Five-year follow-up of patients with epidemic glomerulonephritis due to Streptococcus zooepidemicus

Ricardo Sesso1 and Sergio Wyton L. Pinto2

1 Division of Nephrology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil and 2 Division of Nephrology, Hospital São João de Deus, Divinópolis, Brazil

Correspondence and offprint requests to: Ricardo Sesso, Division of Nephrology, Escola Paulista de Medicina, Unifesp, Rua Botucatu 740, São Paulo, SP, Brazil, 04023-900. Email: rsesso{at}nefro.epm.br



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. In 1998 there was a large outbreak of acute glomerulonephritis in Nova Serrana, Brazil, caused by group C Streptococcus zooepidemicus. This study describes the follow-up of these patients, after a mean time of 5.4 years of the acute episode.

Methods. Of 135 cases identified in 1998, 56 were re-examined in a prospective study and had measurements of blood pressure, creatinine clearance (estimated by the Cockcroft and Gault formula), microalbuminuria (radioimmunoassay), urine sediment analysis and a protein dipstick test.

Results. Of the original group of 135 subjects, 3 died in the acute phase and 5 (3.7%) required chronic dialysis. Of the 56 cases re-evaluated, 54 (96%) were adults (mean±SD age, 43±17 years) and 36 (64%) females. At the follow-up examination, we found arterial hypertension in 30% (n = 17/56) of the subjects, reduced creatinine clearance (<80 ml/min) in 49% (n = 26/53) and increased microalbuminuria (>20 µg/min) in 22% (n = 11/51). Compared to the evaluation carried out 3 years before, the number of cases with creatinine clearance lower than 80 ml/min increased from 20 to 26 (of 53 cases). Increased microalbuminuria and/or reduced creatinine clearance were detected in 57% (n = 32/56) of the subjects. Patients with reduced creatinine clearance were older than those without reduced renal function (54±15 vs 34±12 years, P<0.001).

Conclusions. After a mean time of 5.4 years, a relatively high proportion of patients with epidemic poststreptococcal glomerulonephritis due to S.zooepidemicus present hypertension, reduced renal function and increased microalbuminuria.

Keywords: acute nephritis; epidemic nephritis; follow-up; poststreptococcal glomerulonephritis; Streptococcus zooepidemicus



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
We have described a large outbreak of acute glomerulonephritis (GN) that occurred between 1997 and 1998, in Nova Serrana, Brazil [1]. Throat cultures indicated that nephritis was associated with Lancefield group C Streptococcus zooepidemicus, a cause of bovine mastitis. Epidemiological investigation revealed that patients had consumed a locally produced cheese prepared with unpasteurized milk (‘queijo fresco’). 253 cases of GN (>90% adults) were reported in the region.

In the 1950s and 1960s, large outbreaks of poststreptococcal glomerulonephritis (PSGN), were reported in association with certain strains of group A Streptococcus sp. [2–5]. In Romania, in 1968, 28 cases of GN linked to S.zooepidemicus infection were reported [6]. Outbreaks of PSGN have been rare since the 1970s; this may stem from either changes in the nephritogenic potential of certain strains or changes in the susceptibility of the host. However, the incidence of PSGN continues to be high in developing countries [7].

In an earlier report, 2 years after the onset of the acute episode, we observed reduced renal function and/or microalbuminuria in almost 50% of the patients [8]. This report describes the follow-up of patients with epidemic nephritis due to S.zooepidemicus re-evaluated after a mean time of 5.4 years of the acute episode.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
From December 1997 to July 1998, 253 cases of GN were reported in the centre-west region of the state of Minas Gerais, Brazil. Most patients resided in Nova Serrana (population of 27 500), regional health district of Divinópolis. The outbreak was previously described in detail [1]. The clinical syndrome began with fever, headache and myalgia, followed by cervical adenopathy. After 7–10 days, patients developed GN with oliguria, haematuria, generalized oedema and hypertension.

In July 1998, for the purpose of epidemiological investigation, case registration and monitoring, the authors reviewed inpatient charts for patients at the Hospital São José in Nova Serrana with discharge codes for nephritis from January to July 1998, and inpatient and outpatient charts for the same period for patients examined by nephrologists at Hospital São João de Deus in Divinópolis. These were the two health services that cases were referred to. An outbreak-related case of nephritis was defined with the presence of at least two of the following symptoms: systolic blood pressure higher than 140 mmHg or diastolic blood pressure higher than 90 mmHg for adults and blood pressure above the 95th percentile of the age specific normal limit for children; oedema; and at least trace haematuria or 30 mg/dl proteinuria. Of 152 possible cases of outbreak-related illness indicated by the diagnostic coding of the local physicians, 17 did not meet the strict case definition. Of the 135 confirmed cases, 120 (89%) were adults, 97 (72%) were hospitalized, 124 of 126 (98%) had oedema, all had haematuria, serum creatinine was >1.2 mg/dl in 57 of 98 (58%), and low concentration of serum C3 complement was found in 10/12 (83%) cases. None had nephrotic syndrome. In a case-control study, cultures of throat specimens collected from patients and cheese-makers yielded group C S.zooepidemicus [1].

Several aspects of our follow-up strategies have been previously described [8]. In June 2003, we attempted to contact all patients registered in our files (n = 135) seen during the epidemic. Patients were visited in their homes by one of the authors and members of the regional health district of Divinópolis. During the visit a recently voided urine sample was collected for sediment examination and a protein dipstick test (Combur10-Test MR; Roche, Mannheim, Germany) was done; a blood sample was drawn (usually after fasting), an interim history was obtained and a physical examination (including patients’ height and weight) was performed. Blood pressure was measured with a mercury sphygmomanometer in the sitting position after 5 min rest. The average of three measurements taken with 1 min intervals was used in the analysis. Hypertension was defined when systolic blood pressure was higher than 140 mmHg or diastolic blood pressure was higher than 90 mmHg for adults and blood pressure above 95th percentile of age-specific normal limit for children. Blood and urine samples were appropriately stored at 4°C, and brought to the reference study laboratory in Divinópolis. When examined within 1 day, urine samples were kept at 4°C, otherwise they were frozen at –20°C. Blood samples were examined for serum creatinine (alkaline picrate method) using a spectrophotometer (E-225D; Companhia de Equipamentos de Laboratorios Modernos, São Paulo, Brazil). Creatinine clearance was estimated by the Cockroft and Gault formula [9]. Glomerular filtration rate (GFR) was considered reduced when creatinine clearance was lower than 80 ml/min. Samples from 24 h urine collection were tested for microalbuminuria by radioimmunoassay using {gamma} counter equipment (Gamma C12; Diagnostic Products Corporation, Los Angeles, CA) and values were considered abnormal if greater than 20 µg/min.

The patients in this study had no clinical evidence or any history indicating renal disease previously to the outbreak.

Statistical analysis
The {chi}-square test or Fisher's exact test were used for the comparison of categorical variables. Student's t-test or the Mann–Whitney test (whenever appropriate) were used for the comparison of continuous variables. Tests were two-sided and statistical significance was set at P<0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Of the 135 confirmed cases of PSGN seen in 1998, three had died in the acute phase of illness (the causes of death were sepsis, cerebrovascular accident and respiratory failure, respectively), four patients died after resolution of the acute illness, with normal renal function (due to congestive heart failure, myocardial infarction, cerebrovascular accident and unknown cause, at home, respectively), and four died on chronic dialysis program (due to sepsis, cerebrovascular accident, cardiac failure and unknown cause, at home). Fifty-four cases could not be located, 13 did not agree to undergo medical re-evaluation or had incomplete data in the present evaluation, and one was on chronic dialysis. Fifty-six subjects were re-evaluated in the present study after a mean time of 65 months (range 61–67 months) (Figure 1). These cases did not differ from those not re-examined regarding several characteristics at presentation such as: mean age, gender, hospitalization rate, presence of oedema, mean systolic and diastolic blood pressure, serum urea and serum creatinine levels, and need for dialysis. The 56 cases assessed in this study were among the 67 patients evaluated in 2000 [8].



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Fig. 1. Flow chart of study patients.

 
Of the 135 cases, 11 required dialysis during the acute phase of illness. Three of these died within 1 month of disease. Three recovered renal function and stopped dialysis before 3 months of disease. Five of them remained on chronic dialysis; of these, four died after more than 2 years on dialysis. During the acute phase, renal biopsy was performed in nine patients with reduced renal function. All specimens showed diffuse proliferative glomerular disease. No patients received immunosuppressive drug therapy in the acute phase of disease; however, diuretics and anti-hypertensive drugs were frequently used. In June 2003, after checking with the dialysis centres of the region, we confirmed that no other subject of the original sample started chronic dialysis treatment within this period.

Table 1 shows the baseline characteristics during the acute episode for the 56 patients who were re-examined. The mean±SD age at onset was 38±17 years (range, 8–74 years) and a majority were female. Systolic and diastolic hypertension occurred in 73 and 64% of the cases, respectively. Seven (13%) patients were taking antihypertensive drugs on admission for the treatment of previously diagnosed hypertension. Increased serum creatinine (>1.2 mg/dl) and serum urea (>45 mg/dl) were detected in 61% of the subjects. One patient required dialysis. Haematuria (>10 red blood cells/field 400x) was present in all subjects.


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Table 1. Baseline characteristics of the patients

 
Blood pressure measurements and laboratory parameters at follow-up are shown in Table 2. One patient remained on chronic dialysis and was not included in this analysis. High blood pressure (or normal blood pressure with the use of antihypertensive drugs) was detected in 17 of 56 (30%) individuals. Overall, 10 (18%) subjects were receiving antihypertensive drugs. No patients had serum creatinine over 1.4 mg/dl. Creatinine clearance was lower than 80 ml/min in 26 of 53 (49%) cases [of these, it was lower than 60 ml/min in 8 (15%) cases]. Minimum creatinine clearance value was 42 ml/min. No case had haematuria or leucocyturia. Four of 52 (8%) patients had proteinuria (+ or more) by dipstick; none had nephrotic syndrome.


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Table 2. Patients' characteristics and laboratory parameters at follow-up

 
Increased microalbuminuria was detected in 11 of 51 cases (22%). Thirty-two of 56 (57%) subjects had increased microalbuminuria and/or reduced creatinine clearance.

Subjects with creatinine clearance lower than 80 ml/min were older than those with normal renal function (54±15 vs 34±12 years, P<0.001). Other variables tested did not differ significantly between the groups. Of the eight patients with creatinine clearance lower than 60 ml/min, five were older than 60 years, five had hypertension and three were diabetics. None of these patients required dialysis during the acute phase of disease. During the follow-up, especially after the detection of reduced renal function, these patients were close monitored by a nephrologist, received diet orientation, including protein restriction, and, whenever necessary, control of glycaemia and of blood pressure with drugs (preferably with angiotensin-converting enzyme inhibitors). Comparing the same patients at 2 years of follow-up and at this evaluation (n = 53 with available data), the number of cases with creatinine clearance (calculated with the same methodology) between 60 and 80 ml/min increased from 15 (28%) to 18 (34%), respectively, and those with values lower than 60 ml/min increased from 5 (9%) to 8 (15%), respectively.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Four previous outbreaks attributed to S.zooepidemicus have been reported with illness presenting as PSGN in two [6,10] and as sepsis or meningitis in the other two [11,12]. We described a large outbreak of PSGN that occurred in 1998 in Nova Serrana, caused by S.zooepidemicus and linked to consumption of cheese produced with unpasteurized milk [1]. S.zooepidemicus was isolated from throat cultures of case patients, farmworkers and cheese makers. In addition, we amplified and sequenced the outbreak strain S.zooepidemicus M-like protein gene (szp1) and documented positive case-patient serological response to the outbreak-specific M-like protein [13].

Unlike the more common PSGN attributed to group A streptococcus, which affects children, this and other outbreaks of GN due to S.zooepidemicus have predominantly affected adults [6,10]. There is no explanation for the unusual age distribution seen in GN caused by this micro-organism. Host factors such as age-related immunologic susceptibility may have contributed to onset of PSGN in Nova Serrana.

The largest previous outbreak associated with S.zooepidemicus occurred in Romania in 1968 [6]. Of 85 patients (87% adults) with sore throat and lymphadenitis, one-third developed GN. In another report, three cases of nephritis after mild upper-respiratory tract infection occurred in members of a family in North Yorkshire, UK [10]. Previous reports of acute PSGN are basically associated with group A streptococcus [2,3,5]. Of these, three large epidemic episodes, mainly in children, have been well described. In 1953, in Red Lake, Minnesota, 63 cases of PSGN, were reported [2]. In Trinidad, from 1964 to 1966, there were 760 cases of PSGN [3]. In Maracaibo, Venezuela, in 1968, 384 cases were reported [14]. Complete recovery occurred in the great majority of cases after 10 years of follow-up.

We have previously reported the follow-up of 69 patients after 2 years of the outbreak [8]. At that time, we observed a high percentage (42%) of patients with hypertension, 34% of cases with increased microalbuminuria and 30% with creatinine clearance (calculated using 24 h urine collection) lower than 80 ml/min [8]. Within the subsequent 3 years, up to the present evaluation, no further patient developed end-stage renal disease (ESRD) and one case continues on chronic dialysis. Eleven cases assessed in 2000 could not be retrieved for the present evaluation but, as far as we know, none of them progressed to ESRD or died. At this evaluation, compared to that at 2 years and using the same methodology, the proportion of patients with hypertension and with microalbuminuria decreased, but the percentage of cases with reduced renal function increased, suggesting that in some patients a progressive loss of renal function may be occurring. Among the eight patients with creatinine clearance lower than 60 ml/min most were elderly, had hypertension and three were diabetics, suggesting that these factors may negatively affect their prognosis.

During the follow-up, hypertension was more frequently detected in this series than in other outbreaks of PSGN associated with group A streptococcus [2–5,14]. However, at least two other series of sporadic PSGN in adults have reported high rates of hypertension, 29 [15] and 42% [16], respectively, after more than 2 years of follow-up. The prevalence of hypertension during the follow-up was higher than would be expected for adults in Brazil (18%) [17].

Although total proteinuria was relatively uncommon and no case had nephrotic syndrome, microalbuminuria was detected in 22% of the patients. Buzio et al. [18] observed microalbuminuria in 9 of 26 (35%) cases of sporadic PSGN, after a mean follow-up of 10 years.

Reduced GFR as estimated by creatinine clearance was detected in 49% of the patients, and was significantly associated with older age. Five patients required chronic dialysis since the onset of disease (n = 5 of 135 cases, 3.7%). In the literature, although the short-term prognosis of GN caused by group A streptococci is excellent, the early mortality rate being about 0.5% [7], the long-term prognosis has remained controversial. Several research groups reported a very good long-term prognosis mainly in epidemic cases and in children [14,15,19]. The chance of having ESRD has been <1% in 10 years [7]. Other factors such as presentation with nephrotic syndrome [15,19] and renal histology findings shortly after onset have also been suggested as predictors of outcome [20].

For adults the prognosis is not as favorable as for children. In a recent thorough literature review [20] the proportion of adult patients with chronic abnormalities in series with more than 4 years of follow-up range up to 36%. Baldwin et al. [16] noted that 56% of renal biopsies obtained more than 3 years after the onset of the acute attack showed signs of segmental to global glomerular sclerosis of ≥10% of glomeruli; 46% of 95 cases followed for more than 2 years had proteinuria, 42% had hypertension and 38% had reduced GFR. However, these results have been widely challenged.

There are a number of difficulties and possible biases in the comparison of follow-up studies of PSGN and in the interpretation of their validity. Lengths of follow-up vary among the series, different criteria may have been used to define PSGN and progression to chronicity. Renal biopsy is usually not performed if patients do not have clinical/laboratory abnormalities. Reliable methods of GFR measurement and sensitive indicators of glomerular impairment have not been used. In particular, the possibility of superimposed pre-existing renal disease is very difficult to exclude.

It is important to remember that selection bias may play a role in the interpretation of this and other series. In this context, patients studied represent a selective sample of cases with more severe presentation who were referred to a nephrologist and needed hospital assistance. It is likely that mild cases were less often studied. Another limitation of this study is that we could not use a more precise method to assess the glomerular filtration rate.

In conclusion, after a mean follow-up of 5.4 years, a considerable percentage of patients with epidemic PSGN due to S.zooepidemicus continue to present reduced renal function, increased microalbuminuria and hypertension. Longer follow-up of this cohort will be important to assess the possibility of progressive reduction of renal function.



   Acknowledgments
 
Dr R. Sesso receives a research grant from the Brazilian Research Council (CNPq).

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 8. 2.05
Accepted in revised form: 20. 4.05





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