DOI: 10.1111/jch.
13177
C O M M E N TA RY
Creatine kinase, sodium retention, and blood pressure: Is there
a link?
Roberto Pisoni MD1,2 | Mehrdad Hamrahian MD3 | Tibor Fülöp MD1,2
1
Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
2
Medical Services, Ralph H. Johnson VA Medical Center, Charleston, SC, USA
3
Division of Nephrology, Department of Medicine, Thomas Jefferson University, Pennsylvania, PA, USA
Correspondence
Tibor Fülöp, MD, Department of Medicine, Division of Nephrology, Medical University of South Carolina and the Ralph H. Johnson VA Medical Center, Charleston,
SC, USA.
Email: tiborfulop.nephro@gmail.com or fulopt@musc.edu
Creatine kinase (CK), also known as creatine phosphokinase, is the
central regulatory enzyme of energy metabolism and is reported to
be a potential causal factor in primary hypertension (HTN). It consists
of a dimer molecule and can be present in 3 distinct isoenzymes (MM,
MB, and BB). CK is expressed by various tissues and cell types, in-
cluding muscle, brain, and kidney and its concentration parallels to the
metabolic and energy demands of the tissues. The skeletal muscle has
1
the highest concentration of CK of all the tissues. At these locations,
CK fuels high-­energy demanding processes such as Na+/K+-­ATPase
at cell membranes and myosin kinase at the contractile proteins in
the skeletal muscles. CK does so by catalyzing the production of high-­
energy adenosine triphosphate (ATP) via the transfer of a phosphoryl
group from creatine phosphate (the major storage reservoir of energy
during muscle rest) to adenosine diphosphate.
Clinically, CK is widely used to detect muscle injury.2 If the serum
CK activity is high, the isoenzyme distribution is usually assessed. A
high serum CK-­MB activity is suggestive of cardiac muscle injury and is
still used to assess acute myocardial injury under select circumstances.
In resting subjects without overt muscle damage, serum CK activity
is considered a measure of tissue CK activity.3 Substantial evidence
linking serum (systemic) and tissue CK activity to blood pressure (BP)
has emerged over the last two decades, linking high tissue CK activity
to a greater risk of HTN.
High tissue CK precedes the onset of hypertension and antihy-
pertensive therapy lowers high tissue CK in animal models.4 CK inhi-
bition lowers blood pressure in spontaneously hypertensive rats and
decreases human vascular contractility.5,6 Serum CK activity after rest
has been independently associated with blood pressure (BP) levels in a
random sample of a multiethnic population in the Netherlands.7 These
data were replicated in another cross-­sectional population study from
8
Norway. The latter group of investigators also demonstrated this effect
during a longitudinal follow-­up, though the relationship was substan-
tially weakened by obesity, as expressed by body mass index (BMI).9 It
342 | ©2018 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/jch
has been speculated that a relative predominance of muscle fiber type
with higher CK phenotype (muscle fiber type II) may be a biological fac-
tor predisposing to both HTN and obesity. Moreover, CK activity after
rest is hypothesized to be a predictor of failure of HTN treatment.10
There is no evidence regarding HTN directly causing increased CK ac-
tivity by decreasing its clearance or damaging endothelial or cardiac
cells.11 In addition, normal CK isoenzymes have been detected in sub-
jects with higher CK values and uncomplicated HTN.
Thus, available evidence from animal and human studies has raised
the question about a possible causal relationship between CK and BP.
How could CK activity cause or contribute to an increased BP? It has
been hypothesized that high tissue CK activity, whether induced or
constitutive, could generate a greater ATP buffer capacity and subse-
quently increase cardiac contractility, vascular resistance, and sodium
retention as well as decrease nitric oxide bioavailability.12 At the level
of the kidney, high activity of CK, that is located near the basolateral
Na+/K+-­ATPase, might provide increased availability of ATP neces-
sary for sodium reabsorption. Sodium intake is a major determinant of
blood pressure with higher sodium intake being associated with higher
BP values and an increased cardiovascular risk,13 especially in salt sen-
sitive individuals. Factors involved in inter-­individual sodium retention
and subsequent intravascular volume expansion and increased BP are
not completely understood.
In this current paper, featured in this journal, Brewster et al14 ex-
plored, for the first time, the potential association between plasma CK
activity and sodium retention after a high sodium intake in 60 healthy
men, aged 18-­50. The study population was half Caucasian (European)
and half of African Continental ancestry. These inclusion criteria were
chosen based on known higher CK activity in men versus women and
in subjects from African ancestry versus Caucasians.15 The participants
were normotensive or (8 out of 60) with uncomplicated and untreated
essential primary HTN. Subjects with secondary forms of HTN, with
diseases, or taking medications that could affect plasma CK activity
J Clin Hypertens. 2018;20:342–344.

COMMENTARY
were excluded from the study. In particular, hypothyroidism, a known
cause of both elevated CK and a risk factor for HTN, was excluded by
a careful medical history evaluation and thyroid stimulated hormone
testing. Study participants were asked to avoid heavy exercise for
3 days prior to obtaining baseline serum CK activity. They were then
assigned to a low sodium (LS) intake (<50 mmol of sodium daily) for
7 days, followed by 3 days of high sodium (HS) intake (>200 mmol of
sodium daily), under the supervision of a dietician. The primary out-
come was to assess predictors of urinary sodium excretion after a HS
diet. Baseline, LS, and HS period variables for body weight, sitting BP,
heart rate, and 24-­hour urinary sodium excretion were studied.
Twenty-­four hour urine collections at the end of the LS diet
(day 7) and HS diet (day 10) periods confirmed patients’ adherence
to diet. High sodium intake led to a significant increase in systolic
blood pressure (SBP) and weight as compared to when the subjects
were on low sodium intake. Plasma CK activity was inversely cor-
related with the 24-­hour urinary sodium excretion after high sodium
intake. In particular, sodium excretion was 260.4 mmol/24 h after
high sodium intake in the high CK tertile versus 415.2 mmol/24 h in
the low CK tertile (P < .001). African ancestry was strongly inversely
correlated with urinary sodium excretion and directly correlated
with CK activity, as shown previously.7 However, ancestry and age
did not fully explain the correlation between CK activity and sodium
retention. Participants in the high tertile of CK activity experienced
a smaller increase in both SBP and diastolic blood pressure (DBP)
when exposed to high sodium intake than those in the low tertile
of CK. Thus, they were seemingly less sensitive in terms of BP re-
sponse. This fact is in conflict with the same subjects retaining more
sodium after high sodium intake. Whether this is due to chance,
because of the relatively small sample size, or to the use of a less
accurate method of BP measurement (office BP instead of 24-­hour
ambulatory BP monitoring) is unknown. If this finding is confirmed,
it would suggest that the increased renal sodium reabsorption is
not the sole mechanism by which CK activity may contribute to BP.
As the authors pointed out,14 the association between resting
plasma CK activity and sodium retention does not imply any causal re-
lationship, but it certainly adds up to the available findings linking CK
activity and BP. Future studies should clarify if there is an association
between renal tissue CK and urinary sodium excretion to confirm the
assumption that the standardized plasma activity of CK reflects its cel-
lular function. It would also be important to assess the plasma aldoste-
rone and renin activity in the subjects exposed to high sodium intake
and see if they differ in CK activity. Recently emerging “gold standard”
methods of volume assessment, such as bioimpedance monitoring,
would add additional valuable information in future studies, includ-
ing the ability to assess fluid spaces, volume expansion, and defining
the relative proportions of fat and muscle volumes of the subjects,16,17
moving beyond the current definitions of obesity, such as BMI and
waist circumference. It would also be of interest to investigate if the
association between resting CK activity and sodium retention is only
limited to acute changes in sodium intake, as investigated in the cur-
rent paper by Brewster et al.14 In addition, it would be interesting to
see the effects of diuretic use on the CK activity of subjects exposed
17517176, 2018, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/jch.13177 by Turkey Cochrane Evidence Aid, Wiley Online Library on [31/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
| 343
to a high sodium diet. Last, the best way to define a causal relationship
between CK activity and urinary sodium excretion would be to repeat
this experiment assessing BP and urinary sodium excretion after a high
sodium diet before and after administering beta-­guanidinopropionic
acid, a CK inhibitor that is now available for human use.18 We are
looking forward to more studies offering a better understanding on
this new and exciting area of clinical HTN. As it was pointed out in
an editorial by Dr. Pickering almost a decade ago in this journal, “ge-
netically determined variations in muscle fiber composition could well
be of considerable importance in furthering our understanding of the
deadly combination of HTN, obesity, and type 2 diabetes”,19 our un-
derstanding continues to evolve on this subject.
AC KNOW L ED G M ENTS
We sincerely appreciated the assistance of Mr. Attila Lénárt-­Muszka
during grammar review.
D I S C LO S U R ES AND CO NFL I C T O F I NT ER ES T
S TAT EM ENT
The authors alone are responsible for the content and writing of the
paper. The authors have read and understood the journal’s policy on
disclosing conflicts of interest and declare that they have none to re-
port. This study did not receive any research funding.
O RC I D
Tibor Fülöp http://orcid.org/0000-0002-3346-7040
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How to cite this article: Pisoni R, Hamrahian M, Fülöp T.
Creatine kinase, sodium retention, and blood pressure: Is there a
link? J Clin Hypertens. 2018;20:342–344.
https://doi.org/10.1111/jch.13177