The Current State of Poststreptococcal

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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.




7/10

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.

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