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

Case Records of the Massachusetts General Hospital

Founded by RichardC. Cabot

EricS. Rosenberg, M.D., NancyLee Harris, M.D., Editors
VirginiaM. Pierce, M.D., DavidM. Dudzinski, M.D., MeridaleV. Baggett, M.D.,
DennisC. Sgroi, M.D., JoAnneO. Shepard, M.D., Associate Editors
EmilyK. McDonald, SallyH. Ebeling, Production Editors

Case 12-2017: A 34-Year-Old Man

with Nephropathy
MeghanE. Sise, M.D., GraceC. Lo, M.D., RobertH. Goldstein, M.D., Ph.D.,
AndrewS. Allegretti, M.D., and Ricard Masia, M.D., Ph.D.

Pr e sen tat ion of C a se

Dr. Daniel H. Katz (Medicine): A 34-year-old man with hearing impairment was ad- From the Departments of Medicine
(M.E.S., R.H.G., A.S.A.), Radiology (G.C.L.),
mitted to this hospital because of worsening renal function.
and Pathology (R.M.), Massachusetts
The patient had been well until approximately 11 weeks before this admission, General Hospital, and the Departments
when subjective fevers with sweats, fatigue, decreased appetite, and nausea developed. of Medicine (M.E.S., R.H.G., A.S.A.), Ra
diology (G.C.L.), and Pathology (R.M.),
He initially attributed these symptoms, which worsened over the next 2 months,
Harvard Medical School both in Boston.
to the hot weather. Cough and shortness of breath on exertion also developed
N Engl J Med 2017;376:1575-85.
during that time, and the patient noted that his urine appeared foamy. He reported
DOI: 10.1056/NEJMcpc1616395
ly lost 9 kg. Copyright 2017 Massachusetts Medical Society.
Twenty-two days before this admission, the patient presented to the emergency
department at another hospital for evaluation. The blood creatinine level was 0.8 mg
per deciliter (71 mol per liter; normal range, 0.6 to 1.5 mg per deciliter [53 to
133 mol per liter]), and the blood urea nitrogen level was 7 mg per deciliter
(2.5 mmol per liter; normal range, 8 to 25 mg per deciliter [2.9 to 8.9 mmol per
liter]). The patient left the hospital without being evaluated by a physician.
The patient returned to the emergency department at the other hospital 1 week
later (15 days before this admission) and reported that he had been having malaise,
vomiting, and chest pain for the past 2 days. The chest pain worsened during in-
spiration. On examination, the temperature was 36.6C, the pulse 76 beats per
minute, the blood pressure 110/73 mm Hg, the respiratory rate 16 breaths per min-
ute, and the oxygen saturation 95% while he was breathing ambient air. He had
hearing aids in both ears and nontender, enlarged lymph nodes in the neck.
Breath sounds were diminished bilaterally, and faint rhonchi were heard at the
base of both lungs on auscultation. The abdomen was soft and flat, with mild,
diffuse tenderness on palpation; the remainder of the examination was normal.
The platelet count, red-cell indexes, and anion gap were normal, as were blood
levels of glucose, alkaline phosphatase, total bilirubin, direct bilirubin, lipase, and
lactic acid; the results of other laboratory tests are shown in Table1. Urinalysis

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 1576
Table 1. Laboratory Data.*

15 Days before 14 Days before 13 Days before 5 Days before

Reference Range, This Admission, This Admission, This Admission, This Admission, On Admission,
Variable Adults Other Hospital Other Hospital Other Hospital Other Hospital This Hospital
Hematocrit (%) 36.046.0 44.9 37.1 37.3 30.1 31.9
Hemoglobin (g/dl) 12.016.0 15.8 13.5 13.2 10.8 10.7
White-cell count (per mm3) 450011,000 15,700 12,700 16,100 8300 8630
Differential count (%)
Neutrophils 4070 35 45 47.6
Band forms 010 4
Lymphocytes 2244 51 42 40.2
The

Monocytes 711 1 8 10.2

Eosinophils 08 1.3
Basophils 03 0.5
Atypical lymphocytes 0 9 5
Red-cell count (per mm3) 4,000,000 5,360,000 4,530,000 4,480,000 3,630,000
5,200,000
Reticulocyte count (%) 0.52.5 0.8
Erythrocyte sedimentation rate (mm/hr) 013 27
Prothrombin time (sec) 11.013.7 13.6 13.2
n e w e ng l a n d j o u r na l

Prothrombin-time international normalized ratio 0.91.1 1.2 1.1

The New England Journal of Medicine

of

Sodium (mmol/liter) 135145 131 135 133 138 142

Potassium (mmol/liter) 3.45.0 3.5 3.5 3.3 4.6 3.3

n engl j med 376;16nejm.org April 20, 2017

Chloride (mmol/liter) 98108 90 98 97 106 105
Carbon dioxide (mmol/liter) 2332 30 29 25 19 26

Copyright 2017 Massachusetts Medical Society. All rights reserved.

m e dic i n e

Calcium (mg/dl) 8.510.5 8.2 7.3 7.0 7.5 8.0

Phosphorus (mg/dl) 2.64.5 4.8 3.0 3.7 8.5 3.1
Magnesium (mg/dl) 1.72.4 2.5 2.4 2.3 2.6 1.7
Urea nitrogen (mg/dl) 825 17 17 20 86 18
Creatinine (mg/dl) 0.601.50 1.7 1.6 2.4 13.2 3.57
Estimated glomerular filtration rate (ml/min/1.73 m2) >60 49.3 52.9 33.1 4.6 20
Alanine aminotransferase (U/liter) 1055 108 95 76 61

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Aspartate aminotransferase (U/liter) 1040 144 113 90 45
 15 Days before 14 Days before 13 Days before 5 Days before
Reference Range, This Admission, This Admission, This Admission, This Admission, On Admission,
Variable Adults Other Hospital Other Hospital Other Hospital Other Hospital This Hospital
Protein (g/dl)
Total 6.08.3 6.9 5.5 4.7 5.6
Albumin 3.35.0 2.8 2.3 1.7 2.3
Globulin 1.94.1 3.3
Creatine kinase (U/liter) 60400 486
Lactate dehydrogenase (U/liter) 110210 1050 620
d-dimer (ng/ml) <500 1102
Troponin I (ng/ml) 0.04 0.04 0.05
Venous blood gases
Fraction of inspired oxygen 0.21
pH 7.307.40 7.42
Partial pressure of carbon dioxide (mm Hg) 3850 49
Partial pressure of oxygen (mm Hg) 3550 32
Heterophile antibodies Negative Negative
Hepatitis A virus antibodies Nonreactive Nonreactive
Hepatitis B virus surface antigen Nonreactive Nonreactive
Hepatitis B virus surface antibodies Nonreactive Reactive
Hepatitis B virus core antibodies Nonreactive Nonreactive
Hepatitis C virus antibodies Nonreactive Nonreactive
Syphilis IgG antibodies Nonreactive Nonreactive

n engl j med 376;16nejm.org April 20, 2017

Lyme antibodies Negative Negative

The New England Journal of Medicine

Cytomegalovirus IgG antibodies 0.90 4.37
Cytomegalovirus IgM antibodies 0.80 >4.0
Cytomegalovirus DNA Not detected Detected
Case Records of the Massachuset ts Gener al Hospital

EpsteinBarr virus viral-capsid-antigen IgG antibodies 0.90 4.41

Copyright 2017 Massachusetts Medical Society. All rights reserved.

EpsteinBarr virus viral-capsid-antigen IgM antibodies 0.90 0.90
EpsteinBarr virus diffuse-early-antigen antibodies 0.90 0.98
EpsteinBarr virus nuclear-antigen antibodies 0.90 >5.00
Toxoplasma IgG antibodies 0.90 0.90
Toxoplasma IgM antibodies Negative Negative
Antinuclear antibodies <1:40 Positive at 1:40 dilution

* To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. To convert the values for magnesium to

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millimoles per liter, multiply by 0.4114. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
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.

1577
 The n e w e ng l a n d j o u r na l
revealed cloudy, amber urine with a specific grav-
ity of 1.037, a pH of 5.0, a moderate amount of
occult blood, a protein level of at least 500 mg
per deciliter, a glucose level of 50 mg per deci-
liter, and a ketone level of 20 mg per deciliter by
dipstick; on microscopic examination, there were
0 to 2 red cells and 10 to 25 white cells per high-
power field and a moderate amount of hyaline
casts. An electrocardiogram showed no evidence
of cardiac ischemia.
Dr. Grace C. Lo: Computed tomographic (CT)
angiography of the chest, performed after the
administration of intravenous contrast material,
revealed mild subpleural interlobular septal thick-
ening without lobar consolidation or evidence of
acute pulmonary embolism.
Dr. Katz: While the patient was in the emer-
gency department, the temperature rose to 37.9C,
and he reported malaise. Blood samples were
obtained for culture, and acetaminophen was
administered. The patient was admitted to the
other hospital.
Intravenous fluids were administered. By the
next day, the chest pain had resolved. The plate-
let count, red-cell indexes, and anion gap were
normal, as were blood levels of glucose, alkaline
phosphatase, total bilirubin, direct bilirubin, and
lactic acid; the results of other laboratory tests
are shown in Table1.
Dr. Lo: Noninvasive ultrasonography of both
legs was performed and did not reveal evidence
of deep venous thrombosis. A prominent inguinal
lymph node (1.5 cm by 0.6 cm by 1.5 cm) was
seen on the right side. On ultrasonography of
the abdomen, there was borderline enlargement
of the spleen, which measured 13.3 cm in length
(normal range, 12). The right kidney measured
12.3 cm in length, and the left kidney measured
12.4 cm in length; markedly echogenic renal
parenchyma was present bilaterally (Fig.1A).
Dr. Katz: Transthoracic echocardiography re-
vealed a left ventricular ejection fraction of 60 to
65% and no pericardial effusion. The adminis-
tration of intravenous fluids was continued. On
the third hospital day, the platelet count, red-cell
indexes, and anion gap were normal, as were
blood levels of glucose, alkaline phosphatase,
total bilirubin, direct bilirubin, C3, and C4; tests
for antiproteinase 3 antibodies and antimyelo-
peroxidase antibodies were negative. Urinalysis
revealed cloudy, amber urine with a specific
gravity of 1.040, a pH of 5.0, a moderate amount
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of m e dic i n e
of blood, a protein level of at least 500 mg per
deciliter, a glucose level of 50 mg per deciliter,
and a ketone level of 20 mg per deciliter by dip-
stick; on microscopic examination, there were
0 to 2 red cells and 10 to 25 white cells per high-
power field, few white-cell clumps, and occa-
sional hyaline casts. The urinary creatinine level
was 298 mg per deciliter (normal range, 20 to
370), and the urinary total protein level was
higher than 2500 mg per deciliter (normal range,
5 to 25 [other hospital]).
Dr. Lo: CT of the abdomen and pelvis, per-
formed without the administration of contrast
material, revealed patchy atelectasis of the lung
bases, mild left paraaortic retroperitoneal lymph-
adenopathy, persistent bilateral enhancement of
the kidneys (related to the previous administra-
tion of contrast material), and trace free fluid in
the pelvis (Fig.1B and 1C).
Dr. Katz: A diagnostic test result was received,
and medical therapy was initiated.
During the next 8 days, edema of the lower
legs developed. Furosemide, calcium acetate,
sodium bicarbonate, and a multivitamin were
administered. The patient continued to produce
urine. Laboratory test results obtained on the
11th hospital day (5 days before admission) are
shown in Table1; furosemide was discontinued.
The next day, a tunneled hemodialysis catheter
was inserted in the right internal jugular vein.
The patient underwent three sessions of hemo-
dialysis during the next 4 days. On the 16th
hospital day, he was transferred to this hospital
for further evaluation and treatment.
On admission to this hospital, the patient
reported that the leg swelling had improved and
that he felt well. He had a history of anxiety.
When he was 7 years of age, he was struck by a
motor vehicle as a pedestrian; thereafter, pro-
gressive bilateral hearing loss developed. Before
admission to the other hospital, the patient had
been taking no medications; he had an allergy
to ibuprofen, which caused a rash. He worked as
a laborer and lived with a friend in an urban area
of New England. He had separated from the fe-
male partner with whom he had two children,
and he had sex with men and women. He had
never received a transfusion of blood products.
Approximately 6 weeks earlier, he had been in a
fistfight with another person, and blood from
that person made contact with open wounds on
his hands and near his eyes. He had smoked a
 Case Records of the Massachuset ts Gener al Hospital

A B C

Figure 1. Abdominal Imaging Studies.

An ultrasound image (Panel A) of the upper abdomen shows increased echogenicity of the renal cortex in the right
kidney (arrowheads), as compared with normal echogenicity of the adjacent liver (asterisk). Increased echogenicity
of the renal cortex was also present in the left kidney (not shown). Coronal and axial CT scans (Panels B and C, re
spectively) of the abdomen and pelvis were obtained without the administration of contrast material. Both images
show persistent bilateral enhancement of the kidneys, which is related to the previous administration of contrast
material. The axial image also shows mild left paraaortic lymphadenopathy (Panel C, arrow).

half pack of cigarettes per day for the past 15 characterized by fatigue, sweats, and nausea. The
years, and he used marijuana; he did not drink patient reported the presence of foamy urine,
alcohol or use other illicit drugs. His mother had
which suggests the development of severe pro-
coronary artery disease, and he did not know his teinuria. He went briefly to an emergency depart-
father; there was no known family history of ment, where laboratory testing revealed a normal
kidney disease. blood creatinine level (0.8 mg per deciliter); no
On examination, the patient appeared well. urinary studies were performed. Taken together,
The temperature was 37.2C, the pulse 76 beats these features suggest that he had severe pro-
per minute, the blood pressure 138/93 mm Hg, teinuria with an initially preserved estimated
and the respiratory rate 18 breaths per minute. glomerular filtration rate. One week later, the
The weight was 82 kg. A hemodialysis catheter patient returned to the hospital and was admit-
exiting the right chest was present, and there ted. At that point, he was normotensive and had
was 2+ pitting edema of the legs to the mid- acute kidney injury, with a blood creatinine level
shins; the remainder of the examination was of 1.7 mg per deciliter (150 mol per liter). He
normal. The results of laboratory tests are shownalso had evidence of the nephrotic syndrome,
in Table1. During the first 24 hours, the patient
with hypoalbuminemia to 2.8 g per deciliter and
drank 890 ml of fluid and had 4425 ml of urine 4+ proteinuria on urinalysis. In a random urine
output. Urinalysis revealed clear, yellow urine sample, the ratio of protein (milligrams per
with a specific gravity of 1.008, a pH of 8.0, 3+deciliter) to creatinine (milligrams per deciliter)
glucose, 2+ protein, and 1+ blood by dipstick, aswas greater than 8 (normal range, <0.11 in adult
well as 0 to 2 red cells per high-power field. The
men); this number is a surrogate for the 24-hour
urine osmolality was 277 mOsm per kilogram of protein excretion in grams per day.1 Renal ultra-
water (normal range, 15 to 1150). The urinary sonography revealed enlarged, echogenic kidneys,
level of creatinine was 47 mg per deciliter, total
a finding consistent with nephromegaly.
protein 368.5 mg per deciliter (normal range, 0 to In distilling all the features of this patients
13.5 [this hospital]), microalbumin 194.5 mg per presentation, we must account for three key find-
deciliter (normal range, 0 to 2.0), and sodium ings: the nephrotic syndrome, the acute kidney
84 mmol per liter. An additional diagnostic pro- injury, and the nephromegaly. Each of these con-
cedure was performed. ditions has a differential diagnosis; a unifying
diagnosis must explain all three. One confound-
ing feature of this patients presentation is that
Differ en t i a l Di agnosis
he probably had a second, separate episode of
Dr. Meghan E. Sise: In this 34-year-old man, who acute kidney injury after he received intravenous
was thought to be in good health, an acute iodinated contrast material for a CT scan and
mononucleosis-like illness developed that was underwent temporary dialysis. The onset of acute

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 The n e w e ng l a n d j o u r na l
kidney injury within 24 to 48 hours after the
administration of contrast material and the rapid
recovery are classic features of contrast-induced
nephropathy, which in this case, worsened the
preexisting acute kidney injury that had been
present on the patients admission to the other
hospital.2,3
Nephrotic Syndrome
The nephrotic syndrome results from loss of in-
tegrity of one of the components of the glomeru-
lar filtration barrier, the podocyte; the common
ultrastructural finding is widespread effacement
of podocyte foot processes.4 This patient meets
the criteria for the nephrotic syndrome, which
are an increase in the urinary protein level of
at least 3.5 g in 24 hours, a blood albumin
level of less than 3.5 g per deciliter, and periph-
eral edema. The nephrotic syndrome affects both
the biosynthesis and the clearance of lipopro-
teins and results in hyperlipidemia and altera-
tions in the composition of lipoproteins; the
severity of these effects is proportional to the
degree of proteinuria.5 Finally, the nephrotic syn-
drome causes thrombophilia that results from
an overall net increase in procoagulant factors
due to a variety of mechanisms.6
The nephrotic syndrome may be primary, or
it may be secondary to other illnesses. Primary
nephrotic syndromes include minimal change
disease and focal segmental glomerulosclerosis
(which primarily affect podocytes), as well as
membranous nephropathy. Secondary nephrotic
syndrome can occur as a result of systemic ill-
nesses, including diabetes mellitus, amyloidosis,
and lupus nephritis (class V membranous lupus
nephritis or lupus nephritis with podocytopa-
thy7,8). Although it is clear that this patient has
nephrosis, it is somewhat unusual to concurrently
have acute kidney injury and the nephrotic syn-
drome.
Acute Kidney Injury and the Nephrotic
Syndrome
Acute kidney injury has been defined and catego-
rized according to several classification schemes.9,10
The current Kidney Disease: Improving Global
Outcomes (KDIGO) guidelines define acute kid-
ney injury in adults as the presence of any one of
the following criteria: an increase in the blood
creatinine level of more than 0.3 mg per deciliter
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of m e dic i n e
(27 mol per liter) in 48 hours, an increase in
the blood creatinine level to 1.5 times the base-
line level within 7 days, or urine output of less
than 0.5 ml per kilogram per hour for 6 hours.11
According to the KDIGO guidelines, this patient
had stage 2 acute kidney injury, with an increase
in the blood creatinine level from 0.8 mg per
deciliter to 1.7 mg per deciliter in the span of
1 week. In most cases, the estimated glomerular
filtration rate is normal or near normal at the
onset of the nephrotic syndrome, and only a few
clinical situations explain the concurrent pres-
ence of acute kidney injury and the nephrotic
syndrome (Table2).
In a patient with the nephrotic syndrome,
acute tubular necrosis can develop concurrently
with hypotension, sepsis, or nephrotoxin expo-
sure, but it is most common for acute tubular
necrosis to develop concurrently with minimal
change disease, even in the absence of the other
overt injuries. The profound hypoalbuminemia
associated with minimal change disease confers
a predisposition to hemodynamically mediated
acute tubular necrosis, which is seen in up to
25% of patients with evidence of minimal
change disease on biopsy.12 However, the princi-
pal risk factors for the development of acute tu-
bular necrosis in a patient with minimal change
disease are older age and preexisting arteriolo-
sclerosis in the kidney. Given this patients young
age and the fact that he did not have hypoten-
sion at presentation, minimal change disease
and acute tubular necrosis are unlikely to ex-
plain his nephrotic syndrome and acute kidney
injury.
Although all forms of the nephrotic syndrome
are associated with a prothrombotic state, the
risk of renal-vein thrombosis is highest among
patients with membranous nephropathy.13 Acute
bilateral renal-vein thrombosis in the context of
membranous glomerulopathy could explain the
presence of both acute kidney injury and the
nephrotic syndrome. However, in addition to
the fact that acute, bilateral renal-vein thrombosis
is a rare diagnosis, the absence of flank pain in
this patient argues strongly against this diagnosis.
Amyloidosis develops concurrently with cast
nephropathy in a small percentage of patients
with myeloma; the presence of amyloidosis could
explain the nephrotic syndrome, and the pres-
ence of cast nephropathy could explain acute
 Case Records of the Massachuset ts Gener al Hospital
kidney injury.14 However, given this patients
young age, this diagnosis seems unlikely. The
nephrotic syndrome due to minimal change dis-
ease may develop concurrently with acute inter-
stitial nephritis; both diseases classically result
from the use of nonsteroidal antiinflammatory
drugs (NSAIDs).15 This could be a unifying diag-
nosis in a patient who has a viral syndrome that
is characterized by fatigue and myalgias and then
begins to take NSAIDs. However, when this pa-
tient initially presented to the other hospital,
he did not report that he had taken any medica-
tions. Furthermore, he is reportedly allergic to
NSAIDs, and thus this diagnosis is unlikely.
Finally, patients with the collapsing variant of
focal segmental glomerulosclerosis often present
with acute kidney injury in addition to the ne-
phrotic syndrome. Collapsing focal segmental
glomerulosclerosis is characterized by widespread
podocyte injury with diffuse effacement of foot
processes and severe proteinuria, as well as col-
lapse and sclerosis of the entire glomerular
capillary bed.16 This variant of focal segmental
glomerulosclerosis contrasts with other variants,
in which areas of mesangial collapse and sclero-
sis typically affect only a portion of the glomeru-
lar surface, sparing some glomeruli entirely and
maintaining enough capillary surface area to
preserve renal function during the early stages
of this disease.4
The causes of collapsing focal segmental glo-
merulosclerosis are varied (Table3). This patient
has no other symptoms or findings consistent
with systemic lupus erythematosus or a hemato-
logic cancer, and there is no history that he re-
ceived any medications known to be associated
with this disease. Several infections are associ-
ated with collapsing focal segmental glomerulo-
sclerosis; human immunodeficiency virus (HIV)
associated nephropathy is a classic form of this
condition. It is thought that HIV directly infects
podocytes, which leads to dedifferentiation, apop-
tosis, and widespread effacement of foot pro-
cesses.17 HIV-associated nephropathy is also as-
sociated with characteristic histologic changes
that affect each of the different renal compart-
ments. The tubules classically develop micro-
cystic dilatation; they fill with proteinaceous
material and undergo cast formation, and a
lymphocytic infiltrate and tubulitis are com-
monly seen.18 Because of the tubulointerstitial
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Table 2. Causes of Acute Kidney Injury and the Nephrotic Syndrome.
Minimal change disease and acute tubular necrosis
Membranous nephropathy and bilateral renal-vein thrombosis
Amyloidosis and cast nephropathy
Minimal change disease and acute interstitial nephritis, both associated with
the use of nonsteroidal antiinflammatory drugs
Collapsing focal segmental glomerulosclerosis
nephritis and the proteinaceous, cast-filled micro-
cysts, the kidneys become enlarged and appear
echogenic on renal ultrasonography; these find-
ings are consistent with the ultrasonographic
findings described in this patient. Although this
patient was not known to have HIV at the time
of his admission to the other hospital, he has
important risk factors for the virus and has a
mononucleosis-like syndrome that could be char-
acteristic of acute HIV. HIV-associated nephrop-
athy classically occurs in patients with chronic,
uncontrolled HIV infection and is associated with
a CD4 cell count of less than 250 per cubic milli-
meter, but on rare occasions, it can also be seen
as a manifestation of acute HIV infection.17,19
Because this patient initially presented to the
other hospital with three renal syndromes (the
nephrotic syndrome, acute kidney injury, and
nephromegaly), my clinical diagnosis is collaps-
ing focal segmental glomerulosclerosis. Because
of his preexisting viral symptoms and risk fac-
tors for HIV infection, his collapsing focal seg-
mental glomerulosclerosis is most consistent
with HIV-associated nephropathy. In order to
establish this diagnosis, I would obtain the re-
sults of a screening test for HIV-1 infection and
proceed with a renal biopsy. If a renal biopsy is
performed, I would expect to see residual acute
tubular necrosis due to contrast-induced ne-
phropathy.
Dr. Virginia M. Pierce (Pathology): Dr. Goldstein,
what was your clinical impression when you
evaluated this patient?
Dr. Robert H. Goldstein: We met this patient with
the benefit of knowing that a combination assay
for HIV-1 or HIV-2 antibodies and antigen had
been positive before he was transferred to this
hospital. Given this knowledge and given the
magnitude of his proteinuria, we thought that
HIV-associated nephropathy was the most likely
diagnosis. At the first hospital, he presented
1581
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 3. Causes of Collapsing Focal Segmental Glomerulosclerosis.

Human immunodeficiency virusassociated nephropathy

Other infections (parvovirus, cytomegalovirus, tuberculosis, and leishmaniasis)
Autoimmune disease (systemic lupus erythematosus and mixed connective-tissue disease)
Drug use (use of pamidronate, interferon, or anabolic steroids)
Cancer (multiple myeloma, acute leukemia, and the hemophagocytic syndrome)

with a CD4 cell count of 703 per cubic millimeter,
and his HIV RNA viral load was 80,679 copies per
milliliter. Seven days later, his viral load had
increased to 300,000 copies per milliliter. At that
point, therapy with tenofovir disoproxil fuma-
rate, emtricitabine, and darunavir was initiated;
these medications were discontinued before he
was transferred to this hospital. We thought that
his presentation could be consistent with acute
HIV infection, although serologic testing for
cytomegalovirus also suggested the presence of
acute cytomegalovirus infection.
We considered two scenarios: he could have
had both acute HIV infection and acute cyto-
megalovirus infection, or he could have had
chronic HIV infection and recently acquired
cytomegalovirus infection. We were able to find
cases in which HIV-associated nephropathy oc-
curred in the context of acute HIV infection,17
but it is much more common for HIV-associ
ated nephropathy to occur with advanced HIV
infection.20
During this patients inpatient stay, we were
unable to determine the duration of his HIV
infection. Therefore, the most likely diagnosis
was acute cytomegalovirus infection with HIV
infection of unknown duration, complicated by
HIV-associated nephropathy. In order to estab-
lish the diagnosis of HIV-associated nephropathy,
a renal biopsy was performed.
Cl inic a l Di agnosis
Acute cytomegalovirus infection in a patient
with HIV infection and HIV-associated ne-
phropathy.
Dr . Megh a n E . Sises Di agnosis
Collapsing variant of focal segmental glomeru-
losclerosis (HIV-associated nephropathy) and
acute tubular injury due to contrast-induced
nephropathy.
Pathol o gic a l Discussion
Dr. Ricard Masia: Examination of a core-biopsy
specimen of the left kidney revealed evidence of
marked tubular injury, including luminal dilata-
tion of renal tubules with flattening of tubular
epithelium and loss of brush borders; in some
areas, these changes resulted in microcystic tubu-
lar dilatation (Fig.2A). Glomeruli showed col-
lapse of capillary loops and extracapillary prolif-
eration of epithelial cells (Fig.2B), findings
indicative of the collapsing variant of focal seg-
mental glomerulosclerosis. These findings were
highlighted by immunohistochemical stains for
Ki-67 (a proliferation marker) and cytokeratin 19
(Fig.2C and 2D).
Mild interstitial nephritis and mild chronic
changes (6% global glomerulosclerosis and 10 to
15% interstitial fibrosis and tubular atrophy)
were present. There were no viral cytopathic
changes, and immunohistochemical stains for
cytomegalovirus and polyomavirus were nega-
tive. Immunofluorescence studies showed non-
specific staining in areas of scarring within
glomeruli and no evidence of immune-complex
deposition. Electron microscopy revealed podo-
cyte injury with diffuse effacement of foot pro-
cesses (Fig.2E), a finding commonly seen in
collapsing focal segmental glomerulosclerosis.
The loss of foot processes disrupts the filtration
barrier and results in massive proteinuria. In ad-
dition, endothelial cells contained tubuloreticu-
lar inclusions (Fig.2F), which are clusters of
dilated, abnormally branched tubules of rough
endoplasmic reticulum that are caused by elevat-
ed interferon levels and are thus sometimes
called interferon footprints. Tubuloreticular
inclusions are common in lupus nephritis and

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 Case Records of the Massachuset ts Gener al Hospital

viral infections, including HIV. No electron-

A B
dense deposits were present that would suggest
immune-complex disease.
In collapsing focal segmental glomeruloscle-
rosis, podocyte injury leads to effacement of foot
processes, collapse of capillary walls, and a com-
pensatory proliferation of epithelial cells that are
primarily derived from the visceral epithelial
cells that line Bowmans capsule. Collapsing
focal segmental glomerulosclerosis is a pattern C D
of injury and not a specific diagnosis; its cause
may be unknown or it may occur in association
with various conditions, such as drug exposure
and infection, including HIV infection. A spe-
cific diagnosis requires correlation with clinical
and laboratory data. Given the patients recent
diagnosis of HIV, this collapsing focal segmen-
tal glomerulosclerosis is most likely associated
E F
with HIV and thus represents HIV-associated ne-
phropathy.21,22 In this patient, this diagnosis is
supported by the presence of microcystic tubu-
lar dilatation and tubuloreticular inclusions,
which are typical findings in HIV-associated
nephropathy.

Discussion of M a nagemen t
Dr. Andrew S. Allegretti: The management of HIV-
associated nephropathy is focused on maximizing
the suppression of viral replication and minimiz-
ing long-term renal damage. The four manage-
ment strategies are antiretroviral therapy, therapy
with angiotensin-convertingenzyme (ACE) in-
hibitors and angiotensin-receptor blockers, gluco-
corticoid therapy, and renal-replacement therapy.
We are unaware of any randomized, controlled
trials that examine the effect of any of these
therapies in HIV-associated nephropathy, and
therefore, practice decisions are largely driven by
consensus guidelines, the results of smaller
studies, or extrapolation from general recom-
mendations for the management of chronic kid-
ney disease.
HIV-associated nephropathy is one of the
guideline-recommended indications for the ini-
tiation of antiretroviral therapy, regardless of a
patients CD4 cell count or viral load. The use
of antiretroviral therapy is associated with im-
provement in renal survival.23 ACE inhibitors and
angiotensin-receptor blockers are commonly
used to lower the blood pressure to less than
Figure 2. Kidney-Biopsy Specimen.
A corebiopsy specimen of the left kidney shows marked tubular injury with
microcystic tubular dilatation (Panel A, periodic acidSchiff). Glomeruli
show collapse of capillary loops and extracapillary proliferation of epithelial
cells (Panel B, periodic acidSchiff), findings indicative of the collapsing
variant of focal segmental glomerulosclerosis. Immunohistochemical stains
for Ki67 (Panel C) and cytokeratin 19 (Panel D) highlight the proliferating
epithelial cells in the glomeruli. Images obtained during electron microscopy
show widespread effacement of podocyte foot processes (Panel E) and tu
buloreticular inclusions in endothelial cells (Panel F).
130/80 mm Hg and to lower proteinuria to less
than 1 g per day; these targets are similar to
those used in the management of general non-
diabetic chronic kidney disease.24 There are very
few data to support the use of glucocorticoid
therapy in an era in which potent antiretroviral
therapy is available; the use of glucocorticoids
has been associated with decreased proteinuria
and a lower blood creatinine level but also with
an increased risk of serious infections.25,26 Fi-
nally, renal-replacement therapy remains a sup-
portive measure for patients with progression
to end-stage renal disease. Among patients who
are receiving dialysis or have received a kidney

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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

transplant, survival is similar in those who have
HIV infection and in those who do not; this re-
flects the success of HIV treatment at large.27
However, approximately 50% of patients with
HIV-associated nephropathy have progression to
end-stage renal disease, and this highlights the
need for a directed therapy for HIV-associated
nephropathy that halts the progression of renal
disease.28
Dr. Pierce: Dr. Goldstein, how is your patient
doing now?
Dr. Goldstein: Once we established the diagno-
sis of HIV-associated nephropathy and the patients
renal function started to recover, we initiated
therapy with elvitegravir, cobicistat, tenofovir
alafenamide, and emtricitabine. Therapy was
started on hospital day 7, and 8 days later, the
patients CD4 cell count was 1349 per cubic milli-
meter and his viral load had decreased to 533
copies per milliliter. Within 45 days, his viral
load became undetectable, the proteinuria was
less than 2 g per day, and the blood creatinine
level was 0.9 mg per deciliter (80 mol per liter).
We are optimistic that the patient will have con-
tinued success, though he will require lifelong
monitoring.
A nat omic a l Di agnosis
Collapsing variant of focal segmental glomeru-
losclerosis that is consistent with HIV-associated
nephropathy.
This case was presented at the Medical Case Conference.
No 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 Dr. Neal Smith for assistance in the interpretation
of the results of the kidney biopsy.

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