128 2011 Societ Italiana di Nefrologia - ISSN 1121-8428

JN ( 2011; : 01) 128-131 24 EPHROL

DOI:10.5301/JN.2010.5794
INTRODUCTION
Rhabdomyolysis is a clinical syndrome caused by severe
muscle damage with consequent release of the breakdown
products from injured muscle cells that leads to acute renal
failure (ARF) and several electrolyte disorders. Hypocalce-
mia and hyperphosphatemia are frequent in the early stages
of rhabdomyolysis, while a sudden hypercalcemia may oc-
cur in about one third of cases in the polyuric stage after kid-
ney function recovery (1-4). This acute hypercalcemia may
become life-threatening when the total plasma calcium rises
over 14 mg/dL. Metabolic coma, shortening of P-Q interval
or abnormal ST-segment elevation, mimicking the Brugada
syndrome, are the most commonly reported causes of sud-
den death in this setting (5-9).
The pathogenesis of the biphasic plasma calcium prole
in rhabdomyolysis-induced ARF remains debatable. In the
early 1980s, it was attributed to the alternative down- and
up-regulation of parathyroid hormone (PTH) and vitamin D
metabolites (10). Nowadays, however, the most likely hy-
pothesis is an extensive calcium deposition in the damaged
muscles during oliguria followed by a massive muscle cal-
cium release during renal function recovery.
We report a case of an oliguric ARF patient in whom ARF
was a consequence of severe rhabdomyolysis. In the oligu-
ric phase, high levels of PTH and hypocalcemia were de-
tected, whereas in the polyuric phase, during the kidney
function recovery, a sudden hypercalcemia occurred. In
this phase, PTH, 1,25(OH)
2
vitamin D
3
and 25(OH) vitamin D
were at subnormal level, and electrocardiogram showed the
abnormalities described above.
This case emphasizes the importance of serial plasma cal-
ABSTRACT
Background: In a third of patients presenting with
rhabdomyolysis-induced acute renal failure (ARF), a
biphasic plasma calcium prole may occur.
Methods: We report a case of rhabdomyolysis-in-
duced ARF presenting hypocalcemia during oliguria,
followed by a severe hypercalcemia in the polyuric
phase. A hypocalcemia-induced acute increase of
plasma parathyroid hormone in the early stage of ARF
was followed by a down-regulation of parathyroid hor-
mone, 1,25(OH)
2
vitamin D and 25(OH) vitamin D during
the renal function recovery, associated with an acute
hypercalcemia. The plasma calcium increase induced
in our patient severe neurological disturbances, life-
threatening short QT interval and Brugada-like syn-
drome at risk of malignant arrhythmias. This compli-
cation was treated by hemodialysis and pamidronic
acid infusion.
Results: This case conrms that the pathogenesis of
the biphasic calcium prole may be related to the mas-
sive calcium uptake in the ischemic muscle cells dur-
ing oliguria, followed by a muscle calcium release later
in the polyuric stage of ARF. Therefore, the behavior of
calciotropic hormones may be the consequence rath-
er than the cause of plasma calcium changes.
Conclusions: We would like to emphasize the danger
of sudden death that may occur in the recovery phase
of rhabdomyolysis-induced ARF when the physician
might be wrongly convinced that the major risks have
disappeared.
Key words: Acute renal failure, Calciotropic hormones,
Hypercalcemia, Rhabdomyolysis
1
Nephrology and Dialysis Unit, Istituto Clinico Humanitas
IRCCS, Rozzano-Milan - Italy
2
Biochemical and Clinical Laboratory, Istituto Clinico
Humanitas IRCCS, Rozzano-Milan - Italy Nephrology and Dialysis Unit, Istituto Clinico Humanitas IRCCS, Rozzano-Milan - Italy Nephrology and Dialysis Unit, Istituto Clinico Humanitas IRCCS, Rozzano-Milan - Italy Biochemical and Clinical Laboratory, Istituto Clinico Humanitas IRCCS, Rozzano-Milan Italy
Giorgio Graziani
1
, Albania Calvetta
1
,
David Cucchiari
1
, Serenella Valaperta
2
,
Alessandro Montanelli
2
Life-threatening hypercalcemia in patients
with rhabdomyolysis-induced oliguric acute
renal failure
CASE REPORT
129 2011 Societ Italiana di Nefrologia - ISSN 1121-8428
JN ( 2011; : 01) 128-131 24 EPHROL
cium monitoring in the polyuric phase of rhabdomyolysis-in-
duced ARF when the patient seems to recover and hemo-
dialysis is then stopped to avoid the risk of life-threatening
arrhythmias.
Moreover, we provide further evidence that the PTHvitamin
D axis does not play a central role in the pathogenesis of the
calcemia biphasic prole in these patients.
CASE REPORT
A 61-year-old man living alone was found unconscious ly-
ing on the oor where he had been for about 8-9 hours.
The patient was transported to the emergency room where
he regained consciousness. On admission, he could not re-
member what had happened at home, but reported that he
was taking hypoglycemic agents as he was suffering from
diabetes type 2. He complained of malaise, muscular weak-
ness, nausea and anorexia. Arterial pressure was 160/100
mm Hg, heart rate 80 beats/min without arrhythmias, O
2

saturation was 88% and plasma glucose was found to be
288 mg/dL. Plasma troponin was 1.73 ng/mL at admission,
rising to a maximum value of 2.99 ng/mL in the following
hours, with an electrocardiogram showing an inferoposte-
rior myocardial infarction. The patient never complained of
thoracic pain. General physical examination showed gener-
Fig. 1 - A) Plasma urea and creatinine. B) Diuresis and plasma
creatine phosphokinase (CPK) (left y-axis is log-scaled).
alized muscular tenderness with a symmetrical weakness
in all limbs and a mild rate of dyspnea without evidence of
severe pulmonary stasis. No fever was evident.
Other relevant laboratory investigations showed erythro-
cyte count 4,530,000/L, white cells 14,000/L, platelets
350,000/L, creatine phosphokinase (CPK) 28,848 IU/L
(normal values 40-180 IU/L in men), which increased in
the next few days to over 65,000 U/L, C-reactive protein
(CRP) 17.5 mg/dL, B-type natriuretic peptide (BNP) 296
pg/mL, creatinine 4.95 mg/dL, urea 106 mg/dL, sodium
142 mmol/L, potassium 3.2 mmol/L, ionized calcium 1.01
mmol/L (normal values 1.14-1.29 mmol/L), total plasma
calcium 7.8 mg/dL and transaminases: AST 324 U/L rising
to 897 U/L and ALT 68 U/L, rising to 146 U/L.
Plasma PTH level was over 700 pg/mL in the oliguric phase
when hypocalcemia was found. Gas analysis showed pH
7.33, pO
2
63 mm Hg, pCO
2
39 mm Hg, bicarbonates 20.9
mmol/L and base excess -4 mmol/L.
The patient was oliguric from the day of admission, and the
few urinary samples revealed a heavy myoglobinuria. He de-
veloped anuria over the next few days and was submitted to
several hemodialysis sessions (Fig. 1).
Fifteen days after admission, the diuresis re-started and a
sudden increase of total plasma calcium appeared, reach-
ing a potentially lethal level of over 14 mg/dL. The clinical
picture was one of nausea, vomiting, severe muscle hypos-
thenia with shortening of the QT interval (0.27 sec) and an
ST-segment elevation found at electrocardiogram. Despite
polyuria, this severe hypercalcemia, with electrocardio-
graphic signs of dangerous arrhythmias, forced us to imme-
diately perform 2 further hemodialysis sessions and admin-
ister a pamidronic acid (60 mg) infusion, resulting in a drop
in plasma calcium levels below 12 mg/dL.
The patient denied any intake of vitamin D. In the search
for possible causes of hypercalcemia, a chest computed to-
mography was performed (the patient was a heavy smoker),
but no sign of malignancy or sarcoidosis was found. Serum
electrophoresis showed a slight monoclonal gammopathy
IgG K, but urinary immunoelectrophoresis did not demon-
strate a Bence Jones proteinuria, therefore micromolecular
myeloma was excluded. The thyroid and parathyroid ultra-
sonography did not show any nodular imaging. PSA plasma
level was within the normal range. The plasma level of PTH
was 19 pg/mL, at the lower limit of the normal range, while
the vitamin D metabolites were all below the normal range:
1,25(OH)
2
vitamin D 14.8 pg/mL and 25(OH) vitamin D 4.04
ng/mL (Fig. 2).
Over the next few days, the biochemical results progressive-
ly improved, no other hemodialysis sessions were needed,
and the patient was transferred to the rehabilitation unit.
A
B
130 2011 Societ Italiana di Nefrologia - ISSN 1121-8428
Graziani et al: Rhabdomyolysis acute renal failure
DISCUSSION
Rhabdomyolysis is a severe damage to the muscle induced
by traumatic or nontraumatic factors. The increased capil-
lary permeability causes edema that can worsen the muscle
cell ischemia, leading to necrosis of muscular tissue. This
event often requires an urgent surgical fasciotomy. Muscular
edema may induce third-spacing leading to hypovolemia,
sympathetic activation and systemic vasoconstriction.
Another consequence of rhabdomyolysis is a massive re-
lease of myoglobin into the circulation. A great amount of
this protein, freely ltered at the glomerular level, ows
into the distal portion of the nephron, where it is concen-
trated and precipitates, interacting with Tamm-Horsfall
protein. This causes formation of casts and tubular ob-
struction. Thus, at least 3 mechanisms lead to ARF: (i) hy-
povolemia and intrarenal vasoconstriction, (ii) intraluminal
precipitation of casts and (iii) direct heme protein-induced
cytotoxicity (11, 12).
In our patient, the prolonged muscular compression
A
B
P
L
A
S
M
A

c
a
l
c
i
u
m
Fig. 2 - A) Parathyroid hormone (PTH) and vitamin D (VitD)
metabolites (y-axis is log-scaled). B) Plasma calcium and
phosphate levels.
due to coma explains the massive microvascular isch-
emia followed by rhabdomyolysis and severe ARF. In the
oliguric phase, when the patient was submitted to he-
modialysis treatment, a high plasma phosphate with low
ionized calcium concentration was associated with very
high PTH plasma levels. When diuresis was restored, the
calcium-phosphate picture showed a complete change
with a sudden appearance of a life-threatening hypercal-
cemia associated with down-regulation of calciotropic
hormones. Total plasma calcium level acutely reached
14 mg/dL, which is associated with high risk of sudden
death due to severe brain and heart involvement.
In this setting, coma may occur, and the abnormal shorten-
ing of QT-interval with ST-segment elevation in V1 and V2,
mimicking the Brugada syndrome, make patients suscep-
tible to malignant arrhythmias (7-9).
In the oliguric phase of ARF, defective 1-alpha hydroxylase
activity may induce a calcitriol down-regulation, explain-
ing both the severe hypocalcemia and high plasma PTH
levels. Another stimulus to PTH synthesis during oliguria
could be the high hyperphosphatemia due to phosphate
release from ischemic muscle cells and to mineral reten-
tion induced by ARF. Furthermore, the high plasma phos-
phate level may enhance the hypocalcemia by inducing
bone resistance to PTH (13).
Although these events may be relevant in the rst stage of
ARF, it is unlikely that the hyperparathyroidism is respon-
sible for the life-threatening hypercalcemia in the polyuric
phase. In fact the hypercalcemia persisted in spite of the
rapid decline of PTH levels.
There is now growing evidence that in the rst stage of rhab-
domyolysis-induced ARF, calcium entrapment in disrupted
muscle cells occurs, explaining the hypocalcemia. This event
is followed by a subsequent release of massive amounts of
calcium when muscular and tubular lesions improve.
Muscle necrosis is triggered by ischemia-induced defective
oxidative metabolism leading to severe ATP depletion, which
induces an abnormal mineral uptake across the damaged
sarcolemma. ATP depletion causes dysfunction of the Ca
++
-
ATPase pumps, resulting in impaired Ca
++
efux out of the
sarcolemma (with the Na
+
/Ca
++
exchange) and in an altered
storage of the mineral into mitochondria and sarcoplasmic
reticulum where it is normally stored (11, 12, 14, 15).
In fact, Randall et al demonstrated in these patients a mas-
sive calcium deposition in the vascular wall of muscles and
skin arterioles, resembling a calciphylaxis (16).
Furthermore, serial technetium-99m pyrophosphate scans
showed the calcium intake in the hypocalcemic stage fol-
lowed by a progressive calcium release from the areas of
muscle breakdown during the hypercalcemic stage (14).
131 2011 Societ Italiana di Nefrologia - ISSN 1121-8428
JN ( 2011; : 01) 128-131 24 EPHROL
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Received: April 30, 2010
Revised: June 04, 2010
Accepted: June 30, 2010
CONCLUSIONS
The biphasic prole of plasma calcium is likely a conse-
quence of severe physicochemical muscle derangements
rather than a serial calciotropic hormone activation and inhi-
bition. In these patients, the early activation of PTH followed
by down-regulation seems to be a consequence rather than
a cause of the biphasic plasma calcium prole.
This case also emphasizes the importance of serial calcium
monitoring in the polyuric stage, when hemodialysis therapy
is usually stopped and the major risks seem to have dis-
appeared, while the occurrence of severe hypercalcemia
exposes the patient to risk of sudden death. Moreover, cal-
cium administration in the rst stage of ARF to correct the
hypocalcemia may be dangerous as it can induce further
worsening of acute life-threatening hypercalcemia in the
polyuric phase of ARF.
Financial support: No nancial support.
Conict of interest statement: None declared.
Address for correspondence:
Giorgio Graziani, MD
Istituto Clinico Humanitas IRCCS
Via Manzoni 56
IT-20089 Rozzano-Milano, Italy
giorgio.graziani@humanitas.it