RENAL BIOPSY TEACHING CASE
Nephrotic Syndrome in a Young Postpartum Woman
Agnes Fogo, MD, and Scott Shappell, MD, PhD
INDEX WORDS: Nephrotic syndrome; postpartum; amyloidosis; tuberculosis.
T HE DIFFERENTIAL diagnosis of nephrotic
syndrome in adult patients includes many
entities, the most common of which, in the United
States, is focal segmental glomerulosclerosis.1 In
the pregnant patient with increased proteinuria or
new onset of nephrotic syndrome, one must
consider in addition the exacerbation of preexist-
ing disease or pregnancy-related diseases as
causes of renal dysfunction. This case illustrates
the value of the renal biopsy in making definitive
diagnosis in the clinical setting of nephrotic
syndrome in a young woman in the immediate
postpartum period.
CASE REPORT
A 20-year-old woman who was a native of Sudan and
immigrated to the United States 2 years previously presented
to her local doctor, 6 weeks after normal delivery of a term
infant, with increasing dyspnea, a productive cough, and
ankle swelling. The pregnancy had been uncomplicated, but
at delivery, hypertension and 2 proteinuria were noted.
The physical examination at presentation showed a thin
woman, weighing only 90 lbs., in severe respiratory distress.
Blood pressure was 106/62 mm Hg; pulse, 83 beats/min;
respiratory rate, 20 breaths/min; and temperature was 97.5F.
The lungs showed bilateral rales and rhonchi. No heart
murmur was present. There was ascites, but no abdominal
tenderness or hepatosplenomegaly. The lower extremities
showed 2 pitting edema. There were no rashes, petechiae,
or purpura. The rest of the physical examination was unre-
markable.
She was admitted to the medical intensive care unit
(MICU) and intubated. Initial laboratory tests showed heavy
proteinuria, 11 g/24 hr, serum albumin 1.0 g/dL, and bilat-
eral lung infiltrates on chest radiograph. There was no
hematuria or red blood cell casts, and serum creatinine was
normal. She was treated with 50 mg/day prednisone empiri-
cally for presumed minimal change disease. Swan-Ganz
catheterization showed a wedge pressure of 4 mm Hg. She
was treated with fluids and albumin followed by lasix
diuresis. Bronchoscopy was unrevealing. Lung biopsy
showed fibrosis and no organisms except Candida. She
improved slightly and was extubated and transferred out of
the MICU. No response of proteinuria to prednisone was
seen after 2 weeks, and a nephrology consult was obtained.
Blood cultures at this time grew Candida albicans, and
heavy proteinuria continued. Corticosteroids were stopped,
amphotericin B treatment was initiated, and a renal biopsy
was performed. Additional laboratory tests at this time
included normal electrolytes, except decreased potassium at
American Journal of Kidney Diseases, Vol 31, No 4 (April), 1998: pp 723-728
2.8 mEq/L. Serum creatinine was 2.9 mg/dL, blood urea
nitrogen was 55 mg/dL, and serum albumin was 0.7 g/dL.
Total complement, C3 and C4 levels were normal. Tests for
anti-nuclear antibody and hepatitis B were negative. There
was 4 proteinuria, with no red blood cells on dipstick.
Repeat 24-hour urine protein excretion was 16 g.
The patients history was significant for tuberculosis while
living in Sudan. She had received treatment for tuberculosis
2 years previously, although the precise regimen was not
known.
The clinical differential diagnosis included minimal change
disease with superimposed renal vein thrombosis, or mini-
mal change disease with acute renal failure syndrome, or
focal segmental glomerulosclerosis.
Renal Biopsy
The renal biopsy consisted of a sample of cortex and
medulla, with 13 glomeruli, two of which were globally
sclerosed. There was a focal, segmental expansion of the
mesangium with pale, eosinophilic, acellular material, not
staining with the periodic acid-Schiff (PAS) stain (Fig 1).
The glomerular basement membrane was moderately and
irregularly thickened. Occasional small, feathery spikes pro-
truding from the glomerular basement membranes were
visualized on Jones silver stain. No endocapillary prolifera-
tion or crescents were present. Tubules showed mild patchy
atrophy with occasional proteinaceous casts. Tubular base-
ment membranes were irregularly thickened, and the intersti-
tium showed fibrosis and deposition of eosinophilic, amor-
phous material. Arterioles showed focal moderate hyalinosis
with additional areas of eosinophilic material that did not
stain with PAS. Immunofluorescence studies showed trace to
1 (on a 1 to 3 scale) accentuation of the glomerular
basement membranes with immunoglobulin (Ig) G, and
smudgy mesangial staining with IgG in 1 to 2 intensity.
There was similar smudgy mesangial and irregular glomeru-
lar basement membrane staining with C3, and in 1 inten-
sity for IgA and IgM. Kappa and lambda antisera showed
very trace smooth capillary wall staining that was equal for
both. A Congo red stain showed strong positivity in glomeru-
From the Department of Pathology, Vanderbilt University
Medical Center, Nashville, TN.
Received and accepted December 12, 1997.
Dr Fogo is a recipient of an Established Investigator
Award from the American Heart Association.
Address reprint requests to Agnes Fogo, MD, MCN C3310,
Department of Pathology, Vanderbilt University Med-
ical Center, Nashville, TN 37232-2165. E-mail: agnes.
fogo@mcmail.vanderbilt.edu
r 1998 by the National Kidney Foundation, Inc.
0272-6386/98/3104-0026$3.00/0
723
724
lar mesangial areas, glomerular capillary walls, arterioles,
arteries, and tubular basement membranes, particularly in
the medulla. These Congo redpositive areas were apple-
green birefringent when viewed under polarized light (Fig
2). Immunohistochemistry on sections from paraffin-embed-
ded material with antisera for AA amyloid showed strong
positivity within glomeruli, vessels, and tubular basement
membranes (Fig 3).
Electron microscopic studies showed prominent deposi-
tion of approximately 10- to 15-nm diameter fibrils in a
random arrangement (Figs 4, 5). These fibrils were present
in the subendothelial area, with segmental areas extending
through the lamina densa (Fig 5). The mesangium was
markedly expanded with fibrillar deposits with a mild in-
crease in mesangial cells without dense immune complex
type deposits (Fig 4). Tubular basement membranes also
Fig 2. Apple-green bire-
fringence in glomeruli, arte-
rioles, and arteries (Congo
red, viewed under polarized
light; original magnification
200).
FOGO AND SHAPPELL
Fig 1. Mesangial expan-
sion with acellular, pale,
fluffy material and irregular
basement membrane thick-
ening (Jones silver stain;
original magnification 400).
showed deposition of fibrils. Rare areas of increased lucency
of the lamina rara interna, consistent with mild hypertensive
or endothelial injury, were also present.
The biopsy findings are diagnostic of amyloidosis. The
immunofluorescence and immunohistochemistry results fur-
ther show that the amyloidosis is not due to light chain, but
rather is AA amyloid. The likely underlying cause of this
secondary amyloidosis in this patient is tuberculosis.
Clinical Course
After the biopsy results, supportive treatment for the
nephrotic syndrome and amphotericin were continued. How-
ever, serum creatinine rose to 6 mg/dL, and amphotericin
was discontinued. The patient became septic, oliguric, and
died. Permission for an autopsy was denied.
NEPHROTIC SYNDROME POSTPARTUM
Fig 3. Strong positivity
for AA amyloid in glomeruli
and in arteries and arterioles
(immunoperoxidase with an-
tibody to serum protein A;
original magnification 200).
DISCUSSION
The diagnosis in this case was challenging
because of the multiple manifestations of illness
in this patient. Overt manifestation of nephrotic
syndrome shortly followed her pregnancy, thus
making the clinical differential diagnosis chal-
lenging.2 The appearance of proteinuria and hy-
pertension during pregnancy suggests the possi-
bility of preeclampsia. However, the symptoms
of preeclampsia regress in nearly all patients
after delivery.2 Persistence of, and worsening of,
725
her renal disease after delivery thus indicate
other underlying renal disease. The effect of
pregnancy on preexisting renal disease varies,
depending on both the type of disease and its
severity at conception. Preexisting renal diseases
that have been studied extensively in connection
with pregnancy and that may present as ne-
phrotic syndrome include focal segmental glo-
merulosclerosis, lupus nephritis, hypertensive
nephrosclerosis, IgA nephropathy, and membra-
nous glomerulonephritis.2,3 However, when exac-
Fig 4. Marked mesangial
expansion with deposits of
randomly oriented fibrils, typi-
cal of amyloid (transmission
electron microscopy; origi-
nal magnification 10,600).
726
erbation of renal dysfunction and proteinuria
occurs in these settings, it manifests during preg-
nancy, with resolution and return of renal func-
tion toward baseline after delivery in most pa-
tients. Although minimal change diseaseinduced
nephrotic syndrome occurs in young adults
(30% of nephrotic syndrome), it is not com-
mon enough to justify empirical corticosteroid
treatment, as is the practice in the pediatric
patient, where minimal change disease accounts
for over 80% of cases of nephrotic syndrome.4
Indeed, the biopsy in this patient showed an
uncommon cause of the nephrotic syndrome, AA
amyloidosis.
Amyloidosis is defined as the deposition of
proteins that have the capacity to form beta-
pleated sheets and are therefore resistant to deg-
radation. Many different peptide subunits have
the capacity to form amyloid. More than 17
different types of amyloid have been identified.5
The two most common forms of amyloidosis in
the United States are monoclonal immunoglobu-
lin light chain related (AL, more commonly
composed of lambda than kappa light chain) and
familial transthyretin-associated amyloidosis
(ATTR). The latter has recently been described
to be associated with a variant sequence transthy-
retin in blacks with late-onset cardiac amyloido-
sis. The types that commonly affect the kidney
are AL amyloid, amyloid A (AA) secondary to
FOGO AND SHAPPELL
Fig 5. Fibrillary deposits
are interwoven throughout
and penetrate basement
membrane with surrounding
basement membrane mate-
rial, giving rise to feathery
spikes appearance by light
microscopy (transmission
electron microscopy; origi-
nal magnification 13,000).
chronic infections or chronic inflammatory con-
ditions, and familial Mediterranean feverassoci-
ated amyloid.5
Amyloidosis is a relatively rare cause of renal
disease, especially in younger patients. In a large
series of mostly adult native kidney biopsies,
amyloidosis was the diagnosis in 2% of renal
biopsy specimens, and AL amyloid was the most
common type of amyloid.6 The age-adjusted inci-
dence of AL amyloidosis is estimated to be 5.1 to
12.8 per million person-years in the United
States.5 AL and AA amyloid are the most com-
mon types of amyloid to affect the native kidney.
Involvement of the kidney by amyloid in patients
in the United States is far more frequently due to
AL amyloid than AA amyloid, reflecting the
higher incidence of AL versus AA amyloid in
this population, especially in older patients. Thus,
Kyle and Gertz7 have reported 918 cases of AL
amyloid, of which approximately half had renal
insufficiency; 30% had nephrotic syndrome.7 Re-
nal biopsy in 81 of these patients indeed showed
AL amyloid in 94%, verifying the validity of the
clinical impression. During this same time span,
only 45 cases of AA and 55 cases of familial
amyloid were seen; over 90% of AA cases had
clinical renal involvement.7 The ratio for AL
versus AA involving the kidney in this popula-
tion thus can be extrapolated to be 10:1. In
contrast, in developing and Mediterranean coun-
NEPHROTIC SYNDROME POSTPARTUM
tries, AA amyloid is a common cause of ne-
phrotic syndrome.5 When amyloid involves the
kidney, nearly half of patients have nephrotic-
range proteinuria, regardless of the peptide ori-
gin of the amyloid. Systemic manifestations also
may be present, including carpal tunnel syn-
drome, congestive heart failure due to cardiac
amyloidosis, peripheral neuropathy, and liver dis-
ease.5
Secondary amyloidosis is due to deposition of
the amino terminus of the serum amyloid A
protein (AA protein), an acute-phase protein pro-
duced in response to inflammation or infection.
At least five different molecular forms have been
identified in humans. The most common presen-
tation of AA amyloidosis is that of renal disease.
Cardiac involvement is rare in AA amyloidosis,5
contrasting the frequent heart abnormalities in
AL and ATTR amyloidosis. (Two thirds of AL
patients at diagnosis had abnormal echocardio-
grams.7) It is important to note that the substan-
tial reduction in chronic infections such as tuber-
culosis, chronic osteomyelitis, and bronchiectasis
in the United States has made AA amyloidosis
complicating infectious processes very rare.
Rather, AA amyloidosis more often occurs in the
United States secondary to chronic inflammatory
diseases, such as rheumatoid arthritis, inflamma-
tory bowel disease, and untreated familial Medi-
terranean fever. Other rare chronic infections
that have caused AA amyloidosis include liver
abscess and chronic suppurative skin infections
(eg, decubitus ulcer).5,8 Thus, it is critical in this
patient to recognize that although she had lived
in the United States for 2 years, she still had
different risk factors for disease than patients
who have lived their whole lives in the United
States. This patient was from Sudan, and familial
Mediterranean fever could therefore be consid-
ered as a potential cause of amyloidosis. How-
ever, the absence of family history or other
previous signs of this illness argue against this
possibility. Importantly, this patient did have a
history of tuberculosis, the likely underlying
cause for the development of AA amyloidosis.
There are rare reports of amyloidosis causing
renal disease during pregnancy and the immedi-
ate postpartum period.2,8,9 In cases of amyloido-
sis due to familial Mediterranean fever, worse
renal dysfunction at conception was associated
with deterioration during pregnancy.9 Tuberculo-
727
sis has increased in incidence in the United
States over the last decades, associated with
human immunodeficiency virus (HIV) infection
and increasing immigration of people from areas
where tuberculosis is endemic. The largest in-
crease in tuberculosis has been in minority pa-
tients of child-bearing age.10 Reactivation of
tuberculosis by pregnancy has been postulated,
but not proven.11 In one series of pregnant women
with active tuberculosis, 7 of 11 patients tested
for HIV were positive.12 In our patient, HIV test
results were not available. The reactivation of
her underlying infection may have been contrib-
uted to by both her pregnancy and subsequently
the corticosteroids she received. The pregnancy
likely also contributed to her preexisting, clini-
cally silent, renal disease becoming overtly mani-
fest.
Diagnosis of amyloidosis is made by tissue
biopsy. Congo red positivity with apple-green
birefringence is the gold standard for detection
of the diagnostic beta-pleated sheets of protein.
Other diseases with fibrillar deposits by electron
microscopy do not show Congo red positivity.
Fibrillary glomerulonephritis also has distinct
immunofluorescence findings, with prominent
mesangial, and to lesser degree, capillary wall
staining with polyclonal IgG and complement.3
The immunofluorescence findings in this case
appeared to be due to nonspecific trapping re-
lated to endothelial injury, and were not typical
of fibrillary glomerulonephritis. Integration of all
findings from light microscopy, immunofluores-
cence, and electron microscopy and special stud-
ies is thus necessary to arrive at a correct diagno-
sis. Although some studies have touted the use of
the fat aspirate for diagnosis of AL amyloidosis,
others have shown the lower sensitivity of this
technique.13,14 Sensitivity of the fat aspirate pro-
cedure is likely less for other types of amyloid-
osis where systemic involvement of this tissue is
less frequent or of lesser quantity.13
Once the diagnosis of amyloid is made, at-
tempts to classify its composition can aid in
further diagnosis and treatment of the underlying
cause. Histological pattern of renal involvement
is not useful in differentiating various forms of
amyloid.15 Stains for kappa and lambda light
chain can identify AL amyloid by monotypic
staining for one of these light chains. Previous
methods to differentiate between AA amyloid
728
and other amyloids based on permanganate sen-
sitivity were not reliable and have largely been
supplanted by immunohistochemistry with spe-
cific antibodies to AA or other amyloids.5
The prognosis of patients with amyloidosis
varies according to the type of amyloid and
underlying associated condition.WithALamyloid-
osis, the median survival is only 1 to 2 years,
contrasting with up to 15-year survival with
ATTR amyloidosis.5 The underlying condition in
AA amyloidosis greatly affects the final out-
come. For AL amyloidosis, treatment of the
underlying plasma cell dyscrasia has been at-
tempted with melphalan, with remission in some
patients.5,16 Vigorous treatment and removal of
the underlying inciting inflammation in AA amy-
loidosis may halt progression.17 Colchicine has
been used in some cases of familial Mediterra-
nean feverassociated AA amyloidosis, although
the efficacy of this approach in other forms of
amyloidosis has not been shown.5,16
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