reviews

An update on acute postinfectious

glomerulonephritis worldwide
Talerngsak Kanjanabuch, Wipawee Kittikowit and Somchai Eiam-Ong
Abstract | Postinfectious glomerulonephritis is an immunologic response of the kidney to infection, commonly
triggered by streptococci, although many other organisms can cause the condition. in recent decades, the
prevalence of postinfectious glomerulonephritis has tended to decline in most industrialized countries,
but high rates persist in some developing communities. Nowadays, patients in developed countries are
usually adult and male, and those with comorbidities such as diabetes and alcoholism are at increased
risk of developing the disease. The acute presentation ranges from nephritic syndrome to asymptomatic
glomerulonephritis. The exact pathophysiology of postinfectious glomerulonephritis is still unknown; however,
several possible pathologic antigens are under investigation. The majority of children and patients with the
epidemic form of postinfectious glomerulonephritis have an excellent prognosis, which contrasts with the poor
long-term outcome of sporadic cases. Therapy is largely supportive unless renal function fails to recover after
eradication of the causative organism. This review focuses on acute postinfectious glomerulonephritis, and
covers its epidemiology, presentation, pathology, pathogenesis, treatment and outcomes.
Kanjanabuch, T. et al. Nat. Rev. Nephrol. 5, 259–269 (2009); doi:10.1038/nrneph.2009.44

Introduction
Postinfectious glomerulonephritis is an immunologic
response of the kidney that occurs following a nonrenal
infection, often with streptococci. infection has been
known since 1849 to cause glomerulonephritis, when
miller et al. observed that patients who died from so-
called Bright disease after scarlet fever had “albumin-
ous and exudative urine”.1,2 However, streptococci were
not suggested as a cause of glomerulonephritis until
50 years later. 1 subsequently, Streptococcus-related
glomerulonephritis, later termed poststreptococcal
glomerulonephritis, was discovered to be prevalent
throughout the world. most cases were attributed to
group a strepto cocci (Streptococcus pyogenes) and
exhibited pure endocapillary proliferation and exuda-
tion. at that time, poststreptococcal glomerulonephritis
was thought to be a benign condition with a good prog-
nosis and a limited clinical spectrum, in which the classic
presentation involved abrupt onset of acute nephritis
(within 1–3 weeks) following an overt skin or pharyn-
geal streptococcal infection.1 the subsequent realiza-
tion that the disease can be caused by organisms other
than group a streptococci, including other strains of
streptococci (groups C and G), staphylococci, Gram-
negative bacilli, mycobacteria, parasites, fungi, and
viruses (Box 1) led to the introduction of the alterna-
tive term ‘postinfectious glomerulonephritis’.3 this term
is usually used interchangeably with ‘poststreptococcal
glomerulonephritis’, which can cause confusion in the
literature. over time, the concept of post infectious
Competing interests
The authors declared no competing interests.
glomerulonephritis has evolved in other ways. this review
highlights the current status of acute postinfectious
glomerulonephritis worldwide, with a particular focus on
poststreptococcal glomerulonephritis.
Epidemiology
Postinfectious glomerulonephritis is an important health
concern in the developing world (Figure 1). the true
incidence of the disease is difficult to determine since
it is often under-reported,4 because it is transient and
sometimes overshadowed by the systemic manifesta-
tions of infection. in 2005, Carapetis et al.4 estimated the
global burden of poststreptococcal glomerulonephritis
on the basis of 11 population-based studies and they
found that the incidence in the developing world was
Kidney & Metabolic
approximately 24.3 cases per 100,000 person-years in Disorders research
adults and 2 cases per 100,000 person-years in children, Center
in contrast to 6 and 0.3 cases per 100,000 person-years, (T Kanjanabuch),
Division of Nephrology
respectively, in developed regions. all these statistics (T Kanjanabuch,
are likely to be under-estimations by several fold, since S eiam-ong),
Department of
most of the studies assessed included only symptomatic Pathology
patients.5 subclinical disease is thought to be 4–19 times (W Kittikowit),
more common than symptomatic disease,6–8 and in some Chulalongkorn
University, Bangkok,
developing countries, postinfectious glomerulonephritis Thailand.
remains the most common cause of acute nephritic
Correspondence:
syndrome in children, among whom it accounts for s eiam-Ong, Division
50–90% of cases.9–11 indeed, in 2008, rodriguez-iturbe of Nephrology,
and musser 5 calculated an annual incidence of post- Department
of Medicine,
streptococcal glomerulonephritis in the developing Chulalongkorn
world that was higher than that of Carapetis and col- University, Bangkok
10330, Thailand
leagues (9.5–28.5 cases per 100,000 person-years). somchai80754@
rodriguez-iturbe and musser based their calculation on yahoo.com

nature reviews | nephrology volume 5 | maY 2009 | 259

© 2009 Macmillan Publishers Limited. All rights reserved

 reviews
Key points
■ rates of postinfectious glomerulonephritis are declining in most industrialized
countries but remain high in some developing communities
■ The clinical manifestations, histopathology, and organisms reported to be
associated with postinfectious glomerulonephritis have become increasingly
diverse over recent years
■ The fundamental pathogenic mechanism of postinfectious glomerulonephritis
is believed to be the deposition of immune complexes within glomerular tufts;
however, the pathologic antigen remains obscure
■ Most epidemic cases of postinfectious glomerulonephritis have an excellent
prognosis, but outcomes are poor in elderly patients and those with underlying
disease
■ Postinfectious glomerulonephritis generally requires only supportive treatment,
but corticosteroids or cytotoxic agents might have a role if disease progresses
despite eradication of the causative organism
a series of severe cases of the disease from seven devel-
oping countries and on the assumption that such cases
represented less than 1% of the total number of cases of
poststreptococcal glomerulonephritis. nevertheless,
studies of clinical and biopsy data indicate that the prev-
alence of the disease has tended to decline throughout
the globe over the past few decades, especially in the
developed world4,10,12–20 (Figure 2). outbreaks have been
reported in some populations in countries including
Japan,12 armenia13 and Brazil.14 mazzucco et al.15 found
that postinfectious glomerulonephritis accounted for
9.4% of cases of nondiabetic glomerular disease in renal
biopsy specimens from italian patients with type 2 dia-
betes.15 in a 2003 ultrastructural study in the us, Haas
et al.16 found a high prevalence (18%) of postinfectious
glomerulonephritis among renal biopsy samples with
evidence of diabetic nephropathy.16
in the developing world, poststreptococcal glomerulo-
nephritis occurs primarily in children (aged 6–10 years10)
and young adults, with a male predominance of
2–3:1.1,13,17,18 nowadays, patients in the developed world,
especially europe and the us, tend to be adults.3,19–23
individuals with comorbidities such as diabetes and alco-
holism are at increased risk of developing the disease;3,19–21
one-third of individuals with postinfectious glomerulo-
nephritis have one or two of these comorbidities.19 one-
third to one-half of cases in developed countries are
associated with infections of Gram-negative bacilli.3,21
this finding is in contrast to reports published between
1960 and 1980, in which most of the affected patients had
no notable medical history.24,25 the changes in patterns of
postinfectious glomerulonephritis have not been clearly
delineated following improvements in socio economic
status and living standards of many communities
and the widespread and early use of antibiotics.
Pathology and clinical manifestations
the glomerular response to acute infection is variable
and depends on both host factors and the character-
istics of the invading organism. the same organism can
produce different pathological features, including diffuse,
260 | MAY 2009 | voluMe 5
© 2009 Macmillan Publishers Limited. All rights reserved
exudative proliferation without crescents (Figure 3a);
diffuse, endocapillary proliferation with crescents
(Figure 3b); mild, segmental, mesangial proliferation
(Figure 3c); and membranoproliferative glomerulo-
nephritis (Figure 3d).19 thus, a wide spectrum of clini-
cal presentations is observed even within an epidemic
in any given population. However, three major pat-
terns of clinical manifestation can be defined in acute
postinfectious glomerulonephritis, largely on the basis
of histopathology.
Acute nephritic syndrome
acute nephritic syndrome is characterized by hematuria,
proteinuria, edema, and often by hypertension and a mild
degree of acute kidney injury. acute poststreptococcal
glomerulonephritis is the prototypical form of this syn-
drome. the typical patient with acute nephritic post-
streptococcal glomerulonephritis is a child who abruptly
develops puffiness of the eyelids and edema after infec-
tion, followed by smoky and scanty urine and increasing
blood pressure. anuria and nephrotic-range protein-
uria are sometimes observed.13 urine volume usually
increases 4 to 7 days after hospital admission, and this
increase is rapidly followed by resolution of edema and
normalization of blood pressure. microscopic hematuria
takes several months to resolve and can persist for 1 year
after the acute attack.26 acute nephritic poststreptococcal
glomerulonephritis usually presents after streptococcal
pharyngeal and skin infections or scarlet fever,10,13,27
although other suppurative infections (including acute
bacterial endocarditis28 and pneumococcal pneumo-
nia29), protozoa30–32 and viruses33 have also been linked
to the disease.
Histopathologic investigation usually reveals
diffuse cellular proliferation and an exudate that con-
tains many neutrophils and monocytes, with variable
degrees of immunoglobulin and complement depos-
its.19 immunofluorescence commonly reveals granu-
lar deposition of complement C3, often with igG and
occasionally with igm; iga deposition is rare, except in
patients with diabetes—particularly those with staphylo-
coccal infection.19,34 ‘Full house’ immunostaining (that
is, for igG, iga, igm, C3, C4, and C1q) that resembles
the pathologic findings of lupus nephritis is frequently
reported. 35 several histologic patterns of immuno-
fluorescence have been described in acute nephritic
postinfectious glomerulonephritis, including mesangial
(Figure 4a), capillary wall (‘garland’; Figure 4b), and
diffuse (‘starry sky’; Figure 4c) patterns.34 the garland
pattern is more commonly associated with proteinuria
and a poor prognosis than the other patterns, whereas
the mesangial pattern usually correlates with the reso-
lution of disease.34 the intensity of staining for C3 at
the resolution stage often exceeds that of staining for
immunoglobulins.34 under electron microscopy, small
immune deposits are commonly present in the mesan-
gial and subendothelial areas of kidneys with acute
nephritic postinfectious glomerulonephritis. However,
www.nature.com/nrneph

the characteristic finding is large ‘humps’ (dome-shaped
deposits) under the effaced epithelium, particularly in the
mesangial notch or waist regions.16,19,34 the proliferative
and exudative changes associated with nonstreptococcal,
acute nephritic postinfectious glomerulonephritis
are not as prominent as those observed in the classic
poststreptococcal disease.2
rapidly progressive nephritic syndrome
on rare occasions (4.6% of biopsy specimens), acute
postinfectious glomerulonephritis, especially the post-
streptococcal form, is complicated by rapidly rising
azotemia.13 such cases are diagnosed as rapidly progres-
sive nephritic syndrome.19,36 Crescent formation tends to
be limited, even when glomerular congestion and stasis
are present or exudative cells are seen in the capillary
lumen. However, focal and segmental proliferation of the
cells lining the Bowman capsule is frequently observed
(in one-third of cases of acute nephritic syndrome),
especially in elderly patients.37 the glomerular basement
membrane (GBm) becomes unstable in aging indivi-
duals, which increases their susceptibility to the forma-
tion of crescents.1 the severity of renal insufficiency is
proportional to the degree of proliferation and crescent
formation.36,38,39 Staphylococcus aureus infection has been
frequently reported to cause crescents.40 other organ-
isms, including Gram-negative bacilli,41 Mycoplasma 29
and Mycobacterium leprae 42 can also yield crescents.
in the majority of patients, serum creatinine peaks before
the initiation of antibiotics or during the early days of
treatment.41 with effective treatment, recovery of renal
function and remission of the other clinical features of
glomerulonephritis are likely in patients with mild or
moderate crescent formation (<50%).36,43
immunofluorescence shows coarse granular deposits
of igG and C3 along the glomerular capillary walls and
mesangium, in the ‘starry sky’ pattern (Figure 4c).44,45
Subclinical or asymptomatic glomerulonephritis
many individuals with acute, trivial, and self-limited
infections caused by bacteria, parasites or viruses develop
subclinical glomerular disease, as indicated by low-grade
proteinuria (<1 g per day), pyuria, and microscopic
hematuria. Detection of such disease requires diligent
surveillance; these symptoms can be overlooked within
the context of the overt manifestations of infection.
most affected individuals display mesangial prolifera-
tion or focal segmental endocapillary proliferation with
granular, mesangial deposits of igm, C3, and occasion-
ally igG.17,46,47 igG deposition is associated with a worse
outcome than igm deposition.48
Yoshizawa et al.46 prospectively collected urine samples
from 49 patients who had experienced pharyngeal
infections with group a streptococci and found that 12
(24%) had subclinical glomerulonephritis. among the
associated biopsy specimens, 11 (92%) showed histo-
logical abnormalities of the glomeruli, ranging from
mild mesangial hypercellularity to diffuse mesangial
nature reviews | nephrology
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reviews
Box 1 | infections associated with postinfectious glomerulonephritis1,2
Infectious syndromes19
■ skin and throat infections (Streptococcus pyogenes, Streptococcus equi,78
Streptococcus constellatus92)
■ Bacterial endocarditis (Staphylococcus aureus, Streptococcus viridans)
■ Pneumonia (Streptococcus pneumoniae, Mycoplasma pneumoniae)
■ visceral abscesses (dental abscesses, deep-seated abscesses, osteomyelitis)
■ shunt nephritis (Staphylococcus epidermidis, Propionibacterium)
Specific bacterial diseases19,47
■ infection with Gram-positive bacteria (streptococci, staphylococci, pneumococci,
enterococci, Listeria monocytogenes)
■ infection with Gram-negative cocci (Meningococcus, Neisseria gonorrheae)
■ infection with Gram-negative coccobacilli (Hemophilus)
■ infection with Gram-negative bacilli (Salmonella, Klebsiella, Serratia, Yersinia,
Proteus, Pseudomonas)41
■ Other infections (legionellosis, brucellosis,30 bartonellosis)
Mycobacterial, rickettsial, mycoplasmal, chlamydial, and spirochetal diseases2,42,93
■ Tuberculosis and nontuberculous mycobacterial infection
■ syphilis (Treponema pallidum)
■ Leptospirosis (Leptospira interrogans)94
■ rickettsial diseases (Coxiella burnetii)
■ infection with Mycoplasma pneumoniae
■ infection with Chlamydia pneumoniae
Fungal infections2
■ Candida albicans19
■ Histoplasma capsulatum
■ Coccidioides immitis
Viruses17,33
DNA viruses
■ Hepadnaviridae (hepatitis B virus)
■ Herpesviridae (varicella zoster virus, epstein–Barr virus, cytomegalovirus)
■ Parvoviridae (parvovirus B19)95
■ Adenoviridae (adenovirus)
rNA viruses
■ retroviridae (Hiv)
■ Picornaviridae (coxsackievirus, echovirus, hepatitis A virus)
■ Flaviviridae (dengue virus, hepatitis C virus)
■ Paramyxoviridae (mumps virus, measles virus)
■ Bunyaviridae (hantavirus)
■ reoviridae (rotavirus)
parasitic infestations2,17
■ Malaria (Plasmodium falciparum, Plasmodium malariae)32,93,96
■ schistosomiasis (Schistosoma hematobium, Schistosoma mansoni)51,93
■ Toxoplasmosis (Toxoplasma gondii)93,97
■ Filariasis (Wuchereria bancrofti)93
■ Trichinosis (Trichinella spiralis)93
■ Hydatid disease (Echinococcus granulosus)98
■ Amoebiasis (Entamoeba histolytica)99
proliferation. 46 studies of asymptomatic household
members of affected patients indicated that subclini-
cal disease was 4–5 times more common than classic,
acute poststreptococcal glomerulonephritis.6,7 However,
volume 5 | maY 2009 | 261
 reviews

Romania Denmark Czech Republic Serbia Macedonia

Incidence 7.7 Incidence 7.54 Incidence 4.43 Incidence 0.95 Incidence 3.26
Prevalence 0.12113,b Prevalence 0.14117 Prevalence 0.04112 Prevalence 0.06114,b Prevalence 0.16111,b

France China
Incidence 0.6 Incidence 13.25
Prevalence 0.15101 Prevalence 0.04119

Italy Korea
Incidence 37 Incidence 6.00
Prevalence 0.06104 Prevalence 0.06102

Portugal Japan
Incidence 2.67 Incidence 25.0
Prevalence 1.01118 Prevalence 0.02116

USA Hong Kong

Incidence 0.78 Incidence 2.60
Prevalence 0.13a,c Prevalence 0.04107

Peru Thailand
Incidence 4.82 Incidence 2.00
Prevalence 0.06108,b Prevalence 0.04100,b

Brazil Australia
Incidence 22.86 Incidence 7.33
Prevalence 0.23109,b Prevalence 0.16115

Tunisia Nigeria Jordan Saudi Arabia India

Incidence 44.0 Incidence 0.90 Incidence 2.6 Incidence 25.0 Incidence 39.24
Prevalence 0.41106 Prevalence 0.04105 Prevalence 0.269 Prevalence 0.11110 Prevalence 10.14103,b

Figure 1 | estimates of the incidence and prevalence of postinfectious glomerulonephritis in selected countries, based on
data from biopsy studies published after 1985. incidence is given as cases per year; prevalence is given as cases per
100,000 population. aData from children. bData from adults. cData provided by Dr Tray Hunley, Division of Pediatric
Nephrology, vanderbilt Children’s Hospital, Nashville, TN, UsA.

70 –
Prevalence (cases per 100,000 population)

60 –

50 –

40 –

30 –
1976–1980

1981–1985

1986–1990

1987–1993

1996–2000

1967–1984

1985–1994

1973–1987

1988–1995

1971–1985

1986–2002

1959–1973

1999–2006

1980–1983

1984–1989

1990–1998
20 –
1971

1985

10 –

0–
France101,a Italy104,123,a Japan120,a Korea102,a India103,b USA121,124,c Singapore122,c Chile10,a
Date range (years)
Figure 2 | Global trends in the prevalence of postinfectious glomerulonephritis. aData from adults and children. bData from
adults. cData from children.

the incidence of sub clinical disease might be as much biopsy specimens. of the 10 specimens with healed
as 19 times greater than that of overt disease, according symptomatic poststreptococcal glomerulonephritis,
to a study of unrelated children by sagel et al.8 the rate four (40%) had focal segmental mesangial proliferation.
undoubtedly depends on how rigorously the diagnosis of note, 57 patients (5.6%) were classi fied as having
is pursued. the above-mentioned study by Haas et al.16 asymptom atic healed post streptococcal glomerulo-
included a thorough analysis of ultrastructural evidence nephritis with no apparent history of infection, 16
of poststreptococcal glomerulonephritis in 1,012 renal which supports the contention that poststreptococcal

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glomerulonephritis occurs much more frequently than
expected. most specimens that showed asymptomatic
poststreptococcal glomerulonephritis exhibited granu-
lar deposits of C3 (>90%) and igm (66%) on immuno-
fluorescence; deposition of other immunoglobulins
was rare.16
Differential diagnosis
in general, the diagnosis of acute glomerulonephritis is
straightforward; however, identification of the condi-
tion’s etiology is a challenge. the differential diagnosis
of acute postinfectious glomerulonephritis includes
several glomerulonephritides related to chronic infec-
tion, infectious glomerulonephritides without an
immune-mediated etiology, and other primary and
secondary glomerular diseases. Firstly, diseases other
than glomerulonephritis must be excluded since the
long-term prognosis and treatment of these disorders is
completely different. once the diagnosis of glomerulo-
nephritis has been established, the presence of a post-
infectious process is suggested by a clinical history of
infection, laboratory evidence of recent infection, and
the presence of transiently decreased activation of
complement via the alternative pathway. if the diagnosis
remains inconclusive, the typical pathologic findings of
subepithelial humps or exudative glomerulonephritis can
aid the final inference.
many non-immune-mediated glomerular syndromes
caused by infections can present clinically as acute
glomerulonephritis. these include hemolytic uremic
syndrome, which can be caused by Shigella dysenteriae
type i and Escherichia coli (o157:H7).49 Glomerular
embolism caused by infection can result in focal necrosis
and thrombus formation.28 large emboli that are typically
observed in fungal infections and endocarditis caused by
Streptococcus agalactiae or Hemophilus influenzae can be
associated with abrupt onset of renal infarction whereas
small emboli caused by organisms such as Gram-negative
cocci might be asymptomatic.17 Cortical microabscesses
and local infarction caused by microvascular emboli
result in the classic ‘flea-bitten’ kidney.28 Certain patho-
gens, such as Staphylococcus aureus, can precipitate or
exacerbate nephritis caused by antineutrophil cytoplasmic
antibodies (pauci-immune glomerulonephritis).50
Chronic, low-grade infection can lead to nephrito-
nephrotic syndrome that is accompanied by normal or
slowly declining renal function. the two major histo-
logic patterns associated with chronic infection are
membranoproliferative and membranous glomerulo-
nephritis. membranoproliferative changes are well
described in shunt nephritis, infective endocarditis,
nephritis associated with visceral abscesses (for example,
osteomyelitis, deep-seated abscesses and infected arte-
rial grafts), hepatosplenic schistosomiasis (Schistosoma
mansoni) and river blindness caused by Onchocerca
volvulus.2,17,28,31,48,51 membranous glomerulonephritis
tends to occur in malarial nephropathy, congenital
syphilis or early latent secondary syphilis, and Loa
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a b
c d
Figure 3 | Histologic patterns of postinfectious glomerulonephritis as seen on light
microscopy of renal biopsy samples. a | Diffuse exudative proliferation without
crescents: numerous neutrophils are lodged in the glomerular capillary lumens
and the numbers of endothelial cells and mesangial cells are increased
(hematoxylin–eosin stain; magnification ×400). b | Diffuse endocapillary
proliferation with segmental crescents: a segmental cellular crescent (arrow) has
compressed the glomerular tuft; the tuft is filled with leukocytes and proliferating
endothelial cells (hematoxylin–eosin stain; magnification ×400). c | Mesangial
proliferation: the mesangium is prominent, with increased cellularity. A few
neutrophils can be seen in some capillary lumens (hematoxylin–eosin stain;
magnification ×400). d | Membranoproliferative glomerulonephritis: prominent
lobulation is observed, with confluent deposition of eosinophilic material (arrows)
along the capillary wall. infiltrating neutrophils are present (hematoxylin–eosin
stain; magnification ×400).
loa infection.2,17,31,32,48 Glomerular amyloidosis associ-
ated with amyloid a can cause nephrotic syndrome in
patients whose immune system is chronically activated
as a result of longstanding infection, particularly bron-
chiectasis, osteomyelitis, hepatosplenic schistosomiasis,
leprosy, and tuberculosis, and occasionally leishmaniasis
and filariasis.31,42,48,51–54
Pathogenesis
a variety of infections have clinicopathologic presenta-
tions that are similar to those of poststreptococcal
glomerulonephritis, which suggests a marked overlap
exists among the molecular and cellular responses to
these pathogens. this idea has been widely explored
in the past few decades, and reviewed elsewhere.55,56 By
sharp contrast, the nature of the initial pathogenic insult
remains largely unknown despite extensive exploration,
particularly in poststreptococcal glomerulonephritis.
this lack of knowledge might reflect the difficulty of
developing appropriate animal models, along with the fact
that humans are the only host and reservoir of group a
streptococci.57 the fundamental pathogenic mechanism
of postinfectious glomerulonephritis is believed to be
the deposition of immune complexes within glomerular
tufts; this deposition resembles that seen in experimental
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 reviews

a b c

Figure 4 | Patterns of complement C3 immunofluorescence observed in renal biopsy samples from patients with
postinfectious glomerulonephritis. a | Mesangial pattern: mesangial C3 deposits are present, particularly toward the
axial region of the glomerulus. b | Capillary wall (‘garland’) pattern: heavy C3 deposits are present along the glomerular
basement membrane. c | Diffuse (‘starry sky’) pattern: many small deposits of C3 are present along the
glomerular basement membrane and in the mesangium. Magnification ×400.

acute serum sickness glomerulonephritis in rabbits.55,56
However, a role of cellular immunity in postinfectious
glomerulonephritis, especially the contribution of
delayed-type hypersensitivity to macrophage infiltration,
cannot be entirely excluded.55 moreover, the interplay of
cellular immunity with innate and humoral immunity is
important in cases of glomerulonephritis associated with
intracellular viruses and parasites.1,31,56
Despite an intensive search during the past half
century, the pathologic antigens or factors responsible
for poststreptococcal glomerulonephritis remain obscure.
m protein has been discounted as the nephritogenic
antigen because, in addition to the increasing number of
m-serotype strains that are nephritogenic (m-serotypes
1, 2, 4, 12, 18, 42, 49, 56, 57 and 60), some m-type strains
are not nephritogenic.18,55,57 this observation contrasts
with the notion of a single nephritogenic antigen that
confers long-lasting immunity,58 which is based on the
observation that repeated episodes of poststreptococcal
glomerulonephritis are extremely rare.58 two other anti-
gens, streptococcal glyceraldehyde phosphate dehydro-
genase (GaDPH; also known as nephritis-associated
plasmin receptor or preabsorbing antigen)18,59,60 and
streptococcal cationic proteinase exotoxin B (speB; also
known as nephritis-strain-associated protein [nsaP]
or nephritis plasmin-binding protein [nPBP]),18 with
its zymogen precursor, have each been proposed by two
groups of investigators from opposite parts of the world
as the long-sought-after pathogenic antigen.18,58,60–63 Both
antigens activate the glomerular alternative complement
pathway, which results in the low plasma C3 levels that are
a feature of acute postinfectious glomerulonephritis, and
both have an affinity for glomerular structural proteins
and plasmin.18,60 antibodies to GaDPH and speB (or
zymogen) have been found specifically in patients with
poststreptoccocal glomerulonephritis and persist for at
least 10 years and 1 year, respectively, after the acute attack,
which indicates that immunity is long-lasting.58 the
speB gene and the gene that encodes GaDPH are highly
conserved among isolates of group a streptococci.64
Glomerular binding and plasmin activation are con-
sidered key pathogenic properties.18,56,60 when depos-
ited in glomeruli, GaDPH, speB or zymogen (whether
bound by specific antibody or not), can interact with
plasmin or plasminogen to cause glomerular damage
by degrading the GBm through the activation of latent
metalloproteinases or collagenases (Figure 5).18 the cir-
culating or in situ immune complexes can then move
across the altered GBm and accumulate as ‘humps’ in
the subepithelial space.18,59,60,65 without the capacity to
degrade the negatively charged GBm, the anionic protein
GaDPH would be repelled by the GBm and could not
lodge in the subepithelial area.18 By contrast, the rela-
tively cationic antigen speB or zymogen tends to easily
permeate the GBm.55,66
speB or zymogen can directly cause tissue destruc-
tion by cleaving extracellular matrix proteins includ-
ing fibronectin and vitronectin, and might aggravate
inflammation via superantigenic effects on the immune
system.55–57 similar to staphylococcal enterotoxins a
and C, streptococcal superantigens such as speB or
zymogen are mitogenic for certain t-cell subsets but
do not require processing by antigen-presenting cells to
activate this property.57 speB or zymogen binds directly
to major histocompatibility complex class ii proteins
on the membrane of antigen-presenting cells as well as
to the specific vβ chain of t cell receptors,67 which causes
proliferation and massive activation of t cells.55,56 this
activation liberates copious amounts of tH1 cytokines,
such as interleukins, interferon γ, and tumor necrosis
factor, which can elicit local production of antibodies
that are specific for speB or zymogen and lead to in situ
formation of immune complexes and aggravation of
glomerular inflammation.57,67
although activation of plasmin and of the local
alternative complement pathway by both of these so-
called nephritogenic antigens has been demonstrated,
doubts persist about the pathogenic role of these mol-
ecules. Both antigens can be found in strains of group a
strepto cocci that rarely cause glomerulonephritis. 57

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the notion that either of these antigens causes post-
streptococcal glomerulonephritis cannot explain the
variation between patients in the risk of developing acute
glomerulonephritis after infection with group a strepto-
cocci (which can range from 1–2% to as much as 33%)
and in the clinical presentation of the disease.61 Beres and
co-workers unexpectedly discovered that the gene
encoding speB was absent from the Streptococcus equi
zooepidemicus strain that was responsible for an outbreak
of glomerulonephritis in Brazil between 1998 and 1999.64
these lines of evidence suggest that no single antigen is
the sole cause of poststreptococcal glomerulonephritis in
all patients. individual susceptibility, possibly determined
by the host’s genetic factors, might have a huge influence
on the pathogenicity of the precipitating organism.61
Prognosis
the prognosis of patients with acute poststreptococcal
glomerulonephritis is largely influenced by the specific
presentation and histopathology.22 Crescentic glomerulo-
nephritis and the ‘garland’ immunofluorescence pattern
carry a poorer outcome than other pathologic pat-
terns.34,36,38,39,45 However, other factors such as age, type
of pathogen, and coexisting diseases, including diabetes
and cardiovascular or liver disease, can also influence
the prognosis.19,21,37
multiple studies with long-term follow-up, includ-
ing two large studies conducted after epidemics of
infection with Group a streptococci in trinidad68 and
venezuela,69 have shown that the majority of children
and adults with the epidemic form of poststreptococcal
glomerulonephritis have an excellent prognosis.10,13 none
developed renal insufficiency, and early mortality during
hospitalization was less than 1%.13,68–72 However, 3.5–
21.1% of patients developed persistent urine abnormali-
ties or hypertension (table 1). Conversely, up to 60% of
adults with sporadic infections experience progressive
irreversible renal damage.25,73–77
sporadic infections tend to have a graver prognosis
than epidemic infections, probably because sporadic
cases are recognized only when symptoms develop. in
studies of sporadic and symptomatic cases performed
after 1980, the long-term prognosis of sporadic cases was
almost always poor, and complete remission rates ranged
from 40% to 74%.25,39,73,76 worldwide, biopsy studies indi-
cate that 0–36% of patients died, 2–34% progressed to
end-stage renal disease (esrD) (table 2), 27–58% had
persistent renal dysfunction, and 28–64% recovered
completely.3,19,20,23 Patients older than 60 years of age who
develop sporadic poststreptococcal glomerulonephritis
seem to have a particularly poor prognosis, perhaps
because they are more likely to have crescent formation.37
approximately one-quarter of these individuals achieve
complete remission.37
not all epidemic cases of poststreptococcal
glomerulonephritis have a favorable outcome. this
is especially true of those that are not associated with
group a streptococci. the largest series of patients
nature reviews | nephrology
© 2009 Macmillan Publishers Limited. All rights reserved
reviews
Urinary space Effaced
Podocyte podocyte ‘Hump’
foot processes foot process deposits
Protein
e loss
GBM
Endothelial layer d
Negative c
charge
a Collagenase MMP
Antibody b
Nephritogenic
antigen Pro- Latent
collagenase MMP
Plasmin or
plasminogen
Figure 5 | Possible pathogenic mechanism of poststreptococcal
glomerulonephritis. a | The putative nephritogenic antigens speB or zymogen and
GADPH are normally repelled in both their free and antibody-bound forms by the
negatively charged GBM. b | However, these antigens can interact with plasmin or
plasminogen to activate procollagenase and latent MMPs. c | The active enzymes
(and the nephritogenic antigen itself, in the case of speB or zymogen) degrade the
GBM, and abolish its negative charge. d | The nephritogenic antigen and immune
complexes can then pass through the damaged GBM and form the characteristic
‘hump’-like deposits under the podocyte processes. e | Damage to the GBM also
causes effacement of podocyte foot processes, which leads to loss of protein in
the urine. Abbreviations: GADPH, streptococcal glyceraldehyde phosphate
dehydrogenase; GBM, glomerular basement membrane; MMP, matrix
metalloproteinase; speB, streptococcal cationic proteinase exotoxin B.
with poststreptococcal glomerulonephritis not caused
by group a streptococci was examined following an
outbreak of Streptococcus equi zooepidemicus in nova
serrana, Brazil, during 1997–1998. after a mean follow-
up of 5.4 years, affected patients exhibited an unusually
high prevalence of renal abnormalities (57%).78 notably,
most cases of glomerulonephritis (>90%) were in adults.
white and colleagues70 conducted a long-term study of
aboriginal children in australia who had experienced an
epidemic of poststreptococcal glomerulonephritis. after
a mean of 14.6 years (range 6–18 years) of follow-up, the
investigators found that individuals with a history of
poststreptococcal glomerulonephritis in childhood had
a risk of overt proteinuria more than six times greater
than that of healthy controls after adjustment for age, sex,
and birth weight (95% Ci 2.2–16.9).79 these data indicate
that overt proteinuria in this population might in many
cases be attributable to childhood post streptococcal
glomerulonephritis, and raise the hypothesis that post-
streptococcal glomerulonephritis might be an important
cause of esrD in high-risk populations.79
Patients with diabetes also have a poor prognosis. the
largest study of patients with diabetes and poststreptococcal
glomerulonephritis was carried out by nasr et al.19 the
pooled data indicated that 17 of 26 patients (65%) devel-
oped esrD, 3 developed persistent renal dysfunction, 1
died shortly after diagnosis of glomerulonephritis, and only
3 experienced complete remission of glomerulonephritis.19
volume 5 | maY 2009 | 265
 reviews

Table 1 | Follow-up studies of patients with symptomatic non-biopsy-confirmed postinfectious glomerulonephritis 76,a
Study Country number of patients Follow-up Incidence of any Incidence
(years) persistent of CKD (%)
abnormalityb (%)
Sporadic
Lewy et al. (1971)77 UsA 21 (mainly children) 5 24 Nr
Dodge et al. UsA 54 (mainly children 2–5 19.6 2
(1973)125
Hinglais et al. France 65 (adults and children) 1–14 5 (children) 2
(1974)39 30 (adults)
roy et al. (1976)126 UsA 35 (mainly children) 4–12 17.1 0
Lien et al. (1979)25 Australia 57 (adults and children) 1–14 26 Nr
Baldwin et al. UsA 176 (adults and children) 2–19 60 9
(1980)73
singhal et al. india 144 (adults and children) 10 Nr 19
(1982)74
vogl et al. (1985)76 Germany, 137 (adults and children) 2–13 29 (children) 2
Luxembourg, Austria 41 (adults)
Clark et al. (1988)75 UK 36 (mainly children) 14.6–22 20 0
Endemic and epidemic
Nissenson et al. Trinidad 534 (adults and children) 12–17 3.5 0.2
(1979)72; Potter
et al. (1982)68
white et al. Australia (Aboriginal 61 (mainly children) 6–18 32 0
(2001)70 coastal community)
Epidemic
Perlman et al. UsA (indian 61 (mainly children) 10 18.3 0
(1965)71 reservation)
Garcia et al. venezuela 71 (adults and children) 11–12 21.1 1
(1981)69
sarkissian et al. Armenia 474 (mainly children) 0–1 3 0
(1997)13
sesso et al. Brazil 56 (adults and children) 5–6 57 49 (GFr
(2005)78 <80 ml/min) 15
(GFr <60 ml/min)
Most cases were acute poststreptococcal glomerulonephritis. bDefined as urinary abnormalities or hypertension. Abbreviations: CKD, chronic kidney disease;
a

GFr, glomerular filtration rate; Nr, not reported.

Table 2 | incidence and outcomes of biopsy-confirmed non-epidemic postinfectious glomerulonephritis

Study Country period number of patients Biopsy Age (years; Months of Incidence Mortality
incidence median [range] follow-up of eSrD (%) (%)
(%) or mean ± SD) (mean)
Nasr et al.19 (2008) UsA 1995–2005 86 (alcoholism 2%, 0.6 56 ± 16 3–120 (25) 17 5
diabetes 29%)
Montseny et al.3 France 1976–1993 76 (alcoholism 30%, 4.6 48 ± 17 1–108 8 11
(1995) diabetes 8%)
Keller et al.20 Germany 1984–1993 30 (alcoholism 57%) 4.5 49 (17–77) 1–76 (12.5) 4 4
(1994)
Moroni et al.21 italy 1979–1999 50 (alcoholism 12%, 1.7 54 (29.5–65.7) 20–138 (90) 10 10
(2002) diabetes 10%)
richmond et al.22 New 1970–1987 41 Nr 36.3 (14–72) 1–182 (161) 34 36
(1990) Zealand
srisawat et al.23 Thailand 1999–2005 36 (alcoholism 4%, 4.3 47 (15–80) 2–65 11 0
(2006); diabetes 12%)
Kanjanabuch
et al.100 (2005)
Adapted from Nasr et al.19 Abbreviations: esrD, end-stage renal disease; Nr, not reported.

266 | MAY 2009 | voluMe 5 www.nature.com/nrneph

© 2009 Macmillan Publishers Limited. All rights reserved

 reviews

of note, Staphylococcus aureus was the dominant patho-
gen, and was frequently associated with deposition of
iga and large subepithelial humps.19
Treatment and prevention
treatment of acute postinfectious glomerulonephritis has
tended to be supportive. in general, the disease resolves
without specific eradication of the infectious insult.
However, glomerulonephritis secondary to some infec-
tions including Staphylococcus aureus,19 brucellosis,30 and
schistosomiasis51 can progress in spite of eradication of
the organism. in this situation, the cascade of glomer-
ular inflammatory events continues despite removal
of the triggering insult. treatment with corticosteroids
or cytotoxic agents might have a role in these circum-
stances36,38,43,44,80–82 and immunosuppressant and anti-
coagulant drugs have also been advocated.83,84 However,
randomized clinical trials have not been performed to
test these agents in this setting.
the measures that have been proven efficacious
in prevention of streptococcal endocarditis 28 would
presumably be similarly efficacious in prevention of
glomerulonephritis secondary to infection with group a
streptococci. the risk of developing glomerulonephritis
after infection with nephritogenic strains of group a
strepto cocci has been calculated to be as high as 15%
during epidemics.85 early eradication of pharyngitis-
associated group a streptococci by use of antibiotics
not only prevents the transmission of nephrito genic
strains during epidemics,79,86 but also protects against
glomerulonephritis.87 outbreaks of group a strepto-
coccal infection and the incidence of poststreptococcal
glomerulonephritis in us army trainees have both con-
sistently declined since the introduction of benzathine–
penicillin prophylaxis during epidemics of Streptococcus
infection in 1985. only one episode of poststreptococcal
glomerulonephritis was reported after 1985.88,89 the
efficacy of this benzathine–penicillin regimen in pre-
venting outbreaks of streptococcal infection and post-
streptococcal glomerulonephritis has been shown in
other studies.90,91 However, antibiotic prophylaxis is not
generally necessary as poststreptococcal glomerulo-
nephritis usually resolves without eradication of the
infectious insult, and recurrence is rare.1,58
Conclusions
the epidemiology of postinfectious glomerulonephritis
has changed considerably during recent decades,
especially in developed countries. nowadays, non-
streptococcal infections, including staphylococcal and
Gram-negative bacillary infections, are known to cause
postinfectious glomerulonephritis, particularly in adults
who are immunocompromised. the pathogenesis of
postinfectious glomerulonephritis requires further study,
but a single causative antigen is unlikely to be found. in
addition to classic poststreptococcal glomerulonephritis,
various renal histopathologic profiles have been defined,
including extra capillary proliferation, membrano-
proliferative glomerulonephritis, and even pure mesan-
gial proliferation. the clinical spectrum of postinfectious
glomerulonephritis is similarly variable: some cases
present with anuria and a rapidly rising serum creatinine
level, whereas others are detected on the basis of inci-
dental urinary findings. the majority of epidemic cases
have an excellent prognosis, but outcomes are less favor-
able in elderly people and in patients with underlying
conditions, who might progress to esrD. treatment is
generally supportive unless renal dysfunction progresses
after eradication of the causative infection.
Review criteria
Material for this article was found by searching
PubMed and MeDLiNe using the terms “postinfectious
glomerulonephritis”, “poststreptococcal
glomerulonephritis”, “infectious glomerulonephritis”
and “renal biopsy”, as well as terms related to individual
organisms in conjunction with “glomerular disease”,
“glomerulopathy”, “nephropathy”, “nephritis”, or
“glomerulonephritis”. The search was restricted to
papers published in english or French after 1965.

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Acknowledgments
The authors thank Pornpen Panomwan, Msc for her
assistance in epidemiologic analyses. This work was
supported by a grant from the Thailand research
Fund (MrG500016). T. Kanjanabuch is supported in
part by the Grants for Development of New Faculty
staff ratchadapiseksompotch Fund, Faculty of
Medicine, Chulalongkorn University, and the National
research Council of Thailand.
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