Pediatric Nephrology

, Volume 21, Issue 4, pp 497–502

The clinical features of anti-neutrophil cytoplasmic antibody-associated systemic vasculitis in Chinese children

Authors

  • Feng Yu
    • Department of NephrologyPeking University First Hospital
  • Jian-Ping Huang
    • Department of PediatricsPeking University First Hospital
  • Wan-Zhong Zou
    • Department of NephrologyPeking University First Hospital
    • Department of NephrologyPeking University First Hospital
    • Renal Division & Institute of NephrologyPeking University First Hospital
Original Article

DOI: 10.1007/s00467-006-0028-3

Cite this article as:
Yu, F., Huang, J., Zou, W. et al. Pediatr Nephrol (2006) 21: 497. doi:10.1007/s00467-006-0028-3

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis is reported mainly in adults. Studies in children are limited. The current study retrospectively analyzed the clinical characteristics and pathology of ANCA-associated systemic vasculitis in children in our hospital during the past 7 years. Twenty-four pediatric patients were diagnosed as having ANCA-associated systemic vasculitis, including 19 patients with microscopic polyangiitis (MPA), one with Wegener’s granulomatosis (WG), three with propylthiouracil (PTU)-induced ANCA-positive vasculitis and one with anti-glomerular basement membrane (GBM) disease. Of patients with primary ANCA-associated systemic vasculitis (MPA and WG), with an average age of 10.8±2.8 (6–14) years, 18 patients (90%) were female and two (10%) were male. Nineteen patients (95%) were p-ANCA/MPO-ANCA positive and one (5%) was c-ANCA/PR3-ANCA positive. The interval between onset and diagnosis was 8.5±24.3 (0.2–108) months. The majority of the patients (85%) had multi-organ involvement. All patients had clinical evidence of renal involvement and presented with hematuria and proteinuria. Of 20 patients, 16 (80%) also had acute renal failure, and five patients were dialysis dependent. Nine patients underwent renal biopsy and were diagnosed with necrotizing and crescentic glomerulonephritis. However, six biopsies showed immune complex deposition. All patients received immunosuppressive therapy including prednisone and cyclophosphamide, and ten patients also received intravenous administration of methylprednisone pulse therapy according to their clinical situation and renal pathology. Sixteen patients achieved clinical remission, and four patients presented as treatment failure. Patients were followed up for 12.3±5.1 months (median 12 months; range 1 to 91 months). Ten patients maintained their clinical remission, and ten progressed to renal failure requiring dialysis. Our study showed that the clinical features and pathology of primary ANCA-associated systemic vasculitis in children were similar to those of adults, but there were a predominance of female patients and late diagnoses. We suggest that early recognition and prompt aggressive treatment might improve outcome.

Keywords

ChildrenVasculitisAnti-neutrophil cytoplasmic antibodies (ANCAs)

Introduction

Systemic vasculitides are a group of diseases that have common pathology characteristics, such as inflammation and fibrinoid necrosis of blood vessel walls. Among them, anti-neutrophil cytoplasmic antibodies (ANCAs) are important serological diagnostic markers for certain primary, systemic, small vessel, vasculitic disorders such as Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA) and Churg–Strauss syndrome (CSS) [1]. Anti-proteinase 3 (PR3) antibodies produce cytoplasmic ANCA (c-ANCA) by an indirect immunofluorescence (IF) technique and are mainly found in patients with WG. Anti-myeloperoxidase (MPO) antibodies produce perinuclear ANCA (p-ANCA) and are mainly found in MPA. Although substantial evidence suggests that ANCA-associated vasculitis mainly occurs in adults or the elderly, studies in children are limited. In this study the clinical characteristics and pathology of pediatric patients with ANCA-associated systemic vasculitis were retrospectively analyzed.

Materials and methods

Selection of patients

Enrolled in this study were pediatric patients with ANCA-associated systemic vasculitis, aged ≤14 years and diagnosed in Peking University First Hospital between January 1998 and June 2004. Their clinical and pathology data were retrospectively analyzed. Patients in this study with primary ANCA-associated systemic vasculitis were classified into WG and MPA according to the criteria of the Chapel Hill Consensus Conference [1] and American College of Rheumatology (ACR). The activity of the vasculitis was evaluated by the Birmingham Vasculitis Activity Score (BVAS) [2]. Multi-organ involvement was defined as the involvement of three or more organs.

ANCA analysis

Sera of the patients were screened for ANCA by both indirect immunofluorescence (IF) and antigen-specific enzyme-linked immunosorbent assay (ELISA) for PR3 or MPO as described [3].

Renal pathology

Renal biopsy was performed on nine patients. The renal biopsy specimens were examined by both direct immunofluorescence and light microscopy and electron microscopy. Immune complex deposition was defined as (1) a score of 2+ or higher (on a scale of 0 to 4+) in staining for any kind of immunoglobulins (Igs) observed by immunofluorescence microscopy and/or (2) electron-dense deposits observed by electron microscopy. The renal tubular-interstitial injury was evaluated by a renal tubular-interstitial injury score system [4].

Treatment categories

The mainstay of inductional therapy was prednisone (1 mg/kg per day) combined with cyclophosphamide (CTX, 0.75 g/m2 per month). Patients with severe necrotizing crescentic glomerular nephritis and diffuse pulmonary alveolar hemorrhage were treated also with methylprednisone (MP, 7–15 mg/kg per day, 3 days) pulse therapy. For maintenance therapy, low doses of prednisone combined with immunosuppressive drugs such as azathioprine and mycophenolate mofetil (MMF) were administered.

Definition for treatment response

The definitions for treatment response were as in Nachman et al. [5]

Complete remission:
  1. (1)

    Normalization of renal function if renal insufficiency existing and

     
  2. (2)

    Disappearance of hematuria, proteinuria and extra renal manifestations of systemic vasculitis

     
Partial remission:
  1. (1)

    Stabilization or improvement of renal function if renal insufficiency existing.

     
  2. (2)

    Dialysis independent if renal failure existing.

     
  3. (3)

    Resolution of hematuria and proteinuria and/or resolution of extrarenal manifestations of systemic vasculitis.

     
Treatment failure:
  1. (1)

    Progressive decline in renal function with persistent active urine sediments or

     
  2. (2)

    Persistence or new appearance of any extra-renal manifestations of vasculitis

     
  3. (3)

    Death

     

Statistical analysis

Independent-samples t-test was used to compare the data between the different groups. The statistical analysis was performed with the SPSS (SPSS, Chicago, Ill., USA) version 10.0 statistical analysis program. A P value less than 0.05 was considered to be statistically significant.

Results

Demographic features of patients with primary ANCA-associated systemic vasculitis

Of our 400 patients with positive ANCA, 24 were pediatric patients ≤14 years, including 19 patients with MPA, one with WG, three with propylthiouracil (PTU)-induced ANCA-positive vasculitis and one with anti-glomerular basement membrane (GBM) disease. The average age of the patients with primary ANCA-associated systemic vasculitis was 10.8±2.8 (6 to 14) years. There were 18 female patients (90%) and two male patients (10%) . There were 19 patients (95%) that were p-ANCA/MPO-ANCA positive and one patient (5%) was c-ANCA/PR3-ANCA positive. The interval between onset of disease and the diagnosis of ANCA-associated systemic vasculitis was 8.5±24.3 (0.2–108) months (Table 1).
Table 1

Complete data of children with primary ANCA-associated systemic vasculitis (M male, F female, Int interval between onset of disease and the diagnosis, d days, Dx diagnosis, Organs organs involved, Scr serum creatinine at diagnosis, SS systemic symptoms, N nose, Ey eye, Ea ear, Sk skin, An anemia, K kidney, L lung, Di digestive system, Neu neuro-system, IF, IF-ANCA, EL ELISA-ANCA, P p-ANCA C c-ANCA, R.P. renal pathology, Px treatment, NGN necrotizing glomerulonephritis, CrGN crescentic glomerulonephritis, OP oral prednisone, MP methylprednisone impulse, C cyclophosphamide, A azathioprine, MM mycophenolate mofetil, T.R. treatment response, FU follow up time, m months, OC outcome, CR complete remission, PR partial remission, TF treatment failure, R remission, RFRD renal failure requiring dialysis)

Patient no.

Gender

Age

Int (d)

Dx

Organs

Scr (mg/dl)

BVAS

IF

EL

R.P.

Px

T.R.

FU (m)

OC

1

F

9

75

MPA

K SS Sk Di An

3.7

21

P

MPO

NGN CrGN

MP OP C A

CR

3

R

2

F

14

60

MPA

K Ea Di An

19.5

26

P

MPO

CrGN

OP C

PR

1

RFRD

3

F

13

730

MPA

K L SS An

5.7

20

P

MPO

Not done

OP

TF

24

RFRD

4

F

6

30

MPA

K L Di An

7.6

18

P

MPO

NGN CrGN

MP OP C A

PR

1

RFRD

5

F

9

30

MPA

K L SS Sk An

4.3

22

P

MPO

Not done

OP

PR

1

R

6

F

12

3285

MPA

K L SS Sk An

0.5

22

P

MPO

NGN CrGN

MP OP C MM

CR

91

R

7

F

12

30

MPA

K SS Ea Di An

9.6

16

P

MPO

Not done

OP

PR

1

RFRD

8

F

11

210

MPA

K L Sk Di An

4.0

21

P

MPO

Not done

OP

PR

1

R

9

F

14

30

MPA

K L SS Di An

12.7

14

P

MPO

Not done

OP

TF

2

RFRD

10

F

9

90

MPA

K L SS Di An

4.5

12

P

MPO

Not done

MP OP CA

PR

29

R

11

F

7

7

MPA

K SS Sk An

14

25

P

MPO

Not done

OP

PR

2

RFRD

12

M

12

30

MPA

K Sk An

4.0

18

P

MPO

Not done

OP

PR

1

RFRD

13

F

7

15

MPA

K SS

0.5

13

P

MPO

NGN CrGN

MP OP CA

CR

24

R

14

F

12

150

MPA

K L SS Ey Di

1.6

26

P

MPO

NGN CrGN

MP OP C MM

CR

21

R

15

F

9

30

MPA

K An

5.1

21

P

MPO

Not done

OP

TF

1

RFRD

16

M

6

30

MPA

K L SS An

2.0

18

P

MPO

CrGN

OP

TF

12

RFRD

17

F

14

60

WG

K L SS Sk N Di An

4.0

18

C

PR3

Not done

MP OP C A

PR

12

R

18

F

13

120

MPA

K L An

5.2

16

P

MPO

NGN CrGN

MP OP C A

PR

12

RFRD

19

F

12

60

MPA

K SS Neu Di An

2

18

P

MPO

CrGN

MP OP C A

PR

5

R

20

F

14

30

MPA

K An

5.4

23

P

MPO

Not done

MP OP C A

PR

2

R

Clinical features

The detailed clinical features of the 20 children with ANCA-associated vasculitis are listed in Tables 1 and 2.
Table 2

Data of organ involvement of children with primary ANCA-associated systemic vasculitis

Organ/manifestation

Number (percentage)

Fever

10/20 (50%)

Fatigue

9/20 (45%)

Body weight loss

4/20 (20%)

Skin

6/20 (30%)

Joint

3/20 (15%)

Muscle

5/20 (25%)

Eye

1/20 (5%)

Ear

2/20 (10%)

Nose

1/20 (5%)

Lung

11/20 (55%)

Gastro-intestinal

11/20 (55%)

Neurological

1/20 (5%)

Multi-organ involvement

17/20 (85%)

Kidney

 

Hematuria

20/20 (100%)

Proteinuria

20/20 (100%)

Renal insufficiency

16/20 (80%)

Laboratory examination

Normocytic and normochromic anemia were found in 19/20 (95%) patients, and 16 patients had hemoglobin concentrations lower than 90 g/l. Of 20 patients, 13 (65%) showed elevation of the erythrocyte sedimentation rate (ESR). Ten of 20 (50%) patients had positive C-reactive protein (CRP). No patient was antinuclear antibody (ANA) positive.

Pathology features

Since the majority of the patients presented and were diagnosed too late, only nine patients underwent percutaneous renal biopsy (Table 3). All had necrotizing cresentic glomerulonephritis. Five of the nine had immune complex deposition, including IgM (three patients), IgG (two patients) and IgA (one patient), and all were in a mesangial location (Fig. 1). Besides the five, another one also exhibited electron-dense deposits in an electron microscopy (EM) study. All were in a mesangial location, and two also were subepithelial (Fig. 2). The percentage of glomerular fibrinoid necrosis was significantly higher in patients with immune complex deposition than in those without. There were no significant differences in other characteristics between the two groups (Table 4).
Table 3

Complete renal pathology data of the children. IF(G/T/I/P) IF (glomeruli number/type/intensity/position), LM(G) LM (glomeruli number), F.N. fibrinoid necrosis, Gr granuloma, Cr(G) crescents (glomeruli number), Cc(G/%) cellular crescents (glomeruli number/percentage), FCc(G/%) fibrocellular crescents (glomeruli number/percentage), Fc(G/%) fibrous crescents (glomeruli number/percentage), TIA tubular interstitial activity score, TIC tubular interstitial chronicity score, EM(G/EDD/P) EM (glomeruli number/electron-dense deposits/position), Me mesangial location, Sub subepithelial location

Patient no.

IF(G/T/I/P)

LM(G)

F.N.

Cr(G)

Cc(G/%)

FCc(G/%)

Fc(G/%)

Gr

TIA

TIC

EM(G/EDD/P)

1

3/A++ G++/Me

20

Yes

16

10/63

5/31

1/6

No

2

1

2/Yes/Me

2

3/G+

24

No

20

6/30

8/40

6/30

No

1

2

2/Yes/Me

4

3/_

18

Yes

17

7/41

6/35

4/24

No

2

2

2/No

6

3/M+++/Me

30

Yes

25

18/72

5/20

2/8

No

2

1

1/Yes/Me Sub

13

2/G++/Me

28

Yes

21

14/67

6/29

1/4

No

2

1

2/Yes/Me

14

2/M++/Me

17

Yes

13

8/62

4/31

1/7

No

2

2

3/Yes/Me

16

3/_

22

No

17

9/53

6/35

2/12

No

2

2

2/No

18

4/M++/Me

31

Yes

24

12/50

6/25

6/25

No

2

2

2/Yes/MeSub

19

3/_

26

No

18

10/56

5/28

3/16

No

2

1

2/No

https://static-content.springer.com/image/art%3A10.1007%2Fs00467-006-0028-3/MediaObjects/467_2006_28_Fig1_HTML.jpg
Fig. 1

IgG(++) deposits in mesangial location (patient no. 1/IF)

https://static-content.springer.com/image/art%3A10.1007%2Fs00467-006-0028-3/MediaObjects/467_2006_28_Fig2_HTML.jpg
Fig. 2

Electron-dense deposits in subepithelial location (arrow) (patient no. 6/EM)

Table 4

Comparison of clinical data and pathology between children undergoing renal biopsy with and without glomerular immune complex (IC) deposition (NS not significant)

Parameter 

With IC

Without IC

P value

Number of biopsies (%)

6(67)

3(33)

 

Gender (male/female)

0/6

1/2

NS

Age (mean ± SD) (years)

11.2±2.6

8.0±3.5

NS

Number of anti-MPO/anti-PR3

6/0

3/0

NS

Number of multi-organ involvement(%)

5(83)

3(100)

NS

Serum creatinine (mean ± SD) (mg/dl)

5.2±7.3

3.9±3.2

NS

Urine protein (mean ± SD) (g/24 h)

2.6±1.5

3.0±2.1

NS

Number of glomeruli on histology (mean ± SD)

30±6

27±4

NS

Number with fibrinoid necrosis (%)

5(83%)

1(33%)

<0.01

Percentage of glomeruli with crescents (median)

79

80

NS

Treatment response

After induction therapy, 16 patients achieved clinical remission. Among them, four had complete remission and 12 had partial remission. Four presented as treatment failure (Table 1).

Follow-up

The follow-up times are shown in Table 1.

Patients were followed for 12.3±5.1 months (median 12 months; range 1 to 91 months). Ten patients maintained their clinical remission, and ten progressed to renal failure requiring dialysis. The average serum creatinine concentration upon diagnosis had been significantly lower in the remission group than in the group with renal failure requiring dialysis (1.85±1.25 mg/dl vs 8.04±5.90 mg/dl, P<0.05). The renal survival rate was significantly higher in the remission group than in the treatment-failure group (62.5% vs 0%, P<0.01, Table 5).
Table 5

Comparison of the renal function status of patients with different treatment responses

 Parameter

Remission group

Treatment-failure group

Complete remission

Partial remission

Renal function status

Normal (number)

3

3

0

Dialysis independent (number)

1

3

0

Dialysis dependant (number)

0

6

4

Duration of follow-up (mean ± SD; months)

 

34.8±38.6

5.7±8.4

9.8±10.7

Discussion

The common vasculitides of childhood are Kawasaki disease and Henoch–Schonlein purpura. Reports of ANCA-associated systemic vasculitis in children are limited [6]. Walters et al. were the first to describe three children with ANCA-associated necrotizing glomerulonephritis, in 1988 [7]. Later, pediatric patients with ANCA-associated systemic vasculitis have been reported sporadically [8, 9].

The current study showed that the percentage of pediatric patients was about 6% (24/400) of the total patients with ANCA-associated systemic vasculitis diagnosed in our hospital in the past 7 years. This indicated that this disease was not rare in children. Because PTU-induced ANCA-positive vasculitis and anti-GBM disease have their own characteristics, we focused on the 20 patients with primary small vessel vasculitis. Although our previous study suggested that men and women were equally affected by ANCA-associated systemic vasculitis [3, 10], the current study showed a clear female predominance in children, with a girl:boy ratio of 18:2, and this was similar to the results of Ellis et al. [11] and Hattori and colleagues [12]. The reason for this marked gender difference is unclear. Furthermore, we found a low frequency (5%) of c-ANCA/PR3-ANCA, and this was similar to the results of our previous report in Chinese adult patients with ANCA-associated systemic vasculitis [3] and to the results of Hattori et al. [12], which were in contrast to the findings of Hogan and co-workers [13]. It might be explained by racial difference and different latitudes.

The current study revealed that most pediatric patients had multi-organ involvement like the adults, all the patients had renal involvement, and 80% of the patients had renal insufficiency, including seven patients requiring dialysis. Since proteinuria could affect the value of the ESR, CRP might be more suitable for reflecting the disease activity. However, these phenomena might be explained by a referral bias, selecting for patients with renal disease and a late diagnosis to allow our patients to progress to renal failure with a higher BVAS at 19.4±4.0. Ellis et al. [11] also found that acute renal failure at onset and dialysis dependence were apparently more common in pediatric patients than in adults, and it was suggested that this might be due to the neglect and delay of diagnosis in children. The current study revealed that the interval, between onset of disease and diagnosis of ANCA-associated systemic vasculitis, was 8.5±24.3 months. Although there was not significant difference in outcome, especially in renal survival rate, between groups treated before and after 30 days (60% vs 40%), we speculated that earlier diagnosis might be crucial in initiating appropriate immunosuppressive treatment and finally improve prognosis. Although ANCA-associated systemic vasculitis commonly revealed a pauci-immune necrotizing crescentic glomerulonephritis, our study found a high prevalence of immune complex deposition (67%) in renal biopsies. This indicated that other factors might also be attributable to the development of systemic vasculitis in children, and this was also noted in adult patients with ANCA-associated vasculitis [14]. However, the number of patients in the current study is limited , and a further study with more patients is needed.

There are currently no guidelines for the dosage or duration of immunosuppressants in children with ANCA-associated systemic vasculitis. The recommended regimens were similar to those of adults [15]. Our remission rate was 80% in the acute phase, and was similar to the result of Nachman et al. [5]. In the current study, although prednisone and CTX were administrated as in adults, the overall response and prognosis were not satisfactory. One possible explanation was that our patients were diagnosed and treated too late. Hattori et al. [12] pointed out the beneficial effects of CTX over corticosteroids alone on the remission rate, risk of relapse, and patient survival. He suggested that the treatment protocol that has been established in adult patients could be extrapolated to pediatric patients. Valentini et al. [16] drew the conclusion that, in an effort to reduce the cumulative dose of CTX and its inherent dose-dependent oncogenic risk, CTX as a monthly intravenous infusion might be safer. They also pointed out that, in an effort to provide sustained cytotoxic protection with reduced CTX toxicity, the use of azathioprine or methotrexate could be effective. For cases difficult to control, plasma exchange and intravenous immunoglobulin might be effective. Besbas et al. suggested that CTX, given both orally or in monthly pulses, improved outcome [17]. But Ellis and colleagues [11] showed that immunosuppressive therapy did not prevent the development of end-stage renal disease (ESRD).

During the follow-up of our patients, ten had improved renal function and were dialysis independent. Among them, eight patients (80%) received intravenously administered MP during the acute phase. However, in the ten patients that had progressed to renal failure requiring dialysis, only two (20%) received MP intravenously in the acute phase. Our data also showed that the better the treatment response, the better the renal prognosis. The current study showed that the higher the serum creatinine level at diagnosis, the worse the outcome. Therefore, we speculated that renal insufficiency itself might be a risk factor for renal survival. As long as the diagnosis of ANCA-associated vasculitis and acute renal failure was made, the earlier the intensive immunosuppressive therapy was used, the better the outcome. Ellis et al. [11] also showed that the serum creatinine level was inversely correlated with kidney survival. The study by Hattori et al. [12] showed that patients who subsequently developed ESRD had significantly higher average peak serum creatinine levels and more chronic pathological lesions at diagnosis than had patients with favorable renal outcome.

Although observation of more patients and a longer follow-up period are needed, our study showed that the clinical features and pathology of pediatric patients with primary ANCA-associated systemic vasculitis were similar to those of adults but that there was a predominance of female gender and immune complex deposition in the kidney. We suggest that early recognition and prompt aggressive treatment might improve the outcome.

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