The n e w e ng l a n d j o u r na l of
Case Records of the Massachusetts General Hospital
From the New York Nephrology Vasculi‑
tis and Glomerular Center and the De‑
partment of Medicine, St. Peter’s Hospi‑
tal — both in Albany (F.B.C.); and the
Departments of Medicine (F.B.C., E.P.R.,
R.S., J.H.S.), Radiology (S.G.), and Pathol‑
ogy (R.B.C.), Massachusetts General Hos‑
pital, and the Departments of Medicine
(F.B.C., E.P.R., R.S., J.H.S.), Radiology
(S.G.), and Pathology (R.B.C.), Harvard
Medical School — both in Boston.
N Engl J Med 2020;383:1768-78.
DOI: 10.1056/NEJMcpc2002415
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1768
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m e dic i n e
Founded by Richard C. Cabot
Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Kathy M. Tran, M.D., Assistant Editor
Matthew B. Roberts, M.B., B.S., Case Records Editorial Fellow
Emily K. McDonald, Tara Corpuz, Production Editors
Case 34-2020: A 74-Year-Old Man
with Chronic Kidney Disease
Frank B. Cortazar, M.D., Eugene P. Rhee, M.D., Sumit Gupta, M.B., B.S., Ph.D.,
Rahul Sakhuja, M.D., M.P.P., John H. Stone, M.D., M.P.H.,
and Robert B. Colvin, M.D.​​
Pr e sen tat ion of C a se
Dr. Eugene P. Rhee: A 74-year-old man was evaluated in the nephrology clinic of this
hospital because of chronic kidney disease.
The patient had been in his usual state of health when he was referred to the
nephrology clinic of this hospital for a preoperative evaluation of chronic kidney
disease, before a transcatheter aortic-valve replacement (TAVR) for aortic stenosis.
Eighteen years before this evaluation, an elevated creatinine level had been
found incidentally during an evaluation of fatigue, malaise, and joint stiffness. The
patient was evaluated in the nephrology clinic of another hospital, and biopsy of
the right kidney was performed.
Dr. Robert B. Colvin: Pathological examination of the kidney-biopsy specimen
(Fig. 1) revealed glomeruli with thickened capillary walls and mild mesangial
hypercellularity. A Jones’ silver stain showed “spikes” and “bubbles” in the glo-
merular basement membrane, features typical of membranous nephropathy. The
interstitium had an infiltrate of mononuclear cells, plasma cells, and eosinophils,
with tubulitis and without granulomas or neutrophils. Immunofluorescence showed
staining of granular deposits for IgG and C3 along the glomerular basement mem-
brane and in the mesangium. Other stains (C1q, IgA, IgM, fibrinogen, and albu-
min) were negative. Electron microscopy showed widespread amorphous subepi-
thelial deposits along the glomerular basement membrane and in the mesangium,
with surrounding spikes and podocyte foot-process effacement. Arteriosclerosis
and glomerulosclerosis were also present. At the other hospital, these findings
were interpreted as membranous nephropathy, acute tubulointerstitial nephritis
with eosinophils, and arterionephrosclerosis with global glomerulosclerosis.
Dr. Rhee: The patient was told that his kidney disease was consistent with a diag-
nosis of Sjögren’s syndrome. Prednisone was administered for 6 months and then
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The New England Journal of Medicine
 Case Records of the Massachuset ts Gener al Hospital

A B

C D

Figure 1. Kidney-Biopsy Specimen.

Hematoxylin and eosin staining (Panels A and B) shows glomeruli with thickened capillary walls (Panel A, arrows)
and mesangial hypercellularity. There is an interstitial infiltrate of eosinophils (Panel B, arrow) and plasma cells
(Panel B, oval). Immunofluorescence (Panel C) shows staining of granular deposits for IgG along the glomerular
capillary wall (arrows) and in the mesangium (asterisk). Electron microscopy of a glomerulus (Panel D) shows
amorphous subepithelial deposits (arrows) with adjacent spikes in the glomerular basement membrane (arrow‑
heads) and in the mesangium (asterisk); these findings are typical of membranous nephropathy.

tapered to a lower dose. Treatment with sodium
bicarbonate and furosemide was initiated, as was
treatment with losartan, although losartan was
intermittently stopped because of hyperkalemia;
prednisone was continued. During the next 18
years, the creatinine level gradually increased to
3.28 mg per deciliter (290 μmol per liter; refer-
ence range, 0.70 to 1.18 mg per deciliter [62 to
104 μmol per liter]).
Twenty-five years before the current evalua-
tion, the patient had received a diagnosis of
chronic pancreatitis complicated by diabetes mel-
litus and exocrine pancreatic insufficiency. One
year later, painless enlargement of the right
lacrimal gland occurred. Surgical excision of the
right lacrimal gland was performed at the other
hospital, and examination of the excised speci-
men reportedly revealed nonspecific inflamma-
tion. The next year, enlargement of the left lac-
rimal gland and the bilateral submandibular and
parotid glands developed.
Dr. Sumit Gupta: Magnetic resonance imaging
of the neck, performed before and after the ad-
ministration of intravenous contrast material,
revealed masslike abnormalities of the bilateral
submandibular and parotid glands. The abnor-
malities were hypointense on T1-weighted and
T2-weighted imaging.
Dr. Rhee: The patient declined another glandu-
lar biopsy and was told that he probably had

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 The n e w e ng l a n d j o u r na l
Sjögren’s syndrome. Glandular enlargement re-
solved, and during the next 23 years, the patient
was treated with prednisone for presumptive
Sjögren’s syndrome.
Two years before the current evaluation, short-
ness of breath and substernal chest pressure on
exertion developed; these symptoms usually
resolved after approximately 20 minutes of rest.
The patient was evaluated at the other hospital,
and aortic stenosis was diagnosed.
Four months before the current evaluation,
the shortness of breath and substernal chest
pressure worsened, such that the patient became
unable to carry his groceries a short distance to
his house. Additional imaging and cardiology
studies were obtained.
Dr. Gupta: Computed tomography (CT) of the
heart, chest, abdomen, and pelvis, performed
before and after the administration of intrave-
nous contrast material, revealed multiple large
aneurysms involving all the coronary arteries,
with associated mural thrombus (Fig. 2A through
2D; and Video 1, available with the full text of
this article at NEJM.org). There was extensive
coronary-artery calcification, along with scat-
Videos showing tered pulmonary nodules measuring up to 4 mm
cardiac imaging in diameter, multiple mildly enlarged mediasti-
studies are
available at nal lymph nodes, and calcification in the tail of
NEJM.org the pancreas.
Dr. Rahul Sakhuja: Echocardiography showed
severe tricuspid aortic stenosis, with bulky calci-
fication of the aortic-valve leaflets with restrict-
ed motion (Video 2, available at NEJM.org), as
well as severe calcification of the aortic root at
the sinotubular junction. Coronary angiography
revealed large aneurysms with partial calcifica-
tion involving all the coronary arteries — specifi-
cally, the distal left main, proximal and middle
left anterior descending, proximal left circum-
flex, and proximal and middle right coronary
arteries — and calcified narrowing between the
aneurysmal segments (Fig. 2E through 2H). The
distal lumens were normal in caliber and were
not well visualized because of the slow flow
through the proximal aneurysmal segments.
There was moderate, diffuse disease in the
middle left circumflex artery.
Dr. Rhee: Balloon aortic valvuloplasty was per-
formed 3 months before the current evaluation,
and a subsequent TAVR was planned. During the
current evaluation, the patient indicated that the
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of m e dic i n e
shortness of breath and chest pressure on exer-
tion had abated since the balloon aortic valvulo-
plasty. Additional history was obtained. The pa-
tient had chronic back and neck pain due to
severe kyphoscoliosis, spinal stenosis, and cervical
myelopathy; the pain had been treated 2 months
earlier with anterior cervical diskectomy and fu-
sion. He had hypertension, anemia, gout, osteo-
penia, and benign prostatic hypertrophy. Medi-
cations included prednisone, metoprolol, aspirin,
rosuvastatin, furosemide, insulin, sodium bicar-
bonate, epoetin alfa, cholecalciferol, calcitriol,
pancrelipase, alfuzosin, allopurinol, and gaba-
pentin. There were no known drug allergies. He
had smoked 10 cigarettes per day for 6 years but
had stopped four decades earlier; he drank alco-
hol rarely and did not use illicit drugs. The pa-
tient had been retired from his career as a health
care professional for 2 years. He was married
and lived in a house in a suburban area of New
England. His father had had type 2 diabetes
mellitus and had died of prostate cancer at 67
years of age, his mother had had pancreatic can-
cer and had died at 65 years of age, and his
younger brother had had type 2 diabetes melli-
tus and had died after a myocardial infarction at
46 years of age.
On physical examination, the temperature
was 36.1°C, the blood pressure 176/75 mm Hg,
the heart rate 77 beats per minute, and the body-
mass index (the weight in kilograms divided by
the square of the height in meters) 24.8. There
was a crescendo–decrescendo systolic murmur
that was heard best at the right upper sternal
border. The creatinine level was 3.41 mg per
deciliter (301 μmol per liter; reference range,
0.60 to 1.50 mg per deciliter [53 to 133 μmol per
liter]), which was similar to other levels obtained
during the previous 1.5 years. The urinary pro-
tein level was 149.6 mg per deciliter (reference
range, 0.0 to 13.5); the ratio of total protein to
creatinine was 2.23 (reference range, <0.15). Re-
sults of liver-function tests were normal. Other
laboratory test results are shown in Table 1.
A diagnostic test was performed.
Differ en t i a l Di agnosis
Dr. Frank B. Cortazar: This 74-year-old man was re-
ferred to the nephrology clinic for a preoperative
evaluation in the context of advanced chronic
nejm.org October 29, 2020
 Case Records of the Massachuset ts Gener al Hospital
kidney disease. Several features of this patient’s
presentation — including the history of mem-
branous nephropathy, tubulointerstitial nephritis,
chronic pancreatitis without a history of alcohol
use, enlargement of the lacrimal and salivary
glands, and coronary-artery aneurysms — are
suggestive of a systemic disease that has yet to
be diagnosed. One approach to clinical problem-
solving is to begin by focusing on unique fea-
tures of the case that have a limited differential
diagnosis. In this case, the differential diagnosis
will be constructed around the unusual simulta-
neous occurrence of membranous nephropathy
and tubulointerstitial nephritis. The diagnostic
possibilities will then be refined by assessing
the capacity of each of the disease processes to
explain all the features of the patient’s presenta-
tion, including the development of pancreatitis
and enlargement of the lacrimal, submandibu-
lar, and parotid glands.
Membranous Nephropathy
Membranous nephropathy is caused by the grad-
ual accumulation of immune deposits in the
subepithelial aspect of the glomerular basement
membrane, which leads to podocyte damage
and proteinuria. Primary membranous nephrop-
athy — an isolated kidney disease that results
from autoantibodies directed against endoge-
nous podocyte-specific antigens in the absence
of an identifiable cause — accounts for most
cases. Alternatively, membranous nephropathy
can be secondary to a predisposing condition,
such as autoimmune disease (e.g., systemic lupus
erythematosus), infection (e.g., hepatitis B or
syphilis), medication use (e.g., use of nonsteroi-
dal antiinflammatory drugs [NSAIDs]), cancer, or
allogeneic stem-cell transplantation.1 The M-type
phospholipase A2 receptor (PLA2R) is the target
antigen in approximately 70% of patients with
primary membranous nephropathy.2 A diagnosis
of PLA2R-associated membranous nephropathy
can be established by the identification of circu-
lating anti-PLA2R antibodies or positive staining
for PLA2R on a kidney-biopsy specimen. How-
ever, anti-PLA2R antibody testing was not avail-
able 18 years ago, when this patient received the
diagnosis of membranous nephropathy.
Other pathological features can assist in dif-
ferentiating primary from secondary membra-
nous nephropathy. In secondary membranous
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nephropathy, the target antigen is extrinsic to
the podocyte and reaches the glomerular base-
ment membrane through the circulation.3 This
often results in the generation of subendothelial
and mesangial deposits in addition to the sub-
epithelial deposits that are characteristic of mem-
branous nephropathy. Furthermore, the domi-
nant immunoglobulin in primary membranous
nephropathy is of the IgG4 subclass, whereas
the other IgG subclasses predominate in most
causes of secondary membranous nephropathy.4
The presence of mesangial deposits in this case
suggests the possibility of secondary membra-
nous nephropathy. Moreover, the presence of con-
comitant tubulointerstitial nephritis is strongly
suggestive of a disease process other than pri-
mary membranous nephropathy.
Interstitial Nephritis
In addition to showing evidence of membranous
nephropathy, this patient’s kidney-biopsy speci-
men was noted to have an interstitial infiltrate
containing eosinophils, a finding consistent with
tubulointerstitial nephritis. Most cases of tubulo­
interstitial nephritis are caused by the use of a
medication such as antibiotic drugs, NSAIDs,
proton-pump inhibitors, or as described more
recently, immune-checkpoint inhibitors.5,6 Other
causes of tubulointerstitial nephritis include sys-
temic autoimmune disease (e.g., systemic lupus
erythematosus, sarcoidosis, or Sjögren’s syn-
drome), infection (e.g., legionella or Mycobacterium
tuberculosis infection), and tubulointerstitial ne-
phritis and uveitis syndrome.5 Few pathological
features assist in identifying the cause of inter-
stitial nephritis. The identification of granulo-
mas, which were not present in this case, would
arouse suspicion for sarcoidosis, but granulomas
can also be seen with infection and drug-induced
tubulointerstitial nephritis. The presence of eosin-
ophils is compatible with drug-induced tubulo­
interstitial nephritis, but this finding is not
specific for this entity. In rare cases, NSAIDs
can cause the combination of interstitial nephri-
tis and nephrotic syndrome, although in this con-
text, the glomerular lesion is classically caused
by minimal change disease.7 It is possible that
the use of NSAIDs led to tubulointerstitial ne-
phritis and membranous nephropathy in this
patient, and he should be asked about any clini-
cally significant previous NSAID use. The other
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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

A B C

*
*

D E F

G H

unexplained features in the patient’s history, Systemic Lupus Erythematosus

however, suggest that his kidney disease is a Approximately 10 to 20% of patients with lupus
manifestation of a systemic autoimmune disease. nephritis have isolated lupus membranous ne-

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 Case Records of the Massachuset ts Gener al Hospital

Figure 2 (facing page). Cardiac CT Scans and Coronary Table 1. Laboratory Data.*
Angiography.
Curved, multiplanar, reformatted CT images of the left Reference Range, On Presentation,
Variable Adults† Nephrology Clinic
anterior descending artery (Panel A), left circumflex
­artery (Panel B), and right coronary artery (Panel C) Blood
show aneurysms involving all the coronary arteries, with
White-cell count (per μl) 4700–10,900 5410
mural thrombus (white asterisks) adjacent to contrast-
enhanced coronary arteries (white arrowheads). There Hemoglobin (g/dl) 14.0–18.0 10.5
is extensive coronary-artery calcification. A three-dimen‑ Hematocrit (%) 42.0–52.0 33.8
sional volume-rendered CT image of the heart (Panel D)
shows aneurysms involving the left main artery (black Platelet count (per μl) 130,000–400,000 168,000
arrowhead), left anterior descending artery (white arrow‑ Erythrocyte sedimentation rate 0–13 61
head), left circumflex artery (white arrow), and right cor‑ (mm/hr)
onary artery (black arrow), with the contrast-enhanced C-reactive protein (mg/liter) <8.0 13.8
lumen depicted in red and adjacent mural thrombus
depicted in yellow. Coronary angiographic images of the Sodium (mmol/liter) 135–145 138
left coronary artery obtained in the right anterior oblique Potassium (mmol/liter) 3.4–4.8 5.3
cranial view (Panels E and F) and right anterior oblique
Chloride (mmol/liter) 98–107 102
caudal view (Panel G) show massive aneurysms involv‑
ing the left main artery (white arrowheads), proximal Carbon dioxide (mmol/liter) 21–30 19
and middle left anterior descending artery (white arrows), Anion gap (mmol/liter) 3–17 17
and proximal left circumflex artery (black arrows), as
compared with normal segments of the coronary arter‑ Urea nitrogen (mg/dl) 8–25 53
ies (black arrowheads). Coronary angiography of the Creatinine (mg/dl) 0.60–1.50 3.41
right coronary artery obtained in the left anterior oblique Glucose (mg/dl) 70–109 156
cranial view (Panel H) also shows aneurysms in the
proximal and middle segments (white arrowhead), as Calcium (mg/dl) 8.9–10.0 9.2
compared with normal segments of the coronary artery Protein (g/dl)
(black arrowhead).
Total 6.4–8.3 8.5
Albumin 3.5–5.0 3.8
Globulin 1.9–4.1 4.7
phropathy (class V), without an associated pro-
liferative lesion.8 Tubulointerstitial nephritis of- Urine
ten accompanies glomerular lesions in patients Creatinine (mg/dl) 67
with lupus nephritis and is a risk factor for poor Total protein (mg/dl) 0.0–13.5 149.6
renal outcome.9 In contrast to patients with fo- Protein:creatinine ratio <0.15 2.23
cal or diffuse proliferative lupus nephritis, pa-
tients with pure lupus membranous nephropathy * 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.
often present with normal levels of C3 and C4 To convert the values for glucose to millimoles per liter, multiply by 0.05551.
and have negative testing for anti–double- To convert the values for calcium to millimoles per liter, multiply by 0.250.
stranded DNA antibodies.10 However, there are † Reference values are affected by many variables, including the patient popu­
lation and the laboratory methods used. The ranges used at Massachusetts
other pathological features, in addition to the General Hospital are for adults who are not pregnant and do not have medi‑
characteristic findings of secondary membra- cal conditions that could affect the results. They may therefore not be appro‑
nous nephropathy, that suggest a diagnosis of priate for all patients.
lupus membranous nephropathy. These include a
“full house” pattern (i.e., the presence of glo-
merular deposits that stain for IgG, IgM, IgA, Sjögren’s Syndrome
C3, and C1q) on immunofluorescence, as well as This patient had received a diagnosis of Sjögren’s
the presence of tubuloreticular structures in syndrome, which was thought to be the cause of
endothelial cells on electron microscopy.11 The his kidney disease. Interstitial nephritis is the
apparent absence of these features on examina- most common renal manifestation of Sjögren’s
tion of the kidney-biopsy specimen, coupled with syndrome and is often associated with distal
the patient’s sex and the absence of character- renal tubular acidosis.12 Glomerular disease in
istic extrarenal features, make a diagnosis of Sjögren’s syndrome is rare. When it occurs, the
lupus unlikely. most common pattern of injury is membrano­

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 The n e w e ng l a n d j o u r na l
proliferative glomerulonephritis, which is typi-
cally caused by production of a monoclonal IgM
kappa paraprotein with rheumatoid factor activity
that leads to type II mixed cryoglobulinemia.13
Membranous nephropathy has been described in
the context of Sjögren’s syndrome in rare cases.14
It is unclear whether these cases reflect the si-
multaneous occurrence of two distinct disease
processes or show causality. Of note, most case
reports of membranous nephropathy attributed
to Sjögren’s syndrome were published before the
availability of anti-PLA2R antibody testing.12,15
The combination of tubulointerstitial nephri-
tis and membranous nephropathy would be an
unusual manifestation of Sjögren’s syndrome.
Moreover, pancreatitis and coronary-artery an-
eurysms cannot be readily attributed to this diag-
nosis. These considerations should prompt re-
evaluation of the diagnosis of Sjögren’s syndrome
in this patient.
Results of testing for antibodies to the Ro
(SSA) and La (SSB) antigens are not provided in
the case presentation, and sicca symptoms are
not reported. The patient’s diagnosis of Sjögren’s
syndrome had been based on swelling of the
lacrimal, parotid, and submandibular glands —
a constellation of findings consistent with Miku-
licz’s disease. Within the past two decades, it has
become apparent that most cases of Mikulicz’s
disease are caused by IgG4-related disease16 and
not Sjögren’s syndrome.
IgG4-Related Disease
IgG4-related disease is a systemic fibroinflam-
matory condition that was first recognized as a
unifying disease process in the early 2000s. Many
conditions that were previously thought to be
isolated entities — including type 1 autoimmune
pancreatitis, Mikulicz’s disease, chronic scleros-
ing sialadenitis (called Küttner’s tumor when
submandibular glands are involved), fibrous
thyroiditis (Riedel’s thyroiditis), and many cases
of idiopathic retroperitoneal fibrosis (Ormond’s
disease) — are now known to be manifestations
of IgG4-related disease.17 Regardless of the in-
volved organ, the disease is characterized by two
dominant histopathological features: a lympho-
plasmacytic infiltrate with IgG4+ plasma cells
and storiform fibrosis.18 Tissue eosinophilia and
obliterative phlebitis are also common findings
in some organs. The serum IgG4 level is elevated
in most patients with IgG4-related disease.19
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of m e dic i n e
The kidney is unique among organs affected
by IgG4-related disease in that it is associated
with two distinct histologic patterns of injury.20
The most common renal manifestation of IgG4-
related disease is tubulointerstitial nephritis,
which is often accompanied by hypocomple-
mentemia and hypodense nodular lesions on
contrast-enhanced CT. In addition to the hall-
mark pathological features of the disease, tissue
eosinophilia and deposits in the tubular base-
ment membrane are often noted.21 The second
pattern of injury is IgG4-related membranous
nephropathy, which can occur alone or in com-
bination with IgG4-related tubulointerstitial ne-
phritis.22 As with primary membranous nephrop-
athy, the dominant immunoglobulin found in
immune deposits is IgG4. Testing for anti-PLA2R
antibodies, however, is characteristically nega-
tive in patients with IgG4-related membranous
nephropathy. The results of this patient’s kidney
biopsy could be compatible with IgG4-related
kidney disease.
IgG4-related disease also unifies the other
unexplained features in this case. The patient’s
chronic pancreatitis is probably the result of
type 1 (IgG4-related) autoimmune pancreatitis,
which often occurs in older men and can lead to
endocrine and exocrine pancreatic failure.23 IgG4-
related disease can also cause vasculitis and
aneurysm formation. Large-vessel vasculitis in-
volving the thoracic and abdominal aorta is most
common, but coronary arteritis with resultant
aneurysm formation has also been described.24,25
Finally, although the incidental pulmonary nod-
ules and hilar lymphadenopathy noted on CT are
nonspecific, they may also be manifestations of
IgG4-related disease.26
An elevated serum IgG4 level in this patient
would be highly supportive but not diagnostic
of IgG4-related disease. Integration of clinical,
laboratory, and histopathological data is needed
to reliably establish the diagnosis. A kidney bi-
opsy, or reexamination of the previously obtained
specimens of the kidney and lacrimal gland, if
available, would confirm the diagnosis.
Cl inic a l Impr e ssion
Dr. Rhee: Understanding the underlying cause of
this patient’s chronic kidney disease was impor-
tant before cardiac surgery, because anything
that can be done to stabilize or even improve
nejm.org October 29, 2020
 Case Records of the Massachuset ts Gener al Hospital

kidney function will attenuate the risk of post-

A
operative acute kidney injury. Although Sjögren’s
syndrome has been associated with tubulointer-
stitial nephritis and, in rare cases, with mem-
branous nephropathy, it could not explain the
patient’s history of pancreatitis, glandular enlarge-
ment, or coronary-artery aneurysms. Instead,
B
this constellation of findings was strongly sug-
gestive of IgG4-related disease, a diagnosis that
could prompt other treatment approaches. There-
fore, when the patient was evaluated in the ne-
phrology clinic, we obtained serum IgG4 levels,
C D
and we sought out the previously obtained
specimens of the kidney and lacrimal gland to
perform staining for IgG4+ plasma cells.

Cl inic a l Di agnosis
IgG4-related disease.
Dr . Fr a nk B . C or ta z a r’s
Di agnosis
IgG4-related disease.
Pathol o gic a l Discussion
Dr. Colvin: The serum IgG level was 2741 mg per
deciliter (reference range, 614 to 1295). The IgG4
level was 925.4 mg per deciliter (reference range,
3.9 to 86.4), a finding highly supportive of the
diagnosis of IgG4-related disease.
On request, the kidney-biopsy specimen that
had been obtained 18 years earlier was stained
for IgG and IgG4 (Fig. 3). The IgG+ plasma cells
were predominantly IgG4+, with more than 30
IgG4+ cells per high-power field. Deposits in
the glomerular basement membrane were posi-
tive for IgG4, as were deposits along the tubular
basement membrane. These findings are typical
of IgG4-related disease affecting the kidney.20
Approximately 8% of patients with IgG4-related
disease who undergo kidney biopsy have mem-
branous nephropathy (40% of whom have me-
sangial deposits), and 70 to 80% have deposits
along the tubular basement membrane.21,22
The lacrimal-gland specimen that had been ob-
tained 24 years earlier was also reviewed. The ex-
cised lacrimal gland measured 3.2 cm by 2.5 cm
by 1.2 cm. Pathological examination of the speci-
men (Fig. 4) revealed a diffuse infiltrate of mono-
nuclear cells, plasma cells, and eosinophils em-
Figure 3. Kidney-Biopsy Specimen.
Retrospective immunohistochemical staining shows scattered plasma cells
that are IgG+ (Panel A, oval). A similar field shows that most of the plasma
cells in the same area are IgG4+ (Panel B, oval). The granular deposits in the
glomerular basement membrane are also IgG4+ (Panel C, arrows). Similar
granular deposits are focally present in the tubular basement membrane
(Panel D, arrows).
bedded in extensive fibrosis with a storiform
pattern. Germinal centers were present, as were
scattered remnants of lacrimal gland. Immuno-
histochemical staining showed polytypic immu-
noglobulin in plasma cells, B cells (CD20+), and
T cells (CD3+CD5+). There was no evidence of
cancer. Prominent IgG4+ plasma cells were
present and accounted for more than 90% of the
IgG+ plasma cells. Transmural arteritis and ob-
literative phlebitis were not present. In summa-
ry, reexamination of the specimens was diagnos-
tic of IgG4-related disease affecting the kidney
and lacrimal gland.
Discussion of M a nagemen t
Dr. John H. Stone: This case illustrates several re-
markable features of IgG4-related disease. First,
the disease has the propensity to affect multiple
organs. Indeed, the occurrence of IgG4-related
disease has been described in virtually every
organ.17 This case shows classic disease mani-
festations: autoimmune pancreatitis, involvement
of the lacrimal and major salivary glands (Miku-

n engl j med 383;18 nejm.org October 29, 2020 1775

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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

A B

* S
*
*
*

C D

E F

Figure 4. Lacrimal-Gland Specimen.

Retrospective hematoxylin and eosin staining (Panels A through D) shows a rounded mass with numerous germinal
centers (Panel A, asterisks) separated by eosinophilic fibrosis (Panel B, asterisk) in a storiform (“S”), or woven mat‑
like, pattern. Prominent infiltrates of eosinophils (Panel C, arrows) and plasma cells (Panel C, oval) are present. Scat‑
tered remnants of lacrimal gland (Panel D, arrows) can be seen in the inflammatory mass. Retrospective immuno‑
histochemical staining (Panels E and F) shows numerous plasma cells that are IgG+ (Panel E, oval). Most of the
plasma cells in the same area are IgG4+ (Panel F, oval).

licz’s disease), and the most common renal eurysms, which were striking in this case, have
manifestations, tubulointerstitial nephritis and also been described in IgG4-related disease, but
membranous nephropathy.27 Coronary-artery an- this complication occurs far less frequently than

1776 n engl j med 383;18 nejm.org October 29, 2020

The New England Journal of Medicine

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 Case Records of the Massachuset ts Gener al Hospital
the other features. In our cohort of more than
400 patients with IgG4-related disease at this
hospital, we have observed coronary-artery an-
eurysms in less than 1% of patients.
Second, the onset of IgG4-related disease oc-
curs at different times in different organs.
Twenty-five years before the current presenta-
tion, autoimmune pancreatitis heralded the on-
set of this patient’s clinical disease. One year
after that, dacryoadenitis became evident, prompt-
ing excision of the lacrimal gland, but the un-
derlying cause remained unrecognized because
IgG4-related disease was not a described entity
at that time. During the next year, enlargement
of the contralateral lacrimal gland and bilateral
submandibular and parotid glands occurred, but
these findings were attributed to a diagnosis of
Sjögren’s syndrome. Seven years after the pa-
tient’s autoimmune pancreatitis began, kidney
disease developed, and he began to receive in-
tensive treatment with glucocorticoids. However,
it was not until his presentation at this hospital
for a pre-TAVR evaluation — a quarter century
after his first disease manifestation — that the
unifying diagnosis was identified. The pattern
of disease onset and the indolent progression in
many organs probably contributed to the fact
that IgG4-related disease was not recognized as
a unique, multiorgan disease until 2003.28,29 The
precise onset of this patient’s coronary arteritis
that led to aneurysm formation is not known,
but in all likelihood, it had been developing for
years.
Third, although IgG4-related disease has more
indolent disease progression than rapidly pro-
gressive glomerulonephritis, it frequently causes
clinically significant disease-related damage. The
pancreas and biliary tree are often hit hardest by
IgG4-related disease, and this patient’s case was
no exception: his IgG4-related autoimmune pan-
creatitis resulted in not only insulin-dependent
diabetes but also exocrine pancreatic failure.
Exocrine pancreatic failure, which is often un-
derappreciated as an important form of damage
in IgG4-related disease, is the most common
explanation for the dramatic weight loss that
can be seen in patients with IgG4-related dis-
ease27; the patients cannot absorb sufficient
calories and nutrients because of the absence of
pancreatic enzymes. Patients frequently report
weight loss of 18 kg (40 lb) or more.27
In addition, this patient’s kidney disease had
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approached end-stage disease at the time of this
evaluation, despite the administration of gluco-
corticoids. Patients with IgG4-related kidney
disease often have major renal atrophy after
what appears to have been successful therapy
with glucocorticoids. The full potential effect of
coronary-artery aneurysms in IgG4-related dis-
ease is not currently known, because this com-
plication has been described in only a few cases,
but the risk of thrombosis from the massive
aneurysms that were affecting all the coronary
arteries in this patient is probably high.
Glucocorticoids are the cornerstone of treat-
ment for IgG4-related disease. Although gluco-
corticoids are initially effective in most patients,
the rate of relapse after the course is tapered or
discontinued is high.30 Furthermore, as in this
patient’s case, disease progression may occur
despite maintenance glucocorticoid treatment.
In the interest of preserving this patient’s re-
maining kidney function, increasing the chances
of a successful TAVR procedure, and preventing
further complications from IgG4-related disease,
we opted to treat him with rituximab. A growing
body of evidence suggests that B-cell depletion
is effective in IgG4-related disease because of its
direct effect on cells of the B-lymphocyte lineage
and its indirect effect on CD4+ cytotoxic T lym-
phocytes, which are thought to be crucial to
disease pathophysiology.31-35
The patient had a response to treatment with
rituximab. Two months after the initiation of
this treatment, the serum IgG4 level decreased
to 785.7 mg per deciliter. Treatment with rivar-
oxaban was started because of the mural throm-
bus associated with the coronary-artery aneu-
rysms. The patient’s kidney function remains
stable and he is awaiting TAVR.
Fina l Di agnosis
IgG4-related disease, with tubulointerstitial ne-
phritis, membranous nephropathy, and inflam-
matory pseudotumor involving the lacrimal gland.
This case was presented at the Medicine Case Conference.
Dr. Stone reports receiving grant support and consulting
fees from Roche Group. 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 Dr. Michael Lu for assistance with preparation of
the radiologic discussion and Dr. Vijay Vanguri for provision of
the kidney-biopsy studies and sections.
nejm.org October 29, 2020 1777
 Case Records of the Massachuset ts Gener al Hospital
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