Twice Against Thrice-weekly Hemodialysis
Twice Against Thrice-weekly Hemodialysis
Hemodialysis is the most worldwide prescribed renal replacement therapy for patients with
 end-stage renal disease. The frequency of sessions per week remains a debatable issue. In the
 majority of developed Western and Asian countries, patients on chronic hemodialysis are
 undergoing three dialysis sessions weekly. In developing countries and some developed
 countries, a twice-weekly schedule independent of residual kidney function is still accepted,
 sometimes because of lack of resources and some other times because of patients' resistance
 to undergo three sessions per week. The primary objective of this trial is to assess the
 total mortality of patients on thrice against twice-weekly hemodialysis. The secondary
 objectives are a) to compare the rate of urgent supplementary hemodialysis sessions between
 the two arms, mainly those due to pulmonary edema and hyperkalemia, b) to compare the number
 of hospitalizations and duration of stay, c) to compare the rate of uncontrolled hypertension
 between the two groups, d) to analyze the quantity of erythropoiesis-stimulating agents
 (ESAs) in units to achieve a haemoglobin (Hb) 11 to 11.5 g/dl, e) to assess the factors
 associated with a higher mortality in the two groups.
Hemodialysis (HD) is the most worldwide prescribed renal replacement therapy for patients
 with end-stage renal disease. This treatment that relies heavily on technology has undergone
 major modifications in the last five decades in order to improve patients' outcomes. Those
 changes that aimed at reducing the morbidity and mortality of patients targeted mainly the
 water purification system, the membrane's permeability and biocompatibility, the dialysate
 composition and the dose of hemodialysis. However, the frequency of sessions per week remains
 a debatable issue influenced by the fluctuating scientific evidence and the patient's
 disapproval of being increasingly dependent on a machine.

 In the majority of developed Western and Asian countries, patients on chronic hemodialysis
 are undergoing three dialysis sessions weekly.

 In 2007 the European guidelines recommended the thrice-weekly hemodialysis with a session
 duration 3-5 hours. This dose of treatment will ensure hemodialysis sessions adequacy defined
 as urea reduction ratio >65% . However thrice-weekly hemodialysis has been established
 worldwide without randomized clinical trials. The rationale behind the thrice-weekly dialysis
 seems to be the uncertainty about dialysis adequacy and the risk of malnutrition, anemia and
 intra-dialytic hypotension with twice-weekly sessions. Several cohorts have also shown a
 favorable effect on survival with thrice compared to twice-weekly hemodialysis especially
 when duration of treatment per week of the twice-weekly schedule was less than 8 hours.

 Incremental hemodialysis is defined as starting dialysis twice weekly for those who have a
 substantial renal urea clearance and switching after 3 months to three times weekly. A large
 retrospective study from the US showed that incremental hemodialysis compared to conventional
 hemodialysis (three times per week) improved mortality in those with a renal urea clearance
 >=3 ml/min/1.73 m2 or urine volume > 600 ml/day. The rationale behind the incremental
 schedule is that preserving residual kidney function would lead to better outcomes. However
 based on this incremental method, patients should be watched closely for the residual kidney
 function and switched at the right moment to three sessions per week otherwise there will be
 an overlap between the two phases and an information bias regarding the timing of residual
 renal function loss.

 In developing countries and some developed countries, a twice-weekly schedule independent of
 residual kidney function is still accepted, sometimes because of lack of resources and some
 other times because of patients' resistance to undergo three sessions per week. Several
 studies have shown that patients on twice-weekly hemodialysis without residual kidney
 function have a shorter survival than those on three times per week. A recent prospective
 study from Korea showed that residual kidney function is not the only factor that would favor
 thrice over twice weekly HD. Another retrospective Indian study showed similar mortality
 between those on twice versus thrice-weekly HD while a Chinese observational study
 demonstrated longer survival in anuric patients on twice- than thrice-weekly dialysis. All
 these controversial studies make it unclear whether patients are still allowed to undergo
 twice-weekly hemodialysis.

 Lebanon is a developing upper middle-income country from the Eastern Mediterranean region
 where around 3800 patients are undergoing chronic hemodialysis three or twice weekly.
 Although the Lebanese Ministry of Public Health recommended in 2014 that all patients on
 chronic hemodialysis be dialyzed three times weekly, many nephrologists are still allowing
 the twice schedule if it is more convenient to the patients. With these circumstances,
 Lebanon appears an attractive place to study the difference in outcomes between the two
 hemodialysis schedules.

 Trial design This is a non-randomized, multicenter, clinical trial. Randomization was
 considered unethical and contradictory with the current international guidelines. Therefore
 patient's allocation was left at the nephrologist and patient's agreement.

 Crossover will be allowed during follow-up to limit attrition. This study will assess the
 equivalence between the two schedules.

 Methods: participants, interventions and outcomes

 Study setting Hemodialysis patients will be recruited from multiple Lebanese HD centers.
 Lebanon is divided into 9 governorates and includes 77 HD units. From each governorate 50% of
 the units will participate in the trial.

 Interventions Patients will be assigned to one of two groups upon their agreement with the
 treating nephrologist: Group 1 will receive three sessions of hemodialysis weekly. Group 2
 will receive two sessions weekly.

 Participant timeline Recruitment of patients will be done over two years or until the
 pre-determined sample size is reached whichever comes earlier.

 Sample size Knowing that the proportion of death varies between 10% and 40%, if we consider a
 two sided alpha of 5%, a power of 80% and a small effect size = 0.20 (Cohen's d), the total
 sample size needed would be 806 patients. Assuming an attrition rate of 10%, we would need
 806/0.9 = 896 patients. The representative sample size for this study is ~900 patients. 600
 patients are necessary for the three times weekly arm and 300 patients for the twice weekly
 arm.

 Recruitment It may be difficult to reach 300 patients on twice weekly so the recruitment will
 go on till this number is reached.

 Methods: Data collection, management, and analysis

 Data collection methods eCRF (electronic case report form) will be used for data capture.
 Data for demographics, comorbidities, laboratory results, medications and dialysis
 prescription will be collected from the patients' medical records at dialysis initiation.

 The following variables will be studied:

 Baseline characteristics: age, gender, body mass index (BMI), diabetes, smoking,
 hypertension, hyperlipidemia, cause of end-stage renal disease (ESRD), previous
 cardiovascular disease, atrial fibrillation, dementia, Laboratory: serum creatinine (with
 corresponding estimated glomerular filtration rate (eGFR), phosphate, calcium, albumin,
 potassium, sodium, bicarbonate, hemoglobin, parathyroid hormone (PTH), alkaline phosphatase,
 ferritin, transferrin saturation, uric acid, hepatitis B (HBV) and hepatitis C (HCV)
 serologies.

 Residual renal function: Urine volume and renal urea clearance will be assessed at baseline
 by collecting the 24 hour-urine at dialysis initiation.

 Medications: statins, calcium-based and non-calcium-based phosphate binders, vitamin D,
 antihypertensive medications, antiplatelet agents, erythropoiesis stimulating agents (ESA)
 dose, renin-angiotensin system inhibitors, oral anticoagulants.

 Dialysis prescription: Number of hours per week, blood flow, dialysate flow, type of vascular
 access (catheter, graft or arteriovenous fistula), filter membranes (surface, low-flux or
 high-flux), dialysate potassium and calcium content will be collected.

 Definitions Chronic kidney disease stage 5 is defined as an eGFR <15 ml/min. Coronary artery
 disease is defined as a history of myocardial infarction or obstructive coronary artery
 disease, treated medically or interventionally. Diabetes and hypertension are defined as
 having a history for antidiabetic or antihypertensive treatment respectively.

 Uncontrolled hypertension is defined as a pre-dialysis BP > 160/90 in more than 2/3 of the
 sessions. Residual kidney function is defined as a diuresis > 500 ml/d on a non-dialysis day.

 Statistical analysis Continuous variables will be presented as mean ± standard deviation
 (SD). Differences between the study groups will be tested using χ2 tests (for categorical
 variables). Bivariate correlation analysis will be performed using the Pearson's correlation
 coefficient. The Kaplan-Meier method will be used to estimate the cumulative survival. Cox
 regression will be used to determine the effect of dialysis frequency and other covariates on
 mortality. Analysis will be performed on an intention-to-treat basis. Statistical analysis
 will be performed with SPSS. A P-value of ≤0.05 will be considered statistically significant.

 Methods: Monitoring

 Data monitoring Follow-up with laboratory measurements and medication dosage Every month:
 hemoglobin, calcium, phosphorus, urea, creatinine, potassium, sodium, bicarbonate.

 Every 4 months: PTH, ferritin, transferrin saturation. Every year: lipid panel, albumin. All
 these biological parameters will be measured with the standard laboratory techniques and
 medications adjusted to maintain serum calcium, phosphate and PTH within the target range.

 Total ESA quantity used for each patient, as well as doses of alfacalcidol, cinacalcet,
 phosphate binders and antihypertensive treatment will be collected every 3 months.

 Clinical follow-up Data that will be collected monthly includes: mid-week pre-dialysis
 systolic and diastolic blood pressure, average interdialytic fluid gain, number, causes
 (myocardial infarction, angina, atrial fibrillation, pulmonary edema, hyperkalemia) and
 length of hospital stay (LOS), residual kidney function, number of vascular access
 thrombosis. Blood pressure will be recorded every week and presented as a monthly average.
Inclusion Criteria:

 -  all incident patients 18 years and older with CKD stage 5 started on hemodialysis.

 Exclusion Criteria:

 -  late-stage cancer patients and participants who are terminally ill defined as having
 an expected survival of less than 3 months.