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case records of the massachusetts general hospital
From the Departments of Medicine (H.B.,
A.K.M.) and Pathology (E.A.F.), Massa-
chusetts General Hospital, and the De-
partments of Medicine (H.B., A.K.M.) and
Pathology (E.A.F.), Harvard Medical School
— both in Boston.
This article was updated on January 23,
2014, at NEJM.org.
N Engl J Med 2014;370:362-73.
DOI: 10.1056/NEJMcpc1214220
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362
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of m e dic i n e
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Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor
Case 3-2014: A 61-Year-Old Woman
with Gastrointestinal Symptoms, Anemia,
and Acute Kidney Injury
Hasan Bazari, M.D., Anuj K. Mahindra, M.D., and Evan A. Farkash, M.D., Ph.D.
Pr e sen tat ion of C a se
Dr. Meghan E. Shea (Medicine): A 61-year-old woman was admitted to this hospital
because of epigastric pain, vomiting, diarrhea, anemia, and acute kidney injury.
The patient had been well until approximately 3 weeks before admission, when
vomiting, diarrhea, fevers, arthralgias, and episodes of epigastric pain of increas-
ing frequency and severity developed, which she attributed to a viral gastroenteri-
tis. Two weeks before admission, epigastric and midabdominal pain worsened,
with diarrhea and one episode of vomiting. The next day, she came to the emer-
gency department at this hospital. She rated the pain at 4 on a scale of 0 to 10
(with 10 indicating the most severe pain) and reported that it was worse when she
was lying flat. The blood pressure was 150/82 mm Hg, and the pulse 101 beats per
minute; other vital signs were normal. The abdomen was soft, and there was mild
epigastric tenderness without rebound; the remainder of the examination was
normal. A stool specimen revealed occult blood. The red-cell indexes, platelet count,
and blood levels of total and direct bilirubin were normal; other test results are
shown in Table 1. An electrocardiogram was normal. The patient returned home
taking ranitidine, simethicone, and antacids. Three days later, upper endoscopic
examination revealed a small hiatus hernia and was otherwise normal. Results of
Helicobacter pylori antibody testing were reported as representing either infection or
immunity; the blood level of haptoglobin was normal. Other test results are shown
in Table 1. The next day, she was admitted to this hospital.
The patient reported no history of melena or hematochezia. She had labile hy-
pertension (for which triamterene and hydrochlorothiazide in combination and
metoprolol had been prescribed at different times and discontinued because of
hypotension and gastrointestinal symptoms, respectively), hypercholesterolemia
(with normal lipid profile 2 months earlier), allergic rhinitis, and possible gastro-
esophageal reflux disease, and she had had a urinary tract infection in the past.
Imaging studies in the past had revealed ovarian cysts and bilateral pulmonary
nodules, suggestive of old granulomatous disease. Medications included ranitidine,
atorvastatin, and fluticasone propionate nasal spray. She had no history of aller-
gies to medications. She was married, retired, and physically active. She drank
alcohol in moderation and did not smoke or use illicit drugs. She had done no
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 case records of the massachuset ts gener al hospital
recent foreign traveling; her husband and friends
had recently had transient gastroenteritis. The
patient’s father had died at 72 years of age from
esophageal cancer, a grandfather and a paternal
aunt had had lymphoma, and maternal cousins
had sarcoma and lung cancer; her mother and
children were healthy, and there was no family
history of renal or rheumatologic diseases.
On examination, the blood pressure was
160/77 mm Hg, the pulse 89 beats per minute,
and the temperature 37.7°C; the respirations and
the remainder of the examination were normal.
Blood levels of haptoglobin, glucose, folic acid,
vitamin B12, ferritin, phosphorus, magnesium,
amylase, and lipase were normal, as were the
results of coagulation tests; serum protein elec-
trophoresis revealed a normal pattern, and im-
munofixation showed no M component. Other
test results are shown in Table 1. Review of the
peripheral-blood smear revealed occasional reac-
tive-appearing atypical lymphocytes.
On the second day, a bone marrow biopsy and
aspiration were performed. Pathological examina-
tion of the specimen revealed trilineage hemato-
poiesis with normal morphologic features; a karyo­
type was normal. A small, clonal B-cell population
(3% of B cells expressing CD19+ CD20+ CD5−
CD10− kappa+) was detected with the use of flow
cytometry; immunohistochemical staining revealed
scattered T cells, occasional B cells, and occa-
sional polyclonal plasma cells. Serologic testing
for celiac disease was negative, as was examina-
tion of the stool for H. pylori antigen, leukocytes,
rotavirus, enteric pathogens, ova, and parasites.
On the third day, the hematocrit fell to 24.5%.
The ABO blood type was O, Rh positive, with
negative antibody screening and a negative direct
antiglobulin test, and 2 units of red cells (irradi-
ated and leukocyte-reduced) were transfused; the
hematocrit rose to 30.4%. The patient was dis-
charged from the hospital.
Two days after discharge, diarrhea developed,
and 3 days later, anorexia, nausea, epigastric pain
(constant, rated at 7 out of 10), and recurrent
bilious and occasionally blood-streaked emesis
occurred. The patient took bismuth subsalicylate,
but her condition did not improve. The next day,
she returned to the emergency department. She
reported fevers (a temperature of 38.1°C), with
chills and diaphoresis.
On examination, the blood pressure was
179/92 mm Hg, the pulse 90 beats per minute,
and the temperature 37.0°C, with normal respi-
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rations and oxygen saturation. The abdomen
was soft, with mild epigastric tenderness, with-
out rebound or masses; the remainder of the
examination was normal. The stool was black
and positive for occult blood (trace). Test results
are shown in Table 1. Ondansetron and intrave-
nous fluids were administered. Within 3.5 hours,
the systolic blood pressure rose to 200 mm Hg,
and the pulse to 94 beats per minute. The tem-
perature later rose to 38.1°C. Oxygen supplemen-
tation, ondansetron, antacids, oxycodone, acet-
aminophen, and irbesartan were administered.
Abdominal ultrasonography revealed trace asci-
tes and small pleural effusions. The patient was
admitted to the hospital.
Results of testing for antinuclear antibodies
(ANA) and antibodies to double-stranded DNA
were negative. The next day, renal vascular ultra-
sonography revealed no evidence of renal-artery
stenosis. Methylprednisolone (1 g daily, intrave-
nously) and labetalol were administered. Cyto­
logic examination of the urine showed red-cell
casts, hyaline casts, oxalate crystals, and no
malignant cells. Culture of the urine grew few
colonies (1000 to 10,000) of mixed bacteria.
On the fifth day, a diagnostic procedure was
performed.
Differ en t i a l Di agnosis
Dr. Hasan Bazari: In a complex case such as this,
one can either use pattern recognition as a para-
digm for clinical problem solving or use deduc-
tive reasoning that is based on analysis of the
details of this case.
Pertinent Clinical Details
This 61-year-old woman presented with a 4-week
history of epigastric pain, diarrhea, and vomit-
ing. Arthralgias, fever, anemia, and acute kidney
injury developed. The stool was guaiac-positive
and positive for H. pylori antigen, and an esophago­
gastroduodenoscopy was normal. In the past, she
had had hyperlipidemia and gastroesophageal
reflux disease. On examination, she had mild ab-
dominal tenderness. Pertinent laboratory values
include progressive anemia, an absence of leuko-
cytosis, progressive renal failure, elevated blood
levels of aminotransferase and alkaline phospha-
tase, serum immune electrophoresis with no
monoclonal protein detected, and a high serum
free light-chain ratio (kappa:lambda ratio, 3.1;
normal range, 0.3 to 1.7). Urinalysis was patho­
363
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Laboratory Data.*

2 Wk before
Admission (4
2 Mo before Days before First 1st Admission
Admission Admission), 1 Day (8 Days
Reference Range, (Annual Emergency before First before 2nd 2nd
Variable Adults† Examination) Department Admission Admission) Admission
Blood
Hematocrit (%) 36.0–46.0 (in women) 39.5 33.0 26.5 28.7 33.3
Hemoglobin (g/dl) 12.0–16.0 (in women) 13.4 11.4 8.9 10.0 11.8
White-cell count (per mm3) 4500–11,000 4500 6700 3900 5800 8800
Differential count (%)
Neutrophils 40–70 49.2 75 78 78
Lymphocytes 22–44 43.6 22 20 20
Monocytes 4–11      6 2 2 2
Eosinophils 0–8 0.7 1 0 0
Basophils 0–3 0.5 0 0 0
Reticulocytes (%) 0.5–2.5 2.6
Haptoglobin (mg/dl) 16–199
Erythrocyte sedimentation rate (mm/hr) 0–17 28
C-reactive protein (mg/liter) <8.0, for evaluation 1.5 47.2
for inflammation
Sodium (mmol/liter) 135–145 141 138 135 129
Potassium (mmol/liter) 3.4–4.8 4.1 3.6 4.0 4.2
Chloride (mmol/liter) 100–108 106 101 102 96
Carbon dioxide (mmol/liter) 23.0–31.9 24 28.4 25.8 24.1
Urea nitrogen (mg/dl) 8–25 17 17 16 28
Creatinine (mg/dl) 0.60–1.50 0.88 0.91 0.98 1.66
Estimated glomerular filtration rate (ml/ Normal, ≥60 >60 >60 >60 33
min/1.73 m2)‡
Protein (g/dl)
Total 6.0–8.3 7.1 6.2 5.8 6.0
Albumin 3.3–5.0 4.8 3.8 3.5 3.3
Globulin 2.6–4.1 2.3 2.4 2.3 2.7
Calcium (mg/dl) 8.5–10.5 9.5 9.1 8.4 8.3
Alkaline phosphatase (U/liter) 30–100 72 76 84 156
Aspartate aminotransferase (U/liter) 9–32 21 26 26 39
Alanine aminotransferase (U/liter) 7–30 21 21 22 45
Lactate dehydrogenase (U/liter) 110–210 229 322
Iron (μg/dl) 30–160 26
Iron-binding capacity (μg/dl) 230–404 208
Ferritin (ng/ml) 10–200 119
Erythropoietin (mIU/ml) 2.6–18.5 25.6
Immunoglobulins (mg/dl)
IgA 69–309 67
IgG 614–1295 523
IgM 53–334 80
Free kappa light chains (mg/liter) 3.3–19.4 42.7
Free lambda light chains (mg/liter) 5.7–26.3 14.0
Ratio of free kappa:free lambda light chains 0.3–1.7  3.1
Immunofixation No M
component

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 case records of the massachuset ts gener al hospital

Table 1. (Continued.)

2 Wk before
Admission (4
2 Mo before Days before First 1st Admission
Admission Admission), 1 Day (8 Days
Reference Range, (Annual Emergency before First before 2nd 2nd
Variable Adults† Examination) Department Admission Admission) Admission
Complement
Total (U/ml) 63–145 11
C3 (mg/dl) 86–184 77
C4 (mg/dl) 16–38 <2
Rheumatoid factor (IU/ml) <30 41
Lyme IgG and IgM antibodies Negative Negative
Urine
Color Yellow Yellow Yellow Yellow Yellow
Appearance Clear Clear Clear Clear Cloudy
pH 5.0–9.0 7.0 6.5 5.5 5.0
Specific gravity 1.001–1.035 1.004 <1.005 1.008 >1.030
Glucose Negative Negative Negative Negative Negative
Bilirubin Negative Negative Negative Negative 1+
Ketones Negative Negative Negative Negative Negative
Blood Negative Negative 1+ 1+ 3+
Albumin Negative Negative Negative Negative 3+
Urobilinogen Negative Negative Negative Negative
White-cell screen Negative Negative Negative Negative Negative
Nitrite Negative Negative Negative Negative Negative
Sediment
Red cells (per high-power field) 0–2 0–2 0–2 >100
White cells (per high-power field) 0–2 0–2 None None
Bacteria (per high-power field) None Many
Mucin (per low-power field) None Present Present Present
Hyaline casts (per low-power field) 0–5 3–5 >100
Red-cell casts (per low-power field) None 3–5
Granular casts (per low-power field) None 20–100
White-cell casts (per low-power field) None 10–20
Squamous epithelial cells (per high- None Few
power field)
Transitional cells (per high-power field) None Rare
Amorphous crystals (per high-power None Present
field)
Epithelial casts Rare
Eosinophils Negative Negative
Osmolality (mOsm/kg of water) 310
Sodium (mmol/liter) Not defined 37
Urea nitrogen (mg/dl) Not defined 264
Creatinine (mg/ml) 2.87

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine from milligrams per
deciliter to micromoles per liter, multiply by 88.4. To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the
values for iron and iron-binding capacity to micromoles per liter, multiply by 0.1791.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at
Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They
may therefore not be appropriate for all patients.
‡ If the patient is black, multiply the result by 1.21.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

disease is so high and the pace of the disease

Table 2. Causes of Rapidly Progressive Glomerulonephritis.*
so rapid that the benefit of empirical therapy
Anti–glomerular basement membrane disease outweighs the risk of harm. I agree with the use
Antineutrophil cytoplasmic antibody–associated vasculitis of high doses of methylprednisolone in cases
Immune-complex–mediated glomerulonephritis such as this one (boluses of 500 to 1000 mg
In patients with normal complement levels:
daily for 3 days).
IgA nephropathy
Henoch–Schönlein purpura
Anti–Glomerular Basement Membrane Disease
Fibrillary glomerulonephritis, immunotactoid glomerulonephritis
In patients with low complement levels: I would have considered and dismissed anti-GBM
SLE disease fairly quickly on the basis of the patient’s
Poststreptococcal glomerulonephritis abdominal symptoms on clinical presentation.
Membranoproliferative glomerulonephritis I would have ordered testing for anti-GBM anti-
Infections (HCV, HBV, HIV) bodies and expected a negative result.
Genetic
Collagen vascular disease (SLE, Sjögren’s syndrome) ANCA-associated vasculitides
Monoclonal gammopathies
The most common causes of rapidly progressive
Endocarditis
Cryoglobulinemia
glomerulonephritis are the ANCA-associated vas-
Type I (may be associated with myeloma, lymphoma, or Waldenström’s culitides. These include granulomatosis with poly­
macroglobulinemia) angiitis (formerly Wegener’s granulomatosis),
Type II (may be associated with myeloma, lymphoma, Waldenström’s microscopic polyangiitis, eosinophilic granuloma-
macroglobulinemia, HCV, or Sjögren’s syndrome)
tosis with polyangiitis (Churg–Strauss syndrome),
Type III (may be associated with HCV or endocarditis)
and pauci-immune crescentic glomerulonephritis.3
* HBV denotes hepatitis B virus, HCV hepatitis C virus, HIV human immuno­ ANCA-associated vasculitis typically involves the
deficiency virus, and SLE systemic lupus erythematosus. kidneys and upper and lower respiratory tracts
but can involve other organs, including the skin,
gnomonic for an acute glomerulonephritis, with nerves, sinuses, central nervous system, and heart,
proteinuria and red-cell casts. The rheumatoid and the gastrointestinal tract.4 Isolated gastro­
factor was weakly positive. Testing for ANA was intestinal involvement with vasculitis and ulcers
negative, and blood levels of complement were is less common.5 I would have requested ANCA
low (C4, very low; and C3, slightly decreased). testing, and if the results were positive, I would
Evaluation for anemia was consistent with ane- have avoided a renal biopsy.
mia of chronic disease. A bone marrow–biopsy
specimen showed 3% monoclonal B cells, which Immune-complex–mediated glomerulonephritis
were CD5− CD10− kappa+. The immune-complex glomerulonephritides are
divided into normocomplementemic and hypo-
Rapidly Progressive Glomerulonephritis complementemic glomerulonephritis (Table 2).
This patient has abdominal pain, diarrhea, and Diseases that are associated with normal serum
vomiting, and rapidly progressive glomerulone- complement levels include IgA nephropathy and
phritis has developed, which is defined as a de- Henoch–Schönlein purpura, which are both IgA-
crease in the glomerular filtration rate by more mediated, and fibrillary and immunotactoid glo-
than 50% in a 3-month period.1 The diagnosis merulonephritis. IgA nephropathy is the most
must thus be associated with the causes of rapidly common cause of glomerulonephritis and ranges
progressive glomerulonephritis (Table 2), which from asymptomatic hematuria and proteinuria to
consist of the following three large groups of the nephrotic syndrome or rapidly progressive glo-
diseases: anti–glomerular basement membrane merulonephritis.6 This patient could have classic
(GBM) disease (Goodpasture’s syndrome),2 pauci- Henoch–Schönlein purpura with abdominal pain
immune or antineutrophil cytoplasmic antibody and rapidly progressive glomerulonephritis, but
(ANCA)–mediated crescentic glomerulo­nephritis,3 the purpuric rash that characteristically appears on
and the immune-complex–mediated glomerulo- the extensor surfaces of the arms and legs is ab-
nephritides. sent; occasionally, the rash appears after the gas-
The first question that I ask when I see a trointestinal and renal manifestations.7 These
patient with rapidly progressive glomerulone- two diseases are nonspecifically associated with
phritis is whether the pretest probability of the elevated polyclonal IgA levels, which this patient

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 case records of the massachuset ts gener al hospital

did not have. A definitive diagnosis can be made
by cutaneous, gastrointestinal, or renal biopsy to
look for IgA deposition in small vessels.
Fibrillary glomerulonephritis and immunotac-
toid glomerulonephritis are both immunoglobulin
deposition diseases. Fibrillary glomerulonephritis
is polyclonal, and immunotactoid glomerulone-
phritis is often clonal, often with an associated
monoclonal gammopathy.8 Fibrillary glomerulo-
nephritis occasionally causes low C3 levels.9
Diseases with low complement levels include
many diseases that activate the alternative com-
plement pathway, which causes very low C3 and
normal C4 levels, and very few diseases that
activate the classic complement pathway, which
causes a very low C4 level and a normal or
mildly depressed C3 level.10 The classic diseases
associated with low complement levels are sys-
temic lupus erythematosus (SLE), membrano­
proliferative glomerulonephritis, poststreptococ-
cal glomerulonephritis, shunt nephritis, bacterial
endocarditis, visceral abscess, other infections,
and C3 glomerulonephritis.11 There are no fea-
tures in this case to suggest a poststreptococcal
glomerulonephritis, endocarditis, or other infec-
tions. This patient could have SLE with serositis
and anemia. However, testing for ANA and anti–
double-stranded DNA antibody was negative.
Membranoproliferative Glomerulonephritis
Membranoproliferative glomerulonephritis is a
pathologic entity that can have a variety of causes
(Fig. 1).12,13 The bone marrow–biopsy specimen
in this case rules out myeloma, but the abnormal
serum free light-chain ratio is suggestive of a
monoclonal gammopathy.

Infections
Poststreptococcal
glomerulonephritis
HCV
HBV
HIV
Endocarditis
Epstein–Barr virus
Syphilis
Schistosomiasis
Helicobacter pylori
Lyme disease
Malaria

Immune-complex
Cryo
glomerulonephritis Collagen Vascular Diseases
Monoclonal Gammopathies
Myeloma Membranoproliferative Systemic lupus erythematosus
Chronic lymphocytic leukemia glomerulonephritis Sjögren’s syndrome
Monoclonal gammopathy with or without Rheumatoid arthritis
of undetermined significance cryoglobulins Polyarteritis nodosa
Lymphoplasmacytic lymphoma Mixed connective-tissue disease
Cryo
Immune-complex–
mediated or
C3-mediated
glomerulonephritis

Genetic Disorders and Acquired

Complement Disorders
Factor H
Factor I
Membrane cofactor protein
C3
Other complement pathway mutations

Figure 1. Causes of Membranoproliferative Glomerulonephritis.

Membranoproliferative glomerulonephritis can be related to monoclonal gammopathies, infections, collagen vas-
cular diseases, or genetic disorders involving the complement pathway. In all these disorders except the genetic
disorders, cryoglobulinemia (Cryo) can lead to membranoproliferative glomerulonephritis. HBV denotes hepatitis B
virus, HCV hepatitis C virus, and HIV human immunodeficiency virus.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Cryoglobulinemia toid factor. Could these abnormalities be clini-

This patient has a very low C4 level and a slight-
ly low C3 level, features consistent with activa-
tion of the classic complement pathway. The
very low C4 level can be explained by cryo­
globulinemia, SLE, congenital C4 deficiency, or
C1 esterase inhibitor deficiency associated with
hereditary angioedema. She had no history of
angioedema, and it would be unusual for a pa-
tient at the age of this one to present with con-
genital C4 disease. SLE is very unlikely in a pa-
tient with a negative ANA test.
Cryoglobulinemia is an immune-complex
glomerulonephritis that activates the classic com­
plement pathway. There are three types of cryo-
globulinemia,14 with different underlying causes.
Type I cryoglobulinemia is characterized by an
IgM or IgG M component that forms a cryopre-
cipitate by itself; the underlying disease is typi-
cally an immunoglobulin-secreting B-cell neo-
plasm such as Waldenström’s macroglobulinemia
(lymphoplasmacytic lymphoma) or plasma-cell
myeloma. Type II cryoglobulinemia is character-
ized by an IgM or IgG M component that has
rheumatoid-factor activity against polyclonal IgG.
Type II cryoglobulinemia is also associated with
lymphoplasmacytic lymphoma or myeloma, hepa-
titis C virus (HCV) infection, and rheumatologic
disorders. Type III cryoglobulinemia is character-
ized by a polyclonal IgM or IgG rheumatoid factor
that binds polyclonal IgG; it tends to be associated
with infections such as HCV, hepatitis B virus, and
the human immunodeficiency virus and, less com-
monly, with endocarditis, SLE, and other rheuma-
tologic diseases.15-19 A number of lymphomas in
addition to myeloma and lymphoplasmacytic lym-
phoma are associated with cryoglobulinemia.20-24
In this patient, testing a warm specimen of blood
for cryoglobulins should be considered.
Could cryoglobulinemia explain this patient’s
clinical presentation? In addition to hypocomple-
mentemia, patients with cryoglobulinemia fre-
quently have renal disease, cutaneous involvement
with necrotizing vasculitis, joint involvement, and patient, and he outlined his thinking for us.
neuropathy. In this patient, the low C4 level and
rapidly progressive glomerulonephritis would be
consistent with cryoglobulinemia, but gastroin-
testinal involvement is uncommon.
Other Clues
This case has several other features: the abnor- postinfectious glomerulonephritis. The diagnos-
mal serum free light-chain ratio, the clonal B-cell tic test was a renal biopsy; we had also sent a
population in the bone marrow, and the rheuma- specimen of blood for testing for cryoglobulins.
cally significant?
Serum free light-chain assays are the most
sensitive tests for the detection of abnormal im-
munoglobulin-secreting B-cell clones.25 Fur­ther­
more, flow-cytometric analysis of the bone mar-
row specimen confirms the presence of a small,
clonal B-cell population, without an excess of
plasma cells. The patient does not meet the cri-
teria for a diagnosis of overt myeloma or lym-
phoma. It is possible that she has monoclonal
gammopathy of undetermined significance and
a monoclonal B lymphocytosis — both of which
are relatively frequent findings in older adults
— which may be unrelated to her current illness.
Other considerations are cryoglobulinemia, im-
munotactoid glomerulonephritis, and deposition
disease with light chains, light and heavy chains,
or heavy chains.26 The clonal B-cell population
and abnormal serum free light chains might indi-
cate type I or type II cryoglobulinemia. Rheumatoid
factor is seen only in type II and type III cryo-
globulinemia, but not in type I. Therefore, only a
type II cryoglobulinemia would manifest with
rheumatoid factor and an abnormal serum free
light-chain ratio. The atypical feature in this case
is the absence of an M component on serum im-
munoelectrophoresis. This absence could be ex-
plained by the specimen’s being at room tem-
perature, which would lead to precipitation of the
M component as part of the cryoprecipitate.
Summary
This patient, with rapidly progressive glomerulo-
nephritis, low complement levels, an abnormal
serum free light-chain ratio, rheumatoid factor,
and a clonal B-cell population in the bone mar-
row, most likely has type II cryoglobulinemia.
The diagnostic tests should be testing for the
presence of a cryoglobulin and a paraprotein on
a specimen of warm blood and a renal biopsy.
Dr. Eric S. Rosenberg (Pathology): Dr. Eugene
Rhee was the nephrology consultant for this
Dr. Eugene P. Rhee (Nephrology): I saw this pa-
tient with Dr. Andrew Lundquist, nephrology
fellow. We concluded that rapidly progressive
glomerulonephritis was a cause of the patient’s
acute kidney injury, and we considered cryo-
globulinemia, Henoch–Schönlein purpura, and

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 case records of the massachuset ts gener al hospital
Cl inic a l Di agnosis
Acute glomerulonephritis, possibly due to
Henoch–Schönlein purpura or cryoglobulinemia.
DR . H A S A N B A Z A R I’S DI AGNOSIS
Type II cryoglobulinemia with glomerulone-
phritis, possibly due to an underlying B-cell
lymphoma.
Pathol o gic a l Discussion
Dr. Evan A. Farkash: An ultrasound-guided kidney
biopsy was performed. Evaluation of the formalin-
fixed tissue with the use of light microscopy at
low magnification showed minimal interstitial
fibrosis. At higher magnification, all glomeruli
have a lobular architecture with increased me-
sangial cellularity. Some glomerular capillary
loops are occluded by swollen endothelial cells,
macrophages, occasional neutrophils, and prom-
inent aggregates of eosinophilic material (Fig. 2A).
The material is positive on periodic acid–Schiff
staining, and therefore these aggregates are not
fibrin thrombi but rather pseudothrombi (Fig. 2B).
Several small arteries are affected by vasculitis,
with inflammatory cells, fragmented red cells,
and transmural eosinophilic material that is pos-
itive on periodic acid–Schiff staining (Fig. 2C).
Red-cell casts are also present in some tubules, a
finding that is consistent with the casts seen on
examination of the urine sediment.
Immunofluorescence staining on frozen tissue
shows coarse, granular deposits in the glomeru-
lar basement membrane and pseudothrombi that
stain strongly for IgM, IgG, C3, kappa, and
lambda, with weaker staining for IgA and C1q
(Fig. 2D). On electron microscopy, there are sub-
endothelial, mesangial, and massive intracapillary
electron-dense deposits, along with reactive endo-
thelial cells and endocapillary macro­phages with
phagocytosed deposits. Deposits have a tubular
substructure (Fig. 2E). Periodic acid–Schiff stain-
ing and electron microscopy show minimal dupli-
cation of the glomerular basement membrane.
Glomerular pseudothrombi are pathognomonic
for cryoglobulinemic glomerulonephritis.27 Key fea-
tures supporting a diagnosis of cryoglobulinemic
glomerulonephritis are the predominance of mac-
rophages in the glomerular infiltrate and a tubular
substructure on electron microscopy.28 Con­com­i­
tant vasculitis is also present, which has been re-
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ported in about 22% of renal-biopsy specimens in
a small case series involving patients with similar
laboratory findings.29 The diffuse glomerular in-
volvement, lack of interstitial fibrosis, and mini-
mal duplication of the glomerular basement mem-
brane are features suggestive of a highly active
acute process with minimal chronicity.
Results of the cryoglobulin assay showed a
cryoprecipitate with a cryocrit of 3% (Fig. 3A).
Immunofixation of the cryoprecipitate showed two
monoclonal IgM kappa bands, together with poly-
clonal IgG, findings that categorized the process
as a type II (mixed) cryoglobulinemia (Fig. 3B).30,31
The pathogenesis of most type II cryoglobuli-
nemias is thought to be a B-cell clonal prolifera-
tion often driven by an underlying viral or auto-
immune process, with the majority of cases
associated with hepatitis C viral infection.29,30,32
The rest of the cases are associated with hema-
tologic cancers or are considered idiopathic, or
“essential.”33 In this case, results of tests for
both hepatitis B and C viruses were negative,
and there was no laboratory evidence of auto­
immune disease. A bone marrow–biopsy speci-
men had revealed a small kappa-restricted clonal
B-cell population detected by flow cytometry in
the marrow aspirate sample only (Fig. 3C and 3D).
Clonal B-cell proliferations have been detected
in cases of type II cryoglobulinemia, both in pa-
tients with and in those without viral hepatitis.34
A minority of patients with clonal populations
either present with or progress to lymphoma,
leukemia, or both.29,34 The flow-cytometric pro-
file of the clonal B cells in the marrow aspirate
is not consistent with chronic lymphocytic leu-
kemia, a common hematologic cancer associat-
ed with type II cryoglobulinemia.34 Thus, the
clonal population is probably best described as a
“monoclonal B-cell population of undetermined
significance,” and secretion of immunoglobulin
with rheumatoid factor activity by this clonal
B-cell population is the presumptive cause of
this patient’s acute glomerulonephritis.
Dr. Rosenberg: Dr. Mahindra will discuss the
management of cryoglobulinemia in this case.
Discussion of M a nagemen t
Dr. Anuj K. Mahindra: Treatment decisions con-
cerning patients with cryoglobulins are driven
by the presence of symptoms and associated dis-
eases. Similar to our patient, about 20% of pa-
tients with cryoglobulinemia present with nephrop­
369
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 2. Renal-Biopsy Specimen.

Glomeruli have pseudothrombi (arrows), swollen endothelial cells, and endocapillary inflammatory cells (Panel A, hema-
toxylin and eosin; and Panel B, periodic acid–Schiff). Vessels with reactive endothelial cells, mural cryoglobulin deposits
(Panel C, arrow; hematoxylin and eosin), extravasated red cells (arrowhead), and karyorrhectic debris are present.
IgM immunofluorescence (Panel D) revealed granular staining of capillary loops and positive pseudothrombi. An electron
micrograph (Panel E) shows a subendothelial deposit with a tubular substructure. (In all images, the Smart Sharpen filter
[Photoshop CS] was used for white balance and sharpening, with identical settings for each image.)

athy at diagnosis, and 30% have renal complications vasculitis are based on high-dose glucocorticoids
during the disease course, which is an indication and cyclophosphamide and have been derived
for treatment.29,31,35-37 The immunosuppressive mainly from treatment strategies used in other
approaches to the treatment of cryoglobulinemic systemic vasculitides; they remain essential to

370 n engl j med 370;4 nejm.org january 23, 2014

The New England Journal of Medicine

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Copyright © 2014 Massachusetts Medical Society. All rights reserved.
 case records of the massachuset ts gener al hospital

A B

ladder lgG lgM lambda

cryo lgA kappa ladder

C D
104 104

103 103
Kappa FITC

Lambda PE

102 102

101 101

100 100
100 101 102 103 104 100 101 102 103 104
CD20 PERCP CD20 PERCP

Figure 3. Clinical Testing.

The left cryocrit tube (Panel A) shows a negative sample, and the right tube shows a sample from the patient, with
3% of the total serum volume consisting of a cryoprecipitate (cryo). Gel electrophoresis (Panel B) performed on the
washed cryoprecipitate shows a band at the origin (arrowhead) and a cathodal band (arrow). In replicate lanes
probed with isotype-specific antiserums, IgM and kappa antiserums show similar banding patterns, whereas IgG
shows a polyclonal smear. Flow cytometry of a bone marrow aspirate (Panel C) shows a small population of CD20+
B cells with expression of kappa light chain. This population is negative for lambda light chain (Panel D). FITC denotes
fluorescein isothiocyanate, PE phycoerythrin, and PERCP peridinin chlorophyll protein. Panels C and D courtesy of
Frederic I. Preffer, Ph.D., Flow Cytometry Laboratory.

the quick control of severe disease. Cryoglobulins
are generated by the clonal expansion of B cells;
therefore, in the absence of an underlying cause
of cryoglobulinemia, treatment is directed toward
suppression of B-cell clonal expansion.
This patient received methylprednisolone
sodium succinate (1 g daily for 3 days), followed
by prednisone taper. The creatinine level was
2.4 mg per deciliter (212 μmol per liter; baseline,
0.9 mg per deciliter [80 μmol per liter]), and the
cryocrit was 3%.
One week later, because of a rising creatinine
level (3.7 mg per deciliter [327 μmol per liter]),
plasmapheresis (four sessions) was performed.
Plasmapheresis removes cryoglobulins from the
circulation, thereby interrupting the immune-
complex–mediated pathogenesis of cryoglobuli-
nemic vasculitis. It is useful in patients with
organ-threatening disease and in those with a
hyperviscosity syndrome. However, apheresis
can lead to rebound, in which cryoglobulin pro-
duction increases after the cessation of aphere-
sis. One of the promising biologic approaches to
cryoglobulinemia is B-cell depletion triggered by
rituximab treatment.38 We thus administered
cyclophosphamide (1 g intravenously), followed
by the off-label use of rituximab at a dose of
375 mg per square meter of body-surface area

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Copyright © 2014 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
weekly (four doses).38 The patient’s constitutional
and gastrointestinal symptoms improved, and
the serum creatinine level subsequently improved
to 1.5 mg per deciliter (133 μmol per liter).
Two months later, a rash, consistent with cu-
taneous purpura, appeared over the patient’s legs,
and night sweats developed. The cryocrit had in-
creased to 8%, and immunofixation revealed an
IgM kappa M component of 0.15 g per deciliter.
The rash resolved after a single dose of rituximab
(375 mg per square meter). However, she contin-
ued to have mild influenza-like symptoms.
During the next 3 months, serum creatinine
levels gradually increased to 3.1 mg per deciliter
(274 μmol per liter), along with worsening con-
stitutional symptoms of malaise, fatigue, and
night sweats. B-cell lymphoma, the main neo-
plastic complication in patients with mixed cryo-
globulinemia, has been reported in 5 to 22% of
patients.31,36,39,40 Whole-body positron-emission
tomography in conjunction with computed tomog­
raphy revealed no evidence of lymphadenopathy or
organomegaly. Examination of a specimen from a
repeat bone marrow biopsy revealed no evidence of
lymphoma and an absence of B cells; the latter
feature is consistent with rituximab treatment.
Oral cyclophosphamide (50 mg per day) and
prednisone (1 mg per kilogram of body weight)
were begun. The patient’s constitutional symptoms
improved. The serum creatinine level improved but
continued to fluctuate (2.1 to 2.5 mg per deci­liter
[186 to 221 μmol per liter]). Two months later,
the patient had increasing shortness of breath. An
echocardiogram showed a decline in the ejection
fraction to 39% (baseline, 77%). Cyclophosphamide,
an agent with known potential cardiac toxic effects,
was stopped after discussion with the patient.
Because of persistence of disease activity, in-
cluding recurrence of constitutional symptoms
and cutaneous purpura, as well as an increasing
serum creatinine level, we decided to start off-
label therapy with bortezomib. The treatment
consisted of six cycles of bortezomib (1.3 mg per
square meter) on days 1, 4, 8, and 11 every 21 days.
After the first two cycles, resolution of constitu-
tional symptoms and an improvement in vascu-
litic lesions of the leg was observed. The patient’s
breathing returned to baseline, and with adjust-
ment of antihypertensive medications, the blood
pressure was controlled. Six cycles of bor­tez­o­mib
were administered. The cryocrit showed un­
detectable cryoglobulin after the end of the
treatment, and the serum creatinine level fell to
372 n engl j med 370;4 nejm.org january 23, 2014
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Copyright © 2014 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
2.0 mg per deciliter (177 μmol per liter); the level
of C3 returned to normal, but the C4 level re-
mained low. The improvement with bortezomib
may be due to either its direct effects on plasma
cells41 or possibly its anti-angiogenic actions.42
The patient was then given maintenance ritux-
imab every 3 months for 1 year, and she now re-
ceives maintenance with prednisone, 5 mg daily,
and has a good quality of life. She continued to
have a small M component (0.04 g per deciliter)
and a small amount of detectable cryoglobulin
(cryocrit, 1%) 2.5 years after her initial presenta-
tion. The anemia has persisted, and the hemo-
globin is maintained at 10 g per deciliter, with
intermittent administration of erythropoietin.
Dr. Rosenberg: Are there questions for any of
our discussants?
A Physician: Was the cryoprecipitate tested for
the presence of HCV?
Dr. Farkash: No, that was not done in this case.
Dr. Bazari: One of the teaching points for me
in this case is that even though the patient’s
presentation does not fit the classical picture of
cryoglobulinemia and is missing some key find-
ings, such as the rash, these features may evolve
over time, and I think the key here was that the
diagnosis was made relatively early.
Dr. Mahindra: The low level of paraprotein
would warrant classification as monoclonal
gammopathy of undetermined significance, but
if a patient has abnormalities attributable to the
paraprotein, such as anemia or cryoglobuline-
mia, as in this case, then treatment directed at
the clone that produces the paraprotein is war-
ranted, regardless of how small the clone is.
Overt lymphoplasmacytic lymphoma may develop
in this patient in the future.
A nat omic a l Di agnose s
Type II cryoglobulinemia with acute glomerulo-
nephritis and renal vasculitis.
Monoclonal B-cell population of unknown
significance.
This case was presented at the postgraduate course Massachu-
setts General Hospital Nephrology Update 2012; course directors,
Hasan Bazari, M.D., Ishir Bhan, M.D., and M. Amin Arnaout, M.D.
Dr. Bazari reports holding stock in Pfizer; and Dr. Mahindra, re-
ceiving consulting fees from Millennium Pharmaceuticals. No other
potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Drs. Gabriel Brooks (Hematology) and Eugene P.
Rhee (Nephrology) for assisting with the preparation of the
case history.
 case records of the massachuset ts gener al hospital
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