a b s t r a c t

Neoplasms and hematologic diseases are the predominant etiologies of Hypercalcemic crisis in adults and the im- mediate treatment is mainly medical and symptomatic. The use of Renal replacement therapy is often nec- essary to correct the hypercalcemia, uremia and electrolyte disturbances related to Acute kidney injury . The aim of this work was to determine the etiologies and the place of RRT in treating patients with hypercalcaemic crisis. We conducted a retrospective study for 36 months at the Nephrology Unit, University Hos- pital, Oujda, eastern of Morocco. We included all adult patients diagnosed with hypercalcemic crisis that was de- fined as corrected total serum calcium of N3.5 mmol/l.

Results: 12 patients were collected. All patients were female and 5 patients were elderly (>=65 years). Three pa-

tients had a serum calcium value of N4 mmol/l and the highest calcium value was 5.8 mmol/l. Electrocardiograph- ic abnormalities were observed in 8 cases. AKI was observed in 8 cases. Three patients had chronic kidney disease on hemodialysis. Neoplasm was noted in 9 cases. All patients received venous rehydration, glucocorticoids and biphosphonates. The use of RRT with low calcium dialysate was performed in 11 cases. Three patients died during the first 24 h of hospitalization.

Conclusion: RRT must play its full role as first line treatment of hypercalcemia crisis. Improvements in hemodial-

ysis techniques and the use of low calcium or calcium-free dialysates currently allows this therapeutic measure to be prescribed safely, and the benefit-risk balance is positive for the great benefit provided by dialysis.

(C) 2018

Materials and methods

Hypercalcemic crisis is a rare but serious Electrolyte disorder and is life-threatening to patients due to the severity of the neurologic, cardio- vascular and renal complications associated with it [1,2]. Neoplasms and hematologic diseases are the predominant etiologies of hypercalce- mic crisis in adults and the immediate treatment is mainly medical and symptomatic. Acute Kidney Injury is a frequent complication of hypercalcemic crisis and the use of renal replacement therapy (RRT) is often necessary to correct the hypercalcemia, uremia and electrolyte disturbances related to AKI. RRT was initially indicated only after failure of the initial medical approaches, but it is now gaining an ever-increas- ing role in the first line treatment of hypercalcemic crisis, with or with- out associated AKI. The aim of this work was to determine the initial presentation, etiologies, therapeutic methods, mortality and the place of RRT in treating patients with hypercalcemic crisis.

* Corresponding author at: Avenue Hassan II, rue Kadissia, numero 12, Oujda, Morocco.

E-mail address: [email protected]. (Y. Bentata).

We conducted a retrospective study for 36 months (December 2014 to December 2017) at the Nephrology Dialysis Unit, University Hospital Mohammed VI, Oujda, in eastern Morocco, North Africa. Included were all adult patients (N16 years) diagnosed with hypercalcemic crisis. Hy- percalcemic crisis was defined as corrected total serum calcium of N3.5 mmol/l (N140 mg/l) with various symptoms related to hypercalce- mia (acute kidney injury, somnolence, confusion, coma, muscle weak- ness, nausea, abdominal pain, electrocardiographic abnormalities). Acute Kidney Injury was defined using the RIFLE classification: R for risk, I for injury, F for failure according to the intensity of increase of cre- atinine blood levels and oligoanuria, L for loss of renal function in case of nonrecovery of renal function in 4 weeks and E for end-stage renal dis- ease beyond 3 months after the acute episode [3].

Results

Data on 12 patients were collected during the period of the study. All patients were female and 5 patients were elderly (>=65 years). Three

https://doi.org/10.1016/j.ajem.2018.03.011

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Table 1

Clinical and biological parameters, etiologies, treatment and prognosis of patients admitted with hypercaelcemic crisis.

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Y. Bentata et al. / American Journal of Emergency Medicine 36 (2018) 1053-1056 1055

patients had a serum calcium value of N4 mmol/l (N160 mg/l) and the highest calcium value observed was 5.8 mmol/l (232 mg/l). All patients had gastrointestinal symptoms. Electrocardiographic abnormalities were observed in 8 cases. Acute kidney Injury was observed in 8 cases, chronic kidney disease on hemodialysis in 3 cases and one patient had normal renal function. 8 patients had signs of hypovolemia. Neoplasm was noted in 9 cases. Two chronic hemodialysis patient developed hy- percalcemic crisis secondary to hard water syndrome. All patients re- ceived venous rehydration, venous glucocorticoids (1-2 mg/kg/day for 4 days) and intravenous bisphosphonates. Zoledronate was used in a single dose (4 mg) and reduced by half (2 mg) in patients who present- ed AKI with an estimated glomerular filtration rate (GFR) between 30 and 60 ml/min or b30 ml/min. No secondary effect was noted in our se- ries following the use of the 2 mg dose of zoledronate in patients with GFR b 30 ml/min/1.73 m².

Intermittent hemodialysis was performed in 11 cases and the duration of the first session was 90 min if AKI was associated or 120 min in the absence of AKI. For chronic hemodialysis patients, the duration of session was 240 min. Low calcium dialysate (1.25 mmo/l) was performed in all sessions and intermittent hemo- dialysis was initiated during the first 24 h by temporary non-cuffed catheter or tunneled catheter for chronic hemodialysis patients. In- termittent hemodialysis has been used in the first line in the pres- ence of electrocardiographic abnormalities for hypercalcemia and/ or hyperkalemia. In- hospital mortality was observed in 25% of the patients and all deaths were observed in the first 24 h of admission to the emergency unit. Of the seven patients who were alive and had AKI, only 2 patients recovered normal renal function. Table 1 shows the clinical and biological parameters, etiologies and mortality of patients admitted for hypercalcemic crisis.

Discussion

Despite its relative frequency, only rare, small series of hypercalcaemic crisis cases have been published over the past de- cades and most of them group together mild hypercalcemia, (total serum calcium: 105-120 mg/l, 2.60-3 mmom/l), moderate hypercal- cemia (total serum calcium: 120-140 mg/l, 3-3.5 mmom/l) and se- vere hypercalcemia (total serum calcium N 140 mg/l, N3.5 mmo/l). This complicates their interpretation, especially as the etiologies and prognoses differ according to the severity of the hypercalcemia. In addition, hypercalcaemic crisis has no uniform standard defini- tion, which makes direct comparison among different studies in the literature difficult. In the Camus series, (33 cases of severe hypercal- cemia identified in 10 years), neurologic and electrocardiographic signs were present in 57% and 58% of cases, respectively [4]. Solid neoplasms with bone metastases and hematologic diseases, notably multiple myeloma, comprise the primary etiology of severe adult hy- percalcemia and remain the most serious and the most symptomatic. In our study, neoplastic etiologies represented 75% of cases and in the Camus series, 63.6% of cases [4]. The clinical picture and assay of PTH levels allow rapid diagnosis and exclusion of primary hyper- parathyroidism (HPT) that constitutes the second etiology of severe hypercalcemia in adults. Thus, the real challenge of severe hypercal- cemia is not to establish a diagnosis, but to start a rapid and effective treatment with the objective of lowering serum calcium below 3 mmol/l in a few hours and to eliminate the clinical signs, especially neurologic and cardiovascular signs.

First line treatment of hypercalcemia associated with cancer in- cludes hydration, administration of furosemide after rehydration, intra- venous glucocorticoids and intravenous bisphosphonates. Hydration must be aggressive, with 200-500 ml of saline per hour, depending on the cardiovascular and diuresis state of the patient. Zoledronate has the advantage of rapid infusion over 5-15 min, compared with the rec- ommended 2 h infusion time for pamidronate. The current recommend- ed doses are 4 mg intravenously for initial treatment in patients with

normal kidney function. In those with reduced creatinine clearance be- tween 30 and 60 ml/min, the zoledronate dose should be reduced by 50% and in patients with creatinine clearance b30 ml/min, zoledronate is not recommended. Bisphosphonates, because of their long onset of action, should be started after rehydration and be given after RRT to avoid their clearance during dialysis.

These measures have a rather slow onset of action and conse- quently cannot lower serum calcium for several hours, even several days, hence the use of RRT with low calcium dialysate (1.25 mmol/l) or free calcium dialysate to rapidly lower serum calci- um and reduce morbimortality. In our study, we were unable to use free calcium dialysate due to its unavailability. Calcium-free hemodi- alysis decreases the Serum calcium levels more markedly and rapidly compared with hydration or the use of furosemide, bisphosphonates, glucocorticoids, calcitonins, and mithramycin [5,6]. Koo, in a series of six patients with moderate and severe hypercalcemia, reported ef- fective use of RRT with calcium-free dialysate [7].

Adverse effects of RRT include catheter-related infections, thrombo- embolic disease, hypotension, and electrolyte disturbances. Dialysis with a low-calcium or calcium-free dialysate is known to induce tran- sient hypotension in up to 35% of patients, probably through rapid de- creases in calcium levels, though this may be reduced by careful manipulation of calcium concentrations in the dialysate and could be corrected by moderate Fluid loading [8,9]. Therefore, an etiology must still be determined and appropriate therapy started, if possible and de- sired. Although hemodialysis and other medical therapies do appear to be effective, they are only temporizing measures, as they do not treat the cause of hypercalcemia.

RRT with low or calcium-free dialysate should be the First-line treatment whenever a patient presents severe hypercalcemia with electrocardiographic abnormalities, even with acute renal injury stage I or II of the RIFLE classification. In addition, cardiac arrhyth- mia may rapidly progress into Complete heart block and cardiac ar- rest in extreme hypercalcemia [10]. Venous rehydration is the first measure to initiate, but it should not delay the start of RRT, particu- larly in patients with AKI.

Conclusion

Cases of hypercaelcemic crisis are often symptomatic, occur in a context of neoplasm marked by a deep fragility and immunodepression and are life-threatening. RRT must play its full role as first line treatment. Improvements in hemodialysis tech- niques and the use of high permeability dialyzers with low calcium or calcium-free dialysates currently allows this therapeutic measure to be prescribed safely, and the benefit-risk balance is positive for the great benefit provided by a dialysis session.

Disclosure statement

The authors declare that they have no conflicts of interest.

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