RandomizEd ClinicAL triaL on the Efficacy and saFety of Incremental Hemodialysis (REAL-LIFE)

The majority of dialysis patients starting hemodialysis (HD) are currently treated with a fixed dose thrice-weekly HD (3HD/wk). The 3HD/wk regimen has been assumed, until recently, almost as a dogma in the dialysis community. Incremental HD is based on the simple idea of adjusting its dose according to the metrics of RKF. REAL LIFE is a pragmatic, prospective, multicentre, open label RCT, investigator-initiated, comparing the intervention arm (incremental HD) with the control arm (standard 3HD/wk). A Variable Target Model (VTM) has been suggested, which gives more clinical weight to the RKF and allows less frequent HD treatments in patients with lower RKF. The investigators recommend to start and keep on with once-weekly HD, which should be possible until residual renal urea clearance (KRU) falls below 2.5 - 3.0 mL/min/35 L, i.e., glomerular filtration rate (GFR) ≈ 4 mL/min/1.73 m2.

The primary outcome is the survival of kidney function, with the event defined as urinary output (UO) ≤ 200 mL/day, confirmed by a further collection after 2 weeks to exclude temporary illness. Secondary outcomes are: composite primary cardiovascular endpoint (cardiovascular death, non fatal myocardial infarction and/or or non fatal stroke); intima-media thickness of the carotid arteries; specific cardiomyopathy control; RKF preservation; patients survival; hospital admissions; anemia control; mineral and bone disorder control, and middle molecules removal.

The sample size calculation is based on the primary outcome "presence of anuria". The assumptions for calculating the sample size, derived from data of Teruel Briones et al., are the following:

• Percentage of subjects who developed anuria in the experimental group (incremental HD): 25%
• Percentage of subjects who developed anuria in the control group (standard 3HD/wk): 51%
• Power: 0.8
• Ratio: 1:1
• Non-compliance: 20%
• Total expected sample size: 190 (95 participants in each group)

The assessment of the key kinetic parameters as well as the guide to the selection of operative parameters, as required to get the required equilibrated Kt/V (eKt/V = 1.05), will be done by using SPEEDY, a spreadsheet prescription tool that uses essentially the same equations used by Solute Solver, the software based on the double pool UKM recommended by the 2015 KDOQI guidelines. SPEEDY is freely available at the European Nephrology Portal (ENP).

The link is https://enp-era-edta.org/174/page/home. The control arm includes patients put on a thrice-weekly HD schedule, as detailed above. The dialysis dose (eKt/V) should be about 1.05.

PICO question:

Participants with CKD-EPI GFR ≤ 10 ml/min and daily urine output > 600 ml Intervention: one or two weekly hemodialysis (as detailed above) Comparator: three weekly hemodialysis (as per standard practice and as detailed above) Outcome: Residual renal function

Inclusion criteria

• Adults aged > 18 years
• Start of maintenance hemodialysis treatment due to advanced CKD stage 5D
• Patients who are about to start HD or have already started HD within a period of ≤ 2 weeks
• Glomerular filtration rate <= 10 mL/min/1.73 m2, as estimated by means of CKD-EPI formula.

Exclusion criteria

• Age < 18 years
• Acute kidney injury or acute on chronic kidney injury
• eGFR higher than 10 mL/min/1.73 m2
• UO < 600 mL/day
• Already treated with other replacement therapies (peritoneal dialysis or kidney transplant)
• Unable or unwilling to give informed consent.
• Unable to comply with trial procedures, e.g., collection of UO.
• Likely survival prognosis or planned modality or centre transfer < 6 months.
• Patients who are in the waiting list for a living kidney transplant
• Associated diseases: active neoplastic disease; refractory congestive heart failure (type IV NYHA, ejection fraction ≤ 30%) requiring high ultrafiltration volumes per session.