Clin Exp Nephrol (2002) 6:254–257
© Japanese Society of Nephrology 2002
SHORT COMMUNICATION Hiroshi Tanaka · Koichi Suzuki · Tohru Nakahata Shinobu Waga · Nobuhiro Monma
Childhood idiopathic membranous glomerulonephritis with isolated antinuclear antibody positivity
Received: May 8, 2002 / Accepted: July 23, 2002
Abstract Background. The occurrence of idiopathic (primary) membranous glomerulonephritis (MGN) is relatively uncommon in childhood. Although a proportion of children with idiopathic MGN may show isolated antinuclear antibody (ANA) positivity, its clinical impact remains unclear. Methods. During the past 12 years, we have treated six children with idiopathic MGN at our institution. Of these, three children with isolated ANA positivity were retrospectively evaluated. Results. The patients consisted of two boys and a girl, aged 5, 12, and 13 years at presentation, respectively. They showed proteinuria of around 1 g/day with hematuria, and isolated ANA positivity without anti-DNA antibody or hypocomplementemia. A percutaneous renal biopsy revealed MGN stage II in two of the children and stage III in one, without endothelial tubuloreticular inclusion. Two children received a 6-month course of prednisolone therapy. At the latest observation (mean interval of 42 months), all showed negative for proteinuria, and no patients had progressed to systemic lupus erythematosus (SLE). A decrease in the ANA titer with subsidence of urine abnormalities was observed in two patients. Conclusion. Although the long-term prognosis of ANApositive idiopathic MGN in childhood remains unclear, isolated ANA postivity itself may be nonspecific, and may not indicate a subsequent progression to SLE.
Key words Antinuclear antibody · Children · Idiopathic membranous glomerulonephritis · Systemic lupus erythematosus
Introduction Membranous glomerulonephritis (MGN) is characterized by the presence of immune-complex deposition along the capillary wall.1–5 However, the occurrence of the disease in children and adolescents is relatively rare,1–5 and the majority of cases of the childhood disease is secondary, in which the nephritis is seen in association with several conditions, such as hepatitis virus infections2 or systemic lupus erythematosus (SLE).3,5–8 It has been reported that a proportion of children with MGN, even if of the idiopathic (primary) form at presentation, may subsequently progress to SLE following diagnosis.5–8 Although a positive antinuclear antibody (ANA) test itself is known as nonspecific in children without definite autoimmune diseases,9 its clinical impact in idiopathic MGN remains unclear. We report here our experience with three children with idiopathic MGN associated with isolated ANA positivity.
Patients and methods
H. Tanaka (*) · K. Suzuki · T. Nakahata Department of Pediatrics, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan Tel. ⫹81-172-39-5070; Fax ⫹81-172-39-5071 e-mail:
[email protected] S. Waga Division of Pediatrics, National Sanatorium Iwaki Hospital, Namioka, Japan N. Monma Division of Pathology, Morioka Red Cross Hospital, Morioka, Japan
Between January 1989 and January 2001, idiopathic MGN was diagnosed in six children at Hirosaki University Hospital. Of these, three with isolated ANA positivity were retrospectively evaluated. All were negative for serologic tests for hepatitis virus B or C, and they did not meet the revised American College of Rheumatology criteria for the classification of SLE. Two patients had had repeat renal biopsy at a mean interval of 16 months after the first, and received a 6-month course of alternate-day prednisolone therapy following diagnosis. The follow-up period ranged from 2.5 to 5 years (mean, 3.5 years).
255 Table 1. Summary of clinical characteristics of three children with ANA-positive idiopathic MGN Patient no.
1
2
3
Age at the onset of MGN (years) Sex At presentation Proteinuria (g/day) Hematuria s-Cre (mg/dl) ANA (dilution) Staining patterns Therapy
12
13
5
M
F
M
1.3 2⫹ 0.6 320 Speckled PSL, 30 mg/alt. day ⫻ 3 months, then tapered; Dypiridamole
0.8 2⫹ 0.5 80 Homogenous PSL, 40 mg/alt. day ⫻ 3 months, then tapered; Dypiridamole
0.6 2⫹ 0.3 160 Speckled Dypiridamole
0 (⫺) 0.7 80 Speckled 60
0.1 1⫹ 0.5 80 Speckled 36
0 1⫹ 0.3 80 Speckled 30
At last follow-up Proteinuria (g/day) Hematuria s-Cre (mg/dl) ANA (dilution) Staining patterns Follow-up period (months)
ANA, Antinuclear antibody; MGN, membranous glomerulonephritis; s-Cre, serum creatine; PSL, prednisolone
Results Clinical characteristics of the three patients with idiopathic MGN-associated isolated ANA positivity are shown in Table 1. The patients consisted of two boys and a girl with a median age at MGN onset of 10 years (range 5–13 years). All patients were referred to our hospital after testing positive for urine abnormalities during a mass screening. All had a normal blood pressure, and no patients showed nephrotic syndrome or impaired renal function at presentation. None of the study patients showed clinical or serological manifestations suggesting SLE. No clinical and laboratory differences were observed between the three ANA-positive idiopathic MGN patients and the three ANA-negative patients, as in previous reports.3,5 Regarding ANA titers and staining patterns, no clear differences were observed between the three ANA-positive idiopathic MGN patients and the four with MGN due to SLE (Table 2). Mean urine excretion was 0.9 ⫾ 0.4 g/day, and occult blood in urine was 2⫹ in all cases. Two patients (patients 1 and 2) received a 6-month course of alternate-day prednisolone therapy (30 mg and 40 mg, respectively) combined with dipyridamole (5 mg/kg daily; maximum, 300 mg/day). Patient 3 received dipyridamole alone. At the second renal biopsy, urine abnormalities completely disappeared in patient 1, while patient 2 showed 0.3 g/day of proteinuria with 1⫹ of hematuria. Serological tests, including hepatitis B and C, anti-DNA antibody, antiSS-A/Ro antibody, and circulating immune complex by C1q binding assay, were negative except for ANA positivity. In patient 1, the titer of ANA was decreased, from 1 : 320 to 1 : 80, associated with the subsidence of the urine abnormalities,10 while the titer of ANA remained constant (1 : 80) in patient 2.
Table 2. ANA profiles at the onset of MGN in three children with ANA-positive idiopathic MGN and four with MGN caused by SLE Group
Patient
Idiopathic
1 2 3
320 ⫻ 80 ⫻ 160 ⫻
4 5 6 7
80 ⫻ 320 ⫻ 1280 ⫻ 160 ⫻
SLE
ANA, dilution
Staining patterns Speckled Homogenous Speckled Speckled Speckled Speckled Speckled
SLE, Systemic lupus erythematosus
A summary of the results from the renal biopsies are shown in Table 3. All patients showed MGN without mesangial hypercellularity.3,5 In patient 2, immunofluorescence showed 1⫹ for mesangial IgA deposits3,5 except for capillary IgG and C3 deposits. Electron microscopy showed MGN stage II in two patients, and stage III in one. No patients showed endothelial tubuloreticular inclusion.3,5–8 At the latest observation, all patients were negative for proteinuria, and hematuria was also decreased. No patients showed a progression to SLE or renal insufficiency. Patient 3 also showed a decrease of ANA titer with the subsidence of proteinuria, as in patient 1. The titer of ANA remained 1 : 80 in all cases. No episodes of hypocomplementemia or clinical manifestations suggesting SLE were observed during clinical the course.
Discussion It has been reported that MGN is a relatively uncommon cause of urinary abnormalities in children.1–5 In fact, we
256 Table 3. Summary of pathological findings of renal biopsies in three patients with ANA-positive idiopathic MGN Patient no.
Biopsy no.
Interval (months)
No. of glomeruli
Mesangial cell proliferation
Immunofluorescence
Electron microscopy
1
1
17
28
none
IgG (2⫹),a IgA (⫺), IgM (trace), C3 (⫺), C1q (1⫹)
Deposits: Subepi, intramemb Stage: II
12
none
IgG (2⫹),a IgA (⫺), IgM (⫺), C3 (⫺), C1q (⫺)
19
none
IgG (2⫹)a, IgA (⫹),b IgM (trace), C3 (⫹), C1q (⫺)
2
28
none
IgG (2⫹),a IgA (⫹),b IgM (trace), C3 (⫹), C1q (⫺)
1
7
none
IgG (2⫹),a IgA (⫺), IgM (⫹), C3 (trace), C1q (⫺)
2 2
3
1
15
Deposits: Subepi, intramemb, mesangial Stage: III Deposits: Subepi Stage: II
Subepi, Subepithelial; intramemb, intramembranous a IgG with capillary distribution in a granular pattern; b IgA with mesangial distribution
have treated only 10 MGN patients in our hospital during the past 12 years. All patients were negative for serologic tests for hepatitis virus infections. Of these, four patients had secondary MGN associated with SLE. The diagnosis of idiopathic MGN was made in the remaining six. When MGN occurred, all SLE patients showed overt SLE manifestations, such as malar rash, arthralgia, serum ANA, and anti-DNA antibodies positivity with hypocomplementemia. Thus, clear clinical differences were observed between idiopathic MGN patients and those with MGN due to SLE. In this series, we focused on ANA positivity in the six idiopathic MGN patients, since SLE may subsequently develop following the diagnosis of MGN.6–8 Three patients who showed isolated ANA positivity at presentation were enrolled in the study. The Southwest Pediatric Nephrology Study Group3 reported four ANA-positive idiopathic MGN patients, and most of them showed mesangial hypercellularity with mesangial electron dense deposits. Tomonaga et al.5 reported one ANA-positive idiopathic MGN patient with mesangial electron dense deposits. However, none of these study patients showed a subsequent progression to SLE. In our present study, none of the three ANA-positive idiopathic MGN patients without mesangial hypercellularity progressed subsequently to SLE, as in previous reports.3,5 Histologically, it has been reported that the presence of endothelial tubuloreticular inclusions and/or mesangial IgA deposits may predict a subsequent progression to SLE.3–5,8 From the literature, idiopathic MGN patients with endothelial tubuloreticular inclusions may develop to overt SLE from 11 to 44 months later,3,6–8 but none of these patients showed ANA positivity at presentation.6–8 In this series, although mesangial IgA deposits were seen in patient 2, no patients showed evidence of endothelial tubuloreticular inclusions. Thus, these clinical observations suggest that isolated ANA positivity itself in childhood idiopathic MGN is an nonspecific clinical manifestation, as in children without MGN.9 No reports have described changes in the ANA titer in ANA-positive idiopathic MGN to date. Interestingly, the
titer of serum ANA was decreased with the subsidence of urine abnormalities in patient 110 and 3, but patient 2 did not show that clinical picture. These clinical observations suggest that possible activation of autoimmunities leading to ANA positivity might be attributable to the pathogenesis of MGN in selected patients with ANA-positive MGN.10 However, such a condition may not always cause glomerular alteration, which favors an immune reaction in the subepithelial space. Any explanation of the clinical impact of the presence of ANA in a proportion of idiopathic MGN patients remains speculative, since no significant difference regarding the incidence of isolated ANA positivity between children with idiopathic MGN (3 out of 6 patients) and those with primary IgA nephropathy (15 out of 83 patients), who were cared for in our institution during the past 10 years, was observed (χ-squared test, P ⫽ 0.062). Patient 2 showed persistent mesangial IgA deposits in both the first and second renal biopsies with an interval between them of 15 months. Mesangial IgA deposits have been reported to be a predisposing risk factor for a subsequent progression to SLE.3,5 Although the titer of ANA in patient 2 was not very high, it did not decrease with the subsidence of urine abnormalities, which was different from the response in the other two patients. Hence, regarding a subsequent progression to SLE, further careful observation is needed, especially in patient 2. It is difficult to draw any conclusions from this study because few patients were examined and the observation period was short. Long-term follow-up for these patients and further study are needed.
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