RandomizEd ClinicAL triaL on the Efficacy and saFety of Incremental Hemodialysis
Phase: NA
Conditions: End Stage Renal Disease on Dialysis
Sponsor: Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari

 
 
 
PROTOCOL OF REAL LIFE 
 
REAL LIFE is a randomized controlled clinical trial (RCT) on the efficacy 
and safety of incremental hemodialysis. REAL LIFE is the acronym of 
RandomizEd clinicAL triaL on the effIcacy and saFety of incremental 
haEmodialysis 
 
RATIONALE 
               Most patients with kidney failure begin dialysis with a thrice a week hemodialysis 
(HD) regimen (3HD/week), ideally 4 hours per session, with little individualization of the 
prescription based on residual kidney function (RKF) or other factors of the patient (1,2). 
Although this is a consolidated practice and considered "standard of care", empirical 
evidence suggests that other therapeutic regimens, such as incremental HD, could be taken 
into consideration in the initial phase of HD treatment, favoring a progressive "adaptation" 
of the patient to the dialysis treatment. Then, the number of weekly dialysis sessions could 
be progressively increased, bearing in mind that a non-negligible number of patients retain 
RKF at the start of HD treatment (2). In particular, there is the scientific equipoise for the 
comparative evaluation, in the context of RCTs, of the benefits and risks of therapeutic 
regimes starting HD treatment with 1 or 2 HD sessions per week compared to the standard 
approach which involves 3 HD sessions a week (3). An RCT is necessary and requested by 
the clinical-scientific community to evaluate whether starting a HD treatment with a lower 
number of sessions in the presence of RKF is adequate, harmful or equivalent compared to 
starting a standard dialysis treatment with a thrice a week HD regimen (2,3).  
 
The optimal dialysis regimen for incident patients on HD is unknown. It is plausible that 
the routine practice of 3HD/week regimen is due to purely organizational needs, and does 
not take into account RKF, and that direct initiation with a 3HD/week regimen could 
accelerate the loss of RKF (2-6). The incremental HD approach is based on the idea of 
adjusting the dialysis dose in the initial phase of dialysis treatment based on the metrics of 
RKF. Indeed, most patients who begin dialysis maintain some degree of RKF, with residual 
renal clearance of urea (Kru) > 3 ml/min and urinary output > 500 ml/day (1-3). In 
particular, in the latest report from the United States Dialysis Registry (2021 USRDS 
related to the year 2019), 13% of incident patients started dialysis with an estimated 

 
 
glomerular filtration rate (eGFR) < 5 ml/min/1.73 m2; 48% with eGFR between 5 and 10 
ml/min/1.73 m2; 28% with eGFR between 10 and 15 ml/min/1.73 m2; and 11% with eGFR 
> 15 ml/min/1.73 m2 (1). 
Given the importance of preserving RKF in conservative therapy, and given that the 
initiation of a 3HD/week regimen represents a trauma for the patient, it is important to 
consider the possible contribution of RKF in incident patients on HD and evaluate if the 
paradigm of a 3HD/week regimen approach to treatment could not undergo a change: 
patients with residual diuresis could start treatment with a lower number of weekly dialysis 
sessions, and then move on to a higher number of weekly treatments based on the reduction 
of the same diuresis and Kru.  
 
               The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, based on 
scientific evidence from RCTs and prognostic studies, suggest that minimum objectives of 
adequacy of the dialysis dose (Kt/V) can be reduced in patients with Kru > 2 ml/ min/1.73 
m2 (7). The European Best Practice Guidelines recommend measurement of RKF in 
incident patients on HD, using the mean of urea and creatinine clearance, and suggest how 
to incorporate RKF into the HD prescription: this allows for individual adjustments of 
dialysis prescription to achieve minimum dialysis adequacy goals (8). Given this premise, 
there are solid scientific assumptions for the design and conduct of a randomized 
intervention study, aimed at evaluating the benefits and risks of incremental HD (starting 
with 1 or 2 HD sessions a week with progressive increase up to 3 HD sessions a week) 
compared to the standard clinical practice (3HD/week) (9). Some studies of this type have 
already been designed and conducted and others are underway (10-13).  
 
Furthermore, chronic kidney disease (CKD) is characterized by the alteration of the hydro-
electrolyte balance, acid-base balance, tendency to volume overload, alteration of the 
homeostasis of the hormonal systems and accumulation of uremic toxins with 
repercussions on the survival of the patients, determined mainly by fatal cardiovascular 
events (7). Among the uremic toxins of greatest interest, indoxyl sulfate (IS) and para-
cresol sulfate (pCS) are associated with the progression of kidney damage and with uremic 
complications and cardiovascular damage, such as vascular calcification and arterial 
stiffness, which increase the risk of mortality in patients with CKD (14,15). To date, HD 
represents the most effective therapy for eliminating uremic toxins in patients with kidney 
failure; however, different approaches in HD regimens could have repercussions on serum 
IS and pCS levels, as well as on related cardiovascular events (14,15). 

 
 
 
OBJECTIVES OF THE STUDY  
The aim of this RCT is to compare the standard 3HD/week approach with an incremental 
HD approach (1 or 2 sessions a week with subsequent increase to 3 sessions a week). 
 
METHODS  
Design of the study 
REAL LIFE is an RCT on the efficacy and safety of incremental HD. REAL LIFE is the 
acronym for RandomizEd clinicAL triaL on the effIcacy and saFety of incremental 
haemodialysis (NCT04360694). It is a randomized, prospective, multicenter, non-blinded, 
independent study comparing incremental dialysis (experimental group) with the standard 
3HD/week regimen (control group). Incident patients will be randomized 1:1 centrally into 
one of the two treatment groups, after obtaining informed consent and within 2 weeks from 
the start of dialysis to prevent a potential irreparable impairment of RKF due to a previous 
intensive dialysis approach. 
There are no differences between treatments for patients in the two groups, other than the 
frequency of treatment. The type of HD method envisaged is a high-flow HD with highly 
biocompatible membranes or hemodiafiltration. 
Recruitment will be open for as long as is necessary to reach the expected sample size, 
while follow-up will be for 24 months. 
 
Identification of the eligible population 
Individuals of both sexes aged ≥18 years who meet the following characteristics are eligible 
for the REAL LIFE study: 
 
INCLUSION CRITERIA 
1. Adult patients (>18 years) with kidney failure who are starting HD  
2. Patients who have already started HD since ≤ 2 weeks 
3. Patients with eGFR < 10 ml/min/1.73 m2 (CKD EPI), key criterion recommended for 
starting HD treatment 
4. Patients with urine output ≥ 600 ml/day 
5. Patients able to understand and sign the informed consent; who agree to carry out the 
monthly 24-hour urine collection until urine output is ≤ 200 ml/day; who agree to increase 
the dialysis frequency based on the Kru values foreseen by the protocol 
 

 
 
 
EXCLUSION CRITERIA 
1. Patients with acute kidney injury or acute kidney injury on CKD 
2. Patients already treated with other replacement therapies (peritoneal dialysis or kidney 
transplant) 
3. Patients with an active cancer, severe heart failure or ejection fraction ≤ 30%, or life 
expectancy < 6 months 
4. Patients who are in the waiting list for a living kidney transplant or with a planned 
transfer to other dialysis modalities or to a dialysis center not participating in the REAL 
LIFE study 
 
TREATMENTS 
Experimental group 
The experimental group will perform incremental HD. It adopts the so called variable target 
model (VTM), recently introduced by Casino and Basile (16). VTM allows to start dialysis 
treatment with just one HD session per week, if the Kru is between 3.0 and 4.5 ml/min/1.73 
m2. One HD session a week will be maintained, unless differently decided by the 
investigator, until the Kru drops below 2.5 – 3.0 ml/min/1.73 m2 or the GFR is 
approximately 4 ml/min/1.73 m2; then, patients in the experimental group will transition to 
2 HD sessions a week until Kru drops below 1.5 ml/min/1.73 m2, progressing to 3 HD 
sessions a week.  
Where the investigator's judgment does not include the possibility of starting a once a week 
treatment or expressly requested by the patient, it will be possible to start with a twice a 
week treatment, with a subsequent transition to the standard dialysis treatment of 
3HD/week in the presence of a Kru lower than 1.5 ml/min/1.73 m2. All patients will receive 
the same dialysis dose of equilibrated Kt/V (eKt/V) = 1.05, corresponding to a single pool 
Kt/V (spKt/V) = 1.2 per session, which is the minimum value recommended by the KDOQI 
guidelines (7), with the frequency of sessions changing as a function of the Kru value for 
the patients in the experimental group. 
In addition to the decline of Kru there are 3 other conditions that can lead to intensification 
of the dialysis treatment and in particular: 
- Need for ultrafiltration rate > 13 ml/kg/hour, despite an adequate use of diuretics (17) 
- Severe clinical problems of the patient requiring intensive treatment 
- Patient decision 
 

 
 
The progression pattern from once a week to thrice a week dialysis in the experimental 
group is shown in Figure 1. 
 
Control group 
The patients in the control group will undergo the standard 3HD/week regimen, with eKt/V 
= 1.05, corresponding to a spKt/V = 1.2 per session. 
 
OUTCOMES 
Primary outcome 
Preservation of RKF (assessed as presence/absence of anuria and time to anuria). The event 
is defined by the achievement of a urinary output ≤ 200 ml/day (18), confirmed at the next 
monthly check-up, to exclude a contingent condition. 
 
Secondary outcomes  
Decreased Kru, all-cause mortality, loss/malfunction of the vascular access, fatal and non-
fatal cardiovascular events, hospitalizations for any cause, alterations in uremic toxin levels 
(IS and pCS), and other parameters of CKD (anemia, calcium-phosphorus metabolism, 
etc.). 
 
Patient’s Questionnaire Survey: Patient’s Satisfaction 
A patient’s questionnaire survey will be used to evaluate and compare the effects of 
incremental HD with that of standard HD on patient’s compliance and satisfaction level. 
We will use the questionnaire adopted in the publication by Karkar et al (19). It is focused 
on 16 out of the 44 questions of the validated Kidney Disease Quality of Life Short Form 
(KDQOL-SF) version 1.3 (http://www.rand.org/health/surveys_tools/kdqol.html). The 
questionnaire is based on HD-associated complications that are usually of concern to 
dialysis patients. Each question has a score ranging from 0 to 100, where 0 indicates the 
lowest and 100 the highest grade of satisfaction (eCRF Form 3). 
The answer to each question is based entirely on the patient’s own subjective assessment 
within the score range. The form is distributed by the local study nurses who help the 
patients fill in the forms and show them the way to score their answers, if necessary. 
Each patient, in both groups, is asked to answer a sheet of the questionnaire at the beginning 
of the study and every 6 months until the completion of the study.  
 
 

 
 
 
All participants will be monitored until the study is completed, including patients who will 
not complete the study due to death, kidney transplant, interruption of dialysis (e.g., 
recovery of kidney function), transfer to another dialysis center or interruption of the study 
due to the patient's decision. The data will be analyzed according to the "intention to treat" 
principle. 
 
DATA MANAGEMENT 
Baseline data and subsequent clinical data (body weight, diuresis, arterial blood pressure), 
biochemical data (pre- and post-dialysis blood tests as routinely performed in the dialysis 
center, creatinine and urea clearance) and number and cause of hospitalizations will be 
recorded. Furthermore, every six months, starting from the beginning of the study, a pre-
dialysis blood sample will be drawn to carry out serum uremic toxin measurements (IS and 
pCS). 
 
Calculation of kinetic parameters and prescription of dialysis 
The calculation of the main kinetic parameters and of dialysis prescription, aimed at 
obtaining an eKt/V ≥ 1.05, corresponding to spKt/V ≥ 1.20, for each session of each patient, 
will be carried out using SPEEDY, an extremely simplified software dedicated to the 
prescription of incremental HD, recently developed by Casino and Basile (20). It 
essentially uses the same equations used by Solute Solver (21), the software based on the 
double pool urea kinetic model recommended by the 2015 KDOQI guidelines (7).  
 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) is established to monitor the 
progress of the study and ensure that the safety of participants enrolled in the study is not 
compromised. The DSMB consists of 3 members. The DSMB will meet at least once a 
year. In case of an efficacy or safety issue, the DSMB will meet ad hoc as soon as possible. 
The independent DSMB will review safety data and main outcomes at regular intervals. 
Reports and recommendations (continue, amend or stop the study based on findings) will 
be reported to the Project Coordinator. 
 
Security checks  
Adverse events of special interest (AESIs) and serious adverse events (SAEs) will be 
assessed from the signing of Informed Consent Form until end of the study for the 

 
 
participant. If the participant drops out (e.g. due to kidney transplantation or switch to other 
dialysis modality) he/she will still be followed for mortality and morbidity until the date 
that he/she was intended to end study participation. 
 
AESIs 
The following pre-dialysis laboratory parameters as checked at the monthly blood tests are 
collected as AESIs: 
Hyperkalemia: serum potassium > 6 mmol/l 
Hyperphosphatemia: serum phosphate > 6 mg/dl 
Acidosis: serum bicarbonates < 18 mmol/l 
Any supplemental dialysis session prescribed because of the occurrence of signs and/or 
symptoms of uremia, volume overload, hyperkalemia, etc., is collected as AESI. 
 
SAEs 
A SAE is defined as any adverse event that 
• Led to death; 
• Led to serious deterioration in the health of the participant, that either resulted in 
o A life-threatening illness or injury, or 
o A permanent impairment of a body structure or a body function, or 
o Inpatient hospitalisation or prolonged hospitalisation, or 
o Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
• Any important medical event and any event which, though not included in the above, may 
jeopardize the patient or may require intervention to prevent one of the outcomes listed 
above. 
Planned hospitalisation for a pre-existing condition, or a procedure required by the 
protocol, without serious deterioration in health, is not considered a SAE. 
Hospitalisation is defined as at least one night’s stay (eCRF Form 9).  
The REAL LIFE study will be conducted in full conformance with the principles of the 
“Declaration of Helsinki” (64th WMA General Assembly, Fortaleza, Brazil, October 2013) 
(22) and with the laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the participant. 
 
STATISTICAL ANALYSIS  

 
 
The study data will be reported in a descriptive and inferential manner using standard 
techniques. The study data will be analyzed according to the “intention-to-treat” principle. 
 
Sample size calculation 
The sample size calculation is based on the primary outcome “presence of anuria”, defined 
as urine output < 200 ml/day (18), confirmed at the next monthly check, in order to exclude 
conditions of temporary reduction in urine output due to concomitant pathologies. The 
assumptions for calculating the sample size, derived from data of Teruel Briones et al. (23), 
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/week 
regimen): 51%                     
- Power: 0.8 
- Ratio: 1:1 
- Non-compliance: 20% 
- Total expected sample size: 190 (95 participants in each group) 
 
CONCLUSIONS     
The optimal dialysis regimen for incident patients on HD is unknown. It is plausible that the 
routine practice of 3HD/week regimen in incident patients with RKF may contribute to 
accelerating its loss and may not represent the optimal approach for initiating dialysis 
treatment. 
Despite growing evidence from observational studies supporting the use of incremental 
HD, conclusive RCTs evaluating the benefits and risks of incremental HD are lacking. If 
the potential benefits of incremental HD will be confirmed by our REAL LIFE study, 
starting dialysis with a 3HD/week regimen will subject patients to unnecessarily long 
and/or more frequent treatments at higher costs (24).  
 
Our study is particularly important because it aims to evaluate the adequacy of incremental 
HD starting with once a week session in patients with a relatively low Kru (around 3.0 
ml/min/1.73 m2) and with a moderately low protein intake, at variance with other studies 
that start incremental HD with a twice a week regimen with the same Kru values indicated 
above (10, 12, 13), or at variance with another study that starts dialysis with once a week 
session, but with a very strict low-protein diet and in selected patients (25).  

 
 
It is also important to note that the adequacy of the proposed once a week HD treatment is 
based on the so-called VTM of equivalent renal urea clearance (EKR) of urea (16). 
Therefore, the REAL LIFE study could also be able to validate the VTM. 
 
 
 
Project Coordinator 
Carlo Basile 
 
 
Principal Investigators 
Francesco G Casino 
Carlo Basile 
Loreto Gesualdo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Figure 1