephritis myelitis, pneumonia, visceral abscess and urinary tract infection39,

a process that implies persistent presence of antigens in the blood40.
Indeed, impaired clearance of pathogens in patients with primary or
•• Clinical signs and symptoms of glomerular injury: impaired secondary immunodeficiencies may contribute to their enhanced
glomerular barrier function (proteinuria and haematuria); susceptibility to infection-related GN and the deposition of pathogen
impaired excretory kidney function indicated by hypertension, antigens in the glomeruli. Antigens can also persist in the blood in
oedema (both related to salt and water retention) or increased infections with pathogens that integrate into the host genome, such as
levels of metabolites, such as creatinine and urea, in the blood. HCV, HIV, EBV, intracellular Staphylococcus aureus or Mycobacterium
•• Clinical context: history of extrarenal manifestations of infections, tuberculosis, leading to deposition of antigen–antibody immune com-
autoimmune disease, transplantation, autoinflammatory plexes in the glomeruli. Similarly, parasites that encode strategies of
disorders or multiple myeloma. immune evasion, such as members of the genus Schistosoma, which
•• Blood tests to detect leukopenia, acute phase proteins, cover themselves with host proteins, can persist in the blood. Some
immunoglobulin levels, complementopenia, autoantibodies, body compartments are difficult to reach for immune effectors or anti-
alloantibodies, antivaccine titres, HLA type, free light chains, biotics, including biofilms on implants, heart valves or bones, allowing
monoclonal gammopathy or pathogen-related changes. pathogens to escape elimination and establish chronic infection.
•• Microbiology tests: blood pathogen microscopy, blood cultures,
swabs, catheter or implant cultures, tissue aspirates or biopsies. Direct cytotoxic effects of pathogens
•• Kidney biopsy: immunofluorescence for immunoglobulins, Some pathogens have direct effects on kidney cells, precipitating glo-
κ/λ idiotypes, complement factors, standard stains (periodic merular filtration barrier impairments (Fig. 3). HIV, EBV, arbovirus,
acid–Schiff, hematoxylin–eosin and silver stains), immunostaining parvovirus B19 or SARS-CoV-2 can infect and injure glomerular epi-
for pathogens and electron microscopy. thelial cells41–43. Moreover, viral nucleic acids promote intraglomerular
•• Genetic testing: panel sequencing for cytokine, interferon production of type I interferons leading to podocyte detachment or
and complement pathways (autoinflammation), Sanger death, reduced production of podocyte-derived vascular endothelial
sequencing for collagens, apolipoprotein L1 (APOL1) risk alleles growth factor needed for maintaining glomerular endothelial cells
(glomerulosclerosis), whole-exome sequencing (primary and collapse of glomerular capillaries8,44. Podocyte loss is associated
immunodeficiencies). with proteinuria and irreversible glomerulosclerosis45. Type I inter-
•• Miscellaneous examinations: imaging studies (kidney, origin ferons induce podocyte death by catastrophic mitosis and block the
of infections or multiple myeloma), bone marrow aspirate, differentiation of local podocyte progenitors into new podocytes17,46,47.
immune cell flow cytometry and B cell sequencing for clonal By contrast, activation of immature progenitors among the parietal
analysis. epithelial cells can result in the formation of hyperplastic lesions that
obliterate the Bowman space and block glomerular filtration loss48.
Podocyte loss in viral infections also relates to their ability to
promote the release of type I interferons through activation of the
and sometimes IgA bind to streptococcal antigens trapped in glomer- NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome
uli, and the in situ formation of immune complexes triggers endothelial and the cytosolic nucleotide sensor stimulator of interferon genes
damage by activating the classical complement pathway. However, (STING). This pathway is confounded by the presence of APOL1 risk
chemokine-binding evasins secreted by streptococci and other kidney alleles27, which have been selected in individuals of sub-Saharan
proteins of the bacterial surface suppress activation of the classical ancestry, including 30% of African Americans, as they confer protec-
complement pathway35. The leading candidate antigens are nephritis- tion against Trypanosoma brucei rhodesiense infection (sleeping sick-
associated plasmin receptor (NAPlr; identified as glyceraldehyde ness)27. However, they predispose to progressive disease in a variety of
3-phosphate dehydrogenase) and streptococcal pyrogenic exotoxin B glomerular diseases27. Expression of high-risk APOL1 genotypes, called
(SpeB; a cationic cysteine proteinase)36. These antigens also induce the ‘G1’ and ‘G2’, induces activation of STING, leading to the production
release of IL-6, tumour necrosis factor (TNF), IL-8 and transforming of type I interferons, with consequent podocyte loss. High-risk APOL1
growth factor-β from peripheral blood leukocytes, promoting glo- alleles also activate the NLRP3 inflammasome, with consequent release
merular inflammation36. NAPlr activates C3, and SpeB evades innate of IL-1β49 that promotes the death of podocytes by pyroptosis50. In turn,
host defence by degrading lytic complement factors35–37. Both induce APOL1 expression itself is upregulated by type I interferons and this
adhesion molecule expression, increase leukocyte recruitment and further enhances podocyte loss8, in an autoactivation loop21,50. This may
directly activate the alternative complement pathway. The alternative explain why Schistosoma infection-related GN progresses quickly to
complement pathway may also be activated by transiently produced kidney failure in APOL1 carriers or in patients co-infected with HIV, HCV
autoantibodies targeting factor B, a regulator of the alternative comple- or HBV8. Type I interferons, IL-1β, IL-6 and TNF induced by SARS-CoV-2
ment pathway38. Sometimes, infections also induce a transient produc- trigger the expression of pathogenic APOL1 via JAK–STAT signalling,
tion of antineutrophil cytoplasmic antibodies (ANCAs), antinuclear resulting in podocyte loss and COVID-19-associated nephropathy51.

Review article
Targets for immunotherapy of nephritogenic autoantibodies produces active lesions followed

Prevention or treatment of infection-related GN has focused on address- by immediate atrophy and scarring (necrotizing and crescentic GN),
ing the underlying infection with antivirals or antibiotics and/or by whereas low antibody titres and a low nephritogenic potential pro-
removing an infected device52. For example, combination antiretroviral duce less active lesions and result in chronic and smouldering GN with
therapy has greatly reduced the incidence of HIV-associated nephrop- damage accruing over longer periods.
athy53. Similarly, treatment of HCV infection has largely abolished
HCV-related GN54. By contrast, the benefit of corticosteroids or other Risk factors and epidemiology
immunosuppressive drugs to limit irreversible damage in infection- The exact prevalence of autoimmune GN is unclear, but collec-
related GN remains uncertain55. A recent randomized controlled trial tively the different subtypes account for a significant proportion of
of corticosteroid treatment showed no significant increase in kidney all GN. Autoantibodies directed against IgA cause IgA nephropathy,
recovery rates in infection-related GN and was associated with a sixfold the most prevalent autoimmune GN, especially in Asia. Its autoim-
increase in adverse events56. Targeted therapies with the potential to mune nature is most obvious when presenting as an acute small vessel
interrupt the interferon–APOL1 loop are now being explored in carriers vasculitis with IgA deposits affecting the skin, intestinal tract, joints
of high-risk APOL1 alleles. A preliminary communication on a phase II and kidneys. GN involving ANCAs, anti-podocyte antibodies or anti-
clinical trial reported that treatment with the APOL1 inhibitor inaxaplin chromatin antibodies is also relatively common57–59 (Table 3). The
(NCT05312879) reduced the degree of proteinuria in 47.6% of patients higher prevalence and disease severity of IgA nephropathy in Asia or
with diverse proteinuric kidney diseases and was well tolerated. A JAK/ of lupus nephritis in people of African descent may be explained by
STAT inhibitor, baricitinib, is also being explored in a phase II clinical gene variants that affect checkpoints of immune tolerance, including
trial (NCT05237388) for the treatment of patients with APOL1-mediated monogenic primary immunodeficiencies60 or variants in HLA-DRB1,
glomerular disorders51. HLA-DQA1, HLA-DQB1 and Fc receptors61,62. Alternatively, it has been
proposed that somatic mutation-driven expansion of autoreactive
Autoimmune GN B cell clones resembling features of clonal haematopoiesis may explain
Autoimmune GN is characterized by an adaptive immune response the pathogenesis of autoimmune GN63,64. Somatic mutations may allow
directed against a series of different self-antigens (Table 3), some of proliferating self-reactive lymphocytes to bypass regulatory check-
which exclusively localize to the kidney (podocyte antigens and GBM points and to account for a high percentage of the overall lymphocyte
antigens), whereas others are expressed systemically, such as IgA (IgA population64,65. However, this recent concept awaits exploration in the
nephropathy), IgG (cryoglobulinaemic GN), neutrophil antigens (ANCA context of autoimmune GN.
GN) and chromatin components (lupus nephritis), and often lead to
extrarenal manifestations. Circulating extrarenal antigens can cause Immunopathogenesis
GN upon entrapment in the filtration barrier. Finally, autoantibod- In all autoimmune GN disorders, the central pathogenic elements are
ies to complement factors can induce GN by inducing unnecessary loss of tolerance and an adaptive immune response to a self-antigen
complement activation. Autoimmune GN associated with high levels (Fig. 3). The reasons for loss of tolerance differ, and are usually difficult
Table 1 | Interpretation of histopathological lesion patterns of glomerulonephritis
Lesion pattern Main structure injured Immunological activity Chronicity
Collapsing focal segmental glomerulosclerosis Podocytes High Acute

Focal segmental glomerulosclerosis Podocytes Low Subacute
Membranous glomerulonephritis Podocytes Intermediate Chronic
Minimal change disease Podocyte slit Variable Acute
Mesangiolysis Mesangial cells High Acute
Membranoproliferative glomerulonephritis Mesangial cells, podocytes Intermediate Acute
Mesangioproliferative glomerulonephritis Mesangial cells Variable Variable
Thrombotic microangiopathy Endothelial cells High Variable
Necrotizing glomerulonephritis Endothelial cells Intermediate Acute
Endocapillary glomerulonephritis Endothelial cells Low to intermediate Acute
Small vessel vasculitis Arterioles, venules High Variable
Vascular hyalinosis Arterioles, venules – Subacute
Crescentic glomerulonephritis (cellular) Glomerular basement membrane High Acute
Crescentic glomerulonephritis (fibrous) Glomerular basement membrane Variable Chronic
Global glomerulosclerosis All structures Low Chronic
Tubular atrophy Tubules Low Chronic
Interstitial fibrosis Peritubular vessels Low Chronic

Review article
a Endocapillary proliferative GN b Mesangioproliferative GN c Membranoproliferative GN
Neutrophils
HE HE Silver
d Membranous GN e Crescentic GN f Pauci-immune GN
Parietal Tuft
cell crescent compression
IgG4 Fibrinogen IgG
i Proliferative GN with monoclonal

g (IgA) immune complex GN h C3GN immunoglobulin deposits
C3 IgA C3 IgA κ λ
Fig. 2 | Histopathological lesion patterns common in glomerulonephritis. a relative lack of immunoglobulins and complement deposition in pauci-immune
Common histopathological lesion patterns characteristic of glomerulonephritis GN (part f). Mesangial IgA positivity is typical of IgA nephropathy (part g) and
(GN) are shown; for example, endocapillary lesions (part a), mesangioproliferative complement factor C3 positivity in absence of IgG deposits defines complement
lesions (part b) and membranoproliferative lesions (part c). Immunostaining factor C3 GN (C3GN) (part h). Staining for κ and λ immunoglobulin chains (part i)
is routinely performed as one element of immunophenotyping and shows, for helps to distinguish monotypic and polytypic immune deposits. For example,
example, granular IgG4 positivity along the filtration barrier in a membranous GN monotypic λ deposits occur in proliferative GN with monoclonal immunoglobulin
(part d), diffuse fibrinogen positivity in necrotizing and crescentic GN (part e) and deposits. HE, hematoxylin–eosin.
to determine. Primary immunodeficiencies and impaired regulatory Another form of autoimmune GN involving ubiquitous antigens
T cell function are rarely clinically obvious65. Despite the shared involve- is lupus nephritis, as commonly occurs in patients with systemic lupus
ment of innate and adaptive immunity, the nature and distribution of erythematosus, and is characterized by loss of tolerance to chromatin
the self-antigen within and outside the kidney explains the spectrum components and other ubiquitous self-antigens69. The various lesion
of different subtypes of autoimmune GN. For example, loss of tolerance patterns involve polytypic deposits of IgA, IgM, IgG and complement
to IgA or IgG can cause IgA vasculitis (Henoch–Schönlein purpura) or factors C1q and C3, indicating involvement of the classical comple-
cryoglobulinaemic vasculitis, respectively, with highly active poly- ment pathway70. Autoimmune vasculitis characterized by ANCAs,
clonal immune complex GN as a typical classical lesion pattern66–68. For specific for the neutrophil antigen myeloperoxidase or proteinase 3,
reasons still unknown, some individuals release hypoglycosylated IgA frequently results in severe GN. ANCAs bind to and prime neutro-
from intestinal B cell reservoirs into the blood, where it is handled as an phils71,72. When migrating through the high shear stress glomerular
autoantigen, resulting in circulating anti-IgA–IgG immune complexes capillary network, neutrophils degranulate and release NETs, which
and IgA nephropathy66. induces complement-driven microvascular endothelial injury12,58,73.

Review article
Moreover, the C5 cleavage product C5a acts as an anaphylatoxin in production of the causative nephritogenic autoantibody within sec-
ANCA GN and drives local neutrophil recruitment and inflammation72; ondary lymphoid organs, is distinguishable from autoinflammatory
hence, C5aR blockade is efficacious in active ANCA GN74. Despite its C3GN that lacks any involvement of the adaptive immune system and
autoimmune nature, ANCA GN is misleadingly described as pauci- from monoclonal gammopathy-related C3GN caused by an aberrant
immune due to minimal antibody and complement deposition in the plasma cell clone or B cell clone in the bone marrow.
glomerulus upon standard kidney biopsy assessment58,75. Autoimmune GN involving high-affinity antibodies to the non-
C3GN, a GN lesion pattern defined by complement deposits collagenous domain of the α3 chain of type IV collagen (α3(IV)NC1)
without concomitant immunoglobulin deposits, can be categorized presents as rapidly progressive GN with or without pulmonary mani-
as autoimmune in the presence of circulating autoantibodies known as festations (historically known as Goodpasture syndrome), due to the
nephritic factors to C3, C5 or factors B and H that lower the physiologi- restricted expression of α3(IV) in the GBM and the alveolar basement
cal threshold for activation of the alternative complement pathway, membrane79. However, anti-α3(IV)NC1 antibodies can recognize α3(IV)
leading to complement-mediated glomerular injury76–78. Autoimmune NC1 within structural collagen networks only upon dysfunction of per-
C3GN, involving all elements of the adaptive immune system in the oxidasin, a unique extracellular peroxidase that catalyses the formation
Table 2 | Proposed classification of glomerulonephritis
GN category Infection-related GN Autoimmune GN Alloimmune GN Autoinflammatory Monoclonal gammopathy-

GN related GN
Pathogenesis Innate and adaptive Adaptive immune Adaptive immune Inborn errors of Paraprotein-releasing B cell
host defence with or response to response to donor innate immunity clone or plasma cell clone
without molecular autoantigens antigens
mimicry
Therapy Infection control Transient or Persistent suppression Inhibition of specific Clone-directed therapy
persistent of adaptive immune cytokines or
suppression of response complement factors
adaptive immune
response
Immunophenotyping
Kidney biopsy immunostaining Polytypic deposits Polytypic deposits Polytypic deposits No deposits or Monotypic deposits
for immunoglobulin or light chains polytypic deposits
Kidney biopsy immunostaining C1q, C3c, C4d, C5b, C1q, C3c, C4d, C5b, C1q, C3c, C4d, C5b, Variable Variable
for complement factors C6, C7, C8, C9 C6, C7, C8, C9 C6, C7, C8, C9
Kidney biopsy immunostaining IgA, IgG, PLA2R, FAT1 (stem cell
for specific autoantigens TSHD7A, NELL1, transplantation)
HTRA1, PCDH7, netrin
G1, semaphorin 3B
Other tests Identification of Specific serum Donor-specific Genetic testing Serum monoclonal
pathogen autoantibody antibodies immunoglobulin, free light
chain
Histology lesion pattern
Collapsing GN √ √ – – –
Crescentic GN √ √ √ √ √
Necrotizing GN √ √ – – –
Endocapillary GN √ √ √ √ √
Minimal change √ √ √ – √
Mesangioproliferative GN √ √ √ √ √
Pauci-immune GN – √ – – –
Nodular glomerulosclerosis – – – – √
Focal glomerulosclerosis √ √ √ √ √
Membranous GN √ √ √ – √
C3GN – √ – √ √
Membranoproliferative GN √ √ √ √ √
Thrombotic microangiopathy √ √ √ √ √
C3GN, complement factor C3 glomerulonephritis; GN, glomerulonephritis; HTRA1, human high temperature requirement A1; NELL1, NEL-like protein 1; PCDH7, protocadherin 7; PLA2R,
phospholipase A2 receptor; TSHD7A, thrombospondin type 1 domain-containing protein 7A.

Review article
Table 3 | Categories of glomerulonephritis and examples of their subtypes
GN subtype Underlying cause Pathological mechanism Kidney biopsy lesion pattern
Infection-related GN
Bacterium-associated GN Staphylococci: implant infections, Deposition of circulating immune C4d+ immune complex GN,
abscesses complexes, molecular mimicry podocytopathy
Streptococci: tonsillitis, erysipelas
Mycobacteria: tuberculosis
Virus-associated GN HIV: AIDS Deposition of circulating immune C4d+ immune complex GN,
EBV: mononucleosis complexes, molecular mimicry podocytopathy
HBV, HCV: viral hepatitis
SARS-CoV-2: COVID-19
Parasite-associated GN Plasmodia: malaria Deposition of circulating immune C4d+ immune complex GN,
complexes podocytopathy
Autoimmune GN
IgA nephropathy Anti-Gd IgA1 Mesangial IgA and C3 deposits Diverse, immune complex GN
Cryglobulinaemia Cryoglobulins, RF Luminal IgG deposits Diverse, immune complex GN
ANCA vasculitis (GPA) Cytoplasmic ANCAs, anti-PR3 ANCA-mediated priming of neutrophils to Pauci-immune GN (crescentic GN)
ANCA vasculitis (MPA) Perinuclear ANCAs, anti-MPO undergo NETosis, complement-mediated
inflammation
C3GN Anti-C3, anti-C4, anti-C5, anti-factor B, Granular C3 deposits Diverse, C3GN

anti-factor H
Lupus nephritis Anti-dsDNA, anti-histone Full house: IgA, IgG, IgM and C3 deposits Diverse, immune complex GN
Anti-GBM disease Anti-type IV collagen α3 chain Linear IgG and/or C3 deposits Crescentic GN
Steroid-sensitive nephrotic Anti-nephrin IgG dusting at podocyte slit Minimal changes, FSGS,
syndrome membranous GN
Primary membranous GN Anti-PLA2R, anti-TSHD7A, anti- Granular IgG4, IgG1, IgG3 or C3 deposits Membranous GN
semaphorin 3B, anti-PCDH7, anti-
HTRA1, anti-contactin 1, anti-netrin G1,
anti-NELL1
Alloimmune GN
Transplant glomerulopathy Transplantation of cells or organ from Alloimmunity to donor antigens Diverse
a donor
Autoinflammatory GN
Familial Mediterranean fever MEFV mutation Inflammasome overactivation and/or high Diverse
IL-1β production
CAPS NLRP3 mutation Inflammasome overactivation and/or high AA amyloidosis

IL-1β production
Hyper-IgD syndrome MVK mutation Inflammasome overactivation and/or high AA amyloidosis

IL-1β production
TRAPS TNFRSF1A mutation TNF pathway overactivation AA amyloidosis
C3GN FHR fusion proteins Complement (alternative pathway) C3GN

overactivation
Monoclonal gammopathy-related GN
Proliferative GN with monoclonal Somatic mutation of immunoglobulin- Immunoglobulin or immunoglobulin Proliferative GN with monoclonal
immunoglobulin deposition, producing B or plasma cells component deposition immunoglobulin deposition
monoclonal immunoglobulin
deposition disease
AL amyloidosis Somatic mutation of immunoglobulin- β-Sheet fibril deposition Glomerular deposits of monotypic
producing B cells or plasma cells amyloid
Monotypic fibrillary GN Somatic mutation of immunoglobulin- Fibril deposition Glomerular deposits of monotypic
producing B cells or plasma cells fibrils
Crystalloglobulin GN Somatic mutation of immunoglobulin- Crystal deposition Glomerular cells with monotypic
producing B cells or plasma cells crystals

Review article
Table 3 (continued) | Categories of glomerulonephritis and examples of their subtypes
GN subtype Underlying cause Pathological mechanism Kidney biopsy lesion pattern
Immunotactoid GN, Somatic mutation of immunoglobulin- Microtubule deposition Vascular deposits of monotypic IgG
cryoglobulinaemia I/III producing B cells or plasma cells
C3GN, thrombotic Somatic mutation of immunoglobulin- Diverse; complement activation Glomerular thrombotic
microangiopathy producing B cells or plasma cells microangiopathy with monotypic
deposits
ANCA, antineutrophil cytoplasmic antibody; CAPS, cryopyrin-associated periodic syndrome; C3GN, complement factor C3 glomerulonephritis; dsDNA, double-stranded DNA; EBV, Epstein–Barr
virus; FHR, complement factor H-related protein; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; Gd IgA1, galactose-deficient IgA1; GN, glomerulonephritis;
GPA, granulomatosis with polyangiitis; HBV, hepatitis B virus; HCV, hepatitis C virus; HTRA1, human high temperature requirement A1; MPA, microscopic polyangiitis; MPO, myeloperoxidase; NELL1,
NEL-like protein 1; NET, neutrophil extracellular trap; PCDH7, protocadherin 7; PLA2R, phospholipase A2 receptor; PR3, proteinase 3; RF, rheumatoid factor; SARS-CoV-2. severe acute respiratory
syndrome coronavirus 2; TNF, tumour necrosis factor; TRAPS, tumour necrosis factor receptor-associated periodic syndrome; TSHD7A, thrombospondin type 1 domain-containing protein 7A.
of sulfilimine crosslinks in collagen IV (refs. 80,81). Indeed, peroxidasin complement pathways can be involved91; for example, in membranous
antibodies reduce peroxidasin activity before anti-GBM IgG produc- GN associated with glomerular deposits of anti-PLA2R IgG4 (ref. 92). In
tion and the onset of GN, probably by exposing the cryptic B cell α3(IV) patients with anti-PLA2R GN and genetic deficiency of mannan-binding
NC1 epitope81. In addition, individuals expressing HLA-DR15 sero- lectin, activation of the alternative pathway predominates93. Suben-
types present the immunodominant α3(IV)NC1 peptide in a way that dothelial immune complex deposits first activate endothelial cells,
thymic selection results in the generation of conventional α3(IV)NC1 triggering endocapillary lesions. Entrapment of immune complexes
peptide-specific CD4+ T cells that can potentially target self-tissues. in the mesangium leads to mesangioproliferative or membranopro-
However, the same peptide adopts a different structural confirmation liferative lesions. These glomerular compartments are also accessible
when bound to HLA-DR1 and preferentially selects thymus-derived to leukocytes; hence, antagonists of pro-inflammatory chemokines,
antigen-specific regulatory T cells that dominantly protect from loss such as CC-chemokine ligand 2, and their chemokine receptors can
of tolerance in mice and in human in vitro assays65. attenuate such lesions94.
Finally, autoimmune GN involving podocytes as the sole target The specialized nature of the glomerular capillaries influences
structure induces lesion patterns of either membranous nephropathy effector T cell functions within the glomerulus. CD4+ T cells migrate
(targeting antigens localized at podocyte surfaces) or minimal change within capillaries95, but in healthy conditions or in the early stages of
disease and focal segmental glomerulosclerosis (targeting filtration disease they do not extravasate inside the glomerulus. Studies using
slit antigen) and has no extrarenal manifestations. Podocytes localize model antigens have demonstrated that the distribution of the anti-
to the outside of glomerular capillaries, a site that is not accessible to gen within the glomerulus is an important determinant of the pattern
intravascular immune cells under normal conditions (Fig. 3), which of injury. When the antigen is present on the endothelial side of the
may limit the effectiveness of peripheral tolerogenic mechanisms. GBM (or in the GBM itself), both T helper 1 (TH1) cells and TH17 cells
Indeed, a surprising spectrum of antigens are involved in autoimmune induce antigen-specific endocapillary injury95–97. Unusually, in this
podocytopathies, including the podocyte proteins M-type PLA2R82 and setting antigens can be presented within glomerular capillaries by
thrombospondin type 1 domain-containing protein 7A83, as well as the intravascular monocytes to effector CD4+ T cells95. Thus, in autoim-
extrarenal proteins semaphorin 3B19, protocatherin 7 (ref. 84), human mune GN and infection-related GN, endocapillary antigens result in
high temperature requirement A1 (ref. 85), contactin 1 (ref. 86), netrin proliferative GN that can progress rapidly. When T cells accumulate
G1 (ref. 87) and NEL-like protein 1 (ref. 88) (Table 3). Antibody binding to around the Bowman capsule, the capsule itself serves as a niche for the
these antigens at the podocyte–GBM interface is followed by in situ cells of the glomerular tuft that protects them from cytotoxic CD8+
immune complex formation and complement-driven podocyte injury T cells, at least until there is concurrent significant glomerular endothe-
along the outer aspect of the GBM. Autoimmunity to PLA2R is the most lial injury98. Kidney-resident memory TH17 cells, generated following
common autoimmune podocytopathy, and genome-wide association infection of the kidney, can be reactivated during subsequent GN by
studies document unusual variants at a locus in proximity to the gene local pro-inflammatory cytokines and can exacerbate GN through the
encoding PLA2R as a potential factor in the loss of tolerance to this production of IL-17A in an antigen-independent manner99. Incident
podocyte antigen62. By contrast, autoantibodies binding to compo- infections also exacerbate pre-existing GN, for example via circulating
nents of the slit diaphragm between podocyte foot processes appear pathogen-associated molecular patterns that activate Toll-like recep-
as tiny dust-like IgG deposits that are detectable only on frozen sections tors and other pattern recognition receptors in macrophage infiltrates,
by confocal microscopy89. As the resulting podocyte foot process which accelerates glomerular inflammation and injury100,101. Bacterial
effacement is not visible by standard microscopy, this variant of auto- lipopeptides specifically injure the glomerular filtration apparatus by
immune GN has been referred to as ‘minimal change disease’8. Indeed, activating Toll-like receptors 2 and 4 on glomerular endothelial cells
autoimmune podocytopathies are not characterized by immune cell and podocytes102.
infiltrates due to their antigens being in a relatively immune privileged
location to which leukocytes do not have ready access. Targets for immunotherapy
In types of autoimmune GN with acute and irreversible kidney injury
Immunopathology caused by circulating antibodies, plasma exchange or treatment with
Glomerular injury in immune complex GN occurs upon activation of Fc the endopeptidase imlifidase is used to quickly remove nephritogenic
receptors on resident cells or infiltrating immune cells, as well as upon antibodies103,104 (Fig. 4). Glucocorticoids are still in use to control auto-
activation of the classical complement pathway90. In addition, the lectin immune GN activity, but their nonspecific mechanism of action and

Review article
a Infection-related GN Infection b Autoimmune GN
Adaptive immune response

against self-antigens (PAMPs
Adaptive immune response as non-specific stimuli)
against pathogen antigens
Macrophage Infected cell

Passive entrapment Passive entrapment
of circulating IC of circulating IC
Mesangium Antibody binding

IC to glomerular
self-antigens
In situ IC Antigen recogition

Monocyte Red blood cell Endothelial by effector T cells
formation ANCAs binding
cell
to neutrophil
Pathogen Glomerulus
products
Neutrophilia capillary
and toxins
NET
Pro-inflammatory Complement Pro-inflammatory
cytokines activation cytokines
Direct cytopathic Antibody binding to GBM

effects GBM or podocyte antigens
Podocyte
injury
Proteinuria
Haematuria
Haematuria
Proteinuria
Podocyte
Parietal cell
hyperplasia
Periglomular
Pathogen-specific lymphocytes
Parietal cell GBM lymphocyte
c Alloimmune GN d Autoinflammatory GN e Monoclonal gammapathy-related GN

Transplantation Inborn errors of immunity
Nephropathic B cell clone or
nephrotoxic Ig (components)
due to somatic mutations
Adaptive immune response Enhanced secretion or
against donor antigen effects of single cytokines
Spontaneous
complement
Alloantibody activation in
complementopathies
Damaged Free light chain

endothelium
Alloantibodies
binding HLA or
non-HLA antigens Deposition of
AA amyloid amyloid fibrils,
Thrombus in allograft deposits in microtubules
periodic fever Type I
and Ig crystals
syndromes IFNs
Secondary
podocyte Primary or
Secondary secondary
podocyte injury
Proteinuria Proteinuria podocyte
injury Haematuria injury
Proteinuria Haematuria

Review article
Fig. 3 | Simplified schematic of the pathogenesis of the five categories of trigger flares of autoimmune GN via a nonspecific activation of autoreactive
glomerulonephritis. Glomerulonephritis (GN) comprises a group of immune- lymphocyte clones. c, Alloimmune GN can occur following transplantation and
mediated disorders with the involvement of different innate and adaptive is associated with the development of donor-specific antibodies to HLA and
immune pathways in glomerular injury. a, Infection-related GN is triggered non-HLA antigens of the graft and can lead to thrombotic microangiopathy and
by pathogens or pathogen-associated molecular patterns (PAMPs) that elicit endothelial damage. d, Genetic variants in genes encoding cytokine pathways
host defence mechanisms, which may affect the kidney in various ways as or regulatory elements of the complement cascade cause autoinflammatory
indicated. Circulating immune complexes (ICs) can become trapped in the disorders, some of which cause GN. Mechanisms of kidney pathology include
mesangium or they can form in situ in the subendothelial space, where they spontaneous complement activation in complementopathies and AA amyloid
can trigger complement activation. In addition, some pathogens have direct deposits in periodic fever syndromes. e, Monoclonal gammopathy-related
cytopathic effects, precipitating glomerular filtration barrier impairments. GN develops from somatic mutations in B cell clones or plasma cell clones
b, Autoimmune GN involves loss of tolerance to self-antigens in glomerular cells that produce immunoglobulins or immunoglobulin components with
but frequently also to extrarenal antigens, which localize to the kidney or affect nephrotoxic properties. These reach the glomerulus via the circulation. ANCA,
the kidney in other ways. Memory T cells in lymphoid tissues and long-lived antineutrophil cytoplasmic antibody; GBM, glomerular basement membrane;
plasma cells in the bone marrow maintain chronic autoimmunity. Infections can NET, neutrophil extracellular trap.
metabolic side effects compromise their safety profile; hence, gluco- Alloimmune GN
corticoid replacement is a key goal for GN immunotherapy (Table 4 and Risk factors and epidemiology
Fig. 4). For example, intestinal-release capsules of the glucocorticoid Glomerular injury can occur in recipients of any type of transplant,
budesonide limits the release of aberrantly glycosylated IgA from Peyer but it is most common in kidney transplant recipients. HLA mismatch
patches in the intestinal wall of patients with IgA nephropathy and and the presence of anti-HLA alloantibodies (donor-specific antibod-
shows less systemic steroid toxicity105. ies) are risk factors for alloimmune GN113. Chronic rejection mediated
Potential targets of immunotherapy for autoimmune GN include by alloimmunity resulting in chronic transplant glomerulopathy is
cells of the adaptive immune system and molecules involved in anti- a significant cause of graft loss, although acute antibody-mediated
gen presentation and recognition, for example using B cell-directed rejection can also involve the glomerulus.
therapies and co-stimulation blockers, acting primarily inside lym- A less common type of alloimmune response develops in those
phoid organs (Fig. 4). Belimumab, a monoclonal antibody to B cell who have received a kidney transplant for a genetic deficiency of a
activating factor, is approved for the treatment of lupus nephritis, specific protein (for example, one of the chains of type IV collagen
and rituximab, a monoclonal antibody to CD20, is approved for the or the podocyte-specific protein nephrin) that has led to kidney failure.
treatment of ANCA GN and is also broadly used as a steroid-sparing The subsequent transplantation of a genetically intact kidney results
agent in autoimmune podocytopathies. Other B cell targets are under in alloimmunity to the ‘non-self’ protein present in the graft114. Auto-
evaluation (for example, APRIL and TACI). Cathepsin S inhibition can immune glomerular disease can recur in the transplanted kidney (for
attenuate autoimmune GN by suppressing MHC class II-mediated example, autoimmune IgA nephropathy) despite immunosuppression
CD4+ T cell and B cell priming106. Another group of drugs targets the prescribed to limit allogeneic responses114. Lastly, de novo glomerular
maturation, activation, proliferation and survival of autoreactive lym- disease can occur in kidney transplants and in allogeneic stem cell
phocyte clones; for example, mycophenolate mofetil, azathioprine, recipients who develop graft-versus-host disease (GVHD)115.
cyclophosphamide, calcineurin inhibitors, anti-IL-23, anti-IL-17A and
anti-CD40 ligand. Calcineurin inhibitors combine the T cell-directed Immunopathogenesis and immunopathology
immunosuppressive effect with a stabilization of the podocyte actin In kidney transplantation, donor reactivity to recipient HLA molecules
cytoskeleton, which generates strong antiproteinuric effects in addi- of the graft is detectable as donor-specific antibodies in the blood
tion to suppressing T cell function, for example in lupus nephritis107,108 that initially induce microvascular inflammation, often with the par-
(Fig. 4). The first reports support the efficacy of chimeric antigen recep- ticipation of complement and innate immune cells, in the form of
tor T cell therapy directed against CD19+ B cells and of a monoclonal acute glomerulitis113 (Fig. 3). The kidney graft is selectively impacted
antibody to CD38 (daratumumab) for targeting long-lived plasma cells as it is only the transplanted tissue that expresses the allogeneic HLA
in lupus nephritis109,110. molecules. Glomerular endothelial cells are most commonly affected
In addition, overwhelming preclinical evidence supports the by anti-HLA antibodies, although mesangial cells and to a lesser extent
role of innate immune pathways in autoimmune GN. For example, podocytes can be targeted. Active acute antibody-mediated rejec-
mice deficient in Toll-like receptors, complement factors C3, C5 and tion can exhibit various features, including immune cell infiltrates
C5aR, adhesion molecules, pro-inflammatory chemokines and their and leukocytes within glomerular capillaries, thrombotic microangi-
receptors, or TH1-type, TH2-type and TH17-type cytokines are generally opathy, necrosis, endothelial and mesangial cell swelling, capillary
protected from immunopathology in GN models111. Therefore, comple- occlusion and C4d deposition116. Acute glomerulitis due to antibody-
ment inhibitors could possibly replace glucocorticoids for the control mediated rejection can progress to transplant glomerulopathy, which
of glomerular inflammation. Indeed, the C5aR inhibitor avacopan is is characterized by persistent or recurrent glomerular endothelial
now used to minimize steroid use in active ANCA GN74, because this cell injury and GBM duplication usually in the absence of immune
anaphylatoxin antagonist can quickly suppress glomerular inflamma- complex deposits despite the involvement of anti-HLA alloantibod-
tion and injury. Numerous other antibody-based or small interfering ies or other antibodies113,116. As in other glomerular diseases, chronic
RNA-based complement inhibitors are currently under study (Table 4). inflammation leads to glomerulosclerosis. In some patients, donor-
By contrast, despite robust preclinical evidence, IFNAR1 blockade failed specific antibodies targeting HLA class II may be more important than
to control proteinuria in active lupus nephritis112. anti-HLA class I antibodies117. Pre-existing donor-specific antibodies

Review article
at transplantation are likely to induce antibody-mediated rejection critical in transplant glomerulopathy, but in some circumstances,
in glomeruli, but de novo donor-specific antibodies are important in particularly in the absence of detectable anti-HLA antibodies and
many patients. glomerular C4d deposition, other cellular effectors (for example,
Besides anti-HLA antibodies, antibodies to self-antigens can natural killer cells119) participate in injury independently of humoral
develop, including antibodies to glomerular matrix proteins and effectors120.
endothelial cell antigens, in patients with transplant glomerulopa- Other immunological processes can result in glomerular injury in
thy118. Some of these autoantigens are cryptic and are released by the transplanted kidney. Uncommonly, immunosuppressive agents,
the obligate ischaemia–reperfusion injury occurring in kidney specifically calcineurin inhibitors, trigger glomerular endothelial
transplantation. Antibody-mediated mechanisms of injury are often injury and thrombotic microangiopathy in the graft121. In patients with
Lymphoid tissue Glucocorticoids
• Anti-CD40
• Anti-FcR
DC • Anti-MC1R or anti-MC3R
• Co-stimulation blockers
• Anti-IFNAR1
Pro-inflammatory
cytokines
• Cytokine antagonists
• JAK/STAT inhibitors
• SYK antagonists
B cell Naive T cell
• Calcineurin inhibitors • Anti-CD20 • Anti-IL-23

• Antimetabolite drugs • Anti-BAFF • BTK antagonists
• Cyclophosphamide • Anti-APRIL • Anti-CD19
• Anti-CD6 • Anti-TACI CAR T cells
• Low-dose IL-2 • Anti-BAFF-R Bone marrow • Anti-CD38
• Proteasome inhibitors
• Immunoproteasome
inhibitors
T cell B cell
Plasma cells
Kidney glomeruli Nephrotoxic immunoglobulins IgG-degrading

Nephrotoxic T cells
imlifidase
• Calcineurin inhibitors
• Anti-SLIT2
Podocyte
• APOL1 antagonist
injury
• TRPC5 antagonist
Glucocorticoids
• C5aR antagonist • Anti-MASP2
• Anti-C3 • Anti-CTLA4
Complement- • Anti-C5 • C5 siRNA
mediated injury • Anti-FB • FB siRNA
• Anti-FD
Fig. 4 | Primary site of action for drugs in use or in the pipeline for Bruton’s tyrosine kinase; C5aR, C5a receptor; CAR, chimeric antigen receptor;
glomerulonephritis. Most immunosuppressive drugs primarily act inside CTLA4, cytotoxic T lymphocyte-associated protein 4; DC, dendritic cell;
lymphoid organs, whereas complement inhibitors and calcineurin inhibitors FB, factor B; FcR, Fc receptor; FD, factor D; IFNAR1, type I interferon receptor;
directly act at the site of glomerular injury. Steroids (glucocorticoids) suppress JAK, Janus kinase; MASP2, mannan-binding lectin serine protease 2; MC1R,
local inflammation in the kidney as well as adaptive immunity in lymphoid melanocortin 1 receptor; MC3R, melanocortin 3 receptor; siRNA, small
organs. Imlifidase degrades IgG in the circulatory system but possibly also IgG interfering RNA; SLIT2, Slit homologue 2 protein; STAT, signal transducer and
deposits inside the kidney. Drugs in use are shown in bold. APOL1, apolipoprotein activator of transcription; TACI, transmembrane activator and CAML interactor;
L1; APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; BTK, TRPC5, transient receptor potential cation channel subfamily C member 5.

Review article
Table 4 | Pipeline of drug development for glomerulonephritis
Subtype of GN Molecular target Compound Trial phase ClinicalTrials.gov identifier
Autoimmune GN
MN CD20 Obinutuzumab II NCT05050214
LN CD20 Obinutuzumab III NCT04221477
IgAN CD38 Mezagitamab I NCT05174221
MN CD38 Felzartamab II NCT04733040
LN BAFFR Ianalumab/VAY736 III NCT05126277
MN BAFF Belimumab II NCT03949855
IgAN BAFF/APRIL Atacicept II NCT04716231
IgAN APRIL VIS649 II NCT04287985
IgAN APRIL BION-1301 II NCT04684745
LN CD6 Itolizumab I NCT04128579
LN CD40 BI 655064 II NCT03385564
LN CD40 Iscalimab II NCT03610516
IgAN CD40 AT-1501 II NCT05125068
LN Fc receptor Nipocalimab II NCT04883619
C3GN, IC-MPGN C3 Pegcetacoplan III NCT05067127
IgAN, C3GN C3 ARO-C3 I/II NCT05083364
C3GN, LN C5 Ravulizumab II NCT04564339
IgAN C5 Cemdisiran (RNAi) II NCT03841448
C3GN C5aR Avacopan II NCT03301467
IgAN Factor B IONIS-FB-LRx (RNAi) II NCT04014335
IgAN, C3GN, MN Factor B Iptacopan III NCT04817618
IgAN, LN Factor D ALXN2050/ACH-5228 II NCT05097989
C3GN Factor D Danicopan II NCT03459443
IgAN, C3GN, MN Factor D BCX9930 II NCT05162066
IgAN, C3GN, MN, LN MASP2 Narsoplimab III NCT02682407
MN MC1R/MCR3 AP1189 II NCT04456816
LN IFNAR1 Anifrolumab III NCT05138133
LN IL-17A SHR-1314 II NCT04924296
LN IL-17A Secukinumab III NCT04181762
LN IL-17A Vunakizumab II NCT05097989
LN IL-23 (p19) Guselkumab II NCT04376827
LN JAK1 Filgotinib II NCT03285711
LN SYK GS-9876 II NCT03285711
LN Immunoproteasome KZR-616 I/II NCT03393013
Alloimmune GN Corticotropin Acthar II NCT02546492
Autoinflammatory GN
C3GN C3 ARO-C3 I/II NCT05083364
C3GN C3 Pegcetacoplan III NCT04572854
C3GN C5aR Avacopan II NCT03301467
C3GN Factor B Iptacopan III NCT04817618
C3GN Factor D Danicopan II NCT03459443
C3GN MASP2 Narsoplimab II NCT02682407

Review article
Table 4 (continued) | Pipeline of drug development for glomerulonephritis
Subtype of GN Molecular target Compound Trial phase ClinicalTrials.gov identifier
Monoclonal gammopathy-related GN
AL amyloidosis CD38 Isatuximab II NCT04614558
AL amyloidosis CD38 Daratumumab I/II NCT02841033
AL amyloidosis CD38 Daratumumab III NCT03201965
AL amyloidosis Proteasome Bortezomib III NCT01078454
AL amyloidosis ? Pomalidomide I/II NCT01570387
PGNMID CD38 Daratumumab II NCT03095118
MIDD Proteasome Bortezomib NA NCT01383759
Myeloma cast nephropathy Proteasome Bortezomib ± CYC III NCT01208818
Glomerular scarring (CKD)
FSGS CTLA4 Abatacept II NCT02592798
FSGS NRF2 Bardoxolone II NCT03366337
FSGS SLIT2 PF-06730512 II NCT03448692
FSGS APOL1 VX-147 II NCT04340362
FSGS TRPC5 GFB-887 II NCT04387448
CKD Recombinant kallikrein DM199 II NCT04123613
CKD Fibrokinase ANG-3070 II NCT04939116
FSGS ARB/endothelin 1 Sparsentan III NCT04663204
FSGS ETA receptor Atrasentan III NCT04573920
FSGS ARB + CCR2 inhibitor DMX-200 III NCT05183646
CKD SGLT2 Empagliflozin III NCT03594110
ARB, angiotensin receptor blocker; APOL1, apolipoprotein L1; APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; C5aR, C5a receptor; C3GN, complement factor C3
glomerulonephritis; CCR2, CC-chemokine receptor 2; CKD, chronic kidney disease; CTLA4, cytotoxic T lymphocyte-associated protein 4; CYC, cyclophosphamide; FSGS, focal segmental
glomerulosclerosis; GN, glomerulonephritis; IC-MPGN, immune complex membranoproliferative glomerulonephritis; IFNAR1, type I interferon receptor; IgAN, IgA nephropathy; JAK1, Janus
kinase 1; LN, lupus nephritis; MASP2, mannan-binding lectin serine protease 2; MC1R, melanocortin 1 receptor; MIDD, monoclonal immunoglobulin deposition disease; MN, membranous
nephropathy; NA, not applicable; NRF2, nuclear factor erythroid 2-related factor 2; PGNMID, proliferative glomerulonephritis with monoclonal immunoglobulin deposits; SGLT2,
sodium-glucose transporter 2; SLIT2, Slit homologue 2 protein; TRPC5, transient receptor potential cation channel subfamily C member 5.
genetic kidney disease who lack tolerance to an absent or aberrant Targets for immunotherapy
glomerular protein, implantation of a non-mutated kidney results in The management options for alloimmune GN focus on intensifying
processing and presentation of a normal protein as an apparent for- immunosuppression or adding intravenous immunoglobulin, with
eign antigen, followed by an adaptive immune response (for example, or without plasma exchange126. Therapies that induce immunological
alloantibody deposition in the glomerulus via in situ immune complex tolerance and those that more selectively target adaptive immunity,
formation). Although the immunopathogenesis of GVHD affecting the particularly humoral immunity, are likely to be useful (Table 4).
native kidneys remains unclear, observations in humans and rodent
models of GVHD suggest several different patterns of injury and impli- Autoinflammatory GN
cate a variety of immune mediators115. Glomerular lesions reported in Autoinflammatory GN disorders originate from inborn errors of innate
GVHD include subepithelial deposits representing immune complex immunity127. Only genetic testing can clarify the ultimate molecular
deposition or in situ immune complex formation122. However, patterns diagnosis of an autoinflammatory GN (Table 2).
of injury are variable, reflecting not only the variable participation of
immune responses but also the involvement of non-immune mediators Immunopathology
or endothelial and mesangial injury. At a molecular level, data from Genetic abnormalities underlying overactivation of the alternative
animal models early in GVHD implicate antigen-presenting genes and complement pathway are observed in 25% of patients with C3GN78,128 —
the T cell chemoattractants CXC-chemokine ligands 9 and 11, with cor- that is, glomerular complement deposition without immunoglobulin
responding T cell infiltrates123. In humans, urinary levels of IL-6, IL-15 deposits77. Such pathogenic variants in C3, CFB, CFH, CFI, DGKE and
and CC-chemokine ligand 2 were associated with the risk of developing CFHR5 lower the threshold for spontaneous or induced C3 convertase
proteinuric kidney injury after bone marrow transplantation124. Mem- activity129, possibly triggered by infections. Genomic rearrangements
branous nephropathy, usually autoimmune in nature, can occur after involving CFHR genes can also be identified130. Autoimmune GN and
allogeneic stem cell transplantation, and antibodies to protocadherin monoclonal gammopathy-related C3GN have a similar histological
FAT1, as well as the FAT1 protein itself, have been detected in the kidney appearance but their respective immunopathogenesis warrants
in this setting125. different treatments.

Review article
Glossary
Apolipoprotein L1 (APOL1) risk Glomerulus Nephrons Plasma exchange

alleles The corpuscular part of the nephron Independent functional units of A therapeutic modality used to eliminate
Genetic risk factors prevalent in encompassing the glomerular tuft, the kidney. The sum of all nephrons circulating pathogenic agents via an
people of West African ancestry which is a capillary network formed defines kidney function. Nephron extracorporal circulation, separation
that, in homozygosity or compound by arterioles. Each glomerulus has a number is set at birth and declines with of plasma proteins (for example,
heterozygosity, lower the threshold single afferent arteriole and a single ageing. Injury-related nephron loss by ultrafiltration of serum proteins or by
for podocyte loss and faster efferent arteriole entering and leaving induces compensatory hypertrophy columns that bind and retain specific
progression towards end-stage the glomerulus at the vascular pole. To of the remaining nephrons to meet proteins) and reinfusion of the remainder.
kidney disease, especially in direct the filtrate towards the draining the unchanged haemodynamic and
diseases involving type I interferon tubule, the Bowman capsule surrounds metabolic demands. This adaptive Podocytes
signalling. the glomerular tuft and represents the capacity differs across species and Cells comprising the epithelial layer on
outer border of the glomerulus. is much lower in humans than in the outside of the glomerular capillaries
Bowman capsule rodents, which represents a hurdle in and gatekeepers of protein selectivity of
The outer capsule of the glomerular Glomerulosclerosis translational research. the glomerular filter. Selective podocyte
part of the nephron, which continues Irreversible glomerular scarring injury is the central pathological
from the urinary pole to the tubular leading to waning of filtration. Usually, Nephrotic syndrome mechanism of ‘podocytopathies’
basement membrane. Fluids filtered podocyte loss is the starting point for Massive loss of plasma proteins into presenting as nephrotic syndrome.
from the blood in the glomerulus are glomerulosclerosis. the urine due to diffuse podocyte Podocytopathies can be genetic,
drained into tubules along the Bowman injury. The clinical definition includes a immunological, metabolic, monoclonal
capsule. Haematuria massive proteinuria, hypoalbuminaemia gammopathy related or shear stress
The presence of blood in the (urinary losses exceed plasma protein related, presenting as nephrotic
Cryoglobulins urine, a consequence of vascular production by the liver), hyperlipidaemia syndrome.
Autoantibodies (directed injury, for example rupture of the (compensatory increase in lipoprotein
against IgG) that form immune glomerular basement membrane production, lipase dysfunction) Proteinuria
complexes and cause small vessel in glomerulonephritis, due to and oedema (retention of sodium Excessive protein in the urine, a urinary
vasculitis. They precipitate at low complement activation or local by the diseased kidney). Urinary biomarker of glomerular dysfunction or
temperatures, which can be used release of proteolytic enzymes. losses of IgG and coagulation podocyte dysfunction when albumin
as a diagnostic test. Nephritic syndrome is manifested as inhibitors can cause life-threatening is the predominating urinary protein.
haematuria and proteinuria, often with secondary immunodeficiency and Other plasma proteins prevail in
hypertension and impaired kidney thromboembolism. tubular or overflow types of proteinuria.
Glomerular filtration barrier function, and is a common clinical Albuminuria is a general biomarker
A semipermeable membrane in presentation of glomerulonephritis. Parietal epithelial cells of systemic endothelial dysfunction,
nephrons that is localized in a vascular Epithelial cells lining the inner aspect for example, in sepsis.
network inside the glomerular tuft. Mesangium of the Bowman capsule. Parietal cells
The filtration barrier encompasses, A component of the glomerulus formed are usually a relatively quiescent Thrombotic microangiopathy
from the inside to the outside, the of smooth muscle cell-like or pericyte- lining, but severe glomerulonephritis- A lesion pattern characterized by
endothelial glycocalyx, glomerular like mesenchymal cells in between the related leakage of plasma proteins immunothrombosis in arterioles,
endothelial cells, glomerular basement glomerular capillary network. Glomerular can drive local hyperplasia (as capillaries and venules and frequently
membrane and visceral epithelial cells endothelial cell dysfunction during local glomerular crescent formation). The caused by humoral or toxic triggers
(podocytes). or systemic inflammation promotes parietal epithelial cell monolayer hosts of endothelial injury, including
the passage and entrapment of plasma immature progenitors with a dedicated antiphospholipid antibodies or inherited
proteins in the mesangium, which capacity to differentiate and replace lost and acquired dysregulation of the
activates or injures mesangial cells. podocytes on the glomerular tuft. complement cascade.
Genetic overactivation of Toll-like receptor 7 or direct overproduc- indirectly affected by AA amyloidosis, a glomerular deposition of β-fibrils
tion of type I interferons induces a persistent antiviral immunity-like of the acute phase protein serum amyloid A, which is constantly released
systemic inflammation, which may cause lupus-like immune complex by the liver in patients with hereditary fever syndromes134. The accumu-
GN17,131,132. Local effects of type I interferons promote podocytopathy- lating deposits interfere with the normal filtration process and trigger
like lesions because type I interferons drive programmed cell death17,47. nonspecific local inflammation and glomerular cell injury, promoting an
Accordingly, long-term exposure to type I interferons, such as during increasing degree of proteinuria and kidney failure over time.
treatment for relapsing–remitting multiple sclerosis, can induce similar
kidney lesions133. Targets for immunotherapy
Monogenic disorders of the NLRP3 inflammasome, pro-inflamma- The selective overexpression of a single cytokine means that people with
tory cytokines or their receptors lead to spontaneous and persistent sys- autoinflammatory GN are likely to respond to highly selective immuno-
temic and local tissue inflammation127 (Table 3). Usually, the kidney is only therapies (Table 4), such as TNF blockers for TNF receptor-associated

Review article
periodic syndrome, IL-1 blockers for cryopyrin-associated autoinflam- with other targeted therapies (such as cyclophosphamide, proteasome
matory syndromes130,135, interferon blockers for interferonopathies132 inhibitors or immunomodulatory drugs148) to achieve the necessary
and complement inhibitors for hereditary C3GN77,136. response150–153. High-dose therapy followed by stem cell transplantation
is sometimes necessary to achieve a sufficient reduction154.
Monoclonal gammopathy-related GN Proteasome inhibitors are a successful class of drugs against
Risk factors and immunopathology myeloma cells155, with three currently approved (bortezomib, carfil-
The production of nephrotoxic monoclonal immunoglobulins is the zomib and ixazomib)156 (Fig. 4). They target the 20S unit of the protea-
hallmark of monoclonal gammopathy-related GN137 (Table 3 and Fig. 3). some, inhibiting the ubiquitin degradation pathway for proteins and
Monoclonal immunoglobulins deposit as intact immunoglobulin or as activation of nuclear factor-κB157. However, as the 20S proteasome is
fragments, for example in light chain deposition disease or immuno ubiquitously expressed, proteasome inhibition has adverse effects.
globulin heavy chain amyloidosis. Such deposits can have various Immunoproteasomes, on the other hand, are predominantly expressed in
ultrastructural characteristics138. They can be amorphous (in mono- lymphocytes and monocytes and are involved in cell-mediated
clonal immunoglobulin deposition disease and proliferative GN with immunity and production of MHC class I ligands during infections158.
monoclonal immunoglobulin deposits) or organized, such as β-sheet In addition, immunoproteasomes contribute to autoimmune dis-
amyloid fibrils (in amyloidosis) and microtubules (in immunotactoid eases159. Theoretically, inhibition of immunoproteasomes should have
glomerulopathy), or can form cryoglobulins (in cryoglobulin-associ- fewer off-target side effects. Several immunoproteasome inhibitors
ated GN) and microcrystals (in crystalloglobulin GN). Indirect modes of have demonstrated promising in vitro results by targeting the large
injury occur when monoclonal immunoglobulins activate complement, multifunctional peptidase 7 subunit160–162. Some immunoproteasome
resulting in C3GN or thrombotic microangiopathy139,140. inhibitors may act synergistically with proteasome inhibitors156,157,163.
Although a minority of individuals with monoclonal gammopathy-
related GN also have overt multiple myeloma or high-grade lymphoma Concluding remarks
per se requiring immediate treatment, the source of the monoclonal The growing awareness of the immunopathogenesis of GN has revealed
immunoglobulin in most cases is small B cell clones or plasma cell the limitations of lesion-based classifications in identifying the ultimate
clones137. These small clones are collectively designated as ‘monoclonal cause to select appropriate treatments. The recent improvements
gammopathy of renal significance’141 and are the result of non-malignant in immune phenotyping, including the detection of autoantibodies
somatic mutations in B cell or plasma cell precursors64. Nevertheless, to specific glomerular antigens, different complement subunits and
the nephrotoxic effect of such monoclonal immunoglobulins is the immune complexes by immunofluorescence of kidney biopsies, have
result of the primary amino acid sequence142–144. increased its value for diagnosis (Box 1). In addition, more immuno-
The monoclonal immunoglobulin deposits detected by immuno therapies are becoming available (Table 4). Extended genetic testing,
staining are the most common and most important pathological with next-generation sequencing, is another evolving diagnostic tool
histological finding in monoclonal gammopathy-related GN138 (Fig. 2). to ultimately define a molecular diagnosis (Box 1). Indeed, mutations
Monotypic deposits are defined by κ or λ light chain restriction. In cases in complement genes128, in Toll-like receptors131 or in genes of the inter-
where the entire immunoglobulin is deposited, a heavy chain restric- feron pathways17 can directly trigger different types of immune-related
tion (that is, IgG subclass) combined with light chain restriction GN or favour the production of autoantibodies17,128,129,131. Kidney biopsy
strongly implies the deposits are monoclonal. Of note, heavy chain can in many situations assist in diagnosis and remains the gold standard
restriction by itself does not prove monoclonality unless it relates to a to determine disease activity and chronicity. Activity and chronicity
heavy chain disease such as AH amyloidosis or heavy chain deposition are relevant parameters in determining treatment intensity, and these
disease. Ultrastructural characteristics resolved by electron micros- indices integrate with treatments targeting non-immune mechanisms
copy can help to distinguish one monoclonal gammopathy-related of chronic kidney disease progression. Novel urinary biomarkers of
kidney disease from another (for example, fibrils in amyloidosis or immunological GN activity can be used to monitor treatment responses
microtubules in immunotactoid GN). Deposits of C3 with little immuno- and be validated against repeated kidney biopsies.
globulin are seen in C3 glomerulopathy with monoclonal gammopathy. An intuitive pathophysiology-based classification will facilitate
Finally, no immune deposits occur in monoclonal gammopathy-related the management of these conditions. We propose that individuals
thrombotic microangiopathy. with GN be described under three headings: firstly, as having one of the
five types of GN discussed in this Review (infection-related GN, auto
Targets for immunotherapy immune GN, alloimmune GN, autoinflammatory GN and monoclonal
Elimination of the B cell clones or plasma cell clones in the bone marrow gammopathy-related GN); secondly, by detailing the exact disease type
and lymphoid organs is the main goal to deplete the monoclonal immuno on the basis of the pathogenesis; and, thirdly, on the basis of the features
globulin to halt kidney injury and to preserve kidney function (Fig. 4). of the histological lesion, if a kidney biopsy has been performed.
Standard immunosuppressive therapies are insufficient to induce a Despite the challenges in defining the pathogenesis of the large
beneficial haematological response, which is usually a greater than 90% number of individual GN diseases, there has been significant progress
reduction in the level of monoclonal immunoglobulin145–147. To accom- in understanding the fundamental basis of immune glomerular disease.
plish this, clone-directed therapy is required (Table 4). Chemotherapy However, our understanding of GN is incomplete and requires greater
is used often combined with immunotherapy137,148. For example, CD20- depth if we are to develop more targeted immunotherapies. Among the
expressing B cell clones can be depleted by anti-CD20 monoclonal infection-related GN disorders, the contribution of genetic susceptibili-
antibodies such as rituximab, obinutuzumab or ofatuzumab149. These ties in primary immunodeficiency and acquired complementopathies
can be used in combination with cyclophosphamide and corticoster- (genetic or acquired disorders of the complement system) driving clini-
oids. For plasma cell clones, anti-CD38 monoclonal antibodies such cally relevant GN deserves further study. The plethora of novel autoan-
as daratumumab or isatuximab can be used alone or in combination tigens in autoimmune GN mandates further investigation, not only

Review article
to ensure accurate diagnostic tests are clinically available but also to 20. Kumar, R. et al. Case report: unusual aggregation of different glomerulopathies in a
family resolved by genetic testing and reverse phenotyping. Front. Pediatrics 10, 826330
determine the role of the related autoantibodies as biomarkers for diag- (2022).
nosis, disease activity and guidance of immunotherapy. In particular, 21. Smith, K. D. et al. Digital spatial profiling of collapsing glomerulopathy. Kidney Int. 101,
the recently discovered anti-nephrin antibody-related podocytopathy 1017–1026 (2022).
22. Anders, H. J., Jayne, D. R. & Rovin, B. H. Hurdles to the introduction of new therapies
is likely to have significant clinical implications89. Why alloimmune GN for immune-mediated kidney diseases. Nat. Rev. Nephrol. 12, 205–216 (2016).
responds poorly to immunotherapy is not well understood. Prevention 23. Carapetis, J. R., Steer, A. C., Mulholland, E. K. & Weber, M. The global burden of group A
of priming of donor-specific antibodies early after transplantation is streptococcal diseases. Lancet Infect. Dis. 5, 685–694 (2005).
24. Rodriguez-Iturbe, B. & Musser, J. M. The current state of poststreptococcal
probably the key to preventing transplant glomerulopathy. Among glomerulonephritis. J. Am. Soc. Nephrol. 19, 1855–1864 (2008).
autoinflammatory GN disorders, genotype–phenotype associations 25. Boils, C. L., Nasr, S. H., Walker, P. D., Couser, W. G. & Larsen, C. P. Update on
of the hereditary complementopathies encompass many unsolved endocarditis-associated glomerulonephritis. Kidney Int. 87, 1241–1249 (2015).
26. Satoskar, A. A., Parikh, S. V. & Nadasdy, T. Epidemiology, pathogenesis, treatment and
questions. The wide spectrum of monoclonal gammopathy-related GN outcomes of infection-associated glomerulonephritis. Nat. Rev. Nephrol. 16, 32–50
will benefit from plasma cell-targeted therapies under development. (2020).
27. Genovese, G. et al. Association of trypanolytic ApoL1 variants with kidney disease in
GN requires an immunopathophysiology-based classification sys-
African Americans. Science 329, 841–845 (2010).
tem to better connect with the growing number of available immuno 28. Kopp, J. B. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and
therapy drugs. As GN comprises immune-mediated disorders, GN HIV-associated nephropathy. J. Am. Soc. Nephrol. 22, 2129–2137 (2011).
29. McGuire, B. M. et al. Brief communication: glomerulonephritis in patients with
research needs more input from experts in immunology. Indeed, clini-
hepatitis C cirrhosis undergoing liver transplantation. Ann. Intern. Med. 144, 735–741
cal immunologists may help to overcome traditional lesion-based con- (2006).
cepts in this domain and improve the management of these important 30. Kupin, W. L. Viral-associated GN: hepatitis B and other viral infections. Clin. J. Am. Soc.
Nephrol. 12, 1529–1533 (2017).
and at times difficult to treat diseases.
31. Barsoum, R. S. Tropical parasitic nephropathies. Nephrol. Dial. Transplant. 14, 79–91
(1999).
Published online: 12 January 2023 32. Neves, P. et al. Schistosomiasis-associated glomerulopathy: clinical aspects,
pathological characteristics, and renal outcomes. Clin. Nephrol. 93, 251–261 (2020).
References 33. Walker, A. et al. Eosinophilic glomerulonephritis in children in southwestern Uganda.
1. Chadban, S. J. & Atkins, R. C. Glomerulonephritis. Lancet 365, 1797–1806 (2005). Kidney Int. 71, 569–573 (2007).
2. Guo, Q., Wu, S., Xu, C., Wang, J. & Chen, J. Global disease burden from acute 34. Sethi, S., D’Costa, M. R., Hermann, S. M., Nasr, S. H. & Fervenza, F. C. Immune-complex
glomerulonephritis 1990–2019. Kidney Int. Rep. 6, 2212–2217 (2021). glomerulonephritis after COVID-19 infection. Kidney Int. Rep. 6, 1170–1173 (2021).
3. GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden 35. Rodriguez-Iturbe, B. Autoimmunity in acute poststreptococcal GN: a neglected aspect of
of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of the disease. J. Am. Soc. Nephrol. 32, 534–542 (2021).
Disease Study 2017. Lancet 395, 709–733 (2020). 36. Yoshizawa, N. et al. Nephritis-associated plasmin receptor and acute poststreptococcal
4. Wetmore, J. B., Guo, H., Liu, J., Collins, A. J. & Gilbertson, D. T. The incidence, prevalence, glomerulonephritis: characterization of the antigen and associated immune response.
and outcomes of glomerulonephritis derived from a large retrospective analysis. J. Am. Soc. Nephrol. 15, 1785–1793 (2004).
Kidney Int. 90, 853–860 (2016). 37. Honda-Ogawa, M. et al. Cysteine proteinase from Streptococcus pyogenes enables
5. United States Renal Data System. 2022 annual data report. https://usrds-adr.niddk.nih. evasion of innate immunity via degradation of complement factors. J. Biol. Chem. 288,
gov/2022?dkrd=/about-niddk/strategic-plans-reports/usrds/annual-data-report (2022). 15854–15864 (2013).
6. Titze, S. et al. Disease burden and risk profile in referred patients with moderate chronic 38. Chauvet, S. et al. Anti-factor B antibodies and acute postinfectious GN in children.
kidney disease: composition of the German Chronic Kidney Disease (GCKD) cohort. J. Am. Soc. Nephrol. 31, 829–840 (2020).
Nephrol. Dial. Transplant. 30, 441–451 (2015). 39. Nasr, S. H. et al. Postinfectious glomerulonephritis in the elderly. J. Am. Soc. Nephrol. 22,
7. Daehn, I. S. & Duffield, J. S. The glomerular filtration barrier: a structural target for novel 187–195 (2011).
kidney therapies. Nat. Rev. Drug Discov. 20, 770–788 (2021). 40. Couser, W. G. & Johnson, R. J. The etiology of glomerulonephritis: roles of infection and
This review explains the unique structure and function of the glomerular filtration autoimmunity. Kidney Int. 86, 905–914 (2014).
barrier, and new ways by which its integrity might be preserved to treat glomerular 41. Puelles, V. G. et al. Multiorgan and renal tropism of SARS-CoV-2. N. Engl. J. Med. 383,
disease. 590–592 (2020).
8. Kopp, J. B. et al. Podocytopathies. Nat. Rev. Dis. Prim. 6, 68 (2020). 42. Li, J. et al. Transmembrane TNF-α facilitates HIV-1 infection of podocytes cultured
9. Grahammer, F. et al. A flexible, multilayered protein scaffold maintains the slit in between from children with HIV-associated nephropathy. J. Am. Soc. Nephrol. 28, 862–875
glomerular podocytes. JCI Insight 1, 86177 (2016). (2017).
10. Anguiano, L., Kain, R. & Anders, H. J. The glomerular crescent: triggers, evolution, 43. Araújo, S. A. et al. First report of collapsing variant of focal segmental glomerulosclerosis
resolution, and implications for therapy. Curr. Opin. Nephrol. Hypertens. 29, 302–309 triggered by arbovirus: dengue and Zika virus infection. Clin. Kidney J. 12, 355–361
(2020). (2019).
11. Kumar, S. V. et al. Neutrophil extracellular trap-related extracellular histones cause 44. Allam, R. et al. Viral RNA and DNA trigger common antiviral responses in mesangial cells.
vascular necrosis in severe GN. J. Am. Soc. Nephrol. 26, 2399–2413 (2015). J. Am. Soc. Nephrol. 20, 1986–1996 (2009).
This study shows that severe immune glomerular injury is mediated by histones 45. Gupta, S., Pepper, R. J., Ashman, N. & Walsh, S. B. Nephrotic syndrome: oedema
as products of NETs. formation and its treatment with diuretics. Front. Physiol. 9, 1868 (2018).
12. Kessenbrock, K. et al. Netting neutrophils in autoimmune small-vessel vasculitis. 46. Fenaroli, P. et al. Collapsing glomerulopathy as a complication of type I interferon-
Nat. Med. 15, 623–625 (2009). mediated glomerulopathy in a patient with RNASEH2B-related Aicardi-Goutières
13. Cortinovis, M., Perico, N., Ruggenenti, P., Remuzzi, A. & Remuzzi, G. Glomerular syndrome. Am. J. Kidney Dis. 78, 750–754 (2021).
hyperfiltration. Nat. Rev. Nephrol. 18, 435–451 (2022). 47. Migliorini, A. et al. The antiviral cytokines IFN-alpha and IFN-beta modulate parietal
14. Kitching, A. R. & Hickey, M. J. Immune cell behaviour and dynamics in the kidney-insights epithelial cells and promote podocyte loss: implications for IFN toxicity, viral
from in vivo imaging. Nat. Rev. Nephrol. 18, 22–37 (2022). glomerulonephritis, and glomerular regeneration. Am. J. Pathol. 183, 431–440
This review details the unusual immune milieu within the glomerulus and how (2013).
leukocytes behave within glomerular capillaries to mediate GN. 48. Melica, M. E. et al. Differentiation of crescent-forming kidney progenitor cells into
15. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. podocytes attenuates severe glomerulonephritis in mice. Sci. Transl. Med. 14, eabg3277
KDIGO 2021 clinical practice guideline for the management of glomerular diseases. (2022).
Kidney Int. Suppl. 100, S1–S276 (2021). This study defines the participation of clonally expanded glomerular cells in severe
16. Sethi, S. et al. Mayo Clinic/Renal Pathology Society consensus report on pathologic glomerular injury and how tissue progenitors could assist in preserving glomerular
classification, diagnosis, and reporting of GN. J. Am. Soc. Nephrol. 27, 1278–1287 structure and function in severe immune-mediated GN.
(2016). 49. Nichols, B. et al. Innate immunity pathways regulate the nephropathy gene
17. Lodi, L. et al. Type I interferon-related kidney disorders. Kidney Int. 101, 1142–1159 (2022). apolipoprotein L1. Kidney Int. 87, 332–342 (2015).
18. Ravaglia, F. et al. The pathology lesion patterns of podocytopathies: how and why? Front. 50. Wu, J. et al. The key role of NLRP3 and STING in APOL1-associated podocytopathy.
Cell Dev. Biol. 10, 838272 (2022). J. Clin. Invest. 131, e136329 (2021).
19. Lerner, G. B., Virmani, S., Henderson, J. M., Francis, J. M. & Beck, L. H. Jr. A conceptual 51. Nystrom, S. E. et al. JAK inhibitor blocks COVID-19 cytokine-induced JAK/STAT/APOL1
framework linking immunology, pathology, and clinical features in primary membranous signaling in glomerular cells and podocytopathy in human kidney organoids. JCI Insight
nephropathy. Kidney Int. 100, 289–300 (2021). 7, e157432 (2022).

Review article
52. Angeletti, A., Cantarelli, C. & Cravedi, P. HCV-associated nephropathies in the era of 86. Le Quintrec, M. et al. Contactin-1 is a novel target antigen in membranous nephropathy
direct acting antiviral agents. Front. Med. 6, 20 (2019). associated with chronic inflammatory demyelinating polyneuropathy. Kidney Int. 100,
53. Razzak Chaudhary, S. et al. Trends in the outcomes of end-stage renal disease secondary 1240–1249 (2021).
to human immunodeficiency virus-associated nephropathy. Nephrol. Dial. Transplant. 87. Reinhard, L. et al. Netrin G1 is a novel target antigen in primary membranous
30, 1734–1740 (2015). nephropathy. J. Am. Soc. Nephrol. 33, 1823–1831 (2022).
54. Soriano, V. et al. Hepatitis C cure with antiviral therapy–benefits beyond the liver. 88. Sethi, S. et al. Neural epidermal growth factor-like 1 protein (NELL-1) associated
Antivir. Ther. 21, 1–8 (2016). membranous nephropathy. Kidney Int. 97, 163–174 (2020).
55. Okumura, M. et al. Use of immunosuppressive therapy in the treatment of IgA-dominant 89. Watts, A. J. B. et al. Discovery of autoantibodies targeting nephrin in minimal change
infection-related glomerulonephritis. Intern. Med. 61, 697–701 (2022). disease supports a novel autoimmune etiology. J. Am. Soc. Nephrol. 33, 238–252
56. Arivazhagan, S. et al. Efficacy of corticosteroids in infection-related glomerulonephritis-a (2022).
randomised controlled trial. Kidney Int. Rep. 7, 2160–2165 (2022). 90. Mihai, S. & Nimmerjahn, F. The role of Fc receptors and complement in autoimmunity.
57. Anders, H. J. et al. Lupus nephritis. Nat. Rev. Dis. Prim. 6, 7 (2020). Autoimmun. Rev. 12, 657–660 (2013).
This is a detailed review of the complexities and challenges in understanding and 91. Genest, D. S. et al. Comparison of complement pathway activation in autoimmune
treating lupus nephritis. glomerulonephritis. Kidney Int. Rep. 7, 1027–1036 (2022).
58. Kitching, A. R. et al. ANCA-associated vasculitis. Nat. Rev. Dis. Prim. 6, 71 (2020). 92. Haddad, G. et al. Altered glycosylation of IgG4 promotes lectin complement pathway
This article explains how in ANCA-associated vasculitis, activating activation in anti-PLA2R1-associated membranous nephropathy. J. Clin. Invest. 131,
autoantibodies and cellular immunity to neutrophil proteins affect severe e140453 (2021).
microvascular injury. 93. Bally, S. et al. Phospholipase A2 receptor-related membranous nephropathy and
59. Ronco, P. et al. Membranous nephropathy. Nat. Rev. Dis. Prim. 7, 69 (2021). mannan-binding lectin deficiency. J. Am. Soc. Nephrol. 27, 3539–3544 (2016).
60. Schmidt, R. E., Grimbacher, B. & Witte, T. Autoimmunity and primary immunodeficiency: 94. Kulkarni, O. et al. Anti-Ccl2 Spiegelmer permits 75% dose reduction of
two sides of the same coin? Nat. Rev. Rheumatol. 14, 7–18 (2017). cyclophosphamide to control diffuse proliferative lupus nephritis and pneumonitis
61. Robson, K. J., Ooi, J. D., Holdsworth, S. R., Rossjohn, J. & Kitching, A. R. HLA and kidney in MRL-Fas(lpr) mice. J. Pharmacol. Exp. Ther. 328, 371–377 (2009).
disease: from associations to mechanisms. Nat. Rev. Nephrol. 14, 636–655 (2018). 95. Westhorpe, C. L. V. et al. Effector CD4+ T cells recognize intravascular antigen presented
This article includes a comprehensive review of the associations of HLA with by patrolling monocytes. Nat. Commun. 9, 747 (2018).
glomerular disease and the emerging HLA-functional links. This study discovers that antigens can be presented to effector CD4+ T cells within
62. Stanescu, H. C. et al. Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous the microvasculature of the glomerulus by intravascular monocytes.
nephropathy. N. Engl. J. Med. 364, 616–626 (2011). 96. Summers, S. A. et al. Th1 and Th17 cells induce proliferative glomerulonephritis.
63. Alriyami, M. & Polychronakos, C. Somatic mutations and autoimmunity. Cells 10, 2056 J. Am. Soc. Nephrol. 20, 2518–2524 (2009).
(2021). 97. Ooi, J. D. et al. The HLA-DRB1*15:01-restricted Goodpasture’s T cell epitope induces GN.
64. Mustjoki, S. & Young, N. S. Somatic mutations in “benign” disease. N. Engl. J. Med. 384, J. Am. Soc. Nephrol. 24, 419–431 (2013).
2039–2052 (2021). 98. Chen, A. et al. Bowman’s capsule provides a protective niche for podocytes from
65. Ooi, J. D. et al. Dominant protection from HLA-linked autoimmunity by antigen-specific cytotoxic CD8+ T cells. J. Clin. Invest. 128, 3413–3424 (2018).
regulatory T cells. Nature 545, 243–247 (2017). 99. Krebs, C. F. et al. Pathogen-induced tissue-resident memory TH17 (TRM17) cells amplify
This study demonstrates the mechanism of HLA susceptibility and dominant autoimmune kidney disease. Sci. Immunol. 5, eaba4163 (2020).
protection and the key role of antigen-specific regulatory T cells in maintaining This study implicates CD4+ tissue-resident memory T cells within the kidney
tolerance in autoimmune GN. in immune glomerular disease.
66. Lai, K. N. et al. IgA nephropathy. Nat. Rev. Dis. Prim. 2, 16001 (2016). 100. Allam, R. et al. Viral 5’-triphosphate RNA and non-CpG DNA aggravate autoimmunity
67. Muchtar, E., Magen, H. & Gertz, M. A. How I treat cryoglobulinemia. Blood 129, 289–298 and lupus nephritis via distinct TLR-independent immune responses. Eur. J. Immunol.
(2017). 38, 3487–3498 (2008).
68. Audemard-Verger, A., Pillebout, E., Guillevin, L., Thervet, E. & Terrier, B. IgA 101. Anders, H. J. et al. Bacterial CpG-DNA aggravates immune complex glomerulonephritis:
vasculitis (Henoch-Shönlein purpura) in adults: diagnostic and therapeutic aspects. role of TLR9-mediated expression of chemokines and chemokine receptors.
Autoimmun. Rev. 14, 579–585 (2015). J. Am. Soc. Nephrol. 14, 317–326 (2003).
69. Kaul, A. et al. Systemic lupus erythematosus. Nat. Rev. Dis. Prim. 2, 16039 (2016). 102. Pawar, R. D. et al. Bacterial lipopeptide triggers massive albuminuria in murine lupus
70. Weening, J. J. et al. The classification of glomerulonephritis in systemic lupus nephritis by activating Toll-like receptor 2 at the glomerular filtration barrier. Immunology
erythematosus revisited. J. Am. Soc. Nephrol. 15, 241–250 (2004). 128, e206–e221 (2009).
71. Kuligowski, M. P. et al. Antimyeloperoxidase antibodies rapidly induce alpha-4-integrin- 103. Uhlin, F. et al. Endopeptidase cleavage of anti-glomerular basement membrane
dependent glomerular neutrophil adhesion. Blood 113, 6485–6494 (2009). antibodies in vivo in severe kidney disease: an open-label phase 2a study. J. Am. Soc.
72. Dick, J. et al. C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in Nephrol. 33, 829–838 (2022).
experimental anti-myeloperoxidase glomerulonephritis. Kidney Int. 93, 615–625 (2018). This article reports a phase II trial demonstrating that an intravenous injection of
73. Masuda, S. et al. Formation and disordered degradation of neutrophil extracellular traps endopeptidase to cleave nephritogenic autoantibodies may be as effective as or more
in necrotizing lesions of anti-neutrophil cytoplasmic antibody-associated vasculitis. effective than plasma exchange in treating acute GN.
Am. J. Pathol. 189, 839–846 (2019). 104. Walsh, M. et al. The effects of plasma exchange in patients with ANCA-associated
74. Jayne, D. R. W., Merkel, P. A., Schall, T. J. & Bekker, P. Avacopan for the treatment of vasculitis: an updated systematic review and meta-analysis. BMJ 376, e064604 (2022).
ANCA-associated vasculitis. N. Engl. J. Med. 384, 599–609 (2021). 105. Barratt, J. et al.Results from part A of the multi-center, double-blind, randomized,
75. Nakazawa, D., Masuda, S., Tomaru, U. & Ishizu, A. Pathogenesis and therapeutic placebo-controlled NefIgArd trial, which evaluated targeted-release formulation of
interventions for ANCA-associated vasculitis. Nat. Rev. Rheumatol. 15, 91–101 (2019). budesonide for the treatment of primary immunoglobulin A nephropathy. Kidney Int.
76. Iatropoulos, P. et al. Cluster analysis identifies distinct pathogenetic patterns in C3 https://doi.org/10.1016/j.kint.2022.09.017 (2022).
glomerulopathies/immune complex-mediated membranoproliferative GN. J. Am. Soc. 106. Rupanagudi, K. V. et al. Cathepsin S inhibition suppresses systemic lupus erythematosus
Nephrol. 29, 283–294 (2018). and lupus nephritis because cathepsin S is essential for MHC class II-mediated CD4
77. Smith, R. J. H. et al. C3 glomerulopathy - understanding a rare complement-driven renal T cell and B cell priming. Ann. Rheum. Dis. 74, 452–463 (2015).
disease. Nat. Rev. Nephrol. 15, 129–143 (2019). 107. Heo, Y. A. Voclosporin: first approval. Drugs 81, 605–610 (2021).
78. Heiderscheit, A. K., Hauer, J. J. & Smith, R. J. H. C3 glomerulopathy: understanding an 108. Rovin, B. H. et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis
ultra-rare complement-mediated renal disease. Am. J. Med. Genet. 190, 344–357 (2022). (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.
79. Pedchenko, V., Kitching, A. R. & Hudson, B. G. Goodpasture’s autoimmune disease-a Lancet 397, 2070–2080 (2021).
collagen IV disorder. Matrix Biol. 71-72, 240–249 (2018). 109. Mougiakakos, D. et al. CD19-Targeted CAR T cells in refractory systemic lupus
80. He, C. et al. Peroxidasin-mediated bromine enrichment of basement membranes. erythematosus. N. Engl. J. Med. 385, 567–569 (2021).
Proc. Natl Acad. Sci. USA 117, 15827–15836 (2020). This is a report of a single patient with refractory systemic lupus erythematosus,
81. McCall, A. S. et al. Inhibitory anti-peroxidasin antibodies in pulmonary-renal syndromes. including nephritis, in whom conventional B cell-depleting therapies were ineffective,
J. Am. Soc. Nephrol. 29, 2619–2625 (2018). whose disease was treated with chimeric antigen receptor T cells specific for CD19.
82. Beck, L. H. Jr. et al. M-type phospholipase A2 receptor as target antigen in idiopathic 110. Ostendorf, L. et al. Targeting CD38 with daratumumab in refractory systemic lupus
membranous nephropathy. N. Engl. J. Med. 361, 11–21 (2009). erythematosus. N. Engl. J. Med. 383, 1149–1155 (2020).
This seminal study discovers the cause of most cases of membranous nephropathy, 111. Kurts, C., Panzer, U., Anders, H. J. & Rees, A. J. The immune system and kidney disease:
defining it as an autoimmune disease. basic concepts and clinical implications. Nat. Rev. Immunol. 13, 738–753 (2013).
83. Tomas, N. M. et al. Thrombospondin type-1 domain-containing 7A in idiopathic 112. Jayne, D. et al. Phase II randomised trial of type I interferon inhibitor anifrolumab in
membranous nephropathy. N. Engl. J. Med. 371, 2277–2287 (2014). patients with active lupus nephritis. Ann. Rheum. Dis. 81, 496–506 (2022).
84. Sethi, S. et al. Protocadherin 7-associated membranous nephropathy. J. Am. Soc. Nephrol. 113. Hanf, W., Bonder, C. S. & Coates, P. T. Transplant glomerulopathy: the interaction
32, 1249–1261 (2021). of HLA antibodies and endothelium. J. Immunol. Res. 2014, 549315 (2014).
85. Al-Rabadi, L. F. et al. Serine protease HTRA1 as a novel target antigen in primary 114. Lim, W. H., Shingde, M. & Wong, G. Recurrent and de novo glomerulonephritis after
membranous nephropathy. J. Am. Soc. Nephrol. 32, 1666–1681 (2021). kidney transplantation. Front. Immunol. 10, 1944 (2019).

Review article
115. Hingorani, S. Renal complications of hematopoietic-cell transplantation. N. Engl. J. Med. 145. Chauvet, S. et al. Treatment of B-cell disorder improves renal outcome of patients with
374, 2256–2267 (2016). monoclonal gammopathy-associated C3 glomerulopathy. Blood 129, 1437–1447 (2017).
116. Roufosse, C. et al. A 2018 reference guide to the Banff classification of renal allograft 146. Kourelis, T. V. et al. Outcomes of patients with renal monoclonal immunoglobulin
pathology. Transplantation 102, 1795–1814 (2018). deposition disease. Am. J. Hematol. 91, 1123–1128 (2016).
117. Gloor, J. M. et al. Transplant glomerulopathy: subclinical incidence and association with 147. Rezk, T. et al. Prolonged renal survival in light chain amyloidosis: speed and magnitude
alloantibody. Am. J. Transplant. 7, 2124–2132 (2007). of light chain reduction is the crucial factor. Kidney Int. 92, 1476–1483 (2017).
118. Cardinal, H., Dieudé, M. & Hébert, M. J. The emerging importance of non-HLA 148. Fermand, J. P. et al. How I treat monoclonal gammopathy of renal significance (MGRS).
autoantibodies in kidney transplant complications. J. Am. Soc. Nephrol. 28, 400–406 Blood 122, 3583–3590 (2013).
(2017). 149. Fotiou, D., Theodorakakou, F. & Kastritis, E. Monoclonal antibody-based therapies for
119. Koenig, A. et al. Missing self triggers NK cell-mediated chronic vascular rejection of solid Waldenström’s macroglobulinemia. Leuk. Res. Rep. 17, 100324 (2022).
organ transplants. Nat. Commun. 10, 5350 (2019). 150. Milani, P. et al. Daratumumab in light chain deposition disease: rapid and profound
120. Filippone, E. J. & Farber, J. L. Histologic antibody-mediated kidney allograft rejection in hematologic response preserves kidney function. Blood Adv. 4, 1321–1324 (2020).
the absence of donor-specific HLA antibodies. Transplantation 105, e181–e190 (2021). 151. Milani, P. et al. High rate of profound clonal and renal responses with daratumumab
121. Van Buren, D. et al. De novo hemolytic uremic syndrome in renal transplant recipients treatment in heavily pre-treated patients with light chain (AL) amyloidosis and high
immunosuppressed with cyclosporine. Surgery 98, 54–62 (1985). bone marrow plasma cell infiltrate. Am. J. Hematol. 95, 900–905 (2020).
122. Girsberger, M., Halter, J. P., Hopfer, H., Dickenmann, M. & Menter, T. Kidney pathology 152. Palladini, G., Milani, P., Malavasi, F. & Merlini, G. Daratumumab in the treatment of
after hematologic cell transplantation-a single-center observation study of indication light-chain (AL) amyloidosis. Cells 10, 545 (2021).
biopsies and autopsies. Biol. Blood Marrow Transpl. 24, 571–580 (2018). 153. Zand, L. et al. Safety and efficacy of daratumumab in patients with proliferative GN with
123. Sadeghi, B. et al. Early-phase GVHD gene expression profile in target versus non-target monoclonal immunoglobulin deposits. J. Am. Soc. Nephrol. 32, 1163–1173 (2021).
tissues: kidney, a possible target? Bone Marrow Transpl. 48, 284–293 (2013). 154. Gozzetti, A. et al. Monoclonal gammopathy of renal significance (MGRS): real-world data
124. Hingorani, S., Gooley, T., Pao, E., Sandmaier, B. & McDonald, G. Urinary cytokines after on outcomes and prognostic factors. Am. J. Hematol. 97, 877–884 (2022).
HCT: evidence for renal inflammation in the pathogenesis of proteinuria and kidney 155. Engelhardt, M., Waldschmidt, J. M. & Wäsch, R. Proteasome inhibition: the dawn of novel
disease. Bone Marrow Transpl. 49, 403–409 (2014). therapies in multiple myeloma. Haematologica 107, 1018–1019 (2022).
125. Sethi, S. et al. Hematopoietic stem cell transplant-membranous nephropathy is 156. Gavriatopoulou, M., Malandrakis, P., Ntanasis-Stathopoulos, I. & Dimopoulos, M. A.
associated with protocadherin FAT1. J. Am. Soc. Nephrol. 33, 1033–1044 (2022). Nonselective proteasome inhibitors in multiple myeloma and future perspectives.
126. Hart, A., Singh, D., Brown, S. J., Wang, J. H. & Kasiske, B. L. Incidence, risk factors, Expert. Opin. Pharmacother. 23, 335–347 (2022).
treatment, and consequences of antibody-mediated kidney transplant rejection: 157. Ettari, R. et al. Immunoproteasome-selective and non-selective inhibitors: a promising
a systematic review. Clin. Transplant. 35, e14320 (2021). approach for the treatment of multiple myeloma. Pharmacol. Ther. 182, 176–192 (2018).
127. Manthiram, K., Zhou, Q., Aksentijevich, I. & Kastner, D. L. The monogenic 158. Basler, M., Kirk, C. J. & Groettrup, M. The immunoproteasome in antigen processing and
autoinflammatory diseases define new pathways in human innate immunity and other immunological functions. Curr. Opin. Immunol. 25, 74–80 (2013).
inflammation. Nat. Immunol. 18, 832–842 (2017). 159. Basler, M., Mundt, S., Bitzer, A., Schmidt, C. & Groettrup, M. The immunoproteasome:
128. Lemaire, M., Noone, D., Lapeyraque, A. L., Licht, C. & Frémeaux-Bacchi, V. Inherited a novel drug target for autoimmune diseases. Clin. Exp. Rheumatol. 33, S74–S79
kidney complement diseases. Clin. J. Am. Soc. Nephrol. 16, 942–956 (2021). (2015).
This study details the nature of genetic abnormalities of complement and its 160. Klein, M. et al. Structure-based optimization and discovery of M3258, a specific inhibitor
regulatory elements and how they can cause glomerular disease. of the immunoproteasome subunit LMP7 (β5i). J. Med. Chem. 64, 10230–10245 (2021).
129. Moore, I. et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, 161. Sanderson, M. P. et al. M3258 is a selective inhibitor of the immunoproteasome subunit
CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic LMP7 (β5i) delivering efficacy in multiple myeloma models. Mol. Cancer Ther. 20,
uremic syndrome. Blood 115, 379–387 (2010). 1378–1387 (2021).
130. De Benedetti, F. et al. Canakinumab for the treatment of autoinflammatory recurrent 162. Singh, A. V. et al. PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7,
fever syndromes. N. Engl. J. Med. 378, 1908–1919 (2018). blocks multiple myeloma cell growth both in vitro and in vivo. Brit. J. Haematol. 152,
131. Brown, G. J. et al. TLR7 gain-of-function genetic variation causes human lupus. Nature 155–163 (2011).
605, 349–356 (2022). 163. Spencer, A. et al. A phase 1 clinical trial evaluating marizomib, pomalidomide and
132. Crow, Y. J. & Stetson, D. B. The type I interferonopathies: 10 years on. Nat. Rev. Immunol. low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107):
22, 471–483 (2021). final study results. Brit. J. Haematol. 180, 41–51 (2018).
133. Markowitz, G. S., Nasr, S. H., Stokes, M. B. & D’Agati, V. D. Treatment with IFN-α, -β,
or -γ is associated with collapsing focal segmental glomerulosclerosis. Clin. J. Am.
Acknowledgements
Soc. Nephrol. 5, 607–615 (2010).
The authors thank F. Ravaglia for her help with the histopathology images.
134. Papa, R. & Lachmann, H. J. Secondary, AA, amyloidosis. Rheum. Dis. Clin. North Am. 44,
585–603 (2018).
135. Hansmann, S. et al. Consensus protocols for the diagnosis and management of the Author contributions
hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: a German All the authors contributed equally to all aspects of the article.
PRO-KIND initiative. Pediatr. Rheumatol. Online J. 18, 17 (2020).
136. Gonzalez Suarez, M. L. et al. Treatment of C3 glomerulopathy in adult kidney transplant Competing interests
recipients: a systematic review. Med. Sci. 8, 44 (2020). H.-J.A. has received consultancy or lecture fees from Boehringer, Bayer, GlaxoSmithKline,
137. Leung, N., Bridoux, F. & Nasr, S. H. Monoclonal gammopathy of renal significance. AstraZeneca, Novartis, Otsuka, Janssen, Kezar, Lilly and PreviPharma. A.R.K. has received
N. Engl. J. Med. 384, 1931–1941 (2021). lecture fees from Vifor Pharma and research funding via consultancy and grants from Vifor,
This study explains how a B cell or plasma cell secreting a single immunoglobulin Visterra, Toleranzia, Variant Bio and CSL Limited. N.L. has received research funding from
clone can cause glomerular disease, even in the absence of formal diagnostic criteria Omeros. P.R. has nothing to disclose.
for malignancy, and reviews its pathogenesis, features and management.
138. Bridoux, F. et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney Int. Additional information
87, 698–711 (2015). Correspondence should be addressed to Hans-Joachim Anders.
139. Chauvet, S. et al. Both monoclonal and polyclonal immunoglobulin contingents mediate
complement activation in monoclonal gammopathy associated-C3 glomerulopathy. Peer review information Nature Reviews Immunology thanks B. Seitz-Polski and the other,
Front. Immunol. 9, 2260 (2018). anonymous, reviewers for their contribution to the peer review of this work.
140. Yui, J. C. et al. Monoclonal gammopathy-associated thrombotic microangiopathy.
Am. J. Hematol. 94, E250–E253 (2019). Reprints and permissions information is available at www.nature.com/reprints.
141. Leung, N. et al. The evaluation of monoclonal gammopathy of renal significance:
a consensus report of the International Kidney and Monoclonal Gammopathy Research Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in
Group. Nat. Rev. Nephrol. 15, 45–59 (2019). published maps and institutional affiliations.
142. Bridoux, F. et al. Unravelling the immunopathological mechanisms of heavy chain
deposition disease with implications for clinical management. Kidney Int. 91, 423–434 Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this
(2017). article under a publishing agreement with the author(s) or other rightsholder(s); author self-
143. Sirac, C. et al. Role of the monoclonal kappa chain V domain and reversibility of renal archiving of the accepted manuscript version of this article is solely governed by the terms
damage in a transgenic model of acquired Fanconi syndrome. Blood 108, 536–543 of such publishing agreement and applicable law.
(2006).
144. Sirac, C. et al. Animal models of monoclonal immunoglobulin-related renal diseases.
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nature reviews immunology https://doi.org/10.

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‘Glomerulonephritis’ (GN) is a term used to describe a group of Introduction

heterogeneous immune-mediated disorders characterized by Key features of glomerular

optimal therapy. Instead, we propose grouping GN disorders into five Autoimmune GN

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antibodies or cryoglobulins24 as an additional autoimmune component

Deposition of circulating immune complexes

glomerulonephritis myelitis, pneumonia, visceral abscess and urinary tract infection39,

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Targets for immunotherapy of nephritogenic autoantibodies produces active lesions followed

Table 1 | Interpretation of histopathological lesion patterns of glomerulonephritis

Lesion pattern Main structure injured Immunological activity Chronicity

Collapsing focal segmental glomerulosclerosis Podocytes High Acute

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a Endocapillary proliferative GN b Mesangioproliferative GN c Membranoproliferative GN

d Membranous GN e Crescentic GN f Pauci-immune GN

IgG4 Fibrinogen IgG

i Proliferative GN with monoclonal

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Table 2 | Proposed classification of glomerulonephritis

GN category Infection-related GN Autoimmune GN Alloimmune GN Autoinflammatory Monoclonal gammopathy-

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Table 3 | Categories of glomerulonephritis and examples of their subtypes

GN subtype Underlying cause Pathological mechanism Kidney biopsy lesion pattern

Cryglobulinaemia Cryoglobulins, RF Luminal IgG deposits Diverse, immune complex GN

C3GN Anti-C3, anti-C4, anti-C5, anti-factor B, Granular C3 deposits Diverse, C3GN

CAPS NLRP3 mutation Inflammasome overactivation and/or high AA amyloidosis

Hyper-IgD syndrome MVK mutation Inflammasome overactivation and/or high AA amyloidosis

TRAPS TNFRSF1A mutation TNF pathway overactivation AA amyloidosis

C3GN FHR fusion proteins Complement (alternative pathway) C3GN

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Table 3 (continued) | Categories of glomerulonephritis and examples of their subtypes

GN subtype Underlying cause Pathological mechanism Kidney biopsy lesion pattern

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a Infection-related GN Infection b Autoimmune GN

Adaptive immune response

Macrophage Infected cell

Mesangium Antibody binding

In situ IC Antigen recogition

Direct cytopathic Antibody binding to GBM

c Alloimmune GN d Autoinflammatory GN e Monoclonal gammapathy-related GN

Damaged Free light chain

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Lymphoid tissue Glucocorticoids

B cell Naive T cell

• Calcineurin inhibitors • Anti-CD20 • Anti-IL-23

Kidney glomeruli Nephrotoxic immunoglobulins IgG-degrading

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Table 4 | Pipeline of drug development for glomerulonephritis

Subtype of GN Molecular target Compound Trial phase ClinicalTrials.gov identifier

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Table 4 (continued) | Pipeline of drug development for glomerulonephritis

Subtype of GN Molecular target Compound Trial phase ClinicalTrials.gov identifier

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