Baylor University Medical Center Proceedings April 2017 - 169

Acquired 5-oxoproline acidemia successfully treated with
N-acetylcysteine
Gregory L. Hundemer, MD, MPH, and Andrew Z. Fenves, MD

Acquired 5-oxoprolinemia is increasingly recognized as a cause of anion
gap metabolic acidosis. It predominantly occurs in chronically ill, malnourished women with impaired renal function and chronic acetaminophen
ingestion. Depletion of glutathione and cysteine stores leads to elevated
5-oxoproline levels. N-acetylcysteine, given its effect in repleting glutathione and cysteine stores, has been proposed as a potential treatment
for 5-oxoprolinemia, though reports of its successful use are lacking. We
present a case of 5-oxoproline metabolic acidosis that persisted despite
discontinuation of acetaminophen. However, the acidosis rapidly resolved
with N-acetylcysteine administration.

e report a case of an anion gap metabolic acidosis
due to 5-oxoprolinemia that rapidly resolved with
administration of N-acetylcysteine (NAC).

CASE REPORT
A 38-year-old woman who had bilateral lung transplantation
4 months earlier for restrictive lung disease was transferred from
a rehabilitation facility to the hospital because of acidemia. Her
posttransplant course was complicated by an episode of acute
rejection, several episodes of pneumonia, malnutrition requiring
gastric feeding tube placement with nutrition primarily through
tube feedings, and several episodes of acute kidney injury (AKI)
requiring renal replacement therapy (RRT). Her immunosuppression regimen included tacrolimus, mycophenolate mofetil,
and prednisone. She had been discharged from this same hospital
2 weeks prior when she was admitted for pneumonia with oliguric AKI in the setting of sepsis that required a prolonged course
of RRT. During the ﬁnal 2 weeks of this prior hospitalization,
she had renal recovery with adequate urine output and a serum
creatinine of 0.91 mg/dL at the time of discharge. Over this same
time period, she experienced abdominal pain around the site of
her feeding tube that was treated with 650 mg to 1300 mg of
acetaminophen daily. On the day of discharge, her anion gap
had risen to 29 mEq/L.
After 2 weeks in a rehabilitation facility, she was transferred
back to the hospital for persistent acidemia. A blood gas on
admission revealed a pH of 7.29 with serum bicarbonate of
12 mg/dL, partial pressure of carbon dioxide of 27 mm Hg,
Proc (Bayl Univ Med Cent) 2017;30(2):169-170

anion gap of 28 mEq/L, and albumin of 1.8 g/dL. These results
suggested an anion gap metabolic acidosis with appropriate
respiratory compensation. Based on the delta-delta calculation, she had a simultaneous metabolic alkalosis likely related
to oral bicarbonate administered at the rehabilitation facility.
Evaluation into the etiology of her anion gap metabolic acidosis
included serum creatinine 0.91 mg/dL, L-lactate 0.8 mmol/L,
undetectable D-lactate, undetectable urine ketones and serum
salicylates, calculated serum osmolality of 295 mosm/kg, and
a measured serum osmolality of 304 mosm/kg. Urine pH was
5.0 with a calculated urine anion gap of +23. A serum acetaminophen level was <2.0 μg/mL. Ultimately, a urine organic
acid screen was performed and revealed a markedly elevated
5-oxoproline level of 17,455 mmol/mol creatinine (reference
range <62) with no other unusual organic acids detected.
Given a high degree of suspicion for 5-oxoprolinemia,
acetaminophen was discontinued at the time of readmission.
However, the anion gap remained elevated in the 25 to
31 mEq/L range for the next 7 days while the urine organic
acid screen was pending. Once the results of the urine organic
acid screen returned, NAC was administered intravenously at a
dose of 150 mg/kg over 60 minutes followed by 50 mg/kg over
4 hours followed by 100 mg/kg over 16 hours. Subsequently, the
anion gap declined rapidly and her acidemia resolved (Figure 1).
DISCUSSION
5-oxoprolinemia is increasingly recognized as a cause of anion gap metabolic acidosis. Many cases likely go undiagnosed
due to lack of a universally available assay for 5-oxoproline. The
patient described above ﬁts the classic proﬁle for a patient with
5-oxoproline metabolic acidosis: a chronically ill, malnourished
woman with chronic kidney disease (1-4). She had multiple
serious complications after lung transplantation. She suﬀered
from malnutrition due to recurrent infections and deconditioning, which left her reliant on tube feedings. Though her serum
From the Division of Nephrology, Massachusetts General Hospital (Hundemer,
Fenves) and the Division of Renal Medicine, Brigham and Women's Hospital
(Hundemer), Boston, Massachusetts.
Corresponding author: Gregory L. Hundemer, MD, MPH, Massachusetts General
Hospital, 55 Fruit Street, Suite 1008, Gray/Bigelow 10, Boston, MA 02114 (e-mail:
ghundemer@partners.org).
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