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)
19
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
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:
N
one.
#Corresponding author.
C
opyright © 2012 SciRes. OJNeph

C. SETHNA ET AL.
20
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.
REFERENCES
[1] R. J. Falk and J. C. Charles Jennette, “ANCA Disease:
Where Is This Field Heading?” Journal of the American
Society of Nephrology, Vol. 21, No. 5, 2010, pp. 745-752.
doi:10.1681/ASN.2009121238
[2] A. E. Berden, F. Ferrario, E. Christian Hagen, D. R. Jayne,
J. Charles Jennette, K. Joh, I. Neumann, L. H. Noël, C. D.
Pusey, R. Waldherr, J. A. Bruijn and I. M. Bajema, “His-
topathologic Classification of ANCA-Associated Glome-
rulonephritis,” Journal of the American Society of Ne-
phrology, Vol. 21, No. 10, 2010, pp. 1628-1636.
doi:10.1681/ASN.2010050477
[3] C. E. Rodrigues, M. R. Callado, C. A. Nobre, F. E. Moura,
R. M. Vieira, L. A. de Albuquerque and W. P. Vieira,
“Wegener’s Granulomatosis: Prevalence of the Initial
Clinical Manifestations—Report of Six Cases and Re-
view of the Literature,” Revista Brasileira de Reumato-
logia, Vol. 50, No. 2, 2010, pp. 150-164.
doi:10.1590/S0482-50042010000200005
[4] R. Coppo, P. Cirina, A. Amore, R. A. Sinico, A. Radice
and C. Rollino, “Properties of Circulating IgA Molecules
in Henoch Schonlein Purpura Nephritis with Focus on
Neutrophil Cytoplasmic Antigen IgA Binding (IgA-
ANCA): New Insight into a Debated Issue. Italian Group
of Renal Immunopathology Collaborative Study on He-
noch Schonlein Purpura in Adults and Children,” Ne-
phrology Dialysis Transplantation, Vol. 12, No. 11, 1997,
pp. 2269-2276. doi:10.1093/ndt/12.11.2269
[5] S. Grisaru, G. W. Yuen, P. M. Miettunen and L. A.
Hamiwka, “Incidence of Wegener’s Granulomatosis in
Children,” The Journal of Rheumatology, Vol. 37, No. 2,
2010, pp. 440-442. doi:10.3899/jrheum.090688
[6] D. A. Cabral, A. G. Uribe, S. Benseler, K. M. O’Neil, P. J.
Hashkes, G. Higgins, A. S. Zeft, D. J. Lovell, D. J. Kings-
bury, A. Stevens, et al., “Classification, Presentation, and
Initial Treatment of Wegener’s Granulomatosis in Child-
hood,” Arthritis Rheum, Vol. 60, No. 11, 2009, pp. 3413-
3424. doi:10.1002/art.24876
[7] M. Shimizu, T. Sekiguchi, et al., “A Case of a 6-Year Old
Girl with Anti-Neutrophil Cytoplasmic Antibody- Negative
Pauci-Immune Crescentic Glomerulonephritis,” Clinical
and Experimental Nephrology, Vol. 15, No. 4, 2011, pp.
596-601. doi:10.1007/s10157-011-0423-3
[8] R. Kain, M. Exner, R. Brandes, et al., “Molecular Mim-
icry in Pauci-Immune Focal Necrotizing Glomerulone-
phritis,” Nature Medicine, Vol. 14, No. 10, 2008, pp.
1088-1096. doi:10.1038/nm.1874
[9] A. J. Roth, M. C. Brown, R. N. Smith, A. K. Badwar, et
al., “Anti-LAMP-2 Antibodies Are Not Prevalent in Pa-
tients with Antineutrophil Cytoplasmic Autoantibody Glo-
merulonephritis,” Journal of the American Society of Ne-
phrology, Vol. 23, No. 5, 2012, pp. 545-555.
[10] N. Arulkumaran, S. Jawad, S.W. Smith, L. Harper, P.
Brogan, C. D. Pusey and A. D. Salama, “Long-Term Out-
come of Paediatric Patients with ANA Vasculitis,” Pe-

C. SETHNA ET AL.
22
diatric Rheumatology Online Journal, Vol. 9, 2011, p. 12.
doi:10.1186/1546-0096-9-12
[11] A. Casian and D. Jayne, “Plasma Exchange in the Treat-
ment of Wegener’s Granulomatosis, Microscopic Poly-
angiitis, Churg-Strauss Syndrome and Renal Limited Va-
sculitis,” Current Opinion in Rheumatology, Vol. 23, No.
1, 2011, pp. 12-17. doi:10.1097/BOR.0b013e32834120c1
[12] R. B. Jones, J. Willem Cohen Tervaert, T. Hauser, R.
Luqmani, M. D. Morgan, C. A. Peh, et al., “Rituxamab
Versus Cyclophosphamide in ANCA-Associated Renal
Vasculitis,” The New England Journal of Medicine, Vol.
363, 2010, pp. 211-220. doi:10.1056/NEJMoa0909169
[13] J. H. Stone, P. A. Merkel, et al., “Rituximab Versus
Cyclophosphamide for ANCA-Associated Vasculitis,”
The New England Journal of Medicine, Vol. 363, 2010,
pp. 221-232. doi:10.1056/NEJMoa0909905
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