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The Current State of Poststreptococcal
Glomerulonephritis
Bernardo Rodriguez-Iturbe* and James M. Musser
*Renal Department, Hospital Universitario, Universidad del Zulia and Centro de Investigaciones Biomedicas, IVIC-Zulia,
Maracaibo, Venezuela; and Center for Molecular and Translational Human Infectious Diseases Research and
Department of Pathology, Methodist Hospital Research Institute, Houston, Texas
One of the oldest clinical observationsin nephrology is that dropsy that fol-
lows scarlet fever is associated withdark and scanty urine.1 The seminal
contribution of von Pirquet2 attributedthe disease to an antigenantibody re-
action that causes renal disease and wasfollowed by investigations that vastly
expanded our knowledge of the patho-physiology of immune complexmedi-ated inflammation and attempts to
define the specific characteristics ofstreptococcal strains capable of causing
nephritis.3 Here we address the chang-ing epidemiology of poststreptococcal
glomerulonephritis (PSGN), summarizeguidelines for treatment of streptococ-
cal infections from the standpoint ofprevention of glomerulonephritis, and
update the long-term prognosis ofPSGN.
CHANGING EPIDEMIOLOGY OFACUTE PSGN
It is widely acknowledged that the inci-
dence of PSGN has decreased in the pastthree decades, but the present-day global
burden of the disease is difficult to estab-lish. This nephritis has practically disap-
peared in central Europe,4
where it isnow more frequent in the elderly, espe-cially in association with debilitating
conditions such as alcoholism or intrave-nous drug use.5 In the Italian Biopsy Reg-
istry, PSGN is now more common afterthe age of 60 (0.9 patients per million)
than before this age (0.4 patients per mil-lion),and in childrenyoungerthan15 yr,
the incidence went from2.6 to 3.7% ofallprimary glomerulopathies in the period
1987 through 1992 to only nine cases inthe period 1992 through 1994.6 In China7
and Singapore,8 a reduction in the inci-dence of PSGN has been noted in the past
40 yr. In Chile, the disease has practicallydisappeared since 1999,9 and in Mara-
caibo, Venezuela, sporadic PSGN de-creased from 90 to 110 cases per year in
1980through 198510 to15 cases per yearin2001 through 2005. In Guadalajara, Mex-
ico, the combined data from two hospitalsshowed a reduction in cases of PSGN from
27 in 1992 to only six in 2003 (Garcia G,Arevalo A, Salazar AL, Ramirez S, Perez G,
Hospital Civil, Guadalajara, Mexico, per-sonal communication, March 29, 2004).
Similar reductions have been reported inMemphis, TN, where the incidence
dropped from 31 patients per year in 1961through 1970 to only 9.5 patients per year
in 1979 through 1988.11
Nevertheless, PSGN remains a com-
mon disease in many rural and Aborigi-nal communities with low socioeco-
nomic status. Such is the case inAustralia12 and in Valencia, Venezuela,
where the disease causes 70% of the hos-pital admissions in a pediatric nephrol-
ogy service.13
In India, postinfectiousglomerulonephritis represent 73% of theacute glomerulonephridities affecting
the elderly,14 which may or may not rep-
Published online ahead of print. Publication dateavailable at www.jasn.org.
Correspondence: Dr. Bernardo Rodriguez-Iturbe,Renal Service Hospital Universitario de Maracaibo,Avenue Goajira s/n, Estado Zulia, Maracaibo,Venezuela. Phone: 58-261-7519610; Fax: 58-261-7524838; E-mail: [email protected]
Copyright 2008 by the American Society ofNephrology
ABSTRACTPoststreptococcal glomerulonephritis is one of the oldest recognized renal
diseases. In the past three decades, significant changes have occurred in its
epidemiology, in new insight gained in the nephritogenic characteristics ofstreptococcal antigens, and in the natural history of the disease. The disease is
now rare in industrialized nations, but in the underprivileged world, the burden
of poststreptococcal glomerulonephritis ranges between 9.5 and 28.5 new
cases per 100,000 individuals per year. Prophylactic antibiotic treatment is
advisable in epidemic conditions and to household contacts of index cases in
communities where the prevalence of the disease is high. The long-term prog-
nosis is variable; in general, prognosis is excellent in children but significantly
worse when it occurs in elderly individuals and in populations that present other
risk factors of chronic kidney disease. Contemporary large-scale research strat-
egies such as genome-wide sequencing may uncover new information about
pathogenic factors contributing to disease.
J Am Soc Nephrol 19: 18551864, 2008. doi: 10.1681/ASN.2008010092
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resent a shift in age predominance such
as has been referred to previously forCentral Europe.5
Despite the reduction in worldwide
incidence of PSGN, epidemics andclusters of cases of PSGN continue to
appear. Table 1 lists epidemics with100 cases10,1524 and Table 2 the epi-
demics with 100 cases or clusters infamilies or communities.9,2542 Figure
1 shows that in the past 30 yr, large ep-idemics have been reported in coun-
tries in the middle range of the HumanDevelopment Index (HDI; between the
48th and the 87th rank place out of177) and clusters of cases in countries
in the upper 10% of the HDI.43 Thecountries where PSGN has not been re-
ported in the past 30 yr are in the so-called low range of the HDI (0.449 to
0.336),43 and overwhelming social andhealth problems in combination with
poor documentation resources (Figure1A) are likely reasons for the apparent
absence of PSGN.In the past 30 yr, most of the smaller
epidemics and clusters of cases are re-ported from poor communities, rural
and/or Aboriginal, within countries inthe upper 10% range of the HDI (Fig-
ure 1B). In these countries, the annualper capita health expenditure is nearly
5 times higher than that in countries
where large epidemics are reported
(Figure 1A) and is likely that the moreefficient and better funded public
health system in these nations facili-
tates the recognition and early antibi-otic treatment of streptococcal infec-
tions in index cases of PSGN. Similarly,underprivileged communities in less
developed nations may also have clus-ters of cases of acute PSGN that go un-
reported. The data reviewed here sug-gest that PSGN remains a significant
health problem in underdevelopedcountries. Additional insight into the
potential burden of PSGN in these na-tions may be gained from the evalua-
tion of the incidence of the most severecases of the disease in pediatric referral
hospitals. Acute postinfectious glo-merulonephritis is frequently the cause
of severe acute renal failure (requiringdialysis and/or admission to pediatric
intensive care units) in underdevel-oped countries. The proportion of
cases of acute renal failure that corre-spond to acute postinfectious glomer-
ulonephritis of demonstrated or as-sumed poststreptococcal etiology is
13% in New Delhi,44 30% in Istanbul,45
51.6% in Casablanca,46 4.6% in La-
gos,47
27% in Bombay,48
19.2% in Luc-know,49 33% in Asuncion,50 17.4% in
Chandrigarth,51 5.2% in Lima,52 9.3%
in Varanasi,53 and 25% in Osun State,
Nigeria.54
GLOBAL BURDEN OF ACUTE
PSGN
Carapetis et al.,55 using 11 population
studies reporting the incidence of acutePSGN, evaluated the global burden of
PSGN. In children from less developedcountries and minority populations,
they found that the median incidence ofdisease was 24.3 cases per 100,000 per-
son-years. In people older than 15 yr inthese same countries, they estimated the
incidence to be two cases per 100,000person-years, basing their calculations
on data from Kuwait. In more developedcountries, the incidence was estimated at
0.3 cases per 100,000 person-years on thebasis of the Italian Biopsy Registry. The
global incidence of acute PSGN was esti-mated at 472,000 cases per year, 456,000
of which occurred in less developedcountries.
Estimations of the global burden ofPSGN may also be approached by con-
sidering that cases of PSGN with severeacute renal failure, usually as a result of a
rapidly progressive course and crescenticglomerulonephritis, represent 1% of
the total number of cases.56 These cases
Table 1. Epidemics of acute PSGN with more than 100 casesa
Year Location Population
Affected
Site of
Infection No. of Cases Streptococcal Type
1951 to 1952 Bainbridge, MD15 Military recruits Throat 180 M12
1964 to 1965 San Fernando, Trinidad, West Indies16 Rural and city Skin 760 M55, M49
1968 Maracaibo, Venezuela17 Urban Throat 384 ND
1967 to 1968 San Fernando, Trinidad, West Indies19 Rural and urban Skin 540 M49, M60
1974 Maracaibo, Venezuela Urban Skin 200 ND
1974 Baracoa, Guantanamo, Cuba18 Rural Skin and throat 295 ND1986 San Fernando, Trinidad, West Indies20 Rural and urban Skin 181 M73, M48, M55, M57, 59
1995 Yerevan, Armenia21 Urban and rural Throat 196 ND
1995 San Jose, Costa Ricab Urban and Rural Skin and throat 103 ND
1995 Vilnius, Lithuania22 Urban and Rural Skin and Throat 8.3 cases per
100,000
childrenc
ND
1998 Nova Serrana, Minas Gerais, Brazil23 Rural Unpasteurized
milk
135 S.zooepidemicus
1998 to 2001 Lima, Peru24 Urban Throat 186 (in clusters)d NDaEpidemics with more that 100 cases of PSGN; data updated from reference42. ND, not determined.bR. Lou, FUNDANIER, Guatemala City, Guatemala, personal communication, 2007.cArticle was in Lithuanian, and we were not able to define the total number of cases.dThe abstract cited does not permit definition of a specific epidemic peak.
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derive from reports of pediatric acute re-
nal failure from underdeveloped coun-tries. In this study, the following assump-tions were made: The patients with acute
glomerulonephritis represented cases ofPSGN. This was explicitly stated in most
series but not in all of them; the caseslisted had severe renal failure because
they were seen at a referral hospital andadmitted to intensive care units if the fa-
cility was available, and most underwentdialysis; and the total number of cases of
acute PSGN in the general populationwas estimated assuming that uncompli-
cated cases were 100 (low estimate) to
300 (high estimate) more than life-threatening disease. The calculations areshown in Tables 3 and 4. Table 3 shows
the selected series of acute renal failureused for analysis,46,48,49,53,54,57,58 the pop-
ulations from where the cases were as-sumed to originate and the calculated
high and low incidences of uncompli-cated PSGN. In these calculations, 2850
(low estimate) to 8550 (high estimate)cases of PSGN occur annually in a total
population of 29,967,989 inhabitants. Itshould be noted that three of the seven
series used in these calculations are from
India, one from Morocco, one from onefrom Thailand, and two from Nigeria;
nevertheless, if these data are representa-tive of the underdeveloped world, then it
maybe concluded that outside the indus-trialized countries, the annual incidence
of PSGN is 9.5 to 28.5 new cases per100,000 population of all ages (Table 4).
Probably even the high estimate is an un-derestimation because underreporting
ofseverePSGNcasesislikelyasaresultoflocal conditions and scarcity of pediatric
nephrologists and because the cases inthe adult population (arguably10% of
the total) are not taken into account. Thelow value is remarkably close to the value
obtained by Carapetiset al.55 using pop-ulation studies (Table 4). The high value
exceeds the value given by Carpetiset al.by three-fold, but these authors ac-
knowledge that their calculations wereaimed to underestimate the global bur-
den of the disease and that the true bur-den of PSGN was likely to be several-foldhigher.
NEPHRITOGENIC ANTIGENS
Group A streptococci are assumed the
only strain capable of causing glomeru-lonephritis. Group C streptococci, how-
ever, have caused recent epidemics ofPSGN, specificallyS. zooepidemicus(Ta-
Table 2. Epidemics of acute PSGN with less than 100 cases and clusters of cases
Year Location Population Site of Infection No. of Cases Streptococcal Type
1952 Nova Scotia, Canada38 Rural Throat 22 ND
1953 Red Lake, MN39 Aboriginal Skin 63 M49
1960 Memphis, TN27 Urban Skin 57 M 1, M12, M49
1966 Red Lake, MN32 Aboriginal Skin 27 M49
1975 to 1977 Alaska35 Eskimo children skin 75 ND1978 to 1982 Santiago, Chile9 Urban Skin and throat 84 ND
1978 to 1983 New Zealand28,37 Urban and Rural Skin Clusters (autumn) M49, 57, 60
1980 Las Tunas, Cuba41 Rural skin 12 M49, M12
1980 to 1989 Kuwait33,34 Urban and Rural Throat and skin 234 cases in 9 yr M12, M18, M49
1980 to 1998 North Territory, Australia30 Rural Skin and throat Clusters ND
1982 to 1993 Belgrade, Yugoslavia31 Military academy throat Clusters of 6 to 24 cases ND
1883 North Yorkshire, UK26 Rural Unpasteurized milk Clusters S.zooepidemicus
1992 Saga, Japan36 Rural Throat 42 M1
1993 North Queensland, Australia40 Aborigines Skin 58 ND
1993 Brisbane, Australia29 Rural Unpasteurized milk Clusters S.zooepidemicus
2005 Linkop ing, Sweden25 Rural Throat Cluster S. pyogenes
S.constellatus
***
A
CLUSTERS,EPIDEMICS(100 cases)
HDI RANK
Annual public health expenditure
US $ (2004) per capita
2273.8 SE 593.7
556.6 SE 158.4
52.6 SE 7.19
1 50 100 150 177
B
HUMAN DEVELOPMENT INDEX
1.0 0.9 0.8 0.7
CLUSTERS,EPIDEMICS(100 cases)
Figure 1. Large epidemics (100 cases) and clusters of cases of PSGN reported in thepast 30 yr. (A) Reports are related to the HDI rank of the country in which the outbreakoccurred.43 Annual public health expenditure data obtained from the World HealthOrganization.108 (B) The mean HDI in the countries were large epidemics are reported issignificantly lower than the HDI in the countries with smaller epidemics and clusters breakhave been reported. ***P 0.001.
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bles 1 and 2), and, therefore, nephrito-genic antigens are present and possibly
shared by streptococci from severalgroups.3
Two antigens are actively investigatedat the present time as the potential
cause(s) of PSGN: The nephritis-associ-ated plasmin receptor (NAPlr), identi-
fied as glyceraldehyde-3-phosphate de-hydrogenase,59,60 and a cationic cysteine
proteinase known as streptococcal pyro-genic exotoxin B (SPEB) that is gener-
ated by proteolysis of a zymogen precur-sor (zSPEB).6163 Both of these fractions
are capable of activating the alternatepathway of the complement system.3
NAPlr deposits are presentin early bi-
opsies of acute PSGN, and NAPlr anti-body levels are detected by Western blot
in convalescent sera of 92% of the pa-tients with PSGN and 60% of uncompli-
cated streptococcal infections in Japan.59
Because NAPlr is co-localized with plas-
min but not with complement or IgG,nephritogenicity is related to plasmin-
binding capacity, which facilitates im-mune complex deposition and subse-
quent inflammation.60 More recentinvestigations by Fujinoet al.64 demon-
strated that the gene sequence and invitro expressionof NAPlr is not restricted
to strains isolated from patients withPSGN and is also present in streptococci
from groups A, C, and G.SPEB/zSPEB is produced by nephri-
togenic streptococci from group A.65
Four independent studies (Oda and Yo-
shizawa, National Defense Medical Col-lege, Saitama, Japan, personal communi-
cation, December 27, 2007, see lastparagraph of this section)62,63,66 showed
that SPEB/zSPEB is deposited in biopsiesof patients with acute PSGN and thathigh antibody titers to this antigen are
present in convalescent sera of the vastmajority of patients sampled in Latin
America.62 Subsequent studies66 evalu-ated both NAPlr and SPEB in serum and
biopsies obtained from patients in Ven-ezuela, Chile, and Switzerland and de-
tected SPEB deposits in 12 of 17 biopsiesand serum anti-SPEB antibodies in 53 of
53 sera. In contrast, in the same material,circulating antibodies to NAPlr were
found in only five of 47 sera and definiteglomerular deposits in only one biopsy.
SPEB co-localizes with complement de-posits and within subepithelial electron-
dense deposits (humps) that are the typ-ical signature of acute PSGN. Thus far,
this represents the only demonstration ofa putative nephritogenic antigen inside
the humps and suggests this localizationwas facilitated by the cationic, antigenic
charge of SPEB, as postulated in previousstudies.67,68
The contrasting results in antibodyresponse and renal deposits of NAPlr
and SPEB in patients from Japan and pa-tients elsewhere suggest there may bemore than a single streptococcal antigen
responsible for glomerulonephritis, anddifferent antigenic fractions could be ne-
phritogenic in populations of differentgenetic background. In support of this
conclusion are studies (see last para-graph of this article) demonstrating the
absence of the gene encoding SPEB intheS. zooepidemicusresponsible for the
recent epidemic of glomerulonephritisin Brazil.23 Studying this same strepto-
Table 3. Estimation of the burden of PSGN in underdeveloped countries on the basis of selected series of severe acuterenal failurea
City, Country Population Period of Study
(yr)
ARF
Total
(n)
PSGN with
Severe
ARF (n)
APSGNb with
Severe ARF
per Year
Estimated Annual Incidence
of Uncomplicated PSGN in
General Populationc
Casablanca, Morocco46 3,100,000 10 89 46 4.6 460 to 1380
Bombay, India48 12,500,000 2 48 13 6.5 650 to 1950Lucknow, India49 2,541,101 3 52 9 3.0 300 to 900
Varanasi, India53 1,371,749 16 891 83 5.2 520 to 1560
Port Harcourt, Nigeria57 1,000,000 9 211 29 3.2 320 to 960
South Provinces, Thailand58 8,296,996 4 (2000 to 2004) 109 20 5.0 500 to 1500
Osun State, Nigeria54 2,158,143 9 123 9 1.0 100 to 300
Total 29,967,989 28.5 2850 to 8550aThe population of the Mumbai metropolitan region of Bombay was obtained from http://theory.tifr.res.in/bombay/stats/pop; the population of Osun State,Nigeria, was obtained from http://www.onlinenigeria.com; and the population of the rest of the cities and the sum of the 14 provinces of Southern Thailandregions were obtained from http://en.wikipedia.org. APSGN, acute PSGN; ARF, acute renal failure.bRequired admission to a referral hospital, intensive care unit, and/or dialysis.cThis study assumed that proportion of cases of PSGN with severe ARF is 1% of the total number of uncomplicated symptomatic cases (see text), andestimates were made assuming that the total number of PSGN cases is 100 (low estimate) to 300 (high estimate) more frequent than cases requiring intensivecare and dialysis.
Table 4. Burden of APSGN in underdeveloped countries: Comparison with estimates made using population studiesa
Study Population Estimated Annual No. of Cases
of APSGN
Estimated Annual Incidence
(Cases per 100,000 Population)
Carapetiset al.55 4,876,709,000 456,000 9.3
This studyb 29,967,989 2850 to 8550 9.5 to 28.5aEstimations made by Carapetiset al.55 derived from the evaluation of 11 population studies.bThis study assumed that proportion of cases of PSGN with severe acute renal failure is 1% of the total number of uncomplicated symptomatic cases (seetext) and estimates were made assuming that the total number of PSGN cases is 100 (low estimate) to 300 (high estimate) more than cases requiring intensivecare and dialysis.
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coccal strain, Nicholson et al.69 found
the gene encoding Szp5058 M-protein
and showed that 33 of 44 patients were
seropositive for the Szp5058 fusionprotein. These authors69 noted that an-
tiphagocytic properties of Szp proteins
may be relevant in the pathogenesis ofglomerulonephritis.
Both SPEB70,71 and NAPlr72 are capa-
ble of inducing chemotactic (monocytechemoattractant protein 1) and IL-6
moieties in mesangial cells, promoting
enhanced expression of adhesion mole-cules. Recent investigations also demon-
strated peripheral blood leukocytes re-
spond with release of IL-6, TNF-, IL-8,and TGF- when reacted with SPEB.73
These findings underline the inflamma-
tory potential of these putative nephrito-gens.
The role of plasmin-binding activity in
the pathogenesis of PSGN is an attractive
possibility.Theplasmin-bindingactivityofboth NAPlr60 and SPEB61 is widely recog-
nized. Similar properties are present in
streptokinase and enolase, and the nephri-togenic potential of thelatteris basedon its
plasmin-binding properties.74 Recent in-
vestigations by Oda and co-workers (Na-tional Defense Medical College, Saitama,
Japan, personal communication, Decem-ber 27, 2007) demonstrated by double-staining method that NAPlr and SPEB
both are localized in the glomerular mes-
angium of biopsies of patients with acute
PSGN (Figure 2) and because they foundsimilar localizationof bothantigens postu-
lated that plasmin-binding activity may be
a common nephritogenic characteristic inboth antigens.
TREATMENT GUIDELINES FOR
STREPTOCOCCAL INFECTIONS
WITH POTENTIAL FORGLOMERULONEPHRITIS
Acute PSGN is prevented by early antibi-
otic treatment, andthespread of nephritis-associated streptococcal infection is con-
tainedby prophylacticantibiotic treatmentto individuals at risk. The challenge is to
define who should be treated when the di-
agnosis of streptococcal infection is uncer-
tain and when prophylactic treatment of agiven population is warranted. The deci-
sion is straightforward with active skin in-
fections because the differential diagnosisis between staphylococcal and streptococ-
cal impetigo, and both should be treated
withpenicillin except when methicillin-re-sistant staphylococci are prevalent in the
community.
In contrast, the diagnosis of strepto-coccal pharyngitis on clinical grounds
alone is uncertain, and only 10 to 20% of
the patients who present with a sore
throat in general clinical practice have apositive culture for group A Streptococ-cus.75 Because clinical judgment may
miss half of the streptococcal pharyngitisandwronglyidentifyassuch20to40%of
the cases of sore throats,76
several clinicalscoring systems have been developed toincrease the accuracy of diagnosis for the
prescription of antibiotics. Among the
most popular are the scores proposed byCentor et al.77 and McIsaac et al.78 that
have a range from 0 to 4 and incorporate
age as a risk factor. The McIsaac scoregives 1 point each to the following crite-
ria: Temperature38C, no cough, ten-
der anterior cervical adenopathy, tonsil-
lar swelling or exudates, and age between3 and14 yr. Age15 to 44yr isassignedno
points, and age 44 yr gets 1 point.
Using this scoring system, the sensitivityandspecificity of the diagnosis are 85 and
92%, respectively79; and in practicalterms, antibiotic treatment is recom-
mended on clinical grounds alone whenthe score is 4, antibiotic treatment is not
recommended (and culture is unneces-sary) when the score is 0 or 1, and cul-
tures should be obtained and treatmentgiven only when the result is positive
when score is 2 or 3. Rapid tests for strep-tococcal antigen detection suitable for
office practice have been developed andmay be used as a confirmatory test for
children with tonsillar exudate and nocough,80 but their sensitivity is too low to
support use without culture confirma-tion of negative results.81
Patients with acute PSGN should betreated as though they have active strep-
tococcal infection. The reason for thisrecommendation is that positive cultures
may sometimes be obtained from pa-tients in whom upper respiratory or skin
infections are not clinically evident.Treatment of a carrier state may prevent
spread to other household members; inaddition, at least one report suggested
that patients who receive PSGN antibi-otic treatment have a milder clinical
course.82
Prophylactic penicillin treatment
should be used in epidemics in closedcommunities and prescribed to house-
hold contacts of index cases in areaswhere PSGN is very common or when
clusters of cases are reported. This rec-ommendation is based on the finding
that cross-infection among family mem-bers of index cases in communities wherePSGN is prevalent is very high. In Mara-
caibo, 95% of the siblings and 79% of theparents of index cases presented sero-
logic evidence of recent streptococcal in-fection.83 Studies of Australian Aborigi-
nal communities also supported thisnotion. Johnston et al.30 found treatment
with benzathine penicillin G targeted tochildren with skin sores and household
contacts of index cases prevented newcases of acute PSGN, in contrast with the
Figure 2. Representative photomicrograph. (A and B) Double-immunofluorescence stainingfor streptococcal NAPlr (A; Alexa Fluor 594) and SPEB (B; FITC) in a renal biopsy of a patientwith acute PSGN. (C) Similar but not identical distribution of NAPlr and SPEB is observed inthe merged image. Microphotographs contributed by Drs. T. Oda and N. Yoshizawa.
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incidence in communities in which no
intervention was attempted.
PROGNOSIS OF PSGN
The immediate prognosis of acute PSGNis excellent for children. In contrast, el-
derly patients who develop acute PSGNusually present with debilitating condi-
tions (malnutrition, alcoholism, diabe-tes, or chronic illness) and have a high
incidence of azotemia (60%), congestiveheart failure (40%), and proteinuria in
the nephrotic range (20%). Death mayoccur in as many as 20 to 25% of these
patients.84,85
The long-term prognosis of PSGN in
children has been the subject of manystudies. The initial reports of natural his-
tory of PSGN in the first half of the 20thcentury indicated an excellent prognosis,
but follow-up periods were relativelyshort. Subsequent studies gave conflict-
ing results because abnormal urinaryfindings were as low as 3.5%86 and as
high as 60%.87
Table 5 summarizes the results of sev-
eral studies published before the year2000 with 5 to 18 yr of follow-up.8693
These pooled data, of course, come fromstudies with dissimilar methods and
widely different results and therefore ispresented only as a rough approximation
of what to expect in the long-term natu-
ral history of PSGN. Table 6 shows datafrom the three studies reported after
2000.9496 When all studies reporting
children followed for 10 to 20 yr afteracute PSGN are taken into account, ap-
proximately 20% of the patients have ab-normal urine analyses, but the incidence
of azotemia is 1%. Our own data94 in-clude 110 children followed for 15 to 18
yr after the acute episode PSGN andshow an incidence of 7.2% for non-ne-
phrotic proteinuria, 5.4% for microhe-maturia, 3.0% for hypertension, and
0.9% for azotemia. A particularly badprognosis was reported for patients from
a recent epidemic in Minas Gerais (Bra-zil), a majority of which were adults (Ta-
ble 6). Chronic renal failure developed in8%ofthesepatientsafter5yr.95 Carefully
collected data in Aboriginal communi-ties in the Northern Territory of Austra-
liaindicated that PSGN is associated withan increased risk for albuminuria (ad-
justed OR 6.1%; 95% confidence interval2.2 to 16.9) and hematuria (OR 3.7; 95%
confidence interval 1.8 to 8.0) in relationto control subjects who did not have
PSGN.96
From the previous discussion, it fol-
lows that, in general, chronic renal fail-ure resulting from PSGN is exceptional
but specific groups of patients do notshare this favorable outlook. A group of
patients with especially poor long-term
prognosis are elderly patients who de-
velop persistent proteinuria in the ne-
phrotic range; 77% of these patients de-velop chronic renal failure.97 For
children, the prognosis of PSGN may be
significantly worse in specific communi-ties in which other risk factors for
chronic renal failure are common. This is
the case in Australian Aboriginal com-munities, where low birth weight (result-
ing in the endowment of a low nephron
number), diabetes, and metabolic syn-drome are prevalent. White et al.96 pos-
tulated that PSGN may represent an ad-
ditional risk factor that would explainwhy the incidence of ESRD is several-
fold higher in these communities than in
the non-Aboriginal population.98,99
PRESENT AND FUTURE ROLE OF
STREPTOCOCCAL GENOMICS IN
PSGN
In the past 8 yr, application of genome-
wide investigative strategies to unsolved
problems with group AStreptococcushascontributed significant new information
aboutmolecular events occurring during
hostpathogen interactions.100102
Thesenew techniques include, among others,
bacterial genome sequencing, expression
microarray (transcriptome) analysis,comparative genomics by DNA-DNA
microarray analysis, and proteomics.99
For example, we now have genome se-
quences available for 11 strains of groupA Streptococcus recovered from diverse
types of infection, making this organism
one of the most extensively characterizedof any human bacterial pathogen.100 This
remarkable array of new informationgives new insight into the pathogenesis of
Table 5. Long-term prognosis of PSGN: Summary of series published before2000 with 5 to 18 yr of follow-upa
Findings % of
Patients
Patients with Positive Finding/
Total Patients Followed
Any abnormality 17.4 174/998
Proteinuria 13.8 137/997
Hypertension 13.8 137/998
Azotemia 1.3 14/1032aData correspond to pooled patients from the studies cited in the text.8693
Table 6. Long-term prognosis of PSGN: Summary of series published after 2000a
Location
No. of Patients
Followed
(Population)
Follow-up
(yr)
Albuminuria
(%)
Hematuria
(%)
Hypertension
(%)
Decreased Renal
Function (%)
Maracaibo, Venezuela94 110 (urban and
rural)
15 to 18 7.2 5.4 13.7 Increased Scr in 0.9% of
the patients
Northern Territory, Australia95 63 (rural) 13 13 (controls
4%)
21 (controls
7%)
Not different
from controls
Not different from
controls
Minas Gerais, Brazil97 56 (rural) 5 8 30 8% (Ccr 60 ml/min)aCcr, creatinine clearance; Scr, serum creatinine.
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1860 Journal of the American Society of Nephrology J Am Soc Nephrol19: 18551864, 2008
8/9/2019 The Current State of Poststreptococcal
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pharyngitis, acute rheumatic fever, puer-
peral sepsis,and other invasive infectionsand has allowed identification of vaccine
targets99,100; however, notably absent has
been the application of these new tech-niques to problems in PSGN.
As a consequence, one of us (J.M.M.)recently began a molecular genomics ini-
tiative designed to contribute new infor-mation about the pathogenesis of PSGN,
aimed at providing new leads for subse-quent clinical and translational research.
One of the first goals has been to se-quence the genome of streptococcal
strains causing or repeatedly associatedwith PSGN (so-called nephritogenic
strains) and compare their geneticmakeup with the genome of strains not
associated with PSGN (non-nephrito-genic strains). Using this approach,
Bereset al.102 found considerable geneticdifferences in nephritogenic and non-
nephritogenic strains of serotype M12
Streptococcus. For example, the nephrito-
genic strain had a large segment of DNA,referred to as region of difference 2
(RD.2), that was lacking in the non-ne-phritogenic strain. RD.2 encodes a large,
predicted, exported protein that is notmade by other sequenced group AStrep-
tococcus strains and thus warrants furtherinvestigation in the context of PSGN
pathogenesis. More recently, as noted,we have sequenced the genome of a
strain ofS. zooepidemicuscausing a largenephritis outbreak after the ingestion of
unpasteurized milk from cows with mas-titis. Unexpected, the gene encoding
SPEB, one of the secreted bacterial prod-ucts that contribute to the survival of
Streptococcus in saliva, was absent.103
Further analysis of the genomic sequence
revealed that a large block of DNA en-coding SPEB present in all groupA Strep-
tococcusstrains studied to date is missing
in this strain, perhaps as a result of a de-letion event (unpublished data). This
finding is important because SPEB hasbeen implicated in the pathogenesis of
PSGN (see the Nephritogenic Antigenssection), and the genomic data clearly in-
dicate that if it participates, then it can-not be the sole causative molecule in all
patients. Molecular proteogenomics arealso at the crossroads of a paradigm shift
in vaccine research toward the strategy of
reverse vaccinology.104106 This strat-egy consists of using a complete genomic
sequence to identify large numbers of
potentially protective antigens, express-ing them in a recombinant form, and
then testing them with a battery of im-munologic assays. These powerful new
tools perhaps coupled with renewed in-terest in nonhuman primate models of
streptococcal infection101,107 are likely tousher a new era of the study of PSGN.
ACKNOWLEDGMENTS
The research in the laboratory of B.R.-I. is sup-
ported by FONACYT grant F-2005000283
from Asociacion de Amigos del Rinon (Mara-
caibo) andGrantsin Aidfrom the Stateof Zulia,
and J.M.M. is supported by the National Insti-
tute of Allergyand Infectious Diseases, National
Institutes of Health (Bethesda, MD).
DISCLOSURESNone.
REFERENCES
1. Wells CD: Observations on the dropsy thatsucceeds scarlet fever. Trans Soc Imp MedCir Knowledge3: 167186, 1812
2. von Pirquet C: Allergy.Arch Intern Med7:259288, 382436, 1911
3. Rodriguez-Iturbe B, Batsford S: Pathogen-esis of poststreptococcal glomerulonephri-tis: A century after Clemens von Pirquet.Kidney Int71: 10941104, 2007
4. Simon P, Ramee MP, Autuly V, Laruelle E,Charasse C, Cam G, Ang KS: Epidemiology
of primary glomerular diseases in a French
region: Variations according to period andage. Kidney Int46: 11921198, 1994
5. Montseny JJ, Meyrier A, Kleinknecht D,Callard P: The current spectrum of infec-tious glomerulonephritis: Experience with76 patients and review of the literature.Medicine (Baltimore)74: 6373, 1995
6. Coppo R, Gianoglio B, Porcellini MG, Mar-inghini S: Frequency of renal diseases and
clinical indications for renal biopsies in chil-dren: Report of the Italian National registryof Renal Biopsies in Children).Nephrol DialTransplant13: 293297, 1998
7. Zhang Y, Shen Y, Feld LG, Stapleton FB:Changing pattern of glomerular disease in
Beijing Childrens Hospital.Clin Pediatr33:542547, 1994
8. Yap HK, Chia KS, Murugasu B, Saw AH, TayJS, Ikshuvanam M, Tan KW, Cheng HK, TanCL, Lim CH: Acute glomerulonephritis
changing patterns in Singapore children.Pediatr Nephrol4: 482484, 1990
9. Berrios X, Lagomarsino E, Solar E, Sando-val G, Guzman B, Riedel I: Post-streptococ-
cal acute glomerulonephritis in Chile: 20years of experience. Pediatr Nephrol 19:306312, 2004
10. Rodriguez-Iturbe B, Garcia R, Rubio L,
Cuenca L: Clinical and epidemiologicalcharacteristics of poststreptococcal glo-merulonephritis in the Zulia region. InvestClin26: 191211, 1985
11. Roy S, Stapleton FB: Changing perspec-tives in children hospitalized with post-streptococcal acute glomerulonephritis.
Pediatr Nephrol4: 585588, 199012. Currie B, Brewster DR: Childhood infec-
tions in the tropical north of Australia. JPaediatr Child Health 37: 326330, 2001
13. Orta N, Moriyon JC: Epidemiology of renaldiseases in children in Venezuela. ArchVenez Puericult Pediatr64: 7683, 2001
14. Pakash J, Saxena RK, Sharma OP: Spec-trum of renal diseases in the elderly: Singlecenter experience from a developing coun-
try.Int Urol Nephrol33: 227233, 200115. Stetson CA, Rammelkamp CH, Krause RA,
Kohen RJ, Perry WD: Epidemic acute ne-phritis: Studies on etiology, natural historyand prevention. Medicine 34: 431 450,
195516. Poon-King T, Mohammed I, Cox R, Potter
EV, Simon NM, Siegel AC, Earle DP: Recur-rent epidemic nephritis in South Trinidad.N Engl J Med277: 728732, 1967
17. Rodriguez-Iturbe B, Garca R, Rubio L,
Cuenca L, Treser G, Lange K: Epidemicglomerulonephritis in Maracaibo. ClinNephrol5: 197206, 1976
18. Davalos C, Valle C: Post-steptococcal glo-merulonephritis in Barbacoa, Guantanamo,
Cuba. Havana, Instituto Nacional de Nefro-loga, 1975
19. Potter EV, Ortiz JS, Sharrett AR, Burt EG,Bray JP, Finklea JF, Poon-King T, Earle DP:Changing types of nephritogenic strepto-
cocci in Trinidad. J Clin Invest 50: 11971205, 1971
20. Reid HF, Bassett DC, Gaworzewska E, Col-man G, Poon-King T: Streptococcal sero-types newly associated with epidemic post-streptococcal acute glomerulonephritis.
J Med Microbiol32: 111114, 199021. Sarkissian A, Papazian M, Azatian G, Ariki-
ants N, Babloyan A, Leumann E: An epi-demic of acute postinfectious glomerulo-nephritis in Armenia. Arch Intern Med77:
342344, 199722. Jankauskiene A, Pundziene B, Vitkevic R:
Postinfectious glomerulonephritis in chil-dren in Lithuania during 19952004: Prev-
SPECIAL ARTICLEwww.jasn.org
J Am Soc Nephrol 19: 18551864, 2008 Poststreptococcal Nephritis 1861
8/9/2019 The Current State of Poststreptococcal
8/10
alence and clinical features.Medicina (Kau-nas) 43[Suppl 1]: 1622, 2007
23. Balter S, Benin A, Pinto SW, Teixeira LM,Alvim GG, Luna E, Jackson D, LaClaire L,Elliott J, Facklam R, Schuchat A: Epidemic
nephritis in Nova Serrana, Brazil. Lancet355: 17761780, 2000
24. Lopez V, Sekihara G, Pimentel G, Men-doza A, Asmat K: Glomerulonephritis
postestreptococcica. Abstractos del Con-greso Peruano de Nefrologa 32, Lima,Peru, Sociedad Peruana de Nefrologa,2002
25. Almroth G, Lindell A, Aselius H, Soren L,Svensson L, Hultman P, Eribe ER, Olsen I:Acute glomerulonephritis associated with
Streptococcus pyogeneswith concomitantspread of Streptococcus constellatus infour rural families.Ups J Med Sci110: 217231, 2005
26. Barnham M, Thornton TJ, Lange K: Nephri-tis caused by Streptococcus zooepidemi-
cusLancefield group C.Lancet1: 945948,1983
27. Bisno AL, Pierce IA, Wall HP, Moody MD,Stollerman GH: Contrasting epidemiologyof acute rheumatic fever and acute glomer-ulonephritis.N Engl J Med283: 561565,1970
28. Dawson KP, Martin DR: Streptococcal in-volvement in childhood acute glomerulo-nephritis: A review of 20 cases at admis-sion.N Z Med J95: 373376, 1982
29. Francis AJ, Nimmo GR, Efstratiou A, Gala-nis V, Nuttall N: Investigation of milk-borne
Streptococcus zooepidemicusinfection as-sociated with glomerulonephritis in Austra-lia.J Infect27: 317323, 1993
30. Johnston F, Carapetis J, Patel MS, WallaceT, Spillane P: Evaluating the use of penicil-
lin to control outbreaks of acute poststrep-tococcal glomerulonephritis.Pediatr InfectDis J18: 327332, 1999
31. Jovanovic D, Maric M, Kovacevic Z, Ska-taric V, Jokovic B: Epidemiology of post-streptococcal glomerulonephritis in the
military population. Srp Arh Celok Lek.124[Suppl 1]: 187189, 1996
32. Kaplan EL, Anthony BF, Chapman SS,Wannamaker LW: Epidemic acute glo-merulonephritis associated with type 49
streptococcal pyoderma. I. Clinical andlaboratory findings. Am J Med48: 927,1970
33. Majeed HA, Khuffash FA, Sharda DC, Far-wana SS, el-Sherbiny AF, Ghafour SY: Chil-dren with acute rheumatic fever and acute
poststreptococcal glomerulonephritis andtheir families in a subtropical zone: A three-year prospective comparative epidemio-logical study.Int J Epidemiol16: 561568,1987
34. Majeed HA, Yousof AM, Rotta J, Havlick-pva H, Bahar G, Bahbahani K: group Astreptococcal strains in Kuwait: A nine-yearprospective study of prevalence and asso-
ciations.Pediatr Infect Dis J11: 295300,
199235. Margolis HS, Lum MK, Bender TH, Elliot SI,
Fitzgerald MA, Harpster AP: Acute glomer-ulonephritis and streptococcal skin lesions
in Eskimo children. Am J Dis Child 134:681685, 1980
36. Masuyama T, Ishii E, Muraoka K, Honjo S,Yamaguchi H, Hara T, Shimazaki K, Koga T,
Moriya K, Ide M, Miyazaki S: Outbreak ofacute glomerulonephritis in children: ob-served association with the T1 subtype of
group A streptococcal infection in northernKyushu, Japan.Acta Paediatr Jpn38: 128131, 1996
37. Meekin GE, Martin DR: Autumn: The sea-
son for post-streptococcal acute glomeru-lonephritis in New Zealand. N Z Med J97:226229, 1984
38. Reed RW: An epidemic of acute nephritis.
CMAJ68: 448455, 195339. Reinstein CR: Epidemic nephritis in Red
Lake Minnesota.J Pediatr47: 2534, 195540. Streeton CL, Hanna JN, Messer RD, Meri-
anos A: An epidemic of acute post-strep-tococcal glomerulonephritis among Ab-original children. J Paediatr Child Health31: 245248, 1995
41. Zuazo J, Almaguer M, Cabrera MS, Texidor
ME: Epidemiological study of an outbreakof acute poststreptococcal nephritis. RevCub Higiene Epidemiol24: 363369, 1986
42. Rodriguez-Iturbe B, Mezzano S: Infectionsand kidney diseases: A continuing globalchallenge. In: Kidney Diseases in the De-
veloping World and Ethnic Minorities, ed-ited by El Nahas M, London, Taylor & Fran-cis, 2005, pp 5982
43. United Nations Development Programme:Human development reports. Available at:
http://hdr.undp.org/en/statistics/. AccessedDecember 23, 2007
44. Srivastava RN, Bagga A, Moudgil A: Acuterenal failure in north Indian children.IndianJ Med Res92: 404408, 1990
45. Gokcay G, Emre S, Tanman F, Sirin A, El-
cioglu N, Dolunay G: An epidemiologicalapproach to acute renal failure in children.J Trop Pediatr37: 191193, 1991
46. Bourquia A, Zaid D: Acute renal insuffi-ciency in children: A retrospective study of
89 cases. Ann Pediatr (Paris)40: 603608,1993
47. Bamgboye EL, Mabayoje MO, Odutola TA,Mabadeje AF: Acute renal failure at theLagos University Teaching Hospital: A 10-
year review. Ren Fail15: 7780, 199348. Kandoth PW, Agarwal GJ, Dharnidharka
VR: Acute renal failure in children requiringdialysis therapy. Indian Pediatr 31: 305309, 1994
49. Arora P, Kher V, Gupta A, Kohli HS, Gulati
S, Rai PK, Kumar P, Sharma RK: Pattern ofacute renal failure at a referral hospital.Indian Pediatr31: 10471053, 1994
50. Florentin de Merech L: Prevalence of acute
renal failure and its more frequent etiolo-
gies in pediatric nephrology patients. ArchArgent Pediatr99: 219227, 2001
51. Chugh KS, Narang A, Kumar L, Sakhuja V,Unni VN, Pirzada R, Singh N, Pereira BJ,
Singhal PC: Acute renal failure amongstchildren in a tropical environment. Int J
Artif Organs10: 97101, 198752. Lopez V, Sakihara G, Pimentel G, Mendoza
A, Asmat K: Glomerulonefritis aguda difusapostinfecciosa (GNDAPI). Abstractos delVII Congreso de la Sociedad Peruana de
Nefrologa 176-B2, Lima, Peru, SociedadPeruana de Nefrologa, 2002
53. Prakash J, Sen D, Kumar NS, Kumar H,Tripathi LK, Saxena RK: Acute renal failure
due to intrinsic renal diseases: Review of112 cases.Ren Fail25: 225233, 2003
54. Olowu WA, Adelusola KA: Pediatric acuterenal failure in southwestern Nigeria. Kid-
ney Int66: 15411548, 200455. Carapetis JR, Steer AC, Mullholand EK,
Weber M: The global burden of group Astreptococcal diseases.Lancet5: 685694,2005
56. Rodriguez-Iturbe B, Burdmann EA, Ophas-charoensuk V, Barsoum R: Glomerular dis-ease associated with infection. In: Compre-hensive Clinical Nephrology, 3rd Ed.,
edited by Feehally J, Floege J, Johnson RJ,London, Mosby, 2007, pp 305316
57. Anochie IC, Eke FU: Acute renal failure inNigerian children: Port Harcourt experi-ence. Pediatr Nephrol 20: 16101614,
200558. Vachvanichsanong P, Dissaneewate P, Lim
A, McNeil E: Childhood acute renal failure:22-Year experience in a university Hospitalin Southern Thailand. Pediatrics 118:e786 e791, 2006
59. Yoshizawa N, Yamakami K, Fujino M, OdaT, Tamura K, Matsumoto K, Sugisaki T,Boyle MD: Nephritis-associated plasmin re-ceptor and acute poststreptococcal glo-merulonephritis: Characterization of the
antigen and associated immune response.J Am Soc Nephrol15: 17851793, 2004
60. Oda T, Yamakami K, Omasu F, Suzuki S,Miura S, Sugisaki T, Yoshizawa N: Glomer-ular plasmin-like activity in relation to ne-phritis-associated plasmin receptor in
acute poststreptococcal glomerulonephri-tis.J Am Soc Nephrol16: 247254, 2005
61. Poon-King R, Bannan J, Viteri A, Cu G,Zabriskie JB: Identification of an extracellu-lar plasmin binding protein from nephrito-
genic streptococci. J Exp Med178: 759763, 1993
62. Parra G, Rodrguez-Iturbe B, Batsford S,Vogt A, Mezzano S, Olavarra F, Exeni R,Laso M, Orta N: Antibody to streptococcalzymogen in the serum of patients with
acute glomerulonephritis: A multicentricstudy.Kidney Int54: 509517, 1998
63. Cu GA, Mezzano S, Bannan JD, ZabriskieJB: Immunohistochemical and serological
SPECIAL ARTICLE www.jasn.org
1862 Journal of the American Society of Nephrology J Am Soc Nephrol19: 18551864, 2008
8/9/2019 The Current State of Poststreptococcal
9/10
evidence for the role of streptococcal pro-teinase in acute post-streptococcal glo-
merulonephritis. Kidney Int54: 819826,1998
64. Fujino M, Yamakami K, Oda T, Omasu F,
Murai T, Yoshizawa N: Sequence and ex-pression of NAPlr is conserved among
group A streptococcal isolated from pa-tients with acute poststreptococcal glo-
merulonephritis (APSGN) and non-APSGN.J Nephrol20: 364369, 2007
65. Batsford S, Brundiers M, Schweier O, Hor-bach E, Monting JS: Antibody to strepto-
coccal cysteine proteinase as a seromarkerof group A streptococcal (Streptococcuspyogenes) infections.Scand J Infect Dis34:
407412, 200266. Batsford S, Mezzano S, Mihattsch M, Schiltz
E, Rosriguez-Iturbe B: Is the nephritogenicantigen in post-streptococcal glomerulo-
nephritis pyrogenic exotoxin B (SPEB) orGAPDH? Kidney Int68: 11201129, 2005
67. Vogt A, Batsford S, Rodrguez-Iturbe B,Garca R: Cationic antigens in poststrepto-
coccal glomerulonephritis. Clin Nephrol20: 271279, 1983
68. Vogt A, Schmiedeke T, Stockl F, Sugisaki Y,Mertz A, Batsford S: The role of cationicproteins in the pathogenesis of immune
complex glomerulonephritis.Nephrol DialTransplant5[Suppl 1]: 69, 1990
69. Nicholson ML, Ferdinand L, Sampson JS,Benin A, Balter S, Pinto SW, Dowell SF,Facklam RR, Carlone GM, Beall B: Analysisof immunoreactivity to a Streptococcus
equi subsp. zooepidemicusM-like proteinto confirm an outbreak of poststreptococ-cal glomerulonephritis, and sequence ofM-like proteins from isolates obtained fromdifferent host species. J Clin Microbiol38:
4126 4130, 200070. Rincon J, Viera NT, Romero MJ, Mosquera
JA: Increased production of chemotacticcytokines and elevated proliferation andexpression of intercellular adhesion mole-cule-1 in rat mesangial cells treated with
erythrogenic toxin type B and its precursorisolated from nephritogenic streptococci.Nephrol Dial Transplant 18: 10721078,2003
71. Pedreanez A, Viera N, Rincon J, Mosquera
J: Increased IL-6 in supernatant of rat mes-angial cell cultures treated with erythro-genic toxin type B and its precursor iso-lated from nephritogenic streptococci.Am J Nephrol26: 7581, 2006
72. Khan F, Yamakami K, Mahmood J, Li B,
Kikuchi T, Kumagai N, Morioka T, Yo-shizawa N: Alterations of cell adhesionmolecules in human glomerular endothelialcells in response to nephritis-associatedplasminogen receptor. Exp Nephrol 105:e53e64, 2007
73. Viera N, Pedreanez A, Rincon J, MosqueraJ: Streptococcal exotoxin B increases inter-leukin-6, tumor necrosis factor alpha, inter-
leukin-8 and transforming growth factorbeta-1 in leukocytes. Pediatr Nephrol22:
12731281, 200774. Pancholi V, Fischetti VA: -enolase, a novel
strong plasminogen binding protein on the
surface of pathogenic streptococci. J BiolChem 273: 1450314515, 1998
75. Shank JC, Powell TA: A five-year experi-ence with throat cultures. J Fam Pract18:
857863, 198476. Cebul DR, Poses RM: The comparative
cost-effectiveness of statistical decisionrules and experienced physicians in phar-
yngitis management. JAMA 256: 33533357, 1986
77. Centor RM, Witherspoon JM, Dalton HP,
Brody CE, Link K: The diagnosis of strepsore throat in adults in the emergencyroom. Med Decis Making 1: 239246, 1981
78. McIsaac WJ, White D, Tannenbaum D, Low
DE: A clinical score to reduce unnecessaryantibiotic use in patients with sore throat.
CMAJ158: 7583, 199879. McIsaac WJ, Goel V, To T, Low DE: The
validity of a sore throat score in family prac-tice.CMAJ163: 811815, 2000
80. Edmonson MB, Farwell KR: Relationshipbetween the clinical likelihood of group Astreptococcal pharyngitis and the sensitiv-
ity of a rapid antigen-detection test in apediatric practice. Pediatrics 115:280285, 2005
81. American Academy of Pediatrics, Commit-tee on Infectious Diseases: Group A strep-tococcal infections. In: The Red Book, Elk
Grove Village, IL, American Academy ofPediatrics, 2000, pp 526592
82. Zoch-Zwierz W, Wasilewska A, Biernacka A,Tomaszewska B, Winiecka W, Wiercinski R,Porowski T: The course of post-streptococ-
cal glomerulonephritis depending onmethods of treatment of the preceding re-spiratory tract infection. Wiad Lek54: 5663, 2001
83. Rodriguez-Iturbe B, Rubio L, Garcia R: At-tack rate of poststreptococcal nephritis in
families: A prospective study. Lancet 1:401403, 1981
84. Melby PC, Musik WD, Luger AM, Khanna R:Poststreptococcal glomerulonephritis inthe elderly: Report of a case and review of
the literature. Am J Nephrol 7: 235240,1987
85. Washio M, Oh Y, Okuda S, Yanase T, Mi-ishima C, Fujimi S, Ohchi N, Nanishi F,Onoyama K, Fujishima M: Clinicopatholog-ical study of poststreptococcal glomerulo-
nephritis in the elderly. Clin Nephrol 41:265270, 1994
86. Potter EV, Lipschultz SA, Abidh S, Poon-King T, Earle DP: Twelve to seventeen-yearfollow up of patients with acute poststrep-
tococcal glomerulonephritis in Trinidad.N Engl J Med307: 725729, 1982
87. Baldwin DS, Gluck MC, Schacht RG, GalloG: The long-term course of poststrepto-
coccal glomerulonephritis.Ann Intern Med
80: 342358, 197488. Buzio C, Allegri L, Mutti A, Perazzoli F,
Bergamaschi E: Significance of albuminuriain the follow-up of acute poststreptococcal
glomerulonephritis.Clin Nephrol41: 259264, 1994
89. Clark G, White RH, Glasgow EF: Post-strep-tococcal glomerulonephritis in children:
Clinicopathological correlations and long-term prognosis. Pediatr Nephrol 2: 381388, 1988
90. Garcia R, Rubio L, Rodriguez-Iturbe B:Long-term prognosis of epidemic post-streptococcal glomerulonephritis in Mara-caibo: Follow-up studies 1112 years after
the acute episode. Clin Nephrol15: 291298, 1981
91. Lien JK, Mathew TH, Meadows R: Acutepoststreptococcal glomerulonephritis in
adults: A long term study. Q J Med 189:99111, 1979
92. Perlman LV, Herdman RC, Kleinman H, Ver-nier RL: Poststreptococcal glomerulone-
phritis: A ten year follow-up of an epi-demic. JAMA 194: 6370, 1965
93. Travis LB, Dodge WF, Beathard GA SpargoBH, Lorentz WB, Carvajal HF, Berger M:Acute glomerulonephritis in children: A re-
view of thenatural history with emphasis onprognosis. Clin Nephrol1: 169181, 1973
94. Rodriguez-Iturbe B: Acute endocapillaryglomerulonephritis. In:Oxford Textbook ofClinical Nephrology, 3rd Ed., edited byDavison A, Cameron JS, Grunfeld JP, Pon-
ticelli C, Ritz E, Winearls CG, van YperseleC, Oxford, Oxford University Press, 2005,pp 545557
95. Sesso R, Pinto SWL: Five-year follow-up ofpatients with epidemic glomerulonephritis
due to Streptococcus zooepidemicus.Nephrol Dial Transplant 20: 18081813,2005
96. White AV, Hoy WE, McCredie DA: Child-hood post-streptococcal glomerulonephri-tis as a risk factor for chronic renal disease
in later life. Med J Aust 174: 492 494,2001
97. Vogl W, Renke M, Mayer-Eichberger D,Schmitt H, Bohle A: Long-term prognosisfor endocapillary glomerulonephritis of
poststreptococcal type. Nephron 44: 5865, 1986
98. Cass A, Cunningham J, Snelling P, Wang Z,Hoy WE: Social disadvantage and variationof he incidence of end stage renal disease
in Australian capital cities.Aust N Z J PublicHealth25: 322326, 2001
99. Nenov V, Maarten WT, Sakharova OV,Brener BM: Multi-hit nature of chronic renaldisease. Curr Opin Nephrol Hypertens 9:8597, 2000
100. Musser JM, DeLeo FR: Toward a genome-wide systems biology analysis of host-pathogen interactions in group A Strepto-coccus. Am J Pathol167: 14611472, 2005
SPECIAL ARTICLEwww.jasn.org
J Am Soc Nephrol 19: 18551864, 2008 Poststreptococcal Nephritis 1863
8/9/2019 The Current State of Poststreptococcal
10/10
101. Tart AH, Walker MJ, Musser JM: New un-derstanding of the group AStreptococcuspathogenesis cycle. Trends Microbiol 15:318325, 2007
102. Beres SB, Musser JM: Contribution of ex-ogenous genetic elements to the metage-nome of group AStreptococcus. PLoS One
2: e5, 2007103. Shelburne SA III, Granville C, Sitkiewicz I,Tokuyama M, Patel P, Musser JM: Growthcharacteristics and extracellular virulencefactor production by group A Streptococ-cus during cultivation in human saliva. In-fect Immun73: 47234731, 2005
104. Pizza M, Scarlato V, Masignani V, Giuliani
MM, Arico B, Comanducci M, Jennings GT,Baldi L, Bartolini E, Capecchi B, Galeotti
CL, Luzzi E, Manetti R, Marchetti E, MoraM, Nuti S, Ralti G, Santini L, Savino S, Scar-serlli M, Stomi E, Zuo P, Broeker M, HundtE, Knapp B, Blair E, Mason T, Tettlin H,
Hood DW, Jeffries AC, Saunders NJ,Granoff DM, Venter JC, Moxon ER, GrandlG, Rappuoli R: Identification of vaccine
candidates against serigroup B Meningo-coccusby whole-genome sequencing.Sci-ence 287: 18161820, 2000
105. Fraser CM, Rappuoli R: Application of micro-bial genome science to advanced therapeu-tics.Annu Rev Microbiol56: 459474, 2005
106. Malone D, Rinaudo D, Masignani V, MoraM, Scarselli M, Tettelin H, Brettoni C, Iaco-
bini ET, Rosini R, DAgostino M, Miorin L,Buccato S, Mariani M, Galli G, Nogarotto R,
Dei VN, Vegni F, Fraser C, Mancuso G, TetiG, Madoff LC, Paoletti LC, Rappuoli R,Kasper DL, Telford JL, Grandi G: Identifi-cation of a universal group B streptococcal
vaccine by multiple genome screen. Sci-ence309: 148150, 2005
107. Virtaneva K, Porcella SF, Graham MR, Ire-
land RM, Johnson CA, Ricklefs SM, Babar I,Parkins L, Romero RA, Corn CJ, Gardner D,Bailey JR, Parnell MJ, Musser JM: Longitu-dinal analysis of the group AStreptococcustranscriptome in experimental pharyngitisin cynomolgus macaques. Proc Natl AcadSci U S A 102: 90149019, 2005
108. World Health Organization: Countries.
Available at: http://www.who.int/countries/en/. Accessed January 10, 2008
SPECIAL ARTICLE www.jasn.org
1864 Journal of the American Society of Nephrology J Am Soc Nephrol19: 18551864, 2008
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