The microcirculation, dialysis modality and sequestered salt (the MIMOSA study)

Life expectancy of patients with end-stage kidney disease (ESKD) is extremely
poor. Post-dilution online hemodiafiltration (HDF) is associated with reduced
mortality, if compared to conventional hemodialysis (HD), especially when high
convection volumes are achieved (high-volume HDF; hvHDF). It is unclear,
however, why (hv)HDF improves outcomes. Neither increased clearance of
middle-molecular weight uremic toxins nor improved bio-incompatibility seems to
explain the difference. As the effects are already observed within 2.5 years of
treatment, improvement of a functional disorder is more likely than restoration
of structural alterations. Possibly, improvement of vascular dysfunction is the
missing piece of the puzzle. Previous literature showed that (1) the
microcirculation (MC) is severely disturbed in dialysis patients, (2) sodium is
a potentially dangerous uremic toxin and can bind to glycosaminoglycans without
commensurate water retention (sequestered sodium content [SSC]) and (3) in
patients with non-dialysis dependent chronic kidney disease (CKD), a disturbed
SSC is related to capillary rarefaction. We hypothesize that (1 and 2) the SSC
and the MC are better preserved in hvHDF than in HD, (3) a lower dialysate
sodium content leads to a reduced loading of the SSC and (4) the SSC and MC
function are interrelated.

Four hypotheses will be investigated. First and second, we will evaluate
whether treatment with hvHDF has dissimilar effects on the SSC and MC function,
if compared to HD. Next, we will assess whether disorders of the SSC and the MC
are influenced by the sodium balance, estimated as *dialysate sodium [DNa]
minus plasma sodium [PNa]*. Lastly, we will investigate whether the SSC and MC
are interrelated in this patient group.

Randomized cross-over intervention trial

Participants will be subjected to 5 dialysis treatments in random order:
1. Hemodialysis (HD) with net sodium balance: (Dialysate sodium (DNa)= Plasma
sodium (PNa))
2. HD with net sodium efflux (DNa < PNa, difference -3 mmol/L);
3. HD after isolated ultrafiltration (DNa = PNa);
4. High-volume HDF (hvHDF) with net sodium balance (DNa = PNa);
5. hvHDF with net sodium efflux (DNa < PNa, difference -3 mmol/L).

Study treatments will be performed instead of regular dialysis treatments.
These are established treatment modalities. However, a lower DNa has been
associated with more intradialytic hypotension. Furthermore, a higher DNa has
been associated with increased ultrafiltration (UF) need. The extra burden for
patients encompasses 5 MRIs to assess SSC before dialysis (for which they need
to visit the Spinoza Center in Amsterdam Zuidoost) and in 5 patients, both
before and after dialysis an MRI will be performed (so 10 MRIs); the MC
function will be evaluated at the same time points and for these measurements,
acethylcholine (Ach) and sodium nitroprusside (SNP) will be administered
through iontopheresis (considered non-invasive); at baseline blood will be
drawn once before dialysis and at 5 time points, blood will be drawn both
before and after dialysis from the extracorporeal circuit (thus no venepuncture
is necessary, total required blood volume= 181 ml); blood pressure measurements
will be performed 4 times per hour during dialysis treatments and patients are
requested to measure their blood pressure at home three times daily for 1 day
per treatment period; lastly, participants will be asked to fill in 3
questionnaires at 5 time points.