PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1663-1668 (doi:10.1542/peds.2005-1148)
Clinical Value of Autoantibodies Against C1q in Children With Glomerulonephritis
a Department of Pediatrics, 2nd Children's Hospital
d Department of Microbiology, Immunology and Virology, Belarus State University, Minsk, Belarus
b Laboratories of Clinical Immunology
c Immunonephrology, Department of Research
e Internal Medicine B, University Hospital Basel, Basel, Switzerland
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Autoantibodies against C1q (anti-C1q) have been found in a number of autoimmune and renal diseases. They are best described in adult patients with systemic lupus erythematosus, where a strong correlation between the occurrence of anti-C1q and severe lupus nephritis (LN) has been observed. However, the role of anti-C1q in children with systemic lupus erythematosus has not yet been determined. Furthermore, the clinical importance of anti-C1q in other forms of glomerulonephritis remains to be elucidated. The aim of this study was to investigate anti-C1q in children with different forms of glomerulonephritis including LN.
METHODS. We prospectively investigated 112 children with different forms of newly diagnosed glomerulonephritis for the presence of anti-C1q by an enzyme-linked immunosorbent assay and compared them with healthy controls. Associations between anti-C1q and disease manifestations at the time of the measurements and during follow-up were investigated.
RESULTS. Twenty-one of 112 patients were positive for anti-C1q compared with 0 of 40 healthy controls. Anti-C1q was associated with activity in LN and with disease severity in patients with acute poststreptococcal glomerulonephritis (APSGN). In LN, 7 of 12 patients were found to be anti-C1q positive. Six of these 7 had active disease at the time of the serum sampling compared with 1 of 5 of the anti-C1q-negative children. In children with APSGN, 8 of 24 were positive for anti-C1q. Anti-C1q-positive APSGN patients had significantly higher proteinuria and more often hypertension than those without anti-C1q. All 4 patients in which APSGN did not resolve spontaneously were anti-C1q positive.
CONCLUSIONS. Anti-C1q is associated with active LN in children. In addition, children with anti-C1q-positive APSGN have more severe disease than those who are anti-C1q negative. These data suggest APSGN is another disease in which anti-C1q has a pathogenic role.
Key Words: glomerulonephritis • autoantibody • complement
Abbreviations: SLE—systemic lupus erythematosus • LN—lupus nephritis • ELISA—enzyme-linked immunosorbent assay • APSGN—acute poststreptococcal glomerulonephritis
Autoantibodies against the first component of the classical pathway of complement (anti-C1q) can be found in a number of autoimmune, renal, and infectious diseases.1–4 The prevalence of anti-C1q is highest in patients with hypocomplementemic urticarial vasculitis where anti-C1q can be used as a diagnostic marker.5 However, anti-C1q has mostly been investigated in patients with systemic lupus erythematosus (SLE). In adult patients with SLE, the prevalence of anti-C1q varied between 20% and 100% depending on the population of SLE patients studied. The highest prevalence of anti-C1q was found in those having active lupus nephritis (LN).6–10 Furthermore, in most of the studies, anti-C1q had a strikingly high negative predictive value for the development of severe LN, ranging up to 100%.10 The interest in anti-C1q as a diagnostic tool in SLE patients was further strengthened by the observation that increasing titers of anti-C1q seemed to precede renal flares by 2–6 months. In addition, after the successful treatment of a renal flare, anti-C1q mostly decreases or becomes undetectable.9, 11–15 Thus, serial determination of anti-C1q in SLE patients with renal flares might help to identify treatment responders and define patients remaining at risk for renal relapses.
However, anti-C1q has not yet been established as a diagnostic tool in childhood SLE. In contrast to our own experience in adults, the only study on anti-C1q in pediatric SLE patients could not show any correlation with clinical disease manifestations, including LN.16 Furthermore, despite the description of anti-C1q in other forms of glomerulonephritis in children, its clinical significance remains to be elucidated. Therefore, the aim of this study was to investigate the role of anti-C1q in children with different forms of glomerulonephritis, including SLE nephritis.
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METHODS |
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Patients and Clinical Parameters
Between April 2002 and April 2005, all children with known or newly diagnosed glomerulonephritis from the Department of Pediatrics at the Belarus State University Hospital in Minsk/Belarus were prospectively included into the study. The patients' parents had to give written consent for the study participation. Only patients with incomplete availability of clinical data or loss of follow-up were excluded. At the time point of inclusion, serum samples were collected and stored in aliquots frozen at –20°C until further use. The diagnosis of glomerulonephritis was based on clinical parameters including urinalysis, blood urea, creatinine, and erythrocyte sedimentation rate, as well as renal biopsies if available. Renal biopsies were analyzed by light microscopy.
Patients with acute glomerulonephritis were followed until signs of disease resolved or stabilized. Because children with LN and chronic forms of glomerulonephritis could not always be included at the time of the renal biopsy, they were followed for 
6 months before and after blood sampling to determine the disease activity over time.
The diagnosis of acute poststreptococcal glomerulonephritis was based on the presence of hematuria, proteinuria, and edema; a positive test for anti-streptolysin O (Hospitex Diagnostics, Firenze, Italy); and an upper-airway infection (tonsillitis or pharyngitis) preceding the onset of glomerulonephritis by 7–21 days. Serum samples were taken at the time of the diagnosis.
The diagnosis of LN was based on the presence of 4 of the 11 American College of Rheumatology criteria for the diagnosis of systemic lupus erythematosus17 and the result of the renal biopsy. LN was considered to be active when >20 urinary erythrocytes per visual field and/or an increasing hematuria and/or increasing proteinuria (by >1 g/L) were observed at the time of blood sampling or during the following 6 months. Vice versa, an LN was considered to be inactive in the case of a stable or decreasing hematuria of <20 erythrocytes per visual field and stable/decreasing proteinuria, that is, no increase of >0.5 g/L during follow-up.
Autoantibodies
Autoantibodies against C1q (anti-C1q) were tested in serum using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (kindly provided by Bühlmann Laboratories, Schönenbuch, Switzerland). Briefly, human C1q preadsorbed on a microtiter plate was incubated with patient sera diluted in a high-salt buffer (1 M NaCl). After washing, bound IgG was detected using an anti-human IgG horseradish peroxidase-labeled conjugate added in the appropriate dilution. Color was developed by adding an enzyme substrate (tetramethylbenzidine in citrate buffer with hydrogen peroxidase). The reaction was stopped by adding 0.25 M sulfuric acid. The optical densities were measured at 450 nm and converted into units (units per milliliter) by plotting against the autoantibody titer of the standards given by the manufacturer. The cutoff suggested by the manufacturer (15 U/mL) was obtained by testing samples from 220 normal blood donors according to the assay procedure. Because this cutoff might not have been valid for children, sera from 40 healthy children recruited at the same institution as the patients were used as controls.
Anti-nuclear antibodies, anti-double-stranded DNA antibodies and antibodies against cardiolipins were measured using commercially available ELISA kits (Pharmacia Diagnostics, Dübendorf, Switzerland).
Complement Measurements
Serum concentrations of complements C3 and C4 were measured using commercially available ELISA kits (Assaypro, Brooklyn, NY). Results were expressed in percentage of the mean of healthy controls.
Statistical Analysis
All of the values described in the text and figures are expressed as median and range. Statistical analysis was conducted using GraphPad Prism 3.2 (GraphPad Software, San Diego, CA). Nonparametric tests (one-tailed Mann-Whitney U test, Fisher's exact test, or Spearman rank correlation test) were applied throughout with differences being considered significant for P < .05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We analyzed 112 children with different forms of glomerulonephritis (59 male, 53 female; age range: 2–17, median: 12 years) and compared them with 40 healthy controls (21 male, 19 female; age range: 5–17, median: 12 years). Renal biopsies were available in 59 patients.
Using a cutoff at 15 U/mL, anti-C1q was found in 21 of 112 patients compared with 0 of 40 of the healthy controls (P < .001). From the 21 anti-C1q-positive patients, 8 had acute poststreptococcal glomerulonephritis (APSGN), 7 had LN, 5 had mesangioproliferative glomerulonephritis, and 1 had glomerulonephritis associated with rheumatoid arthritis.
LN
Twelve patients with biopsy-proven LN could be included (6 male and 6 female; age range: 10–17, median: 15 years). All 12 of the patients were positive for anti-double-stranded DNA antibodies. Seven of these patients were shown to be anti-C1q positive at the time of study inclusion. Because the time point of inclusion into the study was not identical with the time of the biopsy in all of the patients, nephritis activity was determined according to clinical parameters as mentioned above. The assessment of disease activity included the analysis of 6 months before and after the serum sampling. Six of the 7 anti-C1q-positive patients had active LN at the time of blood collection or during the following 6 months compared with 1 of 5 anti-C1q-negative patients (P < .05). As a control, anti-cardiolipin antibodies were only seen in 3 patients and did not correlate with disease activity. Figure 1 illustrates the anti-C1q titers according to nephritis activity.
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The only patient with active LN but without anti-C1q was also negative for anti-cardiolipin antibodies. This 15-year-old boy had a class IV LN at diagnosis 4 years before serum sampling. Although having been under long-term immunosuppression with prednisone/azathioprine, he developed a severe flare with rash, polyserositis, and nephritis. The serum sampling took place 1 month after the long-term immunosuppression had been increased. At this time, the patient did not yet show a clinical improvement regarding proteinuria, hematuria, and general markers of inflammation. However, the ongoing therapy might have had an important influence on the test result.
Comparing anti-C1q-positive and -negative patients, there was no difference in concentrations of complement C3. However, anti-C1q-positive patients had a trend toward lower levels of C4. In anti-C1q-positive patients, the median of serum C4 concentrations expressed in percentage of normal was 41% with a range of 9–95% compared with 86% with a range of 16–242% in anti-C1q-negative individuals (P = .12).
APSGN
All 24 of the patients with APSGN were negative for anti-nuclear antibodies. APSGN patients with or without anti-C1q did not differ regarding their basic characteristics (age, gender, and anti-streptolysin O titers) other than the time interval between the onset of symptoms and the day of blood sampling (Table 1). However, anti-C1q-positive patients had significantly more frequent hypertension and more pronounced proteinuria (Table 1). The levels of proteinuria in anti-C1q-negative and anti-C1q-positive patients are demonstrated in Fig 2. In addition, all 4 of the patients that did not show a complete spontaneous resolution of the glomerulonephritis, that is, persistent proteinuria, hematuria, and/or elevated creatinine, were positive for anti-C1q (P < .01). Furthermore, it is of interest to note that the only APSGN patient who underwent a renal biopsy because of increasing proteinuria and blood pressure, as well as persistent macrohematuria, was the one with the highest anti-C1q levels measured (225 vs 23–75 U/mL in the other anti-C1q-positive children with APSGN). Histologically, the patient had an endocapillary glomerulonephritis.
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Because the significantly longer time interval between the onset of symptoms and blood sampling in anti-C1q-positive compared with anti-C1q-negative patients could have been responsible for the differences observed, all of the clinical parameters described were analyzed for a possible correlation with the length of the diagnostic interval. However, no association of the clinical parameters at the time of diagnosis with the length of the diagnostic interval could be found, making this possibility unlikely.
About half of the patients had reduced serum concentrations of complement C3 at the time of the sampling. Comparing anti-C1q-positive and -negative patients, the presence of anti-C1q was not associated with lower concentrations of C3 (Table 1). However, anti-C1q-positive patients with APSGN had a trend toward lower levels of C4 as also observed in SLE patients.
Other Patients With Glomerulonephritis
In the other patients included, anti-C1q could only be detected in the 1 patient with rheumatoid arthritis and glomerulonephritis and in 5 of 26 patients with mesangioproliferative glomerulonephritis. The patient with rheumatoid arthritis was only weakly positive (20 U/mL), whereas anti-C1q titers in the patients with mesangioproliferative glomerulonephritis varied between 25 and 400 U/mL. No correlation with disease activity and/or severity could be identified in this group.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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An increasing number of studies suggest a pathogenic role of anti-C1q in SLE patients.18 The current hypotheses of the pathologic mechanism of anti-C1q in LN suggest that additional binding of anti-C1q to glomerular deposits of C1q alters the function and/or exacerbates the activation of the complement cascade. Such an interference of anti-C1q with the complement cascade or even complement activation might lead to a critical aggravation of the glomerular pathology leading to proliferative forms of LN. However, most of the studies on anti-C1q had been performed in adult patients, and little is known about the relevance of anti-C1q in pediatric LN. In addition, the role of anti-C1q in other forms of glomerulonephritis had not yet been clarified.
In our prospective study of 112 children with different forms of glomerulonephritis, anti-C1q was mostly found in 2 types of glomerulonephritis: LN and APSGN. In these patients, anti-C1q was associated with active and more severe nephritis, respectively.
Our findings in children with SLE seem to confirm the clinical association between the occurrence of anti-C1q and active LN as observed in adults. Thus, determination of anti-C1q in children with SLE might help to diagnose severe nephritis. This is of importance, because proliferative LN still has a high morbidity and mortality19, 20 and requires aggressive immunosuppressive therapy bearing the risk of long-term toxicity.21 The correlation between anti-C1q and active LN in children was slightly less striking when compared with a previous report in adults.10 This might be explained by the fact that the only child with active LN having no anti-C1q described here was under long-term immunosuppression potentially leading to a false-negative test result. Alternatively, it had been suggested that the mechanisms leading to nephritis in SLE may be different between children and adults. This view was supported by a previous study in which no correlation between anti-C1q and any clinical disease manifestation of SLE was found.16 The reason for the difference compared with our results remains unclear. The number of patients with active and/or inactive LN was larger in our study. Furthermore, the activity of LN at the time of anti-C1q determination was not clearly stated. Thus, it might be possible that some of the patients investigated by Ravelli et al16 no longer had active disease at the time of the test for anti-C1q. In addition, the only 2 patients reported by Ravelli et al16 who had a renal flare at the time of serum sampling were also found to be positive for anti-C1q.
Other factors that might have influenced the different study results are the differences in the assays used to measure anti-C1q. ELISAs to measure anti-C1q are not standardized, and the definition of a positive test result is not uniform. In our study, we used a well-established and robust commercially available kit.22 Using this assay, we and others have been able to establish cutoff values for anti-C1q, which allowed us to define patients at risk of having a LN (anti-C1q-positive patients) and, mainly, to define those having a very low risk for nephritis (those being anti-C1q negative). The main problem with most series published is that a too high cutoff was chosen (>2 SD) to avoid false positivity. In our study, we included 40 healthy children from the same region with the same age range as the patients, and defined the cutoff value for a positive test result from this population.
A very interesting finding in our study was the association between the presence of anti-C1q and severe APSGN. It was striking that all of the anti-C1q-positive individuals with APSGN had clearly more pronounced proteinuria than the anti-C1q-negative patients, all had hypertension, and, finally, all 4 patients with no spontaneous recovery were anti-C1q positive. Thus, the presence of anti-C1q at the time of diagnosis of APSGN in children might help to identify patients at risk for a more severe course of disease. Furthermore, our results suggest a pathogenic role for anti-C1q in APSGN similar to that proposed for adult SLE patients.10 Hypocomplementemia, including the activation of the classical pathway, is a frequent finding in APSGN.23, 24 In contrast to the more frequently observed activation of the alternative pathway of complement, classical pathway activation in APSGN seems to be an early event and might be triggered by streptococcal antigens.25, 26 The additional presence of antibodies against C1q, as observed in our study, may alter or even accelerate complement activation. The lack of a significant association between the presence of anti-C1q and low levels of complement C4 might have been because of the relatively small number of patients investigated. Unfortunately, we were not able to measure complement profiles in more depth, but it could be speculated that anti-C1q accounted for the long-lasting effects of classical pathway activation that had been observed in some patients.23 Because anti-C1q recognizes bound C1q only and does not or only weakly binds to fluid-phase C1q,27 our observations would also be in line with previous findings that, in APSGN glomerular complement, deposition usually precedes that of IgG.
It could also be speculated that anti-C1q has a common secondary pathogenic role in SLE and APSGN. Both SLE nephritis, as well as APSGN, share several histopathological characteristics, such as glomerular subendothelial deposition of IgG-containing immune complexes, deposition of complement components of the classical pathway, mesangial proliferation, and local influx of neutrophils and monocytes/macrophages.26 Furthermore, even an overlap syndrome between APSGN and SLE has been described.28 Recently, Trouw et al29 demonstrated, in a mouse model of immune-complex glomerulonephritis, that the injection of anti-C1q exacerbated a preexisting subclinical disease, whereas the injection of anti-C1q alone did not lead to a significant glomerular inflammation. Although the underlying subclinical glomerulonephritis was induced by anti-glomerular basement membrane antibodies, one could imagine that such a mechanism is not limited to this setting but might also play a role in related situations. The additional binding of anti-C1q to preformed glomerular C1q deposits could be a critical event in the development of severe forms of LN and APSGN.
Interestingly, the potential pathologic mechanism of anti-C1q in SLE and APSGN cannot be expanded to other forms of glomerulonephritis. We could not establish any association between the presence of anti-C1q and severity of disease in children with mesangioproliferative glomerulonephritis, and anti-C1q was not detected in other forms of glomerulonephritis. However, the number of patients investigated with other forms of glomerulonephritis was limited.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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In children, anti-C1q seems to be associated with active LN as observed in adults. In addition, the presence of anti-C1q at the onset of childhood APSGN was associated with more severe disease manifestations and a lack of spontaneous recovery. These observations could be because of a potential common pathogenic mechanism of anti-C1q in both LN and APSGN. A larger study to confirm these initial observational findings is underway.
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ACKNOWLEDGMENTS |
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The collaborative study was supported by a Scientific Co-operation Between Eastern Europe and Switzerland (SCOPE) project grant from the Swiss National Foundation (7BYPJ65654). Dr Trendelenburg has received a Swiss Clinicians Opting for Research (SCORE) fellowship from the Swiss National Foundation (3232BO-107248/1).
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FOOTNOTES |
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Accepted Oct 17, 2005.
Address correspondence to Marten Trendelenburg, MD, Internal Medicine B, Department of Medicine, University Hospital Basel, CH-4031 Basel, Switzerland. E-mail: marten.trendelenburg{at}uhbs.ch
The authors have indicated they have no financial relationships relevant to this article to disclose.
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