Acute Kidney Failure

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 Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
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Emily K. McDonald, Tara Corpuz, Production Editors
Case 15-2021: A 76-Year-Old Woman with

Nausea, Diarrhea, and Acute Kidney Failure
Oladapo O. Yeku, M.D., Ph.D., Arielle J. Medford, M.D., Andrew Z. Fenves, M.D.,
and Sacha N. Uljon, M.D., Ph.D.
Pr e sen tat ion of C a se
Dr. Arielle J. Medford: A 76-year-old woman with heart failure and type 2 diabetes mel- From the Departments of Medicine
litus was admitted to this hospital with nausea, diarrhea, and acute kidney failure. (O.O.Y., A.J.M., A.Z.F.) and Pathology
(S.N.U.), Massachusetts General Hospi‑
The patient normally lived independently, but she had been staying in a skilled tal, and the Departments of Medicine
nursing facility for the past several weeks to recover from a recent humeral frac- (O.O.Y., A.J.M., A.Z.F.) and Pathology
ture. During her stay, nausea, abdominal cramps, and nonbloody diarrhea devel- (S.N.U.), Harvard Medical School — both
in Boston.
oped. The next day, the symptoms persisted, and she was transferred to the
emergency department of this hospital. This article was updated on June 10, 2021,
at NEJM.org.
Approximately 3 months before the current admission, the patient was admit-
ted to this hospital with respiratory failure due to an exacerbation of heart failure N Engl J Med 2021;384:1943-50.
DOI: 10.1056/NEJMcpc2100274
and pneumonia. She was treated with intravenous ceftriaxone and oral doxycycline Copyright © 2021 Massachusetts Medical Society.
for 5 days, and diuretic agents were adjusted during a 3-week hospitalization. Nine
weeks before the current admission, the patient’s condition returned to baseline,
and she was discharged home with instructions to continue a diuretic regimen of
torsemide and spironolactone. The patient’s dry weight was 127 kg. Laboratory test
results at the time of discharge are shown in Table 1.
Four weeks before the current admission, the patient lost her balance while
walking and fell onto her right side. She had no loss of consciousness, chest pain,
or other symptoms. She was evaluated in the emergency department of this hos-
pital and reported pain in her right arm. On examination, there were abrasions
and bruising over the right elbow, with tenderness on palpation; the weight was
123 kg. The right radial pulse was normal, and sensation was intact in the arm
and hand. Laboratory test results are shown in Table 1. Radiography of the right
arm showed a mild transcondylar fracture of the right distal humerus. A splint
was placed, and the patient was advised not to bear weight with the right arm. She
was discharged to a skilled nursing facility for increased support with daily ac-
tivities while she was recovering.
Two weeks before the current admission, while the patient was staying in the
skilled nursing facility, edema developed in both legs, and her weight increased by
5 kg. She attributed the weight gain to increased salt intake. Nine days before the
current admission, oral metolazone was added to her diuretic regimen, and the leg
edema resolved.
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Table 1. Laboratory Data.*
On Discharge, On Discharge,
9 Wk before 4 Wk before
Reference Range, Current Admission, Current Admission, On Admission,
Variable Adults† This Hospital This Hospital This Hospital
Hemoglobin (g/dl) 12.0–16.0 10.8 10.8 10.4
Hematocrit (%) 41.0–53.0 32.6 32.6 31.7
Mean corpuscular volume (fl) 80.0–100.0 94.8 94.8 93.2
White-cell count (per μl) 4500–11,000 7900 7900 8480
Differential count (per μl)
Neutrophils 1800–7700 3100 5330 5840
Immature granulocytes 0–100 50 90 20
Lymphocytes 1000–4800 2460 1590 1550
Eosinophils 0–900 340 230 270
Basophils 0–300 40 30 30
Monocytes 200–1200 680 630 770
Platelet count (per μl) 150,000–450,000 265,000 265,000 238,000
Sodium (mmol/liter) 135–145 136 138 131
Potassium (mmol/liter) 3.4–5.0 4.4 4.4 4.7
Chloride (mmol/liter) 98–108 96 97 80
Carbon dioxide (mmol/liter) 23–32 26 25 22
Anion gap (mmol/liter) 3–17 14 16 29
Glucose (mg/dl) 70–110 141 126 51
Creatinine (mg/dl) 0.60–1.50 1.88 1.71 7.66
Urea nitrogen (mg/dl) 8–25 38 51 138
Aspartate aminotransferase (U/liter) 9–32 28 35 41
Alanine aminotransferase (U/liter) 7–33 28 54 52
Alkaline phosphatase (U/liter) 30–100 58 68 113
Total bilirubin (mg/dl) 0.0–1.0 0.4 0.4 0.4
Direct bilirubin (mg/dl) 0.0–0.4 <0.2 <0.2 <0.2
Albumin (g/dl) 3.3–5.0 3.9 4.3 4.2
Lactic acid (mmol/liter) 0.5–2.0 — — 7.4
Lipase (U/liter) 13–60 — — 86
Phosphorus (mg/dl) 2.6–4.5 — — 6.6
High-sensitivity troponin T (ng/liter) 0–9 — 28 69
N-terminal pro–B-type natriuretic pep‑ 0–1800 1349 — 5935
tide (pg/ml)
Prothrombin-time international nor‑ 0.9–1.1 — — 3.5
malized ratio
Arterial blood gases — —
pH 7.35–7.45 — — 7.17
Partial pressure of carbon dioxide 35–42 — — 57
(mm Hg)
Partial pressure of oxygen (mm Hg) 80–100 — — 70
Bicarbonate (mmol/liter) 24–30 — — 20
SARS-CoV-2 RNA PCR test of nasopha‑ Negative Negative Negative Negative
ryngeal swab
1944 n engl j med 384;20 nejm.org May 20, 2021

Case Records of the Massachuset ts Gener al Hospital
Table 1. (Continued.)
On Discharge, On Discharge,
9 Wk before 4 Wk before
Reference Range, Current Admission, Current Admission, On Admission,
Variable Adults† This Hospital This Hospital This Hospital
Urine sodium (mmol/liter) — — — 42
Urine creatinine (mg/dl) — — — 65
* To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for creatinine to mi‑
cromoles per liter, multiply by 88.4. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To
convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert the values for lactic acid to milligrams
per deciliter, divide by 0.1110. To convert the values for phosphorus to millimoles per liter, multiply by 0.3229. SARS-CoV-2
denotes severe acute respiratory syndrome coronavirus 2, and PCR polymerase chain reaction.
† 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.
At the time of the current admission, the The blood level of creatinine was 7.66 mg per
patient reported nausea and abdominal cramps. deciliter (677 μmol per liter; reference range,
She reported no fever, chills, cough, dyspnea, 0.60 to 1.50 mg per deciliter [53 to 133 μmol per
dysuria, flank pain, or vomiting. She had no liter]), and the level of lactic acid was 7.4 mmol
known sick contacts. Her medical history in- per liter (67 mg per deciliter; reference range,
cluded hypertension, atrial fibrillation, coronary 0.5 to 2.0 mmol per liter [4.5 to 18 mg per deci-
artery disease, heart failure with reduced ejection liter]). Urinalysis by dipstick showed a pH of 5.0
fraction, type 2 diabetes mellitus, and obstructive (reference range, 5.0 to 9.0) and a specific grav-
sleep apnea, for which nightly treatment with ity of 1.012 (reference range, 1.001 to 1.035), and
continuous positive airway pressure had been no protein, blood, nitrites, leukocyte esterase,
prescribed. Medications included allopurinol, glucose, or ketones were present. Additional labo-
amiodarone, aspirin, atorvastatin, cyclobenzap- ratory test results are shown in Table 1.
rine, enoxaparin, fluticasone, glipizide, loratadine, Chest radiography revealed mild pulmonary
lorazepam, metformin, metolazone, metoprolol, interstitial edema. Ultrasonography of the kidneys
sertraline, spironolactone, torsemide, warfarin, and urinary tract revealed simple cysts in the left
and zolpidem. The last doses of metolazone, kidney, with no evidence of hydronephrosis or
spironolactone, and torsemide were taken more nephrolithiasis.
than 24 hours before admission. There were no Intravenous fluids were administered, and a
known drug allergies. Before the recent humeral diagnosis was made.
fracture, the patient had been living alone in an
urban area of New England; she required assis-
Differ en t i a l Di agnosis
tance from home health services for bathing and
chores and used a walker for ambulation. She did Dr. Oladapo O. Yeku: This 76-year-old woman with
not smoke tobacco or drink alcohol. She had no a history of type 2 diabetes, obstructive sleep
recent history of travel, and her family history apnea, coronary artery disease, and heart failure
was unremarkable. with reduced ejection fraction presents for eval-
On examination, the patient appeared well, uation of nausea, abdominal cramps, and non-
without respiratory distress. The temperature was bloody diarrhea. The first step in developing a
36.7°C, the blood pressure 137/63 mm Hg, the differential diagnosis in this case is to recon-
heart rate 83 beats per minute, the respiratory struct the series of events that may have led to
rate 18 breaths per minute, and the oxygen satu- the patient’s presentation with these symptoms.
ration 99% while she was breathing ambient air.
The weight was 126 kg. The oral mucous mem- Recent Medical Events
branes were dry. The heart sounds were normal, This patient was admitted to the hospital approx
as were the breath sounds throughout both lung imately 3 months before the current admission
fields. There was no edema in the lower legs. for management of congestive heart failure. She
The right arm was in a splint. was discharged home with a diuretic regimen of

Table 2. Differential Diagnosis for Renal Failure.* nal causes, intrinsic renal disease, and postrenal
causes (Table 2). Postrenal causes of kidney in-
Prerenal causes jury are generally less common in women than
Hypovolemia in men for anatomical reasons, and the findings
Congestive heart failure or venous congestion from this patient’s renal ultrasonography ruled
Sepsis out bilateral hydronephrosis and nephrolithiasis.
Use of certain medications (NSAIDs, angiotensin-converting–enzyme On the basis of this framework, we are left to
inhibitors, or angiotensin-receptor blockers) consider whether this patient’s acute renal fail-
Renal artery stenosis ure is due to a prerenal cause or to the develop-
Vascular conditions (vasculitis or dissection)
ment of intrinsic renal disease.
Intrinsic renal disease
Prerenal Causes of Renal Failure
Acute tubular necrosis (caused by ischemia, cisplatin use, amphotericin
use, myoglobinuria, immunoglobulin light chains, or precipitation of
For my initial summary statement, I would de-
crystals in the kidneys) scribe this patient as a 76-year-old woman with
Acute interstitial nephritis (caused by antibiotic use, NSAID use, proton- a history of diabetes and congestive heart failure
pump inhibitor use, pyelonephritis, tuberculosis, sarcoid, lymphoma, who presents for evaluation of nausea, abdominal
or leukemia) cramps, and nonbloody diarrhea and is being
Glomerulonephritis admitted to this hospital with prerenal acute
Cholesterol emboli kidney injury in the context of increased diuretic
Scleroderma use. This framing makes sense on the basis of
her presentation and the finding of an elevated
Vascular conditions (thrombotic thrombocytopenic purpura, hemolytic–
uremic syndrome, or disseminated intravascular coagulation) creatinine level, but nausea, abdominal pain,
Postrenal causes and diarrhea are not consistent with a diuretic-
induced prerenal kidney injury. In addition, the
Neurogenic bladder
ratio of urea nitrogen to creatinine is less than
Use of anticholinergic medications
20, the urine sodium level is greater than 20 mmol
Cancer per liter, and the fractional excretion of sodium
Bilateral nephrolithiasis is greater than 1%. The fractional excretion of
sodium is calculated rather than the fractional
* NSAIDs denotes nonsteroidal antiinflammatory drugs.
excretion of urea, since the patient discontinued
diuretic use more than 24 hours before her pre-
torsemide and spironolactone; her dry weight at sentation. Overall, these findings are inconsis-
that time was 127 kg. Four weeks before the tent with a prerenal cause of acute kidney injury
current admission, she was admitted again, after and are more suggestive of intrinsic renal injury
a fall, at which time her weight was noted to be (Table 2).
approximately 4 kg less than her dry weight; the
blood urea nitrogen level and the results of liver- Intrinsic Renal Disease
function tests were elevated as compared with The causes of intrinsic renal disease can be
those obtained during her previous admission. grouped into the following categories: glomeru-
After discharge, therapy with an additional di- lar diseases, acute tubular necrosis, and acute
uretic, metolazone, was started for the treatment interstitial nephritis. However, this patient’s age,
of leg edema. the time course of renal injury, the normal physi-
With this background in mind, we can now cal examination, and the absence of red cells in
consider the patient’s current presentation of the urine and of eosinophilia are not consistent
nausea and diarrhea in the context of acute renal with glomerular disease or with allergic, autoim-
failure. On admission to the hospital, it is im- mune, infectious, or infiltrative acute interstitial
mediately notable that the blood levels of urea nephritis. Therefore, I would refine my summa-
nitrogen and creatinine are profoundly elevated. ry statement to indicate that this is a 76-year-old
woman with a history of diabetes and conges-
Acute Renal Failure tive heart failure who presents for evaluation of
What is causing this patient’s acute renal failure? nausea, abdominal cramps, and nonbloody diar-
The various causes of renal failure are typically rhea and has been found to have acute tubular
grouped into three diagnostic categories: prere- necrosis in the context of aggressive diuresis.

Reconciliation of Gastrointestinal can reveal the presence of concurrent metabolic

Symptoms and Acute Tubular Necrosis acidosis or alkalosis. This patient’s delta–delta is
Although I believe we are getting closer to the greater than 2 (actual value, 9.3), which suggests
ultimate diagnosis, I am still left to explain this concurrent metabolic alkalosis. The presence of
patient’s gastrointestinal symptoms, which do metabolic alkalosis is probably due to decreased
not fit with the diagnosis of acute tubular necro- renal clearance or to contraction alkalosis result-
sis. In this case, I would assess the gastrointes- ing from diuretic therapy. A review of the labora-
tinal symptoms and acute tubular necrosis sepa- tory test results shows that the bicarbonate level
rately and see whether there are other diagnoses has been gradually increasing, lending weight to
that could fit both. the presence of gradual contraction alkalosis. I
Starting with acute tubular necrosis, my work- would further refine my summary statement to
ing hypothesis is that the acute renal failure is a indicate that this is a 76-year-old woman with a
result of excessive diuretic use. The physical find- history of diabetes and congestive heart failure
ings of dry mucous membranes and the lower who presents for evaluation of nausea, abdomi-
weight measurement that fell below her estab- nal cramps, and nonbloody diarrhea and has been
lished dry weight support overdiuresis. This pa- found to have lactic acidosis and acute tubular
tient may have a suppressed tachycardic response necrosis in the context of overdiuresis.
owing to the use of metoprolol, or her current If my clinical hypothesis of acute tubular ne-
heart rate might be tachycardic as compared crosis and lactic acidosis is correct, then I should
with baseline. Renal infarction could be consid- be able to explain what happened to this patient.
ered, but to have the degree of renal dysfunction For this, I return to her medical history. The
that this patient has, the infarction would prob- timeline of escalating diuretic therapy leading to
ably need to be bilateral, and she does not have prolonged renal hypoperfusion and acute tubu-
any flank pain. Nephrolithiasis, hydronephrosis, lar necrosis makes sense. She was treated with a
and pyelonephritis are also similarly unlikely on cephalosporin — ceftriaxone — which has been
the basis of the physical examination, radio- reported to cause renal injury.1,2 However, ceftri-
graphic findings, and laboratory test results. axone was administered at least 9 weeks before
One aspect of the patient’s presentation that this admission, which makes it an unlikely ex-
has not been reconciled is her acid–base status. planation for the acute kidney injury. If a new
She has metabolic acidosis, and the anion gap is medication was not a contributor, what about
29 mmol per liter — findings that are consistent her previous medications? It is not clear whether
with anion-gap metabolic acidosis. The lactic acid repeat laboratory tests were performed or wheth-
level is markedly elevated, which makes lactic er any adjustments were made to the medications
acidosis the likely cause of the anion-gap meta- that this patient was taking at home while the
bolic acidosis. Winters’ formula is a calculation diuretics were escalated. Do any of her medica-
used to predict the partial pressure of arterial tions require adjustment for changes in renal
carbon dioxide (Paco2) resulting from respira- function or are any associated with a known risk
tory compensation in the context of metabolic of toxic effects that could cause acute tubular
acidosis. On the basis of Winters’ formula necrosis or lactic acidosis? Aspirin, allopurinol,
(Paco2 = 1.5 × [HCO3−] + 8), this patient’s compen- enoxaparin, glipizide, loratadine, and metformin
sated Paco2 should be 41 mm Hg. This is much all meet at least one of these criteria. Of these
lower than the measured Paco2 of 57 mm Hg, medications, metformin stands out immediately
which is consistent with concurrent respiratory as the likely reason for her lactic acidosis
acidosis. Could the concurrent respiratory acido- (Fig. 1). Lactic acidosis due to toxic effects from
sis be due to her chronic carbon dioxide reten- metformin use is a more likely explanation for
tion from obstructive sleep apnea, or could it be the cause of the patient’s nausea, abdominal
a warning of impending hypercapnic respiratory cramps, and diarrhea than the concurrent devel-
failure? opment of viral gastroenteritis. Unlike type A
To determine whether the patient has a mixed lactic acidosis, which is characterized by hypo-
acid–base disorder, we need to determine the perfusion, type B lactic acidosis due to metformin
delta–delta, which is the ratio of the change in use results from increased production of lactic
anion gap to the change in bicarbonate level. acid and inhibition of hepatic gluconeogenesis.3
This delta–delta ([anion gap – 12] ÷ [24 – HCO3−]) The timeline of the patient’s renal dysfunction

Figure 1. Mechanism of Lactic Acidosis Due to Toxic

Effects from Metformin Use.
Metformin can cause lactic acidosis by increasing lactic
Patient History: acid production and decreasing lactic acid clearance.
• History of type 2 diabetes Metformin is eliminated by the kidneys, and when the
• Obstructive sleep apnea creatinine clearance falls below 45 ml per minute per
• Coronary artery disease 1.73 m2 of body‑surface area, the blood metformin level
• Heart failure with reduced
starts to rise. Metformin inhibits the mitochondrial
ejection fraction
metabolism of pyruvate by blocking the conversion of
pyruvate to oxaloacetate. This leads to increased levels
of lactic acid. Lactic acid is cleared by the liver through
gluconeogenesis, but metformin also inhibits this pro‑
cess, which leads to lactic acidosis.
preceding the gastrointestinal symptoms is con-

Reported at Admission:
sistent with the occurrence of toxic effects from
• Nausea metformin use.
• Abdominal cramps I would propose my final summary statement
• Diarrhea
to describe this patient as a 76-year-old woman
with a history of diabetes and congestive heart
failure who presents for evaluation of nausea,
Stomach
abdominal cramps, and nonbloody diarrhea and
has been found to have acute tubular necrosis
in the context of overdiuresis, as well as mixed
Metformin
anion-gap metabolic acidosis driven by lactic
acidosis, which is consistent with toxic effects
from metformin use. Measurement of the metfor-
Metformin uptake
Kidney through small min level in the blood could verify this hypoth-
intestine esis, but this is rarely necessary, and I would not
wait for confirmation of the metformin level to
Skeletal
muscle
initiate treatment.
Metformin is generally thought to be safe and
Glomerular filtration rate ↑ effective for the management of type 2 diabetes.
<45 ml/min/1
ml/min/1.73m
73m2
Mitochondrial oxidative
Although the use of metformin is contraindicated
phosphorylation in patients with an estimated glomerular filtration
↓Metformin excretion
Pyruvate
rate (eGFR) of less than 30 ml per minute per
↑Systemic metformin
1.73 m2 of body-surface area, it is also generally
Oxaloacetate
not recommended in patients with an eGFR be-
tween 30 and 45 ml per minute per 1.73 m2. In
patients currently receiving therapy, the risks and
benefits of continuing therapy need to be evalu-
ated if the eGFR drops below 45 ml per minute
per 1.73 m2. The cautious continued use of met-
Liver
formin in patients who have been receiving ther-
Glucose
↑Lactic apy and have an eGFR between 30 and 60 ml per
acid minute per 1.73 m2 or have other risks has been
advocated in part because the incidence of lactic
acidosis in this population is not substantially
Lactic acidosis greater than the incidence among patients with
type 2 diabetes who have sufficient renal function.4
Furthermore, some reports suggest that the mor-
tality associated with lactic acidosis due to met-

formin use has generally been decreasing over Di agnos t ic Te s t ing

time.5 However, it is important to reconcile these
guidelines with the individual patient, and I would Dr. Sacha N. Uljon: Therapeutic drug monitoring
be reluctant to use metformin in a patient simi- allows clinicians to adjust a dose so that the
lar to this patient, given the risk of sudden chang- plasma drug level remains within a specific thera-
es in creatinine clearance. Ultimately, the differ- peutic window. Such monitoring maximizes the
ence between a drug and a poison is the dose. effectiveness of the drug while reducing the risk
of toxic effects.
The plasma metformin level was measured at
Cl inic a l Impr e ssion
a reference laboratory by means of high-perfor-
Dr. Andrew Z. Fenves: We saw this 76-year-old mance liquid chromatography and mass spec-
woman in consultation for acute kidney injury trometry. The level of detection for the assay is
superimposed on chronic kidney disease (the 0.1 mg per liter. The patient’s plasma metformin
baseline creatinine level was 1.71 mg per deciliter level on hospital day 2 was 16 mg per liter. This
[151 μmol per liter]). The patient had recently re- markedly high metformin level, together with the
ceived aggressive diuresis; given her elevated frac- patient’s lactic acidosis, is consistent with a diag-
tional excretion of sodium (3.8%), we diagnosed nosis of metformin-associated lactic acidosis.
the acute kidney injury as intrinsic acute tubular Although metformin has been in use for more
necrosis. She also had a triple acid–base distur- than half a century, dose–response trials evalu-
bance, which consisted of anion-gap metabolic ating plasma levels of metformin are lacking,
acidosis (anion gap, 29 mmol per liter), respiratory and therefore, a therapeutic range has not been
acidosis (Paco2, 57 mm Hg), and metabolic alka- determined. A literature review in 2016 identi-
losis. The diagnosis of metabolic alkalosis was fied 65 different levels or ranges for “therapeu-
made on the basis of an imbalance between the tic” plasma metformin; the lowest and highest
anion gap, which increased by 19 mmol per liter levels cited were 0 and 1800 mg per liter, respec-
(from 10 mmol per liter), and the bicarbonate tively, with the majority falling between 0.1 and
level, which decreased by only 6 mmol per liter 4 mg per liter.6 Metformin-associated lactic aci-
(from 28 to 22 mmol per liter). We attributed her dosis has been reported in patients who had
metabolic alkalosis to the recent use of diuretics. “therapeutic” metformin levels, although the co-
We were intrigued by the finding of anion- existing conditions that these patients had make
gap metabolic acidosis; this condition was partly it difficult to establish metformin alone as the
due to acute tubular necrosis with accumulation cause of their lactic acidosis.7 The reference labo-
of uremic acids and partly due to lactic acidosis. ratory reports the therapeutic range as being ap-
Because the patient did not have shock or hypo- proximately 1 to 2 mg per liter, with lactic acido-
tension, we concluded that she had type B — sis generally occurring at levels exceeding 5 mg
rather than type A — lactic acidosis. The sus- per liter (unpublished data).
pected cause of this condition was metformin
use, especially given that she also had acute renal
L a bor at or y Di agnosis
failure. We obtained a blood sample for mea-
surement of the metformin level, although we Lactic acidosis associated with metformin use.
fully realized that it would take several days to
obtain the result. Discussion of M a nagemen t
Dr. Fenves: The next key clinical decision we con-
Cl inic a l Di agnosis
sidered was the use of renal replacement therapy.
Lactic acidosis. Taking into account this patient’s acute kidney
injury, there were no compelling reasons to ur-
Dr . Ol a da p o O. Y ek u’s Di agnosis gently initiate renal replacement therapy. On the
other hand, untreated metformin-associated lac-
Toxic effects from metformin use in the context tic acidosis is associated with a 30 to 50% mor-
of acute tubular necrosis from diuretic use. tality rate.8 Metformin is a small molecule with

minimal protein binding and a large volume of cal practice for its effectiveness in glucose con-
distribution8 and hence can be removed by dialy- trol in patients with type 2 diabetes. Its use has
sis. Accordingly, we placed a temporary hemodi- been expanded to patients with an eGFR as low
alysis catheter and proceeded with renal replace- as 30 ml per minute per 1.73 m2. The concern is
ment therapy in this patient. that such patients, similar to this patient, are more
The next step was to determine which method prone to episodes of acute kidney injury, and
of renal replacement therapy to use. We relied on hence further reduction in the eGFR, which may
an earlier publication that advocated hemodialy- result in the accumulation of metformin and the
sis as the first method to use in patients with subsequent development of type B lactic acidosis.
metformin-associated lactic acidosis.9 Metformin
can be readily removed with just a few hours of Fol l ow-up
hemodialysis. However, it is also apparent that it
can be difficult to remove all the metformin with Dr. Medford: After receiving dialysis for 48 hours,
hemodialysis alone, and a reservoir of metfor- the patient had excellent renal recovery. Her hos-
min can appear to be present in red cells, which pital course was complicated by pneumonia and
can result in a large rebound phenomenon after a urinary tract infection; when she became criti-
the discontinuation of hemodialysis. Accordingly, cally ill, her trachea was intubated and she re-
the therapy we used for this patient consisted of ceived mechanical ventilation for a brief period
an initial 4-hour hemodialysis session, followed of time. Her condition improved with antibiotic
by 48 hours of continuous venovenous hemofil- agents; the trachea was extubated soon thereafter,
tration. A repeat metformin level, which was and her dialysis catheter was removed. The medi-
measured 48 hours after renal replacement ther cations that she had previously been taking at
apy was initiated, was 0.18 mg per liter. home were eventually restarted, with the excep-
Although hemodialysis is the preferred therapy tion of metformin, which was permanently dis-
for the elimination of metformin in patients with continued. She was safely discharged to a reha-
severe type B lactic acidosis, this treatment may bilitation center for continued care.
not be possible in patients who have hemody-
namic instability. In these situations, one can use
Fina l Di agnosis
other forms of renal replacement therapy that
have a lesser hemodynamic effect, such as con- Lactic acidosis due to toxic effects from metfor-
tinuous venovenous hemofiltration or continuous min use.
venovenous hemodialysis.8 Although such meth- This case was presented at the Medicine Case Conference.
ods result in a slower removal of the metformin, No potential conflict of interest relevant to this article was
reported.
they may still be lifesaving. Disclosure forms provided by the authors are available with
Metformin continues to be widely used in clini- the full text of this article at NEJM.org.
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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

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Case 15-2021: A 76-Year-Old Woman with

n engl j med 384;20 nejm.org May 20, 2021 1943

Table 1. Laboratory Data.*

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Reconciliation of Gastrointestinal can reveal the presence of concurrent metabolic

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Figure 1. Mechanism of Lactic Acidosis Due to Toxic

preceding the gastrointestinal symptoms is con-

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formin use has generally been decreasing over Di agnos t ic Te s t ing

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The New England Journal of Medicine

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