Introduction
Nephrotic syndrome (NS), a condition that may occur in the context of various glomerular
diseases, has been associated with venous thromboembolism (VTE) and less commonly
with arterial thromboembolism (ATE). Although the association of ATE with NS has been
challenged in the past,
1
there is increasing evidence supporting this hypothesis.2, 3 ATE in NS patients has
been reported in several sites such as the coronary, peripheral, and cerebral circulations.
3
Multiple factors have been associated with the risk of thromboembolism in NS patients.
However, predicting and preventing these complications remain a challenge for nephrologists.
3
In particular, little is known about the risk of ischemic stroke, which is a potential
but rare complication of NS that has only been described in a limited number of case
reports. Considering the substantial mortality and long-term disability associated
with stroke, identifying NS patients at higher risk of ATE is an important issue.4,
5 Here we present a case of ischemic stroke in a patient with NS and a review of the
literature with the objective of delineating patients at risk of stroke in this context
(Table 1). We also reviewed the etiologic mechanism of stroke and classified it using
the TOAST (Trial of Org 101172 in Acute Stroke Treatment) system.
6
Table 1
Teaching points
Nephrotic syndrome is associated with a higher risk of both venous and arterial thrombosis
than the general population.
Ischemic stroke can occur in young patients and be the initial event in nephrotic
syndrome.
Traditional cardiovascular risk factors, especially smoking, seem to play a role in
arterial thrombosis as in patients without nephrotic syndrome. They should be assessed
and managed in all patients with nephrotic syndrome.
Severe hypoalbuminemia and proteinuria seem to play a role in venous thromboembolism,
but their contribution to arterial thromboembolism is less clear.
Anticoagulation and antiplatelet agents seem to be protective for acute ischemic stroke
in patients in NS but their role in primary and secondary prophylaxis has yet to be
determined.
Case Presentation
A 43-year-old woman was referred to our center for an acute ischemic stroke. Her medical
history revealed that she had received a diagnosis of membranous nephropathy 10 years
previously and had entered spontaneous remission with complete resolution of the proteinuria
at that time. Five months before the current episode, she experienced a relapse of
NS. She was then started on furosemide, perindopril, and atorvastatin. Laboratory
values at relapse (Table 2) revealed a serum creatinine level of 57 μmol/l (reference
range, 53–97 μmol/l), albuminemia of 22 g/l (reference range, 35–52 g/l), and a spot
urine protein/creatinine ratio of 1.397 g/mmol. Of note, antimyeloperoxidase was detected
by the automated Luminex-based immunoassay system Bio-Plex 200 (Bio-Rad, Hercules,
CA) with the result that 7.7 arbitrary units (reference range, 0.0–0.9 arbitrary units)
and antiproteinase 3 were negative.
7
Serum antiphospholipase 2 receptor antibody were weakly positive using a semiquantitative
immunofluorescence technique (negative to high positive). The patient was not taking
any medication that has been associated with anti–neutrophil cytoplasmic antibody–positive
vasculitis.
8
A kidney biopsy was performed that revealed 11 glomeruli, 1 of which was sclerotic.
All glomeruli showed glomerular basement membrane thickening without any inflammation,
endocapillary proliferation, or crescent formation. Mild interstitial fibrosis was
present. Arteries and arterioles were unremarkable. Immunofluorescence microscopy
showed granular staining for IgG (3+) κ (3+) and λ (3+) light chains as well as focal
granular deposits for C3 on the glomerular basement membrane. Only traces of IgM and
C1q were detected. Electron microscopy showed scattered subepithelial deposits. The
biopsy showed no evidence of vasculitis. Staining for anti–phospholipase A2 receptor
was not performed. The diagnosis of membranous nephropathy was made.
Table 2
Summary of laboratory results
Laboratory test
Laboratory value at relapse of nephrotic syndrome
Reference range
Laboratory value at presentation for acute stroke
Reference range
Leukocyte (109/l)
11.3
4.5–10.8
19
4.0–11.0
Hb (g/l)
138
117–157
117
120–160
Ht (%)
0.414
0.370–0.470
0.347
3.9–5.5
Platelet (104/mm3)
433
140–400
369
145–470
Creatinine (μmol/l)
57
53–97
56
42–89
Glucose (mmol/l)
4.1
4.0–6.2
HbA1c
0.0527
0.0440–0.0600
Albumin (g/l)
22
35–52
13
36–45
Protein/creatinine spot ratio (g/mmol)
1.397
0.828
Proteinuria (g/24 h)
4.84
Cholesterol (mmol/l)
9.33
8.25
3.40–7.30
HDL (mmol/l)
1.03
0.95
0.90–2.38
LDL (mmol/l)
7.2
5.68
Non–HDL cholesterol (mmol/l)
8.30
7.30
Triglycerides (mmol/l)
2.45
0.45–2.25
3.55
0.43–2.69
C reactive protein (mg/l)
<5.0
<9.99
aPTT (s)
23
22–31
INR
1.0
0.9–1.2
Thrombin time (s)
23
14–18
Fg (g/l)
5.39
2.00–4.50
AT III (U/l)
1.24
0.80–1.20
Functional protein C (U/l)
1.45
0.70–1.40
Free protein S antigen (U/l)
1.23
0.69–1.31
Homocysteine (μg/l)
10
<12
C3 (g/l)
1.08
0.85–2.00
C4 (g/l)
0.23
0.10–0.50
ANA
Negative
Negative
ENA
Negative
Anti-PR3 (AU)
<0.2
0.0–0.9
<0.2
0.0–0.9
Antimyeloperoxidase (AU)
7.7
0.0–0.9
2.2
0.0–0.9
Anti–glomerular basal membrane
<0.2
<1.0
Serum anti–PLAR2 antibody
Weakly positive
Factor V Leiden
Negative
Mutation factor II
Negative
Lupus anticoagulant
Negative
Anti–cardiolipins IgM (MPL-U/ml)
0.3
<12.5
Anti–cardiolipin IgG (GPL-U/ml)
<1.6
<15
aPTT, activated partial thromboplastin time; ANA, antinuclear antibody; AT III, antithrombin
III; AU, arbitrary units; ENA, extractable nuclear antigens; Fg, fibrinogen; GPL-U,
G phospholipids-unit; Hb, hemoglobin; HDL, high-density lipoprotein; Ht, hematocrite;
INR, international normalized ratio; LDL, low-density lipoprotein; MPL-U, M phospholipids-unit;
MPO, myeloperoxidase; PLAR2, phospholipase A2 receptor.
The patient was then started on a modified Ponticelli protocol.
9
She had received 3 days of i.v. methylprednisolone at a dose of 1 g/d and 10 days
of 0.5 mg/kg per day of oral prednisone when left hemiparesis developed. Her medication
at the time was prednisone 30 mg/d, furosemide 20 mg/d, perindopril 4 mg/d, atorvastatin
20 mg/d, alendronate 70 mg every week, vitamin D, calcium, and ranitidine. She was
an active smoker but had no previous episode of thrombosis and no family history of
thrombosis. Head computed tomodensitometry performed at the referring center showed
acute ischemic changes (ASPECT [Alberta Stroke Program Early Computed Tomography
10
] score of 6) in the right middle cerebral artery territory. She received a diagnosis
of acute ischemic stroke at the referring center. Intravenous thrombolysis with recombinant
tissue plasminogen activator was started, and she was then referred to our center
for endovascular thrombectomy.
Upon transfer to our center, her physical examination still revealed left hemiplegia,
hemianesthesia, hemianopsia, and heminegligence, with a National Institutes of Health
Stroke Score of 20 (severe stroke).
11
Her complete laboratory data can be found in Table 2. Notably, she had a serum creatinine
level of 56 μmol/l (reference range, 42–89 μmol/l), a serum albumin level of 13 g/l
(reference range, 36–45 g/l), a total cholesterol level of 8.25 mmol/l (reference
range, 3.40–7.30 mmol/l), and a protein/creatinine spot ratio of 0.828 g/mmol, and 24-hour
proteinuria was 4.84 g. The antimyeloperoxidase remained slightly elevated with 2.2
arbitrary units (reference range, 0–0.9 arbitrary units), in line with the results
obtained from her referring center. Cerebral computed tomodensitometry angiography
showed a thrombus in the right common carotid artery with extension in the internal
and external carotid arteries as well as an occlusion of the right middle cerebral
artery (Figure 1a). This large artery thrombus was considered a possible source of
embolus to the cerebral circulation, although it could not be ruled out that the ischemic
event resulted from total occlusion of this large vessel with subsequent recanalization.
This patient would be considered to have large artery atherosclerosis per the TOAST
system, which uses 5 subtypes to classify the etiology of ischemic stroke (large artery
atherosclerosis, cardioembolic, small-vessel occlusion, stroke of other determined
etiology, and stroke of undetermined etiology).
6
The patient was brought to the angiography suite, and endovascular thrombectomy was
performed (Figure 1b). Magnetic resonance imaging obtained on day 4 showed ischemic
changes in the territory of the right middle cerebral artery (Figure 1c). Her ensuing
clinical outcome was favorable with complete resolution of her neurologic symptoms.
Figure 1
(a) Carotid computed tomodensitometry angiography showing a thrombus in the right
external carotid bulb. (b) Angiography showing occlusion of the right middle cerebral
artery. (c) Magnetic resonance imaging showing ischemic stroke in the territory of
the right middle cerebral artery.
Further investigation for an underlying cause of ischemic stroke was negative. No
arrhythmia was found during Holter monitoring. A transthoracic echocardiogram was
normal, with no evidence of shunt or cardioembolic source. The carotid computed tomodensitometry
angiography showed a thrombus in the right external carotid bulb but no atherosclerosis.
The glycated hemoglobin level was normal. Further investigation for thrombophilia,
including factor V Leiden, prothrombin mutation G20210A, protein S and C deficiencies,
anticardiolipins, anti–β2-glycoprotein I, lupus anticoagulant, and hyperhomocysteinemia
was negative. Considering her young age and a negative investigation for underlying
cause, it was considered probable that the hypercoagulability associated with NS contributed
to the pathogenesis of the ischemic stroke. Because of the presence of a thrombus
in the external carotid artery, the decision was made to start anticoagulation therapy
in this patient. Intravenous heparin treatment was initiated and later replaced by
warfarin after transfer to the referring center. She completed the modified Ponticelli
protocol and attained a partial remission with a proteinuria of 0.63 g/d.
9
Discussion
NS is associated with a hypercoagulable state, which is thought to result from changes
in platelet activation and aggregation as well as in the metabolism and concentration
of coagulation proteins.
12
Urinary loss of low molecular weight proteins such has plasminogen and antithrombin
III could lead to impaired fibrinolysis and regulation of coagulation.
12
Furthermore, hypoalbuminemia induces increased hepatic synthesis of clotting factors.
13
Several studies exposed an increased risk of VTE in patients with NS.3, 14 Even though
there are more data regarding the risk of VTE, NS also places patients at risk of
ATE, including stroke. Notably, a single-center retrospective cohort study of 298
NS patients found an ATE incidence of 1.5% annually, which represents 8 times the
risk of the age-matched population.
3
In this study, the most common sites of ATE are myocardial infarction or unstable
angina (44% and 14%, respectively) followed by peripheral arterial disease (14%) and
ischemic stroke or transient ischemic attack (11.5% and 11.5%, respectively).
3
Determining the factors that predict the risk of thrombosis in patients with NS is
still an area of debate. The data available mainly come from retrospective observational
studies and are conflicting. Furthermore, most of the data available describe the
risk of VTE. Different factors have been suggested to influence the risk of ATE in
NS patients. Those include the presence of classic cardiovascular risk factors, the
severity of the hypoalbuminemia and proteinuria, the type of glomerular disease, the
use of corticosteroids or diuretics, and urinary loss of high molecular weight molecules
with antithrombotic properties.
In addition to our patient, only 21 cases of acute ischemic stroke in patients with
NS were found in the English literature. The clinical information regarding these
cases is summarized in Table 3.15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33
Table 3
Review of the literature
Case
Age, yr
Sex
Histology
Duration of NS, yr
Albumin, g/l
Proteinuria
Steroid use (Y/N)
Diuretic use (Y/N)
Presentation
Cerebral vascular territory involved
TOAST
Cardiovascular risk factors
Thrombophilia
1(our case)
43
F
MN
3
13
0.828 g/mmol
Y
Y
Left hemiplegia and hemianesthesia, hemianopsia, heminegligence
Right MCA
LAA
Smoking, HT, DLP
Fg ↑
2
15
55
M
MN
0.125
12
18 g/24 h
Y
Y
Death
Multiple
Possibly CE
Mild ASO
Fg ↑
3
16
23
M
MCD
0
7
10 g/24 h
N
N
Left hemiplegia, lower left limb ischemia
Right MCA
LAA
Alcohol
Fg ↑, AT III ↓, prot C ↓
4
17
36
M
MPGN
0
24
11.4 g/24 h
N
N
Right hemiparesis and hemianesthesia, global aphasia, right hemianopsia
Left MCA
LAA
—
Fg ↑, prot S ↓
5
17
34
M
MN
0
27
6.6 g/24 h
N
N
Left hemiparesis and hemianesthesia, dysarthria, left homonymous inferior visual field
deficit
Right MCA
LAA
Smoking, cocaine
Fg ↑
6
18
28
M
MN
6
16
7.9 g/24 h
Y
N
Right hemiparesis, headache
Left basal ganglia and internal capsule
LAA
Smoking
Fg ↑, AT III ↓
7
18
21
M
MCD
1.5
15
5.6 g/24 h
Y
N
Loss of consciousness, aphasia
Left MCA
CE
Smoking
AT III ↓, prot C ↓
8
19
20
M
MCD
18
14
>300 mg/dl
Y
N
Lethargy, left hemiparesia and hemianesthesis, hemineglect, left hemianopsia
Right MCA
LAA
—
Fg ↑, AT III ↓, prot S ↓
9
20
51
M
No biopsy
0
20
4.6 g/l
N
N
Headache
Right MCA
UND
Smoking
Fg ↑, ATII ↓
10
21
37
F
MN
0
26
NR
N
N
Right hemiparesis, expressive aphasia, right upper extremity ischemia
Right MCA
LAA
Obesity, smoking, HT
Fg ↑, prot S ↓
11
22
39
F
MPGN
2
20
3.4 g/24 h
Y
Y
Left hemiparesis, dysarthria
Periventrical area of the right frontal lobe
UND
—
N Fg, prot S ↓
12
23
29
F
MPGN
15
32
2.2 g/24 h
N
N
Left hemiparesis and hemianesthesia, aphasia
Right MCA, watershed right ACA-MCA
LAA
HT, DLP
Fg ↑
13
24
36
F
Db
NR
11
2.8 g/24 h
NR
NR
Convulsions, left hemiplegia
Multiple
CE
Db
AT III ↓
14
25
59
M
MN
0.038
17
12.0 g/24 h
Y
N
Convulsions
Bilateral occipital lobes
LAA
—
AT III ↓,
15
26
35
F
IgA
5
11
6.8 g/24 h
N
N
Right hemiparesis, dysarthria, dysphagia
Left MCA
Possibly CE
—
AT III ↓, prot C ↓
16
27
53
M
FSGS
0.0625
12
7.8 g/24 h
Y
Y
Left hemiparesis, left hemianesthesia,
Right MCA
LAA
Smoking, ROH, cirrhosis
Prot S ↓
17
28
28
F
No biopsy
0
26
3.5 g/24 h
N
N
Right hemiparesis,
Left MCA
UND
Smoking
—
18
29
61
M
MN
0
25
3.9 g/24 h
N
N
Left hemianesthesia
None identified on imaging
TIA
HT
—
19
30
72
M
LCDD
0
18
12.0 g/24 h
N
Y
Right hemiparesis, expressive aphasia
Left frontal lobe
UND
—
—
20
31
68
M
MCD
0
16
14.0 g/24 h
N
N
Left hemiparesis, left paresthesia, aphasia
Right MCA and PCA
Possibly CE
HT
—
21
23
71
M
MN
0
20
21.0 g/24 h
Y
N
Aphasia, right facial paralysis
Multiple
SAO
HT
Fg ↑, AT III ↓, prot S ↓
22
33
35
M
MN
0
18
7.5 g/g
N
N
Right hemiparesis, dysarthria
Left MCA
LAA
Smoking
Fg ↑
ACA, anterior cerebral artery; ASO, antistreptolysin O; AT III, antithrombin III;
CE, cardioembolic; Db, diabetic nephropathy; DLP, dyslipidemia; DLPx, F, female; Fg,
fibrinogen; FSGS, focal and segmental glomerulosclerosis; HT, hypertension; LAA, large
artery atherosclerosis; LCDD, light chain deposition disease; M, male; MCA, middle
cerebral artery; MCD, minimal changes disease; MN, membranous nephropathy; MPGN, membranoproliferative
glomerulonephritis; N, no; NI, not thoroughly investigated; NR, not reported; NS,
nephrotic syndrome; PCA, posterior cerebral artery; prot C, protein C; prot S, protein
S; ROH, SAO, small artery occlusion; TIA, transient ischemic attack; TOAST, Trial
of Org 101172 in Acute Stroke TreatmenT; UND, undetermined; Y, yes.
We calculated and report 95% confidence intervals (CIs) for the estimated proportions
of the different cardiovascular risk factors in patients with stroke and NS to provide
an estimate of the uncertainty around that proportion and to allow for comparison
with figures reported in the general stroke population. The median age at stroke presentation
was 36 years. Fifty-nine percent (13 patients; 95% CI 36.4%–79.3%) were younger than
50 years of age compared with ∼10% in the general population diagnosed with stroke.
34
Seven (32%; 95% CI 13.9%–54.9%) were women, and 15 (68%) were men. In the general
population, stroke incidence rates are lower in women than in men in the younger age
group but approximately equal in the older age group.
34
Classic risk factors were found in 14 patients (63%) in the current review; 6 patients
(27.3%; 95% CI 10.7%–50.2%) had previously diagnosed hypertension, 1 (4.5%; 95% CI
0–22.8%) had diabetes, and 9 (40.9%; 95% CI 20.7%–63.6%) were smokers. Hypertension
was found in 77%, diabetes in 7.3%, and smoking 19.8% of patients with stroke in the
general population.
34
These data suggest that patients with NS diagnosed with stroke may be younger, with
a lower prevalence of hypertension but more frequently smokers than patients with
stroke in the general population. However, the number of patients reported and analyzed
in this review is limited and may not be completely representative of all cases of
stroke in NS.
Nine cases (40%) of stroke in NS were diagnosed in patients with membranous nephropathy,
4 (18%) had minimal change disease, 3 (14%) had membranoproliferative glomerulonephritis,
1 (5%) had focal segmental glomerulosclerosis, 1 (5%) had light chain deposition disease,
1 (5%) had diabetic nephropathy, and 1 (5%) had IgA nephropathy. Only 2 patients did
not undergo kidney biopsy. Data regarding the link between ATE and the underlying
type of glomerular disease are sparse. In the study by Mahmoodi et al.,
3
membranous nephropathy histology was not found to be an independent risk factor for
ATE. However, patients with membranous nephropathy tend to have more severe hypoalbuminemia
and proteinuria than other histologies.
14
Both hypoalbuminemia and proteinuria are markers of disease severity in NS and have
been proposed to influence the risk of thrombosis.14, 35, 36, 37 In the current review
of the literature, the mean serum albumin level was 18.4 g/l, and the mean proteinuria
was 8.1 g/24 h. Serum albumin levels lower than 20 g/l and 15 g/l were seen in 15
patients (68.2%) and 7 patients (31.8%), respectively. Proteinuria >5 g/24 h was found
in 13 patients (59.1%). Some authors suggested that diuretics and steroids may promote
thrombosis in the setting of NS.
14
Previous corticosteroid or diuretic treatment was found in 9 patients (41%) and 5
patients (23%), respectively. Eleven of the patients reported in the literature (50%)
had ischemic stroke, while on neither diuretic nor corticosteroid treatment.
Certain studies observed that the risk of thrombosis is highest shortly after the
diagnosis of NS.
3
Similarly, in this review, the acute cerebral thrombosis was diagnosed within 6 months
in 14 cases (63%) and within 1 year in 6 cases (29%). Furthermore, in 11 of the reported
cases (50%) in the literature, acute stroke was the presenting symptom of NS. The
clinical presentation was not specific, with most patients presenting with symptoms
commonly associated with strokes, including hemiparesis, aphasia, and convulsions.
The etiology of the stroke was investigated in most patients in the current review.
Using the TOAST system to classify the subtypes of ischemic stroke, 11 (50%) patients,
including our case, were classified to have large-artery atherosclerosis (9 in the
internal carotid artery, 1 in the middle cerebral artery, and 1 in the basilar artery).
6
None of them had significant atherosclerotic changes in their vessels apart from the
thrombus. As in the current case, it is impossible to determine whether the ischemia
was a result of an embolus of the large artery thrombus in the cerebral circulation
or occlusion of the large vessel with subsequent recanalization. A source of cardioembolism
was identified in 2 patients (9%) and suspected in 3 additional patients (14%) on
the basis of stroke in more than 1 vascular territory or evidence of systemic embolism.
Only 1 patient (5%) had small artery occlusion. A total of 4 patients (18%) were classified
as having a stroke of undetermined etiology because of an incomplete investigation,
and 1 (5%) patient had a transient ischemic attack and could not be classified per
the TOAST system. Hence, 23% of the patients in this review had an ischemic stroke
of at least possible cardioembolic etiology compared with between 15% and 44% in the
general population.38, 39, 40
In patients with NS and stroke, antithrombin III levels were decreased in 9 of the
17 patients (53%) for whom these data were available. Protein C and S levels were,
respectively, decreased in 3 of 12 (25%) and in 5 of 13 (54%). Elevated fibrinogen
levels are frequently seen in patients with NS, but do not appear to be correlated
to the risk of VTE.
13
An elevated fibrinogen level was observed in 12 of 17 patients (71%) including case
1. Because increased fibrinogen and deficiency in AT III, protein C, or protein S
are common in NS patients,
41
measurement of these proteins appears to be of little or no value for predicting the
risk of thrombosis and stroke.
To what extent the use of anticoagulants and antiplatelet agents can prevent acute
ischemic stroke in patients in NS is unknown. However, no patient found in the literature
experienced such an event while on anticoagulation therapy, which might suggest a
protective effect. One case occurred while the patient was on antiplatelet drug ticlopidine.
Further data are needed to determine the role of anticoagulants and antiplatelet agents
in secondary and possibly even primary prevention of ischemic stroke in patients with
NS.
Conclusion
ATE and acute ischemic stroke are rare consequences of NS. Stroke can occur in young
patients and be the initial event of NS. The data regarding the factors that predict
the risk of ATE patients with NS are sparse and mostly extrapolated from data regarding
VTE. The mechanism by which NS promotes ATE and VTE could be different and seems to
be influenced by multiple factors because no set of conditions was universally observed
in patients with NS and thrombosis. Traditional cardiovascular risk factors, especially
smoking, seem to play a role in the occurrence of stroke in NS patients. We strongly
advise that these risk factors be carefully assessed and addressed in patients with
NS, even in young individuals. The role of anticoagulants and antiplatelet agents
in primary and secondary prophylaxis of stroke in the setting of NS has yet to be
determined.
Disclosure
YD received honorarium from Bayer and Bristol-Myers Squibb/Pfizer in the past 2 years.
GB received honorarium from Genzyme, Alexion, and Otsuka. All the other authors declared
no competing interests.