Polyarteritis Nodosa-Associated with IgA Nephropathy – Case ...

Acta Nephrologica 26(1): 32-36, 2012
DOI: 10.6221/2012.26(1)032
Case Report
Polyarteritis Nodosa-Associated with IgA
Nephropathy – Case Report and
Literature Review
Wei Lin 1 , Hsin-Fan Chen 1 , I-Wen Wu 1 , Yeon-Jian Jan Wu 2 , and Mai-Szu Wu 1
1
School of Medicine, Chang Gung University; Division of Nephrology
2
Division of Rheumatology
Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China
Abstract
Polyarteritis nodosa (PAN)-associated glomerulonephritis presenting with nephrotic syndrome is
not common. We describe a 69-year-old hypertensive man in whom PAN coexisted with IgA nephropathy
presenting with severe nephrotic syndrome, livedo reticularis, testicular pain, and microaneurysm of
renal vessels. Extensive literature review of PAN-associated glomerulonephritis was summarized. PANassociated
IgA nephropathy should be considered in a patient having PAN with nephrotic syndrome.
Steroid therapy is an effective therapy in cases where these 2 diseases coexisted.
KEY WORDS: glomerulonephritis, IgA nephropathy, nephrotic syndrome, polyarteritis nodosa
Introduction
Polyarteritis nodosa (PAN), first described by
Kussmaul and Maier in 1866, is an uncommon systemic
necrotizing vasculitis and is characterized by
inflammatory reactions of medium-sized muscular arteries,
which lead to aneurysm formation with the involvement
of multiple organs, including skin, kidneys,
peripheral nerves, muscles, and gastrointestinal tract
(1). The clinical features are tissue infarction, hemorrhage,
and organ dysfunction (2). Renal involvement
of PAN is frequent and constitutes 93.4% of all visceral
manifestations (3). Common renal manifestations include
loin pain and hematuria due to renal infarction,
renal dysfunction, and renin-dependent hypertension
secondary to ischemia, microaneurysm of renal vasculature,
perirenal hematoma because of microaneurysm
rupture (2), and bilateral reversible hydronephrosis
(4, 5).
PAN-associated glomerulonephritis presenting
with nephrotic syndrome is not common. Some investigators
have described the association of PAN with
cryoglobulinemic glomerulonephritis (6) hepatitis B
Corresponding author: Mai-Szu Wu, M.D., Division of Nephrology, Chang Gung Memorial Hospital, No. 222, Mai-Chin Rd., Keelung,
Taiwan, R.O.C. Tel: +886-2-24313131 ext. 3169, Fax: +886-2-24335342, E-mail: maxwu1@adm.cgmh.org.tw
Received: March 21, 2011; Revised: May 16, 2011; Accepted: September 28, 2011. .
32
virus-related membranous nephropathy (7) antiglomerular
basement membrane disease (7). Berger
disease (8) and in particular, the Henoch-Schonlein
purpura (HSP) (9, 10). All these cases manifested with
hematuria and/or non-nephrotic-range proteinuria.
Herein, we describe a patient with PAN presenting
with nephrotic syndrome; renal biopsy for this patient
revealed IgA nephropathy.
Case Report
A 69-year-old hypertensive man was admitted
because of diffuse skin lesions and bilateral leg edema
for 1 week. There was no fever, itching, swelling, local
heat, or tenderness. The patient complained of
testicular pain and livedo reticularis was observed.
On admission, the blood pressure was 144/93 mmHg;
respiratory rate, 12; heart beat, 99/min; and temperature,
36.5°C. Physical examination revealed diffuse
purpuric plaque, with necrotic change over the lower
limbs, which extended into the trunk and upper limbs.
Both legs also had pitting edema over the pretibial
and pedal areas. The auscultation of the lungs and

heart was normal. No lymphoadenopathy, hepato-, or
splenomegaly was found. The patient had a medical
history of ruptured anterior communicating artery aneurysm
and right carotid artery stenosis. He had also
undergone a ventriculo-peritoneal shunt for normal
pressure hydrocephalus. The patient received aspirin
for secondary prevention of old ischemic stroke since
September, 2000. The patient did not receive any
ACEI or ARB. He denied having received any new
medication or herbal medicine.
Laboratory findings showed that the hemoglobin
level was 12.3 g/dL; hematocrit value, 37.8%; white
cell count, 6,200/mm 3 (differential count: 74.8% neutrophils,
20.3% lymphocytes, 4.2% monocytes); and
platelet count, 260,000/mm 3 . The erythrocyte sedimentation
rate (ESR) was 31 mm/h. Serum electrolyte
(sodium, potassium, calcium, and phosphate), amylase,
lipase, and blood glucose levels were normal;
the creatinine level was 0.9 mg/dL and urea nitrogen
was 8 mg/dL. The albumin level was 2.5 g/dL; globulin,
1.9 g/dL; total cholesterol, 206 mg/dL; and triglyceride,
102 mg/dL.
Anti-nuclear antibody (ANA) titer was 1:40
(weakly positive). The C3 level was 140 mg/dL (normal
73-134 mg/dL) and the C4 level was 20.3 mg/dL
(normal, 18.2-45.5 mg/dL). The serum concentrations
of the antibodies were as follows: IgG, 885.0 mg/dL;
IgA, 121.0 mg/dL; IgM, 88.4 mg/dL; and IgE, < 1.50
IU/mL. Urinalysis showed proteinuria (500 mg/dL),
hematuria (blood: 3+), and 61-70 erythrocytes in each
high-power field. In a 24-h specimen of urine, the
amount of protein was 5.6 g. Nephrotic syndrome is
impressed. Antibodies to double-strand DNA and extractable
nuclear antigen (ENA), including Smith antigen
and cryoglobulins, were absent. The hepatitis B
surface antigen (HBsAg) and antibodies against hepitits
C virus (HCV) were absent. The sample was
weakly positive for perinuclear anti-neutrophilic cytoplasmic
antibodies (P-ANCA) and negative for cytoplasmic
anti-neutrophilic cytoplasmic antibodies
(C-ANCA) and anti-cardiolipin antibodies.
Skin biopsy revealed abundant neutrophil infiltrates
around medium-sized dermal vessels with fibrinoid
necrosis, hemorrhage, and nuclear dusts, which
was consistent with features of necrotizing vasculitis
(Fig. 1A). Study of skin biopsy by direct immunofluorescence
showed negative findings. Percutaneous
renal biopsy was performed and light microscopy
showed mild mesangial hyperplasia with interstitial
fibrosis. The tubules contained protein casts. Arterioles
and capillaries had a normal appearance (Fig.
1B). An immunofluorescence study revealed marked
granular deposits of IgA and C3 in the mesangium
(Fig. 1C), indicating IgA nephropathy. Computedtomographic
angiography disclosed irregular caliber
and multiple narrowing in the segmental and interlobar
Polyarteritis Nodosa-Associated IgA Nephropathy 33
(A)
(B)
(C)
Fig. 1. (A) Skin biopsy shows abundant neutrophil infiltrates
around medium-sized dermal vessels with fibrinoid necrosis
(black arrows) (40×). (B) Renal specimen shows
mild mesangial hyperplasia (200×, light microscopy);
and (C) intense IgA staining (3+) in the mesangium
(immunofluorescence microscopy).
arteries of both kidneys (Fig. 2).
The patient received pulse hydrocortisone therapy
(400 mg daily, for 5 days), followed by oral pred-

34 Lin, Chen, Wu, Wu and Wu
Fig. 2. Computed-tomographic angiography shows irregular
caliber and multiple narrowing in the segmental and
interlobar arteries of both the kidneys (white arrows).
nisolone 80 mg daily, which was then tapered to 50
mg daily. The skin lesions, edema, and proteinuria
regressed rapidly after steroid therapy. The followup
at outpatient clinic revealed that the patient was
negative for proteinuria.
Discussion and Review of Literature
The clinical constellation of the patient included
nephrotic syndrome, livedo reticularis, testicular pain,
diastolic BP of above 90 mmHg, necrotizing vasculitis
of medium-sized dermal vessels, and microaneurysm
formation of segmental and interlobar arteries of both
kidneys. PAN is conclusively diagnosed if 5 out of
the 10 American College of Rheumatology (ACR)
criteria are fulfilled (11).
Nephrotic syndrome is rarely associated with
PAN. The renal histology of classic PAN comprises
fibrinoid necrosis of arcuate or interlobular arteries
with marked inflammatory response within and surrounding
a vessel (12). The renal manifestation of
PAN often presents as hematuria and hypertension.
However, the renal specimen of our patient revealed
normal arterioles and capillaries and marked IgA
deposition in the mesangium. This microscopic picture
suggested the coexistence of IgA nephropathy in this
PAN patient. The skin biopsy revealed medium-sized
vessel with fibrinoid necrosis; however, it was negative
for IgA staining. Furthermore, the dermal vasculitis
may come from PAN rather than IgA nephropathy.
Mesangial deposit of IgA in PAN patients has
been reported in the literature, and all the cases in the
literature had hematuria or non-nephrotic-range proteinuria
at presentation. The presence of nephrotic
syndrome in our patient is peculiar. Praderio et al. (8)
first described the causal relationship between IgA
nephropathy and PAN. Subsequently, other authors
described fatal cases of PAN associated with HSP (9,
10, 13, 14) and termed this condition as polyangitis
overlap syndrome (15). Literature review revealed a
few cases of PAN associated-glomerulonephritis. The
proteinuria in all cases was mild, and the outcome of
these cases was dismal (Table 1). Coexistence of
PAN and IgA nephropathy has rarely been reported in
the literature. The exact mechanism for this association
is unclear. IgA nephropathy is associated with
prominent, globular deposits of IgA (often accompanied
by C3 and IgG) in the mesangium but also, to
a lesser degree, along the glomerular capillary wall.
A possible explanation for the heavy proteinuria of
our patient is the possible glomerular capillary or
podocytes involvement. Electron microscopy in IgA
nephropathy typically reveals electron-dense deposits
that are primarily limited to the mesangium but may
also occur in the subendothelial and subepithelial
spaces. Electron microscopy may add additional information
but is lacking in our patient.
The association of IgA nephropathy with HSP is
particularly strong, and the two diseases may actually
share the same mechanism of pathogenesis. In view
of the absence of gastrointestinal and musculoskeletal
manifestation and negative immunoglobulin deposition
on the skin biopsy of our patient, we thought that
HSP was an unlikely diagnosis. Praderio et al. (8) described
a patient with a past infection with hepatitis B
virus (HBV) who presented with gross hematuria and
a mild proteinuria of 0.6 g/day. The patient responded
successfully to prednisolone therapy. It was thus
concluded that the circulating immune complex might
have a pathogenic role in the development of systemic
vasculitis. Whether the presence of the HBV marker
could trigger immune complex formation in such
patients remains unknown. The serology of our patient
was negative for hepatitis B infection. The pathogenic
mechanism of IgA nephropathy involved mesangial
precipitation of the circulating immune complex with
altered O-glycosylation of serum IgA1 (16). In contrast,
confocal microscopy analysis revealed a direct
deposition of undergalactosylated IgA1 in the
mesangium independent of the immune complex formation
(17). It is possible that the immune complex
formation in PAN may contain aberrant IgA that precipitates
in the mesangium. However, the exact mechanism
eliciting abnormal IgA glycosylation in PAN
patients remains unclear.
The outcome of PAN-associated glomerulonephritis
is poor (9, 10, 13, 14). Glucocorticoid ther-

Table 1. Glomerulonephritis associated with PAN: a literature review
Polyarteritis Nodosa-Associated IgA Nephropathy 35
Case Author Year Glomerulonephritis Age Gender Initial presentation Renal presentation HBVsAg ANCA Treatment Outcome
1 Praderio (8) 1989 IgAN 17 M Intermittent Gross hematuria N NA Steroid Alive
claudication
2 Kirkland (7) 1996 Anti-GBM disease 72 F Diarrhea, abdominal Proteinuria, NA N Cyclophosphamide Alive
pain, fever hematuria + steroid
3 Mouthon (20) 1995 MGN 70 M Weight loss, Nephrotic P N Plasmaphresis Alive
arthralgias, syndrome + IFN α
myalgias
4 Yokose (14) 1993 HSP 77 M Leg skin eruptions Proteinuria, N NA Pulse steroid Dead
hematuria
5 Birchmore (13) 1996 HSP 50 M Purpuric rash, Proteinuria, NA N Cyclophosphamide Dead
abdominal pain, hematuria + steroid
arthralgia, myalgia
6 Cnada (6) 2006 Cryoglobulinemic 53 M Hypertensive Proteinuria, N N Cyclophosphamide Alive
GN encephalopathy, hematuria + steroid
purpuric lesions
7 Leavitt (15) 1986 Churg-Strauss 21 M NA Microaneurysm N NA Cyclophosphamide Alive
+ steroid
8 Leavitt (15) 1986 Vasculitis 54 F NA Microaneurysm N NA Cyclophosphamide Alive
+ steroid
9 Leavitt (15) 1986 HSP 33 M NA Vasculitis N NA Cyclophosphamide Alive
+ steroid
10 Watanabe (9) 2003 HSP 56 M Arthralgia, purpura, Proteinuria, N N Hemodialysis Dead
nasal bleeding, tarry hematuria
stool
11 Lin 2010 IgAN 69 M Purpuric lesions Nephrotic syndrome N p-ANCA Steroid Alive
Abbreviations: P-ANCA, perinuclear anti-neutrophilic cytoplasmic antibodies; Anti-GBM, anti-glomerular basement membrane; GN, glomerulonephritis; y, years-old;
M, male; F, female; P, positive; N, negative; NA, not available; IFNα, interferon alpha; HSP, Henoch-Schonlein Purpura; IgAN, IgA nephropathy; MGN, membranous
nephropathy.

36 Lin, Chen, Wu, Wu and Wu
apy is beneficial in most patients with PAN (18, 19).
However, a cytotoxic agent should be used in most
cases when PAN coexists with vasculitis. In contrast,
the results of Praderio (8) and our patient demonstrated
that predisolone therapy alone was effective for PANassociated
IgA nephropathy.
In conclusion, we found a patient with concurrent
IgA nephropathy and PAN. Steroid therapy is an effective
therapy in cases where these two diseases coexisted.
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