The effect of intradialytic supplementation in chronic hemodialysis patients; a pilot study

Dialysis is a life-saving treatment, but unfortunately health-related quality
of life (HRQoL) of dialysis patients is poor and mortality risks are high
compared to the general population. Although several potentially modifiable
(e.g. pre-dialysis care and nutritional status) and unmodifiable risk factors
(e.g. age and genetics) for excess risk of mortality and poor HRQoL have been
identified in dialysis-dependent patients with chronic kidney disease (CKD),
there is great need for identification of new potentially modifiable risk
factors. We hypothesize that creatine deficiency is such a modifiable risk
factor, which underlies several important causes for impaired HRQoL
hemodialysis patients, such as protein energy wasting (PEW), sarcopenia,
fatigue, muscle weakness, depression, cognitive impairment, and increased
susceptibility and a higher risk of an adverse course of infectious diseases.
We propose that creatine supplementation is particularly important for patients
with dialysis-dependent CKD because (1) endogenous synthesis of creatine in
these patients is severely impaired due to the virtual absence of kidney
function and, consequently, the virtual absence of the first enzymatic step
required for endogenous absence of creatine from the amino acids arginine and
glycine (2) unopposed losses of creatine to the dialysis fluid during dialysis
sessions, and (3) inadequate intake of creatine due to advices towards a
primary plant-based diet in these patients. All this comes on top of the
normally existing continuous non-enzymatic conversion of approximately 1.6-1.7%
of the endogenous creatine pool to creatinine, which necessitates continuous
replenishment of creatine by the combination of endogenous synthesis and
dietary intake to remain in steady-state. This is a novel understanding because
until recently it was not recognized that kidney function is an important
contributor to endogenous creatine synthesis, so that the capacity to of
patients with dialysis-dependent CKD to maintain creatine homeostasis in the
light of ongoing conversion of creatine into creatinine, additional unopposed
losses of creatine to the dialysis fluid and an inadequate dietary intake is
severely impaired. Patients with dialysis-dependent CKD could benefit from
creatine supplementation by allowing for maintenance of their endogenous
creatine pools, which would help them to sustain bodily functions which depend
on creatine availability, including normal function of muscles, heart, the
immune system and brain. Based on these novel/ recent findings, we hypothesize
that creatine, intradialytic creatine supplementation may help to maintain
creatine homeostasis among dialysis-dependent chronic kidney disease patients,
and consequently improve muscle status, nutritional status, neurocognitive
status fatigue and HRQoL.

The primary objective of this pilot study is the feasibility of prolonged
intra-dialytic creatine supplementation.

The secondary objectives of this pilot study are to study the safety of
prolonged intra-dialytic creatine supplementation for dialysis patients and
finding the optimal dosage to replenish the creatine pool. To this end we will
step wisely increase creatine concentrations of the dialysis solution (in the
range of 0.5 mM to a maximum of 2mM, with the latter reflecting the
concentration that can be reached after an oral bolus of creatine).

The third objective is to obtain pilot data on the effect of intradialytic
creatine supplementation on muscle status, nutritional status, neurocognitive
status fatigue and HRQoL to allow for calculation of the power for a lager
intervention study.

Block-randomized double-blind placebo-controlled pilot study in 16 hemodialysis
patients (which will be divided into four groups (0.5mM, 1.0mM, 1.5mM, 2.0mM)
each consisting of three patients receiving creatine and one receiving
placebo). The total study duration is 8 weeks with 6 weeks of active treatment
and 2 weeks of wash-out.

Creatine will be added to the dialysis fluid and will thus be continuously
administered during the whole hemodialysis session. We will study the effect of
four increasing dosages of creatine (3 out of 4 patients per block) or placebo
(1 out of 4 patients per block) in four groups of four patients: 0.5mM, 1.0mM,
1.5mM, or 2.0mM of creatine. The patients will receive creatine supplementation
or placebo (sterile water with the same composition as the dialysate) during
each hemodialysis session during a total period of 6 weeks.
Creatine-monohydrate, Creapure® "Pharma Quality" (not GMP), produced by AlzChem
Trostberg, Germany will be used for preparation of a 50 mmol/L stock solution
of creatine which will be added to the dialysis fluid to reach the projected
dialysate concentrations.

Patients with dialysis-dependent CKD chronically suffer from multiple severe,
currently unresolved health problems and complaints, which together severely
impair HRQoL. Patients with dialysis-dependent CKD cannot endogenously
synthesize creatine and at the same time suffer from unopposed losses of
creatine to the dialysis fluid. The ensuing creatine deficiency may explain an
important part of the currently unresolved health problems and complaints from
which the patients with dialysis-dependent CKD suffer. The prevention of
occurrence of unopposed losses of creatine to the dialysis fluid may therefore
be of great benefit for the patients, while the burden and risks of
participation are negligible. The burden of participation is negligible because
the patients will anyway undergo a 4h dialysis session 3 times per week.
Addition of creatine to the dialysis fluid will not change this. Also the blood
sampling required for the study will not give any extra burden, because the
sampling will be performed via the connection with the bloodstream that has
been made to make the dialysis session possible. The only burden of
participation will come from the tests that will be performed and the
questionnaires that will be taken. The risks are also negligible because
creatine is a natural substance required for normal metabolism that will be
added to the dialysis fluid like now e.g. sodium, potassium, magnesium and
calcium as natural substances that are required for normal metabolism that are
already added to the dialysis fluid, also in order to prevent unopposed losses
to the dialysis fluid.