In this interview, News-Medical talks to Dr. Francesca Di Mario, about hypomagnesemia in critically ill patients with Acute Kidney Injury (AKI) and discusses how Nova Biomedical instruments are utilized in her work.
Please could you start by introducing yourself and your area of research?
I am Francesca Di Mario, a nephrologist at Parma University Hospital. I work in the renal Intensive Care Unit (ICU) of the hospital. In the last years my research area has been focused on Acute Kidney Injury, Continuous and Prolonged Intermittent Kidney Replacement Therapy (CKRT and PIKRT, respectively) and the optimization of simplified Regional Citrate Anticoagulation (RCA) protocols.
In this regard, hypomagnesemia is a frequent but often underestimated electrolyte disorder among critically ill patients undergoing continuous kidney replacement therapy.
What is the role of magnesium in the human body and why is research into hypomagnesemia so important?
Magnesium has a relative atomic mass of 24 daltons. It is the second most abundant divalent cation in the human body, with an average body content of 20 millimoles per kilo of fat-free tissue. About 99% of the total magnesium pool is located in the intracellular space and stored in bone, muscle and soft tissue.
Serum magnesium represents just 1% of the total body content, and it is present in the blood in three forms. One is the free biologically active form present as ionized magnesium (s-Mg++). Another part is complexed with the filterable anion, and the rest is bound to proteins.
The free intracellular magnesium acts as a cofactor of several enzyme systems, including those involved in the synthesis of nucleic acids, metabolism of glucose, lipids, and proteins, as well as methylation processes.
Its function is essential to a wide array of physiological processes, such as heart rate variability, muscle contraction and relaxation, neurological transmission, regulation of vascular tone and electrolyte metabolism.
Hypomagnesemia, commonly defined as s-Mg < 1.6 mg/dL (0.70 mmol/L), occurs in up to 12% of hospitalized patients, and in 60–65% of those who are critically ill. In the unique clinical scenario of critically ill patients, hypomagnesemia has been often characterized by a negative impact on clinical outcomes. This is why strategies to reduce its incidence and severity should be promptly implemented.
What factors influence the amount of magnesium present in the body?
In terms of physiological conditions, the normal range of serum magnesium is the result of a balance between dietary intake and kidney elimination. The average daily recommended dose is about six milligrams per kilo, with green vegetables representing the primary source.
Depending on the patient’s dietary intake and magnesium status, approximately one-third of this magnesium is absorbed in the small bowel through a passive paracellular mechanism mediated by claudins in the tight junctions.
The kidney normally reabsorbs 95% of filtered Mg, mostly via paracellular passive transport in the thick ascending limb (TAL) of Henle. The fractional magnesium excretion may vary significantly according to serum magnesium concentration from less than 1% in the case of magnesium depletion up to 70% in the case of hypermagnesemia.
In patients with advanced Chronic Kidney Disease (CKD), an imbalance between the dietary intake and kidney elimination usually occurs as a result of their impaired renal functionality, generating the hypermagnesemia typically observed in this patient population.
What are the leading causes of hypomagnesemia in critically ill patients, and does treatment choice impact these?
Three main pathophysiological mechanisms may be identified as causing hypomagnesemia in critically ill patients:
The first is reduced gastrointestinal absorption and/or inadequate intake, common in patients with chronic diarrhea or treated with parenteral nutrition.
The second is the redistribution from the extracellular to the intracellular compartment, possible in patients with refeeding syndrome.
The third is increased renal losses, which may happen in patients treated with high doses of diuretic therapy.
In recent years, a great deal of attention has been focused on the extra-renal losses of Mg that occurs during Continuous and Prolonged Intermittent KRT in patients with severe stages of AKI.
Commonly available in different and often complementary forms, Continuous and Prolonged Intermittent KRT are widely considered the most appropriate dialysis modalities in hemodynamically unstable patients with AKI.
Indeed, given the longer duration compared to the conventional Intermittent Hemodialysis, they allow for a slower fluid and solute removal, with better hemodynamic tolerance and lower risk of rapid osmolal shifts.
Given the extended duration, these techniques usually provide a high daily solute clearance. Indeed, if not accurately monitored with scheduled laboratory tests, the high solute clearance may represent a serious side effect of KRT with potentially severe clinical consequences. This characteristic has been recently summarized in the dialytrauma concept, which underlines all the possible electrolyte and metabolic complications requiring accurate prevention related to the extracorporeal treatment.
In particular, although the exact prevalence still remains unknown, hypomagnesemia is quite common among critically ill patients undergoing KRT for AKI, with incidence varying according to different dialysis modalities, delivered dialysis dose, anticoagulation strategies, and the composition of dialysis/replacement fluids used.
What strategies can be employed to help minimize these risks during kidney replacement therapy modalities?
Given the prolonged duration of these KRTs, anticoagulation of the extracorporeal circulation is usually required to reduce the risk of filter clotting and to avoid undesirable interruptions of treatment.
The most recent international guidelines on AKI suggest the use of Regional Citrate Anticoagulation (RCA) over unfractioned heparin as the preferred anticoagulation strategy in both patients with and without increased bleeding risk.
Citrate provides anticoagulation of the extracorporeal circuit by chelating ionized calcium thus blocking the clotting cascade at multiple enzymatic steps.
Specifically, for citrate concentration around 4–6 mmol/L, ionized calcium is < 0.2 mmol/L and blood is completely anticoagulated.
Commercially available citrate solutions for kidney replacement therapy are commonly classified into two groups on the basis of their citrate concentration: high concentration citrate solution - hypertonic sodium - and the low concentration citrate solution - isotonic sodium.
While the first group is generally preferred in diffusive dialysis modalities, the second is mostly used in convective techniques.
In classic dialysis circulate, the citrate solution is typically infused into the most proximal portion of the extracorporeal circuit at rates proportional to blood flow, with a target citrate concentration in the hemofilter of around three millimoles per liter. In this way, the circuit ionized calcium concentration is generally < 0.5 mmol/L and the clotting risk is negligible. Like calcium, Mg is a divalent cation and during Regional Citrate Anticoagulation is chelated by citrate exactly like ionized calcium; thus, given the high diffusive/convective clearance of Mg-citrate complexes, a significant amount of Mg is lost in the effluent fluid. It follows that the amount of Mg loss derives not only from the net blood-to-dialysate mass transfer of ionized magnesium, but also from the amount of magnesium chelated by citrate and lost in the effluent as magnesium-citrate complexes.
Can you provide any examples of research into the factors that impact the reduction of serum magnesium in course of KRT and how these are being addressed?
In patients with end-stage kidney disease, the renal extraction fraction of magnesium is severely impaired, and serum magnesium concentration is generally elevated.
Therefore, some of the usual commercially available dialysis solutions used in conventional intermittent hemodialysis are characterized by a relatively low magnesium content, around 0.5 millimoles per liter.
In several studies on this patients’ population, the use of low dialysate magnesium concentration was also associated with intradialytic hypomagnesemia, cramps and intradialytic hypertension, even regardless of dialysate calcium concentration.
On this basis, magnesium mass transport and serum magnesium concentration were evaluated in critically ill patients with AKI who underwent continuous kidney replacement therapy with and without regional citrate anticoagulation. In both patient subgroups, a dialysis solution with 0.50 mmol/L Mg++ was used.
The authors observed significantly higher effluent Mg losses in patients treated with Regional Citrate Anticoagulation compared to un-fractioned heparin anticoagulation subgroup, with a remarkable amount of time being spent near or below the lower reference serum Mg levels (0.70 mmol/L).
Regarding the intrinsic mechanisms of Mg mass transfer during Regional Citrate Anticoagulation, a dialytic kinetics analogous to calcium has been confirmed by studying the changes in total and ionized Mg concentrations across the hemofilter. Here, the ionized serum magnesium concentration decreases to about one-third during passage through the citrate anticoagulant circulates in a way similar to what happens to the ionized calcium.
A negative Mg balance has also been observed, mostly when using dialysis/substitution fluids with low Mg concentrations.
Within this conceptual framework, the safety and effectiveness of a new dialysis solution with increased magnesium concentration (1.50 mmol/L) was tested in combination with a high concentration citrate solution, used for the anticoagulation of the extracorporeal circuit.
While intravenous magnesium supplementation was not required when using this new dialysis solution, the investigators observed a significant and progressive increase in the serum magnesium levels, with a slightly positive magnesium balance and the development of mild hypermagnesemia, especially in cases of higher delivered dialysis dose.
This means that while the aim was to prevent the development of dialysis related hypomagnesemia, an overcorrection occurred, and one electrolyte disorder was transformed into another electrolyte disorder.
Increasing the magnesium concentration into KRT solution may be, on the contrary, an interesting choice for regional citrate anticoagulation protocols where a low concentration citrate solution is selected. Indeed, when higher treatment volumes are required, the serum magnesium reduction is generally even more pronounced, with the higher s-Mg reduction occurring in the first 24 hours of treatment, mostly if replacement fluids with low Mg concentration are used.
Studies aimed specifically at evaluating the incidence of hypomagnesemia and its prognostic role in critically ill patients undergoing Prolonged Intermittent KRT are lacking. However, from our preliminary data analysis obtained in patients undergoing Sustained Low Efficiency Dialysis (SLED), a reduced incidence of hypomagnesemia has been observed compared to Continuous KRT.
We analyzed data from 20 critically ill patients with AKI who had undergone three consecutive daily SLED sessions by combining a low concentration citrate solution with dialysis solution with a relatively high magnesium concentration, 0.75 millimoles per liter.
We noted that the intravenous magnesium supplementation was needed at the end of nine out of sixty SLED sessions. In this regard, based on the unique setting of SLED, a potential decrease in serum magnesium levels during dialysis phase of treatment may be partially compensated during the interdialytic phase when citrate is metabolized and magnesium, like calcium, returns to the blood circulation.
The dialysis solutions currently available for continuous and prolonged intermittent kidney replacement therapy have a magnesium content of between 0.5 and 1 millimoles per liter, with the latter generally preferred in Regional Citrate Anticoagulation protocols.
What are some of the clinical impacts of hypomagnesemia in critically ill patients?
In the unique clinical scenario of critically ill patients, hypomagnesemia has often been characterized by a negative impact on clinical outcomes. In particular, magnesium depletion has been directly associated with increased mortality risk, increased duration of mechanical ventilation and increased Intensive Care Unit (ICU) length of stay.
The clinical complications of hypomagnesemia can be classified as specific clinical manifestations and biochemical abnormalities. The main clinical symptoms associated with decrease in serum magnesium levels principally involve the heart and the neuromuscular system.
Neuromuscular symptoms are commonly the first manifestations and often the basis of respiratory muscle weakness and difficulty in weaning from mechanical ventilation. Cardiac alterations include various degrees of electric abnormalities, with ventricular dysrhythmias representing the most severe clinical consequences of Mg deficiency.
Among the secondary electrolyte derangements, hypokalemia and hypocalcemia represent the most common electrolyte disorders in patients with Mg depletion.
How is total serum magnesium concentration measured, and what are the limitations of this approach?
The standard test used when evaluating magnesium status is one that measures total serum magnesium concentration, available in most hospital laboratories. Unfortunately, this test does not accurately reflect the total body content of Mg (it does not provide any information, for example, of the magnesium content in bones) and it has no direct relation with the ionized active form, particularly in critically ill patients.
In this regard, and mostly in patients undergoing some forms of prolonged KRT modalities, the ionized serum magnesium concentration should be evaluated because the ionized form of serum magnesium represents the only fraction of the total which is effectively exchanged in course of dialysis treatment.
Why is it important to measure ionized magnesium in critically ill patients?
Magnesium is the second most abundant intracellular cation, and it is a cofactor for over 300 enzymes involved in several fundamental biological processes. Magnesium helps manage the sodium-potassium and calcium ATPase pumps at the level of cellular membranes and the regulation of other electrolytes.
It also supports the regulation of vascular smooth muscle tone, skeletal and cardiac contractility and neurotransmission. The production of energy is indeed a cofactor in oxidative phosphorylation and inflammation in platelet coagulation and other processes.
The clinical manifestations of an unacceptable magnesium level – dysmagnesemia – are broad and can be very severe. Hypomagnesemia can lead to several cardiovascular complications and manifestations, including arrhythmias, hypertension, cardiac insufficiency, coronary vasospasm and even heart failure and sudden death.
Other complications and clinical manifestations include skeletal and muscle weakness, tetany, seizures, hypokalemia and hypocalcemia. Hypermagnesemia is associated with hypertension, bradycardia, inhibition of platelet aggregation and clotting and respiratory paralysis, as well as other cardiovascular consequences.
A study published by the Mayo Clinic, involving over 60,000 patients, analyzed magnesium level during hospital admissions, revealing that a considerable portion of patients admitted had either very low or very high magnesium. That means there was a very high portion of dysmagnesemia in these patients.
Dysmagnesemia was heavily correlated with mortality, with mortality rates increasing in the case of hypo and hypermagnesemia. Different and non-standard levels of magnesium are therefore an essential predictor of outcomes for patients, even at the hospital admission stage.
How is testing for magnesium levels typically achieved, and are there any limitations to this approach?*
*This question is answered by Dr. Germano Ferrari, Director of Medical & Science Affairs at Nova Biomedical.
The standard magnesium test is done in the hospital laboratory, which is not part of the routine critical care panel. As it is performed in a central lab, turnaround time can delay decision-making.
Most importantly, the standard test only measures total magnesium. Magnesium in whole blood is present in three forms: in a complex form with other anions like citrate or lactate, bound to protein and in an ionized form; the latter accounting for 55% to 70% of total whole blood magnesium.
Ionized magnesium is the physiologically active fraction because this is the only form free to exert biological functionalities and be involved in physiology. It is not bound to any other entity in the blood.
There are two key problems with standard magnesium testing. The first is that total magnesium - currently measured in the lab - does not always correlate with ionized magnesium.
This is often the case in cardiopulmonary bypass patients, COVID patients with cardiovascular complications, intestinal and liver disease and in patients with severe head trauma. In these examples, there is a significant decrease in ionized magnesium but not in total magnesium.
The second problem is that there could be significant variation in ionized magnesium concentration without any corresponding change in total magnesium. This may be due to differences in pH, changes in acid-base status and circulating protein concentrations, or an increased presence of anionic ligands like lactate, citrate and bicarbonate. This can be seen during hypoxemia, blood transfusion and acidosis treatment.
Studies have been published analyzing this specific phenomenon in the different patient populations. One of the very first studies published in 2007 highlighted a significant patient population within the cohort of patients enrolled where total magnesium was normal but ionized magnesium indicated hypomagnesemia.
This happened in 25% of the patients considered, but if we only looked at total magnesium, we would not see this need, and we would not proceed with the appropriate treatment.
The critical point of this study was that total magnesium does not always reflect the physiologically active concentration of magnesium.
The inclusion of ionized magnesium testing in the point of care panel could enable a more accurate diagnosis and more effective management of dysmagnesemia in critically ill patients.
The blood gas analyzer produced by Nova Biomedical is an ideal means of achieving this. It provides a complete test menu for critically ill patients, including blood gases, electrolytes and metabolites, hematology and coagulation symmetry tests.
It also includes new testing capabilities to improve the monitoring of critically ill patients; for example, estimated plasma volume, urea/BUN and creatinine levels, and – most importantly – ionized magnesium.
About Dr. Di Mario
Dr. Di Mario is a medical doctor of the Nephrology Unit at Parma University Hospital. She graduated from the Sapienza University of Rome and was Resident Physician at said university from 2014 until 2018 when she joined the Parma University Hospital as a clinical research fellow.
About Nova Biomedical
Nova Biomedical develops, manufactures, and sells advanced technology blood testing analyzers. We employ over 1,200 people, with sales and service subsidiaries in eight countries and distributors in more than 91 additional countries.
Nova has manufacturing facilities in Waltham and Billerica, Massachusetts; and Taipei, Taiwan. Nova is one of the 25 largest in vitro diagnostic companies in the world and the largest privately owned in vitro diagnostic company in the United States.
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