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An update on acute postinfectious glomerulonephritis

worldwide. Nat Rev Nephrol 5:259-269
ARTICLE in NATURE REVIEWS NEPHROLOGY JUNE 2009
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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, 259269 (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 socalled Bright disease after scarlet fever had albuminous 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 exudation. at that time, poststreptococcal glomerulonephritis
was thought to be a benign condition with a good prognosis and a limited clinical spectrum, in which the classic
presentation involved abrupt onset of acute nephritis
(within 13 weeks) following an overt skin or pharyngeal streptococcal infection.1 the subsequent realization that the disease can be caused by organisms other
than group a streptococci, including other strains of
streptococci (groups C and G), staphylococci, Gramnegative bacilli, mycobacteria, parasites, fungi, and
viruses (Box 1) led to the introduction of the alternative 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 manifestations 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
approximately 24.3 cases per 100,000 person-years in
adults and 2 cases per 100,000 person-years in children,
in contrast to 6 and 0.3 cases per 100,000 person-years,
respectively, in developed regions. all these statistics
are likely to be under-estimations by several fold, since
most of the studies assessed included only symptomatic
patients.5 subclinical disease is thought to be 419 times
more common than symptomatic disease,68 and in some
developing countries, postinfectious glomerulonephritis
remains the most common cause of acute nephritic
syndrome in children, among whom it accounts for
5090% of cases.911 indeed, in 2008, rodriguez-iturbe
and musser 5 calculated an annual incidence of poststreptococcal glomerulonephritis in the developing
world that was higher than that of Carapetis and colleagues (9.528.5 cases per 100,000 person-years).
rodriguez-iturbe and musser based their calculation on
nature reviews | nephrology
Kidney & Metabolic

Disorders research
Center
(T Kanjanabuch),
Division of Nephrology
(T Kanjanabuch,
S eiam-ong),
Department of
Pathology
(W Kittikowit),
Chulalongkorn
University, Bangkok,
Thailand.
Correspondence:
s eiam-Ong, Division
of Nephrology,
Department
of Medicine,
Chulalongkorn
University, Bangkok
10330, Thailand
somchai80754@
yahoo.com
volume 5 | maY 2009 | 259

2009 Macmillan Publishers Limited. All rights reserved
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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 developing 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 prevalence of the disease has tended to decline throughout
the globe over the past few decades, especially in the
developed world4,10,1220 (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 diabetes.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 glomerulonephritis occurs primarily in children (aged 610 years10)
and young adults, with a male predominance of
23:1.1,13,17,18 nowadays, patients in the developed world,
especially europe and the us, tend to be adults.3,1923
individuals with comorbidities such as diabetes and alcoholism are at increased risk of developing the disease;3,1921
one-third of individuals with postinfectious glomerulonephritis have one or two of these comorbidities.19 onethird 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 characteristics of the invading organism. the same organism can
produce different pathological features, including diffuse,
exudative proliferation without crescents (Figure 3a);

diffuse, endocapillary proliferation with crescents
(Figure 3b); mild, segmental, mesangial proliferation
(Figure 3c); and membranoproliferative glomerulonephritis (Figure 3d).19 thus, a wide spectrum of clinical presentations is observed even within an epidemic
in any given population. However, three major patterns 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 syndrome. the typical patient with acute nephritic poststreptococcal glomerulonephritis is a child who abruptly
develops puffiness of the eyelids and edema after infection, followed by smoky and scanty urine and increasing
blood pressure. anuria and nephrotic-range proteinuria 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 pneumonia29), protozoa3032 and viruses33 have also been linked
to the disease.
Histopathologic investigation usually reveals
diffuse cellular proliferation and an exudate that contains many neutrophils and monocytes, with variable
degrees of immunoglobulin and complement deposits.19 immunofluorescence commonly reveals granular deposition of complement C3, often with igG and
occasionally with igm; iga deposition is rare, except in
patients with diabetesparticularly those with staphylococcal 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 immunofluorescence 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 resolution 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 mesangial and subendothelial areas of kidneys with acute
nephritic postinfectious glomerulonephritis. However,
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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 poststreptococcal form, is complicated by rapidly rising
azotemia.13 such cases are diagnosed as rapidly progressive 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 individuals, which increases their susceptibility to the formation 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 organisms, 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 proliferation or focal segmental endocapillary proliferation with
granular, mesangial deposits of igm, C3, and occasionally 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 histological abnormalities of the glomeruli, ranging from
mild mesangial hypercellularity to diffuse mesangial
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, epsteinBarr 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 subclinical disease was 45 times more common than classic,
acute poststreptococcal glomerulonephritis.6,7 However,
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Romania
Incidence 7.7
Prevalence 0.12113,b
Denmark
Incidence 7.54
Prevalence 0.14117
Czech Republic
Incidence 4.43
Prevalence 0.04112
Serbia
Incidence 0.95
Macedonia
Incidence 3.26
France
Incidence 0.6
Prevalence 0.15101
China
Incidence 13.25
Prevalence 0.04119
Italy
Incidence 37
Prevalence 0.06104
Korea
Incidence 6.00
Prevalence 0.06102
Portugal
Incidence 2.67
Prevalence 1.01118
Japan
Incidence 25.0
Prevalence 0.02116
USA
Incidence 0.78
Prevalence 0.13a,c
Hong Kong
Incidence 2.60
Prevalence 0.04107
Peru
Incidence 4.82
Thailand
Incidence 2.00
Brazil
Incidence 22.86
Australia
Incidence 7.33
Prevalence 0.16115
Tunisia
Incidence 44.0
Prevalence 0.41106
Nigeria
Incidence 0.90
Prevalence 0.04105
Jordan
Incidence 2.6
Prevalence 0.269
Saudi Arabia
Incidence 25.0
Prevalence 0.11110
India
Incidence 39.24
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 Childrens Hospital, Nashville, TN, UsA.
60
50
19901998
19841989
19801983
1985
1971
19992006
19591973
19862002
19711985
19881995
19731987
19851994
19671984
19962000
19871993
20
19861990
30
19811985
40
19761980
Prevalence (cases per 100,000 population)
70
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

as 19 times greater than that of overt disease, according
to a study of unrelated children by sagel et al.8 the rate
undoubtedly depends on how rigorously the diagnosis
is pursued. the above-mentioned study by Haas et al.16
included a thorough analysis of ultrastructural evidence
of poststreptococcal glomerulonephritis in 1,012 renal
biopsy specimens. of the 10 specimens with healed

symptomatic poststreptococcal glomerulonephritis,
four (40%) had focal segmental mesangial proliferation.
of note, 57 patients (5.6%) were classi fied as having
asymptom atic healed post streptococcal glomerulonephritis with no apparent history of infection, 16
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 granular deposits of C3 (>90%) and igm (66%) on immunofluorescence; deposition of other immunoglobulins
was rare.16
Differential diagnosis
in general, the diagnosis of acute glomerulonephritis is

straightforward; however, identification of the conditions etiology is a challenge. the differential diagnosis
of acute postinfectious glomerulonephritis includes
several glomerulonephritides related to chronic infection, 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 glomerulonephritis has been established, the presence of a postinfectious 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 pathogens, 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 nephritonephrotic syndrome that is accompanied by normal or
slowly declining renal function. the two major histologic patterns associated with chronic infection are
membranoproliferative and membranous glomerulonephritis. membranoproliferative changes are well
described in shunt nephritis, infective endocarditis,
nephritis associated with visceral abscesses (for example,
osteomyelitis, deep-seated abscesses and infected arterial 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
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
(hematoxylineosin 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 (hematoxylineosin stain; magnification 400). c | Mesangial
proliferation: the mesangium is prominent, with increased cellularity. A few
neutrophils can be seen in some capillary lumens (hematoxylineosin 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 (hematoxylineosin
stain; magnification 400).
loa infection.2,17,31,32,48 Glomerular amyloidosis associated with amyloid a can cause nephrotic syndrome in
patients whose immune system is chronically activated
as a result of longstanding infection, particularly bronchiectasis, osteomyelitis, hepatosplenic schistosomiasis,
leprosy, and tuberculosis, and occasionally leishmaniasis
and filariasis.31,42,48,5154
Pathogenesis
a variety of infections have clinicopathologic presentations 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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a
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 antigens, streptococcal glyceraldehyde phosphate dehydrogenase (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.18,58,6063 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 considered key pathogenic properties.18,56,60 when deposited 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 circulating 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 relatively cationic antigen speB or zymogen tends to easily
permeate the GBm.55,66
speB or zymogen can directly cause tissue destruction by cleaving extracellular matrix proteins including fibronectin and vitronectin, and might aggravate
inflammation via superantigenic effects on the immune
system.5557 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 v 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 , 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 socalled nephritogenic antigens has been demonstrated,
doubts persist about the pathogenic role of these molecules. 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 poststreptococcal glomerulonephritis cannot explain the
variation between patients in the risk of developing acute
glomerulonephritis after infection with group a streptococci (which can range from 12% 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 hosts genetic factors, might have a huge influence
on the pathogenicity of the precipitating organism.61
Urinary space
Hump
deposits
Endothelial layer
Negative
charge
a
Protein
loss
GBM
c
Collagenase MMP
Antibody
Nephritogenic
antigen
Prognosis
the prognosis of patients with acute poststreptococcal

glomerulonephritis is largely influenced by the specific
presentation and histopathology.22 Crescentic glomerulonephritis and the garland immunofluorescence pattern
carry a poorer outcome than other pathologic patterns.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, including 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%.13,6872 However, 3.5
21.1% of patients developed persistent urine abnormalities or hypertension (table 1). Conversely, up to 60% of
adults with sporadic infections experience progressive
irreversible renal damage.25,7377
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 indicate that 036% of patients died, 234% progressed to
end-stage renal disease (esrD) (table 2), 2758% had
persistent renal dysfunction, and 2864% 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
Effaced
podocyte
foot process
Podocyte
foot processes
ProLatent
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 19971998. after a mean followup 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 618 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 2.216.9).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 poststreptococcal 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%) developed 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
(years)
Incidence of any
persistent
abnormalityb (%)
Incidence
of CKD (%)
Lewy et al. (1971)77
UsA
21 (mainly children)
24
Nr
Dodge et al.
(1973)125
UsA
54 (mainly children
25
19.6
Hinglais et al.
(1974)39
France
65 (adults and children)
114
5 (children)
30 (adults)
roy et al. (1976)126
UsA
412
17.1
Lien et al. (1979)25
Australia
114
26
Nr
Baldwin et al.
(1980)73
UsA
219
60
singhal et al.
(1982)74
india
10
Nr
19
vogl et al. (1985)76
Germany,
Luxembourg, Austria
213
29 (children)
41 (adults)
Clark et al. (1988)75
UK
14.622
20
Nissenson et al.
(1979)72; Potter
et al. (1982)68
Trinidad
1217
3.5
0.2
white et al.
(2001)70
Australia (Aboriginal
coastal community)
618
32
Perlman et al.
(1965)71
UsA (indian
reservation)
10
18.3
Garcia et al.
(1981)69
venezuela
1112
21.1
sarkissian et al.
(1997)13
Armenia
01
sesso et al.
(2005)78
Brazil
56
57
49 (GFr
<80 ml/min) 15
(GFr <60 ml/min)
Sporadic
Endemic and epidemic
Epidemic
Most cases were acute poststreptococcal glomerulonephritis. bDefined as urinary abnormalities or hypertension. Abbreviations: CKD, chronic kidney disease;
GFr, glomerular filtration rate; Nr, not reported.
a
Table 2 | incidence and outcomes of biopsy-confirmed non-epidemic postinfectious glomerulonephritis

Study
Country
period
number of patients
Biopsy
incidence
(%)
Age (years;
median [range]
or mean SD)
Months of
follow-up
(mean)
Incidence
of eSrD (%)
Mortality
(%)
Nasr et al.19 (2008)
UsA
19952005
86 (alcoholism 2%,
diabetes 29%)
0.6
56 16
3120 (25)
17
Montseny et al.3
(1995)
France
19761993
76 (alcoholism 30%,
diabetes 8%)
4.6
48 17
1108
11
Keller et al.20
(1994)
Germany
19841993
30 (alcoholism 57%)
4.5
49 (1777)
176 (12.5)
Moroni et al.21
(2002)
italy
19791999
50 (alcoholism 12%,
diabetes 10%)
1.7
54 (29.565.7)
20138 (90)
10
10
richmond et al.22
(1990)
New
Zealand
19701987
41
Nr
36.3 (1472)
1182 (161)
34
36
srisawat et al.23
(2006);
Kanjanabuch
et al.100 (2005)
Thailand
19992005
36 (alcoholism 4%,
diabetes 12%)
4.3
47 (1580)
265
11
Adapted from Nasr et al.19 Abbreviations: esrD, end-stage renal disease; Nr, not reported.
266 | MAY 2009 | voluMe 5
reviews
of note, Staphylococcus aureus was the dominant pathogen, 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 infections including Staphylococcus aureus,19 brucellosis,30 and
schistosomiasis51 can progress in spite of eradication of
the organism. in this situation, the cascade of glomerular inflammatory events continues despite removal
of the triggering insult. treatment with corticosteroids
or cytotoxic agents might have a role in these circumstances36,38,43,44,8082 and immunosuppressant and anticoagulant 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 pharyngitisassociated 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 streptococcal infection and the incidence of poststreptococcal
glomerulonephritis in us army trainees have both consistently 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 benzathinepenicillin regimen in preventing outbreaks of streptococcal infection and poststreptococcal glomerulonephritis has been shown in
1.
2.
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Couser, w. G., Johnson, r. J. & Alpers, C. e. in

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glomerulonephritis. experience with 76 patients
and review of the literature. Medicine (Baltimore)
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A prospective study. Lancet 1, 401403 (1981).
other studies.90,91 However, antibiotic prophylaxis is not

generally necessary as poststreptococcal glomerulonephritis 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, nonstreptococcal 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, membranoproliferative glomerulonephritis, and even pure mesangial 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 incidental urinary findings. the majority of epidemic cases
have an excellent prognosis, but outcomes are less favorable 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,
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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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An update on acute postinfectious glomerulonephritis

67 PUBLICATIONS 822 CITATIONS

160 PUBLICATIONS 1,241 CITATIONS

Available from: Talerngsak Kanjanabuch

Postinfectious glomerulonephritis is an immunologic

glomerulonephritis has evolved in other ways. this review

Postinfectious glomerulonephritis is an important health

nature reviews | nephrology

Kidney & Metabolic

volume 5 | maY 2009 | 259

Pathology and clinical manifestations

the glomerular response to acute infection is variable

exudative proliferation without crescents (Figure 3a);

Acute nephritic syndrome

260 | MAY 2009 | voluMe 5

rapidly progressive nephritic syndrome

Box 1 | infections associated with postinfectious glomerulonephritis1,2

proliferation. 46 studies of asymptomatic household

nature reviews | nephrology

volume 5 | maY 2009 | 261

Prevalence (cases per 100,000 population)

Date range (years)

the incidence of sub clinical disease might be as much

biopsy specimens. of the 10 specimens with healed

262 | MAY 2009 | voluMe 5

in general, the diagnosis of acute glomerulonephritis is

Figure 3 | Histologic patterns of postinfectious glomerulonephritis as seen on light

nature reviews | nephrology

volume 5 | maY 2009 | 263

acute serum sickness glomerulonephritis in rabbits.55,56

264 | MAY 2009 | voluMe 5

the prognosis of patients with acute poststreptococcal

Figure 5 | Possible pathogenic mechanism of poststreptococcal

with poststreptococcal glomerulonephritis not caused

nature reviews | nephrology

volume 5 | maY 2009 | 265

Lewy et al. (1971)77

65 (adults and children)

roy et al. (1976)126

Lien et al. (1979)25

57 (adults and children)

176 (adults and children)

144 (adults and children)

vogl et al. (1985)76

137 (adults and children)

Clark et al. (1988)75

534 (adults and children)

71 (adults and children)

474 (mainly children)

56 (adults and children)

Endemic and epidemic

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

Nasr et al.19 (2008)

266 | MAY 2009 | voluMe 5

Treatment and prevention

treatment of acute postinfectious glomerulonephritis has

Couser, w. G., Johnson, r. J. & Alpers, C. e. in

other studies.90,91 However, antibiotic prophylaxis is not

the epidemiology of postinfectious glomerulonephritis

Dodge, w. F., spargo, B. H. & Travis, L. B.

nature reviews | nephrology

association with the T1 subtype of group A

volume 5 | maY 2009 | 267