Seminar

Glomerulonephritis
S J Chadban, R C Atkins Lancet 2005; 365: 1797–806
Department of Nephrology,
The term glomerulonephritis encompasses a range of immune-mediated disorders that cause inflammation within Monash Medical Centre,
Clayton, Victoria, Australia
the glomerulus and other compartments of the kidney. Studies with animal models have shown the crucial
(S J Chadban FRACP,
interaction between bone-marrow-derived inflammatory cells and cells intrinsic to the kidney that is both Prof R C Atkins FRACP); and
fundamental and unique to the pathogenesis of glomerulonephritis. The mechanisms of interaction between these Renal Medicine and
cells and the mediators of their coordinated response to inflammation are being elucidated. Despite these Transplantation, Royal Prince
Alfred Hospital and University
pathophysiological advances, treatments for glomerulonephritis remain non-specific, hazardous, and only partly
of Sydney, Camperdown, NSW,
successful. Glomerulonephritis therefore remains a common cause of end-stage kidney failure worldwide. Australia (S J Chadban)
Molecule-specific approaches offer hope for more effective and safer treatments in the future. Correspondence to:
Dr S J Chadban, Transplantation,
Glomerulonephritis is a subject of confusion among the major contributors, glomerulonephritis is likely to be Level E9, Royal Prince Alfred
Hospital, Camperdown,
health-care workers. Much of the confusion stems from the cause in a substantial proportion.
NSW 2050, Australia
the nomenclature, which attempts to encapsulate the The epidemiology of more serious and clinically Steve.Chadban@cs.nsw.gov.au
aetiology, pathology, and clinical presentation. The apparent episodes of glomerulonephritis is better defined.
aetiological description refers to primary (aetiology Accurate classification requires a histological diagnosis;
unknown, generally thought to be a manifestation of consequently, the reported prevalence might vary
autoimmunity) or secondary (associated with one of according to local indications for renal biopsy. A study of
several autoimmune, infectious, malignant, or all renal biopsies done in the Australian state of Victoria
metabolic diseases) forms of glomerulonephritis. The during 1995 and 1997 found that 21·5 people per 100 000
pathological description addresses glomerular population per year underwent renal biopsy, yielding a
involvement, cell involvement, and changes in non- yearly incidence of biopsy-proven glomerulonephritis of
cellular components of the glomerulus (panel 1; figure). 12·3 per 100 000. The most commonly diagnosed types of
Classification according to the clinical presentation is glomerulonephritis in adults were IgA nephropathy, focal
the simplest and most effective tool for the clinician and segmental glomerulosclerosis, and vasculitis; those
(panel 2). Although each clinical presentation can be most commonly diagnosed in children were minimal-
associated with several distinct types of glomerulo- change disease, focal and segmental glomerulosclerosis,
nephritis defined by aetiology and pathology, the lupus nephritis, and IgA nephropathy.4 A population-
approach to diagnosis and management is best directed based study spanning 1976–2002, which included 898
by the clinical presentation. Rapidly progressive biopsy-proven cases of glomerulonephritis among
glomerulonephritis is a medical emergency, demanding 412 735 inhabitants of a region of western France,
urgent histological diagnosis and treatment to prevent documented similar incidence, prevalence, and pattern of
renal failure.1 Nephritic and nephrotic presentations disease and an increase in the incidence of crescentic
generally indicate urgent renal biopsy to guide glomerulonephritis over time.5
management and provide prognostic information. Most patients with glomerulonephritis incur chronic
Chronic glomerulonephritis is also an indication for kidney disease, with the attendant risks of premature
diagnostic biopsy and for the initiation of therapy to slow cardiovascular disease6 and progressive kidney failure.
progression of renal impairment and limit the The burden of glomerulonephritis is most clinically
consequences of renal failure. Asymptomatic urinary apparent in its contribution to end-stage kidney failure,
abnormalities require a less urgent approach— which necessitates dialysis or transplantation.
diagnostic tests including renal biopsy in some cases, or Glomerulonephritis is recognised as the second
observation over time in others. commonest cause of end-stage renal failure worldwide. In
Australia, glomerulonephritis is the most common cause,
Epidemiology
Many cases of glomerulonephritis result in mild, Search strategy and selection criteria
asymptomatic illness that is not recognised by the
We searched MEDLINE for papers published in English
patient, is not brought to medical attention, and remains
between 1998 and 2004 with the search term
undiagnosed. The incidence and prevalence of such mild
“glomerulonephritis” and selected those relevant to the
episodes of glomerulonephritis are unknown but could
theme of the Seminar. We also searched reference lists of
be substantial. Population-based screening studies have
papers of interest and accessed key publications over the past
shown that evidence of kidney damage—proteinuria,
50 years. Since there is much research on this topic, the
haematuria, low calculated glomerular filtration rate, or a
reference list reflects the results of these searches, with
combination of these features—is present in 16% of
selection at our discretion rather than a systematic review.
adults in Australia2 and a similar proportion in the USA.3
Although diabetic and hypertensive nephropathies are

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 Seminar

occurring types of biopsy-proven glomerulonephritis

Panel 1: Pathological classification
Glomerular involvement
All glomeruli (diffuse) or only some (focal)
Extent of disease within involved glomeruli: patchy
(segmental) or general
Cell involvement
Increases in cell number (proliferative)
Neutrophil accumulation (exudative)
Cell damage
Cell necrosis visible by light microscopy (necrotising)
Ultrastructural damage visible only by electronmicroscopy
(foot-process effacement, membrane thinning)
Changes in non-cellular glomerular components
Matrix accumulation (hyalinosis) or immune deposits
Site of deposition (mesangial, subendothelial, subepithelial)
leading to 27% of cases of end-stage renal failure in 2001;7
in the USA, however, glomerulonephritis ranks third
behind diabetes and hypertension.8 The propensity for
each type of glomerulonephritis to cause end-stage renal
failure varies, but the types most frequently identified on
biopsy are also those most likely to result in kidney
failure.4 In Australia during 2001, the most frequently
Mesangial-cell disease
IgA nephropathy, IgM nephropathy,
mesangioproliferative glomerulonephritis,
class II lupus nephritis,
diabetic nephropathy
causing end-stage renal failure were IgA nephropathy
(27%), focal sclerosing (14%), rapidly progressive/
crescentic glomerulonephritis (10%, including vasculitis
and antiglomerular-basement-membrane disease),
membranous (5%), and lupus nephritis (4%).7
Glomerulonephritis is more common in the male than
in the female population.4 Lupus nephritis is the major
exception; the frequency is two or more times higher
among the female than among the male population.4
However, since the female to male ratio of systemic
lupus erythematosus is roughly ten, yet that of nephritis
is only two to three, male patients with lupus seem more
likely to develop nephritis than female patients.
Defined populations are clearly at increased risk of
glomerulonephritis. Children in less developed countries,
and those in impoverished sections of more developed
countries, such as Australian Aboriginals,9 are at
increased risk of infection-associated glomerulonephritis
after streptococcal skin or throat infections. This disease is
now rare in more developed countries.4,5,10 Individuals with
chronic infections with viruses, particularly hepatitis B or
C virus and HIV, are at increased risk of several types of
immune-mediated glomerulonephritis.11,12 Predisposition
to glomerulonephritis might also be hereditary, as is the
case with Alport’s syndrome, in which mutations in the
COL4A5 (X-linked), COL4A3, or COL4A4 (both
autosomal recessive) genes result in defective synthesis
of collagen type IV with consequent dysfunction and
inflammation of the glomerular basement membrane.13,14
Panel 2: Classification according to clinical presentation

Mesangial cell Asymptomatic urinary abnormalities

Basement membrane Subnephrotic-range proteinuria, and/or microscopic
Endothelial cell
Epithelial cell
haematuria, not accompanied by renal impairment, oedema,
or hypertension
Epithelial-cell injury Lumen Endothelial-cell injury Nephritic syndrome
Membranous nephropathy, Infection-associated glomerulonephritis,
minimal-change disease, mesangiocapillary glomerulonephritis, Recent onset of haematuria and proteinuria, renal
focal and segmental class III and IV lupus nephritis, impairment, and salt and water retention, causing
glomerulosclerosis, antiglomerular-basement-membrane disease,
vasculitis and cryoglobulinaemia,
hypertension
class V lupus nephritis,
diabetic nephropathy haemolytic uraemic syndrome
Rapidly progressive glomerulonephritis
Progression to renal failure over days to weeks, in most cases
In health, solutes are filtered into the urinary space. The presence of abnormal
in the context of a nephritic presentation, typically associated
amounts of protein or cells suggests glomerular pathology with the pathological finding of extensive glomerular
crescent formation on renal biopsy
Figure: Cellular location of injury during glomerulonephritis Nephrotic syndrome
Mesangial cells are directly exposed to the circulation. Deposition of immune complexes within these cells is Nephrotic-range proteinuria (more than 3·5 g per 1·73 m2 in
typically seen in disorders such as IgA nephropathy; it results in proliferation and expansion of the cells leading to
haematuria, proteinuria, and renal impairment. Epithelial cells, in conjunction with basement membrane, allow
24 h), hypoalbuminaemia, hyperlipidaemia, and oedema, in
filtration of plasma solutes but retard passage of cells and plasma proteins. Disease related to these cells is typified many cases complicated by predisposition to venous
by the presence of subepithelial deposits and flattening of the foot processes that engage the basement thrombosis and bacterial infection
membrane, resulting in disruption of the filtration barrier and proteinuria. Endothelial-cell disease can result from
immune-complex deposition (as occurs in mesangiocapillary glomerulonephritis), antibody attachment to the Chronic glomerulonephritis
basement membrane (Goodpasture’s disease), or trauma and activation of coagulation (haemolytic uraemic Persistent proteinuria with or without haematuria and slowly
syndrome). Endothelial-cell proliferation and necrosis are accompanied by leucocyte accumulation, and rupture of
progressive impairment of renal function
the basement membrane, crescent formation, and disruption of glomerular architecture can develop. A nephritic
or rapidly progressive presentation ensues.

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Pathogenesis
The pathogenesis of glomerulonephritis is complex and
remains incompletely understood. Complexity arises from
several factors. First, many types of insult can initiate
glomerulonephritis; they include endogenous processes,
such as autoimmunity, cancer, and ultrastructural
abnormalities within the kidney, and exogenous factors,
including infectious organisms and drugs. Second, there
is individual variability in the susceptibility to
glomerulonephritis, which is likely to have a genetic basis;
for example, only a minority of individuals infected with
hepatitis C virus develop glomerulonephritis. Third, there
are complex interactions between soluble factors
(including antibodies, complement, chemokines,
cytokines, and growth factors) and cells (both leucocytes
and intrinsic kidney cells) that mediate glomerular
inflammation. A final cause of complexity is the
progressive nature of kidney disease; it is due to the
contribution of non-specific factors such as hypertension
and proteinuria that can promote continuing kidney
damage, despite resolution of the initial insult.
Small-animal models of glomerulonephritis closely
replicating features of human glomerulonephritis have
provided insights into the pathogenesis. The
reproducibility and uniformity of such animal models
has permitted a step-by-step dissection of many of the
mechanisms involved. We discuss several key
mechanisms thus identified (table 1)15–32 and relate these
to their counterparts in human disease.
Antibody
Antibody deposition within the kidney seems to be the
initiating event in several forms of naturally occurring
and experimentally induced glomerulonephritis.
Deposited antibody could lead to glomerular
inflammation by promoting antibody-dependent cell-
Target process Target cells
Antibody deposition B-cells/plasma cells
Antibody receptors Macrophages, mesangial cells
Complement activation NA (soluble protein)
Coagulation Endothelium
Chemotaxis Infiltrating leucocytes, intrinsic kidney
cells
Adhesion Endothelium
Proliferation Macrophages, mesangial cells, tubular
cells
Signal transduction Mesangial cells, neutrophils
Gene transcription Intrinsic cells, leucocytes
Cell depletion T lymphocytes
Effector molecules Macrophages, mesangial cells
NA=not applicable; MCP1=macrophage chemotactic protein 1; ICAM1=intercellular adhesion molecule 1; GBM=glomerular basement membrane; MCSF=macrophage-colony-stimulating factor; PDGF=platelet-derived growth
factor; MAP=mitogen-activated protein; NF-B=nuclear factor B; TNF=tumour necrosis factor; L-NAME=NG-nitro-L-arginine methyl ester.
Table 1: Experimental therapies in glomerulonephritis
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Seminar
mediated cytotoxicity,33 by activating infiltrating and
intrinsic kidney cells via Fc receptors,16 or by fixing and
activating complement.34
Goodpasture’s disease is initiated by deposition of IgG
along the glomerular basement membrane (hence anti-
glomerular-basement-membrane disease). Antibody
binding promotes a type II immune response, whereby
complement and coagulation are activated. An adaptive
T-cell response ensues, which causes kidney damage
and is sufficient to perpetuate the disease process.1 The
antibodies causing the disease are specific for the
non-collagenous domain of type IV collagen present
within the glomerular basement membrane.35 The
presence of this antigen within the alveolar basement
membrane is the reason why many patients with this
disease suffer pulmonary haemorrhage in addition to
glomerulonephritis.
Antibody can also be deposited from circulation as a
component of immune complexes or cryoglobulins, thus
triggering a type III immune response within the
glomerulus. Circulating immune-complex formation
and deposition within the glomerulus is seen particularly
during subacute bacterial endocarditis, lupus nephritis,
and hepatitis-C-related cryoglobulinaemia.11
Accumulation of isotype-specific, though not antigen-
specific, antibody within mesangial cells is the
pathognomonic feature of IgA nephropathy. The cause
of the IgA deposition remains unclear, but it is probably
a consequence of either abnormal IgA structure or
abnormal Fc-receptor function in susceptible
individuals.36 The interaction of antibody with cells, via
cell-surface receptors for the constant domain of
immunoglobulin (Fc receptors), is an essential element
in the NZB/W model of lupus nephritis; mice
genetically deficient in Fc receptors are resistant to the
development of glomerulonephritis.16
Strategy Effect
Blockade of B-lymphocyte stimulator Reduces autoantibodies and kidney damage in lupus model15
Fc-receptor-deficient mice Inhibits inflammation in response to deposited IgG in lupus model16
Complement depletion; anti-C5, soluble receptor Inhibits proteinuria;17 inhibits progression of proteinuria and kidney dysfunction18,19
Hirudin (thrombin antagonist) Inhibits crescentic nephritis20
Antagonist: met-RANTES Attenuation of proteinuria, infiltrate;21 resolution of proteinuria, infiltrate;22
Antibody: MCP1 tubulointerstitial protection23
MCP1-knockout mice
Interleukin-1-receptor antagonist inhibits Attenuation of leucocyte accumulation and kidney damage in anti-GBM disease24
kidney expression of ICAM1
Antibody to MCSF receptor Inhibits macrophage proliferation;25 increased glomerular hypercellularity and
p27Kip-1 knockout mice tubular damage26
STI-571 PDGF receptor phophorylation inhibitor Prevention of hypercellularity in mesangioproliferative model;27 reduced
Inhibition of MAP kinase neutrophil-dependent proteinuria28
NF-B decoy oligodinucleotide Inhibited TNF-induced glomerular inflammation29
Depleting anti-CD4 Inhibition of proteinuria in a model of membranous nephropathy30,31
Depleting anti-CD8
Nitric oxide synthetase antagonist, L-NAME Diminished monocyte infiltration and glomerular injury32
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Antineutrophil cytoplasmic antibodies (ANCA) are
detectable in the serum of most patients with necrotising
small-vessel vasculitis affecting the kidney, most of
whom are classified as having Wegener’s granulomatosis
or microscopic polyangiitis. ANCA can be directed
against proteinase 3, which gives a cytoplasmic
distribution on indirect immunofluorescence (cANCA),
or myeloperoxidase, which results in a perinuclear
distribution (pANCA). ANCA are useful for diagnostic
purposes37 and seem likely to have a pathogenetic role in
vasculitis. In vitro and in vivo, ANCA upregulate
endothelial-cell expression of adhesion molecules and
thereby increase interactions with primed monocytes and
neutrophils.38,39
Complement
The complement cascade is a central component of the
innate immune system. Activation of the cascade can
occur in the classic way, after exposure to bacteria, or via
the alternative pathway in response to bacterial
polysaccharides, damaged cells, or aggregated IgA. In
either case, a self-amplifying signalling cascade is initiated,
which generates chemotactic (C5a) and proinflammatory
(C3a) molecules and ultimately a cytolytic protein complex
known as C5b-9, or the membrane attack complex.
Activation of the complement cascade is tightly regulated
by the short half-life of activated complement proteins and
by a series of endogenous regulatory proteins.34
Components of the complement cascade liberated
during the process of activation can be detected in tissue,
serum, or urine and are evidence of complement activation
and the pathway taken to activation—classic or alternative.
Evidence of complement deposition within glomeruli is a
key feature of many forms of glomerulonephritis, and a
pathogenetic role of complement is implied by several
observations in human disease. First, deposition of
complement products can be readily shown by
immunohistochemistry or immunofluorescence in
specific types of glomerulonephritis (eg, lupus nephritis).
Second, the concentration of complement components in
serum reflects disease activity; for example, C3
concentration is commonly low during active lupus
nephritis. Third, there is urinary excretion of complement
activation products in progressive, proteinuric nephro-
pathies such as membranous glomerulonephritis.40,41
Fourth, genetic deficiency of specific complement
components has been associated with glomerulonephritis,
such as C2 deficiency in some cases of lupus nephritis.
Finally, mechanisms causing aberrant activation of
complement have been identified in some glomerular
diseases, such as the C3-activating factor “C3-neph” in
poststreptococcal glomerulonephritis.34
Indirect evidence obtained from human studies has
been supported by findings in animal models. The
administration of complement inhibitors or the use of
mice genetically deficient in complement components or
complement-regulatory molecules has provided strong
1800
evidence of a role for complement in the initiation and
progression of glomerular disease. Blockade of C5b-9
formation in the Heymann nephritis model of human
membranous nephropathy effectively prevents dis-
ease,17,42,43 confirming a role for complement in disease
initiation. The finding that complement might drive
progressive kidney damage in glomerular diseases
characterised by proteinuria is potentially more
important. Hsu and Couser44 reviewed evidence in
support of the hypothesis that during proteinuric disease,
complement components enter the tubular lumen via
filtration through damaged glomeruli or local synthesis45
then become activated, culminating in the generation
and deposition of C5b-9 along the luminal membrane of
tubular cells, causing chronic tubulointerstitial inflam-
mation and progressive kidney failure. Studies in a non-
immunologically initiated model of glomerular disease
(aminonucleoside nephrosis) in rats unable to assemble
the C5b-9 complex provide support for this theory.46
Similar results have been achieved by the administration
of the soluble, recombinant inhibitor of C5b-9 formation
soluble complement receptor 118 or complement-
blocking antibodies such as anti-C5,19 which shows the
potential of anticomplement strategies for the
management of human glomerulonephritis.
Coagulation
Intraglomerular activation of the coagulation cascade,
triggered primarily by tissue factor and resulting in
thrombin formation then fibrin deposition, is evident in
severe forms of human and experimental glomerulo-
nephritis. Local upregulation of tissue factor, augmented
by a transient reduction in local production of its
endogenous regulator tissue-factor pathway inhibitor
(TFPI), trigger activation of the extrinsic coagulation
pathway in experimental crescentic glomerulonephritis.
TFPI antibody exacerbated disease in this model as
shown by fibrin deposition, crescent formation,
inflammatory-cell infiltration, and kidney damage; the
reverse effects were achieved by administration
of recombinant TFPI.47 Intraglomerular coagulation
clearly has proinflammatory actions in addition to
haemodynamic consequences. Studies in a mouse
model of crescentic glomerulonephritis have shown the
importance of the interaction between thrombin and
protease-activated receptor 1 in promoting cellular
infiltration and inflammation, independent of fibrin
deposition and clot formation.20
Leucocytes
A constant feature of glomerulonephritis is the presence
of inflammatory leucocytes within both the glomerular
and the interstitial compartments of the kidney.
Macrophages and T lymphocytes are the dominant cell
types present, and the intensity of cellular accumulation,
particularly within the interstitium rather than the
glomerulus, has repeatedly been found to correlate with
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the clinical and pathological severity of disease in animal
models and in human beings.48,49
T cells seem to be crucial to the development of most
forms of glomerulonephritis. T-cell depletion studies in
Heymann nephritis, a rat model of membranous
nephropathy, have shown an absolute requirement for
CD4-positive30 and CD8-positive31 T cells. In some models,
T cells are sufficient to produce disease, as shown by the
transmission of anti-glomerular-basement-membrane
disease to healthy chickens by transfer of T cells isolated
from chickens with established disease.50 T cells apparently
initiate, direct, and amplify the cognate immune response
during many types of glomerulonephritis.51 However,
specific T-cell subsets are also likely to downregulate this
inflammatory response (T-regulatory cells).52
Most of the accumulated inflammatory cells in many
forms of human and experimental glomerulonephritis are
macrophages. In a model of glomerulonephritis that
allows leucocyte depletion followed by reconstitution with
macrophages alone, macrophages were able to cause renal
injury, as shown by proteinuria and mesangial-cell
proliferation.53 The mechanisms by which macrophages
mediate renal injury remain to be confirmed, but are likely
to include: promotion of inflammation via release of pro-
inflammatory cytokines such as tumour necrosis factor ;
recruitment of macrophages and other leucocytes via
release of chemotactic molecules such as macrophage
chemotactic protein 1; cell proliferation by release of
growth factors such as macrophage-colony-stimulating
factor; cell death via the release of reactive oxygen species
including nitric oxide; and control of fibrosis and repair via
release of metalloproteinases and other enzymes.54
In the setting of glomerulonephritis, cells accumulate
within the kidney as a result of recruitment from the
circulation and proliferation within the kidney.
Recruitment of leucocytes from the circulation is
directed by chemokines generated within the inflamed
kidney.55 Protection against leucocyte accumulation
within the kidney and renal injury has been achieved
through blockade of key macrophage chemokines, such
as macrophage chemotactic protein 122 or its receptor
CCR2,21 or T-cell chemokines, such as RANTES.56
Animals genetically deficient in chemokines are
resistant to disease induction,23 although results have
not been uniform, with an unexpected accentuation
of experimental anti-glomerular-basement-membrane
disease seen in mice deficient in CCR1, a receptor for
RANTES and macrophage inflammatory protein 1.57
Chemokines identified as important in the murine
models are clearly active in human disease.58 Once
leucocytes have been attracted into the renal micro-
circulation, engagement between adhesion molecules
and their ligands appears necessary for migration of the
cells into kidney tissues, as shown by the effectiveness
of blocking the cytokine interleukin 1; this blockade
inhibited upregulation of intercellular adhesion
molecule 1, thereby preventing leucocyte infiltration
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Seminar
and protecting rats from the development of anti-
glomerular-basement-membrane disease.24
Proliferation of cells, particularly macrophages, is an
important mechanism by which the inflammatory
response within the kidney is amplified. Proliferation has
been clearly identified by incorporation of
bromodeoxyuridine, injected 2 h before the animals were
killed, by macrophages within inflamed glomeruli, but
not by monocytes in circulation; thus, macrophages
within the kidney passed through S-phase of the cell
cycle.59 The demonstration of mitotic figures and
expression of proliferating-cell nuclear antigen by
macrophages within inflamed glomeruli in human
biopsy studies confirms that proliferation also contributes
to inflammation in human glomerulonephritis.60
Macrophage proliferation within the inflamed kidney is
growth-factor dependent, as shown by upregulation of
monocyte-colony-stimulating factor in both experimental
and human glomerulonephritis61 and by the inhibition of
proliferation and disease with blockade of macrophage-
colony-stimulating-factor receptor.25 Less cell-specific
blockade of proliferation has been achieved through
inhibition of cyclin-dependent kinase, also resulting in
attenuation of experimental glomerulonephritis.26
Within the kidney, T cells and macrophages undergo
activation, which is triggered by interactions between
leucocytes and intrinsic renal cells, by interactions between
cells and matrix, and by cytokines and other soluble factors
present within the local inflammatory milieu. Production
of proinflammatory cytokines, including interleukin 1,
tumour necrosis factor , and interferon , is upregulated
in experimental and human disease, and blocking studies
have shown protection in several animal models.62
Inflammation within the glomerulus commonly
causes functional and structural damage to the kidney.
The mechanisms of damage include: direct cell damage
by macrophages, through production of reactive oxygen
species;63 induction of apoptosis, particularly by CD8-
positive T cells;64 antibody-dependent cell-mediated
cytotoxicity, as immunoglobulin attached to kidney cells
is engaged by Fc receptors expressed by macrophages or
other phagocytes;16,33 liberation of enzymes and
metalloproteases causing disruption of basement
membrane and other stromal structures leading to
architectural disruption;65 myofibroblast accumulation
within the tubulointerstitium66 and glomerulus67 and
production of excess matrix components, driven by
growth factors (particularly transforming growth
factor ), leading to scarring and fibrosis.68
Intrinsic kidney cells
The glomerulus consists of a network of specialised
capillaries, supported by a stroma of mesangial cells,
epithelial cells, and matrix, encased within Bowman’s
capsule. Each type of these resident glomerular
cells has been implicated in the pathogenesis of
glomerulonephritis (figure).
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Glomerular epithelial cells or podocytes have foot
processes that act in concert with the endothelial-cell
basement membrane to form a filtration barrier or “slit
diaphragm”, which permits the passage of water and
electrolytes into the glomerular filtrate, while retarding the
passage of cells and proteins from the blood. The
molecular composition of the slit diaphragm has been
largely unravelled.69 Mutation of the nephrin gene is
present in patients with congenital nephrotic syndrome of
the Finnish type, and other molecular abnormalities of the
filtration barrier have been associated with other types of
glomerulonephritis that are characterised by nephrotic
syndrome.
Necrosis, apoptosis, proliferation, and activation of
glomerular endothelial cells are variably seen in types of
glomerulonephritis causing the nephritic syndrome,
including mesangiocapillary glomerulonephritis,
crescentic glomerulonephritis, and haemolytic uraemic
syndrome. Antibody deposition followed by complement
activation has been shown experimentally to induce
apoptosis.70 Protection from experimental injury could be
provided by vascular endothelial growth factor.71 The
mechanisms involved in human pathology remain to be
elucidated.
There is evidence from both human studies and animal
models that mesangial-cell proliferation and expansion of
mesangial areas within glomeruli precede glomerulo-
sclerosis in many types of glomerulonephritis, particularly
IgA nephropathy, and in other types of glomerular injury,
such as diabetic nephropathy. Activation and proliferation
of mesangial cells could be triggered by soluble factors
including angiotensin, cytokines, and growth factors, such
as platelet-derived growth factor, or deposition of antibody
or immune complexes.72 Once activated, mesangial cells
promote inflammation via the release of chemokines and
cytokines and glomerulosclerosis via matrix production
and transdifferentiation into myofibroblasts.73
The cells of the tubulointerstitial compartment tend to
be neglected, but they add to glomerular injury through
their release of growth factors and cytokines and by their
contribution to fibrosis and scarring.74 In glomerulo-
nephritis, tubular cells become major producers of
cytokines and growth factors75 that perpetuate renal
damage and promote chronicity. Furthermore, trans-
differentiation of tubular cells to myofibroblasts is
important in renal scarring.76 The importance of the
tubulointerstitium, especially after the establishment of
injury, is highlighted by the finding that the degree of
interstitial leucocyte infiltration48,49 and fibrosis are more
powerful predictors of the likelihood of renal failure than
are the glomerular changes.
Glomerulonephritis, as is the case with most forms of
renal injury, tends to produce progressive loss of kidney
function despite, in many cases, apparent resolution of the
inciting immunological insult. Immune-mediated
damage to the glomerulus and interstitium commonly
leads to proteinuria and hypertension, both of which in
1802
turn can cause further kidney damage.77 Conversely,
commonly used treatments for hypertension and
proteinuria, such as blockade of the renin-angiotensin
system, directly retard the continuing inflammatory and
fibrotic response within the kidney, in addition to their
beneficial effects on blood pressure and proteinuria.78
Management
Glomerulonephritis is a major contributor to the
escalating health burden associated with chronic kidney
disease. Thus, broader implementation of interventions
shown to be effective in slowing the progression of
glomerulonephritis is very important from an
economic perspective.79 From the patient’s perspective,
interventions likely to achieve even small delays in the
requirement for dialysis or transplantation are desirable.79
Therapeutic options for human glomerulonephritis
applicable to all cases include symptomatic treatment and
strategies to delay progression; immunosuppression is
appropriate for selected cases; and renal replacement
therapy with dialysis or transplantation is needed for a
sizeable minority of patients. Molecular therapies
designed to target key mediators of damage hold great
promise and are effective in several experimental settings
but are yet to achieve translation into the clinic (table 1).
Strategies to delay progression provide an important
adjunct to therapy for all patients with glomerulo-
nephritis. Regular clinical follow-up,80 blood-pressure
control,77 and the use of an inhibitor of angiotensin-
converting enzyme in patients with proteinuria exceeding
1 g daily,77,81,82 are of proven benefit. Recent findings
suggest that more complete blockade of the renin-
angiotensin system by use of both an angiotensin-
converting-enzyme inhibitor and an angiotensin-receptor
antagonist is superior to either agent alone for prevention
of progressive renal failure among patients with
proteinuria.83 Dietary protein restriction can limit uraemic
symptoms and slow progression in selected cases,77,84 but
the beneficial effects are slight and such dietary restriction
can incur a substantial risk of malnutrition. Treatment of
hyperlipidaemia has slowed progression in experimental
models of glomerulonephritis; a major randomised
controlled trial is under way to address this question in
human beings, but available trial data are insufficient for
lipid lowering to be recommended specifically for
renoprotection.85
Currently used immunosuppressive therapies for
human glomerulonephritis are not uniformly effective
and are frequently associated with serious side-effects.
Furthermore, because patients with nephropathies such
as membranous nephritis can experience spontaneous
remission, the decision to initiate immunosuppressive
therapy is not always straightforward and necessitates
consideration of the diagnosis, the patient, his or her
susceptibility to side-effects, and prognostic factors that
might help to determine the risk of progression versus
remission for each case (table 2).83,86–101 Loss of glomerular
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 Seminar

filtration rate, heavy proteinuria, presence of
hypertension, and fibrosis within the interstitium on
kidney biopsy are adverse prognostic features for most
forms of glomerulonephritis. Their presence warrants
consideration of aggressive therapy. Advanced age and
frailty of the patient, probability of developing diabetes or
worsening control of pre-existing diabetes, risk of
infertility, and general susceptibility to the side-effects of
immunosuppression should be considered in the choice
to use such therapies and which agents to use.
Corticosteroids are effective in several types of
glomerulonephritis owing to their ability to inhibit activity
of the transcription factor nuclear factor B and
consequently inhibit the proinflammatory effects of
cytokines known to promote glomerular inflammation
actively, including interleukin 1 and tumour necrosis
factor . However, other actions of corticosteroids result in
well recognised side-effects that limit the usefulness of
these drugs. Removal of preformed antibodies from
circulation by plasmapheresis is useful in Goodpasture’s
disease, but not in lupus nephritis.102 The antiproliferative
agents cyclophosphamide, chlorambucil, and azathioprine
are effective in suppressing glomerular inflammation but
are non-specific in their actions and cause substantial
morbidity and mortality. Mycophenolate mofetil preferen-
tially inhibits the type II isoform of inosine mono-
phosphate dehydrogenase, which is required by leucocytes
for de-novo purine synthesis. However, in practice
mycophenolate mofetil is not completely specific for
leucocytes and, like other antiproliferative agents, it is
associated with a broad range of side-effects including
susceptibility to infection and cancer.103 Sirolimus, an
immunosuppressant that retards T-cell passage through
the cell cycle, has activity in some forms of glomerulo-
nephritis but has been associated with increased
proteinuria and acute renal failure in some cases.104
Immunosuppressive therapies are of proven benefit in
crescentic glomerulonephritis,1 proliferative lupus
nephritis,95,96 focal and segmental glomerulosclerosis,89
minimal-change disease,86 membranous nephropathy,91
and in cases of IgA nephropathy with deteriorating renal
function and proteinuria.101 Table 2 presents a summary
of the approach to management of primary
glomerulonephritis with immunosuppressive agents and
cites available evidence. To facilitate an evidence-based
approach to both research and practice, the Cochrane
Renal Group maintains a registry of trials in
glomerulonephritis.105
Exciting developments in therapy have been identified
in experimental models of glomerulonephritis (table 1).
However, several differences between experimental
glomerulonephritis and human disease should be
considered in attempts to translate animal results into
potential human therapies. There are biological variations
between models and animals that can lead to inconsistent
responses to therapy. For example, administration of the
potentially immunosuppressive cytokine interleukin 10
was protective against crescentic glomerulonephritis in a
mouse model106 but not in rats.107 The aetiological agent is
known in most cases of experimental glomerulonephritis
but is rarely identified in human glomerulonephritis.
Animals with experimental glomerulonephritis are
homogeneous, whereas patients and human glomerulo-
nephritis are heterogeneous. Experimental disease is
initiated at a time determined by the investigator and runs
a predictable course, thereby permitting intervention at
defined stages including before induction, during disease
establishment, or late in the course. Reports of effective
therapies commonly involve treatment before disease
induction or early during the establishment phase. By
contrast, the onset of human glomerulonephritis is
generally unknown, the time course is variable, and the

Type Clinical prognostic features Management strategy

Minimal-change disease 90% of children are steroid responsive; steroid resistance and relapse Oral prednisone 0·5–1·0 mg/kg daily for 6 weeks, then tapered;86
is common among adults. cyclophosphamide or ciclosporin in steroid-resistant or frequently relapsing patients.86,87
Focal and segmental glomerulosclerosis Declining GFR, nephrotic-range proteinuria, and severe nephrotic Oral prednisone 0·5–1·0 mg/kg daily for at least 6 months, may be tapered after first
syndrome are indications for a trial of immunosuppression. 3 months;88 cyclophosphamide is indicated for steroid-resistant cases, with 50% chance of
response; response reduces probability of progression to ESRD by 50%.88,89
Membranous nephropathy 30% of cases progress to ESRD within 10 years, more likely if nephrosis Cyclophosphamide (or chlorambucil) orally combined with prednisolone,90 achieves
is severe or GFR declining. 50% remission rate; steroids alone are ineffective.91
Mesangiocapillary glomerulonephritis Slowly progressive renal failure is common, predicted by the rate of loss Prednisone can be useful in children92 but not in adults;93 anti-CD20 can be effective in
of GFR and degree of proteinuria. cryoglobulinaemia-associated disease.94
Proliferative lupus nephritis (class III and IV) Biopsy diagnosis is essential because clinical features do not clearly Pulse steroids, followed by monthly intravenous cyclophosphamide and daily oral
differentiate between classes of nephritis, and class determines therapy. prednisone for 3–6 months (remission induction), followed by oral azathioprine or
mycophenolate mofetil and reduced-dose prednisone (maintenance).95-98
Rapidly progressive Lung involvement, degree of GFR reduction, and proteinuria are key Plasmapheresis, pulse methylprednisolone, followed by oral cyclophosphamide and
glomerulonephritis—anti-GBM prognostic indices. prednisone are effective.1,99
Rapidly progressive glomerulonephritis— Typically ANCA-positive; extent of GFR reduction and extrarenal Pulse methylprednisone followed by oral cyclophosphamide and prednisone.100
vasculitis involvement predict prognosis.
IgA nephropathy Heavy proteinuria, decreased GFR, and hypertension are adverse Oral prednisone can be effective in retarding progression;101 however, combined
prognostic features. inhibition of ACE and angiotensin-receptor blockade should be first-line therapy.83

GFR=glomerular filtration rate; ESRD=end-stage renal disease; GBM=glomerular basement membrane; ANCA=antineutrophil cytoplasmic antibodies; ACE=angiotensin-converting enzyme.

Table 2: Management of primary glomerulonephritis with immunosuppressive agents

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 Seminar
patient typically has established disease before treatment
can be given. Kidney damage tends to be progressive in
the longer term, despite elimination of the original source
of injury. Most animal models are short term only. Finally,
the effectiveness of interventions might be specific to the
phase of injury. For example, transforming growth
factor  has protective anti-inflammatory effects within
the glomerulus during the initiation phase of experi-
mental glomerulonephritis108 but adverse profibrotic
effects once disease is established.68 Since human
glomerulonephritis is generally established by the time it
is diagnosed, this growth factor is unlikely to be useful in
treatment of human beings.
Despite such limitations, advances have been made in
the immunosuppressive treatment of experimental
glomerulonephritis that might find human application.
Therapies designed to target each step in the pathogenesis
of glomerulonephritis have been tested in experimental
models and some examples are summarised in table 1.
Few have found an approved clinical indication to date.
Preliminary reports of the successful use of a monoclonal
antibody against CD20 to deplete B lymphocytes, decrease
antibody production, and thereby reduce proteinuria and
kidney dysfunction in cases of human membranous
nephropathy109 and cryoglobulinaemia-associated mesan-
giocapillary glomerulonephritis93 indicate the potential to
achieve selective, mechanism-directed immunosup-
pressive therapies in the near future.
Ultimately, many patients with glomerulonephritis
progress to end-stage renal failure despite currently
available therapies. For such patients, transplantation
offers the best means by which to achieve the best quality
and duration of life. However, transplantation provides
little barrier to several types of glomerulonephritis that
show a propensity to recur.110 Despite the presence of
immunosuppression and the antigenic differences of the
allograft, a substantial proportion of individuals with
primary glomerulonephritis will develop recurrence in the
graft. The clinical course of recurrent glomerulonephritis
might be different from that of the native disease, but
recurrence causes graft failure in an increasing number of
patients over time. For those with glomerulonephritis who
receive a transplant, recurrence is the third commonest
cause of graft failure, causing graft loss in 8% at 10 years
after transplantation.111
The future
The way forward in the management of
glomerulonephritis must be multifaceted. First, we need
to refine our knowledge of the epidemiology of the
disorder; population-based studies could permit the
identification of risk factors and potential causative agents.
To enable progress, uniformity in the classification,
diagnosis (including more routine use of renal biopsy),
and reporting of glomerulonephritis will be needed.
Second, we need to understand the immunopathogenesis
of glomerulonephritis and to generate molecule-targeted
1804
and cell-targeted therapies. The different types of
glomerulonephritis are likely to need disease-specific
agents. Differences between experimental and human
glomerulonephritis complicate translation of
experimental therapies into practice, and primate studies
are likely to be needed in many cases. Third, stem-cell-
based therapies should be explored; these could include
genetic modification to produce protective molecules
within the kidney or to promote regeneration of damaged
intrinsic kidney cells. The complexity of the kidney will
make this approach difficult. Finally, there must be
continuing evidence-based assessment of immune and
non-immune therapies to direct rational care of patients.
Conflict of interest statement
We declare that we have no conflict of interest.
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