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MARCH 2016

A 60-Year-Old Man With Fever, Night Sweats,

and Acute Kidney Injury

demonstrated trace protein, many white blood cells

CLINICAL PRESENTATION
per high-power field, occasional white blood cell
A 60-year-old man presented with fever, chills,
casts, and eosinophils. Results of blood and urine
drenching night sweats, anorexia, myalgias, and a
cultures, as well as serologic tests for active and
5-kg weight loss over the previous 4 weeks. One prior infections, were negative. Serum protein
week into the illness, he had been treated empiri-
electrophoresis/urine protein electrophoresis and
cally with a course of doxycycline, but without
levels of complement were unremarkable; no SS-
improvement. One week after unsuccessful treat-
A, SS-B, or antineutrophil cytoplasmic antibodies
ment with doxycycline, he developed polyuria and
were detectable. Kidney ultrasound and computed
nocturia. His medications included levothyroxine
tomographic scan of the abdomen and pelvis were
and omeprazole, for gastroesophageal reflux dis-
normal. Six months prior to presentation, the pa-
ease (GERD) for 6 months. He denied nonsteroidal
tient’s baseline serum creatinine level had been
anti-inflammatory drug (NSAID) intake. On ex- 1.2 mg/dL (estimated glomerular filtration rate,
amination, he appeared fatigued but afebrile, with
60 mL/min/1.73 m2). A kidney biopsy was per-
blood pressure of 154/69 mm Hg. The patient
formed (Fig 1).
had no rash, lymphadenopathy, organomegaly,
heart murmur, or edema. Prostate examination
findings were normal. Blood tests showed mild - What does the kidney biopsy specimen
anemia with normal white blood cell and platelet demonstrate?
counts, serum urea nitrogen level of 48 mg/dL,
serum creatinine level of 3.4 mg/dL (corre- - What are the possible and most likely
sponding to estimated glomerular filtration rate of causes of this patient’s kidney injury?
19 mL/min/1.73 m2 as calculated by the CKD-
EPI [Chronic Kidney Disease Epidemiology - Are the onset and systemic symptoms
Collaboration] creatinine equation). Fractional consistent with the diagnosis?
excretion of sodium was .2%, and urinalysis - How should this patient be treated?

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Am J Kidney Dis. 2016;67(3):xxi-xxiii xxi


DISCUSSION
- What does the kidney
biopsy specimen
demonstrate?
Microscopic examination demon-
strates diffuse interstitial inflam-
matory cell infiltrates, including
numerous plasma cells (Fig 1;
black arrow) and scattered eosin-
ophils (red arrow). The glomer-
ulus (blue arrow) is unremarkable.
There is active tubulitis and
diffuse acute tubular injury. These
histologic features confirm a
diagnosis of severe diffuse acute
interstitial nephritis (AIN). No
immunoglobulin G4 (IgG4)-
positive cells were observed on
immunofluorescence or immuno-
peroxidase staining.
- What are the possible and
most likely causes of this
patient’s kidney injury?
Urinary and kidney biopsy findings
are consistent with a diagnosis
of AIN. Historically, the most
common causes of AIN are medi-
cations, including antibiotics
(beta-lactams, sulfonamides, and
rifampicin) and NSAIDs. Howev-
er, more recently, there have been
increasing reports of proton pump
inhibitor (PPI)-associated AIN.1-4
Other etiologic possibilities include
infections, autoimmune conditions
(Sjögren syndrome and systemic
lupus erythematosus), tubular
interstitial nephritis with uveitis
syndrome (TINU), and IgG4-
related tubulointerstitial nephritis.
Our patient had not received com-
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monly implicated antibiotics or
NSAIDs. Doxycycline has not been
xxii
Figure 1. Light microscopy of kidney biopsy specimen stained with hematoxylin and
eosin (original magnification, 340).
implicated as a cause of AIN; in our
patient, the drug also was started
after the onset of illness and did not
alter its progression. Infection-,
autoimmune-, TINU-, and IgG4-
related causes were excluded in
this case.
PPIs are the second most
commonly administered drug
class in the United States. The first
reported case of PPI-associated
AIN occurred in 1992, and since
then, more than 100 similar cases
have been reported.1-4 Although
the incidence of PPI-associated
AIN is low, the prevalence of
PPI use dictates that increasing
numbers of cases will be
encountered. Simpson et al2
calculated an approximate inci-
dence of AIN due to PPIs
at 8 events/100,000 patient-years.
PPIs are now the most frequent
cause of drug-associated AIN
in New Zealand, Australia, and
the United States.1-3 Notwith-
standing, there is a fundamental
lack of knowledge among health
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MARCH 2016
ANSWERS
care providers of this important
association.1-4 A 2012 review
of PPI overutilization does not
include AIN in the list of poten-
tial side effects.5
- Are the onset and
systemic symptoms
consistent with the
diagnosis?
There is a broad range between
PPI exposure and onset of signs
and symptoms, from hours to as
long as 12 months.1-4 Case reports
note that the presence of systemic
inflammatory symptoms occur in
as many as 39% of patients
with PPI-associated AIN.1,4 The
delayed onset and nonspecific
systemic inflammatory symptoms
that often accompany this entity
can obscure the diagnosis.
- How should this patient
be treated?
Treatment recommendations are
empirically based and rest on
Am J Kidney Dis. 2016;67(3):xxi-xxiii
observational studies. When the
diagnosis is suspected, potentially
offending medications must be
discontinued immediately. The
role of corticosteroids in the
setting of AIN caused by drugs,
including PPIs, remains contro-
versial.1-4
Omeprazole therapy was dis-
continued and prednisone (40 mg/
d) was initiated, with rapid re-
solution of inflammatory symp-
toms. However, GERD symptoms
relapsed until an 8-week pred-
nisone taper was completed.
At most recent follow-up,
GERD had completely resolved,
although the patient was not
taking antacid therapy and serum
creatinine level had returned to
baseline.
FINAL DIAGNOSIS
Omeprazole-associated acute inter-
stitial nephritis.
Am J Kidney Dis. 2016;67(3):xxi-xxiii
REFERENCES
1. Muriithi AK, Leung N,
Valeri AM, et al. Biopsy-proven acute
interstitial nephritis, 1993-2011: a case
series. Am J Kidney Dis. 2014;64(4):
558-566.
2. Simpson IJ, Marshall MR,
Pilmore H, et al. Proton pump inhibitors
and acute interstitial nephritis: report
and analysis of 15 cases. Nephrology.
2006;11:381-385.
3. Geevasinga N, Coleman PL,
Webster AC, Roger SD. Proton
pump inhibitor and acute interstitial
nephritis. Clin Gastroenterol Hep-
atol. 2006;4(5):597-604.
4. Myers RP, McLaughlin K,
Hollomby DJ. Acute interstitial nep-
hritis due to omeprazole. Am J Gas-
troenterol. 2001;96(12):3428-3431.
5. Heidelbaugh JJ, Kim AH,
Chang R, Walker PC. Overutilization
of proton pump inhibitors: what the
clinician needs to know. Ther Adv
Gastroenterol. 2012;5(4):219-232.
CASE PROVIDED AND AUTHORED BY
Ellis Tobin, MD,1,2 Sunil
Pokharel, MD,2 Syed
Haqqie, MD,2 and Arif Asif, MD,2
1
Upstate Infectious Diseases
Associates; and 2Department of
Medicine, Albany Medical College,
Albany, NY.
Address correspondence to Ellis
Tobin, MD, Upstate Infectious
Diseases Associates, 404 New
Scotland Ave, Albany, NY 12208.
E-mail: ehtmdone@gmail.com
Ó 2016 by the National Kidney
Foundation, Inc.
http://dx.doi.org/10.1053/j.ajkd.2015.
10.030
SUPPORT: None.
FINANCIAL DISCLOSURE: The authors
declare that they have no relevant
financial interests.
PEER REVIEW: Evaluated by a pathol-
ogist, the Education Editor, and the
Editor-in-Chief.
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