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Indigenous Health Research
Childhood post-streptococcal glomerulonephritis as a risk factor
for chronic renal disease in later life
Andrew V White, Wendy E Hoy and David A McCredie
MJA 2001; 174: 492-496
For editorial comment, see Atkins
Abstract -
Methods -
Results -
Discussion -
Acknowledgements -
References -
Authors' details
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More articles on Aboriginal health
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Objective: To test the hypothesis that
post-streptococcal glomerulonephritis (PSGN) in childhood is a
risk factor for chronic renal disease in later life.
Design: Retrospective cohort study.
Setting: A remote Aboriginal community in the "Top End" of
the Northern Territory that experienced two epidemics of PSGN in 1980
and 1987, respectively.
Participants: 472 people who were aged 2-15 years during
either epidemic. They were categorised by clinical features
recorded during the epidemics as having clinically defined PSGN
(63), "abnormal urine" (haematuria or proteinuria; 86) or controls
(323).
Outcome measures: Urinary albumin to creatinine ratio
(ACR), haematuria (by dipstick urinalysis), blood pressure, serum
creatinine level, and calculated glomerular filtration rate (GFR)
during community screening in 1992-1998.
Results: Overt albuminuria (ACR > 34 mg/mmol) was
present at follow-up in 13% of the PSGN group, 8% of the abnormal urine
group, and 4% of the control group. The odds ratio (OR) for overt
albuminuria in those with a history of PSGN compared with the control
group, adjusted for age and sex, was 6.1 (95% CI, 2.2-16.9).
Haematuria (> trace) was present in 21% of the PSGN group compared
with 7% of the control group (adjusted OR, 3.7; 95% CI, 1.8-8.0). There
were no significant differences between the groups in blood
pressure, serum creatinine level or calculated GFR.
Conclusion: In this population, a history of PSGN in
childhood is a risk factor for albuminuria and haematuria in later
life.
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Although unusual in the rest of Australia, post-streptococcal
glomerulonephritis (PSGN) is still common in Aboriginal children
living in remote communities, where group A streptococcal pyoderma
is endemic.1 In these communities,
chronic renal disease and end-stage renal failure also occur in
adults at alarming rates.2-4 PSGN is usually followed by clinical recovery over several days to
weeks, and the long-term outlook has generally been regarded as
excellent, with no increase in risk of urinary abnormalities or
hypertension.5-7 However, some studies
have suggested an increase in rates of chronic renal impairment after
this illness.8,9
We aimed to test whether a history of PSGN in childhood is a risk factor
for later renal dysfunction in Aboriginal Australians living in a
remote community. The main outcome measure used, albumin to
creatinine ratio, is a sensitive early marker of renal damage. It has
been shown to provide a reliable estimate of 24-hour protein
excretion and to predict the rate of decline of glomerular filtration
rate and progression to end-stage renal failure in
diabetic10 and
non-diabetic11 nephropathy.
Albuminuria has also been shown to mark early chronic renal disease in
this population of Aboriginal Australians, and its progression
predicts renal failure, as well as cardiovascular disease and
mortality.12,13 |
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Study design |
This was a retrospective cohort study of children from an isolated
Aboriginal coastal community in the "Top End" of the Northern
Territory of Australia. The community experienced two epidemics of
PSGN in 1980 and 1987, respectively, each lasting for three
months.14,15 Children were
followed up after these epidemics for a mean of 14.6 years (range, 6-18
years).
The study was approved by the Joint Institutional Ethics Committee of
the Royal Darwin Hospital and the Menzies School of Health Research,
as well as a local community health board. Consent was obtained from
each individual or guardian at the time of screening.
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Participants |
Participants were 472 people who lived in the community and were aged
2-15 years at the time of either epidemic and who participated in
health screening examinations between 1992 and 1998. These 472
people represented 98% of the population of the community in the
relevant age groups, according to 1996 census estimates.16 |
Baseline data | |
During the epidemics, children in the community were screened
systematically for oedema, hypertension, and urinary
abnormalities on dipstick testing; results were recorded in
individuals' medical records in the community. We used these data to
categorise children by history during the epidemics:
- The PSGN group
had documented oedema (facial swelling or dependent oedema) or
hypertension (diastolic pressure ≥ 80 mmHg if aged 2-12 years and
≥ 85 mmHg if over 12, levels corresponding to the 90th percentile
for each age range)17 plus haematuria greater
than trace or proteinuria greater than trace on dipstick
urinalysis.
- The "abnormal urine" group had haematuria greater than trace or
proteinuria greater than trace, but no oedema or hypertension.
- The control group comprised children who had normal results on
clinical examination and urinalysis (trace or less for blood and
protein); children with no symptoms suggesting PSGN, but for whom
urinalysis was either not performed or not recorded; and children
with no entry in the medical record at the time of the epidemics.
Children whose ages were in the range 2-15 years during both epidemics
were categorised according to their most abnormal findings in either
epidemic.
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Outcome measures | |
Population health screening was undertaken in the community between
1992 and 1999.14 For people screened more
than once, results from the latest screening were used. The albumin to
creatinine ratio (ACR) was determined in a random urine sample and was
categorised as normal (< 1.1 mg/mmol), suspicious (1.1-3.3
mg/mmol), microalbuminuria (3.4-33 mg/mmol), or overt albuminuria
(≥ 34 mg/mmol). Glomerular filtration rate (GFR) was calculated
using the formula of Cockroft and Gault.18 Dipstick urinalysis was
also performed (Multistix 10SG, Bayer Diagnostics), and blood
pressure and serum creatinine level were measured.
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Analysis |
Baseline characteristics of the groups were compared using Fisher's
exact test for categorical variables and, as not all data followed a
normal distribution, the non-parametric Kruskal-Wallis test for
continuous variables. Logistic regression estimates were used to
obtain adjusted proportions of the population with albuminuria.
Odds ratios for the outcomes albuminuria and haematuria were
obtained from logistic regression models that included the
factors age, sex, birth weight and body mass index. Analyses
were performed using Stata statistical software.19 |
| Results
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|
Baseline characteristics | |
Of the 472 people included in the study, 259 were aged 2-15 years during
the 1980 epidemic, and 331 during the 1987 epidemic (with 118 in the age
group during both epidemics). Overall, 275 (58%) were male.
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Categorisation of participants | |
Categorisation of participants according to history during the
epidemics is shown in Box 1. Of the 63 children with clinically defined
PSGN, all had haematuria and proteinuria, 61 (97%) had oedema and 28
(44%) had hypertension. Although evidence of preceding group A
streptococcal infection was not required for classification in the
PSGN group, serum antideoxyribonuclease B antibody titres were
positive (≥ 1:480) in all 36 of the group in whom they were
measured, and serum complement levels were consistent with PSGN (low
C3 level) in 35 of the 39 in whom they were measured. Of the 86
participants in the abnormal urine group, 84 (98%) had haematuria,
and 24 (28%) had proteinuria.
Characteristics of participants at follow-up differed
significantly between the groups, with the PSGN group being younger,
and the abnormal urine group having a lower proportion of males (Box
2). The three control subgroups also differed at follow-up in median
age (normal results subgroup, 26.9 years; no urinalysis subgroup,
17.5 years; and not recorded subgroup, 18.4 years; P = 0.001)
and body mass index (normal results subgroup, 20.9 kg/m2; no urinalysis
subgroup, 19.1 kg/m2; and not recorded subgroup,
19.8 kg/m2; P = 0.007).
However, after adjustment for age and sex, there were no significant
differences in height or weight. The control subgroups were combined
for analysis.
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Outcomes |
On follow-up screening, 104 participants (22%) had albuminuria of
any degree (micro- or overt; ACR ≥ 3.4 mg/mmol), 27 (6%) had overt
albuminuria (ACR ≥ 34 mg/mmol), and 45 (10%) had haematuria
(≥ trace), while 64 (14%) had haematuria or overt
albuminuria.
Albuminuria and haematuria were more prevalent in the groups with a
history of clinical PSGN or abnormal urine during the PSGN epidemics
than in the control group (Box 3). In the abnormal urine group,
outcomes at follow-up were similar whether or not haematuria had
occurred alone or in the presence of proteinuria during the
epidemics.
As the presence of albuminuria is significantly related to age in this
community,14 and as albuminuria was
more common in females than males (overt albuminuria occurred in 4% of
males and 8% of females; P = 0.044), probabilities were
adjusted for age and sex (Box 4). The adjusted probability of overt
albuminuria at follow-up was 13.6% after PSGN (95% CI, 6.7%-25%),
compared with 2.5% in controls (95% CI, 1.1%-4.8%).
Odds ratios for albuminuria and haematuria at follow-up
according to history during the epidemics are shown in Box 3. After
adjustment for age and sex, the odds of overt albuminuria were more
than six times greater after PSGN compared with the control group,
while the odds of albuminuria of any degree were more than three times
greater. The population-attributable fraction, or proportion of
overt albuminuria in the study population that can be attributed to
PSGN in childhood, was 24% (95% CI, 5%-40%).
After adjustment for age and sex, the odds of haematuria were more than
three times greater after PSGN compared with the control group, while
the odds of either haematuria or overt albuminuria were five times
greater. Only three individuals had both haematuria and overt
albuminuria, two of whom had a history of PSGN.
Birth weight was available for 429 participants (61 with PSGN, 77 with
abnormal urine and 291 controls). Adding birth weight to the logistic
regression model gave an odds ratio of 7.6 for overt
albuminuria in the PSGN group using controls as the reference (95% CI,
2.5-22.5). Adding body mass index to the model did not significantly
alter the odds ratios.
There were no significant differences in blood pressure, serum
creatinine level or calculated glomerular filtration rate between
the groups.
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This study indicates that a history of PSGN in childhood is a risk
factor for albuminuria and haematuria years later, and suggests that
about a quarter of cases of overt albuminuria may be attributable to
PSGN in childhood. The incidence of renal disease is high in this
population of Aboriginal Australians,12 and other risk factors for
renal disease are also common, including low birth weight,
recurrent infectious diseases, diabetes and features of syndrome
X.3,12,20,21 Possibly, it is
the combination of insults that leads to high risk for later renal
disease. A prospective cohort study would provide the best evidence.
Results of other studies on the contribution of PSGN to chronic renal
disease have varied, with some studies reporting no link. For
example, two large follow-up studies after epidemic PSGN in
Trinidad6,22,23 and
Venezuela,7,24 respectively, reported
low rates of long-term abnormalities, although the Venezuelan study
found that 11.2% of participants had proteinuria of > 500 mg/24 h
at 11-year follow-up. These studies had high losses to follow-up (31%
and 82%, respectively), and neither had a control group nor assessed
microalbuminuria. A cohort study after a PSGN epidemic in an
American Indian community found no difference at 10-year follow-up
between those who had had PSGN and those who had not in blood pressure,
serum creatinine level, proteinuria or haematuria. However,
urinary abnormalities were common, being present in 17% of the PSGN
group and 13% of the control group.5
In contrast, other studies have reported, similarly to ours,
clinically important abnormalities at long-term follow-up
after PSGN. An uncontrolled study from north India found proteinuria
(defined as more than trace levels on qualitative examination) in
13.8% of people two to 10 years after nephritis.25 Protein to
creatinine ratios were > 20 mg/mmol in 9% of people recruited from
a tertiary London hospital 14-22 years after sporadic childhood
PSGN,26 while, in an Italian
study, microalbuminuria or greater was present in 46% of 26 patients
three to 24 years after PSGN but only 2.5% of 100 control
participants.27 Other studies have found
significantly lower renal functional reserve in people with a remote
history of PSGN compared with control participants.28,29
Our study had the strengths of having a control group and a long
follow-up, studying a large proportion of people in a single
community and measuring albuminuria in the microalbuminuric range.
Its limitations include possible misclassification of
participants, as PSGN was diagnosed by clinical criteria. The
abnormal urine group may have included people with subclinical PSGN,
other renal disease, or isolated haematuria of no significance.
However, this is unlikely to have biased results significantly, as
the main findings concerned differences between the PSGN and control
groups, which had more certain definitions. Nevertheless, some
participants classified with PSGN may have had another cause for
their renal disease. For example, one child was later diagnosed with
mesangiocapillary glomerulonephritis after renal biopsy; she may
have been predisposed to PSGN by pre-existing renal disease, may have
had consecutive disease processes or may never have had PSGN. Lastly,
control participants who were not seen during the epidemics may have
had unrecognised PSGN. However, this would have decreased rather
than exaggerated differences between the PSGN and control groups.
Although some historical data were unavailable, fewer females than
males were studied, and follow-up times varied; these factors were
unlikely to have affected results. Because albuminuria precedes
clinical signs of chronic renal disease, longer follow-up could be
expected to show changes in blood pressure, serum creatinine levels
and GFR.
Other factors may be involved in the observed relationship between
PSGN and albuminuria and the postulated relationship with chronic
renal disease. Firstly, another underlying renal process may
predispose both to PSGN on exposure to a nephritogenic streptococcus
and to later albuminuria. Secondly, albuminuria may not have such
adverse prognostic significance after PSGN as it does in other
circumstances; our follow-up was not long enough to show progression
to chronic renal disease. Thirdly, PSGN may increase risk of chronic
renal disease only in combination with other insults. Renal disease
is extremely common in this community, and, although our findings are
likely to apply to similar populations, they may not be universally
applicable.
In summary, we have presented evidence that, in this community, a
remote history of PSGN in childhood is a powerful risk factor for renal
damage, as evidenced by increased ACR and haematuria. These findings
are important as PSGN is still prevalent in children living in
Aboriginal communities in Australia. Prevention of PSGN is possible
through improvements to housing, economic and living conditions,
along with attention to control and treatment of scabies and skin
infections. Preventing PSGN may contribute to reducing the
incidence of renal disease and renal failure in the future.
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This study was supported by the National Health and Medical Research
Council and the Australian Kidney Foundation. We acknowledge the
support and participation of the Tiwi community and the staff of the
health clinic at Nguiu. Health workers Jerome Kerinauia, Nellie
Punguatji, Darren Fernando and Colleen Kantilla and project
officers Eric and Elizabeth Tipiloura were key contributors to the
field work. We thank Bev Hayhurst, who coordinated much of the
screening program, and Zhiqiang Wang, who provided statistical
advice. We also acknowledge Kate Walker's work in looking at earlier
data.
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Potter E, Lipschultz S, Abidh S, et al. Twelve- to seventeen-year
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Baldwin DS, Gluck MC, Schacht RG, Gallo G. The long-term course of
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Schacht RG, Gallo GR, Gluck MC, et al. Irreversible disease
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(Received 5 Jul 2000, accepted 7 Dec 2000)
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Menzies School of Health Research, Darwin, NT.
Andrew V White, FRACP, Research Student, Menzies School, and
Flinders University NT Clinical School, Darwin NT; currently,
Paediatrician, Remote Health, Alice Springs, NT.
Wendy E Hoy,
FRACP, Principal Research Fellow.
Royal Children's Hospital, Melbourne, VIC.
David A McCredie, MD, FRACP, Nephrologist.
Reprints will not be available from the authors.
Correspondence: Dr A
V White, Remote Health Services, PO Box 721, Alice Springs, NT 0871.
Andrew.WhiteATnt.gov.au
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| 3: Outcomes on follow-up
screening, by diagnostic category during post-streptococcal glomerulonephritis
(PSGN) epidemics |
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| Outcome |
PSGN
(n = 63) |
Abnormal urine
(n = 86) |
Control
(n = 323) |
|
| ACR ≥
34 mg/mmol |
| Rate |
13% |
8% |
4% |
| Crude odds ratio (95% CI) |
3.8 (1.5-9.8) |
2.3 (0.88-6.0) |
1 |
| Adjusted* odds ratio (95% CI) |
6.1 (2.2-16.9) |
1.6 (0.6-4.2) |
1 |
| PAF (95% CI) |
24% (5%-40%) |
8% (-14% to 26%) |
|
|
|
|
|
| ACR ≥
3.4 mg/mmol |
| Rate |
32% |
30% |
18% |
| Crude odds ratio (95% CI) |
2.2 (1.2-4.0) |
2.0 (1.2-3.4) |
1 |
| Adjusted* odds ratio (95% CI) |
3.2 (1.7-6.2) |
1.4 (0.8-2.6) |
1 |
| PAF (95% CI) |
11% (4%-18%) |
5% (-4% to 14%) |
|
|
|
|
|
| Haematuria
> trace |
| Rate |
21% |
9% |
7% |
| Crude odds ratio (95% CI) |
3.4 (1.6-7.2) |
1.4 (0.6-3.1) |
1 |
| Adjusted* odds ratio (95% CI) |
3.7 (1.8-8.0) |
1.1 (0.4-2.6) |
1 |
| PAF (95% CI) |
20% (5%-33%) |
1% (-14% to 14%) |
|
|
|
|
|
| Haematuria
> trace or ACR ≥
34 mg/mmol |
| Rate |
30% |
16% |
11% |
| Crude odds ratio (95% CI) |
3.6 (1.9-6.8) |
1.6 (0.8-3.1) |
1 |
| Adjusted* odds ratio (95% CI) |
4.6 (2.3-9.0) |
1.2 (0.6-2.4) |
1 |
| PAF (95% CI) |
19% (8%-29%) |
3% (-9% to 13%) |
|
|
| ACR = albumin to creatinine ratio.
PAF = population-attributable fraction. * Adjusted for age and sex. |
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