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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
Med J Aust 2001; 174 (10): 492-496.
Published online: 21 May 2001

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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Abstract

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.


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


Methods

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.

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.

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.

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

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.

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.

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.


Discussion

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.



Acknowledgements

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.


References

  1. Streeton CL, Hanna JN, Messer RD, Merianos A. An epidemic of acute post-streptococcal glomerulonephritis among Aboriginal children. J Paediatr Child Health 1995; 31: 245-248.
  2. Spencer JL, Silva DT, Snelling P, Hoy WE. An epidemic of renal failure among Australian Aboriginals. Med J Aust 1998; 168: 537-541.
  3. Hoy WE, Norman RJ, Hayhurst BG, Pugsley DJ. A health profile of adults in a Northern Territory aboriginal community, with an emphasis on preventable morbidities [see comments]. Aust N Z J Public Health 1997; 21: 121-126.
  4. Cass A, Gillin AG, Horvath JS. End-stage renal disease in Aboriginals in New South Wales: a very different picture to the Northern Territory. Med J Aust 1999; 171: 407-410.
  5. Perlman L, Herdman R, Kleinman H, Vernier R. Poststreptococcal glomerulonephritis. A ten year follow up of an epidemic. JAMA 1965; 194: 63-70.
  6. Potter E, Lipschultz S, Abidh S, et al. Twelve- to seventeen-year follow up of patients with poststreptococcal acute glomerulonephritis in Trinidad. N Engl J Med 1982; 307: 725-729.
  7. Garcia R, Rubio L, Rodriguez-Iturbe B. Long-term prognosis of epidemic poststreptococcal glomerulonephritis in Maracaibo: follow-up studies 11-12 years after the acute episode. Clin Nephrol 1981; 15: 291-298.
  8. Baldwin DS, Gluck MC, Schacht RG, Gallo G. The long-term course of poststreptococcal glomerulonephritis. Ann Intern Med 1974; 80: 342-358.
  9. Schacht RG, Gallo GR, Gluck MC, et al. Irreversible disease following acute poststreptococcal glomerulonephritis in children. J Chronic Dis 1979; 32: 515-524.
  10. Rodby RA, Rohde RD, Sharon Z, et al. The urine protein to creatinine ratio as a predictor of 24-hour urine protein excretion in type 1 diabetic patients with nephropathy. The Collaborative Study Group. Am J Kidney Dis 1995; 26: 904-909.
  11. Ruggenenti P, Gaspari F, Perna A, Remuzzi G. Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 hour urine protein excretion rate, glomerular filtration rate, and end stage renal failure in chronic renal disease in patients without diabetes [published erratum appears in BMJ 1998; 317: 1491]. BMJ 1998; 316: 504-509.
  12. Hoy WE, Mathews JD, McCredie DA, et al. The multidimensional nature of renal disease: rates and associations of albuminuria in an Australian Aboriginal community. Kidney Int 1998; 54: 1296-1304.
  13. McDonald S, Wang Z, Hoy WE. Physical and biochemical predictors of death in an Australian Aboriginal cohort. Clin Exp Pharmacol Physiol 1999; 26: 618-621.
  14. Gogna NK, Nossar V, Walker AC. Epidemic of acute poststreptococcal glomerulonephritis in aboriginal communities. Med J Aust 1983; 1: 64-66.
  15. Devanesen D, Bernard E, Stokes M, et al. Lessons from an outbreak of glomerulonephritis in an aboriginal community. Annual report 1987-88, Menzies School of Health Research. Darwin: Menzies School of Health Research, 1988.
  16. Australian Bureau of Statistics. 1996 census of population and housing: Basic community profile. Canberra: ABS, 1996. (Catalogue no. 2020.0.)
  17. Report of the Second Task Force on Blood Pressure Control in Children 1987. Task Force on Blood Pressure Control in Children. National Heart, Lung, and Blood Institute, Bethesda, Maryland. Pediatrics 1987; 79: 1-25.
  18. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41.
  19. Stata Statistical Software [program]. Release 6.0. College Station, Texas: Stata Corporation, 2000.
  20. Hoy WE. Renal disease in Australian aboriginals [editorial]. Med J Aust 1996; 165: 126-127.
  21. Hoy WE, Rees M, Kile E, et al. A new dimension to the Barker hypothesis: low birthweight and susceptibility to renal disease. Kidney Int 1999; 56: 1072-1077.
  22. Potter E, Abidh S, Sharrett R, et al. Clinical healing two to six years after poststreptococcal glomerulonephritis in Trinidad. N Engl J Med 1978; 298: 767-772.
  23. Nissenson A, Mayon-White R, Potter E, et al. Continued absence of clinical renal disease seven to 12 years after poststreptococcal acute nephritis in Trinidad. Am J Med 1979; 67: 255-262.
  24. Rodriguez-Iturbe B, Garcia R, Rubio L. Epidemic glomerulonephritis in Maracaibo. Evidence for progression to chronicity. Clin Nephrol 1976; 5: 197-205.
  25. Singhal PC, Malik GH, Narayan G, et al. Prognosis of post-streptococcal glomerulonephritis: Chandigarh study. Ann Acad Med Singapore 1982; 11: 36-41.
  26. Clark G, White RH, Glasgow EF, et al. Poststreptococcal glomerulonephritis in children: clinicopathological correlations and long-term prognosis. Pediatr Nephrol 1988; 2: 381-388.
  27. Buzio C, Allegri L, Mutti A, et al. Significance of albuminuria in the follow-up of acute poststreptococcal glomerulonephritis. Clin Nephrol 1994; 41: 259-264.
  28. Rodriguez-Iturbe B, Herrera J, Garcia R. Response to acute protein load in kidney donors and in apparently normal postacute glomerulonephritis patients: evidence for glomerular hyperfiltration. Lancet 1985; 2: 461-464.
  29. Cleper R, Davidovitz M, Halevi R, Eisenstein B. Renal functional reserve after acute poststreptococcal glomerulonephritis. Pediatr Nephrol 1997; 11: 473-476.

(Received 5 Jul 2000, accepted 7 Dec 2000)



Authors' details

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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Box 1
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2: Characteristics of participants at follow-up, by diagnostic category during post-streptococcal glomerulonephritis (PSGN) epidemics
         
  PSGN
(n = 63)
Abnormal Control
(n = 86)
Urine
(n = 323)
P

% Male 65%

45%

60% 0.02*
Median age in years (range) 18.1 (8-31) 23.4 (13-32) 19.0 (10-33) 0.001†
Median BMI (kg/m2) (range) 18.8 (13-45) 20.0 (15-47) 19.8 (13-40) 0.221†

BMI = body mass index. * Fisher's exact test. †Kruskal-Wallis test.
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3: Outcomes on follow-up screening, by diagnostic category during post-streptococcal glomerulonephritis (PSGN) epidemics
       
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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Box 4
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Received 18 October 2018, accepted 18 October 2018

  • Andrew V White
  • Wendy E Hoy
  • David A McCredie


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