**4. Trials on quality of life in HDF**

The results of studies on HRQOL in OL-HDF are often inconclusive. The studies used different questionnaires to assess HRQOL which probably explain some of the differences among studies.



converted into preference weights by using country-specific value sets drawn from the general

This instrument is rather new; therefore, only few country-specific value sets are available.

This is a patient-reported measure of HRQOL developed for use in the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study [29]. The authors have defined it as "the value assigned to duration of life as modified by the impairment, functional states, perceptions, and social opportunities that are influenced by disease, injury, or policy." This instrument was developed to evaluate the effectiveness of alternative dialysis prescrip‐ tions. It supplements SF-36 survey in measuring HRQOL for patients with ESRD. It is sensitive to differences in dialysis modality and dialysis dose. The selection of HRQOL domains to be utilized was based on literature review, analysis of focus groups, and survey of dialysis providers and patients. In order to arrange domains and items identified, a representative sample of 136 dialysis patients rated each item for frequency and distress. The survey yielded 22 HRQOL domains that included 96 items: eight generic domains in the SF-36 (health perceptions, physical, social, physical and emotional role functions, pain, mental health, and energy), eight additional generic domains (cognitive functioning, sexual functioning, sleep, work, recreation, travel, finances, and general quality of life), and six ESRD-specific domains

The results of studies on HRQOL in OL-HDF are often inconclusive. The studies used different questionnaires to assess HRQOL which probably explain some of the differences among

> **Timing of assessment**

> One time at baseline

**Study result**

Women >56 years old had decrease in work status, patient satisfaction, and role-physical. Men had decreasing physical functioning, with increasing age. Compared to women, men generally had higher scores in all quartiles on variable combinations of physical functioning and pain, patient's satisfaction, symptoms/problem list, work status, role-physical, emotional

**instrument used**

KDQOL-SF version 1.3 for Portuguese patients

**3.4. The CHOICE Health Experience Questionnaire (CHEQ) [28]**

(diet, freedom, time, body image, dialysis access, and symptoms).

**4. Trials on quality of life in HDF**

**Reference Country Comparison Quality-of-life**

quartiles (<56 years, 57–68 years, 69–75 years, >75 years

old)

Portugal Four age

studies.

Moura et al. [38]

population [27].

128 Advances in Hemodiafiltration


*Abbreviations*: AFB, acetate-free biofiltration; AVF, arteriovenous fistula; BHD, bicarbonate hemodialysis; CVC, central venous catheter; HDF, hemodiafiltration; HF, hemofiltration; HF-HD, high-flux hemodialysis; IQOLA, International Quality of Life Assessment; KDQOL, Kidney Disease Quality of Life; KDQ, Kidney Disease Questionnaire; LF-HD, low-flux hemodialysis; MCS, mental component summary; OL-HDF, online hemodiafiltration; OL-HF, online hemofiltration; PCS, physical component summary; SF-36, Short Form-36.

**Table 2.** Summary of studies assessing QOL in patients treated with convective therapy.

The following is the description of trials that examined HRQOL in patients under treatment of OL-HDF, hemofiltration (HF), and acetate-free biofiltration (AFB) in comparison to low-flux hemodialysis (LF-HD) or high-flux hemodialysis (HF-HD). Summary of these trials is presented in **Table 2**.

#### **4.1. Moura et al.**

**Reference Country Comparison Quality-of-life**

Sweden OL-HDF vs. LF-HD

HDF

OL-HF vs. LF-HD

HD (different combinations)

Germany OL-HDF vs. HF-HD

Italy AFB vs. BHD in

patients with diabetic ESRD

hemofiltration; PCS, physical component summary; SF-36, Short Form-36.

**Table 2.** Summary of studies assessing QOL in patients treated with convective therapy.

Schiffl [34] Germany HF-HD vs. OL-

Lin et al. [44] Taiwan OL-HDF vs. HF-

Stefánsson et al. [40]

130 Advances in Hemodiafiltration

Beerenhout et al. [39]

Ward et al. [41]

Verzetti et al.

[42]

The Netherlands **instrument used**

IQOLA SF-36 (Swedish version) + local questionnaire

KDQ At baseline,

Patients' score of subjective wellbeing, work tolerance, and mental alertness

The Kidney Disease Questionnaire

Patients' score of their degree of subjective well-

*Abbreviations*: AFB, acetate-free biofiltration; AVF, arteriovenous fistula; BHD, bicarbonate hemodialysis; CVC, central venous catheter; HDF, hemodiafiltration; HF, hemofiltration; HF-HD, high-flux hemodialysis; IQOLA, International Quality of Life Assessment; KDQOL, Kidney Disease Quality of Life; KDQ, Kidney Disease Questionnaire; LF-HD, low-flux hemodialysis; MCS, mental component summary; OL-HDF, online hemodiafiltration; OL-HF, online

being

6 and 12 months

26 and 52 weeks

**Timing of assessment** **Study result**

KDQ 52 weeks Patients in the two treatment groups

therapy

associated with PCS. Age, sex, economic status, dialysis modality, and vascular access are associated with MCS

social functioning with HDF, there was no significant difference in quality of

had similar perceptions of their quality of life. While on OL-HDF, patients had sustained improvement in physical symptoms. No change of this dimension with the other mode of

Physical symptoms improved in the HF group after 6 and 12 months, but not in the HD group. QOL for other aspects (frustration, depression, well-being) did not change in any treatment group

60 days With the exception of a lower score for

life between HD and HDF

Weekly Interdialytic symptomatic hypotensive

three times per week

mode of therapy

Monthly Subjective report of well-being

traditional HD to AFB

episodes and interdialysis physical well-being and symptoms improved when frequency of HDF is increased to

Both groups had similar perceptions of their quality of life. Patients' assessment of physical symptoms improved during the course of the study independent of

increased when patients switched from

Moura et al. performed an evaluation of 322 ESRD under OL-HDF from five dialysis units in north Portugal in which patients reported HRQOL utilizing the Kidney Disease Quality of Life Short Form (KDQOL-SF). Patients showed a mean (±SD) of 53.17 % (±15.31 %) in SF-36 total score, 50.17 % (±9.51 %) in the SF-36 mental component summary (MCS), and 49.75 % (±9.44  %) in the SF-36 physical component summary (PCS). Red cell distribution width (RDW), female gender, and diabetes were found as significant predictors of SF-36 total score of HRQOL, which accounts for 12 % of the total explained variance. Patient satisfaction, RDW, body mass index, and gender were identified as predictors for the PCS, which accounts for 22 % of total explained variance. Furthermore, patient satisfaction and dry weight were found as predictors for MCS. These predictors accounted for 28 % of the total explained variance. The authors concluded that the coexistence of diabetes, female gender, and anemia are predictors of HRQOL in patients under OL-HDF and suggest that more attention should be given to these issues in order to improve HRQOL [30]

#### **4.2. Knezevic et al.**

Knezevic et al. examined whether hemodialysis modality and membrane flux, independent of membrane biocompatibility, make differences in quality of life in 124 patients from Serbia. The patients were divided, based on therapy, into three groups: online HDF, high-flux hemodial‐ ysis, and low-flux hemodialysis. Health-related quality of life was assessed using the Short Form-36 questionnaire combined with special questionnaire, which included demographic and clinically related questions. Health-related quality of life was better in patients on HDF compared with patients on hemodialysis, especially compared with low-flux hemodialysis patients in most of the scales and in both dimensions: physical component scale and mental component scale. There were no differences in Short Form-36 domains between high-flux hemodialysis and low-flux hemodialysis. The conclusion was that HDF has a potential positive influence on quality of life, which is sufficient to justify further research in prospective and longitudinal study design [31].

#### **4.3. Karkar et al.**

Karkar et al. investigated the effect of online HDF vs. high-flux hemodialysis (HF-HD) on a patient's health-related satisfaction level. The study involved 72 patients from Saudi Arabia on regular low-flux HD who were randomized to HF randomized to HF-HD and to HDF (*n* = 36) and followed up for 24 months. Satisfaction level was assessed using modified questionnaires of the Kidney Disease Quality of Life Short Form (KDQOL-SF) version 1.3. The HDF group achieved a higher satisfaction level than the HD group (*P* < 0.0001) with less cramps, itching, joint pain, and stiffness. There was an improvement in general mood, sexual performance, and social activity. The investigators concluded that high-efficiency postdilution online HDF significantly improved patients' satisfaction level and quality of life [32].

#### **4.4. Kantartzi et al.**

Kantartzi et al. reported a prospective crossover study involving 24 patients. Each patient received HD, OL-HDF, and HDF with prepared bags of substitution fluid for 3 months, with the dialysis modality subsequently being altered. Quality of life was measured by the Short-Form Health Survey with 36 questions (SF-36), and subscale scores were calculated. There were statistical significant differences in QOL for the total SF-36, bodily pain score, and role limitations due to emotional functioning in favor of online HDF over low-flux HD [33].

#### **4.5. Schiffl**

Schiffl studied 76 clinically stable patients on low-flux conventional HD (LF-HD) in a pro‐ spective crossover clinical evaluation of high-flux ultrapure hemodialysis (HF-HD) and OL-HDF. They were randomized to HF-HD or OL-HDF (24 months) and switched to the alternative treatment (24 months). Online HDF had a greater clearance of urea, phosphate, and β2-microglobulin. Both OL-HDF and high-flux ultrapure HD significantly improved nutri‐ tional status and the response to erythropoietin. Disease-related quality of life was determined after 52 weeks of each study period using the KDQ. The KDQ determines quality of life in five dimensions: physical symptoms, fatigue, depression, relationship with others, and frustration. The patients in the two treatment groups had similar perceptions of their quality of life. However, the patients' assessment of their physical symptoms showed a sustained improve‐ ment during treatment with OL-HDF. There was no change of this dimension with the other modes of therapy (*P* < 0.05). None of the other dimensions of the Kidney Disease Questionnaire showed a change during the course of the study [34].

#### **4.6. Mazairac et al.**

Mazairac et al. analyzed data of 714 patients from the Convective Transport Study [35, 36] with a median follow-up of 2 years to assess the effect of HDF on quality of life compared with HD in patients with ESRD. Quality of life was assessed with the KDQOL-SF. There were no significant differences in changes of HRQOL over time between patients treated with HD (*n* = 358) or hemofiltration (*n* = 356) [37].

#### **4.7. Moura et al.**

Moura et al. evaluated the influence of aging on patients' perception of HRQOL in 305 ESRD patients under OL-HDF. Data about comorbidities, hematological data, iron status, dialysis adequacy, and nutritional and inflammatory markers were collected from patient's records. Quality of life was assessed by using the KDQOL-SF. Analysis of the data showed significant decrease with increasing age in some parameters evaluated by the KDQOL-SF instrument, namely, for work status, physical functioning, and role-physical (RP) [38].

#### **4.8. Beerenhout et al.**

performance, and social activity. The investigators concluded that high-efficiency postdilution

Kantartzi et al. reported a prospective crossover study involving 24 patients. Each patient received HD, OL-HDF, and HDF with prepared bags of substitution fluid for 3 months, with the dialysis modality subsequently being altered. Quality of life was measured by the Short-Form Health Survey with 36 questions (SF-36), and subscale scores were calculated. There were statistical significant differences in QOL for the total SF-36, bodily pain score, and role limitations due to emotional functioning in favor of online HDF over low-flux HD [33].

Schiffl studied 76 clinically stable patients on low-flux conventional HD (LF-HD) in a pro‐ spective crossover clinical evaluation of high-flux ultrapure hemodialysis (HF-HD) and OL-HDF. They were randomized to HF-HD or OL-HDF (24 months) and switched to the alternative treatment (24 months). Online HDF had a greater clearance of urea, phosphate, and β2-microglobulin. Both OL-HDF and high-flux ultrapure HD significantly improved nutri‐ tional status and the response to erythropoietin. Disease-related quality of life was determined after 52 weeks of each study period using the KDQ. The KDQ determines quality of life in five dimensions: physical symptoms, fatigue, depression, relationship with others, and frustration. The patients in the two treatment groups had similar perceptions of their quality of life. However, the patients' assessment of their physical symptoms showed a sustained improve‐ ment during treatment with OL-HDF. There was no change of this dimension with the other modes of therapy (*P* < 0.05). None of the other dimensions of the Kidney Disease Questionnaire

Mazairac et al. analyzed data of 714 patients from the Convective Transport Study [35, 36] with a median follow-up of 2 years to assess the effect of HDF on quality of life compared with HD in patients with ESRD. Quality of life was assessed with the KDQOL-SF. There were no significant differences in changes of HRQOL over time between patients treated with HD

Moura et al. evaluated the influence of aging on patients' perception of HRQOL in 305 ESRD patients under OL-HDF. Data about comorbidities, hematological data, iron status, dialysis adequacy, and nutritional and inflammatory markers were collected from patient's records. Quality of life was assessed by using the KDQOL-SF. Analysis of the data showed significant decrease with increasing age in some parameters evaluated by the KDQOL-SF instrument,

namely, for work status, physical functioning, and role-physical (RP) [38].

showed a change during the course of the study [34].

(*n* = 358) or hemofiltration (*n* = 356) [37].

online HDF significantly improved patients' satisfaction level and quality of life [32].

**4.4. Kantartzi et al.**

132 Advances in Hemodiafiltration

**4.5. Schiffl**

**4.6. Mazairac et al.**

**4.7. Moura et al.**

Beerenhout et al. examined the effects of LF-HD and predilution online HF (OL-HF) on cardiovascular and nutritional parameters, interdialytic levels of uremic toxins, and quality of life. The KDQ of Laupacis [26] was used for QOL assessment. At 1 year, 27 patients were eligible for analysis (HF, 13 patients; HD, 14 patients). QOL for physical symptoms improved in the HF group (4.2 ± 1.2–5.0 ± 1.1), *P* < 0.05 within the HF group, but not in the HD group (4.0 ± 1– 4.4 ± 1.4) [39].

#### **4.9. Stefánsson et al.**

Stefánsson et al. performed a prospective, randomized, and patient-blinded crossover study involving 20 patients from Sweden on chronic HD. The patients received either HD for 2 months followed by postdilution HDF for 2 months or in opposite order. Online postdilution HDF was used, and the replacement volume was standardized to 25–30 % of the total blood volume treated. The two treatments were similar with respect to dialysis-related complica‐ tions, quality of life, and the biomarkers of oxidative stress and inflammation. Interviews for assessment of quality of life were double blinded. Patients answered health-related questions in two separate questionnaires. The first one was the Swedish version of the standardized quality-of-life questionnaire, SF-36. The second one was generated by the study designers and specifically concerned 12 symptoms and health-related conditions occurring during the previous 4 weeks. With the exception of a lower score for social functioning with HDF (*P* < 0.05), there was no significant difference in quality of life between HD and HDF [40].

#### **4.10. Ward et al.**

Ward et al. tested the hypothesis that HDF provides better solute removal than HF-HD in a prospective, randomized clinical trial. Twenty-four patients were randomized to online postdilution HDF, and twenty-one patients were allocated to HF-HD for a period of 12 months. Removal of both small (urea and creatinine) and large (β2-microglobulin and complement factor D) solutes was significantly greater for HDF than for HF-HD. Pretreatment plasma β2 microglobulin concentrations decreased with time (*P* < 0.001); however, the decrease was similar for both therapies. The patients' assessment of their quality of life was determined after 26 and 52 weeks of the study. A single interviewer administered the questionnaire to all patients. The patients in both groups had similar perceptions of their quality of life as assessed by the KDQ. The patients' assessment of their physical symptoms showed a significant improvement during the course of the study which was independent of the treatment modality. None of the other dimensions of the KDQ showed a change over the course of the study [41].

#### **4.11. Verzetti et al.**

Verzetti et al. performed a study to compare standard bicarbonate hemodialysis (BHD) with acetate-free biofiltration (AFB) in a group of 41 stable diabetic patients on dialysis treatment for 25 ± 22 months. Twenty-four type II and seventeen type I diabetic patients, all requiring insulin therapy, were included and were followed up for 1 year in a 6-month crossover randomized study for both methods. The analysis was carried out on dialysis symptoms, interdialysis symptoms, and nutritional status. On a monthly basis, patients were also required to score their degree of subjective well-being. All the clinical events occurring during the study period, together with the number of hospitalizations and mortality rates, were recorded. AFB significantly reduced dialytic and extra-dialytic symptoms (*P* = 0.003 and 0.001, respectively). Cardiovascular collapses decreased by 43 %, and other dialysis symptoms showed a similar trend (−35 %). The interdialysis symptoms decreased by 28 % and were accompanied by an increase in subjective well-being (39 %) when patients were switched from traditional HD to AFB. Acid-base control was better with AFB (*P* = 0.01), both at the beginning and during the session. In comparison to traditional HD, hypotensive episodes and other dialysis symptoms during AFB decreased by 43 % and 35 %, respectively. Interdialysis symptoms showed the same favorable trend, decreasing by 28 %. Moreover, subjective report of well-being increased by 39 % when the patients switched from traditional HD to AFB. The number of hospital admissions and the mortality rate were lower during the AFB than the BHD period. The authors concluded that AFB allows better control of some metabolic aspects, reduces intraand extra-dialysis symptoms, and improves patient QOL [42].

#### **4.12. Moura et al.**

Moura et al. examined the effect of vascular access type (arteriovenous fistula (AVF) vs. central venous catheter (CVC)) on patients reported HRQOL in 322 ESRD under OL-HDF. Arterio‐ venous fistula (AVF) was used by 252 patients (78.3 %), whereas 70 patients (21.7 %) had a central venous catheter (CVC). Patients using CVC as a vascular access presented a decrease in four SF-36 domain scores, namely, physical functioning, emotional well-being, roleemotional, and energy/fatigue when compared with those using AVF as a vascular access. Additionally, these patients also showed significant decline in cognitive function and qualityof-social interaction domains. Left-arm AVF was associated with higher scores in three SF-36 domain scores, namely, physical functioning, pain, and general health. It was also associated with a higher score in ESRD target areas of symptoms/problem list and effects of kidney disease and quality-of-social interaction domains. The authors concluded that ESRD patients under OL-HDF using AVF as a vascular access had higher HRQOL scores in several domains when compared with those using CVC. Patients using AVF in the left forearm presented with higher HRQOL scores [43].

#### **4.13. Lin et al.**

Lin et al. compared OL-HDF (thrice, twice, and once per week) with different frequencies of combination high-flux HD. Interdialytic symptomatic hypotensive episodes were reduced when frequencies of online HDF were increased. Interdialysis physical well-being and symptoms similarly improved when frequency of HDF is increased to three times per week [44].

#### **4.14. Nistor I et al.**

insulin therapy, were included and were followed up for 1 year in a 6-month crossover randomized study for both methods. The analysis was carried out on dialysis symptoms, interdialysis symptoms, and nutritional status. On a monthly basis, patients were also required to score their degree of subjective well-being. All the clinical events occurring during the study period, together with the number of hospitalizations and mortality rates, were recorded. AFB significantly reduced dialytic and extra-dialytic symptoms (*P* = 0.003 and 0.001, respectively). Cardiovascular collapses decreased by 43 %, and other dialysis symptoms showed a similar trend (−35 %). The interdialysis symptoms decreased by 28 % and were accompanied by an increase in subjective well-being (39 %) when patients were switched from traditional HD to AFB. Acid-base control was better with AFB (*P* = 0.01), both at the beginning and during the session. In comparison to traditional HD, hypotensive episodes and other dialysis symptoms during AFB decreased by 43 % and 35 %, respectively. Interdialysis symptoms showed the same favorable trend, decreasing by 28 %. Moreover, subjective report of well-being increased by 39 % when the patients switched from traditional HD to AFB. The number of hospital admissions and the mortality rate were lower during the AFB than the BHD period. The authors concluded that AFB allows better control of some metabolic aspects, reduces intra-

Moura et al. examined the effect of vascular access type (arteriovenous fistula (AVF) vs. central venous catheter (CVC)) on patients reported HRQOL in 322 ESRD under OL-HDF. Arterio‐ venous fistula (AVF) was used by 252 patients (78.3 %), whereas 70 patients (21.7 %) had a central venous catheter (CVC). Patients using CVC as a vascular access presented a decrease in four SF-36 domain scores, namely, physical functioning, emotional well-being, roleemotional, and energy/fatigue when compared with those using AVF as a vascular access. Additionally, these patients also showed significant decline in cognitive function and qualityof-social interaction domains. Left-arm AVF was associated with higher scores in three SF-36 domain scores, namely, physical functioning, pain, and general health. It was also associated with a higher score in ESRD target areas of symptoms/problem list and effects of kidney disease and quality-of-social interaction domains. The authors concluded that ESRD patients under OL-HDF using AVF as a vascular access had higher HRQOL scores in several domains when compared with those using CVC. Patients using AVF in the left forearm presented with higher

Lin et al. compared OL-HDF (thrice, twice, and once per week) with different frequencies of combination high-flux HD. Interdialytic symptomatic hypotensive episodes were reduced when frequencies of online HDF were increased. Interdialysis physical well-being and symptoms similarly improved when frequency of HDF is increased to three times per week

and extra-dialysis symptoms, and improves patient QOL [42].

**4.12. Moura et al.**

134 Advances in Hemodiafiltration

HRQOL scores [43].

**4.13. Lin et al.**

[44].

Nistor et al. [45] conducted a systematic review of randomized controlled trials in which data for quality of life were extractable from eight trials (988 participants), including six evaluating HDF and one each evaluating HF or acetate-free biofiltration [33, 34, 36, 39–42, 44]. The authors Stated that in very low-quality evidence, data for quality of life were inconsistent. Data from the four parallel-group trials [33, 36, 39, 41] showed that there was no difference in the change in quality of life (any domain) comparing HDF with HD in one trial [36]. Both HDF and HD patients reported significant improvement in physical symptoms irrespective of treatment allocation in a second trial [41]. Hemodialysis patients had lower physical well-being scores than patients on HDF, but treatment effects on work tolerance and mental alertness were not available in a third trial [33]. Comparative data for HF and HD were not available in a fourth trial [39]. The remaining four studies were crossover design, and data for the end of the first phase of treatment were not available.
