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<Brief
history>
This 64-year-old man had been a
heavy smoker for 20 years. He had quit smoking for 5 years.
Ten days prior to the first admission, he suffered from high
fever accompanied with blood-tinged sputum. The amount of
blood was less than 50 ml per time. He denied having any other
specific symptoms except exertional dyspnea. He was admitted
to a local hospital where pneumonia was diagnosed due to a
right lower lobe (RLL) patch on the chest X-ray (CXR).
Pulmonary hemorrhage was also suspected. However, over the
next 10 days, his renal function (creatinine, Cre) rapidly
increased from 1.8 to 5.4 mg/dl, but no definite etiology was
identified. Hence, he was transferred to our hospital for
further investigation.
Upon arrival, he had clear
consciousness but an acutely-ill appearance. His blood
pressure was 152/94 mmHg, pulse rate was 86 bpm, and body
temperature was 38.8o
C. The pulse oximeter
showed SpO2 96% while he was breathing ambient air. The
conjunctiva was mildly pale and the sclera was anicteric.
Lungs were symmetrically expanded, but there were crackles at
the right lower lung field. The lower extremities showed no
pitting edema, skin rashes, petechiae, ecchymosis or purpura.
There were no other remarkable findings. At ER, the CXR showed
that a patchy infiltration at the RLL. The initial laboratory
studies disclosed anemia, impaired renal function and elevated
CRP without leukocytosis (Tables). Urine analysis revealed
microscopic hematuria and proteinuria. Then, he was admitted
under the impression of RLL pneumonia and renal failure
without definite etiology.
<Laboratory and Image
Study>
Hemogram
| |
WBC
(/μL) |
Hb
(mg/dL) |
Hct
(%) |
MCV
(fL) |
PLT
(/μL) |
Seg
(%) |
Eos
(%) |
Baso
(%) |
Mon
(%) |
Lym
(%) |
| 08/10 |
10300 |
8.8 |
25.7 |
88.3 |
288 |
83.3 |
1.1 |
0.1 |
5.4 |
10.1 |
| 08/20 |
12000 |
7.4 |
22.6 |
91.9 |
417 |
92.1 |
0 |
0 |
2.2 |
5.7 |
| 09/06 |
11800 |
9.6 |
29.7 |
92.2 |
70 |
-- |
-- |
-- |
-- |
-- |
| 09/15 |
5620 |
10.2 |
31.8 |
92.2 |
49 |
-- |
-- |
-- |
-- |
-- | Biochemical & electrolytes
| |
BUN (mg/dl) |
CRE (mg/dl) |
A/G (g/dl) |
Na (mmole/l) |
K (mmole/l) |
Ca/P (mg/dl) |
Mg (mg/dl) |
Cl (mmole/l) |
CRP (mg/dl) |
| 08/10 |
24 |
1.8 |
4.0/3.1 |
135 |
4.1 |
1.99/8.1 |
0.77 |
-- |
-- |
| 08/20 |
63.9 |
5.4 |
2.9/2.5 |
133 |
3.9 |
-- |
-- |
109.4 |
10.34 |
| 09/06 |
120 |
4.1 |
3.45 |
141 |
5.6 |
-- |
-- |
-- |
12.15 |
| 09/15 |
99.4 |
3.6 |
2.23 |
138 |
5.2 |
1.85/5.8 |
0.85 |
-- |
6.16 |
| 09/20 |
43.5 |
3.1 |
-- |
136 |
4.8 |
-- |
-- |
-- |
5.32 |
| |
AST (U/L) |
ALT (U/L) |
T-Bil (mg/dl) |
D-Bil (mg/dl) |
LDH (U/L) |
UA (mg/dl) |
GLU (g/dl) |
| 08/10 |
18 |
38 |
0.36 |
0.12 |
266 |
11.9 |
115 |
| 08/20 |
28 |
52 |
-- |
-- |
699 |
-- |
-- |
| 09/06 |
33 |
36 |
-- |
-- |
406 |
8.1 |
97 |
| 09/20 |
36 |
36 |
-- |
-- |
250 |
-- |
-- |
Urine analysis
| |
Appearance |
Specific
gravity |
pH |
Protein |
Glucose |
Ketone |
Occult
blood |
| 08/10 |
red; turbid |
1.010 |
5.5 |
>300 mg/dl |
- |
- |
3+ |
| 08/20 |
red; turbid |
1.013 |
6.0 |
>300 mg/dl |
- |
- |
3+ |
| 09/06 |
red; turbid |
1.018 |
6.0 |
100 mg/dl |
- |
- |
3+ |
| |
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial
cells |
Cast/Crystal |
Bacteria |
| 08/10 |
0.1 |
- |
>100 |
15-20 |
0-2 |
-/- |
- |
| 08/20 |
0.1 |
- |
35-40 |
12-15 |
0-2 |
Granular (+)/- |
- |
| 09/06 |
0.1 |
- |
50-60 |
15-20 |
2-5 |
Granular (+) |
2+ |
Coagulation profile
| |
PT
(sec) |
INR |
PTT
(sec) |
Fibrinogen
(196-416 mg/dl) |
3P
(negative) |
FDP
(<4.1μg/ml) |
D-Dimer
(<324 ng/ml) |
| 08/15 |
12.4 |
1.04 |
25.9 |
|
4+ |
10.9 |
316 |
Autoimmune
profiles
ANA : 1: 40 (-)
C3
: 83.9 mg/dl C4 : 22 mg/dl
Cryoglobulin
: negative
Anti-GBM Ab(-)
C-ANCA: 0
U/ml P-ANCA: 328 U/ml (positive
>10)
24 hours urine
study
8/12 CCr: 2
ml/min; total protein loss:
2.43 g/day
8/28 CCr: 15 ml/min;
total protein loss: 2.02 g/day
Microbiology
Blood
cultures: all negative
Urine cultures: negative
8/10
Sputum cultures: mixed flora
8/20, 9/10 Sputum cultures:
Pseudomonas spp.
8/10, 8/25 Sputum acid-fast smears:
negative
CXR (8/10): RLL patchy
infiltration
Renal
sonography: normal kidney size, parenchymal
bilateral renal disease, no hydronephrosis
<Pathological
Diagnosis>
Pauci-immune necrotizing
crescentic glomerulonephritis; necrotizing vasculitis with few
or no immune deposits affecting capillaries, venules and
arterioles. Small-sized arteries are also involved.
<Course and
Treatment>
After
admission, the routine fever workup was performed, and he was
treated as bacterial pneumonia secondary to pulmonary
hemorrhage. However, the renal function rapidly deteriorated;
thus, renal biopsy was performed to identify the cause of
acute renal failure or acute on chronic renal failure with
unknown etiology in this patient. The autoimmune profiles were
also checked which disclosed ANA(-), cytoplasmic
-anti-neutrophil cytoplasmic autoantibodies (cANCA)
(-),peripheral ANCA (pANCA) (+), and Anti-GBM (-). Therefore,
ANCA-associated vasculitis was suspected. Methylprednisolone 7
mg/kg/d for 3 days and oral cyclophophamide 2 mg/kg/d were
prescribed. Meanwhile, pathology of the renal biopsy showed
pauci-immune necrotizing crescentic glomerulonephritis.
However, because of the rapid deterioration of oxygenation
during plasmapheresis and hemodialysis, he was intubated for
impending respiratory failure and transferred to ICU. During
the stay in ICU, hemodialysis was continued for renal failure
and uremic bleeding. Pulse intravenous cyclophophamide (500
mg) was administered by vein later for suspected
ANCA-associated pulmonary-renal syndrome. Antibiotics were
also adjusted based on the sputum culture results. The
patient's condition gradually stabilized, and ventilator and
hemodialysis were weaned off later. He was transferred to
general ward under a stable hemodynamic status; however, the
abnormal renal function persisted while he continued follow-up
as an outpatient after discharge.
<Analysis>
In patients whose presentations involve
pulmonary and renal symptoms, many clinical diseases should be
considered (Table 1). After exclusion of non-specific
etiologies in Table 1, the Goodpasture’s syndrome (lung
hemorrhage and rapidly progressive glomerulonephritis, RPGN)
should be considered. This patient presented with pulmonary
hemorrhage and rapidly progressive renal failure; thus, either
disease associated with antibody to the glomerular basement
membrane (GBM) or associated with systemic vasculitis should
be considered (Table 2). Regarding the most common diseases
that lead to Goodpasture's syndrome, Wegener's granulomatosis
(WG) and microscopic polyangiitis (MPA) are ANCA-associated.
Based on the clinical presentations and serological studies,
the patient was diagnosed as having ANCA-associated vasculitis
with RPGN, and microscopic polyangiitis was the most likely
diagnosis. In Table 2, WG and MPA are the most common systemic
small vessel vasculitis which affects capillaries, venules,
arterioles, and small arteries. The involvement of glomeruli
leads to GN, whereas the pulmonary capillaries involvement
causes pulmonary hemorrhage. Usually, the clinical and
histological differentiations between small vessel vasculitis
and immune-complex small vessel vasculitis (like
cryoglobulinemia and Henoch-Schonlein purpura) are not
distinct. However, these two categories can be differentiated
by the paucity of immune-complex in WG and MPA. Regarding
pauci-immune small vessel vasculitis, several characteristic
clinical manifestations can be used to differentiate different
syndromes. WG is associated with necrotizing granulomatous
inflammation and often affects respiratory tract;
Churg-Strauss syndrome (CS) is vasculitis associated with
asthma, eosinophilia and necrotizing granulomatous
inflammation; whereas microscopic polyangiitis is diagnosed by
excluding WG and CS.
ANCA small vessel vasculitis is more common in Caucasians
than Blacks. Both genders are equally affected and the average
age of patients is 55 years or older. Kidneys are frequently
the target of systemic vasculitis which mainly affects small
vessels. Small vessels are vessels smaller than arteries,
including capillaries, venules and arterioles. Hence,
glomerulus, a specified structure of capillaries, is the
primary target of ANCA associated vasculitis. Renal
involvement is very frequent in WG and MPA but less common in
CS. The presentations are hematuria with dysmorphic RBC and
RBC casts. Moderate proteinuria, 2~3 g/d, is also common.
Furthermore, the most characteristic feature is rapidly
progressive renal failure. Around 50% of the ANCA-associated
RPGN patients also suffer from pulmonary involvement ranging
from mild alveolar infiltration to severe pulmonary
hemorrhage. Other non-specific symptoms, such as fever,
malaise, weight loss and arthralgia, and symptoms suggestive
of other organs involvement, such as peripheral nervous
system, GI tract, cardiovascular and ocular systems, have been
reported. Diagnosis must be made by clinical presentations,
serology studies and renal biopsy. Either cANCA or pANCA can
be found in these three syndromes; therefore, serology is less
useful for diagnosis. However, each syndrome has a preference
for distinct ANCA. Most WG is positive for cANCA, CS is pANCA;
whereas, c- or pANCA are equally present in MPA. ANCA may play
a role in the pathogenesis of MPA. However, some WG, CA and
MPA are paradoxically ANCA negative.
Support of oxygenation and hemodynamic status should be
considered first in patients with pulmonary hemorrhage.
Furthermore, hemodialysis and/or plasmapheresis should also be
initiated when profound renal failure is present. As for drug
therapy, treatment of MPA includes induction, maintenance and
relapse therapy. The cornerstone of induction therapy is the
combination of corticosteroids and cyclophosphamide.
Initially, intravenous methylprednisolone and daily oral
cyclophosphamide (or monthly IV cyclophosphamide) are
suggested and followed by oral prednisolone. The optimal
length of cyclophosphamide is not determined, but in patients
achieving complete remission within 6 months, treatment can be
stopped. If disease activity lasts longer than 6 months, it's
suggested to extend therapy to 12 months. The usage of
cyclophosphamide carries risks of leukopenia, hemorrhagic
cystits and urinary cancers. If there's a relapse, hematuria
is the earliest sign, and repeated course of
methylprednisolone and cyclophosphamide can be tried.
<Reference>
- Comprehensive Clinical
Nephrology, 2000.
- Therapy in Nephrology and
Hypertension, 2003.
- J Am Soc Nephrol. 2006
May;17(5):1224-34.
- Nephrology 2004; 9:
297-303.
Table 1
|
Cause of pulmonary and renal
failure |
| With pulmonary edema |
| Acute renal failure with hypervolemia |
|
Severe cardiac failure |
| Infection |
| Severe bacterial pneumonia (e.g. Legionella) with
renal failure |
| Hantavirus infection |
| Opportunistic infection in the immunocompromised
hosts |
| Others |
| ARDS with renal failure in multi-organ failure
|
| Paraquat poisoning |
| Renal vein/IVC thrombosis with pulmonary emboli
| From
Comprehensive Clinical Nephrology, 2000, page
5.27.6.
Table 2
|
Cause of Goodpasture's syndrome
(lung hemorrhage and rapidly progressive renal
glomerulonephritis) |
| Diease associated with Ab to the GBM
(20-40%) |
| Goodpasture's disease (spontaneous anti-GBM
disease) |
| Disease associated with systemic vasculitis
(60-80%) |
| Wegener's granulomatosis |
Common |
| Microscopic polyangiitis |
| Systemic lupus
erythematous |
| Churg Strauss
syndrome |
| Henoch-Schonlein
purpura |
| Behcet's disease |
| Essential mixed
cryoglobulinemia |
| Rheumatoid
vasculitis |
| Drugs: penicillamine,
hydralazine,
propylthiouracil | From
Comprehensive Clinical Nephrology, 2000, page 5.27.6.
|
Case Discussion
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