Pediatr Nephrol (2011) 26:165–180

DOI 10.1007/s00467-010-1554-6

REVIEW

Post-streptococcal acute glomerulonephritis in children:

clinical features and pathogenesis
T. Matthew Eison & Bettina H. Ault & Deborah P. Jones &
Russell W. Chesney & Robert J. Wyatt

Received: 10 March 2010 / Revised: 16 April 2010 / Accepted: 19 April 2010 / Published online: 23 July 2010
# IPNA 2010

Abstract Post-streptococcal acute glomerulonephritis red substance and a coagulable substance (protein) [1]. He
(PSAGN) is one of the most important and intriguing also observed that the siblings of a child with nephritis were
conditions in the discipline of pediatric nephrology. more likely to develop nephritis after scarlatina than the
Although the eventual outcome is excellent in most cases, siblings of non-nephritic children. A decade later, Richard
PSAGN remains an important cause of acute renal failure Bright combined the finding of the coagulable substance in
and hospitalization for children in both developed and the urine with the clinical features of dropsy and autopsy
underdeveloped areas. The purpose of this review is to evidence of kidney “derangement” [2]. The term “Bright’s
describe both the typical and less common clinical features disease” became the acceptable name for both acute and
of PSAGN, to outline the changes in the epidemiology of chronic glomerulonephritis until the mid-20th century. The
PSAGN over the past 50 years, and to explore studies on form of the disorder associated with scarlatina became known
the pathogenesis of the condition with an emphasis on the as acute hemorrhagic Bright’s disease [3]. During the last
search for the elusive nephritogenic antigen. decades of the 19th and first decades of the 20th century,
several descriptions of post-scarlatina glomerulonephritis
Keywords Acute glomerulonephritis . Group A appeared, and were termed “acute glomerulonephritis” [4–6].
beta-hemolytic streptococcus . Nephritogenic The association between β-hemolytic streptococcal infec-
tion and acute glomerulonephritis was noted by Longcope et
al., who stated that “no evidence could be obtained...that the
Historical perspective streptococcus caused the glomerular nephritis by actual inva-
sion of the kidney, for blood cultures and urine cultures were
In 1812, Wells described the clinical features of acute negative” [5]. The work of Dick and Dick [7] and Dochez
nephritis that included a latent period between scarlatina and Sherman [8], demonstrating that a β-hemolytic strepto-
and development of edema and urine that contained both a coccus was the pathogenic species in scarlet fever, led to use
of the term “post-streptococcal acute glomerulonephritis”.
Dedication This review is dedicated to the memory of Shane Roy III By 1940 serologic findings of anti-streptococcal anti-
(1936–2009). Dr. Roy was the first pediatric nephrologist in bodies [9] and depression of complement [10] were noted
Tennessee. His scholarly interest in post-streptococcal acute glomer- in patients with post-streptococcal acute glomerulonephritis
ulonephritis spanned his 40-year career in Memphis, resulting in
seminal clinical observations on the condition. (PSAGN) and it became clear that glomerulonephritis
followed both upper respiratory and cutaneous infections
T. M. Eison : B. H. Ault : D. P. Jones : R. W. Chesney :
R. J. Wyatt (*)
with β-hemolytic streptococci [11, 12]. In 1941, Seegal and
Division of Pediatric Nephrology, Department of Pediatrics, Earle developed the concept of nephritogenic strains of
University of Tennessee Health Science Center, streptococci that were different from those that caused
and the Children’s Foundation Research Center at Le Bonheur rheumatic fever [13]. Thus, the concept that acute glomer-
Children’s Medical Center,
ulonephritis was a non-suppurative, immunologically medi-
Room 301 WPT, 50 North Dunlap,
Memphis, TN 38103, USA ated complication of group A β-hemolytic streptococcal
e-mail: rwyatt@uthsc.edu infections became firmly established.
166 Pediatr Nephrol (2011) 26:165–180

Epidemiology epidemics/clusters included a predominance of pharyngitis-

associated strains [36, 37]. In geographical areas having
Post-streptococcal acute glomerulonephritis remains an distinct seasons, pyoderma-associated cases tend to occur in
important non-suppurative complication of group A strep- the late summer or early fall months [18, 33, 34, 38], while
tococcal infection worldwide. The estimated worldwide in regions with a constant tropical climate cases occur year
yearly burden of PSAGN is 472,000 cases; approximately round [31].
404,000 of those cases occur in children [14]. By far, most The incidence of PSAGN often varies over time in a
of the burden of PSAGN is borne by developing countries population. In a health district in Santiago, Chile, the annual
[14]. Pyoderma-associated PSAGN continues to prevail in incidence of PSAGN doubled to 13.2 cases per 100,000
tropical areas, where streptococcal skin infections may be population in an “epidemic” period (1984–1989) compared to
endemic [15]. In contrast, in more temperate areas an earlier “endemic” period (1980–1983) [33]. Subsequently
pharyngitis-associated PSAGN now predominates [16, 17]. (1990–1999), the incidence decreased to a low of 1.7 cases
The epidemiology of PSAGN has long been noted to per 100,000 population per year. Most cases during the
differ from that of acute rheumatic fever [13, 18, 19] and epidemic period were pyoderma-associated and correlated
led to the conclusion that certain strains of group A significantly with family size and household overcrowding.
streptococci are either rheumatogenic or nephritogenic, The apparent decline in the incidence of PSAGN in the
while others are neither [13, 20]. Group A streptococci United States over the past 40 years is assumed to be
are most commonly typed by their surface M proteins [21], largely from the near eradication of streptococcal pyoderma
which are virulence factors. However, group A streptococci due to better hygiene and/or a decreased prevalence of skin
can also be divided into two groups based on the presence infection-associated nephritogenic M serotypes [39]. Most
or absence of a lipoproteinase that causes serum to become new cases now admitted to the Le Bonheur Children’s
opaque (serum opacity factor) [22, 23]. Each of these two Medical Center in Memphis, TN, appear to be pharyngitis-
groups contains a characteristic group of M proteins. The associated [40]. This trend was documented in a 1990 study
opacity factor-negative group contains the “rheumatogenic” that found a marked overall decline in the number of
strains, while the opacity factor-positive group contains the children hospitalized for PSAGN from the period 1961–
“nephritogenic” strains [24]. Thus, acute rheumatic fever 1970, when the average was 31 patients per year (70%
and PSAGN should not result from the same streptococcal pyoderma-associated), to the period of 1979–1988, when
infection, making the reports of such associations difficult the average was 9.5 patients per year (38% pyoderma-
to explain [25, 26]. In addition, nephritogenic strains can be associated) [17]. Thus, over these periods the prevalence of
subdivided into those primarily associated with pyoderma pharyngitis-associated PSAGN did not change significantly
and those that most often cause pharyngitis [27, 28]. This while that of pyoderma-associated PSAGN fell markedly. A
distinction is made more complicated by the fact that similar decline in pyoderma-associated PSAGN was shown
pyoderma-associated strains sometimes cause a simulta- for northeast Florida for the period 1999–2006 as compared
neous pharyngitis, presumably by transfer of bacteria from to 1959–1973 [16]. In the current era, since the near-
the skin to the oropharynx [20]. disappearance of pyoderma-associated PSAGN in developed
The serotype most frequently associated with pyoderma- countries, virtually no epidemiologic data have been
associated pharyngitis is M49, “the Red Lake strain” [28, 29]. published on M types in PSAGN.
Other pyoderma-associated strains are M2, M42, M56, M57,
and M60 [24]. The common pharyngitis-associated PSAGN
M types are 1, 4, 25, and some but not all M12 strains [19, 30]. Pathogenesis
Two epidemics on the Red Lake Chippewa Indian
Reservation in northern Minnesota provided important The concept of immune complex formation resulting in
early insight into the epidemiology of PSAGN [31, 32]. PSAGN dates to the early 20th century observations of
In both epidemics, the nephritis followed cases of pyoder- Schick and Von Pirquet likening human PSAGN to acute
ma due to the M49 serotype, which was discovered in the serum sickness, with its similar latent interval [41, 42].
first epidemic in 1953 [28]. The second epidemic, in 1966, However, the exact mechanism by which PSAGN occurs
affected only children that were too young to have been remains a source of debate. Theories proposed have
alive during the first epidemic. This absence of nephritis in included glomerular trapping of circulating immune com-
older children and young adults in the second epidemic was plexes as well as in situ immune complex formation resulting
presumed to be due to immunity gained from exposure to from antibodies reacting with either streptococcal compo-
the M49 serotype in the first epidemic [31]. nents deposited in the glomerulus or with components of the
Most of the well-studied PSAGN epidemics or clusters glomerulus itself (“molecular mimicry”). Evidence has also
were pyoderma-associated [28, 29, 33–35]. However, a few been presented to support the anti-immunoglobulin activity
Pediatr Nephrol (2011) 26:165–180 167

or glomerular plasmin binding activity of streptococcal biopsies in patients with PSAGN, even after incubation of
components as causative of PSAGN. the sera with M protein [70]. Recently, Streptococcus
In the 1960s and 1970s, work from the laboratories of zooepidemicus (group C) has been associated with out-
Germuth, Dixon, and Michael [43–46] demonstrated breaks of PSAGN [71, 72], providing further evidence
similarities between PSAGN and an acute “one shot” against M protein as the nephritogenic antigen.
serum sickness model in the rabbit: a latent interval, low M protein serotype 12 streptococci isolated from a
levels of serum complement, glomerular deposition of patient with pharyngitis-associated PSAGN altered the
antigen, antibody and complement, and the self-limited carbohydrate composition of IgG in vitro, leading to the
nature of both diseases. Such findings supported a hypothesis that auto-immunogenic streptococcal-altered
circulating immune complex etiology for PSAGN [47, 48]. immunoglobulins underlie PSAGN [73]. Acute glomerulo-
Serum levels of circulating immune complexes detected nephritis was induced in rabbits by administration of IgG
by a C1q binding assay were found in 67% of patients with altered by the same strain [74]. The autoimmunity-inducing
PSAGN [49]. However, circulating immune complexes IgG alteration in these studies was attributed to the actions
occurred with the same frequency in patients with uncom- of neuraminidase [75]. Anti-IgG antibodies were detected
plicated group A streptococcal infections [50], and levels of in the serum of 32% of patients with PSAGN [76], and in
circulating immune complexes were not correlated with the glomeruli of 86% [77]. The arguments of Nordstrand et
clinical features of PSAGN [51]. Nordstrand et al. [52] al. against the involvement of neuraminidase in the initiation
noted that the time course of C3 deposition before that of IgG of PSAGN are that (1) this would result in antibody
argues for complement activation by the alternative pathway, deposition before C3, which is not observed in PSAGN
or by non-immune activation of the classical pathway that is [52], and (2) rheumatogenic and nephritogenic strains of
now recognized as characteristic for the lectin pathway of streptococci both may produce neuraminidase [78].
complement activation [53]. Thus, the order of immune Many studies have focused on the antigenic potential of
component deposition argued against glomerular deposition certain components from nephritogenic strains of strepto-
of the pre-formed immune complexes necessary for cocci. As the glomerular basement membrane is negatively
classical complement pathway activation [52]. charged, cationic streptococcal components were investi-
The cross-reactivity of streptococci and mammalian gated as the nephritogen, particularly histone-like proteins
tissue was demonstrated in the 1930s and 1940s [54, 55]. [79, 80]. In situ immune complex formation was proposed
Experiments implicating molecular mimicry in acute to result from anti-histone-like protein antibodies coupled
rheumatic fever (ARF) [54, 56–59] led to evidence of a with the ready adsorption of histone-like proteins to
similar mechanism behind PSAGN [60]. Sera of patients heparan sulfate-proteoglycans in the GBM [81]. However,
with PSAGN contain antibodies to glomerular basement anti-histone-like protein antibodies in the serum of patients
membrane (GBM) components laminin and type IV collagen with PSAGN or evidence of histone-like protein in their
[61]. Initially, cross-reactivity of streptococcal antigens glomeruli have never been described [48].
with the GBM was demonstrated in the nephritogenic Endostreptosin, a 40 to 50 kDa protein derived from
M12 strain [62]. However, later studies showed cross- streptococcal cell cytoplasm, has been detected in the
reactivity with glomeruli of non-nephritogenic strains [63– glomeruli early in the clinical course of PSAGN, but not
65]. Kraus and Beachey [66] localized the antigenic later in the disease [82, 83]. Antibodies directed against
determinant for cross-reactivity with human renal glomeruli endostreptosin associate well with the course of the
of type 1 streptococcal M protein to a tetrapeptide (Ile-Arg- pathologic disease process [84]. These antibodies may
Leu-Arg) near the amino terminus. However, the similar represent a diagnostic marker for PSAGN, since they are
cross-reactivity patterns of rheumatogenic and nephrito- elevated in patients with PSAGN as compared to healthy
genic strains of streptococci argue against molecular and disease (other types of glomerulonephritis and strepto-
mimicry involving M proteins [67]. coccal infection) controls [85]. Perhaps endostreptosin was
Much of the early work on the pathogenesis of PSAGN first studied in PSAGN by Treser [70], who showed that
focused on the group A-specific streptococcal M proteins, pre-incubating the serum with a fraction of streptococcus
as nephritogenicity is restricted to certain M protein later determined to contain endostreptosin abolished stain-
serotypes. M protein–fibrinogen complexes deposit in the ing of glomerular sections by serum IgG fractions from
glomeruli [68, 69]. However, not all strains of a nephritis- patients with PSAGN. Later, this was done with endo-
associated M protein serotype are nephritogenic [19], and streptosin alone [86]. In a rat model, endostreptosin
while PSAGN only rarely recurs, many M protein serotypes deposits along the GBM one day after injection but
do not confer lifetime immunity [48]. Additional evidence disappears in coincidence with the deposition of IgG and
against an M protein etiology is the inability of convales- C3 at 8–12 days after injection [82]. This was explained by
cent serum to recognize free antigenic sites in early renal masking of the protein by bound antibody.
168 Pediatr Nephrol (2011) 26:165–180

Yoshizawa et al. [87] isolated a 43 kDa protein called plasminogen to plasmin, which cleaves C3, thus activating
“pre-absorbing antigen” (PA-Ag) that others argue is the alternative complement pathway and contributing to
identical to endostreptosin [48, 52]. PA-Ag was named for glomerular inflammation. Others suggested that active
its ability to “pre-absorb” the antibody in convalescent plasmin could induce PSAGN via degradation of extracel-
PSAGN sera and prevent its glomerular deposition. PA-Ag lular matrix proteins and activation of matrix metallopro-
activates the alternative complement pathway [87]. Anti- teinases [52, 100]. This has led to the investigation of other
body to PA-Ag was demonstrated in sera from 30 of 31 plasminogen-converting streptococcal components as pos-
patients with PSAGN [87]. However, Rodriguez-Iturbe and sible nephritogenic antigens. Poon-King et al. [100] found a
Batsford [48] suggested that a subsequent study showed protein matching previous descriptions of NSAP that had
that sera of convalescent PSAGN patients had anti-IgG plasmin binding properties and was identical to a precursor
reactivity, which could result in the positive staining for of streptococcal pyrogenic exotoxin B (speB). SpeB is a
endostreptosin in renal biopsies [76]. They also noted that cationic extracellular cysteine proteinase with super anti-
injection of PA-Ag into rabbits resulted in findings that were genic properties produced by all group A streptococci
inconsistent with PSAGN: mild proliferative (mesangial, strains [24]. Certain strains produce very high amounts of
endocapillary, or both) changes on biopsy and only mild speB [101–103]. However, Poon-King et al. did not know
hematuria and proteinuria [88]. In addition, Nordstrand et if their protein was identical to the previously described
al. [89] found pre-absorbing antigen in non-nephritogenic NSAP, since antiserum prepared against NSAP was not
strains of streptococci in their tissue cage mouse model available for direct comparison.
of PSAGN. Further support for speB as the nephritogenic antigen is
Villareal et al. [90] isolated nephritis strain-associated the finding that anti-speB antibodies are elevated in patients
protein (NSAP), a 46 to 47 kDa protein unique to the with PSAGN as compared to patients with ARF or scarlet
extracellular products of nephritogenic streptococci. NSAP fever or healthy individuals [104]. SpeB was found in the
was demonstrated in glomerular deposits for 14 of 21 glomerular deposits in 67% of patients with PSAGN
patients with PSAGN, but none for control biopsies from compared to 16% of patients with other glomerular diseases
five patients with acute renal failure (ARF) and 11 with [104]. SpeB not only co-localized with C3 and IgG in the
nonstreptococcal glomerulonephritis. NSAP was also pres- glomeruli of patients with PSAGN but was also demon-
ent in serum from 96% of PSAGN patients compared to strated via immunogold-labeling of speB within the classic
15–20% of patients with either ARF or impetigo [91]. subepithelial hump [105]. A multicenter study showed that
NSAP has structural and biochemical properties identical to antibody to the zymogen of speB in South American
streptokinase. However, streptokinase cannot be demon- patients with PSAGN was better than anti-streptolysin O
strated in glomerular deposits for patients with PSAGN and anti-DNAse B titers for demonstrating prior infection
[92], and serum levels of purified group A streptokinase with nephritogenic streptococci [106].
were similar in patients with PSAGN and ARF. While Nordstrand et al. [52] felt that the role of speB in the
NSAP and streptokinase may have similarities, they appear pathogenesis of PSAGN was controversial, since sera from
to be two distinct proteins [92]. Since a 43 kDa cleaved Ethiopian children showed no significant differences in
product of NSAP conserving NSAP’s epitope [93] shares reactivity against speB for patients with PSAGN and ARF.
the same isoelectric point and molecular weight as PA-Ag, SpeB and its zymogen precursor were present during
it was suggested that PA-Ag and the cleaved product of infection with both nephritic and non-nephritic streptococ-
NSAP were the same molecule [92]. cal strains in a mouse tissue cage model of PSAGN [52]. In
Cunningham attributed the inability to detect glomerular addition, sequencing of the genome of the group C
deposition of streptokinase by immunofluorescence to the Streptococcus zooepidemicus strain responsible for the
insensitivity of the method [24]. Streptokinase was demon- PSAGN epidemic in Nova Serrana, Brazil revealed a lack
strated by immunogold-silver staining in the glomeruli of of the gene encoding for speB, bringing into question its
mice infected with the nephritogenic streptococcal strain role as the sole nephritogenic antigen [71, 107].
NZ131, and rendered the strain non-nephritogenic through Nephritis-associated plasmin receptor (NAPlr) was de-
deletion of the ska1 gene responsible for production of scribed by Yamakami et al. [108]. This 43 kDa glycolytic
streptokinase [94]. Reconstitution of the ska1 gene into the enzyme demonstrated plasmin binding and glyceraldehyde-
NZ131 strain via a plasmid vector restored its nephritogenic 3-phosphate dehydrogenase (GAPDH) activity and was
properties [95]. Earlier work in rabbits had shown that identical to a previously described plasmin receptor protein
deletion of a streptokinase gene from a type 49 strain on group A streptococci [109]. Anti-NAPlr antibodies were
eliminated its nephritogenic properties [96]. detected in 92% of patients with PSAGN patients compared
Holm et al. [97–99] suggested that NSAP contributed to to 60% of patients with group A streptococcal pharyngitis
the pathogenesis of PSAGN via its ability to convert patients without nephritis [110]. NAPlr was found in the
Pediatr Nephrol (2011) 26:165–180 169

glomerular deposits of 100% of patients biopsied early in [120] or C4d fragments [114] during the first two weeks
the course of PSAGN [110]. The glomerular distribution of after onset. These findings of classical complement path-
NAPlr deposition and plasmin activity determined by in way activation could reflect the presence of circulating
situ zymography was identical [111]. The fact that NAPlr immune complexes in the acute stage that are distinct from
did not co-localize with C3 in glomerular deposits was said the glomerular immune deposits.
to suggest that (1) complement was activated by NAPlr in The depression of serum levels of properdin, C5, C6, and
the circulation rather than in situ, and (2) NAPlr induced the MAC (C5b-9) corresponds temporally to the persistent
PSAGN independently of complement activation by bind- depression of serum C3 [114, 121]. Serum levels of the
ing to the GBM and mesangial matrix via its adhesive alternative pathway regulatory proteins, H and I, remain
character [110], and subsequently trapping and activating normal throughout the clinical course of PSAGN [114].
plasmin, causing in situ glomerular damage by degrading PSAGN with typical renal pathologic findings on light
the GBM or activating latent matrix metalloproteases [111]. microscopy, immunofluorescence, and electron microscopy
While speB was not expressed by the group C streptococcal may occur in patients with no evidence of complement
strain responsible for the Nova Serrana, Brazil epidemic, activation, as manifested by depression of serum C3
NAPlr expression has been demonstrated in streptococcal concentration [122, 123]. A study from Cincinnati Children’s
groups A, C, and G [112]. However, Batsford et al. [105] Hospital showed that 10% of children with PSAGN had
failed to demonstrate either anti-NAPlr antibodies in serum normal serum C3 concentration at clinical onset [122]. The
from PSAGN patients or glomerular deposition of NAPlr. diagnosis of PSAGN in these normocomplementemic
They suggested that the difference might have been due to patients was confirmed by demonstration of typical findings
the homogeneous Japanese population in the initial study for PSAGN on renal biopsy. Hypocomplementemic patients
[110] as compared to the diverse population from Venezuela differ from normocomplementemic patients by virtue of the
in their study. presence of factor B in the glomerular deposits [115]. This
Since there is considerable evidence both for and against finding, along with the absence of the alternative pathway
most putative nephritogenic antigens, collaborative efforts regulatory protein factor H, may indicate that C3bBb
toward genomic sequencing of nephritogenic strains of convertase is present in the glomerular immune deposits
streptococci have been initiated [107]. Discovery of new and that the ongoing complement activation in PSAGN may
nephritogenic antigen candidates may be achieved by be in situ rather than systemic.
examination of conserved and differing regions of the Crescentic PSAGN may have an increased association
genome. Such efforts will surely improve our understand- with normocomplementemia. Five of the 10 crescentic
ing of the pathogenetic mechanism(s) underlying PSAGN. PSAGN patients from Memphis [124] and four of 11 from
New Zealand [125] had normal or near-normal serum C3
levels; however, none of the four reported by Lewy et al.
Complement activation [126] had normal or near-normal serum C3 levels. The
reason for this possible association of normocomplemente-
Evidence from both serum complement profiles and mia with crescent formation in PSAGN is not clear.
immunofluorescence patterns for glomerular deposits indi-
cates that C3 activation in PSAGN is predominately via the
alternative pathway [113–115]. The immune deposits Serum immunoglobulin levels
typically are made up of IgG, C3, properdin, and C5
[115]. These deposits virtually never contain the classical Serum IgG levels were elevated in 44% of 75 children
pathway components C1q and C4 [115]. C5b-9 (membrane hospitalized with PSAGN [127]. Twenty of those with
attack complex) and its regulatory protein, the S protein, elevated serum IgG levels were biopsied and over half had
(vitronectin) localize in the same distribution as C3, no IgG in their glomerular deposits [127]. Also, patients
indicating complete activation of the terminal complement with an elevated IgG level were more likely to have anti-
pathway, which probably occurs in situ rather than in the streptolysin O titers ≥833 Todd units (p<0.001). Elevated
circulation prior to deposition in the glomerulus [115, 116]. serum IgG concentration did not correlate with severity of
A recent study shows evidence for activation of the lectin- disease, age of the patient, or the serum albumin or C3
binding pathway from deposition of MBL in some patients level. There appears to be a subset of patients with elevated
with PSAGN [117]. serum IgG levels who with high frequency have IgG absent
Initially, some patients may have classical pathway from their glomerular deposits. Thus, failure to form
activation, as evidenced by transient depression of serum antibody to a glomerular-bound protein produced by the
C1q, C2, and/or C4 concentrations [118–120] and the nephritogenic streptococcus, widely assumed to be the
presence of circulating C1-inhibitor-C1r-C1s complexes origin of the IgG in the glomerular deposits, is in some way
170 Pediatr Nephrol (2011) 26:165–180

significantly associated with elevated serum levels of IgG during the acute phase of PSAGN differs somewhat among
and antibody to streptolysin O. the various case series depending upon the era of
publication and the method of patient selection. In fact,
some of the earliest descriptions of cases of acute GN may
Clinical manifestations—typical course, atypical have included patients that actually had conditions other
features than PSAGN.
With the exception of rare cases with atypical presenta-
The median age at presentation for PSAGN in childhood is tion, hematuria is present in essentially all patients. The
between 6 and 8 years old [126, 128, 129]; the condition classic description of tea- or cola-colored urine occurs in
rarely occurs prior to age 2 [126, 130, 131]. The rarity of approximately 25–60% of patients. Proteinuria is also
PSAGN in very young children was attributed to the low typically present, but nephrotic syndrome is rare in most
rate of streptococcal pharyngitis in this age group and an case series. While a single series [133] reported 10% with
immature immune (or antibody) response [130]. Twice as nephrotic syndrome, most have reported only 2–4% [126,
many males are diagnosed with PSAGN as females [126, 134]. Hypertension occurs in approximately 80–90% of
130, 131]; the reason for this is unknown. There appears to cases [40, 135, 136]. Cerebral complications of hyperten-
be no difference in gender ratio whether PSAGN follows sion including headaches, seizures, mental status changes,
pharyngitis or pyoderma. and visual changes occur in 30–35% of children [40, 135].
Children with PSAGN most often seek medical attention The mechanism for hypertension is most likely retention of
for edema or gross hematuria; occasionally symptoms or sodium and water with resulting expansion of the extracel-
signs of hypertension will be the initial presenting feature lular space [134]. As with other causes of glomerulone-
leading to the diagnosis. The triad of edema, hematuria and phritis, fractional excretion of sodium is generally less than
hypertension is classic for PSAGN. Three phases of the 1%, similar to pre-renal azotemia [137, 138]. Renin levels
disease can be identified: the latent phase, the acute phase, (plasma renin activity) are typically low at presentation
and the recovery phase. The general course is represented [139, 140]. Fluid retention correlates with suppression of
in Fig. 1. A preceding infection of the respiratory tract the plasma renin activity [140]. Diastolic blood pressure
(usually pharyngitis) or of the skin is identified in the significantly correlates with the degree of fluid overload as
majority of cases. However, sub-clinical cases do occur, assessed by weight change pre- and post-spontaneous
many of which are identified based upon the knowledge of diuresis [139]. Patients may sometimes present with clinical
an affected family member/contact. One report suggested and radiologic signs of pulmonary edema. While dyspnea is
that PSAGN occurs in about 20% of asymptomatic family a presenting complaint in only 5% of patients, evidence for
members of patients with the condition [84]. The latency congestive heart failure was found in half of the children in
period between the streptococcal infection and the onset of one early series [135].
the clinical syndrome ranges from 3–33 days [132] but on Atypical presentations of PSAGN include those individuals
average is 7–14 days. The prevalence of clinical features with sub-clinical disease and those presenting with acute
illness, usually related to hypertension or edema in the absence
of overtly abnormal urine [141]. There are numerous case
reports of children who present with extreme manifestations,
usually from hypertensive crises, who do not display the
typical urinary findings at presentation [141.] Serial exami-
nation of the urine after presentation may eventually confirm
the suspicion of acute glomerulonephritis.
Another atypical feature at presentation is the presence
of a typical Henoch-Schönlein purpura rash [142–144]. The
diagnosis of PSAGN was confirmed by renal biopsy in
those cases.
Examination of the urine sediment confirms acute glomer-
ular involvement with the presence of dysmorphic red blood
cells and leukocytes; red blood cell and white blood cell casts
are usually identified. In the early part of the acute phase,
urinary leukocytes may predominate over red blood cells.
The glomerular filtration rate (GFR) is often decreased
Fig. 1 Summary of the typical clinical course of post-streptococcal during the acute phase of the disease. Increased blood urea
acute glomerulonephritis (PSAGN) nitrogen (BUN) was noted in 60–65% of patients [40, 135],
Pediatr Nephrol (2011) 26:165–180 171

with decreased estimated creatinine clearance less than when renal biopsy is not performed [10, 114, 118, 152].
90 ml/min/1.73 m2 present in 20% [40]. Quantitation of Depression of serum C3 level in PSAGN has been shown
urinary protein excretion in 78 cases of PSAGN between to precede the onset of hematuria [118, 120].
1979–1988 revealed nephrotic range proteinuria (defined Hypertension usually resolves within 1–2 weeks, and
as >40 mg/m2/h) in 27 (34.6%) and normal urinary protein rarely requires long-term treatment [135, 136]. Renal
excretion (defined as <5 mg/m2/h) in 20 (25.6%) [17]. biopsy is indicated in cases in which the clinical diagnosis
Hypoalbuminemia is quite common: in one large study of is not clear in order to confirm the diagnosis or in the
PSAGN serum albumin was lower than 3.0 g/dl in 46% and presence of significant renal insufficiency to rule out
less than 2.5 g/dl in 15% [145]. crescentic glomerulonephritis.
Decreased blood hemoglobin is common in PSAGN. The recovery phase occurs after resolution of fluid
One large series showed that only 10% of 155 patients had overload with diuresis—either spontaneous and/or pharma-
a hemoglobin level of ±12 g/dl, and over 50% were below cologically induced—along with normalization of blood
10 g/dl [145]. In extreme cases, severe anemia may occur pressure and resolution of proteinuria and gross hematuria.
[145]. While traditionally the drop in hemoglobin has been Most case series note that the proteinuria disappears much
attributed via clinical observation solely to volume overload earlier than the microscopic hematuria [40, 153] with the
[146], there could be other factors at work. In two exception of Travis et al., who noted the opposite [136].
instances, autoimmune hemolytic anemia was documented During this phase, the C3 level returns to normal in the
in the early stages of PSAGN [147, 148]. majority of affected children. PSAGN has occurred in
The serological markers most commonly used by the patients previously diagnosed (by biopsy) with IgA
clinician are anti-streptolysin O (ASO) titer and depression nephropathy [154–156]. Because IgA nephropathy is the
of serum C3 level. Increased antibody levels to anti- most commonly occurring type of chronic glomerulone-
streptococcal antigens [ASO, anti-hyaluronidase (A-H) phritis and often goes undiagnosed, the association with
and anti-DNAase] are documented less often than low PSAGN is most likely the chance occurrence of the two
levels of C3. ASO titers are higher in pharyngitis-associated conditions in the same individual.
PSAGN than pyoderma-associated PSAGN [9, 128, 149, Second attacks of PSAGN have been reported but are
150]. In an early study, the sensitivity of an elevated ASO rare [145, 157–160]. In the earlier reports, the PSAGN was
titer was extremely high (97%), but the specificity was only pyoderma-associated for both attacks in most instances
80%, presumably due to the fact that up to 20% of unaffected [145, 158, 159], while two case reports since 2000 were
controls show evidence of streptococcal exposure with a both pharyngitis-associated PSAGN [157, 160]. A recent
significantly elevated titer [151]. Early descriptions of the case series reported two recurrences of PSAGN, but didn’t
time course for increasing ASO and A-H titers show that in specify the route of infection acquisition [161].
a group of patients with typical (previously known as type
A) acute glomerulonephritis, ASO was increased above
normal in 72% [135]. In Roy’s series of biopsy-proven Renal biopsy findings
cases from Memphis, 60% had ASO titer elevation as
defined by Todd units >333 [40]. Cases following pyoder- A renal biopsy is generally not indicated for diagnosis of
ma are more likely to demonstrate elevated anti-DNAase B PSAGN, but is usually performed when atypical clinical
titer than an elevated ASO titer [118, 128]. features occur. Such features that could lead to a biopsy are
In children whose initial ASO titer is normal, subsequent normocomplementemia [122], failure to document a recent
measurements may be elevated, thus supporting the streptococcal infection by a rise in ASO or streptozyme titer,
suspected diagnosis. This is demonstrated by Longcope and renal insufficiency, particularly when the GFR remains
[9] and Dodge et al. [128], who found that the ASO titer less than 30 ml/min/1.73 m2 for more than one week [124].
continued to increase over the four weeks after presentation In the past, some pediatric nephrologists recommended a
in some cases [9] and the mean titer peaked at three weeks renal biopsy for patients with presumed PSAGN whose C3
[128]. In addition, performance of more than one strepto- concentration remained depressed for more than eight weeks
coccal antibody test increased the number of individuals after clinical onset, mainly to exclude the diagnosis of
with “positive” titers from 80 to 95% [151]. Travis et al. membranoproliferative glomerulonephritis (MPGN). One
tested for ASO, AH, and anti-DNAse in 60 patients and study documented failure of C3 to become normal by
often found ASO to be negative while anti-DNAse and/or eight weeks in five of 20 patients despite typical improvement
AH were positive [136]. in clinical features, including resolution of proteinuria and
The acute reduction of serum C3 concentration in normal kidney function [162]. Renal biopsies that were
PSAGN with the typical return to normal levels within performed in three of these patients showed typical findings
six weeks of onset is of foremost diagnostic importance of PSAGN. Thus, persistent hypocomplementemia with
172 Pediatr Nephrol (2011) 26:165–180

resolving features of acute glomerulonephritis does not differed from those with paramesangial deposits in that they
exclude the diagnosis of PSAGN, and the authors and others were more edematous, were less likely to have gross
felt that the renal biopsy could be deferred. Subsequent hematuria and tended to be normocomplementemic.
studies have backed these findings [163, 164].
When a biopsy is performed, the typical light microscopy
findings are diffuse hypercellularity of endothelial and Treatment
mesangial cells and infiltration of the glomerular tuft with
polymorphonuclear cells [165]. This endocapillary hyper- Treatment remains largely supportive and usually addresses
cellularity may lead to a reduction in the capillary lumen the most urgent problem of hypertension. No modern
space that appears to associate with the initial severity of studies are available to guide the first choice of anti-
renal insufficiency [126]. Using a cell-proliferation marker, hypertensive agent. However, salt restriction and loop
Ki-67, Chung and Kim [166] provided evidence that most diuretics are the first-line treatment for fluid overload and
of this hypercellularity is due to infiltrating inflammatory hypertension; thereafter, hypertensive therapy is often
cells. In most cases of PSAGN there is little or no evidence transitioned to vasodilators. Although successful treatment
of tubular, interstitial or vascular injury [47]. with ACE inhibition has been reported [106], ACE
In more severe cases, epithelial crescents may form inhibitors are generally not used during the acute phase
during the course of PSAGN. Rarely, patients with PSAGN due to the potential for decrease in GFR and hyperkalemia.
will have crescentic involvement in over 50% of glomeruli, In those individuals with hypertensive emergencies, con-
leading to the clinical picture of rapidly progressive tinuous infusion of anti-hypertensive medication is the
glomerulonephritis [36, 124, 125]. preferred initial approach.
The immunofluorescence pattern typically seen in One difficult question that has yet to be definitively
biopsies performed during the acute phase of PSAGN answered is whether prompt treatment of group A strepto-
shows discrete granular deposits of IgG and C3 in a coccal pharyngitis or pyoderma will prevent or attenuate
capillary loop and mesangial distribution [32, 167]. the subsequent development of PSAGN. In 1970, Dillon
However, about 30% of PSAGN biopsies show C3 and stated, “In spite of vigorous efforts to do so, we have not
the absence of IgG even when the biopsies are performed been able to prove unequivocally that we can prevent cases
early in the clinical course [32, 127, 168–170]. Sorger et al. of AGN by prompt treatment of streptococcal skin
[171] described the immunofluorescence patterns in infection” [34]. While more recent studies have not
PSAGN using the term “starry sky” to represent a typical disputed this assertion, treating communities in which
pattern and the term “garland pattern” to indicate the PSAGN is epidemic with benzathine penicillin G may
presence of heavy and sometimes confluent capillary loop reduce carriage of nephritogenic strains and thus lower the
deposits with the total absence of mesangial deposits. This incidence of PSAGN [174].
garland pattern was associated with more numerous and Immunosuppression has not been proven to be effective,
larger subepithelial “humps” and higher degrees of protein- although it is often used in the clinical setting of rapidly
uria. However, this association with heavy proteinuria has progressive glomerulonephritis or when crescents are seen on
not been confirmed by any case series in the two decades biopsy. However, there is considerable debate as to whether
following the initial report. immunosuppressive treatment is effective in this setting. Roy
The hallmark pathologic finding on electron microscopy is et al. [124], in a study of 10 patients, reported no difference in
the subepithelial hump, which was first noted by Kimmelstiel outcome between patients receiving quintuple therapy (pred-
and associates in 1962 [172]. However, electron dense nisone, azathioprine, cyclophosphamide, dipyridamole, and
deposits may also occur in subendothelial and intramembra- anticoagulation) and those receiving supportive care. More
nous locations [168] and the presence of such deposits should recently, Wong et al. [125] reported the clinical course of 27
not lead one to dismiss the diagnosis of PSAGN, since they patients biopsied for difficult clinical course, 11 of whom
were found in PSAGN patients as early as 1966 [168]. had >50% crescents on biopsy, and found no benefit of
Lewy et al. [126] observed an association between the immunosuppression.
degree of polymorphonucleocyte infiltration of the glomer-
ular tuft and the number of subepithelial humps; they also
noted that higher degrees of endocapillary proliferation Long-term outcome
were associated with lower complement levels. West and
McAdams [173] demonstrated a significant association A major problem with the attempts of older studies to make
between absence of paramesangial (the portion of the capillary prognostic associations for PSAGN is that the statistical
loop in continuity with the mesangium) deposits and low methodologies employed were non-existent or inadequate
serum albumin levels in children with PSAGN. These patients by today’s standards. Thus, many of the stated conclusions
Pediatr Nephrol (2011) 26:165–180 173

reflect the bias of albeit excellent clinical observers. Since children over a 12-year period. They showed that progres-
the current standard of clinical practice is to forego renal sion to ESRD was more prevalent with crescentic PSAGN,
biopsy in typical cases of suspected PSAGN [134], it is occurring in two of 11 patients as opposed to none of the 16
important to note that 10–15% of clinical diagnoses of children with PSAGN without crescents. Indications for
PSAGN were not supported after a renal biopsy was biopsy in this study were anuric renal failure, acute severe
performed [128]. In a series of 47 patients, those errone- glomerulonephritis, or unexpected delay in recovery from
ously diagnosed with PSAGN had a significantly worse acute glomerulonephritis. These investigators estimated that
prognosis than patients who had PSAGN. Clinical and only 2% of cases of PSAGN were severe enough to warrant
histologic evidence of non-healing was observed in 50% of biopsy, supporting earlier claims of good prognosis in
patients whose biopsies revealed exacerbation of other children with PSAGN.
underlying renal disease, as opposed to only 5% of patients It is important to note that post-streptococcal crescentic
with PSAGN [128]. glomerulonephritis may carry a better prognosis than crescent
Published studies on the prognosis of PSAGN in formation of other etiology. The Southwest Pediatric Ne-
children are comprised only of cases that are clinically phrology Study Group found that of 50 children with crescent
apparent [134]. Sagel et al. [175] found that all biopsies of formation, five with PSAGN had normal GFR, compared to
children with transient hypocomplementemia and micro- progression to ESRD for 23 of 42 patients with crescent
scopic hematuria following streptococcal infection demon- formation of other etiology [180]. However, this concept was
strated histologic evidence of glomerulonephritis. Published challenged by experience from northern India that suggested
estimates of the ratio of subclinical to clinical cases of that the prognosis for post-streptococcal crescentic glomer-
PSAGN are from 1.5:1 to 19:1 [31, 134, 175–177]. ulonephritis is equally as poor as that for other types of
Reports on clinicopathologic correlations in PSAGN crescentic glomerulonephritis [181].
have sometimes described surprising disparities. A report Studies on the outcome of sporadic PSAGN are
published in 1969 found normalization of urinalysis in the summarized in Table 1. On the surface, with the notable
presence of progressive post-streptococcal glomerular exception of Baldwin’s group in New York City [182],
lesions, and, conversely, histopathologic healing with virtually all studies report good prognosis for the vast
persistent urinary abnormalities [178]. In that study, the majority of children with PSAGN. The Baldwin group studies
duration and degree of hypocomplementemia correlation include a 1979 report that asserted that irreversible renal
did not associate with subsequent histologic healing. disease, as evidenced by hypertension, proteinuria, decreased
Certain histologic findings may predict a poor progno- renal function or glomerulosclerosis, occurred in at least 40%
sis. In a series of 23 patients with PSAGN, the single of children following sporadic PSAGN [133]. They even
patient who died secondary to renal disease had more argued that their data were similar to those of earlier reports
extensive subepithelial hump deposition than the other [126, 128, 136] and took issue with the criteria for favorable
cases [136]. The garland pattern of immunofluorescence outcome in those reports [133]. Lewy et al. [126] reported
has been associated with heavy proteinuria and poor normal creatinine clearance of >77 ml/min/1.73 m2 in 25
outcome [171]. While higher degrees of endocapillary of 26 patients with over three years follow-up, while
hypercellularity appear to associate with the initial sever- the Baldwin group reported normal creatinine clearances
ity of renal insufficiency, this finding has not been shown of >105 ml/min/1.73 m2 in 20 of 26 children and considered
to associate with progression to end stage renal disease proteinuria of 200 to 500 mg per 24 h to represent irreversible
(ESRD) [126]. glomerular damage [133]. They also chose to interpret the
Extracapillary crescent formation is the most ominous presence of sclerosis as chronicity rather than healing, as
histologic finding in PSAGN. The patient who died in the Travis et al. [136] had done.
case series of Travis et al. [136] had crescentic disease. In The poor prognosis implied by the Baldwin group may
Lewy’s case series of 46 patients with PSAGN published in also be due to insufficient length of time for follow-up, for
1971 [126], three of the four patients who died had although they followed some patients for up to 17 years,
crescents with glomerular sclerosis on biopsy, and well- 46 out of 83 patients were followed for only two years.
developed epithelial crescents were present in three of four Selection bias related to the patients with recovery being
patients with a persistent course. In PSAGN patients lost to follow-up early surely applies to their work [182].
studied between 1962 and 1970, two died from rapidly Roy et al. showed that recovery from PSAGN can be
progressive glomerulonephritis during the acute phase of protracted. In their study, histologic healing occurred in
illness [179]. In a series of 36 children who were biopsied, 20% at two years, in 94% at 10 years, and in 97% at
the two who had many large crescents were uremic at onset 12 years after disease onset [40].
and never remitted [133]. A recent study by Wong et al. Roy et al. [40] also argued that light microscopy more
[125] examined 27 renal biopsies diagnostic of PSAGN in accurately determines healing than clinical indices of blood
Table 1 Outcome of sporadic cases of pediatric post-streptococcal acute glomerulonephritis
174

Study No. of Antecedent Antecedent Patient ages Sex ratio Time of Histologic No. of Proteinuria at Hypertension Decrease in GFR Hematuria at
patients pyoderma URI/pharyngitis M:F follow-up healing renal- follow-up at follow-up at follow-up follow-up
related
deaths

Lewy et al. 46 5/46 35/46 (6/46 ≤7 (n=6) 29:17 6 months– 34/46 4/46 3/21 (2–4 years) 1/14 (2–4 years) 2/19 (2–4 years) 4/20 (2–4 years)
[126] with other) 8–14 (n=20) 9 years 2/13 (4–6 years) 3/14 (4–6 years) 3/14 (4–6 years) 1/15 (4–6 years)
15–21 (n=9) 2/5 (6–8 years) 1/3 (6–8 years) 2/6 (6–8 years) 1/4 (6–8 years)
≤22 (n=5) 1/1 (8–10 years)e 1/2 (8–10 years)b 0/1 (8–10 years)g 0/1 (8–10 years)f
unknown (n=6)
Travis et al. 60 25/60 26/60 2.5–24.5 years 39:21 3–10 years 49/54 1/60 31/54 (>1 year) 2/40 (2–4 years)h 6/22 (2–8 years)d 5/53 (6–12 months)
[136] 17/52 (≥2 years) 1/8 (4–6 years)b,i None after 1 year
Roy et al. 35 24/35 11/35 3.6–12.8 years 16:19 4–12 years 34/35 0/35 2/21 (2–4 years) 0/22 (2–4 years) 1/20 (2–4 years) 6/21 (2–4 years)
[40] 5/32 (4–6 years) 0/34 (4–6 years) 2/30 (4–6 years) 9/21 (4–6 years)
1/22 (6–12 years)e 1/25 (6–12 years)b 4/24 (6–12 years)g 9/22 (6–12 years)f
Sanjad et al. 153 100/153 45/153 14 months– 1.6:1 6 months– 2/153 0/103 0/103 0/48 0/103
[192] 13 years 11 years
Schacht et al. 83 6% 79% (4% both; 2–16 years 43:40 ≤17 years 10/12 at 0/54 24% (≥2 years) 16% (≥2 years) 16% (≥2 years) –
[133] 11% unknown) 2 years 16% (≥5 years) 25% (≥5 years) 26% (≥5 years)
follow-up 18% (≥10 years)a 33% (≥10 years)b 35% (≥10 years)c
Clark et al. 36 0/36 34/36 URI 1.9–14.3 years 21:15 5–12 years 2/36 3/30–34 (one 1/30–34 0/33 (SCr <1.5 in 3/30–34
[179] 4/36 tonsillitis (n=32) biopsied type II males, <1.25 in (≥10 RBC/µl)
2/36 OM 15–22 years MPGN) females)
(n=30)
Popovic-Rolovic 104 88.5% 11.5% 2–16 years 61.9:38.1 5–9 years 0/104 2/40 (5–9 years) 2/40 (5–9 years) 0/104 0/40 (5–9 years)
et al. [193] (n=40) 2/88 (10–17 years) 3/88 (10–17 years) 2/88 (10–17 years)
10–17 years
(n=88)
Herthelius and 33 ? ? 2–16 years 25:8 2–11 months 0/22 2/22 (=92 ml/min/
Berg [194] 1.73 m2)
Kasahara 138 ?none (either ?all 3–14 years 84:54 ≤4 years 0/138 2.2% (1–2 years) 0/138 5.8% (2–3 years)
et al. [195] +ASO or +throat 0.7% (2–3 years) 2.9% (3–4 years)
cx or latex agglut.)
0% (3 years) 0% (4 years)

URI upper respiratory infection, OM otitis media, cx culture, latex agglut latex agglutination
a
Proteinuria defined as ≥200–500 mg/24 h
b
Hypertension defined as >140/90 mmHg
c
GFR of 105 ml/min/1.73 m2 defined as lower limit of normal
d
GFR of <60 ml/min/m2 (<104 ml/min/1.73 m2 ) defined as lower limit of normal
e
Proteinuria defined as >50 mg/12 h
f
Hematuria defined as Addis count of >1×106 red blood cell (RBC)
g
Creatinine clearance of 90 ml/min/1.73 m2 defined as lower limit of normal
h
Familial hypertension, 2nd attack PSAGN
i
Pediatr Nephrol (2011) 26:165–180

Familial hypertension
Pediatr Nephrol (2011) 26:165–180 175

pressure elevation, proteinuria, and hematuria. Although six Thus, prevention of PSAGN in the developing world
of 35 patients in their study were labeled “non-healed” by continues to be based upon public health measures such as
these clinical criteria at 49 to 135 months from onset of improved hygiene and better housing conditions. The elimina-
PSAGN, all had healed histologically, as indicated by light tion of epidemic pyoderma, as occurred in the southern United
microscopy. States over the past 25 years, offers the best hope for control.
It is generally accepted that epidemic cases of PSAGN carry
a better prognosis than sporadic cases, with some asserting that
healing occurs in all cases [136]. This may be secondary to References
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