Clinical Practice: Original Paper
Nephron
The Use of Low-Calcium Hemodialysis in
the Treatment of Hypercalcemic Crisis
Sinan Trabulus a Meric Oruc b Emre Ozgun c Mehmet Riza Altiparmak a
Nurhan Seyahi a  
a Department
of Nephrology, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey; b Department of
Nephrology, Kilis Public Hospital, Kilis, Turkey; c Department of Internal Medicine, Istanbul University, Cerrahpasa
Medical Faculty, Istanbul, Turkey
Keywords
Acute kidney injury · Hypercalcemia · Hypercalcemic crisis ·
Low-calcium hemodialysis · Parathyroid hormone
Abstract
Background: We reviewed the results of low-calcium hemo-
dialysis (LCHD; 1.25 mmol/L) in the treatment of 42 cases ad-
mitting with hypercalcemic crisis. Methods: All patients
(≥18 years) who started LCHD due to hypercalcemia be-
tween 2002 and 2017 were retrospectively analyzed. Bio-
chemical data were obtained at the beginning of the first
hemodialysis and at the end of the last hemodialysis.
­“Refractory” cases were defined as patients having albu-
min corrected serum total calcium (SCatotal) levels above
10.2 mg/dL despite of all medical, surgical, and hemodialysis
treatments. Results: By acceptance of 3 cases admitted
© 2018 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/nef
Received: January 30, 2018
Accepted after revision: March 15, 2018
DOI: 10.1159/000488502 Published online: April 19, 2018
 
again over 6 months as new cases, a total of 42 cases (male,
57.1%) with a mean age of 55.9 ± 14.8 years underwent ur-
gent hemodialysis. Most of the patients (82.1%) had malig-
nancies. The mean SCatotal level at the beginning of hemodi-
alysis sessions was 15.89 ± 2.53 mg/dL. The mean decline of
SCatotal level was 4.63 ± 2.72 mg/dL. Refractory cases re-
ceived hemodialysis after admission significantly later than
improved cases (48 [interquartile ranges (IQR) 24–168] vs. 24
[IQR 12–48] h, p = 0.010). Serum creatinine and SCatotal levels
at the last visit were significantly more in refractory cases
than improved cases (1.92 [IQR 0.81–3.41] vs. 1.30 [IQR 0.8–
1.7] mg/dL, p = 0.031 and 12.43 ± 2.53 vs. 8.86 ± 0.67 mg/dL,
p = 0.000 respectively). Mortality was significantly higher in
refractory cases than improved cases (58.8 vs. 10.5%, p =
0.002). Overall mortality rate was 33.3%. Conclusion: Hyper-
calcemic crisis is a life-threatening condition and should be
managed immediately. © 2018 S. Karger AG, Basel
129.125.19.61 - 4/23/2018 5:26:48 AM
Dr. Sinan Trabulus
Department of Nephrology
Istanbul University, Cerrahpasa Medical Faculty
University of Groningen
TR–34098 Istanbul (Turkey)
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E-Mail sinantrabulus @ gmail.com
 Introduction
Hypercalcemic crisis has no uniform definition;
­owever, a reasonable definition may be as follows:
h were also recorded. The following laboratory data at admission –
an ­albumin-corrected serum total calcium level (SCatotal)
>14 mg/dL, associated with the presence of multi-organ
dysfunction. In severely symptomatic patients despite
less marked hypercalcemia, the diagnosis of hypercalce-
mic crisis should also be considered [1]. Primary hyper-
parathyroidism and malignancy are the 2 most com-
mon causes, together accounting for about 90% of all cas-
es [2, 3].
Rapidly decreasing SCatotal level is crucial in the treat-
ment of hypercalcemia presented with symptoms such
as oliguria, cardiac arrhythmia, or coma. The acute mor-
tality from hypercalcemia associated with acute organ
dysfunction is 15–20% [4]. First-line treatment of hy-
percalcemia includes intravenous (IV) hydration, furo-
semide, bisphosphonates, and calcitonin [3, 5–7]. More-
over, cinacalcet, denosumab, gallium nitrate, and pred-
nisone were the other options especially in patients with
cancer [8].
Therefore, in patients with severe hypercalcemia and
associated mental status alterations, renal failure, cardiac
failure, and cardiac arrhythmia dialysis should be strong-
ly considered [9–13]. Several investigators have reported
the use of peritoneal dialysis [14–21] and hemodialysis
with a low-calcium dialysate [10–12, 22–26] or a calci-
um-free dialysate [5, 12, 13, 18, 27–32] or a standard cal-
cium dialysate [17, 33, 34]. However, there is no consen-
sus on the guideline of hemodialysis in hypercalcemia.
Different institutions have used different components of
dialysate calcium and different duration ranging from 1
to 8 h. Moreover, some chose continuous venovenous
hemodiafiltration (CVVHDF) because of rebound of hy-
percalcemia and hemodynamic instability of patients
[23, 25, 35–37].
In our study, we reviewed the results of low-calcium
hemodialysis (LCHD) in the treatment of 42 patients ad-
mitting with hypercalcemic crisis.
Patients and Methods
Between January 2002 and September 2017, all patients who
started LCHD following a diagnosis of hypercalcemia were retro-
spectively analyzed. Patients older than 18 years were enrolled to
the study. Patients who admitted with clinical symptoms related to
hypercalcemia over 6 months were evaluated as new cases.
The following data at admission, follow-up, and at the last vis-
it were obtained from medical records. The clinical findings at ad-
2 Nephron
DOI: 10.1159/000488502
mission were age, gender, symptoms, primary disease related to
hypercalcemia, comorbid diseases, axillary body temperature,
pulse rate, systolic blood pressure (sBP), and diastolic blood pres-
sure (dBP), and urinary output. Extracellular dehydration findings
complete blood cell counts, serum values of urea, creatinine, so-
dium, potassium, total calcium, phosphorus, albumin, intact para-
thyroid hormone, and blood gas parameters – were recorded. The
highest value of SCatotal determined in the period between admis-
sion to the hospital and start of hemodialysis was also recorded.
Medical therapy for lowering calcium levels based on isotonic
saline hydration, calcitonin, bisphosphonates, glucocorticoids,
and drugs targeting primary disease was done according to the di-
agnosis and clinical status of the patients and the decision of the
physicians following hypercalcemic patients in their departments.
The patients with refractory hypercalcemia despite optimal
medical therapies and/or with underlying cardiorenal diseases
cannot be hydrated and/or with advanced underlying kidney dis-
ease received urgent hemodialysis. Hemodialysis was performed
using Dialog+ (B. Braun Medical Inc., Germany), Century 2RX
(Cobe Laboratories, USA), Fresenius 2008C, 4008B, 4008S (Frese-
nius Medical Care, Germany) and Gambro AK 96 Bio Version
(Gambro, Sweden) dialysis machines. All of the patients under-
went hemodialysis using standard low-flux dialysis membranes
(Hemophan, Kawasumi, Japan; Toraysulfone, Toray, Japan; Elisio,
Nipromed, Japan; Fresenius Polysulfone, Fresenius Medical Care,
Germany; Polyflux, Gambro, Sweden; Rexeed, Asahi Kasei Medi-
cal Co., Japan). The dialysate contained the following ion concen-
trations: Na 140 mmol/L, K 2 mmol/L, Ca 1.25 mmol/L, Mg
0.5  mmol/L, HCO3 32 mmol/L (Diasol, Baxter; Ren Acet, Ren-
Med; Diasol, Farmasol; Dersol, Deren; Bikardi, Renal, Turkey).
Potassium concentration of the dialysate was increased to
3 mmol/L to maintain potassium level in the normal range in the
patients with hypopotassemia (<4 mEq/L) at the beginning of the
hemodialysis session. Blood flow rates ranged between 250 and
300 mL/min. The dialysate flow rate was constant at 500 mL/min
for each patient. Ultrafiltration was programmed according to pa-
tient’s volume status. The duration of hemodialysis sessions varied
from 1 to 4 h according to tolerance or sufficient fall of serum cal-
cium.
The mean values of pre/post dialysis sBPs and dBPs, ultrafiltra-
tion volumes, urea reduction rates of all hemodialysis sessions
were recorded. However, the single-pool Kt/V values could only
be calculated in patients who can be weighed after hemodialysis.
Biochemical data available for all patients included the serum val-
ues of urea, creatinine, sodium, potassium, albumin, and total cal-
cium from blood samples obtained at the beginning of the first
hemodialysis and at the end of the last hemodialysis.
Moreover, the time from admission to the first hemodialysis
session, interval between the first hemodialysis session and second
hemodialysis session, the number of hemodialysis sessions, dura-
tion of a single hemodialysis session, interval between hemodialy-
sis sessions and total time of all hemodialysis sessions were also
recorded. Adverse events that occurred during the hemodialysis
sessions were also recorded. Therefore, the repeated doses of he-
modialysis treatments were continued unless the patient’s serum
calcium levels reached <10.2 mg/dL and/or death and/or discharge
and/or referral to intensive care unit, whichever came first.
All medications and operations during follow-up were collect-
ed from medical records. Serum values of urea, creatinine, elec-
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University of Groningen
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trolytes, albumin, and total calcium and phosphorus were record-
ed at the last visit. The patients’ current status was also confirmed
by a telephone call at the end of the study. As 3 patients who were
admitted again with clinical symptoms related to hypercalcemia
over 6 months were evaluated as new cases; clinical/renal outcome
and causes of mortality were evaluated and recorded for 39 pa-
tients.
Definitions
The diagnosis of hypercalcemia was confirmed according to
our laboratory using a range of SCatotal levels of 8.5–10.2 mg/dL.
SCatotal was adjusted using the following equation: corrected
­calcium, mg/dL = 0.8 × (normal albumin – patient’s albumin) +
­SCatotal. Hypercalcemia was divided into mild with SCatotal lev-
els  <12 mg/dL, moderate with SCatotal levels between 12 and
14 mg/dL, and severe with SCatotal levels above 14 mg/dL [8].
The estimated glomerular filtration rate was calculated using
the CKD-EPI (Chronic Kidney Disease Epidemiology Collabora-
tion) formula [38]. Acute kidney injury (AKI) was diagnosed as an
increase in serum creatinine (SCr) by ≥0.3 mg/dL within 48 h, or
an increase in SCr to ≥1.5 times baseline, which is known or pre-
sumed to have occurred within the prior 7 days, or decrease in
urine volume <0.5 mL/kg/h for 6 h [39].
Extracellular dehydration was defined as decreased skin turgor,
history of vomiting, documented polyuria (>200 mL/h), and sBP
≤100 mm Hg associated with heart rate ≥100 beats/min. The diag-
nosis of extracellular dehydration was based on the existence of at
least 2 clinical criteria mentioned above [29].
Cardiovascular side effects of hemodialysis were defined as
the occurrence of intradialytic hypotension or cardiac arrhyth-
mia. Mean arterial pressure (MAP) was calculated using the fol-
lowing equation: MAP (mm Hg) = dBP + 1/3 (sBP – dBP). In-
tradialytic hypotension was defined as the presence of a decrease
in sBP ≥20 mm Hg or a decrease in MAP by 10 mm Hg, provid-
ing the decrease in BP is associated with clinical events and need
for nursing interventions [40]. Patients with transient intradia-
lytic hypotension needed moderate fluid loading but patients
with persistent intradialytic hypotension we stopped hemodialy-
sis.
The following are the adverse events: hypocalcemia was de-
fined as SCatotal level <8.5 mg/dL, hypophosphatemia was defined
as serum phosphorus level <2.2 mg/dL, and hypopotassemia was
defined as serum potassium level <3 mEq/L at least after one he-
modialysis session.
The decline of SCatotal during hemodialysis was defined by the
difference between SCatotal levels at the beginning of first hemo-
dialysis and at the end of last hemodialysis performed irrespec-
tive of the duration and number of hemodialysis sessions.
­“Refractory” cases were defined as patients having SCatotal levels
above 10.2 mg/dL despite of all medical, surgical, therapies and
hemodialysis treatments until death or discharge from the hos-
pital or referral to intensive care unit. The others were defined as
“improved” cases.
Statistical Analysis
Data normality was analyzed with the Kolmogorov-Smirnov
test. With normal distributions, continuous variables are present-
ed as the means ± SDs, and those with non-normal distributions,
continuous variables are presented as the median and interquartile
ranges (IQRs). Categorical variables are presented as percentages.
Low-Calcium Hemodialysis in the
Treatment of Hypercalcemic Crisis
Comparisons between groups were performed with the chi-square
test for categorical variables, the t test for normally distributed,
continuous variables and the Mann-Whitney U test for non-nor-
mally distributed, continuous variables. The SPSS version of 22.0
for Windows software (SPSS Inc., Chicago, IL, USA) was used for
analyses. Two tailed p value <0.05 was considered statistically sig-
nificant.
Results
By acceptance of 3 cases admitted again with clinical
symptoms related to hypercalcemia over 6 months as new
cases, a total of 42 patients (male, 57.1%) with a mean age
of 55.9 ± 14.8 years underwent urgent hemodialysis. The
preexisting conditions were as follows: hypertension in
15 patients (35.7%), chronic renal failure in 14 patients
(33.3%), diabetes mellitus in 7 patients (16.7%), coronary
heart disease in 2 patients (4.8%), and history of cardiac
pacemaker in 2 patients (4.8%).
Nonspecific symptoms such as fever, fatigue, weight
loss were present in over 50% cases. Gastrointestinal
symptoms, including nausea, vomiting and abdominal
pain, were present in 21 patients (50%). Neurological
symptoms, including confusion, speech impairment, dis-
orientation, and lethargy were present in 12 patients
(28.6%). Fifteen patients (35.7%) had clinical evidence of
extra-cellular dehydration based on the existence of at
least 2 clinical criteria at admission: decreased skin turgor
in 20 patients (47.6%), history of profuse vomiting in
17 patients (40.5%), documented polyuria (>200 mL/h)
in 5 patients (11.9%), and sBP ≤100 mm Hg associated
with heart rate ≥100 beats/min in 3 patients (7.1%). At
admission, electrocardiography traces showed cardiac ar-
rhythmia defined as sinus tachycardia, sinus bradycardia,
ventricular trigeminy, atrial fibrillation and atrial flutter
in 6, 2, 1, 1, and 1 patients respectively.
The diagnoses associated with hypercalcemia were he-
matologic malignancies (multiple myeloma n = 11, acute
lymphocytic leukemia n = 1, Waldenstrom macroglobu-
linemia n = 1, acute myeloid leukemia n = 1, chronic my-
eloid leukemia n = 1, solitary plasmacytoma n = 1), solid
tumors with or without bone metastases (n = 14), para-
thyroid gland-related diseases (parathyroid adenoma n =
2, parathyroid carcinoma n = 2), sarcoidosis (n = 1), and
active vitamin D intoxication (n = 1). In 1 patient, para-
thyroid adenoma and solid tumor were associated with
ileocecal region; in another patient, multiple myeloma
and prostate carcinoma were seen in a combined form. In
1 patient, no etiologic diagnosis was detected during fol-
low-up.
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DOI: 10.1159/000488502
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 Table 1. Demographic, clinical, and laboratory characteristics of patients at admission

Variables Patients (n = 42)

Demographic and clinical findings

Age, years 55.9±14.8
Gender, male, % 57.1
Axillary body temperature, C 36.5±0.6
Pulse rate per minute 92.7±18.8
Systolic/diastolic blood pressure, mm Hg 129.3±19.3/77.6±12.2
Dehydration, % 35.7
Decreased skin turgor 47.6
History of vomiting 40.5
Polyuriaa 11.9
Systolic blood pressure <100 mm Hgb 7.1
Biochemical measurements
Hemoglobin, g/dLc 9.8±2.3
Hematocrit, %c 28.9±6.9
Leukocytes, ×1,000 cell/μLc 10.4±6.4
Urea, mg/dL 112.6±69.6
Creatinine, mg/dL 2.45 (1.21–4.82)
eGFR, mL/min/1.73 m2 24.6 (9.3–49.1)
Sodium, mEq/L 135.4±4.5
Potassium, mEq/L 4.3±1.0
SCatotal, mg/dL 16.19±2.96
Phosphorus, mg/dLd 4.16±1.92
Albumin, g/dL 3.28±0.70
iPTH, pg/mLe 16.6 (8.5–207.4)
pHf 7.43 (7.39–7.46)
Bicarbonate, mmol/Lf 22.15±4.42
pCO2, mm Hgf 32.15±7.15

Values are shown as mean ± SD, median (IQR) or frequency (%) as appropriate.
a Urinary output >200 mL/h; in 2 patients urine outputs were not recorded.
b
 Associated with heart rate >100 beats/min.
c Complete blood count parameters were not evaluated in 2 patients.
d Serum phosphorus was not evaluated in 7 patients.
e Serum iPTH was not evaluated in 12 patients.
f Blood gas parameters were not evaluated in 8 patients.

eGFR, estimated glomerular filtration rate; SCatotal, albumin corrected serum total calcium; iPTH, intact pa-
rathyroid hormone.

The SCatotal values at admission ranged from 11.70 to
27.20 mg/dL (mean 16.19 ± 2.96 mg/dL). Thirty-two pa-
tients (76.2%) were admitted with severe, 8 patients
(19.1%) were admitted with moderate, and 2 patients
(4.7%) were admitted with mild hypercalcemia. Most of
the patients (81%) admitted with AKI and 13 patients
(30.9%) had advanced renal dysfunction with an esti-
mated glomerular filtration rate lower than 15 mL/
min/1.73 m2. Demographic, clinical, and laboratory
characteristics of patients at admission are shown in Ta-
ble 1.
The median hospitalization time was 23 (IQR 13.5–
43.5) days. All of the patients received IV hydration
with isotonic saline according to volume status. The use
of furosemide was reserved for patients who develop
signs of fluid overload. Most of the patients (83.3%)
were treated with steroids (methylprednisolone, 20–
80 mg/day or dexamethasone, 20–40 mg/day). Twenty-
four (57.1%) patients received bisphosphonate therapy
including mostly zoledronic acid (doses ranged be-
tween 2 and 8 mg) and pamidronate (in 4 patients, dos-
es ranged between 30 and 90 mg); doses were set ac-
cording to patients’ renal dysfunction. Twenty patients
(47.6%) used IV, intranasal, or subcutaneous calcitonin
with doses ranging from 200 to 400 IU. Medical treat-
ments of hypercalcemia were continued during hemo-
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 Table 2. Hemodialysis treatment characteristics of patients

Characteristics Patients (n = 42)

Time to onset of HD, h 24 (17–96)

Interval between the first HD session and second HD session, ha 20 (18–25)
Number of HD sessions 4 (2–6.25)
Duration of a single HD session, h 3.1 (2.9–3.5)
Total time of all HD sessions, h 13 (6–21)
Pre- and post-dialysis sBP, mm Hg 127.7±18.6/120.8±17.2
Pre-and post-dialysis dBP, mm Hg 76.4±10.4/73.5±8.7
Pre- and post-dialysis MAP, mm Hg 93.4±12.6/89.2±10.9
Pre- and post-dialysis urea, mg/dLb 88 (46.3–164.3)/49.5 (31.5–70)
Pre- and post-dialysis creatinine, mg/dLb 2.57 (1.43–4.59)/1.33 (0.86–2.13)
Pre- and post-dialysis sodium, mEq/Lb 136.5±5.4/138.9±4.4
Pre- and post-dialysis potassium, mEq/Lb 4.15±1.06/3.3±0.6
Pre- and post-dialysis SCatotal, mg/dLb 15.89±2.53/11.26±1.92
Mean decline in SCatotal, mg/dLc 4.67±2.72
Urea reduction rate, % 41.9 (16.8–70.7)
Kt/Vd 1.13±0.29
UF volume, mL 75 (0–531.3)

Values are shown as mean ± SD, median (IQR) or frequency (%) as appropriate.
a For 37 patients who received more than one hemodialysis session.
b
 Biochemical data available for all patients included the serum values for urea, creatinine, sodium, potassium,
albumin and calcium from blood samples obtained at the beginning of the first hemodialysis and at the end of
the last hemodialysis.
c Decline of SCa
total during hemodialysis was defined by the difference between the calcium levels at the be-
ginning of first hemodialysis and at the end of last performed hemodialysis irrespective of the duration and num-
bers of hemodialysis.
d Measured in 19 patients.

HD, hemodialysis; sBP, systolic blood pressure; dBP, diastolic blood pressure; MAP, mean arterial pressure;
SCatotal, albumin corrected serum total calcium; UF, ultrafiltration.

dialysis treatments. In 2 patients with parathyroid can-
cer, cinacalcet therapy (60–90 mg/day) was used in the
management of hypercalcemia. Patients with solid or
hematologic malignancies were consulted with a hema-
tologist or oncologist with regard to the cancer-targeted
treatment options. Five patients received parathyroid-
ectomy surgeries.
The mean level of highest SCatotal was 16.76 ± 2.48 mg/
dL. The mean SCatotal level at the beginning of all hemo-
dialysis sessions was 15.89 ± 2.53 mg/dL. Five patients
received a single hemodialysis session, 10 patients re-
ceived 2 sessions and the remaining patients received
more sessions (≥3 and ≤5 for 14 patients, ≥6 and ≤9 for
6 patients, ≥10 and ≤12 for 6 patients, 30 sessions for 1
patient). The median time between admission and the
first hemodialysis was 24 h (IQR 17–96). For 25 patients,
the interval between the first and second hemodialysis
sessions was <24 h. The median number of hemodialysis
sessions during follow-up was 4 (IQR 2–6.25). The me-
dian total time of all hemodialysis sessions was 13 h (IQR
6–21). The mean SCatotal level at the end of all hemodi-
alysis sessions, regardless of the number and durations
of the hemodialysis, was 11.26 ± 0.92 mg/dL. The mean
decline of SCatotal level was 4.63 ± 2.72 mg/dL. Hemodi-
alysis treatment characteristics of patients are shown in
Table 2.
Adverse effects of hemodialysis were evaluated in 217
sessions performed in 42 patients. Intradialytic hypoten-
sion episodes occurred in 47 sessions (21.6%) performed
in 20 patients (47.6%). Thirty-seven of 47 episodes
(78.7%) were transient. In 1 patient with cardiac pace-
maker, cardiopulmonary arrest related to cardiac ar-
rhythmia occurred during hemodialysis as a result of per-
sistent hypotension, and the patient died. The mean
­SCatotal decline was not significantly different in the pa-
tients who experienced hypotension at least in one ses-
sion than in those who did not (5.07 ± 3.03 vs. 4.24 ±
2.42 mg/dL, p = 0.332). Bleeding complications related to
hemodialysis catheter, gastrointestinal system, and nose/
throat were detected in 3 patients, in 1 patient, and in
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Low-Calcium Hemodialysis in the Nephron 5

Treatment of Hypercalcemic Crisis DOI: 10.1159/000488502
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Table 3. Clinical variables comparing “improved” and “refractory” cases

Variables Improved (n = 23) Refractory (n = 19) p value

Age, years 55.6±17.3 56.2±11.7 ns

Gender, male, % 43.5 42.1 ns
Malignancy, % 91.3 78.9 ns
Neurological symptoms, % 21.7 36.8 ns
Gastrointestinal symptoms, % 43.5 57.9 ns
Creatinineadmission, mg/dL 2.40 (1.75–4.8) 2.60 (1.04–4.90) ns
eGFRadmission, mL/min/1.73 m2 24.4 (12.2–40.9) 24.8 (8.6–63.5) ns
AKI, % 86.9 73.7 ns
SCatotal (admission), mg/dL 15.93±2.60 16.51±3.38 ns
SCatotal (highest), mg/dL 16.60±2.53 17.62±3.35 ns
SCa total (pre-dialysis), mg/dL 15.50±2.18 16.60±2.88 ns
Time to onset of HD, h 24 (12–48) 48 (24–168) 0.010
Number of HD sessions 3 (2–5) 5 (2–10) ns
Total HD duration, h 8 (6–16) 16 (6–39) ns
Mean decline in calcium, mg/dLa 4.73±2.23 4.52±3.28 ns
Hospitalization time, day 30 (15–52) 20 (12–25) ns
Creatinine last visit, mg/dL 1.30 (0.80–1.70) 1.92 (0.81–3.41) 0.031
eGFR last visit, mL/min/1.73 m2 59 (33.6–90.5) 40.8 (14.3–73.1) ns
SCatotal (last visit), mg/dL 8.86±0.67 12.43±2.53 0.000
Mortality, %b 10.5 58.8 0.002

Values are shown as mean ± SD, median (IQR) or frequency (%) as appropriate.
a Declineof SCa
total during hemodialysis was defined by the difference between the calcium levels at the beginning of first hemodia-
lysis and at the end of last performed hemodialysis irrespective of the duration and number of hemodialysis.
b
 Three cases were lost to follow-up and 3 patients who admitted again with clinical symptoms related to hypercalcemia over 6 mon-
ths were evaluated as new cases, so mortality was analyzed for 36 patients.
eGFR, estimated glomerular filtration rate; SCatotal, albumin corrected serum total calcium; HD, hemodialysis; AKI, acute kidney
injury; ns, not significant.

1 patient respectively. Only 1 patient had convulsion dur-
ing the first hemodialysis session. Hypopotassemia, hy-
pocalcemia, and hypophosphatemia were present in 21
(50%), 8 (19%), and 6 (14.3%) patients respectively.
Clinical variables comparing “improved” and “refrac-
tory” cases are shown in Table 3. Nineteen patients
(45.2%) were found to be refractory cases. Refractory cas-
es received hemodialysis after admission to emergency
department significantly later than improved cases (48
[IQR 24–168] vs. 24 [IQR 12–48] h, p = 0.010). SCr and
SCatotal levels at the last visit were significantly more in
refractory cases than improved cases (1.92 [IQR 0.81–
3.41] vs. 1.30 [IQR 0.8–1.7] mg/dL, p = 0.031 and 12.43 ±
2.53 vs. 8.86 ± 0.67 mg/dL, p = 0.000 respectively). Mor-
tality was significantly higher in refractory cases than that
in improved cases (58.8 vs. 10.5%, p = 0.002). There were
no significant differences in the other clinical variables
between 2 groups.
Among 39 patients, 3 were lost to follow-up. Of the
remaining 36 patients with complete follow-up data,
there were 12 deaths (33.3%) after a median interval of
22 (IQR 11.3–43.5) days following hospital admission.
The causes of deaths were mostly unknown. As men-
tioned before, 1 patient died during hemodialysis be-
cause of cardiac arrhythmia. The other causes were pul-
monary hemorrhage in 1 patient, right pulmonary ar-
tery embolism in 1 patient, and pneumonia and
intracranial hemorrhage in 1 patient. Of the remaining
patients, 3 patients progressed to end-stage renal dis-
ease, and chronic hemodialysis treatments were sched-
uled for them.
Clinical variables comparing patients who survived
and patients who died are shown in Table 4. Time to onset
of hemodialysis after admission was tended to be longer
in patients who died than patients who survived (46 [IQR
24–168] vs. 24 [IQR 12.8–84] h, p = 0.084). The mean lev-
el of SCatotal level at the last visit was significantly more in
patients who died than that in patients who survived
(12.39 ± 3.10 vs. 9.64 ± 1.70 mg/dL, p = 0.012). There were
no significant differences in the other clinical variables.
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Table 4. Clinical variables comparing patients who survived and patients who died

Variables Patients who survived (n = 24) Patients who died (n = 12) p value

Age, years 57.7±16.9 55.6±10.9 ns

Gender, male, % 51.9 33.3 ns
Malignancy, % 85.2 83.3 ns
Creatinineadmission, mg/dL 2.45 (1.75–5.71) 2.35 (1.01–3.65) ns
eGFRadmission, mL/min/1.73 m2 21.9 (9.2–39.1) 30.3 (19.7–70.5) ns
AKI, % 85.2 66.7 ns
SCatotal (admission), mg/dL 16.22±3.23 16.77±2.66 ns
SCatotal (highest), mg/dL 16.75±3.13 18.18±2.56 ns
SCatotal (pre-dialysis), mg/dL 15.31±1.78 17.48±2.76 ns
Time to onset of HD, h 24 (12.8–84) 46 (24–168) ns
Number of HD sessions 3.5 (2–5.75) 5.0 (2–7) ns
Total HD duration, h 11 (6–17) 16.5 (6–23.3) ns
Pre-dialysis MAP, mm Hg 95.9±11.8 87.7±14.7 ns
Post-dialysis MAP, mm Hg 91.5±9.5 84.4±14.4 ns
Mean decline in SCatotal, mg/dLa 4.51±2.16 5.05±3.85 ns
Creatinine last visit, mg/dL 1.40 (0.87–2.25) 1.81 (0.80–1.66) ns
eGFR last visit, mL/min/1.73 m2 45.6 (28.4–73.9) 42.8 (20.8–93.7) ns
SCatotal (last visit), mg/dL 9.64±1.70 12.39±3.10 0.012

Values are shown as mean ± SD, median (IQR) or frequency (%) as appropriate.
a
 Decline of SCatotal during hemodialysis was defined by the difference between the calcium levels at the beginning of first hemodia-
lysis and at the end of last performed hemodialysis irrespective of the duration and number of hemodialysis.
eGFR, estimated glomerular filtration rate; SCatotal, albumin corrected serum total calcium; HD, hemodialysis; MAP, mean arterial
pressure; AKI, acute kidney injury; ns, not significant.

Discussion > 16 mg/dL and life-threatening complications such as

We have presented our 15-year experience with 42
clinical cases admitted with hypercalcemic crisis and re-
ceiving LCHD, and to our knowledge, this is the largest
case series to date. In Table 5, reported case reports and
series are shown. The patients were generally male and
had a similar average age at presentation similar to that
of other series [13, 29, 31]. Symptoms related to hyper-
calcemia consist of gastrointestinal disorders [8, 41],
somnolence or coma [8, 29, 42], progressive azotemia,
and electrocardiographic changes with the risk of cardiac
arrhythmia [1, 8, 10, 29]. Renal manifestations of hyper-
calcemia consist of nephrogenic diabetes insipidus, renal
vasoconstriction, distal renal tubular acidosis, and in
more chronic cases, nephrolithiasis, tubular dysfunction,
and chronic renal failure [1, 8]. AKI was detected in most
of the patients probably related to prerenal azotemia be-
cause of gastrointestinal disorder or dehydration, hema-
tologic malignancies especially multiple myeloma and
drugs.
Interestingly in contrast to other reports [1, 3, 5],
­Guimard et al. [43] reported a recent study about asso-
ciation between severe hypercalcemia defined as SCatotal
cardiac arrhythmia and coma with a median stay of 7 h
32 min in the emergency department. Thirty-one of
126,204 adult patients admitted to the emergency depart-
ment had severe hypercalcemia (0.025%) and they found
no significant relation between severe hypercalcemia and
life-threatening complications.
Moreover, the etiology of hypercalcemia in our cohort
was mostly related to solid or hematologic malignancies
similarly to other series [13, 29, 43]. Several major mech-
anisms are responsible for hypercalcemia of malignancy,
including parathyroid hormone-related protein mediat-
ed humoral hypercalcemia, osteolytic metastases-related
hypercalcemia, 1,25-dihydroxyvitamin D mediated hy-
percalcemia, and PTH-mediated hypercalcemia [1, 8].
The medical treatment options for hypercalcemia in-
clude IV hydration, calcitonin, bisphosphonates, deno-
sumab, gallium nitrate, prednisone, and cinacalcet.
Among the currently available bisphosphonates for the
treatment of malignancy-associated hypercalcemia (pami-
dronate, zoledronic acid, ibandronate, clodronate, and
etidronate), IV zoledronic acid or pamidronate is mostly
preferable. However, the limiting factor of bisphospho-
nate usage is the renal failure especially with glomerular
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Low-Calcium Hemodialysis in the Nephron 7

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 8
Table 5. Reported cases of hemodialysis in patients admitting with hypercalcemia

Reference Age, Gender Diagnosis SCrpre-dialysis, SCatotal (pre-dialysis), Hemodialysis All medical/ Improved/ Outcome
number, years mg/dL mg/dL surgical refractoryb
publication time to number duration dialysate drop in SCa interventionsa
year onset of HD of of HD calcium for each
sessions sessions session,
mg/dL

[27], 1963 47 M Retroperitoneal NR 20 23rd day 2 6, 6 h Calcium-free 4.6/6.4 GC Improved Death

sarcoma (200 mg/day)
[10], 1968 68 M Parathyroid (Approx) 6 16.7 36th h 1 8 1/2 h Low-calcium 4.79 None except Improved Alive

Nephron
adenoma (0.25 mmol/L) saline and
furosemide/PTX
[28], 1970 60 F Parathyroid NR 16.4 NR 1 (Approx) Calcium-free 9.4 NR/PTX Improved NR
adenoma 5h
[17], 1971 62 M Multiple NR 14.8 2nd day 1 8h 2 mmol/L 4 EDTA disodyum, Improved Death

DOI: 10.1159/000488502
myeloma calcium GC (NR),
Melphalan
[18], 1973 36 M Parathyroid NR 26.8 NR 2 8 h, NR Calcium-free 8.8/NRc None except Refractory Death
adenoma saline and
furosemide
[34], 1973 52 F Parathyroid NR 21.8 NR 1 3h 1.5 mmol/L No drop GC (NR), Refractory Death
adenoma calcium NaHZ PO4
peroral
[11], 1976 49 M Parathyroid 7.2 21 16th h 2 5, 3 h Low-calcium 7.2/3.8 None except Improved Alive
adenoma (NR) saline and
and thiazide furosemide/PTX
medication
[12], 1979 63 F Multiple 17.5 16.4 3rd day 1 3 1/2 h Calcium-free 7.1 GC (60 mg/day IV), Improved Death
myeloma Melphalan,
Mithramycin
(15 µg/kg IV)
[12], 1979 69 M Vitamin D 7.8 14.2 5th day 1 3 1/2 h Low-calcium 3.9 GC (NR) Improved Alive
intoxication (0.5 mmol/L)
[31], 1989 54 F Breast NR 15.2 4th day 1 3h Calcium-free 5.96 GC (200 mg/day Improved Death
cancer IV), Calcitonin
(300 IU/day IV),
Mithramycin
(25 µg/kg
IV 2 pulses)
[31], 1989 82 M Immobilization 4 14.12 4th day 1 3h Calcium-free 4.64 GC (200 mg/day Improved Alive
and thiazide IV ), Calcitonin
medication (300 IU/day IV)
[31], 1989 74 M Hepatic NR 17.84 3rd day 2 3, 3 h Calcium-free 5.36/NRc GC (200 mg/day Refractory Death
cirrhosis with IV), Calcitonin
hepatomas (300 IU/day IV),
Mithramycin
(25 µg/kg IV
2 pulses)/PTX

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 Table 5. (continued)

Reference Age, Gender Diagnosis SCrpre-dialysis, SCatotal (pre-dialysis), Hemodialysis All medical/ Improved/ Outcome
number, years mg/dL mg/dL surgical refractoryb
publication time to number duration dialysate drop in SCa interventionsa
year onset of HD of of HD calcium for each
sessions sessions session,
mg/dL

[31], 1989 74 M Hepatocellular NR 16.76 2nd day 2 3, 3 h Calcium-free 4.44/3.12 GC Improved Death
carcinoma (200 mg/day IV),
calcitonin
(300 IU/day IV)
[31], 1989 75 F Parathyroid NR 15.2 3rd day 1 3h Calcium-free 2.68 GC Improved Alive

Low-Calcium Hemodialysis in the

Treatment of Hypercalcemic Crisis
adenoma (200 mg/day IV),
calcitonin
(300 IU/day IV),
mithramycin
(25 mcg/kg IV)/
PTX
[22], 1991 31 F Excessive ingestion 1.9 20.2 10th h 1 3 1/2 h Low-calcium 7.3 Mg sulphate (2 g Improved Alive
of calcium (NR) IV), phosphorus
carbonate antacid (2.4 g/day p.o.),
during pregnancy calcitonin
(4 IU/kg/day IM),
GC (40 mg IV
2 pulses)
[13], 1996 64 F Lung cancer NRd 13 NR 1 2h Calcium-free 2.88 None except saline Improved NRe
and furosemide
[13], 1996 65 F Multiple NRd 11.72 NR 1 3h Calcium-free 2.6 None except saline Improved NRe
myeloma and furosemide

Nephron
[13], 1996 58 M Multiple NRd 10.2 NR 1 3h Calcium-free 3.28 None except saline Improved NRe
myeloma and furosemide
[13], 1996 55 M Lung cancer NRd 12.32 NR 1 3h Calcium-free 3.52 None except saline Improved NRe
and furosemide

DOI: 10.1159/000488502
[13], 1996 42 M Renal cell NRd 11.32 NR 3 2, 2 1/2, 3 h Calcium-free 1.52/2.8/3.68 None except saline Improved NRe
carcinoma and furosemide
[13], 1996 60 M Multiple NRd 11.52 NR 1 2 h 50 min Calcium-free 1.72 None except saline Improved NRe
myeloma and furosemide
[29], 1996 58±14 33 Multiple 2.33±1.76 16.44±1.92 NR 51 1–5 h Calcium-free 6.84±2.16 NR NR NR
patients diagnosisf (for 39
(48.5%, M) sessions)
[33], 1997 73 F Parathyroid 2.1 14.4 3rd day 1 4h 1.5 mmol/L 2.8 Pamidronate Improved Alive
adenoma calcium (90 mg IV),
(phosphorus calcitonin
enriched) (8 IU/kg/day SC)/
PTX
[23], 1998g 72 M Multiple 3.39 16 At admission 6 NR Low-calcium NR GC (NR), Improved Alive
myeloma (1.25 mmol/L) calcitonin (NR),
VAD chemotherapy

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 10
Table 5. (continued)

Reference Age, Gender Diagnosis SCrpre-dialysis, SCatotal (pre-dialysis), Hemodialysis All medical/ Improved/ Outcome
number, years mg/dL mg/dL surgical refractoryb
publication time to number duration dialysate drop in SCa interventionsa
year onset of HD of of HD calcium for each
sessions sessions session,
mg/dL

[5], 2001h 42 F Parathyroid NR 23.6 6th h 2 NR Calcium-free NR Clodronate Refractory Death

adenoma (300 mg IV 2 times),
GC (100 mg/day IV),
calcitonin

Nephron
(400 IU/day SC)
[30], 2009 63 M MALT 0.9 16.52 4th h 1 2h Calcium free 5.92 Pamidronate Improved Alive
lymphoma (90 mg IV)
[24], 2011 38 M Multiple 9.8 15 At admission 2 NR Low-calcium NR Calcitonin (NR) Refractory Death
myeloma (NR)

DOI: 10.1159/000488502
[25], 2012i 58 M Parathyroid 3.43 21.2 28th h 1 4h Low-calcium NR Pamidronate (90 mg Improved Alive
adenoma (NR) IV), calcitonin
(5 IU/kg/day SC),
cinacalcet
(30 mg/day)/PTX
[7], 2014 27 F Parathyroid NR 16 4 th day 2 4 h, NR Low calcium 5.6/6.16 Zoledronic acid Improved Alive
carcinoma (1 mmol/L) (4 mg IV),
calcitonin
(400 IU/day SC),
pamidronate
(90 mg IV)/PTX
[32], 2014 23 M Rhabdomyolysis NR 17.1 NR 1 NR Calcium free 7.8 Calcitonin (NR), Improved NR
pamidronate (NR)
[26], 2014 70 M Parathyroid 7.5 21.4 NR NR NR Low calcium NR GC (NR), Improved Alive
adenoma (NR) bisphosphonates
(NR)/PTX
Our study 55.9±14.8 42 patients Multiple 2.45 15.89±2.53 24 (17–96) h 217 3.1 (2.9–3.5) Low calcium 4.67±2.72 GC (83.3%), Improved Death
(57.1%, M) diagnosisj (1.21–4.82) (1.25 mmol/L) bisphosphonate (54.8%) (33.3%)
(57.1%), calcitonin
(47.6%), cinacalcet
(in 2 patients)/PTX
(in 5 patients)

a In cases with reported therapies, all patients had saline infusion and forced diuresis with furosemide.
b “Refractory” cases were defined as patients having SCatotal above 10.2 mg/dL despite of all medical, surgical therapies and hemodialysis treatments until death or discharge from the hospital or referral to in-
tensive care unit. The others were defined as “improved” cases.
c Cardiac arrest occurred during hemodialysis.
d Mean peak creatinine was reported as 6.10±3.09 mg/dL.
e Four of the patients died within 8 weeks.
f The diagnoses were hyperparathyroidism (24.2%), hematologic malignancy (27.3%), solid tumor (39.4%) and sarcoidosis (6.1%). One patient had no etiologic diagnosis.
g Patient had 10 days continuous renal replacement therapy (CRRT) after 6 consecutive daily HD.
h Patient had 1 day CRRT after 2 times HD.
i Patient had CRRT continued for a total of 40 h.
j The diagnoses were mostly hematologic malignancy and solid tumor (80.9%). One patient had no etiologic diagnosis.

EDTA, ethylenediaminetetraacetic acid; F, female; GC, glucocorticoids; M, male; MALT, mucosa-associated lymphoid tissue lymphoma; NR, not reported; PTX, parathyroidectomy; SCatotal, albumin corrected
serum total calcium; SCr, serum creatinine; VAD, vincristine, adriamycin and dexamethasone.

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filtration rate < 30 mL/min and/or SCr > 4.5 mg/dL [8].
Denosumab, a human monoclonal antibody to receptor
activator nuclear factor-kappa B ligand inhibits the matu-
ration, activation, and function of osteoclasts. It can be
given subcutaneously 120 mg on days 1, 8, 15, and 29 and
then every 4 weeks. It has an advantage over bisphospho-
nates in that it is not removed by the kidneys and could be
given to those with a creatinine clearance of less than 30
mL/min [3]. Since 2012, there have been numerous case
reports reporting the effectiveness of denosumab in pa-
tients with cancer-associated hypercalcemia in tumors in-
cluding multiple myeloma, renal cell carcinoma, ovarian
cancer, and parathyroid carcinoma. So based on these re-
ports in 2014, denosumab was approved by the Food and
Drug Administration for the treatment of hypercalcemia
refractory to bisphosphonates therapy [44].
Hemodialysis is an optional treatment for refractory
hypercalcemia. The diffusion of calcium during hemodi-
alysis depends on the calcium gradient between the serum
concentration and the dialysate concentration [45]. The
maximum calcium elimination capacity of hemodialysis
reaches 17 mmol calcium per hour, an eightfold higher
rate than that of forced saline diuresis (2 mmol calcium
per hour) and a fivefold higher rate than the maximum of
peritoneal dialysis [12]. Although the use of calcium di-
alysate less than 1.25 mmol/L has been found to have a
potential of negative calcium balance [45], in some reports
the use of low-calcium dialysate < 1 mmol/L, and even
normal-calcium dialysate of 1.5 mmol/L seem to be equal-
ly effective [11, 12, 33]. However, the effect of hemodialy-
sis on calcium removal is usually transient and so we need-
ed LCHD within 24 h for 25 patients (59.5%). Camus et al.
[29] needed 2 or more hemodialysis sessions within 24 h
for 14 patients (42.4%). Rapid resolution of hypercalcemia
and calcium stability showed the advantage of CVVHDF
over LCHD in some case reports [8, 23, 25, 35, 36].
Intradialytic hypotension was the most limiting ad-
verse effect of hemodialysis. As it is reported, a direct va-
soconstrictor effect of calcium has been shown [29], and
increasing the calcium concentration of the dialysate may
protect against intradialytic hypotension [46]. A rapid
decline in calcium level induced by a calcium-free dialy-
sate could result in a fall in blood pressure [30, 47, 48].
However, we did not find any significant difference be-
tween mean decline of SCatotal levels of patients with and
without intradialytic hypotension, similar to the results of
the case series reported by Camus et al. [29]. Despite rap-
id reductions of serum calcium concentrations, we only
observed life-threatening cardiac arrhythmia in 1 patient
during hemodialysis sessions similar to that of other case
Low-Calcium Hemodialysis in the
Treatment of Hypercalcemic Crisis
series [29, 31]. Also, starting hemodialysis without ade-
quate restoration of volume status can lead to hemody-
namic instability with hypotensive episodes [7, 13]. How-
ever, it must be specified that CVVHDF has been associ-
ated with improved hemodynamic instability especially
in critically ill patients with multiple organ failures [36].
Hypocalcemia, hypokalemia, and hypophosphatemia
were the other important adverse effects that can lead to
cardiac events. Some chose to lower the patient’s SCatotal
value more gradually by using a standard dialysis solution
calcium concentration to avoid precipitating cardiac dys-
function [17, 33, 34]. However, even with calcium-free
dialysates, no adverse effects were reported in some re-
ports [13]. Hypokalemia is also common after hemodi-
alysis, as some patients have normal or only slight renal
impairment. Due to the phosphaturic effect of hyperpara-
thyroidism, patients are usually hypophosphatemic at
presentation. This can be worsened after dialysis. Some
suggest the use of phosphorus-enriched dialysate [33, 49],
while others have used IV phosphorus for the correction
of hypophosphatemia [50].
The mortality rate according to this study was 33.3%,
all of them except one occurred in 2 months after hospital
admission. Of the remaining 36 patients, with 21 patients
(58.3%) presenting with SCatotal >16 mg/dL, the mortality
rate was found as 38.1%, whereas the mortality rate was
found to be 55% in a study reported by Guimard et al. [43].
Controlling SCatotal levels under 10.2 mg/dL was an im-
portant predictor for mortality according to our study.
It was also shown in our study that early hemodialysis
after admission was important for controlling SCatotal lev-
els under 10.2 mg/dL at the last visit. It was an interesting
finding. However, additional studies, preferably with
more cases, are necessary to validate this conclusion.
Our report has relevant limitations. First, data were
collected retrospectively. Second, even though it is ion-
ized calcium that is physiologically active, ionized calci-
um levels were not recorded. We used albumin-adjusted
calcium; however, albumin adjustment has been criti-
cized and considered by some to be inaccurate especially
in patients with complex diseases or in acute settings [51].
Also, possible variations of protein and albumin during
and after hemodialysis may introduce minimal errors in
the interpretation of the results [29]. Most of the studies
had showed calcium removal ranging between 27 and
680  mg/h for each session [10–12, 28, 34] or drop in
­SCatotal levels (the difference between pre and post-hemo-
dialysis) ranging between 0 and 9.4 mg/dL [10, 11, 13, 33].
However, in our study, we did not obtain pre-dialysis and
post-dialysis SCatotal levels for each session, so we could
129.125.19.61 - 4/23/2018 5:26:48 AM
Nephron 11
DOI: 10.1159/000488502
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not calculate our calcium removal or drop in SCatotal lev-
els for each hemodialysis session.
In conclusion, hypercalcemic crisis is a life-threaten-
ing condition and should be managed immediately.
LCHD is an important optional and effective treatment.
However, in patients with hypercalcemia, not only re-
moval of calcium by hemodialysis was sufficient but also
early adjunctive therapy should be given to limit calcium
rebound and to obtain a lasting effect.
Acknowledgments
None.
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Ethics Statement
Ethics Committee approval from Istanbul University Cerrah-
pasa Medical Faculty was obtained (approval number:
83045809/2017). The study was in adherence with the Helsinki
Declaration of 1975 (as revised in 1983).
Disclosure Statement
The authors have no conflicts of interest to declare.
Funding Source
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