KIDNEY BIOPSY TEACHING CASE

ARF and Cerebral Infarcts in a Young Woman
Zeynep Aydin, MD, Jan A. Bruijn, MD, PhD, and Louis-Jean Vleming, MD, PhD
INDEX WORDS: Anticardiolipin antibodies; antiphospholipid syndrome; renal failure.

W

E PRESENT the case of a 22-year-old
woman with acute renal failure (ARF)
and cerebral infarcts. A renal biopsy allowed
specific diagnosis of her underlying disease.
CASE REPORT

A 22-year-old woman of Indian descent was admitted to
our hospital because of severe anemia and renal failure.
Three weeks before presentation, she had exertional dyspnea, orthopnea, and generalized weakness, which had worsened progressively thereafter. Additionally, she had progressive complaints of epigastric pains unresponsive to antacids.
Two weeks before these complaints she had suffered from an
upper respiratory tract infection with an unproductive cough
and a sore throat. Her history was otherwise unremarkable,
and she had not been taking any medication other than
antacids.
On physical examination, blood pressure was 180/120
mm Hg, pulse was regular at 100/min, central venous
pressure was not elevated, and body temperature was 36.8°C.
The skin and mucous membranes were pale but otherwise
normal. Fundoscopy results showed 2 small cotton wool
exudates. A third heart sound and a holosystolic apical
murmur were heard over the heart. Bilateral crackles were
apparent at the lung bases. The liver was enlarged with a
tender margin. There was no pitting edema. Physical examination findings were otherwise normal.
Laboratory examination showed an erythrocyte sedimentation rate of 118 mm/h, a hemoglobin level of 4.8 g/dL (48
g/L) with a mean corpuscular volume of 71 fL, a white blood
cell count of 8.3 ⫻ 103/␮L (⫻109/L) with a normal differential and a platelet count of 144 ⫻ 103/␮L (⫻109/L). There
were no schistocytes. The activated partial thromboplastin
time was lenghtened to 60 seconds without correction on
dilution with normal donor plasma. Prothrombin time was
also abnormal (40.8 seconds). Serum creatinine level was
elevated to 3.9 mg/dL (347 ␮mol/L) corresponding with a
calculated creatinine clearance of 14 mL/min (0.23 mL/s).
Urine analysis found hematuria (5 to 10 erythrocytes per
high-power field) without casts, and proteinuria was 1.68
g/24 h. Liver enzymes, electrolytes, calcium, phophorus,
albumin, and glucose levels were normal. Additional laboratory examinations were performed (Table 1).
The chest radiogram showed an enlarged heart, bilateral
pleural effusions, and bilateral air space consolidations caused
by pulmonary edema. An abdominal ultrasound scan showed
normal-sized kidneys without obstruction and engorgement
of the liver. An echocardiogram showed left ventricular
hypertrophy, mitral valve insufficiency due to a nodular
lesion of the anterior leaflet, and a small pericardial effusion.
The ejection fraction was 65%, but there was a clear diastolic dysfunction. The electrocardiogram was normal.

It was concluded that the patient was severely overhydrated and hypertensive because of ARF. A treatment was
instituted with diuretics intravenously and antihypertensive
agents resulting in a lowering of blood pressure to normal
levels and the achievement of euvolemia in the course of 3
days. One day after admission, the patient had thrombopenia, which prevented a renal biopsy. A preliminary diagnosis
of systemic lupus erythematosus (SLE) was made, in spite of
the negative antinuclear antibody titer, on the basis of the
coombs positive anemia, the thrombopenia with autoantibodies to thrombocytes, the pericardial effusion, the mitral valve
lesion, and the ARF. The patient was then treated with
solumedrol (1 g intravenously for 3 days) followed by
prednisone orally (60 mg per day) and cyclophosphamide
orally (100 mg per day). Renal function did not improve
during this treatment. However, 17 days after admission, the
platelet count normalized spontaneously, enabling a renal
biopsy.

Renal Biopsy Findings
The specimen received for light microscopy contained a
total of 21 glomeruli, showing mesangial expansion and
thickening of glomerular capillary walls to varying extent
(Fig 1A). In 3 glomeruli, fresh microthrombi were seen. The
arteries showed severe wall thickening with “onion skin
lesions” and multiple fresh thrombi (Fig 1B). In addition,
there was extensive tubular atrophy with almost diffuse
interstitial fibrosis. Immunofluorescence was negative, electron-microscopic examination was not performed.
The morphologic diagnosis was thrombotic microangiopathy with severe, chronic lesions. A clinical-pathologic diagnosis of antiphospholipid syndrome (APS) was established.

Clinical Course
Three days after the biopsy procedure, the patient had
generalized seizures. Multiple cerebral infarcts were seen on

From the Departments of Internal Medicine and Pathology, Leiden University Medical Centre, Leiden and the
Department of Internal Medicine, Rode Kruis Ziekenhuis,
The Hague, The Netherlands.
Received March 1, 2003; accepted in revised form October 6, 2003.
Address reprint requests to Zeynep Aydin, Leiden University Medical Centre, Department of Internal Medicine, PO
Box 9600, Building 1, C1S-46, 2300 RC Leiden, The Netherlands. E-mail: Z.Aydin@lumc.nl
© 2004 by the National Kidney Foundation, Inc.
0272-6386/04/4401-0018$30.00/0
doi:10.1053/j.ajkd.2003.10.046

American Journal of Kidney Diseases, Vol 44, No 1 (July), 2004: pp 179-183

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AYDIN, BRUIJN, AND VLEMING

Table 1.

Results of Additional Laboratory Tests

Variable

Value

Antiplatelet antibodies:
Immunoelectrophoresis
aCL
IgG
IgM
Antinuclear antibodies
Extractable nuclear antigen
(ENA)
Anti–double-stranded DNA
Anti-GBM
ANCA: ELISA
C1q (iE/mL)
C3 (mg/mL)
C4 (mg/mL)
Lupus anticoagulant
Coombs test
Hepatitis B/C
HIV
Cryoglobulins

Positive

Positive* (titer 1:200)
Negative
Negative
Negative
Negative
Negative
Negative
97 (normal range,
81-128)
0.78 (normal range,
0.9-1.8)
0.059 (normal range,
0.15-0.40)
Positive
Positive
Negative
Negative
Negative

Abbreviations: GBM, glomerular basement membrane;
ELISA, enzyme-linked immunosorbent assay; HIV, human
immunodeficiency virus.
*The IgG aCL antibodies were present at high levels on
2 occasions with an interval of 2 months.

magnetic resonance imaging of the brain. This provided
additional confirmation of our clinicopathologic diagnosis.
Appropriate therapy with oral anticoagulation (international
normalized ratio ⬎3), steroids (prednisone 30 mg twice a
day), and plasmapheresis (10 sessions of 1.8 ⫻ plasma
volume/session) was instituted. After initiation of this treatment, our patient made a remarkable recovery. Her hematologic abnormalities and her mitral valve lesion resolved
completely. Also, her neurologic condition resolved without
sequelae, enabling the withdrawal of all antiepileptic drugs
and permitting her to continue her university education.
Finally, her kidney function improved to a value of approximately 60 mL/min (1.00 mL/s; serum creatinine, 1.6 mg/dL
[144 ␮mol/L]). This was much better than was initially
expected on the basis of the severe chronic lesions in the
biopsy.

DISCUSSION

The antiphospholipid syndrome is characterized by recurrent arterial and venous thrombosis
or recurrent fetal loss in the presence of a lupus
anticoagulant, an elevated titer of anticardiolipin
(aCL) antibodies, or both.1-3 Other characteristics of this syndrome are summarized in Table 2.
The diagnosis of APS in our patient was established on the basis of renal thrombotic microan-

giopathy, multiple cerebral infarcts, the presence
of aCL antibodies, a positive lupus anticoagulant, thrombocytopenia, autoimmune hemolytic
anemia, and the mitral valve lesion.
The obvious prerequisite for a diagnosis of
APS is the presence of antiphospholipid antibodies. Although these autoantibodies are associated
with thrombosis, they can also be found in healthy
individuals. Prevalences of either immunoglobulin G (IgG) or IgM aCL antibodies of 2% to 12%
have been described with an increase of antibody
titers with increasing age.13,14 These antibodies
are found more frequently in patients with SLE,
where prevalences of up to 44% have been
described.15 They are also found in association
with other autoimmune disorders (eg, rheumatoid arthritis), certain infections (eg, human immunodeficiency virus), and certain drugs (eg,
phenothiazines).16,17 An APS secondary to SLE
is much more common than a primary APS
without any underlying autoimmune disorder. In
our patient, the renal biopsy findings and, more
specifically, the negative immunofluorescence
were essential in establishing a diagnosis of
primary APS.
Only a small minority of patients with APS
presents with a catastrophic syndrome characterized by widespread vascular occlusions affecting
multiple organs such as the lungs, heart, brain,
kidney, liver, adrenal glands, and gastrointestinal
tract. The smaller vessels in these organs are
predominantly affected, and this catastrophic syndrome often results in death.18 There are no data
on the incidence of this severe complication.
The pathophysiology of thrombosis in APS is
incompletely understood. Whereas lupus anticoagulants are able to prolong lipid-dependent coagulation tests, such as the prothrombin time and
the partial thromboplastin time in vitro, by interfering with the phospholipid component of the
prothrombin activator complex, they have procoagulant effects in vivo. aCL antibodies can be of
different immunoglobulin classes, including IgG,
IgA, and IgM. IgG aCLs are associated with a
greater risk of thrombosis than other immunoglobulin classes. The risk of thrombosis is also
associated with the IgG antibody titer.19-21 The
etiology of thrombosis in patients with antiphospholipid antibodies is incompletely understood.
It has been proposed that their procoagulant
effects in vivo are related to endothelial cell

ANTIPHOSPHOLIPID SYNDROME

181

Fig 1. (A) Segment of a
glomerulus shows expansion of mesangial area and
laminar thickening of glomerular capillary walls with microthrombi. (B) An artery
with severe wall thickening
owing to concentric fibrosis.
The lumen contains a fresh
thrombus (Ag, original magnification ⴛ100).

damage by antibody binding to endothelial phospholipids, reduced prostacyclin release by these
damaged endothelial cells, or alterations in platelet function.4,22
The histologic picture of a renal biopsy in APS
consists of a thrombotic microangiopathy of the
arteries, arterioles, and glomerular microvasculature. Other characteristics include fibrous intimal
hyperplasia of arterioles and interlobular arteries
with onion skin lesions of the vascular wall.
There also is often severe narrowing of the
vascular lumen and irregularly distributed focal
cortical tubulointerstitial atrophy predominantly
involving the subcapsular renal cortex. The dis-

tinction between primary APS and APS secondary to SLE can be made on the basis of the
immunofluorescence, which is characteristically
negative in primary APS.11,12 In general, the
morphologic finding of thrombotic microangiopathy has a broad differential diagnosis. This includes APS, malignant hypertension, diarrheapositive classic hemolytic uremic syndrome
(HUS), including familial and drug-induced
forms, and following radiation. Thus, proper
diagnosis requires careful evaluation and integration of morphologic, clinical, and serologic data.
It has been advocated that the distinction between APS and the HUS can generally be made

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AYDIN, BRUIJN, AND VLEMING
Table 2.

Criteria for the Classification of APS

Clinical criteria
Vascular thrombosis
One or more clinical episodes of arterial, venous, or small-vessel thrombosis, occurring within any tissue or organ
Complications of pregnancy
One or more unexplained deaths of morphologically normal fetuses at or after the 10th week of gestation; or
One or more premature births of morphologically normal neonates at or before the 34th week of gestation; or
Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation
Laboratory criteria
aCL antibodies
aCL IgG or IgM antibodies present at moderate or high levels in the blood on 2 or more occasions at least 6 weeks
apart
Lupus anticoagulant antibodies
Lupus anticoagulant antibodies detected in the blood on 2 or more occasions at least 6 weeks apart
NOTE. A diagnosis of definite APS requires the presence of at least 1 of the clinical criteria and at least 1 of the laboratory
criteria.

on the basis of the renal biopsy. Microthrombi in
HUS are most often restricted to the smaller
vessels and the glomeruli. Second, there is normally no fibrous intimal hyperplasia or focal
cortical atrophy.11 Malignant hypertension, however, cannot be distinguished from APS on the
basis of a biopsy. However, both HUS and malignant hypertension have distinguishing clinical
features. Our patient had neither schistocytes in a
peripheral blood smear, nor grade III or IV
abnormalities on fundoscopy. A diagnosis of primary APS was made on the basis of the negative
immunofluorescence, despite the fact that a diagnosis of antinuclear antibody–negative SLE was
suggested by multiple clinical and laboratory
features of this case. However, the patient did not
fulfill the revised American Rheumatology Association criteria for a diagnosis of SLE.23
The treatment of APS remains empirical because of the absence of therapeutic clinical trials
in this disorder and is directed at coagulation and
immune mechanisms. Venous and arterial thromboses in this condition are effectively prevented
by intensive oral anticoagulation with an international normalized ratio greater than 3.24,25 Oral
anticoagulation is also the cornerstone of the
treatment of thrombotic complications in this
disorder.24,25 Corticosteroids and cytotoxic drugs
may be considered in patients unresponsive to
antithrombotic therapy, although there is little
evidence that these drugs alter the course of the
hypercoagulable state.7,26 Severe organ complications such as ARF are often treated with adjunctive plasmapheresis, which induces a prompt
reduction of antiphospholipid antibody titers.18

In 1 series of 12 patients with ARF, complete
recovery of renal function occurred only in the 2
patients treated with plasmapheresis.27 In catastrophic APS, patients treated with adjunctive
plasmapheresis or intravenous immunoglobulin
had the highest survival rate (70%).18,28
APS is a severe and potentially life-threatening condition that can be either primary or secondary to SLE. The differential diagnosis of primary
APS with renal involvement includes SLE with
secondary APS, HUS, and malignant hypertension. A kidney biopsy is an important aid in the
resolution of this differential diagnosis. Early
and appropriate treatment determines clinical
outcome in patients with APS. The prognosis of
such patients is, therefore, dependent on early
recognition of this diagnosis in patients with
antiphospolipid antibodies.
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