Quiz

Hypercalcemia, Acute Kidney Injury, and Esophageal

Lymphadenopathy
Samardia Missick and Nabeel Aslam

Clinical Presentation have a serum calcium level of 13.3 mg/dL, serum

albumin level of 3.8 g/dL, and serum creatinine level
A 56-year-old woman presented to the emergency
of 2.7 mg/dL, which was increased from 1.4 mg/dL
department with nausea and vomiting. She had
1 month prior.
experienced similar episodes once a month for at
Medical history was significant for a left nephrec-
least 10 years. She also reported new onset of
tomy to treat xanthogranulomatous pyelonephritis. That
epigastric pain. On presentation, she was found to
surgery also required partial pancreatectomy, splenec-
Table 1. Initial Laboratory Data on Presentation
tomy, and adrenalectomy. Other medical history
included hypothyroidism, gastroesophageal reflux dis-
Reference ease, esophageal ulcers, and mood disorder. Prescribed
Parameter Value Range
medications were duloxetine and thyroid replacement
Sodium, mEq/L 128 135-145
therapy.
Potassium, mEq/L 3.4 3.6-5.2
On examination, notable findings were heart rate of
Bicarbonate, mEq/L 39 22-26
112 beats/min, blood pressure of 127/86 mm Hg,
Anion gap, mEq/L 13 9-15
mild confusion, and tenderness of the epigastric
Calcium, mg/dL 13.3 8.9-10.1
region.
Phosphorus, mg/dL 4.9 2.5-4.5
Albumin, g/dL 3.8 3.5-5.0
Laboratory data on admission are presented in
Creatinine, mg/dL 2.7 0.6-1.1
Table 1. Urinalysis showed specific gravity of 1.005, pH
SUN, mg/dL 41 6-21 7.0, and trace leukocyte esterase, without protein or
Hemoglobin, g/dL 10.1 12-15.5 blood. Microscopic examination showed 2 white blood
PTH, pg/mL 16 15-65 cells, less than 1 red blood cell, and a few hyaline casts
PTHrP, pmol/L 0.4 <2.0 and squamous epithelial cells per high-power field.
1,25-dihydroxyvitamin D, pg/mL 8.9 18-78 Noncontrast computed tomography of the abdomen
25-hydroxyvitamin D, ng/mL 34 20-50 and pelvis was notable for esophageal wall thickening
Thyroid-stimulating hormone, mIU/L 0.64 0.3-4.2 with prominent adjacent lymph nodes. There was no
κ free light chains, mg/dL 3.72 3.3-19.4 hydronephrosis.
λ free light chains, mg/dL 3.06 5.7-26.3
Monoclonal protein by urine ND • What is the differential diagnosis of this
immunofixation patient’s hypercalcemia?
Monoclonal protein by serum ND
immunofixation
• How would you have managed this patient?
Note: Conversion factors for units: serum creatinine in mg/dL to μmol/L, ×88.4;
SUN in mg/dL to mmol/L, ×0.357; calcium in mg/dL to mmol/L, ×0.2495;
phosphorus in mg/dL to mmol/L, ×0.3229. • Is there a role for bisphosphonates or
Abbreviations: ND, none detected; PTH, parathyroid hormone; PTHrP, PTH-
related peptide; SUN, serum urea nitrogen. denosumab in this case?

hypercalcemia causes an appropriately suppressed PTH

Discussion
level by means of feedback mechanisms. However,
QUIZ

What is the differential diagnosis of this
patient’s hypercalcemia?
The most likely cause of hypercalcemia of this severity
with a suppressed parathyroid hormone (PTH) level is a
malignancy. Computed tomographic findings of
esophageal thickening with lymphadenopathy sug-
gested a solid-organ malignancy. These malignancies
often secrete parathyroid-related peptide (PTHrP),
which can increase serum calcium level by stimulating
PTH receptors, resulting in bone resorption and
distal tubular calcium reabsorption.1 The resultant
PTHrP was measured and found to be in the reference
range.
Other malignancies, such as lymphoma, or a
granulomatous disease can cause elevated PTHrP or
1,25-dihydroxyvitamin D levels. For example, granu-
lomatous diseases can lead to increased conversion of
25-hydroxyvitamin D to 1,25-dihydroxyvitamin D
due to 1-hydroxlase produced by macrophages, which
results in increased calcium absorption from the gut.2
Finally, hypercalcemia in the presence of reduced
kidney function and anemia raises a concern for

Am J Kidney Dis. 2018;72(1):xiii-xv xiii


multiple myeloma, but the lack of paraprotein or
elevated light chains in plasma makes that diagnosis
very unlikely.
Other considerations, such as hyperthyroidism and
vitamin D toxicity, were ruled out with normal
thyroid-stimulating hormone and vitamin D levels,
respectively.
Another often-overlooked cause of hypercalcemia
is calcium-alkali syndrome. On further review of the
patient’s history, it was determined that she had been
taking an excessive amount of over-the-counter cal-
cium carbonate tablets, nearly 20 per day. Her initial
workup was notable for significant metabolic alka-
losis that was initially attributed to her vomiting.
However, when her over-the-counter medication
history became known, calcium-alkali syndrome was
suspected.
Milk-alkali syndrome, now referred to as calcium-
alkali syndrome, was first described as early as the
1920s and later recognized as a triad of hypercalcemia,
metabolic alkalosis, and decreased kidney function.3 It
was most prevalent before the advent of newer antacid
medications such as H2 blockers and proton pump in-
hibitors and occurred in the setting of ingestion of large
quantities of medications such as calcium carbonate or
milk intake for treatment of peptic ulcer disease
symptoms.3 Milk-alkali syndrome is a diagnosis of
exclusion based on the history and laboratory workup
of other causes.
How would you have managed this patient?
During the admission, the patient underwent an upper
endoscopy with endoscopic ultrasound and biopsy of
the lower esophagus, which revealed marked acute
and chronic inflammation with only benign squamous
mucosa. There was no malignancy. She was managed
with intravenous fluids, along with cessation of cal-
cium carbonate intake. This resulted in complete res-
olution of hypercalcemia; on discharge, she had a
serum calcium level of 8.7 mg/dL, serum albumin
level of 3.7 g/dL, and serum creatinine level of
1.1 mg/dL.
Is there a role for bisphosphonates or
denosumab in this patient?
QUIZ
Bisphosphonates and denosumab are indicated for hy-
percalcemia of malignancy. Bisphosphonates inhibit
osteoclast activity on bone resorption, resulting in
lowering of serum calcium concentration. Their use in
the management of hypercalcemia of malignancy has
been proven to be effective.2 However, there is concern
for renal toxicity, and dosing adjustments are advised in
the setting of reduced kidney function based on creati-
nine clearance or estimated glomerular filtration rate. Of
the bisphosphonates, zoledronic acid has been shown to
be superior to pamidronate in reducing serum calcium
levels and without a significant difference in adverse
xiv
Quiz
renal outcomes.4 Bisphosphonates are not generally
advised with creatinine clearance < 30 mL/min.
Denosumab is a monoclonal antibody that can
decrease serum calcium levels by inhibition of bone
resorption through binding to RANKL (receptor acti-
vator of nuclear factor-κB ligand) and inhibiting its
activity. RANKL is secreted by osteoblasts to activate
osteoclast precursors that ultimately engage in
osteolysis,2 which is thus reduced. Even in the presence
of severely decreased kidney function, denosumab is
effective in lowering serum calcium levels.5 In this
patient, neither bisphosphonates nor denosumab were
believed to be clinically indicated based on the
workup and high clinical suspicion for calcium-alkali
syndrome.
Follow-up blood work 1 month later showed
creatinine level of 0.9 mg/dL, calcium level of 9.9 mg/
dL, and albumin level of 3.9 g/dL.
Final diagnosis
Calcium-alkali syndrome.
Article Information
Authors’ Full Names and Academic Degrees: Samardia
Missick, MD, and Nabeel Aslam, MD.
Authors’ Affiliations: Division of Nephrology and Hypertension
(SM, NA), Mayo Clinic, Jacksonville, FL.
Address for Correspondence: Samardia Missick, MD, Division
of Nephrology and Hypertension, Mayo Clinic, 4500 San Pablo
Rd, Jacksonville, Fl 32224. E-mail: missick.samardia@mayo.edu
Support: None.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
Peer Review: Received January 26, 2018. Direct editorial input
from the Education Editor and a Deputy Editor. Accepted in
revised form April 5, 2018.
Publication Information: © 2018 by the National Kidney Foun-
dation, Inc. doi: 10.1053/j.ajkd.2018.04.002
References
1. Mundy GR, Edwards JR. PTH-related peptide (PTHrP)
in hypercalcemia. J Am Soc Nephrol. 2008;19(4):
672-675.
2. Rosner MH, Dalkin AC. Onco-nephrology: the patho-
physiology and treatment of malignancy-associated
hypercalcemia. Clin J Am Soc Nephrol. 2012;7(10):
1722-1729.
3. Patel AM, Adeseun GA, Goldfarb S. Calcium-alkali
syndrome in the modern era. Nutrients. 2013;5(12):
4880-4893.
4. Major P, Lortholary A, Hon J, et al. Zoledronic acid is su-
perior to pamidronate in the treatment of hypercalcemia of
malignancy: a pooled analysis of two randomized, controlled
clinical trials. J Clin Oncol. 2001;19(2):558-567.
5. Hu MI, et al. Denosumab for treatment of hypercalcemia
of malignancy. J Clin Endocrinol Metab. 2014;99(9):
3144-3152.
Am J Kidney Dis. 2018;72(1):xiii-xv
Quiz

FELLOWSHIP PROGRAM HIGHLIGHT

Note from editors: To recognize fellowship programs’ educational mission, AJKD is using its popular Quiz feature to highlight Nephrology
Fellowship programs when an author is a Nephrology Fellow. To participate, Fellowship Program Directors mentor fellows in submitting
prospective Quizzes; those that are selected for publication include a brief description of the fellowship program from the Director. For
“Hypercalcemia, Acute Kidney Injury, and Esophageal Lymphadenopathy,” the corresponding author is Samardia Missick, a Nephrology &
Hypertension Fellow at Mayo Clinic Florida.
Program: Nephrology Fellowship Program, Mayo Clinic Florida (http://www.mayo.edu/mayo-clinic-school-
of-graduate-medical-education/residencies-fellowships/internal-medicine-and-subspecialties/nephrology-
fellowship-florida)
Program Director: Nabeel Aslam, MD
Program Description from Dr Aslam: The 2-year Nephrology Fellowship at Mayo Clinic’s campus in Jack-
sonville, FL, provides exceptional nephrology training in all aspects of clinical nephrology practice, research, and
education. Each fellow’s training can be customized to meet individual career goals. Fellows work closely with
highly experienced and knowledgeable clinical and research faculty. Mayo Clinic’s favorable faculty ratio, large
patient population, and state-of-the-art diagnostic, therapeutic, and research facilities combine to create a truly
integrated educational experience. The Mayo Clinic approach to graduate medical education ensures that fellows
have the finest teaching and the broadest patient care experience possible during a busy, hands-on fellowship.

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Am J Kidney Dis. 2018;72(1):xiii-xv xv