Anti-Neutrophil Cytoplasmic Antibody Vasculitis in Pediatric Patients: Is the Incidence Rising?

doi:10.4236/ojneph.2012.22003

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Open Journal of Nephrology, 2012, 2, 19-22

http://dx.doi.org/10.4236/ojneph.2012.22003 Published Online June 2012 (http://www.SciRP.org/journal/ojneph)

Anti-Neutrophil Cytoplasmic Antibody Vasculitis in

Pediatric Patients: Is the Incidence Rising?*

Christine Sethna1, Rachel Frank1, Lulette Infante1, Beth Gottlieb2, Anne Eberhard2,

Xiaotong Wang3, Howard Trachtman4#

1Department of Pediatrics, Division of Nephrology, Cohen Children’s Medical Center of New York, New York, USA

2Department of Pediatrics, Division of Rheumatology, Cohen Children’s Medical Center of New York, New York, USA

3Department of Pathology, North Shore University Hospital of the North Shore—LIJ Health System, New York, USA

4Department of Pediatrics, Division of Nephrology, NYU Langone Medical Center, New York, USA

Email: #[email protected]

Received March 24, 2012; revised April 25, 2012; accepted May 21, 2012

ABSTRACT

Objectives: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disease usually seen

in middle-aged and older adults but which is rare in children and adolescents. We sought to determine if there has been

a change in the incidence of this disorder. Methods: Single-center, retrospective review. Results: Over the last 2 years,

we have encountered a striking increase in the frequency of this disease in pediatric patients. All eight patients seen

during this period had renal involvement and 5 patients rapidly progressed to end stage kidney disease. The prognosis

was worse in younger patients, those with microscopic polyangiitis, and those with chronic kidney damage in the diag-

nostic renal biopsy. Conclusions: We report these observations to highlight this change in the epidemiology of

ANCA-associated vasculitis and to promote earlier recognition and treatment of this severe form of glomerulonephritis.

Keywords: Anti-Neutrophil Cytoplasmic Antibody (ANCA); Vasculitis; Epidemiology

1. Introduction

Anti-neutrophil cytoplasmic antibody (ANCA)-associated

vasculitis is an autoimmune disorder that usually presents

with sudden onset disease. The organ systems that are

primarily affected include the kidney and lung [1]. There

are two main subtypes based on the identity of the causa-

tive antibody—granulomatosis with polyangiitis (GPA)

[Wegener’s] and microscopic polyangiitis (MPA). The

former is associated with elevated titers of antibody to

proteinase 3 and is characterized by cytoplasmic staining

of neutrophils (cANCA) while the later is marked by

antibodies to myeloperoxidase that stain neutrophils in a

perinuclear pattern (pANCA) [1,2]. The kidney injury is

characterized by necrotizing vasculitis and glomerular

inflammation with minimal immune complex deposition.

GPA and MPA require timely recognition and initiation

of induction therapy in order to prevent permanent organ

damage [2].

Both subtypes of ANCA-associated disease are rare

and generally occur in middle-aged and elderly patients.

Although it does occur in children, in most large patient

series, less than 10% of all cases occur in the pediatric

age range [3]. Over the last 2 years we have encountered

an unexpected surge in the number of cases of ANCA-

associated disease, well above the occurrence of at most

one case annually at our referral center. We report our

experience in order to promote heightened awareness of

this condition in children in the hope that earlier case

definition and prompt implementation of effective treat-

ments will lead to improved clinical outcomes.

2. Patients and Methods

Patients were identified by a review of a clinical database

maintained in the Division of Nephrology with cross

referencing with the Division of Rheumatology to ensure

inclusion of all cases. Out-patient charts and hospital

records were retrieved and reviewed and the following

data were recorded: age at diagnosis, gender, race and

ethnicity, presenting symptoms and physical findings,

CBC, serum BUN, creatinine, cholesterol, albumin, C3,

and C4 levels, ANCA and ANA titers, and urinary pro-

tein excretion expressed as the protein:creatinine ratio

(mg:mg) in a first morning urine sample. The kidney

biopsy findings were described including the active and

chronic changes in the kidney tissue. The renal functional

*Financial Disclosures: None. No payment of any type was made to

anyone to produce the manuscript. Conflict of Interest Declarations:

one.

#Corresponding author.

C. SETHNA ET AL.

status at baseline and the last follow-up visit and the in-

duction and maintenance treatment regimens were tabu-

lated. The retrospective chart review was approved by

the North Shore-LIJ Institutional Review Board.

3. Results

The demographic features, treatment and clinical out-

comes of our patients are summarized in Table 1. The

diagnosis was confirmed both serologically and by renal

histopathology in all of the cases. Five patients had MPA

and 3 (all male) had GPA (formerly called Wegener’s).

There were no children with Churg-Strauss disease. All

three patients with GPA had pulmonary involvement. In

one case, there was acute pulmonary hemorrhage that

prompted urgent initiation of plasmapheresis. There was

evidence of concomitant gastrointestinal disease in one

child, central nervous system involvement in 2, derma-

tological findings in 2, and cardiac manifestations (non-

infectious intraventricular mass) in 1 patient. None of the

patients had documented sinusitis, subglottic stenosis, or

nasal deformity (saddle nose).

All patients received intravenous “pulse” methylpred-

nisolone, 7 were given intravenous cyclophosphamide, 3

rituximab, and 3 were treated with plasmapheresis. The

later three cases were characterized by severe renal in-

sufficiency and the need for dialysis at the time of pre-

sentation.

Maintenance therapy included oral prednisone with

mycophenolate mofetil or methotrexate. The outcomes

for kidney function were poor. All five patients with

MPA progressed to end stage kidney disease (ESKD); 2

are on chronic dialysis and 3 received a kidney transplant.

Allograft function is normal without recurrent disease in

the later subgroup. Two patients on maintenance medica-

tions have normal kidney function and 1 is still receiving

induction therapy and steadily improving.

The number of cases in this series is limited. However,

reviewing our recent experience with ANCA-associated

disease, it would appear that pediatric patients with GPA

tend to be older (≥16 years of age) and to have a better

prognosis for preservation of kidney compared to those

with MPA. In addition, most of the patients displayed

active glomerular inflammation and their clinical out-

comes ranged from development of ESKD to recovery of

kidney function. In contrast, three patients had evidence

of chronic kidney injury with glomerulosclerosis, inter-

stitial fibrosis, and tubular atrophy in the diagnostic bi-

opsy that was done at the time of presentation and they

all required renal replacement therapy.

4. Discussion

The diagnosis of ANCA-associated vasculitis and ne-

phritis was confirmed in all 8 cases based on positive

serological test results and the presence of characteristic

histopathological findings in the kidney biopsy tissue.

Misclassification of the disease is unlikely in view of the

normal C3, ANA and double-stranded DNA antibody

titers in all cases and the lack of alternative pathology

findings that would suggest a different glomerular dis-

order. The only cause of glomerulonephritis that might

resemble MPA/GPA in children and adolescents is

Henoch Schonlein purpura nephritis; however, this diag-

nosis is excluded by the absence of mesangial IgA depo-

sition in all patients [4].

In most previous reports of ANCA-associated vascu-

litis, less than 10% of cases are documented in childhood

[3]. There is one previous report from Canada that, simi-

lar to our case series, describes a rising incidence of

ANCA-associated disease and which suggests that it is a

generalized phenomenon [5]. The diagnostic criteria for

the disease are equally valid in children and adults, im-

plying that atypical signs and symptoms at presentation

are unlikely to explain the lower incidence that has been

reported in childhood (6). Serological testing for ANCA

Table 1. Clinical features of pediatric patients with ANCA-associated nephritis.

Pt # Age (yr) at

Onset/Gender Ethnicity Disease Type Glomerular

Lesions, Active

Glomerular

Lesions, Chronic

Interstitial

Fibrosis/Tubular AtrophyTreatments Outcome

1 6 F W MPA N/A N/A N/A S, C Transplant

2 12 F H MPA 100 0 0 S, C Transplant

3 6 M H MPA 10% - 21%80% - 90% 20% - 30% S, C Dialysis (Peritoneal)

4 12 F W MPA 0 60% 20% S, C Transplant

5 18 M W GPA 90% - 100%0 0 S, C, R, PE Scr 1.39, eGFR 95

6 16 M B GPA 26% - 32%0 0 S, C, Scr 1.27, eGFR 98

7 12 F B MPA 23% - 37%50% - 60% 30% - 40% S, C, R, PE Dialysis (Hemo)

8 16 M W GPA 67% - 73%0 0 S, R, PE Scr 2.56, eGFR 49

The numbers in the columns detailing the pathology findings indicate the percentage of glomeruli affected by the abnormality or the interstitial area displaying

the specific lesion. MPA: microscopic polyangiitis; GPA: granulomatosis with polyangiitis; S: solumedrol; C: cyclophosphamide; R: rituximab; PE: plasma-

heresis. p

C. SETHNA ET AL. 21

may occasionally be negative in children and a positive

result is not required for diagnosis. Therefore, a kidney

biopsy may be required to confirm pauciimmune glome-

rulonephritis with vasculitic or necrotizing lesions [7].

All of our cases had characteristic features of ANCA-as-

sociated disease and positive serology. The trend shows

no evidence of abating and a new case was encountered

during the preparation of this report. The patient was not

included in this series because she was 21 years of age

and would be considered an adult even though she was

cared for by pediatric subspecialists. Thus, we propose

that the increased incidence encountered over the last 2

years reflects a true change in the frequency of this com-

plex illness in pediatric patients. At present, the cause for

the sudden change in the epidemiology of ANCA-asso-

ciated disease remains a mystery.

Recent studies suggest that ANCA may develop due to

molecular mimicry with fimbrial protein antigens in bac-

teria [8]. Although there is a follow-up report that has

shed some doubt on this association [9], it raises the pos-

sibility that altered environmental exposure may account

for the surge in pediatric cases of ANCA-associated dis-

ease over the last few years.

ANCA-associated vasculitis is usually abrupt and se-

vere in onset and requires early identification to achieve

optimal outcomes. The present cases, several of whom had

irreversible kidney damage at the time of diagnosis, may

heighten awareness of ANCA-associated vasculitis in pedi-

atric patients so that serological testing is performed

promptly and aggressive therapy is administered in a

timely manner. It is worth noting that our outcomes for

kidney function were much worse than in a series of 8 chil-

dren with ANCA-associated vasculitis (7 GPA, 1 MPA),

of whom only 1 developed ESKD over a follow-up pe-

riod ranging from 11 - 30 years [10]. This suggests that

both the incidence and severity of ANCA-associated vas-

culitis in childhood may be changing. A younger age, the

diagnosis of MPA, and the presence of chronic glomeru-

lar and interstitial damage appear to be indicators of a

poor prognosis for maintenance of normal kidney func-

tion. However, children who have significant active

glomerular inflammation can respond to therapy with a

return of renal function. The logistical difficulties in im-

plementing effective but costly therapies such as plas-

mapheresis and rituximab that are required to achieve

rapid remission underscore the urgency of establishing

the diagnosis of GPA/MPA in an accurate and timely

manner [11-13].

In conclusion, ANCA-associated vasculitis is not a

new entity, but a change in epidemiology of this severe

illness warrants concern among physicians who care for

individual patients and public health officials. We en-

courage the formation of a registry through established

societies in pediatric nephrology and rheumatology to

monitor the incidence and outcomes of patients with

these rare diseases.

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Abbreviations

ANA, anti-nuclear antibody

ANCA, Anti-neutrophil cytoplasmic antibody

cANCA, cytoplasmic ANCA

pANCA, perinuclear ANCA

BUN, blood urea nitrogen

C3, C4, complement component 3, 4

CBC, complete blood count

ESKD, end stage kidney disease

GPA, granulomatosis with polyangiitis [Wegener’s]

MPA, microscopic polyangiitis