ACKD

Magnesium Balance in Chronic and End-Stage

Kidney Disease
Ben Oliveira, John Cunningham, and Stephen B. Walsh

This article explores the effects of CKD and end-stage kidney disease on magnesium balance. In CKD, there is decreased glomer-
ular filtration of magnesium. Decreased tubular reabsorption can compensate to a degree, but once CKD stage 4 is reached there
is a tendency toward hypermagnesemia. In dialysis, magnesium balance is dependent on the constituents of the dialysate that
the blood is exposed to. The concentration of dialysate magnesium is just one of the factors that need to be considered. During
transplantation, there are particular effects of immunosuppressants that can affect the magnesium balance and need to be
considered by the clinician.
Q 2018 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Electrolytes, Magnesium, Kidney disease

INTRODUCTION this is controversial9,10 and kidney TRPM6 expression

Magnesium is the eighth most abundant element within the
earth’s crust, the second most prevalent intracellular cation
after potassium, is crucial for the functioning of ATP as well
as the synthesis of both DNA and RNA, and is a cofactor in
over 300 enzymatic reactions. Important links exist be-
tween this alkali earth metal and vascular calcification, car-
diovascular disease, and CKD development.1-3
Magnesium balance is regulated via absorption from the
gastrointestinal tract and elimination by the kidneys. The
kidney excretion of magnesium depends on the glomer-
ular filtration rate (GFR) that is then modulated by tubular
reabsorption. As the GFR falls, the kidney’s ability to
excrete magnesium declines, and thus, there is a tendency
for hypermagnesemia in CKD. However, there are other
factors that contribute to magnesium balance in CKD,
such as drugs (e.g. proton-pump inhibitors [PPIs], calci-
neurin inhibitors [CNIs]), vitamin D status, and the pres-
ence of diabetes. For patients on dialysis, magnesium
excretion depends largely on the magnesium gradient
across the dialysis membrane and other factors related to
the patient and dialysate.
NORMAL MAGNESIUM BALANCE
To understand magnesium dysregulation in CKD, it is
necessary briefly to touch on magnesium homeostasis in
health. Extracellular magnesium accounts for 1% of total
body magnesium with most of the remaining 99% seques-
tered in bones and muscles. Magnesium is absorbed in the
gut and predominantly excreted by the kidneys. The frac-
tional absorption of dietary magnesium is typically
around 30%, and this can increase and decrease in
response to both low and high magnesium diets, respec-
tively.4,5 Two transport mechanisms have been defined
for intestinal magnesium absorption: paracellular and
transcellular routes. Paracellular transport accounts for
80-90% of total absorption and is a passive process
driven by the relatively high luminal concentration of
magnesium and the electropositive transluminal
gradient.6 Transcellular magnesium relies on transport
through the transient receptor potential channel melasta-
tin member 6 (TRPM6) and TRPM7 channels.6 Intestinal
absorption may be influenced by vitamin D status7,8 but
per se does not appear to be influenced by vitamin D.11
The main excretory pathway for magnesium is kidney
where the fractional excretion can change from nearly
0.5% in hypomagnesemia to greater than 70% in hyper-
magnesemia.12 Magnesium is freely filtered (70-80% of
magnesium is ultrafiltratable, the rest is protein bound)
at the glomerulus, but under normal circumstances,
approximately 95% is reabsorbed along the course of the
kidney tubule. Bulk magnesium transport (up to 70%) oc-
curs in the thick ascending limb with passive paracellular
magnesium uptake. This process is driven by the luminal
positive gradient driven by K1 recycling via apical
NKCC2 and ROMK transporters in thick ascending limb
cells. The tight junction proteins claudin-16 and claudin-
19 comprise the paracellular route for magnesium
reabsorption driven by this gradient. Fine-tuning of
magnesium reabsorption occurs in the distal convoluted
tubule (DCT) and is an active process driven by TRPM6.
The magnesium extruding transport protein on the baso-
lateral cell membrane has yet to be identified. Regulation
of kidney magnesium handling in the DCT is partly under
control of parathyroid hormone (PTH) which increases
tubular reabsorption of the cation.13 Hypomagnesemia
stimulates PTH synthesis and release via the calcium
sensing receptor (CaSR) in the parathyroid glands, though
with potency 2 to 3 times less than that of calcium.14 How-
ever, in the DCT, the potency of magnesium and calcium as
activators of the CaSR appears equal.15 In the parathyroids,
the CaSR exhibits a biphasic response in that very low
levels of magnesium can reduce the sensitivity of the
CaSR to calcium, as well as to magnesium itself, leading
to decreased PTH release and profound hypocalcemia, a
scenario that requires correction of the hypomagnesemia
to restore the responsiveness of the CaSR to calcium and
From the Centre for Nephrology, Royal Free Hospital, London, UK.
Financial Disclosure: The authors declare that they have no relevant finan-
cial interests.
Address correspondence to Ben Oliveira, North Middlesex University Hos-
pital, Renal Medicine, London N181QX, UK. E-mail: benoliveira@nhs.net
Ó 2018 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
https://doi.org/10.1053/j.ackd.2018.01.004

Adv Chronic Kidney Dis. 2018;25(3):291-295 291

292 Oliveira et al
allow appropriate release of PTH.16 PTH secretion is medi-
ated by cyclic adenosine monophosphate. Cyclic adeno-
sine monophosphate is dependent on magnesium for its
production and this explains the unresponsiveness of the
parathyroids in profound hypomagnesemia.17 Other
players involved in magnesium regulation in the DCT
include epidermal growth factor and estrogen which acti-
vate transcription of TRPM6.18,19
ASSESSING MAGNESIUM STATUS
Although the usual starting point is measurement of blood
magnesium concentration, this compartment only consti-
tutes about 1% of the body’s total stores. A person in negative
magnesium balance will mobilize stores in muscle and bone
to maintain serum levels. Thus, total magnesium stores have
to be quite low before this is reflected by the serum concentra-
tion. Indeed, healthy volun-
teers on magnesium deficient CLINICAL SUMMARY
diets did not deplete their
serum levels after 92 days.20  There is a tendency toward hypermagnesemia in CKD.
There is also evidence that
those with serum levels in  Constituents of the diasylate are the main factors governing
the low-normal range (0.75– magnesium status in dialysis patients.
0.80 mmol/L) may be func-  In transplantation, calcineurin inhibitors can lead to
tionally magnesium deficient hypomagnesemia.
as they display increased
chronic disease risk akin to
those with levels less than 0.75 mmol/L.21-23. Urinary
excretion is modified within a few days of a change in
20
gastrointestinal absorption. Thus, the urinary excretion of
magnesium probably reflects magnesium intake rather
than the total body stores.
Magnesium concentrations in tissues have been assessed as
possible measures of total body stores. Erythrocytes, mono-
cytes, sublingual epithelium, and hair cells have all been
used for this purpose.24-27 Magnesium content in
sublingual cells correlates with the content in cardiac
myocytes, suggesting that it is an acceptable marker for
total body magnesium.24 However, a study looking at re-
placing magnesium in CKD found that intracellular magne-
sium (as measured in sublingual epithelial cells) did not
increase after 8 weeks of supplementation despite increased
serum concentration and urinary fractional excretion of
magnesium.28 The rise in urinary magnesium in this study
was not as high as the increased intestinal absorption. The
patients were thus in positive magnesium balance and
this presumably contributed to replacing body stores.
Given the size of the intracellular compartment, 8 weeks
was probably not long enough to see the supplemented
diet resulting in increased epithelial cell magnesium.
Although there are problems with using serum magne-
sium as measure of magnesium balance, there are no other
alternatives that are practical in routine clinical practice.
Although it will take some time for serum magnesium to
deplete, a low serum concentration will usually reflect
chronic negative balance.
MAGNESIUM AND DISEASE
Magnesium has been linked to multiple diseases. In CKD,
hypomagnesemia is associated with increased vascular
calcification and mortality. The pathogenesis of vascular
calcification in kidney disease is complicated and beyond
the scope of this article. In brief, calcium phosphate can in-
fluence vascular smooth muscle cells (VSMCs) to become
osteoblast like, promoting vascular calcification.29 It has
been shown that in vitro magnesium is able to prevent
this process from occurring. In vitro studies have shown
that magnesium inhibits osteogenic transformation and
calcification of VSMCs, which is probably mediated via
TRPM7 channels.30 It also modulates the expression of
several anticalcification proteins possibly via restoring mi-
croRNA signature at the site of calcification.30,31
Magnesium can also activate the CaSR found in VSMCs,
and this has also been shown to attenuate vascular
calcification.32 Hypomagnesemia can, therefore, lead to
increased vascular calcification which will increase cardio-
vascular risk burden. Indeed
studies have shown that low
magnesium levels are associ-
ated with death in dialysis
patients.33
A J-shaped curve describes
the relationship between the
serum magnesium and mor-
tality. An observational
study of over 65,000 patients
found that a magnesium
level above 2.3 mg/dL was a predictor of adverse out-
comes.34 A similar relationship is seen in dialysis patients,
but in contrast to the previous study, the lowest level of
risk is seen at levels of 2.7 mg/dL.35 However, it is not clear
whether hypermagnesemia is causal in relation to mortal-
ity as there are confounders (such as administration of
magnesium supplements for hypomagnesemia). Untan-
gling these will require prospective studies. Until this is
known, it seems prudent to keep magnesium levels within
range and to be aware of the adverse outcomes associated
with both low and high magnesium concentrations.
MAGNESIUM BALANCE IN CHRONIC KIDNEY
DISEASE
As glomerular filtration decreases in advancing CKD,
increased fractional excretion of magnesium occurs to
compensate for decreases in filtered magnesium. Non-
diabetic patients with CKD (creatinine clearances of
30-115 mL/min/1.73 m2) not on diuretics showed an inverse
relationship between creatinine clearance and serum mag-
nesium. This same relationship did not hold true for dia-
betic patients who tended to have lower magnesium
levels (possibly due to decreased intestinal absorption
due to autonomic neuropathy). In both groups, serum total
and ionized magnesium remained in the normal range.36
As CKD develops beyond stage 4, there is a tendency to-
ward hypermagnesemia, and overt hypermagnesemia is
frequently seen when creatinine clearance falls below
15 mL/min.37 The degree of intestinal absorption becomes
key in determining serum magnesium levels in these pa-
tients, in whom the ingestion of magnesium containing lax-
atives or antacids can lead to hypermagnesemia.38 The use
of phosphate binder sevelamer hydrochloride has also
Adv Chronic Kidney Dis. 2018;25(3):291-295
 Magnesium Balance in Kidney Disease
been associated with hypermagnesemia in CKD.39,40 It has
been postulated that this effect may be mediated by
sevelamer binding to bile salts leaving more free
magnesium available for absorption. There are also drugs
that have the potential to cause hypomagnesemia in
CKD, and the most prominent among these are PPIs.
The changes in intestinal pH induced by PPIs reduce
the activity of TRPM6 and can thus lead to
hypomagnesemia.41 Studies have shown that patients
with concomitant use of diuretics and those with kidney
impairment may be at particular risk of PPI-induced hypo-
magnesemia.42 Hypomagnesemia resolves rapidly after
discontinuation of PPIs usually within 4 days.43 Table 1
shows factors associated with both high and low magne-
sium levels in various CKD states.
MAGNESIUM BALANCE IN DIALYSIS
Hemodialysis
Both ionized and total magnesium concentrations in dial-
ysis patients tend to be above normal but remain partially
dependent on the degree of residual kidney function.44
The ionized fraction of magnesium can vary between 60%
and 70% in dialysis patients and increased circulating phos-
phate, citrate, and sulfate in kidney failure can complex
magnesium and lower the ionized fraction.26 Conversely,
lower albumin levels in dialysis patients could lead to a
higher ionized fraction of magnesium.45 In general though,
the ionized fraction of magnesium tends to be lower in dial-
ysis patients than healthy controls.44,46 Both ionized
and complexed magnesium are freely dialyzed. Dialysis
patients are dependent to a large extent on the
magnesium content of the dialysate to determine their
magnesium balance. Mild hypermagnesemia has been
reported with dialysate magnesium concentrations of 0.75
mmol/L, while concentrations of 0.5 and 0.25 mmol/L are
associated with hypomagnesemia. Two factors govern the
movement of ultrafiltratable magnesium between plasma
and dialysate, namely the concentration gradient and the
Gibbs-Donnan effect. About 70% of plasma magnesium is
ultrafiltrable, the remainder being mainly albumin bound.
If the dialysate concentration of magnesium is lower than
the ultrafiltrable fraction concentration in plasma, magne-
sium will be removed in hemodialysis. The Gibbs-Donnan
Table 1. Factors Associated With Increased and Decreased Serum
Magnesium Concentrations in CKD
Increased Magnesium Decreased Magnesium
Reduced GFR Drugs (PPIs, diuretics, calcineurin
inhibitors)
Drugs (sevelamer) Hypertonic solutions (PD)
Dialysate Hypoalbuminemia in dialysis patients
concentration
. 0.75 mmol/L
Use of magnesium Dialysate concentration , 0.75 mmol/L
supplements
Diabetes
Abbreviations: GFR, glomerular filtration rate; PD, peritoneal dial-
ysis; PPIs, proton-pump inhibitors.
Adv Chronic Kidney Dis. 2018;25(3):291-295
293
effect describes the pull that anionic proteins exert on cat-
ions. Albumin has a slight negative charge that prevents cat-
ions such as magnesium moving across the dialyzer
membrane.47 Owing to this effect, the dialysate magnesium
concentration needs to be at least 3% lower than the ultrafil-
trable fraction in plasma for removal to occur. Thus, hypoal-
buminemic patients have relatively increased removal of
magnesium on dialysis reflecting increased ionized magne-
sium due to less albumin binding and decreased Gibbs-
Donnan effect. The final factor to consider is the concentra-
tion of the buffer in dialysate. High concentrations of bicar-
bonate will increase blood pH which increases the number
of anionic sites on albumin increasing albumin binding. The
decrease in ionized magnesium is reported to be 0.12 mmol/
L per pH unit.48
Peritoneal Dialysis
Traditional peritoneal dialysis solutions magnesium con-
centrations of 0.75 mmol/L are associated with hypermag-
nesemia.49-51 Magnesium is affected by ultrafiltration, and
excretion increases with the use of hypertonic solutions.52
MAGNESIUM BALANCE IN TRANSPLANTATION
Hypomagnesemia has been reported with the use of CNIs
with variable incidence rates reported; 1.5-100% with a
median of 60%.53-62 The incidence is generally higher
with tacrolimus compared with cyclosporine.54,60,63
Transplant patients treated with CNIs have increased
urinary fractional excretion magnesium (FEMg) and
magnesium wasting.53,64 The mechanism is probably
decreased kidney expression of epidermal growth factor
(EGF) and TRPM6.53,65 EGF binds to the EGF receptor
and this activates TRPM6 in the DCT.11,66,67 Tacrolimus
was found to decrease expression of both the calcium
channel TRPV5 and the magnesium channel TRPM6
leading to hypercalciuria and hypomagnesemia.64 A study
showed that there is an inverse relationship between urinary
EGF and FEMg in kidney transplant patients treated with
cyclosporine.67
Magnesium balance is important after transplant for a
number of reasons. Numerous studies have now linked
hypomagnesemia post-transplant to post-transplant dia-
betes mellitus (previously new-onset diabetes after trans-
plantation).68 There is also increasing evidence that
magnesium supplementation can abrogate CNI nephro-
toxicity in animal models.69 Various models have shown
that magnesium prevents CNI-associated fibrosis, macro-
phage, and monocyte recruitment and attenuates
cyclosporine-induced reduction in kidney nitric oxide pro-
duction.69-71
CONCLUSION
The kidneys provide the main route for magnesium excre-
tion, and we have seen how tubular function is responsible
for regulating magnesium balance in health and in mild
CKD. As GFR declines, serum magnesium concentrations
tend to be higher, but drugs and disease states can induce
magnesium deficiency. It is also important to remember
that the serum magnesium concentration represents just
294 Oliveira et al
1% of total body stores. Magnesium levels in the
low-normal range can therefore still be consistent with
deficiency that warrants correction. Dialysis has its own
unique influences on magnesium balance. Biological fac-
tors of the patient and constituents of the dialysate
contribute to the transfer of magnesium during dialysis.
We have also seen how magnesium is also influenced by
several factors in the setting of kidney transplantation, in
particular CNIs.
Magnesium is increasingly recognized as a factor influ-
encing a number of diseases that have particular relevance
in chronic kidney disease. An understanding of how mag-
nesium balance is affected across the spectrum of chronic
kidney disease, dialysis, and transplantation is, therefore,
of importance for all those involved in the care of these pa-
tients.
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