an evidence report for the kidney disease outcomes quality ...the publication of the kidney disease...

An Evidence Report for the Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines and Recommendations for Hemodialysis Adequacy Prepared for: National Kidney Foundation 30 East 33rd Street New York, New York 10016 Prepared by: Minnesota Evidence-based Synthesis Program Minneapolis VA Center for Chronic Disease Outcomes Research Minneapolis Minnesota 55417 Investigators Yelena Slinin, MD Areef Ishani, MD, MS Nancy Greer, PhD Roderick MacDonald, MS Carin Olson, MD, MS Indulis Rutks, BS Timothy J. Wilt, MD, MPH

CONFIDENTIAL: DO NOT DISTRIBUTE

ABSTRACT Background: Nearly 400,000 patients are treated with hemodialysis in the United States. Determining optimal hemodialysis adequacy as determined by timing of initiation, frequency, duration, and type is important in improving patient outcomes and reducing health care costs. Purpose: Systematically review the evidence on the timing of initiation of hemodialysis, frequency and duration of hemodialysis, and type of hemodialysis performed. Data Sources: MEDLINE (Ovid) from 2000 to March 2014, recent systematic reviews, clinicaltrials.gov. Study Selection: We included randomized (RCT) or controlled clinical trials (CCT) published in English language in subjects undergoing long-term hemodialysis for chronic kidney disease if they reported primary (all-cause mortality) or secondary (cardiovascular mortality, myocardial infarction, stroke, all-cause hospitalization) outcomes of interest. Data Extraction: Trained investigators extracted study characteristics, patient characteristics, and outcomes. Extraction was verified by a second investigator. We assessed individual study risk of bias and quality of the overall body of evidence for specific outcomes using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Data Synthesis: We qualitatively summarize results according to key questions, interventions, and outcomes. We pooled results for all-cause mortality and cardiovascular mortality if clinical heterogeneity was minimal. Due to heterogeneity of study designs and interventions, we were unable to pool data for most interventions. Results: We included 42 articles reporting on 28 trials. Moderate quality evidence indicated that delaying dialysis initiation until an estimated creatinine clearance (eCrCl) of 5-7 ml/min in the absence of uremic symptoms compared to initiation at an eCrCl of 10-14 ml/min did not increase mortality, stroke, myocardial infarction, or access-related harms. Later initiation resulted in lower dialysis-related costs. We found very low quality of evidence over a short follow-up duration that more than thrice weekly or extended length hemodialysis did not improve clinical outcomes compared to conventional hemodialysis but resulted in a greater number of vascular access procedures. We found moderate quality evidence that hemodialysis using high-flux membranes did not reduce all-cause mortality but did reduce cardiovascular mortality compared to hemodialysis using low-flux membranes and that hemodiafiltration reduced all-cause mortality and cardiovascular mortality compared to hemodialysis. We found low quality of evidence that hemofiltration did not reduce all-cause mortality and very low quality of evidence that hemofiltration did not reduce cardiovascular mortality compared to low-flux dialysis. There was insufficient evidence on access- or dialysis-related complications. Limitations: Few studies were adequately powered to evaluate mortality or other clinical outcomes. Many studies were of short duration. Conclusions: Limited data from RCTs and CCTs indicate that earlier, more frequent, and longer hemodialysis and hemofiltration do not improve clinical outcomes compared to standard hemodialysis. Hemodiafiltration reduces mortality compared to hemodialysis. There is limited information on other outcomes including quality of life.

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TABLE OF CONTENTS INTRODUCTION ..................................................................................................................... 1 Scope and Key Questions ............................................................................................................ 2 METHODS ................................................................................................................................ 5 Search Strategy ........................................................................................................................... 5 Study Selection ........................................................................................................................... 5 Data Abstraction and Risk of Bias Assessment ............................................................................ 6 Rating the Overall Quality........................................................................................................... 6 Data Synthesis and Analysis........................................................................................................ 7 RESULTS .................................................................................................................................. 8 Literature Flow ........................................................................................................................... 8 Topic 1. Timing of Dialysis Initiation.......................................................................................... 9 Topic 2. Hemodialysis Frequency ............................................................................................. 13

Studies that Altered Only Frequency ..................................................................................... 13 Studies that altered both Frequency and Treatment Time ...................................................... 18

Topic 4. Limits on Treatment Time, Ultrafiltration, Volume and Blood Pressure Control .......... 23 Topic 5. Membranes and Convective Therapies ........................................................................ 29 High-flux Membranes Compared to Low-flux Membranes ........................................................ 29 Hemodiafiltration (HDF) Compared to High-flux and Low-flux Hemodialysis (HD) ................ 34 Hemofiltration (HF) Compared to Low-flux Hemodialysis ........................................................ 40 SUMMARY AND DISCUSSION BY TOPIC ........................................................................ 44 REFERENCES ........................................................................................................................ 51 TABLES Table 1. Definitions of Quality of Evidence According to GRADE ............................................. 7 Table 2. Summary of Study Baseline Characteristics - Initiation of Hemodialysis (Topic 1, Key Questions 1 and 2)..................................................................................................................... 10 Table 3. GRADE Evidence Profile: Timing (Early versus Late) of Dialysis Initiation ............... 12 Table 4. Summary of Study Baseline Characteristics - Studies that Altered Frequency of Hemodialysis (Topic 2, Key Questions 5 and 5.1) ..................................................................... 14 Table 5. GRADE Evidence Profile: More Frequent versus Conventional Hemodialysis ............ 17 Table 6. Summary of Study Baseline Characteristics - Studies that Altered Frequency and Treatment Duration of Hemodialysis (Topic 2 and 4, Key Questions 5, 5.1, 6, and 6.1)............. 19 Table 7. GRADE Evidence Profile: More Frequent and Longer Duration versus Conventional Hemodialysis ............................................................................................................................ 22 Table 8. Summary of Study Baseline Characteristics - Studies that Altered Duration of Hemodialysis (Topic 4, Key Questions 6 and 6.1) ..................................................................... 24 Table 9. GRADE Evidence Profile: Longer Hemodialysis, Ultrafiltration, and Volume and Blood Pressure Control ........................................................................................................................ 27 Table 10. Summary of Study Baseline Characteristics - High-flux Hemodialysis versus Low-flux Hemodialysis Studies (Topic 5, Key Questions 10 and 12) ........................................................ 30

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Table 11. GRADE Evidence Profile: High-flux versus Low-flux Hemodialysis ........................ 33 Table 12. Summary of Study Baseline Characteristics - Hemodiafiltration versus High-flux and Low-flux Hemodialysis (Topic 5, Key Questions 11 and 12) ..................................................... 35 Table 13. GRADE Evidence Profile: Hemodiafiltration versus Hemodialysis............................ 39 Table 14. Summary of Study Baseline Characteristics - Hemofiltration versus Low-flux Hemodialysis (Topic 5, Key Questions 11 and 12) .................................................................... 40 Table 15. GRADE Evidence Profile: Hemofiltration versus Hemodialysis ................................ 43 FIGURES Figure 1. Analytic Framework ..................................................................................................... 4 Figure 2. Literature Flow Diagram .............................................................................................. 8 Figure 3: Early-initiation versus Late-initiation of Hemodialysis – Mortality ............................. 10 Figure 4. More Frequent versus Conventional Hemodialysis – Mortality ................................... 15 Figure 5. More Frequent and Longer Duration versus Conventional Hemodialysis – Mortality 19 Figure 6. Longer Duration versus Conventional Hemodialysis – Mortality ................................ 25 Figure 7. High- versus Low-flux Hemodialysis – Mortality ....................................................... 31 Figure 8. High- versus Low-flux Hemodialysis – Cardiovascular Mortality ............................... 32 Figure 9. Hemodiafiltration versus Hemodialysis – Mortality .................................................... 36 Figure 10. Hemodiafiltration versus Hemodialysis – Cardiovascular Mortality .......................... 37 Figure 11. Hemofiltration versus Hemodialysis – Mortality....................................................... 41 APPENDIX A. Search Strategy ................................................................................................ 56 APPENDIX B. Evidence Tables ............................................................................................... 59 Table 1. Overview of Studies: Initiation of Hemodialysis ........................................................ 60 Table 2. Primary and Secondary Outcomes: Initiation of Hemodialysis ................................... 60 Table 3. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up: Initiation of Hemodialysis ...................................................................................... 61 Table 4. Harms, Complications of Dialysis: Initiation of Hemodialysis ................................... 62 Table 5. Overview of Studies: Studies that Altered Frequency, Treatment Duration, or Both Frequency and Treatment Duration of Hemodialysis ................................................................. 61 Table 6a. Primary and Secondary Outcomes: Studies that Altered Frequency of Hemodialysis ............................................................................................................................ 73 Table 6b. Primary and Secondary Outcomes: Studies that Altered Treatment Duration of Hemodialysis ............................................................................................................................ 75 Table 6c. Primary and Secondary Outcomes: Studies that Altered Both Frequency and Treatment Duration of Hemodialysis ......................................................................................... 76 Table 7a. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up – Studies that Altered Frequency of Hemodialysis.................................................... 77 Table 7b. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up – Studies that Altered Treatment Duration of Hemodialysis ..................................... 79 Table 7c. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up - Studies that Altered Both Frequency and Treatment Duration of Hemodialysis ...... 81 Table 8a. Intermediate Outcomes: Hypertension, LV Mass, and Weight – Studies that Altered Frequency of Hemodialysis ....................................................................................................... 83

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Table 8b. Intermediate Outcomes: Hypertension, LV Mass, and Weight – Studies that Altered Treatment Duration of Hemodialysis ......................................................................................... 85 Table 8c. Intermediate Outcomes: Hypertension, LV Mass, and Weight – Studies that Altered Both Frequency and Treatment Duration of Hemodialysis ......................................................... 87 Table 9a. Harms, Complications Related to Vascular Access – Studies that Altered Frequency of Hemodialysis ............................................................................................................................ 89 Table 9b. Harms, Complications Related to Vascular Access – Studies that Altered Treatment Duration of Hemodialysis.......................................................................................................... 91 Table 9c. Harms, Complications Related to Vascular Access – Studies that Altered Both Frequency and Treatment Duration of Hemodialysis ................................................................. 92 Table 10a. Harms, Complications of Dialysis: Studies that Altered Frequency of Hemodialysis ............................................................................................................................ 94 Table 10b. Harms, Complications of Dialysis: Studies that Altered Both Frequency and Treatment Duration of Hemodialysis ......................................................................................... 95 Table 11. Overview of Studies: Ultrafiltration ......................................................................... 96 Table 12. Primary and Secondary Outcomes: Ultrafiltration .................................................... 96 Table 13. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up – Ultrafiltration ........................................................................................................ 97 Table 14. Intermediate Outcomes: Hypertension, LV Mass, and Weight – Ultrafiltration ......... 97 Table 15. Harms, Complications Related to Vascular Access – Ultrafiltration .......................... 98 Table 16. Harms, Complications of Dialysis – Ultrafiltration ................................................... 98 Table 17. Overview of Studies: High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration ............................................................................................. 99 Table 18. Primary and Secondary Outcomes: High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration ........................................................................................... 106 Table 19. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up – High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration .... 109 Table 20. Intermediate Outcomes: Hypertension, LV Mass, and Weight – High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration .................................................... 111 Table 21. Harms, Complications Related to Vascular Access – High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration .................................................................... 114 Table 22. Harms, Complications of Dialysis – High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration ........................................................................................... 115

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INTRODUCTION Nearly 400,000 patients are currently treated with hemodialysis in the United States, with Medicare spending approaching $90,000 per patient per year of care.1 Unfortunately, patients on hemodialysis experience high morbidity with nearly 2 admissions per patient per year and more than one-third of hospital discharges followed by re-hospitalization within 30 days. Mortality rates among individuals with hemodialysis are up to 8 times that of the age-matched general population.1 While interventions that can improve outcomes in dialysis are urgently needed, few tested interventions have been shown to reduce mortality and improve other health outcomes in this patient population. In particular, high quality information is needed related to the time to initiate hemodialysis, the frequency and duration of dialysis, and the type of hemodialysis performed. Despite the lack of evidence from randomized controlled trials (RCTs) about optimal timing of renal replacement therapy, there was a trend in the United States toward earlier initiation of maintenance dialysis, i.e., at higher levels of estimated glomerular filtration rate (eGFR).2 Clinical practice guidelines for advanced chronic kidney disease (CKD) management that provide eGFR cutoff values below which dialysis therapy should be considered might have contributed to this trend3 and may lead to greater resource utilization without clinical benefit. In 2010, the results of the IDEAL (Initiating Dialysis Early and Late) trial published findings comparing a strategy of delayed dialysis initiation with earlier initiation in patients with advanced CKD.4 Observational and controlled non-randomized studies suggested that more frequent or longer dialysis improved quality of life, hypertension control, and was associated with regression of left ventricular hypertrophy.5,6 Based on these findings, there has been increased interest in more frequent and longer dialysis in the nephrology community. Whether more frequent or extended dialysis reduces mortality and morbidity compared to conventional dialysis is unknown. Since the previous KDOQI Clinical Practice Guideline on hemodialysis adequacy update in 2006,3 the results of 2 RCTs that compared more frequent or extended dialysis to conventional dialysis were published, the Frequent Hemodialysis Network (FHN) trial7,8 and the Alberta Kidney Disease Network trial.9,10 Cardiovascular disease is the leading cause of death in patients with end stage renal disease (ESRD).1 Uremic toxins are theorized to contribute to cardiovascular morbidity and mortality.11 Conventional low flux hemodialysis removes small solutes while clearance of middle-sized molecules is suboptimal.12 Convective therapies, including high flux dialysis, hemofiltration, and hemodiafiltration provide higher clearance of middle-sized solutes and might improve cardiovascular outcomes. The 2006 update of the KDOQI Clinical Practice Guidelines and Recommendations3 followed the publication of the Kidney Disease Clinical Studies Initiative Hemodialysis (HEMO) Study.13

Since the 2006 update, the body of evidence has evolved rapidly. This evidence report, prepared to inform an update of the KDOQI Clinical Practice Guidelines for Hemodialysis Adequacy, focused on several key questions and emphasized findings from RCTs and controlled clinical trials (CCTs) published since the previous guideline update. The current evidence update focuses

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on the timing of hemodialysis initiation and the effect of more frequent and longer hemodialysis on patient outcomes compared to conventional hemodialysis. The update also reviews the evidence for use of high flux compared to low flux dialyzer membranes as well as hemofiltration or hemodiafiltration modes of renal replacement therapy compared to conventional hemodialysis. Scope and Key Questions This evidence review was commissioned by the National Kidney Foundation with the goal of updating the KDOQI Clinical Practice Guidelines and Recommendations for Hemodialysis Adequacy. The report partially informs the workgroup updating the 2006 KDOQI guideline3 addressing a larger set of topics and questions. From the larger set, the work group identified the subset of topics and questions below as most needing an updated evidence review. The current evidence update includes RCTs and CCTs published from 2000 to March 2014. The evidence review group together with the guideline workgroup formulated the key questions, analytical framework (Figure 1), and protocol a priori, including population, interventions, and outcomes of interest. The evidence team conducted the literature search, performed the data extraction, and developed the summary of evidence. TOPIC 1. Timing of Dialysis Initiation KQ1. In patients with chronic kidney disease, does starting dialysis earlier (as defined by higher glomerular filtration rate (GFR) at dialysis initiation) improve outcomes? KQ2. What harms result from starting dialysis at GFR > 10 ml/min/1.73m2? TOPIC 2. Hemodialysis Frequency KQ5. In patients with end stage renal disease, does more frequent hemodialysis (> 3 times a week) improve outcomes compared to less frequent hemodialysis? KQ5.1. What harms result from more frequent hemodialysis? TOPIC 4. Hemodialysis Duration KQ6. In patients with end stage renal disease, does extended hemodialysis (>4.5 hour sessions) improve outcomes compared to usual length hemodialysis? KQ6.1. What harms result from extended hemodialysis? B. Ultrafiltration KQ8.1. Do patients with high inter-dialytic weight gains and high ultrafiltration rates (>10 ml/hour/kg) have worse outcomes compared to patients with lower inter-dialytic weight gains and low ultrafiltration rates (< 10 ml/h/kg)? C. Volume and Blood Pressure Control KQ9.1. Do patients with extended (longer) or more frequent hemodialysis have greater blood pressure and volume control compared to patients with shorter or less frequent dialysis?

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KQ9.2. Is improvement of blood pressure and volume control associated with improved clinical outcomes according to length or frequency of dialysis sessions? TOPIC 5. Membranes and Convective Therapies KQ10. In patients with end stage renal disease do high flux membranes improve patient outcomes when compared to low flux hemodialysis? KQ11. In patients with end stage renal disease does hemofiltration or hemodiafiltration improve patient outcomes when compared to hemodialysis? KQ12. What harms result from use of high flux membranes compared to low flux membranes or from use of hemofiltration or hemodiafiltration compared to high flux hemodialysis?

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Figure 1. Analytic Framework

Interventions

Timing • Early vs.

Late Initiation (T1, Q1&2)

Type of Hemodialysis • More Frequent Hemodialysis

(>3 times per week) (T2, Q5&5.1)

• Extended Hemodialysis (>4.5 hour sessions) (T4A, Q6&6.1)

• High Flux Membranes (T5, Q10&12)

• Hemofiltration (T5, Q11&12) • Hemodiafiltration (T5,

Q11&12)

Adverse Effects (Q2, 5.1, 6.1, 12) • Complications Related to Vascular

Access • Complications of Hemodialysis

Secondary and Intermediate Outcomes • Blood Pressure (T4, Q9.2)

(Systolic pressure, number of anti-hypertensive medications)

• Left Ventricular Mass • Interdialytic Weight Gain

(T4, Q9.2) • Dry Weight • Quality of Life, Depression,

or Cognitive Scale Scores • Physical and Mental Health

Subscale Scores

Final Health Outcomes • Mortality • Cardiovascular Mortality • Myocardial Infarction • Stroke • All-cause Hospitalizations • Clinically Diagnosed

Depression or Cognitive Impairment

• Clinically Meaningful Differences in Quality of Life Scale Scores

Adults and Children with Advanced Chronic Kidney Disease

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METHODS Search Strategy We developed a search strategy that included terms for hemodialysis, chronic kidney disease, and the specific topics of interest for this review: initiation of hemodialysis, hemodialysis frequency, length of hemodialysis sessions, interdialytic weight gain, ultrafiltration rate, blood pressure and volume control, membrane flux, hemodiafiltration, and hemofiltration (Appendix A). We also included search strings to identify RCTs, CCTs, and systematic reviews or meta-analyses. We searched MEDLINE (Ovid) from 2000 to March 2014 for English language studies in populations of all ages. Additionally, reference lists of recent systematic reviews and studies eligible for inclusion were searched to identify relevant studies not identified in our MEDLINE search. We also searched clinicaltrials.gov to identify any recently completed studies and obtained input from members of the clinical practice guideline workgroup. Study Selection Abstracts identified by the literature search were triaged by an investigator or trained research associate. We retrieved for full text review any RCT, CCT, systematic review, or meta-analysis of hemodialysis for chronic kidney disease related to the topics of interest. An investigator or trained research associate reviewed the full text of articles identified from the abstract review or from other reference lists. Articles were potentially eligible if they involved long-term hemodialysis for chronic kidney disease and provided outcomes of interest. Articles were excluded for the reasons listed below.

Exclusion Criteria 1. Not human subjects 2. Cross-over design with treatment duration less than 4 weeks (28 days) in each

treatment arm (Note: for Topic 5, we included only studies with at least 50 patients and at least 12 months follow-up in each treatment arm)

3. Not long-term hemodialysis for chronic kidney disease (studies of peritoneal dialysis or acute kidney failure were excluded)

4. Did not report outcomes of interest: a. Primary outcomes: all-cause mortality b. Secondary outcomes: cardiovascular mortality, myocardial infarction, stroke, all-cause hospitalization c. Intermediate outcomes: quality of life, depression, or cognitive function scores; systolic blood pressure; number of anti-hypertensive medications; left ventricular mass; interdialytic weight gain; dry weight d. Harms or complications related to vascular access: access failure, infection requiring a procedure, thrombectomy or angioplasty, fibrin sheath stripping of catheters or other, catheter replacement e. Harms or complications of dialysis: temporary catheterization, need for access revision, access site infection, hospitalizations due to fluid/electrolyte disorders, need for additional dialysis

4. Did not address a topic of interest: a. Benefits or harms of early initiation of hemodialysis (KQ 1, 2)

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b. Benefits or harms of more frequent (>3 times per week) hemodialysis (KQ 5, 5.1) c. Benefits or harms of extended (sessions >4.5 hours) hemodialysis (KQ 6, 6.1) d. Association between length of hemodialysis sessions or frequency of hemodialysis and blood pressure or volume control (KQ 9.1) e. Effect of improved volume and blood pressure control on clinical outcomes (according to length of hemodialysis sessions) (KQ 9.2) f. Effect of high inter-dialytic weight gain versus lower inter-dialytic weight gain (KQ 8.1) g. Effect of high ultrafiltration rate (>10 ml/hour/kg) versus low ultrafiltration rate (KQ 8.1) h. Effect of high flux membranes versus low flux membranes (KQ 10, KQ12) i. Effect of hemofiltration or hemodiafiltration versus hemodialysis (KQ11, KQ12)

Data Extraction and Risk of Bias Assessment We extracted, onto an overview of studies table, study characteristics (author, year, location, funding source, and study design), intervention (duration, site), follow-up period and withdrawals, inclusion/exclusion criteria, and patient characteristics (demographics, kidney function parameters, and comorbidities). Risk of bias elements were also documented on the overview table. We created, and extracted data onto, outcomes tables including primary and secondary outcomes, intermediate outcomes, and harms (as defined above). All extraction was done by one research associate or investigator and verified by a second. We assessed the risk of bias of individual studies pertaining to the key questions. Randomized studies were rated as low, moderate, or high risk of bias based the following criteria: sequence generation, allocation concealment, blinding, completeness of outcome data and use of intention to treat analysis, and selective outcome reporting and description of withdrawals – a modification of the Cochrane approach to determining risk of bias.14 A randomized study determined to have a low risk of bias generally indicated that the trial reported adequate sequence generation and allocation concealment, outcomes assessors were blinded to treatment assignment, analysis by intent-to-treat, and reasons for dropouts/attrition were reported. Controlled clinical trials were rated at least moderate risk of bias because allocation was not randomized. Rating the Overall Quality Quality of the overall body of evidence for a specific outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.15 The following domains that influence the quality of the evidence include: 1) Risk of bias (limitations in study design); 2) Consistency (inconsistency refers to unexplained heterogeneity or variability in the results); 3) Directness of the evidence; and 4) Precision (results are considered imprecise when they are only few or one trials, and relatively few patients and few events resulting and/or there are wide confidence intervals around the estimate of effect). Additionally, publication bias is also considered but given the limited number of studies evaluated, we did not incorporate this domain. Limitations for each domain can be noted as not serious, serious, or very serious depending on the magnitude of the limitation.

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Following global assessment of the 4 domains, the quality of evidence is rated as either high, moderate, low or very low (Table 1). We have added an additional level, insufficient, in which evidence is unavailable or does not permit a conclusion. Table 1. Definitions of Quality of Evidence According to GRADE15

GRADE Quality of Evidence Levels Quality Level Definition High We are very confident that the true effect lies close to that of the estimate of the

effect. Moderate We are moderately confident in the effect estimate: The true effect is likely to be

close to the estimate of the effect, but there is a possibility that is substantially different.

Low Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.

Very Low We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of the effect.

Insufficient* No evidence available *Not included in the GRADE guidelines The quality of the body of evidence for randomized trials starts as high but may then be downgraded depending on the limitations of the domains. The quality of the body of evidence for observational studies starts as low. In certain instances the quality of evidence may be upgraded if, for example, there is a large effect or large dose response. Data Synthesis and Analysis Results were pooled if clinical heterogeneity of patient populations, interventions, and outcomes was minimal. Data were analyzed in Review Manager 5.2.16 Random effects models were used to generate risk ratios (RR) and 95 percent confidence intervals (CI). Statistical heterogeneity was summarized using the I2 statistic (50 percent indicates moderate heterogeneity and 75 percent or greater indicates substantial heterogeneity).17 We created forest plots for all-cause mortality and cardiovascular mortality outcomes for each topic where at least one study reported these outcomes. Due to heterogeneity of study designs and interventions, we were unable to pool data for most interventions. Other outcomes were summarized narratively.

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RESULTS Literature Flow Our literature search yielded 3701 abstracts (Figure 2). During abstract triage, we excluded 3420 abstracts. We identified 281 articles for full text review. However, since the abstracts came from individual searches for the 4 topic areas, there were 92 duplicate citations. Of 189 unique articles, we excluded 167 as detailed in the Figure. Hand searching of systematic reviews, relevant publications, and the clinical trials registry yielded 20 articles. We included a total of 42 articles representing 28 trials. Figure 2. Literature Flow

3701 Abstracts Triaged

Excluded: 3420 Abstracts

Identified for Full Text Review: 281 Articles Removing Duplicates: 189 Articles

Excluded: 167 Articles Not relevant to key questions 28 Cross-over study with <28 days per treatment arm 12 Observational study 23 Other study design (not RCT) 14 Not long-term hemodialysis 0 Peritoneal dialysis 0 No outcomes of interest 90

Included: 28 Trials Reported in 42 Articles

Hand Search: 20 Articles

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Topic 1. Timing of Dialysis Initiation Key Finding

• One low risk of bias RCT (the IDEAL study-n=828) met eligibility criteria and addressed the topic of dialysis initiation. The study found no significant differences between early (mean estimated creatinine clearance [eCrCl] 12.0 ml/min) vs. late-start (mean eCrCl 9.8 ml/min) dialysis for all-cause mortality (primary outcome), cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke. Early dialysis resulted in higher direct dialysis costs than later dialysis.

Study Description The Initiating Dialysis Early and Late (IDEAL) study was conducted at 32 centers in Australia and New Zealand.4 Adults (age 18 and older) with progressive chronic kidney disease and eCrCl (by Cockcroft-Gault equation corrected for body-surface area) between 10.0 and 15.0 ml/minute/1.73m2 of body-surface area were randomized to “early-start” dialysis (commencing dialysis when the eCrCL was 10.0 to 14.0 ml/min) or “late-start” dialysis (continuing medical care and commencing dialysis when the eCrCL was 5.0 to 7.0 ml/min). Patients assigned to the late-start group could commence dialysis when the eCrCl was greater than 7.0 ml/min if recommended by their treating physician. Patients and their physicians could choose either hemodialysis or peritoneal dialysis. Additional study information is presented in Appendix B, Table 1. Baseline Characteristics A total of 828 patients were randomized – 404 to early start and 424 to late start (Table 2). The participants were on average 60 years of age, 65.5% were male, 71% white, and 43% had diabetes. In the early start group, 58% were planning to start continuous ambulatory peritoneal dialysis compared to 55% in the late-start group. When estimated with the Cockcroft-Gault equation, early-start group participants had a mean (standard deviation) baseline eCrCl of 13.0 (1.4) ml/min at enrollment, similar to eCrCl of 13.1 (1.4) ml/min in the late-start group. Using the Modification of Diet in Renal Disease (MDRD) equation, the mean (standard deviation) baseline eGFRs were 9.8 (2.3) ml/min/1.73m2 in the early-start group and 9.9 (2.2) ml/min/1.73m2 in the late-start group. Median follow-up was 3.6 years (range 0.03 to 9.2) in the early start group and 3.6 years (range 0.02 to 8.8) in the late start group. During the study period, 78 patients in the early start group and 74 in the late start group underwent kidney transplant. Data for these patients were censored at transplantation. The median time from randomization to the initiation of dialysis was 1.8 months (95%CI 1.6, 2.2) in the early-start group and 7.4 months (95%CI 6.2, 8.3) in the late-start group. At initiation of dialysis, the mean eCrCls, as calculated with the use of the Cockcroft-Gault equation, were 12.0 ml/min in the early-start group compared to 9.8 ml/min in the late-start group (mean difference: 2.2 ml/min, 95%CI 1.8, 2.6, P<0.001). Using the MDRD equation, the mean eGFRs at initiation of dialysis were 9.0 ml/min/1.73m2 in the early-start group compared to 7.2 ml/min/1.73m2 in the late-start group (mean difference: 1.8 ml/min/1.73m2 [95%CI 1.4, 2.2], P<0.001). Among the patients assigned to the early start group, 75 (19%) started with an eCrCl <10 ml/min, and in the late start group 322 (76%) started with an eCrCl >7 ml/min. In the early-start group, 195 (48%) initiated peritoneal dialysis, 188 (47%) initiated hemodialysis, and 21

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(5%) did not commence dialysis. In the late-start group, 171 (40%) initiated peritoneal dialysis, 215 (51%) initiated hemodialysis, and 38 (9%) did not commence dialysis. Table 2. Summary of Study Baseline Characteristics - Initiation of Hemodialysis (Topic 1, Key Questions 1 and 2)

Characteristic All study information from Cooper et al., 20104

Number of patients 828

Study withdrawals (%) Did not complete follow-up:

67% of early initiation group (270/404)* 61% of late initiation group (258/424)†

Age (years) 60 Gender, male (%) 65.5 Creatinine clearance (ml/min) 13 (Cockcroft-Gault) Estimated GFR (ml/min/1.73 m2) 9.9 (MDRD) History, DM (%) 43 History, CVD/cardiac disease (%) 39 Systolic BP 142 (history of HTN NR) Study location Australia and New Zealand

DM = diabetes mellitus; CVD = cardiovascular disease; BP = blood pressure; HTN = hypertension; GFR = glomerular filtration rate; MDRD = Modification of Diet in Renal Disease; NR = not reported *Includes 152 deaths and 78 transplantations †Includes 155 deaths and 74 transplantations Outcomes The primary outcome was all-cause mortality (Figure 3; Appendix B, Table 2). Early dialysis initiation did not reduce all-cause or cardiovascular mortality compared to late initiation. There were 152 deaths (38%) in the early start group and 155 deaths (37%) in the late start group (HR 1.04 [95%CI 0.83, 1.30]). No significant differences were noted between groups for cardiovascular mortality (HR 0.94 [95%CI 0.67, 1.32]), non-fatal myocardial infarction (HR 1.39 [95%CI 0.91, 2.15]), or non-fatal stroke (HR 1.21 [95%CI 0.73, 2.00]). Strength of evidence was rated as moderate for all-cause mortality and low for cardiovascular mortality (Table 3). Figure 3. Early-initiation versus Late-initiation of Hemodialysis – Mortality

*Hazards Ratio as presented in the trial: 1.04 [95%CI 0.83, 1.30]

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No data were reported for our intermediate outcomes although the authors noted that no significant difference was observed between groups in quality of life during the follow-up period based on the Assessment of Quality of Life (AQoL) instrument (Appendix B, Table 3). A subsequent publication reported no significant difference (P=0.03) between groups in AQoL at 6 months. The analysis was based on questionnaires completed by 71% of patients enrolled.18 Harms There were no significant differences for reported complications, temporary catheterization (HR 1.03 [95%CI 0.80, 1.32]), need for access revision (HR 1.08 [95%CI 0.85, 1.35]), and access site infection (HR 0.99 [95%CI 0.67, 1.48]) for the early-start group compared to the late-start group (Appendix B, Table 4). An economic analysis included 642 of the 828 patients (78%) originally randomized.18 The median follow-up was 4.2 years in each group. Patients in the early start group started dialysis at a median of 1.9 months after randomization; the corresponding interval was a median of 7.3 months in the late start group (HR 1.96 [95%CI 1.67, 2.30], P<0.001). Total costs associated with hospital admissions, out-of-hospital visits to physicians, investigations, and pharmaceuticals did not differ significantly between groups. However, early dialysis resulted in higher direct dialysis and dialysis related transportation costs than later dialysis. .

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Table 3. GRADE Evidence Profile: Timing (Early versus Late) of Dialysis Initiation Outcome; No. of studies and Design

Study Limitations

(Risk of bias) Inconsistency Indirectness Imprecision

Number of patients Risk Ratio

[95%CI]

Absolute Risk Difference per

1000 [95%CI]

Quality Early Initiation n/N (%)

Late Initiation n/N (%)

Mortality* 1 RCT a

No serious limitations

Unknown, one study

No serious indirectness

No serious imprecision

152/404 (37.6)

155/424 (36.6)

1.03 [0.86 to 1.23]** Not significant Moderate

CVD Mortality 1 RCT a


Unknown, one study


Serious imprecision

63/404 (15.6)

71/424 (16.7)

0.93 [0.68 to1.27]** Not significant Low

All-cause Hospitalizations Not reported

- - - - - - - - Insufficient

Harms, Access Failure Not reported


Harms, Access Revision 1 RCT a


Unknown, one study



145/404 (35.9)

147/424 (34.7)


Harms, Temporary Catheter 1 RCT a


Unknown, one study



118/404 (29.2)

124/424 (29.2)


RCT = randomized controlled trial; CVD = cardiovascular disease * All-cause mortality was the primary outcome ** Hazards Ratios as presented in the trial: all-cause mortality HR 1.04 [95%CI 0.83, 1.30]; CVD mortality HR 0.94 [95%CI 0.67, 1.32]; harms, access revision HR 1.08 [95%CI 0.85, 1.35]; harms, placement of temporary dialysis catheter HR 1.03 [95%CI 0.80, 1.32] a Cooper BA, et al. for the IDEAL Study. N Engl J Med. 2010;363:609-19.18

13

Topic 2. Hemodialysis Frequency Key Findings

• With small sample sizes and short follow-up periods, the studies were not powered to assess mortality.

Studies That Altered Hemodialysis Frequency • Seven studies (3 RCTs, 1 quasi-randomized trial, and 3 CCTs altered hemodialysis

frequency. Hemodialysis performed more frequently than 3 times per week did not reduce all-cause mortality or hospitalizations compared to dialysis conducted 3 times per week. No studies reported myocardial infarction or stroke outcomes. Harms data were infrequently reported though there were no large differences noted by dialysis frequency.

Studies that Altered both Frequency and Treatment Time • Five studies (2 RCTs and 3 CCTs) altered both frequency of hemodialysis (5 to 7 times

per week versus 3 times per week) and treatment time (ranging from 2 to 10 hours). More frequent and longer dialysis did not reduce all-cause mortality or hospitalizations. None of the studies reported cardiovascular mortality, myocardial infarction, or stroke.

Studies that Altered Only Frequency Study Description Seven studies that altered the frequency of hemodialysis were eligible for inclusion: 3 RCTs7,19,20 including one cross-over trial with initial assignment randomized,20 one quasi-randomized trial,21 and 3 CCTs.5,22,23 One study was conducted in the United States,5 one in the United States and Canada,7 one in Canada,22 3 in Europe,20,21,23 and one in the Middle East.19 Risk of bias was moderate for one trial7 and high for the other 6 trials. Additional study information is presented in Appendix B, Table 5. Studies were generally not adequately designed to assess all-cause mortality or other clinical outcomes or rule out important differences. In all studies, more frequent dialysis was compared to dialysis 3 times per week. Five studies compared short daily dialysis to conventional dialysis 3 times a week. In one study, the intervention was 7 days per week for 1.7 hours and the comparator was 3 days per week for 4 hours (both groups receiving 12 hours total dialysis per week).20 Another offered dialysis 6 to 7 times per week for 2 hours compared to 3 times per week for 4 hours.23 Two studies offered dialysis 6 days per week, one for 1.5 to 2.75 hours per session7 and one for 3 hours per session.5 Another trial included one group with dialysis 5 to 6 times per week for 1.5 to 2.5 hours per session.22 Two studies compared more frequent dialysis to dialysis 3 times a week. One trial compared dialysis every-other-day for 4 hours to 3 days per week for 4 hours21 and the last trial added an ultrafiltration session to a 3 times per week regimen and compared that protocol to dialysis 3 times per week for 4 to 5 hours.19 In one study, the control (conventional dialysis) group included patients matched to both the long nocturnal and short daily groups.22

Baseline Characteristics Baseline characteristics of enrollees (n=559) are presented in Table 4. The mean age was 53 years with 62% male. The mean time on dialysis prior to enrollment was 46 months. Follow-up

14

periods ranged from 8 weeks to 3.6 years; all but 2 studies19,20 had follow-up periods of at least 1 year. Table 4. Summary of Study Baseline Characteristics – Studies that Altered Frequency of Hemodialysis (Topic 2, Key Questions 5 and 5.1)

Characteristic Mean (range)

unless otherwise noted

Number of trials

reporting

Number of patients 559 (12 to 245) 7** Study withdrawals (%)* 13 (0 to 23) 6 Age (years) 53 (48 to 64) 7 Gender, male (%) 62 (33 to 69) 7 History, DM (%) 37 (15 to 41) 3 History, CVD/cardiac disease (%) 12 (11, 21) 2 History, HTN (%) 84 (48, 89) 2 Pre-dialysis systolic BP 146 (144 to 147) 3 Kt/V 1.4 1 Time on dialysis, months 46 (40 to 63) 3 Studies conducted in United States/Canada, % of patients 64 (n=355) 3

Studies conducted in Europe, % of patients 32 (n=178) 3 DM = diabetes mellitus; CVD = cardiovascular disease; HTN = hypertension; BP = blood pressure *Excluding deaths **Included Studies: FHN Daily (FHNT Group) 2010,7 Fagugli 2001,20 Ayus 2005,5 London Daily/Nocturnal (Lindsay) 2003,22 Quintaliani 2000,23 Katopodis 2009,21 Yilmaz 201219

Outcomes Primary and Secondary Outcomes (Appendix B, Table 6a) Five of the 7 studies reported all-cause mortality with no study finding a significant difference between treatment groups (Figure 4).5,7,19,21,22 Studies were considered too clinically heterogeneous for pooling. In 3 of the studies, no deaths were reported.5,19,21 Two studies that compared more frequent dialysis to dialysis 3 times a week and differed from the other studies of short daily dialysis aimed to report cardiovascular mortality, but no deaths occurred during either trial.19,21 No studies reported myocardial infarction or stroke outcomes. Two studies reported all-cause hospitalizations with neither finding a significant difference between treatment group.7,22

15

Figure 4. More Frequent versus Conventional Hemodialysis – Mortality

Intermediate Outcomes (Appendix B, Tables 7a and 8a) Two studies reported quality of life, depression, cognition, and/or symptom scores. One study reported a significantly higher RAND SF-36 Physical Health Composite (PHC) score (reflecting better function) in the daily hemodialysis group (42.1 vs. 38.6, P=0.004). The improvement in the daily hemodialysis group was considered by the authors to be clinically meaningful (i.e., a 3 point or greater change). No differences between groups were noted for the Short Physical Performance Battery (SPPB) or the RAND SF-36 physical function score although the change in the physical function score was considered a clinically meaning change (also 3 points or greater) for the daily hemodialysis group. There were no differences between groups in depression or cognition scores.7,25 The second study reported no differences between groups in quality of life (RAND SF-36 Physical Component), cognition, or number of dialysis or disease symptoms.22,31 Blood pressure prior to dialysis was reported in 4 studies with 2 reporting significantly lower systolic blood pressure values in the more frequent dialysis groups7,20 and 2 reporting no difference in either systolic blood pressure5 or mean arterial pressure.22 One of the studies reporting lower systolic pressure also reported fewer anti-hypertensive medications in the more frequent dialysis group.7 A second study reported no difference in medications.21 Left ventricular mass was significantly lower in 3 studies that compared short daily dialysis to conventional dialysis 3 times a week5,7,20 but not different in 2 small studies that compared more frequent dialysis of conventional duration to 3 times a week dialysis19,21 In 3 studies reporting interdialytic weight gain, there was less weight gain in the more frequent hemodialysis groups.19,20,22 Dry weight, reported in 4 studies, did not differ between groups.5,7,19,20 Harms Harms and Complications Related to Vascular Access (Appendix B, Table 9a) Three studies reported access failure. One found no difference between groups,7 one CCT at high risk for bias found significantly greater probability of access survival at 3 years (92% in daily dialysis vs. 70% in conventional dialysis, P<0.05), and lower probability of access closure in more frequent dialysis group (8.3% in daily dialysis vs. 34% in conventional dialysis, P<0.05),23 and one small study reported “catheter lost” data but did not report the significance of the outcomes.22 No studies reported on infection requiring a procedure, thrombectomy, or angioplasty. Two studies reported vascular access interventions with one reporting no difference (HR 1.35 [95%CI, 0.84, 2.18]) for frequent dialysis compared to conventional dialysis)7 and one not reporting the significance of differences observed.22 One study reported any vascular access event data (access repairs, losses, and access related hospitalizations) with significantly more

16

events in the more frequent hemodialysis group (HR 1.76 [95%CI 1.11, 2.79], P=0.017).7,28 One study reported need for access repair, with significantly more repairs in the group receiving more frequent hemodialysis.7,28 Harms and Complications of Dialysis (Appendix B, Table 10a) No harms or complications related to dialysis, including temporary catheterization, access site infection, hospitalizations due to fluid or electrolyte disorders, or the need for additional dialysis, were reported. One RCT reported the percentage of dialysis treatments with recorded hypotensive episodes (defined as the need for lower ultrafiltration rate, reduced blood flow, or saline administration) was 10.9% in the frequent hemodialysis group and 13.6% in the conventional hemodialysis group (P=0.04).7 The same trial reported no difference in incidence of hypokalemia and hypophosphatemia between frequent and conventional hemodialysis groups.7 GRADE Evidence Profile The quality of evidence was very low for mortality based on either RCT (1 study) or CCT (1 study) data (Table 5). Cardiovascular mortality was not reported. The quality of evidence was also very low for all cause hospitalizations (data from 1 RCT) and access failure (data from 1 RCT). The quality of evidence was low for access revision (data from 1 RCT).

17

Table 5. GRADE Evidence Profile: More Frequent versus Conventional Hemodialysis

Outcome; No. of studies* and Design

Study Limitations

(Risk of bias)

Inconsistency Indirectness Imprecision


[95%CI]

Absolute Risk

Difference per 1000 [95%CI]

Quality More Frequent n/N (%)

Conventional n/N (%)

Mortality 1 RCT a Serious

limitations Unknown, one

study No serious indirectness

Serious imprecision

5/125 (4.0)

9/120 (7.5)

0.53 [0.18 to 1.55]

Not significant Very Low

Mortality 1 CCT b Very serious

limitations Unknown, one

study No serious indirectness

Very serious Imprecision

0/11 (0.0)

3/22 (13.6)

0.27 [0.02 to 4.88]


CVD Mortality Not reported - - - - - - - - Insufficient

All-cause Hospitalizations 1 RCT a

Serious limitations

Unknown, one study


Serious imprecision

58/125 (46.4)

47/120 (39.2)

1.18 [0.88 to 1.59]**


Harms, Access Failure 1 RCT c

Serious limitations

Unknown, one study


Serious imprecision

15/125 (12.0)

15/120 (12.5)

0.96 [0.49 to 1.88]


Harms, Access Revision 1 RCT c

Serious limitations

Unknown, one study



33/125 (26.4)

17/120 (14.2)

1.86 [1.10 to 3.16]**

122 more [14 more to 306 more]

Low

RCT = randomized controlled trial; CCT = controlled clinical trial; CVD = cardiovascular disease * Studies not included in the GRADE assessments had small study populations (~50 or less) that were underpowered or not designed to evaluate the effect of variation of HD frequency on clinical events, and/or were studies of short duration (<6 months) ** Hazards Ratios as presented in the trial: hospitalization HR 0.88 [95%CI 0.60, 1.28], interventions related to vascular access HR 1.71 [95%CI 1.08, 2.73] a FHN Trial Group. N Engl J Med. 2010;363:2287-300.7

b London Daily/Nocturnal Hemodialysis Study (Lindsay). Am J Kidney Dis. 2003;42(Suppl 1):S5-S12.22

c FHN Trial Group (Suri). J Am Soc Nephrol. 2013;24:498–505.28

18

Studies that Altered both Frequency and Treatment Time Study Description In addition to the studies that altered frequency of hemodialysis, we identified 5 studies that altered both frequency and treatment time (Appendix B, Table 5). Included were 2 RCTs8,9 and 3 CCTs.22,40,41 Three studies were conducted in Canada,9,22,40 one in the US and Canada,8 and one in Europe.41 Risk of bias was low for one study,9 moderate for one study,8 and high for 3 studies.22,40,41 None of the studies was adequately designed to assess all-cause mortality or other clinical outcomes or rule out important differences. In all of the studies, hemodialysis 5 to 7 times per week was compared to hemodialysis 3 times per week. Four studies compared long nocturnal dialysis to conventional dialysis8,9,22,40 and one study compared short daily dialysis to extended dialysis three times a week.41 Treatment times per hemodialysis session in the more frequent dialysis groups were 2 hours in one study,41 more than 6 hours in one study,9 6 to 8 hours in 2 studies,8,22 and 8 to 10 hours in one study.40 Treatment time in conventional 3 times per week hemodialysis ranged from 2.5 to 5 hours. In one study, the control (conventional dialysis) group included patients matched to both the long nocturnal and short daily groups.22

Baseline Characteristics Baseline characteristics are presented in Table 6. A total of 238 patients were enrolled in the 5 studies. The mean age was 52 years and 60% were male. The mean time on dialysis prior to study enrollment was 43 months. Thirty eight percent had history of diabetes and 21% had a history of cardiovascular disease. Follow-up times were 6 months,9,41 14 months,8 18 months,22 and 38 months.40 Outcomes Primary and Secondary Outcomes (Appendix B, Table 6c) Three studies reported all-cause mortality with no significant differences between treatment groups (Figure 5).8,9,22 Pooled results from the 2 RCTs also show no significant difference in mortality between the intervention and control groups (RR 2.18 [95%CI 0.33, 14.48], I2=0%). The studies were small and reported few events. Confidence intervals were wide and therefore it is impossible to rule out important differences. None of the studies reported cardiovascular mortality, myocardial infarction, or stroke. Three studies reported all-cause hospitalizations with no significant differences.8,9,22

19

Table 6. Summary of Study Baseline Characteristics - Studies that Altered Frequency and Treatment Duration of Hemodialysis (Topic 2 and 4, Key Questions 5, 5.1, 6, and 6.1) Characteristic Mean (range)

unless otherwise noted Number of trials

reporting Number of patients 238 (24 to 87) 5** Study withdrawals (%)* 10 (6 to 20) 3 Age (years) 52 (47 to 59) 5 Gender, male (%) 60 (38 to 69) 4 History, DM (%) 38 (20 to 43) 3 History, CVD/cardiac disease (%) 21 (10 to 39) 3 History, HTN (%) 78 (48, 90) 2 Pre-dialysis systolic BP 148 (143 to 154) 3 Kt/V 1.9 (1.4, 3.9) 2 Time on dialysis, months 43 (30, 62) 2 Studies conducted in United States/Canada, % of patients 90 (n=214) 4

Studies conducted in Europe, % of patients 10 (n=24) 1 DM = diabetes mellitus; CVD = cardiovascular disease; HTN = hypertension; BP = blood pressure *Excluding deaths **Included Studies: Fagugli 2006,41 London Daily/Nocturnal (Lindsay) 2003,22 Alberta Kidney Disease Network 2 (Culleton) 2007,9 FHN Nocturnal (Rocco) 2011,8 Chan 200240 Figure 5. More Frequent and Longer Duration versus Conventional Hemodialysis – Mortality

20

Intermediate Outcomes (Appendix B, Tables 7c and 8c) Three of the 5 studies reported intermediate outcomes with no significant differences between treatment groups. Three studies assessed quality of life.8,9,22 In one of the studies, although the differences between groups in the SPPB, SF-36 Physical Function, or PHC were not significant at 12 months, a clinically meaningful change, defined by the authors as 3 points or more, was noted for intervention group (nocturnal hemodialysis 6 times per week for 6 to 8 hours) for the PHC score.25 One study reported depression scores,8 2 assessed cognition,8,22 and 2 assessed symptoms.9,22 Four studies reported blood pressure outcomes. Two observed significantly lower systolic blood pressure in the groups undergoing more frequent and longer hemodialysis (differences between groups of 14 and 17 mmHg).8,9 One study observed a significantly lower mean arterial pressure in the more frequent and longer hemodialysis group.22 The fourth study found no significant difference in systolic blood pressure.40 Two studies reported on anti-hypertensive medications. One found decreased use in the group receiving more frequent and longer hemodialysis.8 Left ventricular mass was assessed in 3 studies that compared long nocturnal to conventional hemodialysis. Two studies found significantly lower mass in the groups treated more frequently and for longer duration9,40 while 1 study found no significant difference.8 One study observed a significantly higher interdialytic weight gain in the more frequent and longer hemodialysis group.22 Two studies reported no differences in dry weight.8,40 The small study that compared short daily dialysis to extended dialysis 3 times a week found decreased use of antihypertensive medications in the group receiving less frequent but longer hemodialysis and no difference in left ventricular mass.41 Harms Harms and Complications Related to Vascular Access (Appendix B, Table 9c) One study reported access loss of 27% in the nocturnal daily dialysis and 24% in the conventional hemodialysis and did not report the statistical significance of the findings.8 Another study reported “catheters lost” but did not report the statistical significance of the findings.22 For this analysis, data from groups with longer and shorter treatment time than conventional were combined and compare to conventional hemodialysis.22 One study reported bacteremia with no difference between groups.9 A combined outcome of bacteremia, angiogram, or surgical intervention also was not different between the 2 groups.9 Two studies reported “interventions” with one reporting no difference between groups8 and one not reporting the significance of differences observed.22 One study reported any vascular event (repair, loss, or access related hospitalizations) with no significant difference between groups.8 Two studies reported access site revision data. One reported significantly fewer surgical intervention events in the more frequent and longer treatment time group.9 The other study reported no difference in access repair.8 Harms and Complications of Dialysis No studies reported temporary catheterization, access site infection, hospitalizations due to fluid or electrolyte disorders, or the need for additional dialysis.

21

GRADE Evidence Profile The quality of evidence for mortality was very low (data from 2 RCTs and data from 1 CCT) (Table 7). Quality of evidence could not be determined for cardiovascular mortality. Quality of evidence was very low for all-cause hospitalization, access failure, and access revision (each reported in 1 RCT).

22

Table 7. GRADE Evidence Profile: More Frequent and Longer Duration versus Conventional Hemodialysis

Outcome; No. of studies* and Design

Study Limitations

(Risk of bias)


Number of patients

Risk Ratio [95%CI]

Absolute Risk


Quality

More Frequent/

Longer Duration n/N (%)

Conventional n/N (%)

Mortality 2 RCT a,b

Serious limitations

No serious inconsistency


Very serious imprecision

3/71 (4.2)

1/67 (1.5)

2.18 [0.33 to 14.48]


Mortality 1 CCT c

Very serious limitations

Unknown, one study



3/13 (23.1)

3/22 (13.6)

1.69 [0.40 to 7.19]



All-cause Hospitalizations 1 RCT** a

Serious limitations

Unknown, one study


Serious imprecision

19/45 (42.2)

16/42 (38.1)

1.11 [0.66 to 1.86]


Harms, Access Failure 1 RCT d

Serious limitations

Unknown, one study


Serious imprecision

12/45 (26.7)

10/42 (23.8)

1.12 [0.54 to 2.32]


Harms, Access Revision 1 RCT† d

Serious limitations

Unknown, one study


Serious imprecision

10/45 (22.2)

5/42 (11.9)

1.87 [0.70 to 5.01]


RCT = randomized controlled trial; CCT = controlled clinical trial; CVD = cardiovascular disease * Studies not included in the GRADE assessments had small study populations (~50 or less) that were underpowered or not designed to evaluate the effect of variation of HD frequency on clinical events, and/or were studies of short duration (<6 months) ** One RCT (Alberta – Culleton)9 reported mean number of hospitalizations per patient from baseline to study exit (comparable between groups). † One RCT (Alberta – Culleton)9 reported complications related to vascular access, including need for surgical intervention, insertion or replacement of tunneled dialysis catheter, bacteremia, and need for vascular access angiogram. Events were reported by 10 of 26 (38.5%) patients randomized to nocturnal hemodialysis and 8 of 25 (32%) patients randomized to conventional hemodialysis (P=0.85). a FHN Nocturnal (Rocco). Kidney International. 2011;80:1080-91.8

b Alberta (Culleton). JAMA. 2007;298(11):1291-1299.9

c London Daily/Nocturnal Hemodialysis Study (Lindsay). Am J Kidney Dis. 2003;42(Suppl 1):S5-S12.22

d FHN Trial Group (Suri). J Am Soc Nephrol. 2013;24:498–505.28

.

23

Topic 4. Limits on Treatment Time, Ultrafiltration, Volume and Blood Pressure Control Key Findings

• One study of protocol based dry weight adjustment using ultrafiltration versus conventional hemodialysis in patients with hypertension found no deaths and no differences in quality of life or harms.

• We found no randomized or controlled clinical trials that evaluated minimum acceptable treatment time for conventional hemodialysis.

• Four studies assessed altered treatment time (longer duration versus conventional) and provided limited and mixed results. Harms data were infrequently reported.

Study Characteristics Ultrafiltration One study, conducted in the United States, randomly assigned hypertensive hemodialysis patients to ultrafiltration where their dry weight was probed following a protocol without change in duration or frequency of dialysis (n=100) or conventional hemodialysis (n=50).42 Patients were followed for 8 weeks. Mean age was 54 years and 69% were male. Risk of bias was moderate. Study characteristics are presented in Appendix B, Table 11. Treatment Time We identified 4 studies that altered treatment time (Appendix B, Table 5). Included were 2 randomized cross-over trials33,34 and 2 CCTs.22,35 Two studies were conducted in Canada22,33 one in New Zealand,34 and one in Turkey.35 Risk of bias was high for all 4 studies. One study offered hemodialysis 5 or 6 times per week.22 The treatment times in the 2 study groups were 1.5 to 2.5 hours or 6 to 8 hours. The other 3 studies offered hemodialysis 3 times per week. In one study, the treatment times differed by 30 minutes – 4.5 hours in one group and 4.0 hours in the other group.33 Another study included treatment times of 6 to 8 hours and 3.5 to 4.5 hours.34 In the most recent study, treatment times were 7 to 8 hours and 3.5 to 4.5 hours.35 None of the studies was adequately designed to assess all-cause mortality or other clinical outcomes or rule out important differences. Table 8 provides baseline characteristics. Among the 559 patients enrolled, the mean age was 46 years and 69% were male. Mean time on dialysis at enrollment was 59 months. For the 2 cross-over trials, follow-up periods ranged from 6 weeks (0.12 years)33 to 8 weeks (0.15 years)34 per treatment. In the CCTs, follow-up periods were 1 year35 and 1.5 years.22

24

Table 8. Summary of Study Baseline Characteristics - Studies that Altered Duration of Hemodialysis (Topic 4, Key Questions 6 and 6.1) Characteristic Mean (range)

unless otherwise noted Number of trials

reporting Number of patients 545 (9 to 494) 4** Study withdrawals (%)* 32 (0 to 34) 4 Age (years) 46 (45 to 56) 4 Gender, male (%) 69 (44 to 94) 4 History, DM (%) 23 (17 to 78) 3 History, CVD/cardiac disease (%) 16 (14 to 44) 3 History, HTN (%) 67 1 Pre-dialysis systolic BP 125 1 Kt/V 1.23 (1.23, 1.26) 2 Time on dialysis, months 59 (21.5, 60) 2 Studies conducted in United States/Canada, % of patients 7.7 (n=42) 2

Studies conducted in Europe, % of patients 0 (n=0) 0 DM = diabetes mellitus; CVD = cardiovascular disease; HTN = hypertension; BP = blood pressure *Excluding deaths **Included Studies: London Daily/Nocturnal (Lindsay) 2003,22 Wang 2008,33 McGregor 2001,34 Ok 201135 Several studies, described under Topic 2, altered both treatment time and frequency. Outcomes Primary and Secondary Outcomes (Appendix B, Tables 6b and 12) No deaths were reported in the study comparing protocol based dry weight adjustment using ultrafiltration to control (conventional HD).42 Three patients in the ultrafiltration group (3%) and none in the control group were hospitalized (Table 12). Three of the treatment time studies reported mortality (Appendix B, Table 6b). A cross-over study with 8 weeks for each treatment arm reported no deaths.34 A CCT comparing hemodialysis for 1.5 to 2.5 hours 5 to 6 times per week to hemodialysis for 6 to 8 hours 5 to 6 times per week, reported a non-significant difference in deaths (0% vs. 23.1%, P=0.09) with fewer in the shorter treatment time group.22 Another CCT reported significantly fewer deaths (P=0.01) in the group undergoing hemodialysis 3 times per week for 7 to 8 hours (1.6%) compared to the group undergoing hemodialysis 3 times per week for 3.5 to 4.5 hours (6.1%).35 Pooled results from the 2 CCTs (Figure 6) found no significant difference in mortality (RR 0.95 [95%CI 0.05, 19.80]). One of the CCTs also reported cardiovascular deaths with a non-significant difference between groups.35 The cross-over study reported no cardiovascular deaths.34 None of the studies reported myocardial infarction or stroke. One study significantly fewer all-cause hospitalizations in the longer treatment group (P=0.002)35 while a second study reported no difference.22

25

Figure 6. Longer Duration versus Conventional Hemodialysis - Mortality

Intermediate Outcomes (Appendix B, Tables 7b, 8b, 13, and 14) The ultrafiltration study reported physical and mental health composite scores from the Kidney Disease Quality of Life (KDQOL) questionnaire (Appendix B, Table 13).42 Scores were unchanged from baseline to 8 weeks with no significant differences between groups. At 8 weeks, ambulatory systolic blood pressure decreased 13.5 mmHg from baseline in the protocol based dry weight adjustment using ultrafiltration group and 6.9 mmHg in the control group (Appendix B, Table 14). The ultrafiltration-attributable change in systolic blood pressure was -6.6 mmHg (95%CI -1.0, -12.2, P=0.02) at 8 weeks. There was a significant decrease in dry weight in the ultrafiltration group but not the comparator group. In a pre-specified sub-study of patients from this trial, left ventricular mass index decreased significantly at both 4 weeks (-7.4 g/m2) and 8 weeks (-6.3 g/m2) in the ultrafiltration group with no significant changes from baseline in the control group.42 Two of the treatment time studies assessed quality of life, cognition, and symptom scores (Appendix B, Table 7b). Neither reported significant differences between treatment groups for these outcomes.22,33 None of the studies reported depression scores. Three of the treatment time studies reported blood pressure values with one observing a significantly lower systolic blood pressure in the longer treatment time group34 and 2 observing no difference in either systolic blood pressure35 or mean arterial pressure22 (Appendix B, Table 8b). One study reported on anti-hypertensive medications finding no difference between groups although the need for blood pressure medications decreased significantly in the intervention group.35 Left ventricular mass was assessed in one study with a significantly lower mass in the longer treatment time group.35 Result for interdialytic weight gain varied with one study finding no difference,34 one finding a higher weight gain in the longer treatment time group although this analysis included only a subset of patients enrolled,35 and one finding a lower weight gain in the shorter treatment time group (1.73 kg compared to 2.7 kg) but the significance of the difference was not reported.22 One study reported dry weight with no difference between treatment groups.35

26

Harms Harms and Complications Related to Vascular Access (Appendix B, Tables 9b and 15) The protocol based dry weight adjustment using ultrafiltration study reported episodes of clotted angioaccess.42 There were 10 episodes in 6 patients in the ultrafiltration group and 2 episodes in 2 patients in the control group (Appendix B, Table 15). One treatment time study reported on “catheters lost” but did not report the significance of the differences observed (Appendix B, Table 9b).22 This study also reported interventions required but not whether the differences were significant.22 For the harms analysis, data from shorter and longer treatment time groups were combined and compared to the conventional treatment time group.22 None of the other studies reported vascular access outcomes. Harms and Complications of Dialysis (Appendix B, Table 16) No study reported harms and complications of dialysis including temporary catheterization, need for access revision, access site infection, or hospitalizations due to fluid or electrolyte disorders. The ultrafiltration study reported that one control group patient needed emergent ultrafiltration dialysis after 4 weeks in the study.42 The patient developed accelerated hypertension and had pulmonary edema. GRADE Evidence Profile The quality of evidence for mortality was insufficient and for hospitalizations and harms was very low for the RCT that compared protocol based dry weight adjustment using ultrafiltration to control (conventional HD). The quality of evidence for mortality was very low for 2 CCTs that compared longer hemodialysis to either conventional hemodialysis or short daily hemodialysis (Table 9). The quality of evidence was also very low for cardiovascular mortality (data from 1 CCT). There were no data to assess quality of evidence for all-cause hospitalizations, access failure, or access revision.

27

Table 9. GRADE Evidence Profiles: Longer Hemodialysis versus Conventional, Ultrafiltration, and Volume and Blood Pressure Control Outcome*; No. of studies and Design

Study Limitations



[95%CI]


1000 [95%CI]

Quality Control n/N (%)

Intervention n/N (%)

Longer Hemodialysis versus Conventional Mortality 2 CCTs a, b


Serious inconsistency



7/260 (2.7)

15/258 (5.8)

0.95 [0.05 to 19.80] Not significant Very Low

CVD Mortality 1 CCTa


Unknown, one study


Serious Imprecision

1/247 (0.4)

6/247 (2.4)


All-cause Hospitalizations Not reported**




Harms, Access Revision Not reported


Ultrafiltration Mortality Not reported - - - - - - - - Insufficient


All-cause Hospitalizations 1 RCTc

Serious limitations

Unknown, one study



3/100 (3.0)

0/50 (0.0)


Harms, Access Failure 1 RCTc

Serious limitations

Unknown, one study



6/100 (6.0)

2/50 (4.0)




Volume and Blood Pressure Control Mortality Not reported - - - - - - - - Insufficient


All-cause Hospitalizations Not reported


28

Outcome*; No. of studies and Design

Study Limitations



[95%CI]


1000 [95%CI]







CCT = controlled clinical trial; CVD = cardiovascular disease * Studies not included in the GRADE assessments had small study populations (~50 or less) that were underpowered or not designed to evaluate the effect of variation of HD frequency on clinical events, and/or were studies of short duration (<6 months) ** No study reported as a categorical outcome a Long Dialysis Study (Ok). Nephrol Dial Transplant. 2011;26:1287-96.35

b London Daily/Nocturnal Hemodialysis Study (Lindsay). Am J Kidney Dis. 2003;42( Suppl 1):S5-S12.22

c DRIP Study (Agarwal). Hypertension. 2009;53:500-7.42

29

Topic 5. Membranes and Convective Therapies Key Findings High-flux Membranes Compared to Low-flux Membranes

• High- versus low-flux hemodialysis did not reduce all-cause mortality (4 RCTs) but did decrease cardiovascular mortality.

• Hospitalizations did not differ between high- and low-flux hemodialysis groups. Other outcomes, including harms, were rarely reported. One trial reported no difference between high- and low-flux hemodialysis in hospitalizations for vascular access problems and infections

Hemodiafiltration (HDF) Compared to High-flux and Low-flux Hemodialysis (HD) • Pooled analysis from 6 RCTs (3 comparing HDF to high-flux hemodialysis and 3

comparing HDF to low-flux hemodialysis) found that participants randomized to HDF had a significantly reduced risk of all-cause and cardiovascular mortality compared to participants randomized to conventional hemodialysis. The significantly reduced risk was observed in the trials where the comparator was high-flux hemodialysis but not in the trials with comparator of low-flux hemodialysis.

• Cardiovascular events, reported in 2 RCTs, did not differ between HDF and either high- or low-flux HD groups. Mixed results were observed for hospitalizations. Blood pressure was found to be higher in the HDF groups in 2 studies with no difference between groups in a third study. Two studies reported differences in some, but not all, measures of quality of life. Few harms outcomes were reported.

Hemofiltration (HF) Compared to Low-flux Hemodialysis • No trials comparing HF to high-flux hemodialysis met inclusion criteria. In 4 trials

comparing HDF to low-flux HD, there were no statistically significant differences in all-cause mortality between the HF and low-flux HD therapies. There was limited reporting of other outcomes.

High-flux Membranes Compared to Low-flux Membranes Study Description We included 4 RCTs that met eligibility criteria and randomized participants to high-flux hemodialysis versus low-flux hemodialysis (n=3454, range 166 to 1846).13,44-46 Detailed study characteristics are presented in Appendix B, Table 17. The studies were conducted in the United States,13 Germany,45 Turkey,44 and multiple countries in Europe.46 Risk of bias was low for one study13 and moderate for the other 3 studies. The largest trial, the Hemodialysis Study (HEMO, n=1846) reported by Eknoyan et al.,13 was a 2-by-2 factorial design study that randomized prevalent patients undergoing thrice-weekly dialysis to a standard or high dose of dialysis and to a low-flux or high-flux dialyzer. The mean interval from randomization until scheduled end of the study was 4.5 years but due to deaths and transplantation the mean follow-up time was 2.8 years.13 The Membrane Permeability Outcome Study (MPO, n=738), reported by Locatelli et al.,46 randomized incident hemodialysis patients to high- and low-flux membranes and followed them for a mean duration of 3 years. MPO was initially designed to compare the impact of membrane permeability on survival in incident HD patients who had a low albumin (≤4 g/dl) but ultimately enrolled patients with a normal albumin

30

(>4 g/dl). The trial by Asci et al.44 (EGE) also used a 2-by-2 factorial design, randomizing patients to high- or low-flux HD and ultrapure or standard dialysate arms and followed them for a mean follow-up of 35.2 +/- 16.3 months (1 to 50 months). The MINOXIS trial, reported by Schneider et al.,45 randomized 166 maintenance hemodialysis patients who were receiving darbepoetin-alfa to high- or low-flux membranes and followed them for 52 weeks with primary outcomes of hemoglobin levels and erythropoiesis-stimulating agent dose. They reported deaths as the reason for premature study discontinuation. Baseline Characteristics A summary of study baseline characteristics is presented in Table 10. The mean age of the participants was 59 years and men constituted 50% of all patients randomized. The majority of participants in the HEMO trial were black race (63%).13 Approximately 80% of the participants in the HEMO trial had a history of cardiac disease.13 In contrast, only 23% of the participants in the EGE trial had a history of cardiovascular disease.44 Mean duration on dialysis varied widely, ranging from one46 to 44 months.13 Mean overall withdrawal rate for reasons other than death was 26%. Renal transplantation accounted for 49% and 63% of the premature withdrawals in the HEMO and MPO studies, respectively. Transfers to other dialysis centers accounted for 75% of the withdrawals in the EGE trial.44 Table 10. Summary of Study Baseline Characteristics - High-flux Hemodialysis versus Low-flux Hemodialysis Studies (Topic 5, Key Questions 10 and 12)

Characteristic Mean (range) Unless otherwise noted

Number of trials

reporting Number of patients 3454 (166 to 1846) 4 Study withdrawals (%)* 26 (13 to 42) 4** Age (years) 59 (58 to 66) 4 Gender, male (%) 50 (44 to 64) 4 History, DM (%) 36 (23 to 45) 4 History, CVD/cardiac disease (%) 56 (23 to 80) 4 Receiving anti-hypertensive medication (%) 85 1 b Pre-dialysis systolic BP 144 (125 to 152) 4 Kt/V 1.41 (1.36 to 1.43) 3 a,b,d Time on dialysis, months 35 (1 to 44) 3 a,b,d Studies conducted in United States/Canada, % of patients 53 (n=1846) 1 a Total number of patients evaluated Europe, % of patients 47 (n=1608) 3 b,c,d

aHEMO (Eknoyan 2002)13, bMPO (Locatelli 2009)46, cMINOXIS (Schneider 2012)45, dEGE (Asci 2013)44

DM = diabetes mellitus; CVD = cardiovascular disease; HTN = hypertension * Excluding deaths ** MPO also excluded 12% of patients during the run-in phase (including deaths) Outcomes Primary and Secondary Outcomes (Appendix B, Table 18) There was no statistically significant difference in all-cause mortality between the high- and low-flux hemodialysis groups (Figure 6). Overall, the proportions of deaths were comparable, 35% in the high-flux group compared with 38% in the low-flux group. In the pooled analysis, there was evidence of small statistical heterogeneity (I2 = 20%) but the heterogeneity was moderate in the

31

long-term subgroup (I2 = 35%), largely due to the trial by Asci et al.44 Following a sensitivity analysis that removed the Asci study, the RR was 0.96 (95%CI 0.88, 1.05) and the I2 was reduced to 0%. In an a priori subgroup analysis based on serum albumin levels, MPO reported a statistically significant reduction in all-cause mortality in the high-flux group versus the low-flux group in participants with a serum albumin ≤4 g/dl (RR 0.49 [95%CI 0.28, 0.87]).46 In the HEMO study, pre-specified analysis identified interaction between years of dialysis (<3.7 years vs. >3.7 years) and flux intervention: the risk of death was 32% lower in the high-flux group than in the low-flux group among patients who had been on dialysis for 3.7 years or longer; there was no difference in mortality between patients with shorter duration of dialysis randomized to high- versus low-flux membranes.13 Asci et al. reported better survival in the high-flux group in patients with AV fistula, but this analysis was not pre-specified or based on formal testing for interaction.44 Cardiovascular mortality was statistically significantly lower in the high-flux hemodialysis group compared to the low-flux group (Figure 8). The absolute reduction was 28 fewer deaths per 1000 patients (95%CI 7, 52). Other cardiovascular events were rarely reported. The EGE trial reported a non-statistically significant lower incidence of fatal or non-fatal cardiovascular events in the high flux arm versus the low flux arm (13% vs. 17%; RR 0.73 [95%CI 0.51, 1.05]).44 There were no statistically significant differences in hospitalization outcomes reported between the 2 dialysis groups. Figure 7. High- versus Low-flux Hemodialysis – Mortality

32

Figure 8. High- versus Low-flux Hemodialysis - Cardiovascular Mortality

Intermediate Outcomes (Appendix B, Tables 19 and 20) Systolic blood pressure, number of antihypertensive medications, left ventricular mass, or dry weight outcomes were rarely reported. In the EGE trial, there were no differences in systolic blood pressure and interdialytic weight gain between flux groups.44 The effects of flux membranes on quality of life were assessed in the HEMO trial.47 Participants responded to the Index of Well-Being and the Kidney Disease Quality of Life-Long Form questionnaires annually over 3 years. High-flux hemodialysis was not associated with any statistically significant improvements in health-related quality of life domains with the exceptions of sleep quality and patient satisfaction. Harms Harms and Complications Related to Vascular Access (Appendix B, Table 21) No trial reported incidence of access failure. Harms and Complications of Dialysis (Appendix B, Table 22) Only the MPO trial reported on complications associated with dialysis.46 There were no differences in the rate of hospitalizations for infections or vascular access problems between dialysis groups. There was no statistically significant difference in proportions of deaths due to infections between the high and low flux groups in the HEMO and MPO studies (9% vs. 10%, RR 0.91 [95%CI 0.72, 1.16], I2 = 0%, n=2493 patients).13,46 GRADE Evidence Profile There was moderate quality of evidence for mortality (data from 4 RCTs) and cardiovascular mortality (data from 3 RCTs) (Table 11). Quality of evidence could not be determined for all-cause hospitalization, access failure, or access revision.

33

Table 11. GRADE Evidence Profile: High-flux versus Low-flux Hemodialysis

Outcome; No. of studies and Design

Study Limitations

(Risk of bias)



[95%CI]

Absolute Risk


Quality High-flux n/N (%)

Low-flux n/N (%)

Mortality 4 RCT a,b,c,d

Serious limitations




583/1676 (34.8)

635/1687 (37.6)

0.91 [0.80 to 1.03]

Not significant Moderate

CVD Mortality 3 RCT a,c,d

Serious limitations




229/1591 (14.4)

281/1606 (17.5)

0.82 [0.70 to 0.96]

28 fewer [7 fewer to 52 fewer]

Moderate

All-cause Hospitalizations Not reported*


Harms, Access Failure Not reported**


Harms, Access Revision Not reported†


RCT = randomized controlled trial; CVD = cardiovascular disease * No trial reported as a categorical outcome. One trial (MPO) reported total events and admissions per 100 patient years (no statistically significant difference between the flux arms). One trial (HEMO) reported total events not related to vascular access (no statistically significant difference between the flux arms). ** No trial reported as a categorical outcome. One trial (MPO) reported hospitalizations for vascular access problems per 100 patient years (no statistically significant difference between the flux arms). † One trial (MPO) reported total events and admissions per 100 patient years (no statistically significant difference between the flux arms) but did not report as a categorical outcome. a EGE (Asci, EGE Study Group). J Am Soc Nephrol. 201;24(6):1014-23.44

b MINOXIS (Schneider, MINOXIS Study Investigators). Clin J Am Soc Nephrol. 2012;7(1):52-9.45

c MPO (Locatelli, Membrane Permeability Outcome (MPO) Study Group). J Am Soc Nephrol. 2009;20(3):645-54.46

d HEMO (Eknoyan, Hemodialysis (HEMO) Study Group). N Engl J Med. 2002;347(25):2010-9.13

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Hemodiafiltration (HDF) Compared to High-flux and Low-flux Hemodialysis (HD) Study Description Six RCTs meeting eligibility criteria randomized participants to either HDF or high-flux HD48-50 or HDF and low-flux HD.51-53 One trial, the Spanish On-Line Hemodiafiltration Survival (ESHOL) study reported by Maduell et al., mainly enrolled patients receiving high-flux HD but low-flux dialysis patients accounted for 8% of the hemodialysis treatment arm.49 The largest trials, the ESHOL (n=906),49 European/Canadian Convective Transport Study (CONTRAST) (n=714),51 and online (OL) HDF studies (n=782),48 were designed to evaluate the effects of HDF compared to HD on all-cause mortality and other clinical outcomes over approximately 2 to 3 year follow-up periods. One trial was a long-term crossover study (n=76) of two 24-month study periods.50 Only the results from first phase (24 month period) were included in our analyses. All trials were conducted in Europe (including Turkey) although Grooteman et al. also included patients from Canada.51 Risk of bias was low for one study51 and moderate for the other 5 studies. Detailed study characteristics are presented in Appendix B, Table 17. Baseline Characteristics A summary of study baseline characteristics is shown in Table 12. Mean age of the participants was 62 years (range 57 to 66) and men constituted 62% (range 55 to 67) of all patients randomized. Only CONTRAST, reported by Grooteman et al., included ethnicity data with mostly white race (84%).51 Mean duration on dialysis was 39 months (range 26 to 58 months) in the 4 trials reporting.48-51 Overall study withdrawal rate was 31% (range 5 to 39), excluding withdrawals for the primary combination clinical outcome of death or a nonfatal cardiovascular event from the OL-HDF trial reported by Ok et al., 2013.45 Renal transplantation was the primary reason for study discontinuation in most trials.49-52 Transfers to other dialysis centers accounted for 70% of study withdrawals in the OL-HDF trial.48

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Table 12. Summary of Study Baseline Characteristics - Hemodiafiltration versus High-flux and Low-flux Hemodialysis (Topic 5, Key Questions 11 and 12)

Characteristic Mean (range) Unless otherwise note

Number of trials

reporting Number of patients 2632 (44 to 906) 6 Number of patients, HDF studies vs. High-flux 1764 (76 to 906) 3 Number of patients, HDF studies vs. Low-flux 868 (44 to 714) 3 Study withdrawals (%)* 31 (5 to 39) 6 Age (years) 62 (57 to 66) 6 Gender, male (%) 62 (55 to 67) 6 History, DM (%) 27 (18 to 35) 6 History, CVD (%) 35 (26 to 44) 2 b,d Hypertensive nephropathy (%) 12 (11 to 24) 2 b,c Receiving anti-hypertensive medication (%) 43 (14 to 59) 4 a,b,d,e Pre-dialysis systolic BP 137 (128 to 147) 4 a,b,d,e Kt/V 1.5 (1.2 to 1.7) 6 Time on dialysis, months 39 (26 to 58) 4 a,b,c,d aESHOL (Maduell 2013)49, bOL-HDF (Ok 2013)48, cSchiffl 200750, dCONTRAST (Grooteman) 201251, eLocatelli 201052, fWizemann 200053

DM = diabetes mellitus; CVD = cardiovascular disease; CAD = coronary artery disease * Excluding deaths (or the primary outcome from OL-HDF 2013)48

Outcomes Primary and Secondary Outcomes (Appendix B, Table 18) Overall, participants randomized to HDF had a significantly reduced risk of all-cause mortality compared to participants randomized to conventional hemodialysis (moderate strength of evidence) (Figure 9). The absolute reduction was 46 fewer deaths per 1000 patients (95%CI 13, 74 fewer deaths). The reduction of risk was statistically significant when HDF was compared to high-flux HD but not low-flux HD. The test for subgroup differences approached significance (P=0.07). Cardiovascular mortality was statistically significantly lower in the HDF group compared to the conventional hemodialysis group (moderate strength of evidence) (Figure 10). The absolute reduction was 33 fewer deaths per 1000 patients (95%CI 11, 51 fewer deaths). Comparable to findings with all-cause mortality, reduction of risk was statistically significant when HDF was compared to high-flux HD but not low-flux HD. The OL-HDF trial from Ok et al. reported no significant differences in percentages of fatal myocardial infarctions, fatal strokes, and the composite of all-cause mortality and nonfatal cardiovascular events between the HDF and high-flux HD groups.48 No significant differences in any cardiovascular event between the HDF and low-flux groups were also observed in the CONTRAST trial from Grooteman et al., including the composite outcome of fatal and non-fatal cardiovascular events (127 versus 116 events per 100 patient years in the HDF and low-flux groups, respectively; HR 1.07 [95%CI 0.83, 1.39]).51

36

Figure 9. Hemodiafiltration versus Hemodialysis – Mortality

All-cause hospitalizations were significantly reduced in the HDF group versus high-flux HD in ESHOL trial reported by Maduell et al. (36.7 vs. 47.5 events per 100 patient years, RR 0.78 [95%CI 0.67, 0.90]).49 In contrast, hospitalization was not statistically significantly different between the HDF and HD groups in the OL-HDF trial48 CONTRAST reported no statistically significant difference in hospitalization due to infection between the HDF and low-flux HD arms.51 Intermediate Outcomes (Appendix B, Tables 19 and 20) Ok et al. (OL-HDF trial) reported significantly higher mean systolic blood pressure levels at 24 months in the HDF group compared to the high-flux group (129 versus 126 mmHg, P=0.001) but the percentage of participants prescribed antihypertensive medications did not differ between groups (11.1% in the HDF and 11.7% in the high-flux group, P=0.66).48 Four trials did not show a statistically significant difference between pre-dialysis systolic BPs of patients assigned to hemodiafiltration and hemodialysis.49-51,53 Locatelli et al. reported a mean increase of 4.2 mmHg in the HDF group versus no change in the low-flux group (P=0.038 across study groups that included a hemofiltration arm with a mean decrease of 2.6 mmHg) but the percentage of patients treated with antihypertensive therapy did not statistically differ across treatment arms.52 Ok et al. reported significantly higher interdialytic weight gain in HDL group compared to the control

37

group48 while Maduell et al.49 (ESHOL trial) and Grooteman et al.51 (CONTRAST trial) reported no difference. Left ventricular mass was measured in the subset of patients from the CONTRAST trial who were treated in a medical center and therefore could more readily undergo echocardiography.54 Baseline characteristics for the subset of patients (n=342) were similar to those in the larger trial. No differences in change in left ventricular mass were observed between the HDF and HD groups at 1, 3, or 4 years. Figure 10. Hemodiafiltration versus Hemodialysis - Cardiovascular Mortality

The CONTRAST trial reported no statistically significant differences in any health-related quality of life measure assessed by the Kidney Disease Quality of Life-Short Form between the HDF and low-flux HD groups.55 The patient satisfaction domain was noted to decline significantly in both groups. No domain achieved a clinically meaningful difference, defined as a change of 5 points or greater, in either group.55 The crossover study by Schiffl, utilizing the Kidney Disease Questionnaire, reported improvement in physical symptoms during the HDF treatment phase.50 There were no differences in the other quality of life dimensions between groups.

38

Harms Harms and Complications Related to Vascular Access (Appendix B, Table 21) Approximately 10% of HDF participants terminated early from the OL-HDF trial due to vascular access problems compared to none of the high-flux participants (P=0.002).48 Harms and Complications of Dialysis (Appendix B, Table 22) Maduell et al. reported that temporary catheterization lead to early termination in 2% of both the HDF and HD study arms (P=0.51).49 Locatelli et al. reported that thrombosis or vascular access infection resulted in 2 study withdrawals (3%) in the low-flux HD group versus none in the HDF group.52 A cost-effectiveness analysis of data from the CONTRAST study has been reported.56 Data collection for the cost analysis began when the trial was nearly half completed and therefore is based on data from 409 of the 714 enrolled patients. Total costs per year were $126,729 for HDF and $123,103 for HD with the higher cost of HDF attributed to higher cost of disposables and purified water. “Utility,” an adjustment factor reflecting state of health and determined every 3 months using the Euroqol 5D, was slightly higher (reflecting better state of health) for HDF patients than for HD patients and mortality was slightly lower. Cost-utility ratios, modelled over 5 years, yielded an incremental cost per quality-adjusted life year (QALY) of $411,380 for HDF versus HD. HDF was not viewed as a cost-effective treatment. GRADE Evidence Profile The quality of evidence for mortality (data from 6 RCTs) and cardiovascular mortality (4 RCTS) was moderate (Table 13). There was low quality of evidence regarding all-cause hospitalizations (data from 1 RCT). No studies reported on access failure or access revision harms

39

Table 13. GRADE Evidence Profile: Hemodiafiltration versus Hemodialysis Outcome; No. of studies and Design

Study Limitations



[95%CI]


1000 [95%CI]



Mortality 6 RCT a,b,c,d,e,f

Serious limitations




337/1328 (25.4)

272/1304 (20.9)

0.82 [0.71 to 0.95]


Moderate

CVD Mortality 4 RCT a,b,c,e

Serious limitations




106/1243 (8.5)

147/1235 (11.9)

0.72 [0.57 to 0.91]


Moderate

All-cause Hospitalizations 1 RCT* a

Serious limitations

Unknown, one study



317 events (n=456)

412 events (n=450)

0.78† [0.67 to 0.90] ~200 fewer Low

Harms, Access Failure Not reported†




* Rate ratio indicated in study manuscript. Unclear if “events” represent patients with ≥1 event of total number of events in each arm. The OL-HDF trial (Ok 2013)48 reported events per 100 patient years (no statistically significant difference between arms). The CONTRAST trial (Grooteman 2012)51 reported hospitalization due to infection years (no statistically significant difference between arms) ** Two trials reported vascular access problems leading to study withdrawal † Approximately 10% of HDF participants terminated early from the OL-HDF trial due to vascular access problems compared to none of the high-flux participants (P=0.002) (Ok 2013).48

a ESHOL (Maduell, ESHOL Study Group). J Am Soc Nephrol. 2013;24(3):487-97.49 b OL-HDF (Ok, Turkish Online Haemodiafiltration Study). Nephrol Dial Transplant. 2013;28(1):192-202.48 c CONTRAST (Grooteman, CONTRAST Investigators). J Am Soc Nephrol. 2012;23(6):1087-96.51 d Locatelli. J Am Soc Nephrol. 2010;21(10):1798-807.52 e Schiffl. Eur J Med Res. 2007;31;12(1):26-33.50

f Wizemann. Nephrol Dial Transplant. 2000;15(Suppl 1):43-8.53

40

Hemofiltration (HF) Compared to Low-flux Hemodialysis Study Description Four RCTs meeting eligibility criteria randomized participants to either HF or low-flux HD (n=258, range 40 to 106).52,57-59 One of the studies, a 3-arm trial with participants randomly assigned to HDF, HF, or low flux HD,52 has also been included in the section describing studies that compared HDF to low-flux HD. Two studies were conducted in Italy,52,58 one in Sweden and Denmark,57 and one in the Netherlands.59 Risk of bias was moderate for all 4 studies (Appendix B, Table 17). Baseline Characteristics A summary of study baseline characteristics is presented in Table 14. Mean age of the participants was 65 years (range 59 to 68) and men constituted 60% (range 48 to 70) of the enrolled patients. Mean duration on dialysis in 2 studies was 51 months (range 29 to 65 months)58,59 and the median duration in the Locatelli trial was 36 months.52 Overall study withdrawal rate was 28% (range 25 to 36), excluding deaths. Reasons for study withdrawal included renal transplantation and transfers to other facilities or techniques. Table 14. Summary of Study Baseline Characteristics - Hemofiltration versus Low-flux Hemodialysis (Topic 5, Key Questions 11 and 12)

Characteristic Mean (range) Unless otherwise note

Number of trials

reporting Number of patients 258 (40 to 106) 4 Study withdrawals (%)* 28 (25 to 36) 4 Age (years) 65 (59 to 68) 4 Gender, male (%) 60 (48 to 70) 4 History, DM (%) 15 (6 to 25) 4 History, CVD (%) 33** (32 to 34) 2 a,c Hypertension (%) 45 (27 to 56) 2 b,c Pre-dialysis systolic BP 138 (130 to 145) 4 Kt/V 1.3 (1.2 to 1.4) 4 Time on dialysis, months 51† (29 to 65) 2 c,d

aAlvestrand 201157, bLocatelli 201052,cSantoro 200858, dBeerenhout 200559 DM = diabetes mellitus; CVD = cardiovascular disease; CAD = coronary artery disease * Excluding deaths ** Locatelli reported 21% had ischemic cardiopathy and 10% had peripheral arteriopathy † Locatelli reported a median of 36 months

41

Outcomes Primary and Secondary Outcomes (Appendix B, Table 18) There was no statistically significant reduction in risk of all-cause mortality with HF compared to low-flux HD (Figure 11). The strength of evidence was low. Figure 11. Hemofiltration versus Hemodialysis - Mortality

Cardiovascular deaths were noted but not reported by treatment arm in 2 trials.52,58 Beerenhout reported one patient in each arm had a fatal cardiovascular event.59 Hospitalization outcomes did not differ between the HF and HD groups in 2 trials reporting.57,58 Intermediate Outcomes (Appendix B, Tables 19 and 20) One trial reported quality of life and depression scores.59 A significant improvement in physical symptoms was noted in the HF group (P<0.01) over the 12 month study with no change in the HD group. The difference between groups was not significant (P=0.06). Locatelli reported a mean systolic blood pressure of 137.3 +/- 18.6 mmHg and change from baseline of -2.6mmHg in the HF group compared to the corresponding values of 140.5 +/- 15.5 mmHg and 0 in the HD group at the end of the follow-up (P=0.038 across study groups that included a hemofiltration arm with a mean decrease of 2.6 mmHg) but percentage of patients treated with antihypertensive therapy did not statistically differ across treatment arms.52 One study reported greater decline in LV mass index in the hemofiltration arm (22 +/- 57g/m2) compared to low-flux dialysis (15 +/- 57 g/m2) (P=0.03)57 while another study reported no difference in LV mass between HF and HD groups at the end of follow-up.59 Harms Harms and Complications Related to Vascular Access (Appendix B, Table 21) Locatelli reported that 2 patients in each treatment arm withdraw from the trial due to thrombosis or vascular access infection.52

Harms and Complications of Dialysis (Appendix B, Table 22) One patient in HF and none in HD groups needed additional dialysis.52

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GRADE Evidence Profile The quality of evidence was low for mortality (data from 4 RCTs) and very low for cardiovascular mortality (data from 1 RCT) (Table 15) No studies reported all-cause hospitalizations, access failure, or access revision.

43

Table 15. GRADE Evidence Profile: Hemofiltration versus Hemodialysis Outcome; No. of studies and Design

Study Limitations

(Risk of bias)

Inconsistency Indirectness Imprecision Number of patients Risk Ratio [95%CI]


1000 [95%CI]



Mortality 4 RCT a,b,c,d

Serious limitations



Serious imprecision

15/115 (13.0)

24/143 (16.8)

0.74 [0.41 to 1.32] Not significant Low

CVD Mortality 1 RCT* d

Serious limitations

Unknown, one study


Very serious imprecision

1/20 (5.0)

1/20 (5.0)


All-cause Hospitalizations Not reported**


Harms, Access Failure Not reported†




RCT = randomized controlled trial; CVD = cardiovascular disease * Two other trials reported CVD deaths but did not defined them by treatment arm ** Not reported as a categorical outcome. One trial (Santoro 2008)58 reported events per patient rates (no statistically significant difference between arms). † Two trials reported vascular access problems leading to study withdrawal a Alvestrand. Blood Purif. 2011;32(1):21-9.57

b Locatelli. J Am Soc Nephrol. 2010;21(10):1798-807.52 c Santoro. Am J Kidney Dis. 2008;52(3):507-18.58

d Beerenhout. Nephrol Dial Transplant. 2005;20(6):1155-63.59

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SUMMARY AND DISCUSSION BY TOPIC Topic 1. Timing of Dialysis Initiation From one RCT with low risk of bias, we found evidence that in patients with progressive advanced chronic kidney disease, planned earlier dialysis initiation at a mean eCrCl of 12.0 ml/min as calculated by the Cockcroft-Gault equation (mean eGFR 9.0 ml/min/1.73m2 by the MDRD equation) compared to delayed dialysis initiation at a mean eCrCl of 9.8 ml/min by the Cockcroft-Gault equation (mean eGFR 7.2 ml/min/1.73m2 by the MDRD equation) did not improve outcomes of all-cause mortality, cardiovascular mortality, myocardial infarction, or stroke. The grade of evidence was moderate for all-cause mortality and low for cardiovascular mortality. Dialysis was initiated on average 5.6 months earlier in the early initiation group. Early dialysis initiation did not result in improved quality of life. There is a moderate strength of evidence that earlier dialysis initiation is not associated with a significantly higher risk of temporary catheter insertion, need for access revision, or access site infection compared to later dialysis initiation. All the evidence comes from one RCT that had some limitations. The trial was conducted in Australia and New Zealand. The trial did not employ central measurement of kidney function; kidney function was estimated. In addition, 18% of participants assigned to early initiation started later and 76% of participants assigned to late initiation started dialysis with an eCrCl greater than the pre-specified target of 7.0 ml/min. The majority of participants assigned to late start who initiated dialysis at higher eGFR levels did so because of uremia or physician discretion. This cross-over resulted in a small eGFR difference between groups at initiation. Despite these limitations, the late-start group started dialysis on average 6 months later than the early-start group without compromise in their mortality, morbidity, or quality of life. Late start also resulted in significant cost savings.18 Another RCT provides data on delaying initiation of dialysis in a select population.60 The study enrolled 112 patients, all of whom were greater than 70 years old with an eGFR of 5.0 to 7.0 ml/min/1.73m2. Patients with diabetes mellitus were excluded. Patients were randomly assigned to either a very low protein diet group or a dialysis group. Despite the randomization, the groups differed at baseline in mean age and the percentage of male patients. At a median follow-up of 26.5 months, 50% of patients in the diet group and 55% of patients in the dialysis group had died. Seventy-one percent of patients in the diet group started dialysis at a median of 9.8 months after randomization. One year survival was 87.3% in the diet group and 83.7% in the dialysis group. The authors concluded that the diet intervention was safe and effective when postponing dialysis in this population. The findings from the RCTs differ from the findings of numerous observational studies. Two recent systematic reviews reported results from meta-analyses of the observational studies. Pan and colleagues included data from 10 cohort studies and the IDEAL trial and calculated an adjusted odds ratio of 1.33 (95%CI 1.18, 1.49, P<0.00001) indicating greater risk of death associated with earlier initiation of dialysis.61 Heterogeneity, as indicated by the I2 value of 96%, was high. Susantitaphong and colleagues included data from 15 cohort studies and reported an adjusted hazard ratio of 1.04 (95%CI 1.03, 1.05), again indicating that initiation of dialysis at a

45

higher GFR was associated with higher all-cause mortality.62 Heterogeneity was also high in this analysis (I2=97%). There is likely significant heterogeneity between observational trials evaluating early dialysis initiation compared to a RCT. In the observational studies the reason for dialysis initiation is never known, limiting conclusions that may be drawn. We conclude that there is moderate strength evidence that in patients with an eCrCl of 10.0 to 15.0 ml/minute, there is no difference in all-cause mortality associated with delaying initiation of dialysis by 5.6 months in the absence of uremic symptoms or initiating dialysis at an eCrCl of 9.8 ml/min compared to 12.0 ml/min. However, applicability of the findings to the United States may be limited as 44% of the patients enrolled in the trial chose peritoneal dialysis as their initial method of dialysis and there are population differences between patients included in this trial and those typically seen in the United States. Topic 2. Hemodialysis Frequency We found very low level of evidence that short daily or more frequent hemodialysis did not reduce all-cause mortality compared to conventional hemodialysis. We did not find any evidence about the effect of frequent hemodialysis on cardiovascular mortality, myocardial infarction or stoke. From results of one RCT, short daily hemodialysis did not reduce hospitalizations compared to conventional hemodialysis. Short daily hemodialysis was associated with some improvement in patient centered and intermediate outcomes compared to conventional hemodialysis. More frequent hemodialysis was associated with a higher Physical Health Composite score based on the RAND SF-36 in one study, but not with other measures of mood or cognition. Compared to conventional hemodialysis, short daily hemodialysis also reduced pre-dialysis systolic blood pressure in 2 of 3 studies reporting and caused a significant reduction in left ventricular mass in 3 of 3 studies reporting. Lower interdialytic weight gain was observed in 2 studies comparing short daily hemodialysis to conventional dialysis and in one study comparing 4 sessions per week to 3 sessions per week. Neither short daily hemodialysis nor more sessions per week were associated with lower pre-dialysis dry weight (4 studies reporting). From an RCT with moderate risk of bias, there was low level of evidence that short daily hemodialysis increased risk of access related events compared to conventional hemodialysis. This risk was driven primarily by access repair procedures and not by access failure. In one non-RCT at high risk for bias, frequent dialysis was associated with longer access survival. This finding is likely explained by allocation bias inherent in the study design. Among 5 studies that altered both frequency and duration of hemodialysis, we found very low evidence from 2 RCTs and 1 CCT with follow-up periods of 6 to 18 months that mortality did not differ with long, frequent nocturnal hemodialysis compared to conventional dialysis. No differences were observed in intermediate outcomes of quality of life, depression, or cognition. Results were mixed for blood pressure, left ventricular mass, and weight outcomes. Most studies reported no difference in complications related to vascular access.

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We conclude that there is low level of evidence over a relatively short duration of follow-up from studies not powered to look at all-cause mortality or other clinical outcomes that more frequent dialysis, either short daily dialysis or more dialysis sessions per week, does not improve these clinical outcomes compared to conventional dialysis. More frequent dialysis is associated with reduction of pre-dialysis blood pressure, left ventricular mass, and inter-dialytic weight gains but is associated with greater risk of vascular access related procedures. Only one study was a well-designed RCT of a sufficient follow-up to address clinical outcomes. Altering hemodialysis frequency and duration, typically long, frequent nocturnal dialysis, was not associated with a change in all-cause mortality or other clinical outcomes. RCTs powered to evaluate effect of frequent hemodialysis on clinical outcomes are needed before it can be uniformly recommended as a life-prolonging intervention. Topic 4. Limits on Treatment Time, Ultrafiltration, Volume and Blood Pressure Control While a number of retrospective studies have attempted to define the optimal rate of ultrafiltration they were not reviewed for this evidence report as only controlled clinical trials and randomized controlled trials were included. We identified one RCT that compared protocol based dry weight adjustment using ultrafiltration and conventional dialysis in patients with hypertension but reported no deaths in the 8 week follow-up. A significant difference in ultrafiltration-attributable change in systolic blood pressure was reported. We did not find any trials that assigned participants to different blood pressure targets, or estimated dry weights and followed them prospectively for clinical or patient centered outcomes. While a number of studies attempted to define the benefits and harms of extended dialysis duration we were unable to identify any studies that evaluated a minimal acceptable dialysis time. The HEMO trial attempted to determine if two different doses of dialysis influenced patient outcomes. By virtue of targeting two different doses of dialysis, patients enrolled in the HEMO trial received different durations of dialysis. Those in the standard dialysis group received on average 190 minutes of dialysis per session (SD of 23 minutes), while those in the high dose dialysis group received on average 219 minutes of dialysis per session (SD of 23 minutes). There was no difference between groups in patient outcomes. Given the distribution of time among those in the standard dose group, some individuals may have been dialyzing for substantially less time than the average of 190 minutes per session. No study has randomized patients to an achieved time of dialysis less than 190 minutes per session. Given the current level of evidence it is not possible to establish a minimum duration of dialysis. Four studies altered duration of hemodialysis and evaluated whether longer dialysis sessions resulted in improved patient outcomes compared to conventional dialysis. Of the studies, 2 were randomized cross-over trials with short follow-up of 6 to 8 weeks per intervention and 2 were controlled clinical trials. All were at high risk for bias. The only study powered to look at mortality revealed lower mortality in the longer dialysis arm, but patients self-selected to receive nocturnal hemodialysis. There was limited reporting of changes in pre-dialysis blood pressure, use of anti-hypertensive medications, or changes in left ventricular mass. None of the studies found improved quality of life or cognitive performance in participants on long dialysis. One cross-over trial found significantly fewer uremia-related symptoms and less physical suffering in the longer duration group.

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Several recent systematic reviews have focused on frequency and/or duration of hemodialysis. A 2006 review of benefits and risks of daily hemodialysis included case series, cohort studies, and RCTs published in one of 6 languages through May 2005.63 Only studies of adults receiving daily hemodialysis (sessions of 1.5 to 3 hours, 5 to 7 days per week) and with a follow-up time of at least 3 months were eligible for inclusion. Twenty-five studies reporting data from 14 unique cohorts were included in the review; only one study was an RCT. Due to heterogeneity in outcome measures, units of measure, and lengths of follow-up, pooling of data was not possible. The authors noted that 10 of 11 studies reported decreases in systolic or mean arterial blood pressure with daily hemodialysis. Results were mixed for health-related quality of life. None of the included studies reported mortality and only one reported hospitalizations finding decreased hospitalization in the year following conversion to daily hemodialysis compared to the year prior to conversion. Reporting was limited but few significant differences were found for access dysfunction or permanent access failure. The RCT included in the review was a cross-over trial enrolling 12 patients. In that trial, no change was observed in dialysis and/or uremic symptoms or dry body weight. Systolic blood pressure decreased and there was a trend toward use of fewer blood pressure medications. Left ventricular mass was also decreased. A 2008 review included studies that compared short daily hemodialysis (sessions of 1.5 to 3 hours, 5 to 7 days per week) to conventional hemodialysis (sessions of 3 to 5 hours, 3 days per week).64 Studies were published in one of five languages between 1995 and January 2007. The 17 studies included in the review were predominantly pre-post studies or cohort studies; there was one CCT. Overall, the review found mixed results for vascular access problems with some studies reporting a lower incidence of access problems and higher vascular access survival in the short daily hemodialysis patients compared to the conventional dialysis patients and other studies reporting no differences. The majority of studies reported decreased blood pressure and reduced use of antihypertensive medications with short daily hemodialysis. Three studies reported hospitalization and length of stay with mixed results. Quality of life, assessed with different instruments, was improved in nearly all studies that reported a quality of life measure. A third review focused on the effects of frequent or extended hemodialysis on cardiovascular outcomes.65 The review included studies published in any language to April 2011. The majority of the 46 included studies were cohort studies; 3 were RCTs and 2 were randomized cross-over studies. Left ventricular mass index decreased significantly when patients switched from conventional hemodialysis to frequent or extended hemodialysis. A similar change was observed for left ventricular mass. There was also a significant decrease in systolic blood pressure associated with frequent or extended hemodialysis and the mean number of antihypertensive medications was significantly reduced. In an exploratory analysis of the 3 RCTs of frequent hemodialysis (the Alberta study and the FHN trials) there was no significant difference in all-cause mortality. We conclude that there is no evidence that extended length hemodialysis improves patient morbidity or mortality. RCTs powered to look at deaths, cardiovascular events, and hospitalizations are needed.

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Topic 5. Membranes and Convective Therapies High-flux Membranes Compared to Low-flux Membranes Based on evidence from 4 trials that included 3454 participants, there is evidence of moderate +strength that dialysis using high-flux membranes does not reduce all-cause mortality but does reduce cardiovascular mortality by 18% compared to low-flux dialysis. There is insufficient evidence to comment on the association between membrane flux and patient centered outcomes like quality of life. Previous systematic reviews and meta-analyses evaluating high- versus low-flux HD have been conducted. These reviews included short-term trials (<1 year), including crossover studies, that were not adequately designed to assess the impact of differences in flux membranes on clinical outcomes such as mortality. A Cochrane review reported that high-flux HD did not reduce all-cause mortality (RR 0.95 [95%CI 0.87, 1.04], 10 trials, n=2915 patients) but did reduce cardiovascular mortality (RR 0.83 [95%CI 0.70, 0.99], 5 trials, n= 2612 patients).66 A recently published meta-analysis by Susantitaphong et al. included 65 trials of convective therapies such as hemofiltration, hemodiafiltration, and high-flux dialysis and compared them with low-flux dialysis.67 Similar to our findings, they reported that convective therapies resulted in a non-significant decrease in all-cause mortality (RR 0.88 [95% CI 0.76, 1.02], P=0.09, 21 trials, n= 4766 patients) and a significant decrease in cardiovascular mortality (RR 0.84 [95%CI 0.71, 0.98], P=0.03, 3 trials, n= 3207 patients) compared to low-flux dialysis. We conclude that there is evidence of moderate quality that dialysis using high-flux membranes does not reduce all-cause mortality but does reduce cardiovascular mortality compared to low-flux dialysis. There is insufficient evidence on the association between membrane flux and patient centered outcomes like quality of life. Hemodiafiltration (HDF) Compared to High-flux and Low-flux Hemodialysis (HD) We found evidence of moderate quality that hemodiafiltration reduced all-cause mortality and cardiovascular mortality compared to hemodialysis. This evidence comes from 6 trials that together enrolled 2632 participants. It should be noted that the finding was mainly driven by the trials that compared hemodiafiltration to high-flux dialysis. When analysis was limited to the trials that compared hemodiafiltration to low-flux dialysis, there was no evidence of benefit of hemodiafiltration for prevention of all-cause and cardiovascular deaths. Only one trial included in the analysis was at low risk for bias, the rest of the trials were at moderate risk for bias. Only 3 of the listed studies were designed to evaluate the effect of hemodiafiltration on clinical outcomes. There was limited evidence that hemodiafiltration improved other patient centered outcomes like quality of life, depression scores, or cognitive performance. Few studies reported harms associated with hemodiafiltration. One study reported 40/391 early study terminations due to vascular access problems in the HDF arm and none in the hemodialysis arm. We conclude that there is moderate quality evidence that hemodiafiltration reduced all-cause mortality and cardiovascular mortality compared to hemodialysis.

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Hemofiltration (HF) Compared to Low-flux Hemodialysis From 4 trials that enrolled a total 258 participants, we found low level of evidence that hemofiltration did not reduce all-cause mortality and very low level of evidence from one trial that hemofiltration did not reduce cardiovascular mortality compared to low-flux dialysis. There is limited evidence about the effect of HF on intermediate outcomes and harms of HF compared to hemodialysis. A 2006 Cochrane systematic review included RCTs that compared different convective modes of renal replacement therapy (hemofiltration, hemodiafiltration, and acetate-free biofiltration) to hemodialysis.68 A total of 20 trials published between 1966 and 2006 were included. Mortality data were extracted from studies with a minimum of 12 months follow-up. No significant differences were observed in studies of any of the convection modes compared to hemodialysis (RR 1.68 [95%CI 0.23, 12.13], 6 trials, n=388 patients) but heterogeneity was high (I2=61%). In 4 of the 6 eligible studies, no deaths were reported. Three trials, one with no deaths, compared hemodiafiltration with hemodialysis and found no significant difference. Only one trial compared hemofiltration to hemodialysis. There were no deaths in that trial. No differences in hospital admissions or length of stay were observed; results for quality of life were mixed. Several recent meta-analyses evaluated the effect of convective versus diffusive dialysis therapies in ESRD.67,69-71 These meta-analyses differ in the studies they included, comparator groups, outcomes of interest, and, as a result, reported results. The 2013 meta-analysis by Susantitaphong compared all convective therapies, including hemodialysis with high-flux membranes, hemodiafiltration, and hemofiltration with low-flux hemodialysis and included 65 trials. With 21 trials reporting, they found a non-significant reduction in the risk of all-cause mortality (RR 0.88 [95%CI 0.76, 1.02], P=0.09) and a significant reduction in the risk of cardiovascular mortality (RR 0.83 [95%CI 0.71, 0.98], P=0.03) in participants assigned to convective therapy compared to participants randomized to low-flux hemodialysis.67 This meta-analysis did not include the ESHOL and OL-HDF trials that were published in 2013. Meta-analyses by Nistor et al. compared convective therapies (hemodiafiltration, hemofiltration, and acetate-free biofiltration) with hemodialysis (both low flux and high flux) and included 35 trials. Eleven trials (N=3396) contributed data to the evaluation of all-cause mortality and 6 trials (N=2889) contributed data to the evaluation of cardiovascular mortality. They found that convective dialysis had no effect on all-cause mortality (RR 0.87 [95%CI 0.70, 1.07], I2=34%) and was associated with reduced risk of cardiovascular mortality (RR 0.87 [95%CI 0.66, 0.80], I2=0%).69 Similarly, meta-analyses by Wang et al. compared the effect of hemodiafiltration or hemofiltration with hemodialysis. From 4 trials, they found that hemodiafiltration did not reduce cardiovascular outcomes (including cardiovascular mortality and non-fatal events with definition of non-fatal events varying by trial) (RR 0.85 [95%CI 0.66, 1.10], I2=42%).70 Though our review included the same trials, we only included cardiovascular deaths as the outcome. Wang also did not find a reduction in all-cause mortality in participants treated with convective methods compared to hemodialysis (RR 0.83 [95%CI 0.65, 1.05], I2=38%). Our all-cause mortality analysis included all of the same trials with the exception of the Locatelli 1996 trial that predated our inclusion time-frame.72 In that trial, there was a 3.6 times greater risk of death in participants assigned to hemodiafiltration compared to participants assigned to high-flux and low-flux hemodialysis.72 Inclusion of the results of this trial is likely responsible for difference in our findings. Lastly, a meta-analysis by Mostovaya et al. compared hemodiafiltration with low or

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high-flux hemodialysis. Their analysis of all-cause mortality included 6 trials (N=2875).71 They included the Locatelli 1996 trial (though their interpretation of event rate and number of participants in the comparator hemodialysis group is unclear and different from that by Wang), and did not include the Schiffl 200750 trial included in our analysis. Similarly to our study, they found a small reduction in the risk of all-cause (RR 0.84 [95%CI 0.73, 0.96]) and cardiovascular (RR 0.73 [95%CI 0.57, 0.92]) mortality.71 Overall, differences in methodologies prevent us from drawing consistent conclusions. Reduction of the risk of death in the latest meta-analyses is driven primarily by the findings of the ESHOL trial reported by Maduell et al.49 The risk of bias was moderate in the ESHOL trial because of the on-treatment analysis with incomplete follow-up and differential study withdrawal that could have biased the study findings. Patients were withdrawn from the hemodiafiltration arm if they did not receive the allocated treatment modality for 2 months or more, including those who did not achieve the minimum replacement volume of 18 L per session. Patients who could not achieve a predefined replacement volume could have had vascular access or health problems that put them at risk for worse outcomes. Exclusion of these patients could possibly explain improved outcomes in patients randomized to hemodiafiltration. Alternatively, the ESHOL study had the highest convective volume of all RCTs and it is possible that a mortality effect of HDF depends on the delivered convective volume.51 Conversely, reduction of cardiovascular mortality in the convective arm compared to low flux dialysis was shown by Susantitaphong et al. in the meta-analysis that did not include the ESHOL trial in addition to the meta-analyses by Mostovaya and Nistor. Therefore, convective dialysis may reduce cardiovascular mortality. Trials with complete follow-up and intention-to-treat analyses are needed before HDF could be recommended for reduction of all-cause mortality. We conclude that there is low quality of evidence that hemofiltration does not reduce all-cause mortality and very low quality of evidence that hemofiltration does not reduce cardiovascular mortality compared to low-flux dialysis. There is limited evidence about the effect of HF on intermediate outcomes and the harms of HF compared to hemodialysis

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63. Suri RS, Nesrallah GE, Mainra R, et al. Daily hemodialysis: a systematic review. Clin J Am Soc Nephrol. 2006;1:33-42.

64. Puñal J, Lema LV, Sanhez-Guisande D, Ruano-Ravina A. Clinical effectiveness and quality of life of conventional haemodialysis versus short daily haemodialysis: a systematic review. Nephrol Dial Transplant. 2008;23(8):2634-46.

65. Susantitaphong P, Koulouridis I, Balk EM, Madias NE, Jaber BJ. Effect of frequent or extended hemodialysis on cardiovascular parameters: a meta-analysis. Am J Kidney Dis. 2012:59(5):689-99.

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http://www.ncbi.nlm.nih.gov/pubmed?term=Pons%20M%5BAuthor%5D&cauthor=true&cauthor_uid=23411788

http://www.ncbi.nlm.nih.gov/pubmed?term=ESHOL%20Study%20Group%5BCorporate%20Author%5D


http://www.ncbi.nlm.nih.gov/pubmed?term=Schiffl%20H%5BAuthor%5D&cauthor=true&cauthor_uid=17363355


http://www.ncbi.nlm.nih.gov/pubmed?term=Grooteman%20MP%5BAuthor%5D&cauthor=true&cauthor_uid=22539829

http://www.ncbi.nlm.nih.gov/pubmed?term=van%20den%20Dorpel%20MA%5BAuthor%5D&cauthor=true&cauthor_uid=22539829

http://www.ncbi.nlm.nih.gov/pubmed?term=Bots%20ML%5BAuthor%5D&cauthor=true&cauthor_uid=22539829

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http://www.ncbi.nlm.nih.gov/pubmed?term=Andrulli%20S%5BAuthor%5D&cauthor=true&cauthor_uid=20813866


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66. Palmer SC, Rabindranath KS, Craig JC, Roderick PJ, Locatelli F, Strippoli GF. High-flux versus low-flux membranes for end-stage kidney disease. Cochrane Database Syst Rev. 2012 Sep 12;9:CD005016.

67. Susantitaphong P, Siribamrungwong M, Jaber BL. Convective therapies versus low-flux hemodialysis for chronic kidney failure: a meta-analysis of randomized controlled trials. Nephrol Dial Transplant. 2013;28(11):2859-74.

68. Rabindranath KS, Strippoli GFM, Daly C, Roderick PJ, Wallace SA, MacLeod AM. Haemodiafiltration, haemofiltration and haemodialysis for end-stage kidney disease. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006258. DOI: 10.1002/14651858.CD006258.

69. Nistor I, Palmer SC, Craig JC, et al. Convective versus diffusive dialysis therapies for chronic kidney failure: an updated systematic review of randomized controlled trials. 2014 Jan 13. pii: S0272-6386(13)01621-1. doi: 10.1053/j.ajkd.2013.12.004. [Epub ahead of print]

70. Wang AY, Ninomiya T, Al-Kahwa A, et al. Effect of hemodiafiltration or hemofiltration compared with hemodialysis on mortality and cardiovascular disease in chronic kidney failure: a systematic review and meta-analysis of randomized trials. Am J Kidney Dis. 2014 Mar 27. pii: S0272-6386(14)00529-0. doi: 10.1053/j.ajkd.2014.01.435. [Epub ahead of print]

71. Mostovaya IM, Blankestijn PJ, Bots ML, et al. on behalf of the EUDIAL – an official ERA-EDTA working group. Clinical evidence on hemodiafiltration: a systematic review and a meta-analysis. Clin J Am Soc Nephrol. 2014;9(3):520-6.

72. Locatelli F, Mastrangelo F, Redaelli B, et al. Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters. The Italian Cooperative Dialysis Study Group. Kidney Int. 1996;50:1293–302.

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APPENDIX A. Search Strategy Category Step Number and Terms Hemodialysis 1 renal dialysis.mp. or Renal Dialysis/ or Hemodialysis, Home/

or exp Kidneys, Artificial/ or haemodialysis.mp. or hemodialysis.mp.

Chronic kidney failure 2 exp Renal Insufficiency, Chronic/ or exp Kidney Failure, Chronic/ 3 (end-stage kidney or end-stage renal or endstage kidney or endstage renal).mp. 4 (ESKD or ESKF or ESRD or ESRF).mp. 5 exp Uremia/ or uremi$.mp.

Combine results 6 or/2-5 Combine results 7 1 and 6 Initiation 8 exp Time Factors/

9 exp Early Diagnosis/ 10 exp Glomerular Filtration Rate/ or gfr.mp. 11 (initiat$ or start$ or frequen$).mp.

Dose/Treatment schedule 12 (dos$ or length$ or long$ or short$).mp. 13 (earl$ or schedul$).mp.

Frequency 14 daily.mp. Adequacy 15 dialysis adequacy.mp. Dose 16 dialysis dose.mp. Combine results 17 or/8-16 Flux 18 flux.mp.

19 high-flux.mp. 20 low-flux.mp.

Membranes 21 artificial membrane.mp. or exp Membranes, Artificial/ 22 membrane$.mp.

Filtration rate 23 (filtration adj rate$).mp. Combine results 24 or/18-23 Blood pressure 25 blood pressure.mp. or exp Blood Pressure/

26 exp Hypertension/ or hypertens$.mp. Fluid volume 27 blood volume.mp. or exp Blood Volume/

28 body fluids.mp. or exp Body Fluids/ 29 exp Hypotension/ or hypotens$.mp. 30 extracellular fluid.mp. or exp Extracellular Fluid/ 31 plasma volume.mp. or exp Plasma Volume/ 32 exp Sodium/ or sodium.mp.

Combine results 33 or/25-32 Hemodiafiltration 34 (haemodiafiltration or hemodiafiltration).mp. or

Hemodiafiltration/ Hemofiltration 35 (haemofiltration or hemofiltration).mp. or exp

Hemofiltration/ Combine results 36 34 or 35 Interdialytic weight gain 37 ((intradialytic or intra-dialytic) adj weight).mp. Ultrafiltration 38 (ultrafiltration adj rate$).mp. Weight gain 39 (weight adj (gain or loss)).mp.

57

Combine results 40 or/37-39 Apply limits 41 limit 7 to (english language and humans and yr="2000 -

Current") 42 limit 41 to (addresses or bibliography or biography or case reports or congresses or consensus development conference or consensus development conference, nih or dictionary or directory or editorial or festschrift or government publications or interview or lectures or legal cases or legislation or letter or news or newspaper article or patient education handout or periodical index)

Combine results 43 41 not 42 Randomized or controlled trials 44 Randomized controlled trials as topic/

45 Randomized controlled trial/ 46 Random allocation/ 47 Double blind method/ 48 Single blind method/ 49 Clinical trial/ 50 Clinical trial, phase i.pt. 51 Clinical trial, phase ii.pt. 52 Clinical trial, phase iii.pt. 53 Clinical trial, phase iv.pt. 54 Controlled clinical trial.pt. 55 Randomized controlled trial.pt. 56 Multicenter study.pt. 57 Clinical trial.pt. 58 exp clinical trials as topic/ 59 (clinical adj trial$).tw. 60 ((singl$ or doubl$ or treb$ or trip$) adj (blind$3 or mask$3)).tw. 61 Randomly allocated.tw. 62 (allocated adj2 random$).tw.

Combine results 63 or/44-62 Meta-analysis 64 meta analysis.pt. Systematic review 65 (systematic adj review:).mp. Combine terms 66 64 or 65 Observational studies 67 exp cohort studies/ or (cohort adj (study or studies)).tw. or

Cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or Longitudinal.tw. or comparative study/ or follow-up studies/ or prospective studies/ or cohort.mp. or compared.mp. or multivariate.mp. or Case-Control Studies/ or (case control or case-control).mp.

Initiation/Frequency/Adequacy 68 43 and 17 (9705) Randomized or controlled trials 69 43 and 17 and 63 (2455) Meta-analyses or systematic reviews 70 43 and 17 and 66 (136) Observational studies 71 43 and 17 and 67 (6357) Membranes 72 43 and 24 (1746) Randomized or controlled trials 73 43 and 24 and 63 (412) Meta-analyses or systematic reviews 74 43 and 24 and 66 (10)

58

Observational studies 75 43 and 24 and 67 (1113) Blood pressure/Fluid volume 76 43 and 33 (2770) Randomized or controlled trials 77 43 and 33 and 63 (631) Meta-analyses or systematic reviews 78 43 and 33 and 66 (21) Observational studies 79 43 and 33 and 67 (1708) Hemodiafiltration/Hemofiltration 80 43 and 36 (453) Randomized or controlled trials 81 43 and 36 and 63 (146) Meta-analyses or systematic reviews 82 43 and 36 and 66 (9) Observational studies 83 43 and 36 and 67 (253) Weight gain/Ultrafiltration 84 43 and 40 (354) Randomized or controlled trials 85 43 and 40 and 63 (94) Meta-analyses or systematic reviews 86 43 and 40 and 66 (0)

Observational studies 87 43 and 40 and 67 (222)

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APPENDIX B. Evidence Tables Table 1. Overview of Studies: Initiation of Hemodialysis Author Year (Trial) Location Funding Source Study Design

Intervention/Duration Follow-up and Withdrawals

Inclusion/Exclusion Criteria Patient Characteristics (expressed in means unless otherwise noted) Study Risk of Bias

Cooper 20104

(IDEAL Study) Location: Australia, New Zealand (32 centers) Funding Source: Government, Foundation, Industry Study Design: RCT

Early Initiation - Commence dialysis at eCrCl (Cockcroft-Gault) 10.0 to 14.0 ml/min/1.73m2 (n=404); mean eCrCl at initiation=12.0 ml/min/1.73m2 Late Initiation - Continued routine medical care with dialysis at eCrCl (Cockcroft-Gault) 5.0 to 7.0 ml/min/1.73m2 or at >7.0 ml/min/1.73m2 if recommended by treating physician (n=424); mean eCrCl at initiation=9.8 ml/min/1.73m2 Follow-up period: median 3.64 years early initiation group, median 3.57 years late initiation group Study withdrawals (%): 270/404 (67%) of early initiation group did not complete follow-up (including 152 deaths and 78 transplantations); 258/424 (61%) of late initiation group did not complete follow-up (including 155 deaths and 74 transplantations)

Inclusion Criteria: progressive chronic kidney disease (including failing kidney transplant), eCrCl 10.0 to15.0 ml/min/1.73m2 (Cockcroft-Gault corrected for body-surface area) Exclusion Criteria: age <18 yrs, eCrCl <10, plan to receive kidney from live donor within next 12 months, recently diagnosed cancer likely to affect survival, unable to provide written informed consent

N=828 Age (yr): 60 Gender (Male %): 66 Race/Ethnicity (%): white 72%, Asian 9%, Maori 6%, Pacific Islander 6% Systolic BP (mm Hg): 142 Diastolic BP (mm Hg): 79 Serum creatinine (mg/dL): 530 µmol/liter Estimated CrCL (ml/min/1.73m2): 13 (Cockcroft-Gault) Estimated GFR (ml/min/1.73m2): 9.9 (MDRD) Kt/V: NA Time on dialysis (mos): NA Diabetes (%): 43 History of HTN (%): NR History of CVD or CHD (%): 39 History of MI (%): 28 History of Stroke (%): 2

Sequence generation: adequate Allocation concealment: adequate Blinding: An independent end-points committee, unaware of the treatment assignments, reviewed all primary outcome events (deaths) and determined the cause of death in each case. Incomplete outcome data: no Selective outcome reporting: no Risk of bias: Low

BP = blood pressure; CHD = coronary heart disease; CVD = cardiovascular disease; ESRD = end-stage renal disease; CrCl = creatinine clearance; GFR = glomerular filtration rate; HTN = hypertension; MI = myocardial infarction; NA = not applicable; NR = not reported

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Table 2. Primary and Secondary Outcomes: Initiation of Hemodialysis Author Year (Trial) Follow-up

Primary All-Cause Mortality,

n/N (%) Cardiovascular Death,

n/N (%) Myocardial Infarction,

Any*, n/N (%)

Stroke, Any*, n/N (%)

All-Cause Hospitalizations**

n/N (%) INT Control INT Control INT Control INT Control INT Control

Cooper 20104

(IDEAL) I Early Initiation C Late Initiation 3.6 years

152/404 (38%)

HR 1.04 [0.83, 1.30],

P=0.75

155/424 (37%)

63/404 (16%)

HR 0.94 [0.67, 1.32],

P=0.70

71/424 (17%)

Non-fatal 47/404 (12%)

HR 1.39 [0.91, 2.15],

P=0.13

37/424 (9%)

Non-fatal 33/404 (8%)

HR 1.21 [0.73, 2.00],

P=0.45

29/424 (7%) NR NR

HR = hazard ratio; I or INT = intervention, NR = not reported Table 3. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up: Initiation of Hemodialysis

Author Year (Trial) Follow-up

Quality of life Depression Cognition Other* Other*

INT Control INT Control INT Control INT Control INT Control Cooper 20104

(IDEAL) I Early Initiation C Late Initiation 3.6 years

Assessment of Quality of Life:

No significant differences between groups

NR NR NR NR NR NR NR NR

I or INT = intervention; NR = not reported

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Table 4. Harms, Complications of Dialysis: Initiation of Hemodialysis


Temporary Catheterization,

n/N (%)

Need for Access Revision, n/N (%)

Access site infection, n/N (%)

Hospitalizations due to Fluid/Electrolyte

Disorders n/N (%)

Required Additional Dialysis, n/N (%)

INT Control INT Control INT Control INT Control INT Control Cooper 20104

(IDEAL) I Early Start C Late Start 3.6 years

118/404 (29%)

HR 1.03 [0.80, 1.32],

P=0.85

124/424 (29%)

145/404 (36%)

HR 1.08 [0.85, 1.35],

P=0.54

147/424 (35%)

47/404 (12%)

HR 0.99 [0.67, 1.48],

P=0.97

50/424 (12%) NR NR NR NR

HR = hazard ratio; I or INT = intervention; NR = not reported

62

Table 5. Overview of Studies: Studies that Altered Frequency, Treatment Duration, or Both Frequency and Treatment Duration of Hemodialysis Author Year (Trial) Location Funding Source Study design

Intervention/ Duration/Site Follow-up and Withdrawals


Studies that Altered Frequency of Hemodialysis FHN Trial Group 20107

(FHN-Daily) Other articles: Chan 201224

Hall 201225

Kaysen 201226

Rocco 201127

Suri 201328

Tamura 201329

Unruh 201330

Location: United States and Canada, multicenter Funding Source: Industry and non-industry Study design: RCT

Daily HD: 6 times/week for 1.5-2.75 h in-center (n=125) Conventional HD: 3 times/week for 2.5-4.5 h in-center (n=120) Follow-up period: 12 mos Study withdrawals (%): 56/245 (23%) Transplanted: 24/245 (9.8%) Died: 14/245 (5.7%)

Inclusion Criteria: ESRD requiring chronic renal replacement therapy; age > 13 years; mean eKt/V > 1.0 for last 2 baseline HD sessions; weight > 30 kg Exclusion Criteria: unable or unwilling to follow study protocol or provide informed consent; requires HD >3 times per week (occasional ultrafiltration on a fourth day per week is okay); pregnant or planning to become pregnant in the next 12 mos; history of poor adherence to thrice weekly HD; inability to come for in-center HD 6 days per week; expected geographic unavailability at a participating HD unit for >2 consecutive weeks or >4 weeks total during the next 14 mos; currently in an acute or chronic care hospital; contraindication to heparin; expectation that native kidneys will recover; residual renal clearance >3ml/min per 35 L urea volume; on daily or nocturnal HD for less than 3 mos; use of investigational drugs or participation in another clinical trial; scheduled for living donor kidney transplant, change to peritoneal dialysis, or plans to relocate to a non-study center within the next 14 mos; life expectancy less than 6 mos; medical history that might limit the patient’s ability to take the trial treatments and complete the 12 mo duration of the study; medical conditions that would prevent the subject from performing the cardiac MRI procedure; inability to communicate verbally in English or Spanish; vascular access being used for HD is a non-tunneled catheter

N= 245 Age (yr): 50 Gender (Male %): 62 Race/Ethnicity (%): black 42, white: 36, Native American 3, Asian 7, Pacific Islands 2, Other 10 Systolic BP (mm Hg): 146 Diastolic BP (mm Hg): 80 Serum creatinine (mg/dL): 10.54 Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR Diabetes (%): 41 History of HTN (%): 89 History of CVD or CHD (%): NR

CAD (MI) (%): 11 History of MI (%): NR History of Stroke (%): 7

Sequence generation: adequate (Web-based program) Allocation concealment: unclear Blinding: adequate (MRI image analysis was blinded) Incomplete outcome data: no Selective outcome reporting: no Risk of bias: Moderate

63

Author Year (Trial) Location Funding Source Study design



Fagugli 200120

Location: Italy Funding Source: NR Study design: Randomized cross-over trial

Daily HD: daily for 12/7 h (12 hours weekly); location NR (n=12) Conventional HD: 3 times/ week for 4 hours (12 hours weekly); location NR (n=12) Follow-up period: 6 mos on each treatment (1 year total) Study withdrawals (%): NR

Inclusion Criteria: previously treated with standard thrice-weekly HD for at least 6 mos Exclusion Criteria: none reported

N=12 Age (yr): 64 Gender (Male %): 33 Race/Ethnicity (%): NR Systolic BP (mm Hg): 147 Diastolic BP (mm Hg): 78 Serum creatinine (mg/dL): 8.8 Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): 40 Diabetes (%): 25 History of HTN (%):NR History of CVD or CHD (%):NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: unclear Allocation concealment: unclear Blinding: unclear Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

Ayus 20055

Location: United States Funding Source: Non-industry Study design: CCT

Short daily HD: 6 times/week for 3 h in-center (n=26) Conventional HD: 3 times/week for 4 h in-center (n=51) Follow-up period: 12 mos Study withdrawals (%): 0

Inclusion Criteria: adult patients receiving maintenance HD willing to participate in the short daily HD program Exclusion Criteria: none reported

N=77 Age (yr): 53 Gender (Male %): 66 Race/Ethnicity (%): white 1, Hispanic 92, black 5, other 1 Systolic BP (mm Hg): 144 Diastolic BP (mm Hg): 75 Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): 42 Diabetes (%): NR History of HTN (%): NR History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: inadequate (consecutive Allocation concealment: not applicable Blinding: adequate (interpretation of echocardiograms was blinded) Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

64




Lindsay 200322 (London Daily/ Nocturnal Hemodialysis) Other articles: Heidenheim 200331

Nesrallah 200332

Location: London, Ontario, Canada Funding Source: Non-industry Study design: CCT

Quotidian daily HD: 5-6 days/week for 1.5-2.5 h at home (n=11) Conventional HD: 3 days/week for 3.5-4.5 h in-center (n=22) (Also had Quotidian nocturnal HD treatment arm) Follow-up period: 18 mos Study withdrawals (%): 0 Died: 3/46 (6.5%) Transplanted; 2/46 (4.3%) (4 of these 5 were replaced)

Inclusion Criteria: older than 18 years; able to give informed consent; on conventional HD therapy for a minimum of 3 mos; a reasonable expectation of surviving 1 year, regardless of comorbidities Controls matched as closely as possible for age, sex, comorbidity, and original dialysis modality Exclusion Criteria: none reported

N=46 Age (yr): 47 Gender (Male %): 67 Race/Ethnicity (%): NR Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR

Predialysis MAP (mm Hg): 109.3 Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR Diabetes (%): 17 History of HTN (%): NR History of CVD or CHD (%): NR

CHD (%): 22 History of MI (%): NR History of Stroke (%): NR

Sequence generation: not applicable Allocation concealment: not applicable Blinding: no (treatment group impossible to conceal) Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

65




Quintaliani 200023

Location: Italy Funding Source: NR Study design: CCT

Daily HD: 6-7 times/week for 2 h in-center or at home (n=24) Conventional HD: 3 times/week for 4 h mostly in-center (n=124) Follow-up period: 3.6 yr (mean) Study withdrawals (%): 0 Died: 16/148 (11%) Transplanted: 14/148 (9.5%)

Inclusion Criteria: adult male or female; native arteriovenous arm fistula that had been functioning for at least one month Exclusion Criteria: prosthetic device, diabetes, collagen disease, or malignancy

N=148 Age (yr): 56 Gender (Male %): 62 Race/Ethnicity (%): NR Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR Diabetes (%): NR History of HTN (%): NR History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: not applicable Allocation concealment: not applicable Blinding: no Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

Katopodis 200921

Location: Greece Funding Source: NR Study design: Quasi-randomized (alternates in alphabetical order) controlled trial

EoD HD: HD every-other-day for 4 h (44 h between sessions) (location NR) (n=9) Conventional HD: HD 3 times/ week for 4 h (44 h between 2 sessions and 72 h between 1 session each week) (location NR) (n=9) Follow-up period: 12 mos Study withdrawals (%): 0

Inclusion Criteria: stable for ≥ 6 mos and willing to participate Exclusion Criteria: diabetes mellitus, known uncured malignancy, active inflammation at the time of the enrollment, liver and heart (stage IV NYHA) failure, malnutrition, medications affecting urea metabolism such as corticosteroids

N=18 Age (yr): 57 Gender (Male %): 67 Race/Ethnicity (%): NR Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR Diabetes (%): 0 (excluded) History of HTN (%): NR History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: not applicable Allocation concealment: not applicable Blinding: unclear Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

66




Yilmaz 201219

Location: Turkey Funding Source: Non-industry (foundation) Study design: RCT

Supplemental ultrafiltration: once a week for 4 h during a 2-day dialysis-free interval, plus HD 3 times/ week for 4-5 h (location NR) (n=13) Conventional HD: HD 3 times/ week or 4-5 h (location NR) (n=13) Follow-up period: 8 weeks Study withdrawals (%): 0

Inclusion Criteria: high (>2 kg) interdialytic weight gain; high level (>l mg/dL) of C-reactive protein; left ventricular dysfunction; high level of brain natriuretic peptide Exclusion Criteria: diagnosis of an acute or chronic infectious disease; evidence of severe hepatic disease; use of immunosuppressant or non-steroidal anti-inflammatory drugs; presence of a rnalignant disease; evidence of malnutrition as assessed by a dialysis malnutrition score; normal C-reactive protein and brain natriuretic peptide levels; normal left ventricular function; low (<2 kg) interdialytic weight gain

N=26 Age (yr): 58 Gender (Male %): 69 Race/Ethnicity (%): NR Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): 63 Diabetes (%): NR History of HTN (%): NR History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: unclear Allocation concealment: unclear Blinding: unclear Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

Studies that Altered Treatment Duration of Hemodialysis London Daily/ Nocturnal Hemodialysis See details above (Lindsay 2003)22

Quotidian nocturnal HD: 5-6 nights/ week for 6-8 h at home (n=13) Quotidian daily HD: 5-6 days/ week for 1.5-2.5 h at home (n=11) (Also had conventional HD arm)

See details above

67




Wang 200833

Location: Canada Funding Source: Non-industry (foundation) Study design: Randomized cross-over trial

Increased time: HD 3 times/ week for 4.5 h in-center (n=18) Conventional HD: dialysis 3 times/ week for 4 h in-center (n=18) (Other treatment arms had increased flow [800 mL/min] or dialyzers in parallel) Follow-up period: 6 weeks on each treatment (12 weeks total) Study withdrawals (%): 4/18 (22%)

Inclusion Criteria: on stable regimen of hemodialysis for 3 mos or longer; dry weight of 80 kg or greater; Kt/V ≤ 1.2 on 2 occasions in previous 6 mos or requirement for longer than 12 h/week of hemodialysis because of history of inadequate dialysis; blood flow rate of 350 mL/min or greater through a well-functioning access Exclusion Criteria: renal transplantation scheduled in next 6 mos; contraindication to intradialytic anticoagulation; required longer than 4½ h of hemodialysis 3 times /week for volume removal because of excessive interdialytic weight gains or intradialytic hypotension/ cramping; or failure to provide informed consent

N=18 Age (yr): 56 Gender (Male %): 94 Race/Ethnicity (%): white 72 Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): 22 Diabetes (%): 78 History of HTN (%): NR History of CAD (%): 44 History of Cerebrovascular Disease (%): 17 History of MI (%): NR History of Stroke (%): NR

Sequence generation: unclear Allocation concealment: unclear Blinding: patients were blinded to treatment arm Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

McGregor 200134

Location: New Zealand Funding Source: Industry and non-industry (government, foundation) Study design: Randomized cross-over trial

Long-slow home HD: 3 times/week for 6-8 h at home [day or night NR] (n=9) Short in-center HD: 3 times/week for 3.5-4.5 h in-center (n=9) Follow-up period: 8 weeks on each treatment arm (16 weeks total) Study withdrawals (%): 0

Inclusion Criteria: home HD for more than 6 months; dialyzing more than 6 h 3 times weekly; on no antihypertensive drugs; mean pre-dialysis BP over previous month of < 160/90 mm Hg Exclusion Criteria: diabetes mellitus; overt cardiac disease; prior nephrectomy; any recent illness

N=9 Age (yr): 48 Gender (Male %): 44 Race/Ethnicity (%): Caucasian 89, Polynesian: 11 Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR Diabetes (%): NR History of HTN (%): NR History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: unclear Allocation concealment: unclear Blinding: partially (echocardiographer blinded; other outcomes unclear) Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

68




Ok 201135

(Long Dialysis Study) Other articles: Demirci 201236

Demirci 201337

Location: Turkey (multicenter) Funding Source: Non-industry Study design: CCT

Nocturnal HD: 3 times/week for 7–8 h at night (between 10 PM to 6 AM) in-center (n=247) Conventional HD: 3 times/week for 3.5–4.5 h (time of day and location NR) (n=247) Follow-up period: 12 mos Study withdrawals (%): 34 Quit nocturnal HD: 49/494 (10%) Transferred to another HD center: 103/494 (21%) Transplanted: 15/494 (3%) Changed to peritoneal dialysis: 1/494 (<1%)

Inclusion Criteria: age > 18 yr; on HD thrice-weekly 12 h/week; willing to participate in the study Exclusion criteria: scheduled for living donor renal transplantation; serious life-limiting comorbid situations (ie, active malignancy, active infection, end-stage cardiac, pulmonary or hepatic disease); urine output > 250 mL/day; temporary catheter access; mental incompetence Additional exclusion criteria for substudy on arterial stiffness: MI or stroke within 6 mos, unstable angina, persistent arrhythmia advanced heart failure, lack or radial or carotid artery Additional exclusion criteria for substudy on volume: technical problems; pacemaker; amputation of a major limb Conventional controls: matched for age, sex, diabetic status, and HD duration

n=494 Age (yr): 46 Gender (Male %): 68 Race/Ethnicity (%): NR Systolic BP (mm Hg): 125 Diastolic BP (mm Hg): 77 Serum creatinine (mg/dL): 8.96 Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.23 Time on dialysis (mos): 60 Diabetes (%): 21 History of HTN (%): NR History of CVD or CHD (%): 14 History of MI (%): NR History of Stroke (%): NR

Sequence generation: not applicable Allocation concealment: not applicable Blinding: partially (echocardiographer blinded; other outcomes unblinded) Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

Studies that Altered Both Frequency and Treatment Duration of Hemodialysis

69




Culleton 20079

(Alberta Kidney Disease Network) Other articles: Bass 201238

Location: Canada Funding Source: Non-industry (foundation ) Study design: RCT

Frequent nocturnal HD: 5-6 nights/week for minimum of 6 h at home (n=26) Conventional HD: 3 times/week in-center or at home (treatment time NR) (n=25) Follow-up period: 6 mos Study withdrawals (%): 1/52 (2%) withdrew before baseline data collected Died:1/51 (2%) Contraindication to MRI: 7/51 (14%) Transplanted: 2/51 (4%)

Inclusion Criteria: at least 18 years old; receiving in-center, self-care or home conventional HD 3 times weekly at 10 centers in Alberta, Canada; interested and willing to train for and commence nocturnal HD Exclusion Criteria: lacking the physical or mental capacity to train for nocturnal HD

N=51 Age (yr): 54 Gender (Male %): 63 Race/Ethnicity (%): white 86 Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): 62 Diabetes (%): 41 History of HTN (%): NR History of CVD (%): 39 History of cerebrovascular disease (%): 16 History of MI (%): NR History of Stroke (%): NR

Sequence generation: adequate Allocation concealment: adequate Blinding: partially (MRIs were blinded; other outcomes were not) Incomplete outcome data: no Selective outcome reporting: partially (not all outcomes listed in methods are reported) Risk of bias: Low

70




Rocco 20118

(FHN-Nocturnal) Other articles: Chan 201224

Hall 201225

Kaysen 201226

Rocco 201127

Suri 201328

Tamura 201329

Unruh 201330

Location: United States and Canada Funding Source: Industry and non-industry (government, foundation) Study design: RCT

Nocturnal HD: 6 nights/week for 6-8 h at home (n=45) Conventional HD: 3 times/week for 2.5-5 h usually at home (n=42) Follow-up period: 14 mos Study withdrawals (%): 0 Transplanted: 5/87 (5.7%) Died: 3/87 (3.4%)

Inclusion Criteria: end-stage renal disease requiring chronic renal replacement therapy; age > 18 y; mean eKt/V > 1.0 for last 2 baseline HD sessions; weight > 30 kg Exclusion Criteria: unable or unwilling to follow study protocol or provide informed consent; requires HD >3 times per week (occasional ultrafiltration on a fourth day per week is okay); pregnant or planning to become pregnant in the next 12 mos; history of poor adherence to thrice weekly HD; inability to come for in-center HD 6 days per week; expected geographic unavailability at a participating HD unit for >2 consecutive weeks or >4 weeks total during the next 14 mos; currently in an acute or chronic care hospital; contraindication to heparin; expectation that native kidneys will recover; residual renal clearance >10 mL/min/1.73m2; on daily or nocturnal HD for less than 3 mos; use of investigational drugs or participation in another clinical trial; scheduled for living donor kidney transplant, change to peritoneal dialysis, or plans to relocate to a non-study center within the next 14 mos; life expectancy less than 6 mos; medical history that might limit the patient’s ability to take the trial treatments and complete the 12 mo duration of the study; medical conditions that would prevent the subject from performing the cardiac MRI procedure; inability to communicate verbally in English or Spanish; vascular access being used for HD is a non-tunneled catheter

N= 87 Age (yr): 53 Gender (Male %): 66 Race/Ethnicity (%): black 26, white 55, Native American 3, Asian 14 Systolic BP (mm Hg): 149 Diastolic BP (mm Hg): 81 Serum creatinine (mg/dL): 8.8 Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR Diabetes (%): 43 History of HTN (%): 90 History of Heart Failure (%): 14 History of MI (%): 10 History of Stroke (%): 2

Sequence generation: adequate Allocation concealment: unclear Blinding: adequate (MRI image analysis was blinded) Incomplete outcome data: no Selective outcome reporting: no Risk of bias: Moderate

71




Chan 200240

Location: Canada Funding Source: Non-industry (government, foundation) Study design: CCT

Nocturnal HD: nightly for 8-10 h at home (n=28) Conventional HD: 3 times/week for 4 h at home (n=13) Follow-up period: 3.2 yr Study withdrawals (%): NR

Inclusion Criteria, nocturnal arm: participating in the Nocturnal Hemodialysis demonstration project in Toronto for at least 2 years Inclusion Criteria, conventional arm: eligible for nocturnal HD and enrolled in the Toronto General Hospital self-care home dialysis program for a minimum of one year Exclusion Criteria: none reported

N=41 Age (yr): 47 Gender (Male %): NR Race/Ethnicity (%): NR Systolic BP (mm Hg):143 Diastolic BP (mm Hg): 83 Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR Diabetes (%): NR History of HTN (%): NR History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: not applicable Allocation concealment: not applicable Blinding: unclear Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

Lindsay 200322

(London Daily/ Nocturnal Hemodialysis) Other articles: Heidenheim 200331

Nesrallah 200332

Location: Canada Funding Source: Non-industry (government) Study design: CCT

Quotidian nocturnal HD: 5-6 nights/week for 6-8 h at home (n=13) Conventional HD: 3 days/week for 3.5-4.5 h in-center (n=22) (Also had Quotidian daily HD arm) Follow-up period: 18 mos Study withdrawals (%): 0 Died: 3/46 (6.5%) Transplanted: 2/46 (4.3%) (4 of these 5 were replaced)

Inclusion Criteria: older than 18 years; able to give informed consent; on conventional HD therapy for a minimum of 3 mos; a reasonable expectation of surviving 1 year, regardless of comorbidities Controls matched as closely as possible for age, sex, comorbidity, and original dialysis modality Exclusion Criteria: none reported

N=46 Age (yr): 47 Gender (Male %): 67 Race/Ethnicity (%): NR Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR

Predialysis MAP (mm Hg): 109 Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR Diabetes (%): 17 History of HTN (%): NR History of CVD or CHD (%): NR

CHD (%): 22 History of MI (%): NR History of Stroke (%): NR

Sequence generation: not applicable Allocation concealment: not applicable Blinding: no Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

72




Fagugli 200641

Location: Italy Funding Source: NR Study design: CCT

Short daily HD: HD 6 days/ week for 2 h in-center (n=12) Extended standard HD: HD 3 days/ week for 4.5-5 h in-center (n=12) Follow-up period: 6 mos Study withdrawals (%): NR

Inclusion Criteria: hypertension (office pre-HD BP >140/90 mmHg or antihypertensive treatment); age >15 and <80 yrs; previously treated with standard HD (4 h x 3/ week) for at least 3 mos; clinical and biochemical stable conditions at least in the previous mo; spKt/V >1.2. Exclusion Criteria: limb amputation, severe malnutrition and malignancies

N=24 Age (yr): 59 Gender (Male %): 38 Race/Ethnicity (%): NR Systolic BP (mm Hg): 154 Diastolic BP (mm Hg): 81 Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: 3.85 Time on dialysis (mos): 30 Diabetes (%): NR History of HTN (%): NR History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: not applicable Allocation concealment: not applicable Blinding: partially (not reported for some outcomes) Incomplete outcome data: no Selective outcome reporting: no Risk of bias: High

BP = blood pressure; CCT = controlled clinical trial; CHD = coronary heart disease; CVD = cardiovascular disease; ESRD = end-stage renal disease; FHN = Frequent Hemodialysis Network; GFR = glomerular filtration rate; h = hours; HD = hemodialysis; HTN = hypertension; MI = myocardial infarction; mo = month; MRI = magnetic resonance imaging; NR = not reported; NS = not significant or nonsignificant; QoL = quality of life; RCT = randomized controlled trial; yr = years

73

Table 6a. Primary and Secondary Outcomes: Studies that Altered Frequency of Hemodialysis Author Year (Trial) Study Design Follow-up




Any,* n/N (%) Stroke,

Any,* n/N (%) All-Cause

Hospitalizations † n/N (%)

INT Control INT Control INT Control INT Control INT Control FHN Trial Group 20107

(FHN-Daily) I: HD 6 times/week for 1.5-2.75 h (n=125) C: Conventional: HD 3 times/week for 2.5-4.5 h (n=120) RCT 12 months

5/125 (4.0)

9/120 (7.5)‡

[P=0.24] NR NR NR NR NR NR 58/125

(46.4)

47/120 (39.2)

P=0.50 HR 0.88

[0.60, 1.28]

Katopodis 200921

I: EoD: HD every-other day for 4 h (n=9) C: Conventional: HD 3 times/week for 4 h (n=9) Quasi-R 12 months

0/9 0/9 0/9 0/9 NR NR NR NR NR NR

Yilmaz 201219

I: Ultrafiltration 4 h plus conventional HD (n=13) C: Conventional: HD 3 time/week for 4-5 h (n=13) RCT 8 weeks

0/13 0/13 0/13 0/13 NR NR NR NR NR NR

Ayus 20055

I: Short daily HD C: Conventional HD CCT 12 months

0/26 0/26 NR NR NR NR NR NR NR NR

74

Author Year (Trial) Study Design Follow-up







INT Control INT Control INT Control INT Control INT Control Lindsay 200322

(London Daily/Nocturnal) I: Quotidian daily: HD 5-6 days/week for 1.5-2.5 h (n=11) C: Conventional: HD 3 days/week for 3.5-4.5 h (n=22) CCT 18 months

0/11 3/22

(13.6)‡

[P=0.20] NR NR NR NR NR NR

Admission/ px-y, mean

(SD)

0.49 (0.5)


(SD)

0.93 (1.2)‡

[P=0.23]

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; F/U = follow-up; HD = Hemodialysis; I or Int = intervention; n or N = number; NR = not reported; px-y = patient years; RCT = randomized controlled trial; R X-over = randomized cross-over; SD = standard deviation; HR = hazard ratio [ ] 95% confidence interval *Fatal and non-fatal †Unless otherwise noted ‡Significance for between-group comparisons NR in article [calculated p]

75

Table 6b. Primary and Secondary Outcomes: Studies that Altered Treatment Duration of Hemodialysis Author Year; Study Design Follow-up







INT Control INT Control INT Control INT Control INT Control McGregor 200134

I: Long-slow home: HD 3 times/week for 6-8 h at home C: Short in-center: HD 3 times/week for 3.5-4.5 h in-center R X-over 8 weeks each treatment arm

0/9 0/9 0/9 0/9 NR NR NR NR NR NR

London-Daily/ Nocturnal Lindsay 200322 I: Quotidian nocturnal: HD 5-6 nights/week for 6-8 h (n=13) C: Quotidian daily: HD 5-6 days/week for 1.5-2.5 h (n=11) CCT 18 months

3/13 (23.1)‡

[P=0.09] 0/11 NR NR NR NR NR NR


(SD)

0.95 (1.0)‡

[P=0.18]


(SD)

0.49 (0.5)

Long Dialysis Study Ok 201135

I: Nocturnal: HD 3 nights/ week for 7–8 h in-center (n=247) C: Conventional: HD 3 times/ week for 3.5–4.5 h (location NR) (n=247) CCT 12 months

4/247 (1.6)

15/247 (6.1)

P=0.01

1/247 (0.4)

6/247 (2.4)

P=0.057 NR NR NR NR 0.45/100

px-y

1.57/100 px-y

P=0.002

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; I or Int = intervention; n or N = number; NR = not reported; px-y = patient years; RCT = randomized controlled trial; R X-over = randomized cross-over; SD = standard deviation *Fatal and non-fatal †Unless otherwise noted ‡Significance for between-group comparisons NR in article [calculated p]

76

Table 6c. Primary and Secondary Outcomes: Studies that Altered Both Frequency and Treatment Duration of Hemodialysis Author Year (Trial) Study Design Follow-up







INT Control INT Control INT Control INT Control INT Control Culleton 20079

(Alberta Kidney Disease Network) I: Nocturnal: HD 5-6 nights/week for ≥ 6 h (n=26) C: Conventional: HD 3 times/week (treatment time NR) (n=25) RCT 6 months

1/26 (3.8)

0/25 (0)‡


Mean (95% CI):

0.62 [0.24-1.00]

over 6 months‡

Mean (95% CI):

0.84 [0.18-1.50]

over 6 months‡

Rocco 20118

(FHN-Nocturnal) I: HD 6 nights/week for 6-8 h (n=45) C: Conventional: HD 3 times/week for 2.5-5 h (n=42) RCT 14 months

2/45 (4.4)

1/42 (2.4)‡

[P=0.61] NR NR NR NR NR NR 19/45

(42.2)

16/42 (38.1)

P=0.34 HR 1.42

[0.69, 2.90]

Lindsay 200322

(London Daily/Nocturnal) I: Quotidian nocturnal: HD 5-6 nights/ week for 6-8 h (n=13) C: Conventional: HD 3 days/week for 3.5-4.5 h (n=22) CCT 18 months

3/13 (23.1)

3/22 (13.6)‡



(SD) 0.95 (1.0)


(SD) 0.93 (1.2)‡

[P=0.96]

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; F/U = follow-up; HD = Hemodialysis; I or Int = intervention; n or N = number; NR = not reported; px-y = patient years; RCT = randomized controlled trial; R X-over = randomized cross-over; SD = standard deviation; HR = hazard ratio *Fatal and non-fatal †Unless otherwise noted ‡Significance for between-group comparisons NR in article [calculated p]

77

Table 7a. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up – Studies that Altered Frequency of Hemodialysis

Author Year Trial Study Design Follow-up

Quality of life* Depression* Cognition* Other* Other*


Hall 201225

Tamura 201329

Unruh 201330

(FHN-Daily) Daily trial: I: HD 6 times/week for 1.5-2.75 h (n varies) C: Conventional HD 3 times/week for 2.5-4.5 h (n varies) RCT 12 months

PHC** 42.1(10.8)

n=100

RAND SF-36 PF

64.0 (27.7) (n=102)

SPPB

8.4 (2.8) (n=96)

PHC 38.6(9.5)

n=90 Tx Effect 0.29 (0.8,

5.1) P<0.001

RAND SF-36 PF

59.1 (24.7) (n=90)

Tx Effect 4.4 (-1.3, 10.2)

P=NS

SPPB 7.9 (2.8) (n=81)

Tx Effect 0.21 (-0.34, 0.76) P=NS

Beck: 10.4 (8.5)

(n=101)†

Beck: 12.2 (9.9)

(n=88)† P=0.10

Failure to complete

Trails B in 5 min n/N (%): 23/95 (24.2)

Failure to complete

Trails B in 5 min

n/N (%): 19/81 (23.5)

P=0.27

Beck, Cognitive subscale:

6.3 (6.5) n=95


6.9 (7.4)‡ n=86

[P=0.56]

Modified Mini-

Mental State exam, mean (SD):

89 (10)

Modified Mini-

Mental State exam, mean (SD): 89 (9) P=NS

Heidenheim 200331

(London Daily/ Nocturnal) I: Daily: HD 5-6 days/week for 1.5-2.5 h (n=10) C: Conventional: HD 3 days/ week for 3.5-4.5 h (n=13) CCT 18 months

RAND SF-36 Physical Components

Summary Score

42.1 (11.0)‡

RAND SF-36 Physical

Components Summary

Score 39.9 (8.6)‡

[P=0.60]

NR NR

RAND SF-36 Mental

Components Summary

Score 52.4 (11.5)‡

RAND SF-36 Mental

Components Summary

Score 47.2 (12.4)‡

[P=0.31]

Number of dialysis sx

3.4 (2.8)‡

Number of disease sx 6.0 (4.7)‡


3.9 (2.4)‡

[P=0.65]

Number of disease sx 8.0 (4.2)‡ [P=0.29]

NR NR

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; I or Int = intervention; KDQoL = Kidney Disease Quality of Life; n or N = number; NR = not reported; NS = not statistically significant; PHC = Physical Health Composite (weighted average of RAND SF-36 PF score and additional summaries for bodily pain, general health, and readiness for everyday physical activities); PF = RAND SF-36 Physical Functioning subscale; RCT = randomized controlled trial; R X-over = randomized cross-over; SPPB = Short Physical Performance Battery (gait speed, chair stand, balance); SD = standard deviation; SF = short form; sx = symptoms

78

*Values are mean (SD) unless otherwise noted **Data from Hall 201225

†Values differ between FHN 2010,7 Hall 2011,25 Rocco 2011,8 and Unruh 201330; here transcribed value with larger n ‡Significance for between-group comparisons NR in article [calculated p]

79

Table 7b. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up – Studies that Altered Treatment Duration of Hemodialysis



INT Control INT Control INT Control INT Control INT Control Wang 200833

I: Increased time: HD 3 times/week for 4.5 hours (n=18) C: Conventional: HD 3 times/week for 4 hours (n=18) R X-over 6 weeks each treatment arm

RAND SF-36 Physical Function,

mean (95% CI): 43.3

(26.7-59.9)

RAND SF-36 Physical Function,

mean (95% CI): 48.5

(32.9-64.0) P=0.8

NR NR

KDQoL-SF Cognitive function subscale

mean (95% CI):

87.3 (72.2-102.4)

KDQoL- SF Cognitive function subscale

mean (95% CI): 76.1

(61.7-90.5) P=0.1

KDQoL-SF ESRD

Symptom domain Mean

(95% CI): 79.2

(72.6-85.8)

KDQoL-SF ESRD

Symptom domain Mean

(95% CI): 75.9

(70.7-81.2) P=0.9

NR NR

McGregor 200134

I: Long-slow home HD C: Short in-center HD R X-over 8 weeks each treatment arm

KDQoL Long HD interfered more

with social activities (P<0.05)

NR NR NR NR Fewer uremia-related symptoms in long HD

group (P<0.05)

Less physical suffering in long HD group (P<0.005)

Ok 201135

(Long Dialysis Study) I: Nocturnal C: Conventional CCT 12 months

SF-36 No

significant change from baseline in

any dimension of

HRQoL

SF-36 Significant

decreases in bodily pain (P=0.03),

mental health

(P=0.04), and vitality (P=0.01)

Hospital Anxiety and Depression Scale:

Depression scores not significantly changed

from baseline with either treatment

Rey Auditory Verbal

Learning Test

Significant improve-ment in

immediate (P=0.004)

and delayed (P=0.02)

recall

Rey Auditory Verbal

Learning Test No

significant change

MMSE No significant change in

either group

Trail Making Test B No significant change in

either group

80



INT Control INT Control INT Control INT Control INT Control Heidenheim 200331

(London Daily/ Nocturnal) I: Nocturnal: HD 5-6 nights/week for 6-8 h (n=4) C: Daily: HD 5-6 days/week for 1.5-2.5 h (n=10) CCT 18 months


Summary Score

Nocturnal: 49.1 (4.1)‡

[P=0.25]


Summary Score Daily: 42.1 (11.0)‡

NR NR SF-36 Mental

Components Summary

Score Nocturnal:

52.2 (12.9)‡ [P=0.98]

SF-36 Mental

Components Summary

Score Daily:

52.4 (11.5)‡

Number of dialysis sx Nocturnal: 3.8 (3.0)‡ [P=0.82[

Number of. disease sx Nocturnal: 7.3 (8.3)‡ [P=0.81]


Daily: 3.4 (2.8)‡

Number of disease sx

Daily: 6.0 (4.7)‡

NR NR

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; ESRD = end stage renal disease; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; HRQoL = health-related quality of life; I or Int = intervention; KDQoL = Kidney Disease Quality of Life; MMSE = Mini Mental State Examination; n or N = number; NR = not reported; RCT = randomized controlled trial; R X-over = randomized cross-over; SF = short form; sx = symptoms *Values are mean (SD) unless otherwise noted ‡ Significance for between-group comparisons NR in article [calculated p]

81

Table 7c. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up - Studies that Altered Both Frequency and Treatment Duration of Hemodialysis




Bass 201238

(Alberta Kidney Disease Network) I: Nocturnal: HD 5-6 nights/week for ≥ 6 h (n=26) C: Conventional: HD 3 times/week (treatment time NR) (n=25) RCT 6 months

Change in EuroQoL-5D Index:

0.02§

Change in EuroQoL-5D Index:

-0.04§ P=0.06

NR NR NR NR

Sexually active, %:

32§‡

Improve-ment in

burden of kidney

disease on sex life, %:

45

Sexually active, %:

31§‡

Improve-ment in

burden of kidney

disease on sex life, %:

32 P=0.2

Not- to- moder-ately

bothered by sexual dysfunc-tion, %:

39

Not- to moder-ately

bothered by sexual dysfunc-tion, %:

60 P=0.28

Rocco 20118

Hall 201225

Tamura 201329

Unruh 201330

(FHN-Nocturnal) Nocturnal trial: I: HD 6 nights/week for 6-8 h (n varies) C: Conventional HD 3 times/week for 2.5-5 h (n varies) RCT 12 months

PHC 39.8

(12.2) (n=36)

RAND SF-

36 PF 55.0 (34.3)

(n=36)

SPPB 7.8 (3.4) (n=34)

PHC 40.6 (9.2)

(n=38) Tx Effect 0.6 (-3.4,

4.7) P=NS

RAND SF-36 PF

63.5 (23.4) (n=39)

Tx Effect -4.2 (-14.1, 5.7) P=NS

SPPB 8.7

(2.8) (n=37)

Tx Effect -0.5 (-1.71,

0.70)

Beck: 9.7

(8.6) (n=39)

Beck: 11.1

(10.2) (n=38) P=0.39

Failure to complete Trails B in

5 min, n/N (%): 8/34

(23.5)

Failure to complete Trails B in

5 min, n/N (%): 8/36

(22.2) P=0.66


5.3 (5.9)‡ (n=35)


6.6 (7.8)‡ (n=38)

[P=0.43]

Modified Mini-

Mental State exam, mean (SD):

93 (12)

Modified Mini-

Mental State exam, mean (SD): 95 (4) P=NS

82



INT Control INT Control INT Control INT Control INT Control Heidenheim 200331

(London Daily/ Nocturnal) I: Nocturnal: HD 5-6 nights/week for 6-8 h (n=4) C: Conventional: HD 3 days/ week for 3.5-4.5 h (n=13) CCT 18 months

RAND SF-36

Physical Comp at 18 mo:

49.1 (4.1)‡

RAND SF-36

Physical Comp at 18 mo:

39.9 (8.6)‡

[P=0.06]

NR NR

RAND SF-36 Mental Comp at 18 mo: 52.2

(12.9)‡

RAND SF-36 Mental Comp at 18 mo: 47.2

(12.4)‡

[P=0.50]

Number of dialysis sx at 18 mo: 3.8 (3.0)‡

Number of disease sx at 18 mo: 7.3 (8.3)‡

Number of dialysis sx at 18 mo: 3.9 (2.4)‡ [P=0.95]

Number of disease sx at 18 mo: 8.0 (4.2)‡ [P=0.82]

NR NR

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; Comp = component; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; I or Int = intervention; n or N = number; NR = not reported; NS = not statistically significant; PHC = Physical Health Composite (weighted average of RAND SF-36 PF score and additional summaries for bodily pain, general health, and readiness for everyday physical activities); PF = RAND SF-36 Physical Functioning subscale; RCT = randomized controlled trial; R X-over = randomized cross-over; SPPB = Short Physical Performance Battery (gait speed, chair stand, balance); SD = standard deviation; SF = short form; std = standard; sx=symptoms *Values are mean (SD) unless otherwise noted † Values differ between FHN 2010,7 Hall 2011,25 Rocco 2011,8 and Unruh 201330; here transcribed value with larger n

‡Significance for between-group comparisons NR in article [calculated p] §Numbers estimated from figure

83

Table 8a. Intermediate Outcomes: Hypertension, LV Mass, and Weight – Studies that Altered Frequency of Hemodialysis Author Year (Trial) Study Design Follow-up

Systolic blood pressure pre-dialysis,

mm Hg*

Number of anti-hypertensive

medications* LV mass

(grams or grams/m2)* Interdialytic weight

gain (lbs or kg or L or %)*

Dry weight (lbs or kg)*


Chan 201224

Kaysen 201226

(FHN-Daily) Daily trial: I: HD 6 times/week for 1.5-2.75 h (n varies) C: Conventional HD 3 times/week for 2.5-4.5 h (n varies) RCT 12 months

137 (19) (n=104)

147 (18) (n=93)

P<0.001

1.82 (1.73) (n=103)

2.58 (1.68) (n=92)

P<0.001

125 (46) g (n=101)

138 (52) g (n=84)

P<0.001 NR NR

Post-dialysis weight: 78.15

(21.2) kg (n=104)


(19.86) kg (n=93) P=0.32

Fagugli 200120

I: Daily: HD 6 times/week for 12/7 h (12 hours weekly) (n=12) C: Conventional: HD 3 times/week for 4 h (n=12) R X-over 6 months

126.2 (13.3)

148.9 (14.7)

P=0.001 NR NR

192 (90.4) g

120 (60.4)

grams/m2

239 (91.7) g P=0.01

148

(59.7) grams/m2

P=0.01

1.42 (0.48) kg

2.65 (0.60) kg P<0.001

53.7 (7.8) kg

54.1 (7.4) kg P=NS

Katopodis 200921

I: Eod: HD every-other day for 4 h (n=9) C: Conventional: HD 3 times/week for 4 h (n=9) Quasi-R 12 months

NR NR 2.0 (0.9) 2.6 (1.2) 225.3

(101.7)‡ grams/m2

265.9 (158.4)‡

grams/m2

[P=0.51]

NR NR NR NR

84



mm Hg*






INT Control INT Control INT Control INT Control INT Control Yilmaz 201219

I: Supplemental ultrafiltration: HD 3 times/week for 4-5 h plus ultrafiltration once/week (n=13) C: Conventional: HD 3 times/week for 4-5 h (n=13) RCT 8 weeks

NR NR NR NR 173.5 (26.1)‡

grams/m2

174.9 (30.2)‡

grams/m2

[P=0.90]

2.7 (0.3) kg

3.7 (0.5) kg

P<0.05

72.6 (6.6)‡ kg

73.7 (4.7)‡ kg

[P=0.63]

Ayus 20055

I: Short daily: HD 6 times/week for 3 h (n=26) C:Conventional: HD 3 times/week for 4 h (n=51) CCT 12 months

142 (11.3)‡

145 (11.6)‡

[P=0.28] NR NR

108 (25)

grams/m2

155† grams/m2 P<0.0001

NR NR

Post-dialysis weight:

82.1 (23.0)‡ kg

Post-dialysis weight:

75.4 (15.3)‡ kg [P=0.13]

Nesrallah 200332

(London Daily/ Nocturnal) I: Daily HD: HD 5-6 days/week for 1.5-2.5 h (n=11) C: Conventional HD: HD 3 days/week for 3.5-4.5 h (n=22) CCT 18 months

MAP (SD): 100.9 6.9)‡

MAP (SD): 104.5 (9.4)‡

[P=0.27]

NR NR NR NR 1.73 kg 2.5† kg P<0.05

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; I or Int = intervention; kg = kilograms; L = liters; LV = left ventricular; m = meters; MAP = mean arterial pressure; n or N = number; NR = not reported; NS = not statistically significant; RCT = randomized controlled trial; R X-over = randomized cross-over; SD = standard deviation *Values are mean (SD) unless otherwise noted †Value estimated from figure ‡Significance for between-group comparisons NR in article [calculated p]

85

Table 8b. Intermediate Outcomes: Hypertension, LV Mass, and Weight – Studies that Altered Treatment Duration of Hemodialysis



mm Hg*






INT Control INT Control INT Control INT Control INT Control McGregor 200134

I: Long-slow home: 3 times/week for 6-8 h at home (n=9) C: Short in-center: 3 times/week for 3.5-4.5 h in-center (n=9) R X-over 8 weeks

Mean (SEM): 155 (6)

Mean (SEM): 169 (8) P<0.05

NR NR NR NR

Mean (SEM):

2.6 (0.3) kg

Mean (SEM):

2.5 (0.2) kg P=0.88

NR NR

Ok 201135 Demirci 201236

Demirci 201337

(Long Dialysis Study) I: Nocturnal: HD 3 nights/ week for 7–8 h in-center (n=247) C: Conventional: HD 3 times/ week for 3.5–4.5 h (location NR) (n=247) CCT 12 months

124 (15) (n=NR)

125 (17)‡

(n=NR)

0.46 (0.77) (substudy,

n=60)

2.00 (1.24) (substudy,

n=60) P=0.165

116 (34) grams/m2

139 (45) grams/m2 P<0.001

2.91 (0.93) L

(substudy, n=57)

2.55 (0.72) L

(substudy n=55)

P=0.04

66.6 (14.4) kg

65.2 (14.3) kg

P=0.32

Nesrallah 200332

(London-Daily/ Nocturnal) I: Nocturnal: HD 5-6 nights/week for 6-8 h (n=13) C: Daily: HD 5-6 days/week for 1.5-2.5 h (n=11) CCT 18 months

MAP: 97.1 (8.4)‡

[P=0.24]

MAP: 100.9 (6.9)‡

NR NR NR NR 2.7†‡ kg 1.73 kg NR NR

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; I or Int = intervention; kg = kilogram; L = liters; LV = left ventricular; m = meter; MAP = mean arterial pressure; n or N = number; NR = not reported; RCT = randomized controlled trial; R X-over = randomized cross-over; SD = standard deviation; SEM = standard error of the mean

86

*Values are mean (SD) unless otherwise noted †Value estimated from figure ‡Significance for between-group comparisons NR in article [calculated p]

87

Table 8c. Intermediate Outcomes: Hypertension, LV Mass, and Weight – Studies that Altered Both Frequency and Treatment Duration of Hemodialysis



mm Hg*







(Alberta Kidney Disease Network) I: Nocturnal HD: HD 5-6 nights/week for 6+ h (n=26) C: Conventional HD: HD 3 times/week (treatment time NR) (n=25) RCT 6 months

122 (23)‡

139 (20)‡

[P=0.007] NR NR

163.6 (45.2) g

85.3

(23.2) grams/m2

183.0 (84.2) g P<0.05

102.8 (46.1)

grams/m2

P<0.05

NR NR NR NR

Rocco 20118

Unruh 201330 Chan 201224

(FHN-Nocturnal) Nocturnal trial: I: HD 6 nights/week for 6-8 h (n varies) C: Conventional HD 3 times/week for 2.5-5 h (n varies) RCT 12 months

137 (21) (n=38)

151 (19) (n=39)

P=0.009

1.41 (1.92) (n=37)

2.00 (1.43) (n=39)

P<0.001

132 (55) g (n=37)

133 (42) g (n=39) P=0.09

NR NR


(28.56) kg (n=38)


(25.64) kg (n=39) P=0.64

Chan 200240

I: Nocturnal: HD nightly for 8-10 h (n=28) C: Conventional: HD 3 times/week for 4 h (n=13) CCT 3.2 years

122 (13)‡ 131 (20)‡ [P=0.09] NR NR 114 (40)

grams/m2

150 (56) grams/m2

P<0.05 NR NR

BMI 25.4 (4.9)‡

kg/m2

BMI 25.1 (4.1)‡

kg/m2

[P=0.85]

88



mm Hg*






INT Control INT Control INT Control INT Control INT Control Nesrallah 200332

(London Daily/ Nocturnal) I: Nocturnal: HD 5-6 nights/week for 6-8 h (n=13) C: Conventional: HD 3 days/week for 3.5-4.5 h (n=22) CCT 18 months

MAP: 97.1 (8.4)‡

MAP: 104.5 (9.4)‡

[P=0.03] NR NR NR NR 2.7† kg 2.5† kg

P<0.05 NR NR

Fagugli 200641

I: Short daily: HD 6 days/week for 2 h (n=12) C: Extended standard: HD 3 days/week for 4.5-5 h (n=12) CCT; F/U 6 months

NR NR 0.6 (1.2)

0.3 (0.6)

P<0.01

Before ECW

reduction, 175

(60.0)‡ grams/m2

After ECW reduction:

120.6 (45.0) ‡

grams/m2

Before ECW

reduction: 200.1

(33.7)‡ grams/m2 P=0.22

After ECW reduction:

145.1 (39.9) ‡

grams/m2

P=0.17

2.5 (1.0) % NR NR NR

Shaded rows contain outcomes from controlled clinical trials BMI = body mass index; C = control; CCT = controlled clinical trial; ECW = extracellular water; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; I or Int = intervention; kg = kilograms; L = liters; LV = left ventricular; m = meters; MAP = mean arterial pressure;; n or N = number; NR = not reported; RCT = randomized controlled trial; R X-over = randomized cross-over; SD = standard deviation *Values are mean (SD) unless otherwise noted †Value estimated from figure ‡Significance for between-group comparisons NR in article [calculated p]

89

Table 9a. Harms, Complications Related to Vascular Access – Studies that Altered Frequency of Hemodialysis Author Year (Trial) Study Design Follow-up

Access Failure n/N (%)

Infection Requiring a Procedure

n/N (%)

Thrombectomy or Angioplasty (note which)

n/N (%)

Fibrin Sheath Stripping of Catheters or Other

n/N (%) Catheter Replacement

or other n/N (%)

INT Control INT Control INT Control INT Control INT Control FHN Trial Group 20107 Suri 201328

(FHN-Daily) I: Daily: HD 6 times/week for 1.5-2.75 h C: Conventional: HD 3 times/week for 2.5-4.5 h RCT 12 months

15/125 (12)

15/120 (13)

P=0.35 NR NR NR NR

Interven-tions:

95/125 (76)

Interven-tions:

65/120 (54) HR

(95% CI) 1.35 (0.84 to 2.18) P=0.22

Any vascular access event

40/100 px-y

Any vascular access event

23/100 px-y

HR (95% CI)

1.76 (1.11 to 2.79) P=0.017

Lindsay 200322

(London Daily/ Nocturnal) I: Quotidian: HD 5-6 days/week for 1.5-2.5 h or 5-6 nights/week for 6-8 h C: Conventional: HD 3 days/week for 3.5-4.5 h CCT 18 months

Catheter lost:*

Catheter

50% Graft 0%

Fistula 0%

Catheter lost:*

Catheter

43% Graft 17%

Fistula 12%

NR NR NR NR

Interven-tions/y, mean (SD):*

Catheter 3.73 (4.42)

(n=6) Graft

1.58 (1.79) (n=3) Fistula

0.52 (1.47) (n=6)



(n=8) Graft

2.12 (1.95) (n=8) Fistula

0.18 (0.52) (n=30)

NR NR

90




n/N (%)


n/N (%)



or other n/N (%)

INT Control INT Control INT Control INT Control INT Control

Quintaliani 200023

I: Daily: HD 6-7 times/week for 2 h (n=24) C: Conventional: HD 3 times/week for 4 h (n=124) CCT 3.6 years

Access survival,

3-y probability:

0.92

Access closure:

2/24 (8.3)

2.2/100

px-y

Access survival,

3-y probability:

0.70 P<0.05

Access closure: 42/124

(34) P<0.05

9.8/100

px-y P<0.01


Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; HR = hazard ratio; I or Int = intervention; n or N=number; NR=not reported; px-mo=patient months; px-y = patient years; NR = not reported; RCT = randomized controlled trial; R X-over = randomized cross-over; y = year *Significance of between-group comparisons NR in article [calculated p]

91

Table 9b. Harms, Complications Related to Vascular Access – Studies that Altered Treatment Duration of Hemodialysis




n/N (%)


n/N (%)



or other n/N (%)


London Daily/ Nocturnal Lindsay 200322

I: Quotidian: HD 5-6 days/week for 1.5-2.5 h or 5-6 nights/week for 6-8 h C: Conventional: HD 3 days/week for 3.5-4.5 h CCT 18 months

Catheter lost:*

Catheter

50% Graft 0%

Fistula 0%

Catheter lost:*

Catheter

43% Graft 17%

Fistula 12%

NR NR NR NR



(n=6) Graft

1.58 (1.79) (n=3) Fistula

0.52 (1.47) (n=6)



(n=8) Graft

2.12 (1.95) (n=8) Fistula

0.18 (0.52) (n=30)

NR NR

Shaded rows contain outcomes from controlled clinical trials C=control; CCT=controlled clinical trial; HD = Hemodialysis; I or Int = intervention; n or N = number; NR = not reported; NR = not reported; R X-over = randomized cross-over; SD = standard deviation *Significance of between-group comparisons NR in article [calculated p]

92

Table 9c. Harms, Complications Related to Vascular Access – Studies that Altered Both Frequency and Treatment Duration of Hemodialysis




n/N (%)


n/N (%)



n/N (%)

INT Control INT Control INT Control INT Control INT Control Culleton 20079 (Alberta Kidney Disease Network) I: Nocturnal:HD 5-6 nights/week for 6 h C: Conventional: HD 3 times/week (treatment time NR) RCT 6 months

NR NR

# patients with ≥ 1 event 4/26 (15)*

# patients with ≥ 1 event

4/25 (16) [P=1.0]

NR NR

Bacter-emia,

angiogram or surgical interven-

tion 10/26 (39)

Bacter-emia,

angiogram or surgical interven-

tion 8/25 (32)

P=0.85


7/26 (27)*


5/25 (20) [P=0.74]

Rocco 20118

Suri 201328

(FHN-Nocturnal) I: Nocturnal: HD 6 nights/week for 6-8 h C: Conventional: HD 3 times/week for 2.5-5 h RCT 12 months

12/45 (27) 10/42 (24)* [P=0.76] NR NR NR NR

Interven-tions:

34/45 (76)

Any vascular

event 58/100

px-y

Interven-tions:

21/42 (50) P=0.10

Any

vascular event

32/100 px-y HR

(95% CI) 1.81

(0.94 to 3.48)

P=0.76

NR NR

93




n/N (%)


n/N (%)



n/N (%)

INT Control INT Control INT Control INT Control INT Control Lindsay 200322

(London Daily/ Nocturnal) I: Quotidian: HD 5-6 days/week for 1.5-2.5 h or 5-6 nights/week for 6-8 h C: Conventional: HD 3 days/week for 3.5-4.5 h CCT 18 months

Catheter lost:*

Catheter

50% Graft 0%

Fistula 0%

Catheter lost:*

Catheter

43% Graft 17%

Fistula 12%

NR NR NR NR



(n=6) Graft

1.58 (1.79) (n=3) Fistula

0.52 (1.47) (n=6)



(n=8) Graft

2.12 (1.95) (n=8) Fistula

0.18 (0.52) (n=30)

NR NR

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; HR = hazard ratio; I or Int = intervention; n or N = number; NR = not reported; px-y = patient years; NR = not reported; RCT = randomized controlled trial; SD = standard deviation * Significance of between-group comparisons NR in article [calculated p]

94

Table 10a. Harms, Complications of Dialysis: Studies that Altered Frequency of Hemodialysis Author Year (Trial) Study Design Follow-up


n/N (%)




Disorders n/N (%)


INT Control INT Control INT Control INT Control INT Control Suri 201328

FHN Trial Group 20107

(FHN Daily) I: Daily: HD 6 times/week for 1.5-2.75 h C: Conventional: HD 3 times/week for 2.5-4.5 h RCT 12 months

NR NR Repair: 33/125 (26)*

Repair: 17/120 (14)*

[P=0.02]

NR NR NR NR NR NR

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; HD =Hemodialysis; I or Int = intervention; n or N = number; NR = not reported; Quasi-R = quasi randomized trial; RCT = randomized controlled trial; R X-over = randomized cross-over *Significance for between-group comparisons NR in article [calculated p]

95

Table 10b. Harms, Complications of Dialysis: Studies that Altered Both Frequency and Treatment Duration of Hemodialysis Author Year (Trial) Study Design Follow-up


n/N (%)




Disorders n/N (%)



(Alberta Kidney Disease Network) I: Nocturnal : HD 5-6 nights/week for ≥ 6 h C: Conventional: HD3 times/week RCT 6 months

NR NR


3/26 (12)*


5/25 (20) [P=0.47]

NR NR NR NR NR NR

Rocco 20118

Suri 201328

(FHN-Nocturnal) I: Nocturnal: HD 6 nights/week for 6-8 h C: Conventional: HD 3 times/week for 2.5-5 h RCT 12 months

NR NR Repair 10/45 (22)*

Repair 5/42 (12)*

[P=0.22]

NR NR NR NR NR NR

Shaded rows contain outcomes from controlled clinical trials C = control; CCT = controlled clinical trial; FHN = Frequent Hemodialysis Network; HD = Hemodialysis; I or Int = intervention; n or N = number; NR = not reported; RCT=randomized controlled trial *Significance for between-group comparisons NR in article [calculated p]

96

Table 11. Overview of Studies: Ultrafiltration Author Year (Trial) Location Funding Source

Intervention/Duration/ Follow-up/Withdrawals Inclusion/Exclusion Criteria Patient Characteristics (expressed

in means unless otherwise noted) Risk of Bias

Agarwal 200942

Agarwal 201143

(DRIP) Location: United States Funding Source: Government

Ultrafiltration (n=100) Conventional HD (n=50) Follow-up period: 8 weeks Study withdrawals: 9% of ultrafiltration group did not complete study (5% withdrew consent, 3% hospitalized, 1% high BP); 14% of control group did not complete study (2% withdrew consent, 2% transplanted, 10% high BP)

Inclusion Criteria: ≥18 years of age, long-term HD for ≥3 months; hypertensive (mean interdialytic ambulatory BP ≥135/85 mmHg Exclusion Criteria: stroke, myocardial infarction, or limb ischemia in previous 6 months; ambulatory BP >170/100 mmHg; missed >1 dialysis in past month; chronic atrial fibrillation; morbid obesity (BMI >40 kg/m2)

N=150 Age (yr): 54 Gender (Male %): 69 Race/Ethnicity (%): 10% white, 87% black, 3% other Systolic BP (mm Hg): 159 Diastolic BP (mm Hg): 87 Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): 4.0 Diabetes (%): NR History of HTN (%): NR History of CVD (%): NR (15% CHF) History of MI (%): 13 History of Stroke (%): 10

Sequence generation: unclear Allocation concealment: adequate Blinding: unclear Incomplete outcome data: yes; BP data at baseline and 8 weeks from 88% of ultrafiltration group and 86% of control group Selective outcome reporting: no Risk of bias: Moderate

Table 12. Primary and Secondary Outcomes: Ultrafiltration


Primary All-Cause Mortality, n/N

(%); P* Cardiovascular Death,

n/N (%); P* Myocardial Infarction,

Any**, n/N (%); P* Stroke, Any*, n/N (%); P*


n/N (%); P* INT Control INT Control INT Control INT Control INT Control

Agarwal 200942

(DRIP) 8 weeks

0/100 0/50 0/100 0/50 NR NR NR NR 3/100 (3) NR†

* P-values between treatment arms if provided or calculated ** Unless otherwise noted † One patient had transplant

97

Table 13. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up – Ultrafiltration Author Year (Trial) Follow-up

Quality of life Depression Cognition Other*

INT Control INT Control INT Control INT Control

Agarwal 200942

(DRIP) 8 weeks

Kidney Disease QOL Physical health

composite (change from baseline to 8

weeks) -0.7 [-2.3, 1.0]

-0.7 [-2.9, 1.6] NR NR NR NR

Kidney Disease QOL Mental

health composite

(change from baseline to 8

weeks) -1.0 [-2.9, 1.0]

-1.2 [-3.8, 1.5]

NR = not reported; QOL = quality of life * If multiple measures used for QoL, cognition, etc.

Table 14. Intermediate Outcomes: Hypertension, LV Mass, and Weight – Ultrafiltration


HTN Pre-dialysis systolic BP,

mm Hg (SD)


medications LV mass,

grams or grams/m2* (SD) Interdialytic weight gain,

lbs or kg or % (SD) Dry weight,

lbs or kg (SD)


Agarwal 200942

Agarwal 201143

(DRIP) 8 weeks

Ambulatory systolic BP

48/88 (55%) had drop of ≥10

mmHg

15/43 (37%) had drop of ≥10 mmHg OR for BP response: 2.24 [1.3,

3.8], P=0.003

NR NR

Baseline*: 138.7 g/m2

Change at 4 weeks: -7.4 (P=0.005)

Change at 8 weeks: -6.3 (P=0.045)

Baseline: 136.3 g/m2

Change at 4 weeks: +3.5

(P>0.2) Change at 8 weeks: +0.3

(P>0.2)

NR NR

Change from

baseline to 8 weeks -1.0 kg [-1.3, -0.7] (P<0.001)

0.0 [-0.4, 0.5]

(P=0.90)

LV = left ventricular; NR = not reported; OR = odds ratio; BP = blood pressure *Pre-specified substudy data; intervention group n=72 at baseline, n=57 at 4 weeks, n=63 at 8 weeks; control group n=38 at baseline, n=31 at 4 weeks and 8 weeks

98

Table 15. Harms, Complications Related to Vascular Access – Ultrafiltration




n/N (%)


n/N (%)

Fibrin Sheath Stripping of Catheters


n/N (%)


Agarwal 200942

(DRIP) 8 weeks

Clotted angio-

access: 6/100 (6%)

with 10 episodes

2/50 patients

(4%) with 2

episodes


NR = not reported

Table 16. Harms, Complications of Dialysis: Ultrafiltration

Author Year (Trial) Follow-up)


n/N (%)




Disorders n/N (%)



Agarwal 200942

(DRIP) 8 weeks

NR NR NR NR NR NR NR NR 0/100

1/50 (2) required

emergent ultrafiltration

dialysis NR = not reported

99

Table 17. Overview of Studies: High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration Author Year (Trial) Location Funding Source



KQ 10. High-flux Hemodialysis versus Low-flux Hemodialysis Studies Asci 201344

(EGE) Location: Turkey Funding Source: Industry (Fresenius Medical Care) With ultrapure/ standard quality dialysate arms in a 2-by-2 factorial design

High-flux HD (n=352) Low-flux HD (n=352) Follow-up period: mean 2.9 years Study withdrawals: 26% of patients (n=186) withdrew during the observation period (excluding deaths), mainly due to transplantation (n=46, 23%) and transfers to other centers (n=140, 75%)

Inclusion Criteria: ≥18 years of age, 3 times per week 12 hours/week maintenance bicarbonate HD for ≥3 months, mean single pool Kt/V >1.2 Exclusion Criteria: scheduled for living donor renal transplantation; known to have serious life limiting comorbidities (active malignancy, active infection, end stage cardiac, pulmonary, or hepatic disease) or requiring HD >3 times/week because of medical comorbid conditions; urine volume output >250 ml/d; lacking intellectual capabilities to understand the study objectives; and pregnant or lactating

N=704 Age (yr): 59 Gender (Male %): 54 Race/Ethnicity (%): NR Systolic BP (mm Hg): 125 Diastolic BP (mm Hg): 75 Serum creatinine (mg/dL): 8.4 Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.41 Time on dialysis (mos): 43 Diabetes (%): 23 History of HTN (%): NR History of CVD (%): 23 History of MI (%): NR History of Stroke (%): NR

Sequence generation: unclear Allocation concealment: adequate Blinding: open-label Incomplete outcome data: no, complete follow-up for all patients Selective outcome reporting: no Risk of bias: Moderate

Schneider 201245

(MINOXIS) Location: Germany Funding Source: Industry (Fresenius Medical Care, Amgen)

High-flux HD (n=85) Low-flux HD (n=81) Follow-up period: mean 1 year Study withdrawals: 13% of patients (n=22) withdrew during the observation period (excluding deaths), mainly due to transplantation (n=5, 23%) and hospitalizations (n=5, 23%)

Inclusion Criteria: ≥18 years of age and receiving treatment for anemia with ESA darbepoetin-alfa ≥6 months; incident patients undergoing hemodialysis for ≥1 or ≤3 months had to be treated by low-flux dialyzers; prevalent patients undergoing hemodialysis for >3 months had to be treated with low-flux dialyzers for ≥3 months before inclusion in the study Exclusion Criteria: serious comorbid conditions with a life expectancy <2 years, single-needle hemodialysis, use of a temporary or permanent catheter, planned kidney transplantation, and pregnancy

N=166 Age (yr): 66 Gender (Male %): 54 (64 HF vs. 44 LF, P=0.02) Race/Ethnicity (%): NR Systolic BP (mm Hg): 135 Diastolic BP (mm Hg): NR Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR Diabetes (%): 45 History of HTN (%): 82 History CHD (%): 33 History of MI (%): 10 History of Stroke (%): 12

Sequence generation: unclear Allocation concealment: adequate Blinding: open-label Incomplete outcome data: no, complete follow-up for all patients Selective outcome reporting: no Risk of bias: Moderate

100

Author Year (Trial) Location Funding Source



Locatelli 200946

(MPO) Location: Europe (9 countries) Funding Source: Industry (Fresenius Medical Care) Note: patients were stratified based on serum albumin (≤4 and >4 g/dL)

High-flux HD (n=360) Low-flux HD (n=378) Follow-up period: mean 3.0 years Study withdrawals: 12% of patients (n=91) lost in the run-in phase (due to study treatment not started, major protocol violations at inclusion, death or a reason for premature termination, failure to reach the minimum dialysis dose (Kt/V) of 1.2); 270 patients withdrew during the observation period (excluding deaths), mainly due to transplantation (n=170, 63%)

Inclusion Criteria: 18 to 80 years of age, having been on renal replacement therapy for up to 2 months, and having a serum albumin level ≤4 g/dl (measured within the 2 months before inclusion) Exclusion Criteria: scheduled for renal transplantation from a living donor within the period of the study, on HD after renal transplantation, serious clinical conditions potentially confounding the effect of the intervention (proteinuria >6 g/24 h per 1.73 m2, active malignancies, current therapy with immunosuppressive agents, severe CHF despite maximal therapy [NYHA class IV], unstable angina pectoris, active systemic infections [e.g., tuberculosis, systemic fungal infection, AIDS, hepatitis], chronic pulmonary disease requiring supplementary oxygen, and cirrhosis with encephalopathy)

N=738 (647 in the survival analysis and demographics) Age (yr): 60 Gender (Male %): 64 Race/Ethnicity (%): NR Systolic BP (mm Hg): 143 Diastolic BP (mm Hg): 79 Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.36 Time on dialysis (mos): 1 Diabetes (%): 24 History of HTN (%): NR but 85% were on anti-HTN medications History of CVD or CHD (%): 27 History of MI (%): NR History of Stroke (%): NR

Sequence generation: adequate (centralized) Allocation concealment: adequate Blinding: open-label Incomplete outcome data: yes, patients were censored at the time of premature study termination Selective outcome reporting: no Risk of bias: Moderate

Eknoyan 200213 Unruh 200452 (HEMO) Location: United States Funding Source: Non-industry (government) and Industry

High-flux HD (n=921) Low-flux HD (n=925) Follow-up period: 4.5 years Study withdrawals: 21% of patients (n=392) were withdrawn (excluding deaths), mainly due to transplantation (49%)

Inclusion Criteria: 18 to 80 years of age, undergoing in-center hemodialysis thrice weekly and had been undergoing hemodialysis ≥ 3 months Exclusion Criteria: residual urea clearance exceeded 1.5 ml per minute per 35 liters of urea, serum albumin level <2.6 g per deciliter, or equilibrated Kt/V of >1.30 not achieved within 4.5 hours during 2 of 3 consecutive monitored dialysis sessions in which the high-dose goal was targeted (on the basis of the last criterion, very heavy patients were excluded)

N=1846 Age (yr): 58 Gender (Male %): 44 Race/Ethnicity (%): Black 63 Systolic BP (mm Hg): 152 Diastolic BP (mm Hg): 81 Serum creatinine (mg/dL): 10.3 Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.43 Time on dialysis (mos): 44.4 Diabetes (%): 45 History of HTN (%): NR History of CVD or CHD (%): 80 History of MI (%): NR History of Stroke (%): NR

Sequence generation: unclear Allocation concealment: adequate (centrally) Blinding: adjudication committee blinded to treatment assignment Incomplete outcome data: no, complete follow-up for all patients Selective outcome reporting: no Risk of bias: Low

101




KQ 11. Hemodiafiltration or Hemofiltration versus Hemodialysis Studies

1) Hemodiafiltration versus High-flux Hemodialysis Maduell 201349

(ESHOL) Location: Spain Funding Source: Non-industry

OL-HDF (n=456) High-flux HD (92%; low-flux 8%) (n=450) Follow-up period: mean 1.9 years, median 2.08 years Study withdrawals: 39% of patients (n=355) were withdrawn, mainly due to transplantation (51%)

Inclusion Criteria: patients aged > 18 years with ESRD receiving thrice-weekly standard hemodialysis for > 3 months Exclusion Criteria: active systemic diseases, liver cirrhosis, malignancy, immunosuppressive therapy, infradialysis dose (Kt/<1.3), single needle dialysis, and temporary nontunnelized catheter

N=906 Age (yr): 65 Gender (Male %): 67 Race/Ethnicity (%): NR Systolic BP (mm Hg): 136 Diastolic BP (mm Hg): 72 Serum albumin (g/dL): 4.1 Estimated GFR (ml/min/1.73m2): Kt/V: 1.67 Time on dialysis (mos): 28 Diabetes (%): 25 History of HTN (%): NR, 59% on anti-HTN medication History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: adequate Allocation concealment: adequate Blinding: open-label Incomplete outcome data: no Selective outcome reporting: no Risk of bias: Moderate

Ok 201348

(Turkish OL-HDF) Location: Turkey Funding Source: Non-industry

OL-HDF (n=391) High-flux HD (n=391) Follow-up period: 2 years, mean 1.9 years Study withdrawals: 26% of patients (n=200) were withdrawn (excluding the primary outcome), mainly due to transfer to other centers (70%)

Inclusion Criteria: patients aged >18 years, maintenance bicarbonate HD scheduled thrice weekly for a total of 12 h/week, have achieved mean single-pool Kt/V >1.2 Exclusion Criteria: scheduled for living donor renal transplantation, serious life-limiting comorbid situations (active malignancy, active infection, end-stage cardiac, pulmonary or hepatic disease), requirement for HD more than 3 times per week due to comorbid conditions, temporary catheter as a vascular access, insufficient vascular access (blood flow rate < 250 mL/min), presence of urine output > 250mL/day, pregnancy or nursing mother, mental incompetence

N=782 Age (yr): 57 Gender (Male %): 59 Race/Ethnicity (%): NR Systolic BP (mm Hg): 128 Diastolic BP (mm Hg): 78 Serum creatinine (mg/dL): 8.0 Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.4 Time on dialysis (mos): 58 Diabetes (%): 35 History of HTN (%): NR, 14% on anti HTN medication History of CVD (%): 26 History of MI (%): NR History of Stroke (%): NR

Sequence generation: unclear Allocation concealment: adequate Blinding: open-label Incomplete outcome data: no, complete follow-up for all patients for primary outcomes Selective outcome reporting: no Risk of bias: Moderate

102




Schiffl 200750

Location: Germany Funding Source: NR Crossover study

OL-HDF (n=38) High-flux, ultrapure HD (n=38) Follow-up period: 2 years, then the groups crossed over for another 2 years Study withdrawals: 5% of patients (n=4, 3 due to transplantation) were withdrawn before crossover (excluding deaths)

Inclusion Criteria: clinically stable ESRD patients on thrice weekly conventional HD for ≥ 6 months, permanent blood access capable of delivery of a blood flow rate of ≥ 250 ml/min Exclusion Criteria: malignancy, severe comorbidity (heart failure NYHA class III-IV, liver cirrhosis, chronic inflammatory or infectious diseases, diabetic foot, and dementia), no ultra-pure high-flux HD or OL-HDF prior to study

N=76 Age (yr): 62 Gender (Male %): 55 Race/Ethnicity (%): NR Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.3 Time on dialysis (mos): 26 Diabetes (%): NR History of HTN (%): NR History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: adequate (coin flip) Allocation concealment: unclear Blinding: none Incomplete outcome data: Selective outcome reporting: no Risk of bias: Moderate

2) Hemodiafiltration versus Low-flux Hemodialysis Grooteman 201251

(CONTRAST) Location: Netherlands (84%), Canada, and Norway Funding Source: Non-industry and Industry

OL-HDF (n=358) Hemodialysis (low-flux) (n=356) Follow-up period: mean 3.04 years, median 2.9 years Study withdrawals: 33% of patients (n=239) were withdrawn, mainly due to transplantation (63%)

Inclusion Criteria: patients with ESRD undergoing chronic intermittent hemodialysis for at least 2 months and aged ≥ 18 years who were treated 2 or 3 times per week with low-flux hemodialysis Exclusion Criteria: treatment with hemodiafiltration, hemofiltration, or high-flux hemodialysis in the 6 months preceding randomization, life expectancy < 3 months due to non-renal disease, participation in another clinical intervention trial evaluating cardiovascular outcomes, severe nonadherence regarding frequency and/or duration of dialysis treatment

N=714 Age (yr): 64.1 Gender (Male %): 62 Race/Ethnicity (%): white 84; black 8 Systolic BP (mm Hg): 147 Diastolic BP (mm Hg): 75 Serum creatinine (mg/dL): 9.7 (predialysis) Estimated GFR (ml/min/1.73m2): 2.05 Kt/V: 1.39 Time on dialysis (mos): 34.8 Diabetes (%): 24 History of HTN (%): NR History of CVD (%): 44 History of MI (%): NR History of Stroke (%): NR

Sequence generation: adequate Allocation concealment: adequate Blinding: lab personnel and the adjudication committee were blinded to treatment assignment Incomplete outcome data: no, complete follow-up for all patients Selective outcome reporting: no Risk of bias: Low

103




Locatelli 201062

Location: Italy Funding Source: NR

OL-HDF (predilution) (n=40) Online predilution hemofiltration (n=36) Hemodialysis (low-flux) (n=70) Follow-up period: median 1.5 years Study withdrawals: 23% of patients (n=33) were withdrawn (excluding deaths)

Inclusion Criteria: 18 to 80 years, on thrice-weekly HD or HDF for ≥ 6 months, body weight ≤ 90 kg, stable clinical condition Exclusion Criteria: clinically relevant infections, malignancies, active systemic diseases, active hepatitis or cirrhosis, instable diabetes, diuresis > 200 ml/24 h, or a dysfunction of vascular access, with blood flow rate < 300 ml/min

N=146 Age (yr): 67 Gender (Male %): 58 Race/Ethnicity (%): NR Systolic BP (mm Hg): 139 (run-in phase) Diastolic BP (mm Hg): 76 (run-in phase) Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.27 Time on dialysis (mos): 36 (median) Diabetes (%): 18 History of HTN (%): 57 History of CVD or CHD (%): NR, 22% had ischemic cardiopathy and 10% had peripheral arteriopathy History of MI (%): NR History of Stroke (%): NR, 12% had TIA

Sequence generation: adequate Allocation concealment: adequate Blinding: open-label Incomplete outcome data: 10 (7%) not included in final analyses Selective outcome reporting: no Risk of bias: Moderate

Wizemann 200053

Location: Germany Funding Source: NR

OL-HDF (n=23) Low-flux hemodialysis (n=21) Follow-up period: 2 years Study withdrawals: 23% of patients (n=10) were withdrawn and not included in the analyses (excluding deaths)

Inclusion Criteria: chronic hemodialysis patients Exclusion Criteria: NR

N=44 Age (yr): 60 Gender (Male %): 57 Race/Ethnicity (%): NR Systolic BP (mm Hg): NR Diastolic BP (mm Hg): NR Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.9 Time on dialysis (mos): NR Diabetes (%): 18 History of HTN (%): NR History of CHD (%): 45 History of MI (%): 16 History of Stroke (%): 9 (cerebrovascular disease)

Sequence generation: unclear Allocation concealment: unclear Blinding: NR Incomplete outcome data: yes, completers only eligible for analysis Selective outcome reporting: no Risk of bias: Moderate

104




Hemofiltration versus Low-flux Hemodialysis Alvestrand 201157

(ProFil) Location: Sweden and Denmark Funding Source: Industry

Online predilution hemofiltration (n=27, 18 analyzed) Hemodialysis (low-flux) (n=21, 16 analyzed) Follow-up period: 2 years Study withdrawals: 29% (n=12) (excluding deaths) were withdrawn in less than 6 months and not included in the analyses; a further 14 patients (excluding deaths) withdrew after 6 months up to 24 months

Inclusion Criteria: 18 to 80 years, CKD stage 5, on dialysis < 3 months, expected time on dialysis at treatment site >1 year Exclusion Criteria: MI within 3 months, well-defined unstable angina, severe cardiac valvular disease, severe cardiac failure (NYHA III-IV), disseminated malignancy, expected HD treatment < 1 year, expected need of central venous catheter >3 months, body weight > 100 kg, participation in other potentially interfering studies, patient not willing/not able to undergo examinations according to protocol

N=48 (34 in the analysis and demographics) Age (yr): 63 Gender (Male %): 74 Race/Ethnicity (%): NR Systolic BP (mm Hg): 145 Diastolic BP (mm Hg): 78 Serum creatinine (mg/dL): 7.4 Estimated GFR (ml/min/1.73m2): NR Kt/V: NR Time on dialysis (mos): NR, at least 3 months Diabetes (%): 23 History of HTN (%): NR History of CVD (%): 32 History of MI (%): NR History of Stroke (%): NR

Sequence generation: adequate Allocation concealment: adequate Blinding: outcomes assessor Incomplete outcome data: yes Selective outcome reporting: no Risk of bias: Moderate

Santoro 200858

Location: Italy Funding Source: None

Online high-flux hemofiltration (n=32) Low-flux hemodialysis (n=32) Follow-up period: 3 years Study withdrawals: 36% (n=23) were withdrawn (excluding deaths)

Inclusion Criteria: 16 to 80 years, dialysis treatment for ≥ 6 months with conventional HD, residual kidney function < 2 mL/min/1.73 m2, Charlson Comorbidity Index of ≥ 3, and presence of cardiovascular instability during dialysis in ≥ 15% of sessions Exclusion Criteria: neoplasia (any), acute clinical conditions (MI, CHF, stroke, recent surgery, or severe sepsis) within 3 months of enrollment, any vascular access dysfunction (patients with central catheters were admitted if blood flow rate was ≥ 300 mL/min), residual urinary output > 200 mL/24 h, body weight > 75 kg

N=64 Age (yr): 68 Gender (Male %): 48 Race/Ethnicity (%): NR Systolic BP (mm Hg): 130 Diastolic BP (mm Hg): 75 Serum creatinine (mg/dL): ): 9.7 (predialysis) Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.30 Time on dialysis (mos): 65 Diabetes (%): 6 History of HTN (%): 27 (mild/moderate) History of CHD (%): 34 History of MI (%): NR History of Stroke (%): NR

Sequence generation: unclear Allocation concealment: unclear Blinding: none Incomplete outcome data: yes Selective outcome reporting: no Risk of bias: Moderate

105




Beerenhout 200558

Location: The Netherlands Funding Source: Industry

Online high-flux hemofiltration (n=20) Low-flux hemodialysis (n=20) Follow-up period: 1 year Study withdrawals: 28% (n=11) were withdrawn, and not included in the analyses (excluding deaths)

Inclusion Criteria: treated with low-flux HD 3 times weekly, on dialysis treatment for ≥ 3 months, adequate arterio-venous access Exclusion Criteria: severe cardiovascular morbidity, defined as a left ventricular ejection fraction < 25% and/or coronary heart disease NYHA classification of III–IV and severe intercurrent illness

N=40 Age (yr): 59 Gender (Male %): 70 Race/Ethnicity (%): NR Systolic BP (mm Hg): 142 Diastolic BP (mm Hg): 78 Serum creatinine (mg/dL): NR Estimated GFR (ml/min/1.73m2): NR Kt/V: 1.4 Time on dialysis (mos): 29 Diabetes (%): 25 History of HTN (%): History of CVD or CHD (%): NR History of MI (%): NR History of Stroke (%): NR

Sequence generation: unclear Allocation concealment: adequate Blinding: NR Incomplete outcome data: yes, completers only eligible for analysis Selective outcome reporting: no Risk of bias: Moderate

BP = blood pressure; CHD = coronary heart disease; CHF = congestive heart failure; CKD = chronic kidney disease; CVD = cardiovascular disease; ESA = erythropoiesis-stimulating agent; ESRD = end-stage renal disease; GFR = glomerular filtration rate; HD = hemodialysis; HDF = hemodiafiltration; HF = high flux; HTN = hypertension; INT = intervention; LF = low flux; MI = myocardial infarction; NR = not reported; NYHA = New York Heart Association; OL-HDF = online hemodiafiltration; TIA = transient ishemic attack Trial Acronyms MPO = Membrane Permeability Outcome Study HEMO = Hemodialysis Study ESHOL = Spanish On-Line Hemodiafiltration Survival Study CONTRAST = Convective Transport Study

106

Table 18. Primary and Secondary Outcomes: High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration








KQ10. High-flux Hemodialysis versus Low-flux Hemodialysis Studies

Asci 201344

(EGE) 3 years

75/352 (21.3)

HR 0.77 [0.57, 1.04]

97/352 (27.6)

P=0.05

39/352 (11.1)

53/352 (15.1)

P=0.11

Fatal or non-fatal

CVD event 44/352 (12.5)

Fatal or non-fatal

CVD event 60/352 (17.0)

P=0.09

NR NR NR NR

Schneider 201245

(MINOXIS) 1 year

5/85 (5.9)

8/81 (9.9) NR NR NR NR NR NR

Leading to withdrawal

4/85 (4.7)

Leading to withdrawal

1/81 (1.2)

P=0.22

Locatelli 200946

(MPO) 3.0 years (mean)

74/318 (23.2)

HR 0.76 [0.56, 1.04]

88/329 (26.7)

P=0.09

34/318 (10.7)

41/329 (12.5)

P=0.48

NR NR NR NR

527 events; 53.1

admissions per 100 pt years

518 events; 53.1

admissions per 100 pt years;

P=NS

Eknoyan 200213

(HEMO) 4.5 years

429/921 (46.6)

442/925 (47.8)

P=0.60

156/921 (16.9)

187/925 (20.2)

P=0.07

NR NR NR NR

Not related to vascular access

3137 events +1%† [-9, 11]

Not related to vascular access

3018 events

P=0.87 KQ11. Hemodiafiltration or Hemofiltration versus High-flux Hemodialysis Studies 1) Hemodiafiltration versus High-flux Hemodialysis Studies

Maduell 201349

(ESHOL) 1.9 years (mean)

85/456 (18.6)

HR 0.70

[0.53, 0.92]

122/450 (27.1)

P=0.01

37/456 (8.1)

HR 0.67

[0.44, 1.02]

55/450 (12.2)

P=0.06

NR NR

Fatal 7/456 (1.5)

HR 0.39 [0.16, 0.93]

Fatal 18/450 (4.0)

P=0.03

36.7 events/ 100 pt-yrs

(317 events) RR 0.78

[0.67, 0.90]

47.5 events/ 100 pt-yrs

(412 events)

P=0.001

Ok 201348

(OL-HDF) 2 years

52/391 (13.3)

HR 0.79 [0.55, 1.14]

65/391 (16.6)

P=0.19

32/391 (8.1)

HR 0.72 [0.45, 1.13]

44/391 (11.2)

P=0.15

Fatal 6/391 (1.5)

Fatal 11/391 (2.8)

P=0.23

Fatal 7/391 (1.8)

Fatal 8/391 (2.0)

P=0.79

20.4 events/ 100 pt-yrs;

18.6 events/ 100 pt-yrs;

P=0.44

107








Schiffl 200750‡ 2 years (crossover study)

1st phase 1/38 (2.6)

1st phase 2/38 (5.3)

P=0.56

0/38

2/38 (5.3)

P=0.29 NR NR NR NR NR NR

2) Hemodiafiltration versus Low-flux Hemodialysis Studies

Grooteman 201251

(CONTRAST) 3.0 years (mean)

131/358 (36.6%); HR 0.95

[0.75, 1.2]

138/356 (38.8%)

P=0.55

37/358 (10.3%); HR 0.80

[0.52, 1.24]

46/356 (12.9%)

P=0.28

38/358†† (10.6%) HR 0.81

[0.52, 1.23]

47/356†† (13.2%)

P=0.29

19/358 (5.3%)

HR 1.17 [0.60, 2.27]

16/356 (4.5%)

P=0.62

Due to infection 130/358 (36.3)

HR 1.21 [0.94, 1.56]

Due to infection 110/356 (30.9)

P=0.13

Locatelli 201052

1.5 years (median) 2/40 (5.0) 8/70

(11.4) P=0.27

7 patients, not defined by treatment arm‖

3 patients, not defined by treatment arm‖ NR NR NR NR

Wizemann 200053

2 years

1/23 (4.3)

2/21 (9.5)


Hospital days per 3-month period (morbidity) did not differ between

groups Hemofiltration versus Low-flux Hemodialysis Studies Alvestrand 201157

(ProFil) 2 years

2/27 (7.4)

3/21 (14.3)


Average days/yr

6

Average days/yr

11; P=NS

Locatelli 201052

1.5 years (median) 5/36

(13.9)

8/70 (11.4)

P=0.71

7 patients, not defined by treatment arm‖

3 patients, not defined by treatment arm‖ NR NR NR NR

Santoro 200858

3 years 7/32

(21.9)

12/32 (37.5)

P=0.18

14 patients, not defined by treatment arm NR NR NR NR

Events per patient

1.94 (0.33)

Events per patient

2.36 (0.41); P=0.4

Beerenhout 200559

1 year 1/20 (5.0)

1/20 (5.0)

P=1.00

1/20 (5.0)

1/20 (5.0)

P=1.00

fatal 0/20

fatal 1/20 (5.0)

P=0.49

NR NR NR NR

HD = hemodialysis; HDF = hemodiafiltration; HF = hemofiltration; HR = hazard ratio; INT = intervention; RR = risk ratio; NS = not statistically significant between treatment groups [ ] 95% confidence intervals * P-values between treatment arms if provided or calculated ** Unless otherwise noted † Increase in risk between treatment arms †† Fatal and non-fatal coronary heart disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft)

108

‡ Crossover study. Results from first phase (24 month period) presented only. In following phase, there was one myocardial death in death the HDF cross to high-flux HD group and there 2 vascular complication deaths in the high-flux HD cross to HDF group in the respective 24 month phase ‖ Three arm study (HDF, HF, HD)

109

Table 19. Intermediate Outcomes: Quality of Life, Depression, and Cognition Scale Scores at Follow-up – High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration


Quality of life Depression Cognition Other*

INT Control INT Control INT Control INT Control

KQ10. High-flux Hemodialysis versus Low-flux Studies

Eknoyan 200213

Unruh 200452

(HEMO) 4.5 years

Index of Well-Being and the Kidney Disease Quality of Life-Long Form: questionnaires annually over 3 years;

high-flux HD was not associated with any statistically significant improvements in

health-related quality of life domains with the exceptions of sleep quality and

patient satisfaction

NR NR NR NR

KQ11. Hemodiafiltration or Hemofiltration versus High-flux Hemodialysis Studies 1) Hemodiafiltration versus High-flux Hemodialysis Studies

Schiffl 200750** 2 years

Kidney Disease Questionnaire: improvement in physical symptoms

during the HDF treatment phase but no differences in the other quality of life

dimensions between groups

NR NR NR NR


Grooteman 201251

Mazairac 201355


SF-36 Physical Composite

Score (change) -0.2 [-0.6, 0.1]

P=0.13

SF-36 Physical Composite Score

(change) -0.8 [-1.1, -0.5]

P<0.001 Between groups

P=0.29

SF-36 Mental

Composite Score

(change) -0.5 [-0.8, -0.1] P=0.01

SF-36 Mental

Composite (change) 0.1 [-0.3,

0.5] P=0.78 Between groups P=0.06

Cognitive Function Domain (change)

-1.1 [-1.7, -0.4]

P=0.001

Cognitive Function Domain

(change) -0.4 [-0.9,

0.2] P=0.22

Between groups P=0.35

Effect of kidney

disease on daily life (change) -0.3 [-1.1,

0.4] P=0.38

Effect of kidney

disease on daily life (change)

-1.3 [-2.3, -0.4]

P=0.01 Between groups P=0.06

Hemofiltration versus Low-flux Hemodialysis Studies Beerenhout 200559

1 year Physical

Symptoms† Baseline 4.1 (1.4)

12 months 5.0 (1.1) P<0.01

Physical Symptoms† Baseline 4.2 (0.9)

12 months 4.4 (1.4)

Between groups P=0.06

Quality of life† for other aspects (depression,

frustration, well-being) did not change significantly in

any treatment group

NR NR

110

INT = intervention group [ ] 95% confidence interval * If multiple measures used for QoL, cognition, etc. ** Crossover study (24 months phases x 2) † Kidney disease questionnaire (1=severe, 7=none)

111

Table 20. Intermediate Outcomes: Hypertension, LV Mass, and Weight – High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration



mm Hg (SD)





lbs or kg (SD)

INT Control INT Control INT Control INT Control INT Control KQ10. High-flux Hemodialysis versus Low-flux Hemodialysis Studies

Asci 201344

(EGE) 3 years

123 (13) 123 (12) P=0.72 NR NR NR NR

% body wt. Baseline

3.66 (1.54) 3 years

3.25 (1.06)

% body wt. Baseline

3.52 (1.41) 3 years

3.29 (1.06) P=0.66

NR NR

KQ11. Hemodiafiltration or Hemofiltration Studies versus High-flux Hemodialysis

1) Hemodiafiltration versus High-flux Hemodialysis Studies

Maduell 201349


Baseline 136

36 mos

133

Baseline 136

36 mos

136 P=0.36

Interaction P=0.53

Baseline 59.2%

(n=270)

36 mos 49.5% (n=91)

Baseline 57.8%

(n=260)

36 mos 50.6% (n=87) P=0.99

Interaction P=0.93

NR NR NR NR

Baseline 67.9

36 mos

66.8

Baseline 66.8

36 mos

66.3 P=0.36

Interaction P=0.33

Ok 201348

(OL-HDF) 2 years

Baseline 128 (15) n=391; 24 mos 129 (13) n=220

Baseline 127 (16) n=391; 24 mos 126 (13) n=228;

P=0.001

11.1% 11.7% P=0.66 NR NR

% body wt. Baseline 3.5 (1.5) 24 mos 3.5 (1.9) n=220

% body wt. Baseline 3.4 (1.8) 24 mos 3.2 (1.5) n=228; P=0.01

NR NR

Schiffl 200750† 2 years

Baseline 142

Follow-up 137

Baseline 142

Follow-up 138

Groups did not differ in the number of anti-HTN drugs

compared to baseline NR NR NR NR

Baseline 73 (12)

Follow-up 76 (10) P<0.05

Baseline 73 (12)

Follow-up 77 (10) P<0.05

Between groups P=NS

112



mm Hg (SD)





lbs or kg (SD)

INT Control INT Control INT Control INT Control INT Control 2) Hemodiafiltration versus Low-flux Hemodialysis Studies

Grooteman 201251


146 (1) Mean

difference between

arms 0.09

145 (1)

P=0.49 NR NR

Mean change per

year§ 1 year: 2.48 [-17.9, 22.9] 3 years: -

2.04 [-10.1, 6.0]

1 year: 12.98 [-9.7,

25.7] (P=0.34) 3 years:

12.47 [-4.2, 21.2]

(P=0.12)

Change (pre-post, kg)

1.91 (SE 0.05)

Mean difference between

arms 0.05

Change (pre-post, kg)

1.85 (SE 0.05);

P=0.51

NR NR

Locatelli 201052

1.5 years (median)

141.5 +4.2††

140.5 -0.0††

Median 1.0 % patients

treated 75.9

+0.9%††


treated 56.1

+7.5%††

NR NR NR NR

65.2 kg -0.6††

64.8 kg -0.1††

Wizemann 200053

2 years

Baseline ~145‡ 24 mos ~138‡;

Baseline ~135‡ 24 mos ~130‡ P=NS

Did not differ between groups NR NR NR NR Did not differ between

groups

Hemofiltration versus Low-flux Hemodialysis Studies

Alvestrand 201157

(ProFil) 2 years

Baseline 148 (21)

n=18; 24 mos

148 (25); n=10

Baseline 141 (16)

n=16; 24 mos

151 (18); n=7;

P=NS

Patients not receiving, baseline

6% (1/18); End of study

3patients

Patients not receiving, baseline

31% (5/16); End of study 6 patients;

LVMI, Baseline 151 (47)

n=18; LVMI

Decreased 22 (48) g/m2

LVMI, Baseline 161 (55)

n=16; LVMI

Decreased 15 (57) g/m2 P=0.03 over the whole

study period for the per-

protocol group

NR NR NR NR

Locatelli 201052

1.5 years (median)

137.3 -2.6††

140.5 -0.0††


treated 62.1

+3.8%††


treated 56.1

+7.5%††

NR NR NR NR 60.2 kg -0.5††

64.8 kg -0.1††

113



mm Hg (SD)





lbs or kg (SD)

INT Control INT Control INT Control INT Control INT Control Santoro 200858

3 years -7.4‡‡ -12.9‡‡ NR NR NR NR NR NR NR NR

Beerenhout 200559

1 year

Baseline 143 (18)

n=20 12 mos 144 (15)

n=13

Baseline 140 (13)

n=20 12 mos 135 (15)

n=14; P=NS

Baseline 1.3 (1.3)

n=20 12 mos 1.6 (1.0)

n=13

Baseline 1.5 (1.2)

n=20 12 mos 1.7 (1.4)

n=14; P=NS

Baseline 127 (33)

n=20 12 mos 131 (24)

n=13

Baseline 135 (34)

n=20 12 mos 138 (32)

n=14; P=NS

Baseline 2.1 (0.7)

n=20 12 mos 2.0 (0.2)

n=13

Baseline 1.9 (0.6)

n=20 12 mos 2.1 (0.7)

n=14; P=NS

NR NR

HTN = hypertension; INT = intervention; LV = left ventricular; LVMI = left ventricular mass index; NS = not statistically significant between treatment groups; SE = standard error of the mean * Note if weight at endpoint or mean change from baseline ** 95% confidence intervals † Crossover study †† Mean change from run-in phase period ‡ From graph ‡‡ Mean decrease from 1st year to end of study § LVM data from subset of 342 who participated in CONTRAST

114

Table 21. Harms, Complications Related to Vascular Access – High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration

Study Year (Trial) Follow-up



n/N (%)


n/N (%)

Fibrin Sheath Stripping of Catheters


n/N (%)

INT Control INT Control INT Control INT Control INT Control KQ11. Hemodiafiltration or Hemofiltration versus High-flux Hemodialysis Studies 1) Hemodiafiltration versus High-flux Hemodialysis Studies Ok 201348

(OL-HDF) 2 years

40/391 (10.2)**

0/391; P=0.002 NR NR NR NR NR NR NR NR

2) Hemodiafiltration versus Low-flux Hemodialysis Studies Locatelli 201052

1.5 years (median) 0/40 0/70 NR NR NR NR NR NR NR NR

Hemofiltration versus Low-flux Hemodialysis Studies Alvestrand 201157

(ProFil) 2 years

1/27 (3.7)** 0/21 NR NR NR NR NR NR NR NR

Locatelli 201052

1.5 years (median) 2/36

(5.6)** 0/70 NR NR NR NR NR NR NR NR

INT = intervention group; NS = not statistically significant between treatment groups * Hospitalizations for infections ** Vascular access problems leading to study dropout † Crossover study (24 months phases x 2)

115

Table 22. Harms, Complications of Dialysis – High-Flux versus Low-Flux Hemodialysis, Hemodiafiltration, Hemofiltration



n/N (%)




Disorders n/N (%)


INT Control INT Control INT Control INT Control INT Control KQ10. High-flux Hemodialysis versus Low-flux Hemodialysis Studies

Locatelli 200946

(MPO) 3.0 years (mean)

NR NR

114 events*;

7.5 admissions per 100 pt

years

100 events*;

8.4 admissions per 100 pt

years; P=NS

74 events**; 11.5

admissions per 100 pt

years

82 events**; 10.3

admissions per 100 pt

years;

P=NS

NR NR NR NR

KQ11. Hemodiafiltration or Hemofiltration versus High-flux Hemodialysis Studies 1) Hemodiafiltration versus High-flux Hemodialysis Studies Maduell 201349


11/456 (2.4)†

8/450 (1.8)†

P=0.51 NR NR NR NR NR NR NR NR


Locatelli 201052

1.5 years (median) NR NR NR NR

Thrombosis or vascular

access infection

0/40


access infection

2/70 (2.9)†

NR NR 0/40 0/70

Hemofiltration versus Low-flux Hemodialysis Studies Locatelli 201052

1.5 years (median) NR NR NR NR


access infection 2/36 (5.6)


access infection

2/70 (2.9)†

NR NR 1/36 (2.8) 0/70†

INT = intervention group; NS = not statistically significant between treatment groups * Hospitalizations for vascular access problems **Hospitalizations for infections † Leading to study withdrawal ‡ Crossover study (24 months phases x 2)

an evidence report for the kidney disease outcomes quality ...the publication of the kidney disease...

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