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NDT Advance Access originally published online on August 25, 2007
Nephrology Dialysis Transplantation 2008 23(1):359-363; doi:10.1093/ndt/gfm571
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Incidence and severity of early electrolyte abnormalities following autologous haematopoietic stem cell transplantation

David Philibert1, Simon Desmeules1, Alain Filion2, Mireille Poirier3 and Mohsen Agharazii1

1Division of Nephrology and 2Hematology, Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec Hospital, Department of Medicine, Laval University, and 3Department of Pharmacy, Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec Hospital, Québec, Canada

Correspondence to: Mohsen Agharazii, MD, Centre de Recherche de l'Hôtel Dieu de Québec, CHUQ-Hôtel-Dieu de Québec, 11, côte du Palais,Quebec City, QC,G1R 2J6, Canada. Email: mohsen.agharazii{at}crhdq.ulaval.ca



   Abstract
Top
 Abstract
Introduction
 Method
 Results
 Discussion
 Acknowledgements
 References
 
Background. Haematopoietic stem cell transplantation (HSCT) has gained worldwide acceptance as a therapeutic option for many haematological and non-haematological conditions. Local experience supports that electrolyte abnormalities are quite common; however, the incidence and timing of these abnormalities are unknown.

Method. We conducted a retrospective descriptive study of 48 consecutive adult patients in order to study the incidence and the timing of electrolyte abnormalities following autologous HSCT. Clinical and pharmacological data were collected by the review of patient charts. Potassium, magnesium, calcium, phosphorus and albumin levels were retrieved from the laboratory.

Results. HSCT was performed for multiple myeloma (28/48), lymphoma (8/48), Hodgkin disease (4/48), amyloidosis (4/48) and other neoplasia (4/48). At baseline, 21% of patients (10/48) had low electrolyte levels. Following autologous HSCT, hypokalaemia occurred in 81% (39/48), hypomagnesaemia in 67% (32/48), hypocalcaemia in 49% (17/35) and hypophosphataemia in 91% (39/43) of the patients. The nadir of the electrolyte levels occurred between day 8 and 10 after stem cell transplant while the engraftment occurred at day 11.6 ± 0.6. The use of amphotericin B and furosemide was associated with more pronounced hypokalaemia and hypomagnesaemia. Hypocalcaemia was more pronounced in patients with multiple myeloma. High levels of electrolytes occurred in only 25% of the patients, none of which required specific treatment.

Conclusion. We conclude that low electrolyte levels are extremely common after HSCT and the pathophysiology of these abnormalities are complex and multifactorial.

Keywords: electrolyte abnormalities; haematopoietic stem cell transplant; hypocalcaemia; hypokalaemia; hypomagnesaemia; hypophosphataemia



   Introduction
Top
 Abstract
 Introduction
Method
 Results
 Discussion
 Acknowledgements
 References
 
Haematopoietic stem cell transplantation (HSCT) has gained worldwide acceptance as a therapeutic option for many haematological and non-haematological conditions. It is estimated that 15 000 allogeneic and over 25 000 autologous transplants were carried out in 2000 [1]. Acute and chronic renal failure following HSCT has been extensively reported. Early acute renal failure is usually caused by hypotension from sepsis, aminoglycoside antibiotics, amphotericin B, haemoglobinuria (in the case of major ABO incompatibility) and hepatic veno-occlusive disease [2–4]. Late kidney disease is usually caused by thrombotic microangiopathy, calcineurin inhibitor toxicity and glomerular disease [5–11].

Following HSCT, our local clinical observations indicate that low electrolyte levels are common. However, to our knowledge the incidence and severity of electrolyte abnormalities following HSCT have not been reported. We performed a retrospective descriptive study in order to identify the frequency, severity, timing and the potential explanation for these abnormalities in the setting of autologous HSCT.



   Method
Top
 Abstract
 Introduction
 Method
Results
 Discussion
 Acknowledgements
 References
 
From 2000 to 2003, 48 consecutive patients (69% male), aged between 19 and 68 years, underwent autologous HSCT in the haematology unit at CHUQ Hôtel-Dieu de Québec Hospital, for multiple myeloma (n = 28), lymphoma (n = 8), Hodgkin disease (n = 4), amyloidosis (n = 4) and other neoplasia (n = 4). The conditioning regimen was melphalan alone in 32 (28 myeloma, 4 amyloidosis), carmustine–cyclophosphamide–etoposide–cytarabine (BEAC) in 12 patients (lymphomas), docetaxel–doxorubicin–cyclophosphomide (TAC) in 1 (breast cancer), busulfan–melphalan in 1 (Ewing sarcoma), carboplatin–cyclophosphamide in 1 (embryonic testicular cancer) and melphalan–cyclophosphamide in 1 (medulloblastoma). All patients with myeloma were also treated with intravenous pamidronate prior to transplant.

Patient charts were reviewed for the laboratory results of the first 6 weeks following autologous HSCT or until the patient's discharge from the hospital. The laboratory computer system was used to import the following data: complete blood count, creatinine, potassium, magnesium, calcium, albumin and phosphorus. The use and dosage of diuretics, drugs with potential tubulotoxicity and electrolyte supplements were recorded from the patients’ clinical and pharmacological charts. Low electrolyte levels are defined as follows: hypokalaemia (serum potassium <3.5 mmol/l), hypocalcaemia (albumin-corrected calcium of <2.15 mmol/l), hypophosphataemia (serum phosphorus <0.81 mmol/l) and hypomagnesaemia (serum magnesium <0.7 mmol/l). Calcium level was corrected for the albumin level by using the following formula: corrected [Ca] (mmol/l) = measured [Ca] (mmol/l) + (40 – [albumin g/l] x 0.02). Patients requiring electrolyte supplements at baseline were considered to have electrolyte abnormalities even if the serum electrolyte levels were within normal range. Time to nadir of these abnormalities was recorded as days after stem cell infusion. Engraftment was defined as the first day of the neutrophil count of >0.5 x 109/l for three consecutive days. High electrolyte levels are defined as follows: hyperkalaemia (serum potassium >5.5 mmol/l), hypercalcaemia (albumin corrected calcium of >2.55 mmol/l), hyperphosphataemia (serum phosphorus >1.45 mmol/l) and hypermagnesaemia (serum magnesium >0.98 mmol/l). Creatinine clearance was calculated by Cockroft–Gault formula. Acute renal failure is defined by a rise of serum creatinine concentration of ≥50 µmol/l.

Statistical analysis
The data are presented as mean ± SEM. Anova and Kruskal–Wallis H were used for comparison of multiple groups. Subsequently Students t-test and Mann–Whitney U test were used where applicable. A Bonferroni correction was applied to make provision for multiple testing. For survival analysis, we used the data that were available until June 2007. The impact of electrolyte imbalance on patient survival was analysed using the log-rank test. Statistical analysis was carried out using SPSS 10.0 for Windows (Statistical Products and Service Solutions, Chicago, IL) and a P-value of <0.05 was considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Method
 Results
Discussion
 Acknowledgements
 References
 
The baseline demographic and electrolyte levels are shown in Table 1. The mean baseline electrolyte levels were within normal limits. However, hypokalaemia was present in 13% (6/47), hypomagnesaemia in 17% (8/47), hypocalaemia in 6% (2/34) and hypophosphataemia in 6% (2/31) of the patients. Overall, 21% (10/48) had one or more electrolyte abnormalities at baseline. Following autologous HSCT, hypokalaemia occurred in 81% (39/48), hypomagnesaemia in 67% (32/48), hypocalcaemia in 49% (17/35) and hypophosphataemia in 91% (39/43) of the patients. When low levels of electrolytes were defined by at least two low levels, hypokalaemia occurred in 65% (31/48), hypomagnesaemia in 44% (21/48), hypocalcaemia in 29% (10/35) and hypophosphataemia in 77% (33/43) of the patients. The severity of these abnormalities is shown in Table 2.


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  		Table 1. Baseline characteristics and electrolyte levels

 

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  		Table 2. Degree and frequency of low electrolyte levels

 
Ninety-four percent (45/48) showed one or more electrolyte abnormalities following autologous HSCT. The electrolyte nadir occurred between days 8 and 10, whereas the marrow engraftment occurred on day 11.6 ± 0.6 after autologous HSCT. Table 3 shows the average of nadir and the timing of the electrolyte abnormalities in the post-transplant period. One-way ANOVA showed a statistically significant difference among the groups for the nadir of phosphate (P = 0.024) and calcium levels (P = 0.002). Pairwise comparison with post hoc Bonferroni correction showed that patients with multiple myeloma had a more pronounced hypocalcaemia as compared with other groups (P < 0.05).


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  		Table 3. Timing of low electrolyte levels following transplantation

 
Seventy-seven percent (37/48) of the patients required potassium supplementation following HSCT with an average of 392 ± 60 mmol per patient treated (range: 40–1460) over a mean duration of 11.7 ± 1.4 days, while 60% (28/48) received an average dose of intravenous magnesium of 40.4 ± 10 g per patient (range 4–216). However, calcium and phosphate supplementations were not used in any patients.

Forty-five percent (22/48) of the patients received an average dose of 230 mg ± 77 mg per patient of furosemide over an average of 4.2 ± 0.9 days. The frequency of hypokalaemia and hypomagnesaemia was not statistically higher in patients receiving furosemide. However, patients who received furosemide had a lower nadir of potassium (2.95 ± 0.08 vs 3.15 ± 0.06 mmol/l, P = 0.06) and magnesium (0.61 ± 0.02 vs 0.66 ± 0.02 mmol/l, P = 0.07) as compared with patients not receiving furosemide. Three patients who received amphotericin B required a higher dose of potassium and magnesium supplements as compared with patients who did not receive amphotericin B (P < 0.05).

However, high levels of electrolytes occurred much less frequently. Following autologous HSCT, hyperkalaemia occurred in 4% (2/48), hypermagnesaemia in 10% (5/48), hypercalcaemia in 3% (1/35) and hyperphosphataemia in 16% (7/43) of the patients. None of these patients required specific therapy for high levels of electrolytes. The incidence of acute renal failure was low (3/48) and none developed hyperkalaemia.

After a median follow-up of 48 months, the median survival of this cohort was 48 months (range 1–85). The survival of patients with ≤2 electrolyte imbalance was not statistically different from those with ≥3 electrolyte imbalance.



   Discussion
Top
 Abstract
 Introduction
 Method
 Results
 Discussion
Acknowledgements
 References
 
The incidence and the timing of electrolyte abnormalities in this population have never been reported. Our results showed that the incidence of low electrolyte levels at baseline was 20% overall and increased to more than 90% following autologous HSCT. We have specifically chosen the autologous group of patients as they are a more homogenous group due to a lesser degree of gastrointestinal and infectious complications. Results for calcium and phosphorus were not available for all patients; therefore it may be possible that the true incidence of these abnormalities may be overestimated since the physicians might have had clinical suspicion of such abnormalities. High levels of electrolytes occurred in only 25% of patients (12/48), none of which required any clinical intervention. The lack of the number of electrolyte abnormalities on mortality may be explained by the fact that all patients underwent an aggressive management of low electrolyte levels.

The underlying mechanisms explaining low electrolyte levels seem to be multifactorial and can be grouped into five categories: (i) reduction of intake, (ii) enhanced gastrointestinal loss, (iii) intracellular incorporation of electrolytes into the new forming haematopoietic cells, (iv) enhanced renal loss and (v) abnormal mineral bone metabolism. Although no quantitative measure of intake and stool electrolytes were used in this study, the reduction of intake and enhanced gastrointestinal loss was not mentioned in the patient's charts and are unlikely to explain this degree of electrolyte abnormalities in patients with autologous HSCT. Incorporation of electrolytes into the newly forming haematopoietic cells could partly explain some of the electrolyte imbalance [12–14]. Indeed, the nadir of electrolyte plasma level occurred a few days before the bone marrow engraftment. In opposition to tumour lysis syndrome, Wollner and colleagues [15] have coined the term ‘genesis syndrome’ to describe a massive transfer of electrolytes into rapidly proliferating cells.

There were no systematic measurements of urine electrolytes in our population. However, electrolyte loss through the kidneys is likely to play an important role in electrolyte deficit in patient with autologous HSCT. First, volume expansion is used before haematopoietic stem cells reinfusion in order to prevent haemolysis-induced renal failure. The natriuresis that ensues is accompanied by an increased excretion of potassium, calcium and a reduction in proximal phosphate reabsorption [16,17]. In this group of patients, loop diuretics are commonly used to reduce the fluid overload. This practice further enhances the renal loss of potassium, calcium and magnesium [18,19]. The use of carboplatin-based conditioning regimen in one patient and the use of amphotericine B in the post-HSCT period in three patients may in part explain the astonishing requirements for magnesium and potassium supplement.

Finally, reduced levels of some electrolytes may play an important role in the renal loss of other electrolytes. For example, it has been shown that potassium deprivation in normal subjects increases urine calcium and phosphate excretion, and reduces PTH and 1,25-hydroxy-vitamin D levels [20,21]. There is also an interaction between hypomagnesaemia and metabolism of other electrolytes that has thoroughly been reviewed [22]. Briefly, with hypomagnesaemia, there is an enhanced renal loss of potassium and phosphate, reduced secretion of PTH and resistance to the actions of PTH [23–28]. In the subset of patients with multiple myeloma, calcium and phosphate abnormalities were more frequent in this study. Paraproteins may cause subtle proximal tubulopathy that might become clinically manifest when the nutritional electrolyte intake is reduced or if there is enhanced renal or extrarenal losses. Moreover, bisphosphonates are routinely used in multiple myeloma for the treatment of lytic bone lesions [29,30]. The slight decrease of serum calcium that follows administration of pamidronate stimulates PTH that leads to hypophosphataemia by reducing renal phosphate reabsorption [31,32].

Some reports suggest that the HSCT population has lower vitamin D and higher PTH levels before undergoing transplantation [33]. Although vitamin D deficiency could be explained by low sun exposure, reduced dietary vitamin D and use of corticosteroids in some of chemotherapeutic regimens, oral vitamin D supplements were insufficient to restore 25-hydroxy-vitamin D3 levels to normal [33]. The levels of the active 1,25-hydroxy-vitamin D3 have also been shown to be low in patients with allogenic HSCT [34]. The authors hypothesized that during aplasia, there is a reduction of extrarenal 1-{alpha}-hydroxylation of 25-hydroxy-vitamin D3 due to the lack of contribution from the leucocytes.

In conclusion, we have shown that low levels of electrolytes are extremely common in patients undergoing autologous HSCT. Magnesium and potassium depletion were more pronounced in patients receiving amphotericin B and furosemide. Hypocalcaemia was more frequent in patients with multiple myeloma. The mechanisms of these abnormalities are in part iatrogenic, but are also potentially due to underlying renal tubulopathy, interaction of potassium and magnesium on renal handling of calcium–phosphate metabolism, abnormal metabolism of vitamin D and incorporation of electrolytes into the newly formed haematopoietic cells. Prospective studies are required to improve the understating of electrolyte abnormalities in haematopoietic stem cell transplant patients.



   Acknowledgements
Top
 Abstract
 Introduction
 Method
 Results
 Discussion
 Acknowledgements
References
 
We gratefully acknowledge the assistance of Ms Johanne Blouin and Ms France Samson. M.A. is a recipient of a research scholarship from Canadian Institute for Health Research and Canadian Hypertension Society.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Method
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 17. 1.07
Accepted in revised form: 26. 7.07


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