Acute poststreptococcal glomerulonephritis: an update

Sun-Young Ahn and Elizabeth Ingulli

Department of Pediatrics, University of California, San
Diego and Rady Childrens Hospital, La Jolla,
California, USA
Correspondence to Elizabeth Ingulli, MD, Department
of Pediatrics, University of California, San Diego and
Rady Childrens Hospital, 9500 Gilman Drive, MC
0815, La Jolla, CA 92093-0815, USA
Tel: +1 858 822 4906; fax: +1 858 822 5421;
e-mail: eingulli@ucsd.edu

Current Opinion in Pediatrics 2008, 20:157162

Purpose of review
Acute poststreptococcal glomerulonephritis, the most common form of acute
glomerulonephritis in children, continues to be a major concern worldwide. This review
summarizes the recent advances in the pathogenesis, host susceptibility factors,
diverse clinical presentations, and treatment of the condition.
Recent findings
Several recent advances have been made in identifying streptococcal antigens that may
play a pathogenic role in acute poststreptococcal glomerulonephritis. Nephritisassociated streptococcal plasmin receptor and streptococcal pyrogenic exotoxin B are
currently considered major putative nephritogens. Host susceptibility factors including
HLA-DRB103011 have been found at a higher frequency in acute poststreptococcal
glomerulonephritis patients than in healthy controls. Reversible posterior
leukoencephalopathy and autoimmune hemolytic anemia are newly reported
clinical associations with the disease. Studies from developing countries question
whether the outcome is always benign. Treatment remains mostly conservative;
however, controversy exists over the use of aggressive therapy with poor prognostic
factors.
Summary
Severe group A streptococcal disease including acute poststreptococcal
glomerulonephritis remains a cause of morbidity and mortality in developing countries
and among impoverished populations. Various reports on the diverse clinical
manifestations that can be associated with the condition will aid physicians in prompt
diagnosis and intervention, while studies focusing on better understanding of
immunopathogenesis may facilitate vaccine development and prevention.
Keywords
diagnosis, outcome, pathogenesis, poststreptococcal glomerulonephritis, treatment
Curr Opin Pediatr 20:157162
2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1040-8703

Introduction
Group A b-hemolytic streptococcus (GAS) infection is
most common in children and causes a wide spectrum of
diseases, ranging from the more common superficial
infections to invasive diseases and postinfectious sequelae including glomerulonephritis [1]. It has been estimated that over 470 000 cases of acute poststreptococcal
glomerulonephritis (APSGN) occur each year worldwide,
with 97% occurring in less developed countries and
approximately 5000 cases (1% of total cases) resulting
in death [2]. Despite the fact that APSGN is one of the
most common nephritic syndromes in the world, much
remains unclear about its pathogenesis. Several putative
nephritogens have been under recent scrutiny and
possible mechanisms for their nephritogenicity have
been proposed. Host factors also play a critical role in
the development of nephritis and some recent studies
have offered additional candidates for host susceptibility.
These pathogenic factors will be addressed together with

unique clinical presentations that will facilitate prompt

diagnosis and intervention, avoiding complications.

Clinical findings and diagnosis

APSGN is characterized by the rapid onset of gross
hematuria, edema, and hypertension and is usually preceded by an episode of GAS pharyngitis or pyoderma.
Although cases of APSGN after infection with group C
and G streptococcus are known to occur [3,4], a sporadic
case of APSGN due to Streptococcus zooepidemicus was
recently reported in a young girl who likely contracted
a skin infection from contact with a horse [5]. Serologic
evidence of a recent streptococcal infection should be
sought in suspected cases of APSGN because positive
streptococcal serologies are more sensitive (94.6%)
than history of recent infection (75.7%) or positive cultures (24.3%) in supporting the diagnosis [6]. APSGN
occurs most commonly in children between the ages
of 5 and 12 years; however, a recent report of APSGN

1040-8703 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

158 Nephrology

in a 14-month-old demonstrated that the disease can occur

in children under 3 years, albeit rarely [7]. The low
incidence of APSGN in children under 2 years of age
may be due to the lower rate of GAS pharyngitis in this age
group and less immune complex formation.
Generalized edema due to sodium and fluid retention is
present most of the time, and may be the presenting
symptom in two-thirds of patients [8]. Respiratory distress
and pulmonary edema have been reported as the presenting symptoms of APSGN even in the absence of any
urinary abnormalities [9]. Chiu et al. [10] reported
six patients who presented with respiratory distress and
were initially diagnosed with pneumonia. Two of these
patients progressed to respiratory failure due to delayed
diagnosis. In a study of 152 APSGN patients, Bircan et al.
[11] reported that 44 of the patients had pulmonary edema
but were referred from local hospitals with the diagnosis of
bronchopneumonia and cardiac failure. Interestingly, only
35 of these patients had microscopic hematuria.
Hypertension, which is mainly due to fluid retention, is
found in most patients and may range from mild to
severe. It can manifest as headaches and in some cases
result in confusion and seizures. Attempts have been
made to find an association between hypertension and
atrial natriuretic peptide (ANP) and endothelin (ET), a
potent vasoconstrictor. There have been conflicting
results with one study [12] reporting that, although
ANP and ET levels were increased during the acute
phase of the disease, there was no significant correlation
between ANP/ET and blood pressure while another
study [13] demonstrated a positive correlation between
ET-1 and the height of the systolic or diastolic blood
pressure. Further studies are needed to clarify the role of
ANP and ET in hypertension in APSGN patients.
APSGN patients with encephalopathy as a result
of central nervous system vasculitis have also been
reported [14,15]. Reversible posterior leukoencephalopathy syndrome, characterized by hyperintense signals in
the parieto-occipital regions on T2-weighted magnetic
resonance imaging, has also been observed in patients
with APSGN and these patients may present with decreased visual acuity, focal neurological signs and confusion that resolve with time [16,17].
The first report of autoimmune hemolytic anemia in
association with APSGN has recently been reported
[18]. Three patients, ages 37 years, were diagnosed
with APSGN and, during evaluation for anemia, were
found to have a positive direct antiglobulin test. In most
cases, the anemia seen in APSGN is due to hemodilution.
As described above, APSGN can present with a wide
range of symptoms that often misleads physicians, delays

diagnosis and increases morbidity. Hypertension and its

accompanying symptoms, such as headaches or seizures,
especially, are often misleading. In our experience, we
have had several patients admitted for seizures and
hypertension, who were extensively evaluated for other
diseases before APSGN was even considered, resulting in
delays in appropriate treatment. Thus, APSGN should be
considered in any patient with a history of acute onset of
edema, respiratory distress, or hypertension.

Treatment and prognosis

Although acute renal failure with crescent formation does
occur, APSGN usually follows a benign course with
recovery of renal function and a good long-term prognosis. Treatment for APSGN remains mostly supportive.
Fluid overload usually responds to diuresis and sodium
restriction. Control of hypertension is essential to reduce
morbidity and may require calcium channel blockers
in addition to loop diuretics. Although captopril has been
shown to reduce blood pressure and improve GFR in
APSGN patients, angiotensin converting enzyme inhibitors should be used with caution due to possible renal
failure and hyperkalemia. Potassium exchange resin and
sodium polystyrene sulfonate can be used to treat hyperkalemia. In those circumstances, potassium intake should
be restricted and potassium-sparing agents should
be avoided. Occasionally, acute renal failure, severe
fluid retention unresponsive to diuretics, and intractable
hyperkalemia necessitate hemodialysis or continuous
venovenous hemofiltration. In a recent Japanese study,
complement levels normalized by 12 weeks, gross hematuria resolved by 13 weeks, while microscopic hematuria lasted up to 4 years and proteinuria up to 3 years
[19]. Persistently low C3 levels should prompt evaluation
for other causes of glomerulonephritis such as membranoproliferative glomerulonephritis or systemic lupus
erythematosus nephritis.
Recently, however, in a study of Aboriginal children living
in remote communities in Australia where GAS pyoderma,
is endemic, APSGN was associated with the development
of persistent proteinuria suggesting renal damage [20].
Whether intervention is necessary for those patients with
poor prognostic factors remains controversial. Proteinuria,
and in particular nephrotic syndrome or an elevated creatinine at presentation, is associated with a poor renal outcome. A garland pattern of immunofluorescence of the
glomerulus on renal biopsy is associated with nephrotic
syndrome. A recent report describes a 6-year-old girl with
garland-pattern APSGN and cellular crescents who presented with acute renal failure and nephrotic syndrome
and recovered renal function with plasmapheresis and
methylprednisolone pulse therapy [21]. Cases in the adult
literature of crescentic APSGN and nephrotic syndrome
treated with pulse methylprednisolone also exist [22],

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Acute poststreptococcal glomerulonephritis Ahn and Ingulli 159

suggesting that patients with poor prognostic factors such

as nephrotic proteinuria, cellular crescents on biopsy, and
renal insufficiency should receive aggressive therapy to
prevent progression to chronic kidney disease. Randomized controlled studies need to be performed to evaluate
the effect of aggressive therapy on long-term prognosis in
such cases.

Host susceptibility factors

Previous studies have shown an association between
human leukocyte antigen (HLA) antigens and the incidence of APSGN, suggesting the presence of host
susceptibility factors. Layrisse et al. [23] reported an
increased frequency of HLA-DRW4 in 42 unrelated
APSGN patients compared with 109 healthy controls.
More recently, in a study of Egyptian children [24],
HLA-DRB103011 was reported to be found at a significantly higher frequency in 32 unrelated APSGN patients
compared with 380 healthy individuals (46.9 versus
19.2%), although there was no correlation between the
frequency of the allele and hypertension and proteinuria.
Endothelial nitric oxide synthase gene intron 4 a/b
(eNOS4a/b) variable number of tandem repeats polymorphism was also found to be associated with susceptibility to APSGN. The frequency of eNOS4a (eNOS4a/a
and eNOS4a/b) genotype was found to be higher in
APSGN patients than in healthy controls. Furthermore,
the a/a and a/b genotypes were found to be a significant risk
factor for nephrotic syndrome or a glomerular filtration rate
lower than 50% of normal [25]. These findings need to be
balanced, however, with the fact that, although endothelial
nitric oxide synthase has been associated with other renal
diseases, its relation to APSGN is still unclear.

Pathogenesis
Seegal and Earle [26] first postulated that certain streptococcal strains caused glomerulonephritis. Since then, many
nephritogenic strains have been identified as causing
glomerulonephritis [27]. Although not completely understood, there are several proposed mechanisms for the
pathogenesis of APSGN [28]: circulating immune complex formation with streptococcal antigenic components
and subsequent glomerular deposition along with complement activation; elicitation of an autoimmune response
between streptococcal components and renal components
(molecular mimicry); and alteration of a normal renal
antigen eliciting autoimmune reactivity. This review will
focus on the first two.

Immune complex deposition and complement

activation
Glomerular immune complexes result from deposition
of circulating immune complexes [29] or formation of

immune complexes in situ [30]. The deposition of the

complexes and activation of the complement system is
central to the recruitment of inflammatory cells and the
induction of glomerulonephritis. The classical complement pathway is inhibited through C4b-binding protein
and the alternate pathway is predominantly activated
[31,32]. In addition, complement regulatory proteins such
as factor H and factor H-like protein (FHL-1) may be
removed by bacterial proteases thereby facilitating activation [33]. The lectin pathway was previously reported
to be a possible trigger of the alternate pathway in
APSGN [34] but recent evidence indicates that the
incidence of low complement protein mannan-binding
lectin levels (<100 mg/l) in APSGN patients and controls
is similar (11% versus 16%) suggesting that mannanbinding lectin is not necessary for recruitment of complement in APSGN [35].

Nephritogenic antigens
The search for the putative streptococcal antigen involved
in immune complex formation is ongoing. Nephritisassociated streptococcal plasmin receptor (NAPlr) is a
plasmin-binding protein with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity [36] and has been
the focus of recent research as a possible nephritogen. It is
thought to bind to glomeruli and capture plasmin activated
by streptokinase, which can then cause direct damage to
the glomerular basement membrane. It has also been
proposed to activate the alternate complement pathway,
producing local inflammation in the glomerular basement
membrane, and thus facilitating the deposition of immune
complexes in the subepithelium [37]. Recently, Oda et al.
[38] reported prominent glomerular plasmin-like activity
in APSGN patients who had positive glomerular NAPlr,
and absent or weak glomerular plasmin-like activity in
APSGN patients who had negative glomerular NAPlr.
They also found that the distribution of glomerular plasmin-like activity was identical to that of NAPlr. These
findings support the proposition that the nephritogenicity
of NAPlr is related to its plasmin-binding activity.
Another proposed nephritogen that is the focus of recent
interest is streptococcal pyrogenic exotoxin B (SPE B),
a cationic extracellular plasmin-binding receptor which
is secreted by pyogenic streptococcus. Its zymogen precursor (zSPE B) is secreted by nephritogenic streptococcal strains [39]. High anti-SPE B antibody titers have
been found in patients with APSGN and SPE B has also
been found in the glomeruli of these patients [40,41]. A
recent study [42] explored the effect of SPE B on cytokine production and found that SPE B increased IL-6 in
the supernatant of rat mesangial cell cultures. Viera et al.
[43] went further and showed that the supernatant
of human mononuclear leukocytes cultured with SPE
B and its precursor showed significantly increased levels

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

160 Nephrology

of IL-6, TNFa, IL-8, and TGF-b1. The cytokine production could be blocked with the addition of a polyclonal anti-SPE B antibody. Collectively, these findings
led to the proposal that SPE B could interact with
leukocytes and trigger a series of processes such as
cytokine production, leukocyte proliferation, and expression of adhesion molecules, thereby inducing inflammation prior to the formation of immune complexes [44].
In a recent study, Batsford et al. [45] compared the
glomerular deposition of SPEB and NAPlr (GAPDH).
They found glomerular deposits of SPE B in 12 of
17 APSGN biopsies, with circulating antibodies in all
patients (53/53 patients). On the other hand, they found
glomerular deposition of NAPlr in only one of 17 biopsies,
with circulating antibodies in only five of 47 patients.
Among 31 control biopsies, only two showed weak staining for each antigen. More importantly, they detected
immunogold-labeled SPE B deposits inside the subepithelial humps, marking the first time that a streptococcal antigen is localized within the lesion. Their
findings support the role of zSPE B/SPE B as the more
likely nephritogenic antigen compared with NAPlr. Since
there is strong evidence for both antigens as possible streptococcal nephritogens, further study is needed
before a definitive conclusion can be reached as to which
one is predominant.

Molecular mimicry
Another proposed pathogenic mechanism for APSGN is
molecular mimicry. Some studies have shown common
antigenic determinants in the soluble fraction of nephritogenic streptococci and the glomerulus [4648]. Antibodies to basement membrane collagen, laminin, and
glomerular heparan sulfate proteoglycan have also been
reported in the sera of patients with APSGN [49,50]. A
recent study by Luo et al. [51] suggested that the
pathogenic mechanism of SPE B might be through
molecular mimicry. They actively immunized mice with
recombinant SPE B mutant C192S, and found diffuse
glomerulonephritis with glomerular IgG and C3 deposits
in the mice. These mice also showed an elevated urinary
albumin:creatinine ratio. A panel of monoclonal anti-SPE
B antibodies was then generated and one clone, 10G, was
found to bind to endothelial cells. Intravenous injection
of 10G into mice was found to result in glomerular
antibody and complement deposition, together with proteinuria. Two endothelial cell membrane molecules,
HSP70 and thioredoxin, were recognized by 10G. From
these findings, the authors suggested that these endothelial cell molecules might act as autoantigens recognized by anti-SPE B antibodies, thus supporting the role
of molecular mimicry in the pathogenesis of SPE B. It is
this issue of autoimmunity associated with GAS infections that may limit vaccine development.

Conclusion
APSGN still continues to be a major health concern in
many parts of the developing world. Much progress has
been made in studying the mechanisms that lead to the
pathogenic processes in the disease, with the major
putative nephritogens NaPlr and SPE B being the center
of recent interest. Furthermore, exploration of possible
host susceptibility factors have yielded candidates such as
HLA-DRB103011. Although APSGN is one of the most
common nephritic syndromes, it still continues to be
frequently misdiagnosed due to its diverse clinical presentations. Respiratory distress, pulmonary edema and
hypertension are most problematic and if unrecognized
could lead to a delay in treatment and increased morbidity. Finally, in certain populations the outcome of
APSGN may not be as benign. Treatment for cases
of APSGN with poor prognostic factors remains controversial and randomized controlled studies need to be
performed to assess the impact of different treatment
modalities on reducing the risk of end-stage renal disease.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 223224).
1 Steer AC, Danchin MH, Carapetis JR. Group A streptococcal infections in
 children. J Paediatr Child Health 2007; 43:203213.
This comprehensive review discusses the epidemiology, clinical features and
management of group A b-hemolytic streptococcus in children and also provides
a brief overview on vaccine development.
2

Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group
A streptococcal diseases. Lancet Infect Dis 2005; 5:685694.

Reid HF, Bassett DC, Poon-King T, et al. Group G streptococci in healthy

school-children and in patients with glomerulonephritis in Trinidad. J Hyg
(Lond) 1985; 94:6168.

Svartman M, Potter EV, Poon-King T, Earle DP. Streptococcal infection of

scabetic lesions related to acute glomerulonephritis in Trinidad. J Lab Clin
Med 1973; 81:182193.

Thorley AM, Campbell D, Moghal NE, Hudson S. Post streptococcal acute

glomerulonephritis secondary to sporadic Streptococcus equi infection.
Pediatr Nephrol 2007; 22:597599.
Previous reports of APSGN caused by Streptococcus zooepidemicus, a Lancefield group C b-hemolytic streptococcus, were of epidemics caused by contaminated dairy products. This is the first case report of a sporadic case of APSGN in a
child caused by this organism, and transmitted by a horse.

5


Blyth CC, Robertson PW, Rosenberg AR. Poststreptococcal glomerulonephritis in Sydney: a 16-year retrospective review. J Paediatr Child Health
2007; 43:446450.

Bingler MA, Ellis D, Moritz ML. Acute poststreptococcal glomerulonephritis in

a 14-month-old boy: why is this uncommon? Pediatr Nephrol 2007; 22:448
450.
This is an interesting case report of APSGN occurring in a 14-month-old boy. The
possible reasons for APSGN being extremely rare in children less than 2 years of
age are discussed.

7


Rodriguez-Iturbe B. Poststreptococcal glomerulonephritis. In: Glassock RJ,

editor. Current therapy in nephrology and hypertension. St. Louis: Mosby-Year
Book; 1998. pp. 141145.

Fujinaga S, Ohtomo Y, Umino D, et al. Pulmonary edema in a boy with biopsyproven poststreptococcal glomerulonephritis without urinary abnormalities.
Pediatr Nephrol 2007; 22:154155.
This study highlighted the importance of recognizing pulmonary edema
as a consequence of APSGN. It is interesting to note the urine analysis was
benign.

9


Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Acute poststreptococcal glomerulonephritis Ahn and Ingulli 161

10 Chiu CY, Huang YC, Wong KS, et al. Poststreptococcal glomerulonephritis
with pulmonary edema presenting as respiratory distress. Pediatr Nephrol
2004; 19:12371240.
11 Bircan Z, Tugay S, Usluer H. Poststreptococcal glomerulonephritis with
pulmonary edema and microscopic hematuria. Pediatr Nephrol 2005;
20:1204.
12 Ozdemir S, Saatci U, Besbas N, et al. Plasma atrial natriuretic peptide
and endothelin levels in acute poststreptococcal glomerulonephritis.
Pediatr Nephrol 1992; 6:519522.
13 Nicolaidou P, Georgouli H, Matsinos Y, et al. Endothelin-1 in children with
acute poststreptococcal glomerulonephritis and hypertension. Pediatr Int
2003; 45:3538.
14 Wong W, Morris MC. Cerebral vasculitis in a child following poststreptococcal glomerulonephritis. J Paediatr Child Health 2001; 37:597599.
15 Rovang RD, Zawada ET Jr, Santella RN, et al. Cerebral vasculitis associated
with acute poststreptococcal glomerulonephritis. Am J Nephrol 1997;
17:8992.
16 Froehlich T, Sandifer S, Varma PK, Testa FM. Two cases of hypertensioninduced reversible posterior leukoencephalopathy syndrome secondary to
glomerulonephritis. Curr Opin Pediatr 1999; 11:512518.
17 Fux CA, Bianchetti MG, Jakob SM, Remonda L. Reversible encephalopathy

complicating poststreptococcal glomerulonephritis. Pediatr Infect Dis J 2006;
25:8587.
This is one of a few case reports of the association of reversible posterior
leukoencephalopathy syndrome (RPLS) and APSGN. The authors report that
diffusion-weighted imaging supported vasogenic edema, not cerebral vasculitis, as
the cause of RPLS in this patient with APSGN.
18 Greenbaum LA, Kerlin BA, Van Why S, et al. Concurrent poststreptococcal
glomerulonephritis and autoimmune hemolytic anemia. Pediatr Nephrol 2003;
18:13011303.
19 Kasahara T, Hayakawa H, Okubo S, et al. Prognosis of acute poststreptococcal glomerulonephritis (APSGN) is excellent in children, when adequately
diagnosed. Pediatr Int 2001; 43:364367.
20 White AV, Hoy WE, McCredie DA. Childhood poststreptococcal glomerulonephritis as a risk factor for chronic renal disease in later life. Med J Austr
2001; 174:492496.
21 Suyama K, Kawasaki Y, Suzuki H. Girl with garland-pattern poststreptococcal

acute glomerulonephritis presenting with renal failure and nephrotic syndrome. Pediatr Int 2007; 49:115117.
This study highlighted the potential poor outcome for patients with nephrotic
syndrome and acute renal failure and the controversy regarding initiation of
treatment for rapidly progressive glomerulonephritis in such patients.
22 Raff A, Hebert T, Pullman J, Coco M. Crescentic poststreptococcal glomerulonephritis with nephrotic syndrome in the adult: is aggressive therapy
warranted? Clin Nephrol 2005; 63:375380.
23 Layrisse Z, Rodriguez-Iturbe B, Garcia-Ramirez R, et al. Family studies of the
HLA system in acute poststreptococcal glomerulonephritis. Hum Immunol
1983; 7:177185.
24 Bakr A, Mahmoud LA, Al-Chenawi F, Salah A. HLA-DRB1 alleles in Egyptian

children with poststreptococcal acute glomerulonephritis. Pediatr Nephrol
2007; 22:376379.
This is the first reported association between the DRB1 allele and APSGN. Using
DNA-polymerase chain-reverse hybridization, the authors found that HLADRB103011 was present at a significantly higher frequency in APSGN patients
than in controls.
25 Dursun H, Noyan A, Matyar S, et al. Endothelial nitric oxide synthase gene
intron 4 a/b VNTR polymorphism in children with APSGN. Pediatr Nephrol
2006; 21:16611665.
26 Seegal D, Earle DP. A consideration of certain biological differences between
glomerulonephritis and rheumatic fever. Am J Med Sci 1941; 201:528539.
27 Cunningham MW. Pathogenesis of group A streptococcal infections. Clin
Microbiol Rev 2000; 13:470511.
28 Rodriguez-Iturbe B, Batsford S. Pathogenesis of poststreptococcal glomer ulonephritis a century after Clemens von Pirquet. Kidney Int 2007; 71:1094
1104.
This is a comprehensive review of the pathogenesis of poststreptococcal glomerulonephritis and outlines the important new findings in the field, including the
putative roles of nephritogens NAPlr and SPE B.
29 Dixon FJ. The role of antigenantibody complexes in disease. Harvey Lect
1963; 58:2152.
30 Lange K, Seligson G, Cronin W. Evidence for the in situ origin of poststreptococcal glomerulonephritis: glomerular localization of endostreptosin and the
clinical significance of the subsequent antibody response. Clin Nephrol 1983;
19:310.

31 Perez-Caballero D, Garcia-Laorden I, Cortes G, et al. Interaction between

complement regulators and Streptococcus pyogenes: binding of C4bbinding protein and factor H/factor H-like protein 1 to M18 strains involves
two different cell surface molecules. J Immunol 2004; 173:6899
6904.
32 Thern A, Stenberg L, Dahlback B, Lindahl G. Ig-binding surface proteins of
Streptococcus pyogenes also bind human C4b-binding protein (C4BP), a
regulatory component of the complement system. J Immunol 1995;
154:375386.
33 Wei L, Pandiripally V, Gregory E, et al. Impact of the SpeB protease on
binding of the complement regulatory proteins factor H and factor H-like
protein 1 by Streptococcus pyogenes. Infect Immun 2005; 73:2040
2050.
34 Ohsawa I, Ohi H, Endo M, et al. Evidence of lectin complement pathway
activation in poststreptococcal glomerulonephritis. Kidney Int 1999;
56:11581159.
35 Skattum L, Akesson P, Truedsson L, Sjoholm AG. Antibodies against four

proteins from a Streptococcus pyogenes serotype M1 strain and levels of
circulating mannan-binding lectin in acute poststreptococcal glomerulonephritis. Int Arch Allergy Immunol 2006; 140:919.
Previous reports have suggested that the lectin pathway may trigger the alternate
pathway in APSGN. This study, however, challenges this finding by showing that
even patients deficient in mannan-binding lectin developed APSGN.
36 Winram SB, Lottenberg R. The plasmin-binding protein Plr of group A
streptococci is identified as glyceraldehyde-3-phosphate dehydrogenase.
Microbiology 1996; 142 (Pt 8):23112320.
37 Yoshizawa N, Yamakami K, Fujino M, et al. Nephritis-associated plasmin
receptor and acute poststreptococcal glomerulonephritis: characterization of
the antigen and associated immune response. J Am Soc Nephrol 2004;
15:17851793.
38 Oda T, Yamakami K, Omasu F, et al. Glomerular plasmin-like activity in relation
to nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis. J Am Soc Nephrol 2005; 16:247254.
39 Poon-King R, Bannan J, Viteri A, et al. Identification of an extracellular plasmin
binding protein from nephritogenic streptococci. J Exp Med 1993; 178:759
763.
40 Cu GA, Mezzano S, Bannan JD, Zabriskie JB. Immunohistochemical and
serological evidence for the role of streptococcal proteinase in acute poststreptococcal glomerulonephritis. Kidney Int 1998; 54:819826.
41 Parra G, Rodriguez-Iturbe B, Batsford S, et al. Antibody to streptococcal
zymogen in the serum of patients with acute glomerulonephritis: a multicentric
study. Kidney Int 1998; 54:509517.
42 Pedreanez A, Viera N, Rincon J, Mosquera J. Increased IL-6 in supernatant of
rat mesangial cell cultures treated with erythrogenic toxin type B and its
precursor isolated from nephritogenic streptococci. Am J Nephrol 2006;
26:7581.
43 Viera N, Pedreanez A, Rincon J, Mosquera J. Streptococcal exotoxin B

increases interleukin-6, tumor necrosis factor alpha, interleukin-8 and transforming growth factor beta-1 in leukocytes. Pediatr Nephrol 2007; 22:1273
1281.
This study showed that one of the pathogenic mechanisms of SPE B may
be inducing the release of cytokines. Human mononuclear cells were cultured
with SPE B or its precursor and several cytokines were increased in the
supernatant.
44 Mosquera J, Romero M, Viera N, et al. Could streptococcal erythrogenic toxin

B induce inflammation prior to the development of immune complex deposits
in poststreptococcal glomerulonephritis? Nephron Exp Nephrol 2007;
105:e41e44.
This review outlines the inflammatory processes that SPE B can invoke in the
kidney prior to immune complex deposition, such as cytokine production, expression of adhesion molecules and leukocyte proliferation. These processes may
comprise an important part of the pathogenesis of APSGN.
45 Batsford SR, Mezzano S, Mihatsch M, et al. Is the nephritogenic antigen in
poststreptococcal glomerulonephritis pyrogenic exotoxin B (SPE B) or
GAPDH? Kidney Int 2005; 68:11201129.
46 Markowitz AS, Lange CF Jr. Streptococcal related glomerulonephritis. I.
Isolation, immunochemistry and comparative chemistry of soluble fractions
from type 12 nephritogenic streptococci and human glomeruli. J Immunol
1964; 92:565575.
47 Kraus W, Dale JB, Beachey EH. Identification of an epitope of type 1 streptococcal M protein that is shared with a 43-kDa protein of human myocardium
and renal glomeruli. J Immunol 1990; 145:40894093.
48 Kraus W, Ohyama K, Snyder DS, Beachey EH. Autoimmune sequence of
streptococcal M protein shared with the intermediate filament protein, vimentin. J Exp Med 1989; 169:481492.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

162 Nephrology
49 Kefalides NA, Pegg MT, Ohno N, et al. Antibodies to basement membrane
collagen and to laminin are present in sera from patients with poststreptococcal glomerulonephritis. J Exp Med 1986; 163:588602.
50 Fillit H, Damle SP, Gregory JD, et al. Sera from patients with poststreptococcal glomerulonephritis contain antibodies to glomerular heparan sulfate
proteoglycan. J Exp Med 1985; 161:277289.

51 Luo YH, Kuo CF, Huang KJ, et al. Streptococcal pyrogenic exotoxin B anti
bodies in a mouse model of glomerulonephritis. Kidney Int 2007; 72:716
724.
This study explored the pathogenic mechanism of SPE B and reported that a
monoclonal anti-SPE B antibody, 10G, was cross-reactive with endothelial
molecules. These findings suggest that SPE B may exert glomerular damage
through molecular mimicry.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.