Patient-Centered Care Could Improve Quality of Life and Survival of Dialysis Patients: Dialysis Prescription and Daily Practice

Abstract

We now face a paradigm shift in clinical practice and research of dialysis from evidence-based medicine outcomes to patient-reported outcomes (PROs). It is imperative to establish a daily practice pattern based on the PROs, namely “patient-centered dialysis care.” In 2005, we introduced the concept of “patient-oriented dialysis,” which includes two fundamental components; adjustment of the dialysis prescription according to the PROs and nutritional intervention based on the global nutritional assessment. Routine examinations and team meetings were held to monitor the status of PROs and nutrition, and intervention plans were reevaluated. We found that the total score of the PROs was closely related to the survival rate of dialysis patients, and some of those were identified as independent mortality risk factors. These results might have shown that patient-centered dialysis care may improve the quality of life and the survival rate of dialysis patients. Polymethyl methacrylate (PMMA) is a unique synthetic membrane for a dialyzer with protein adsorption property and biocompatibility. Several clinical advantages of PMMA were reported as ameliorating inflammatory status, nutritional status, skin itchiness, and dialysis-related fatigue. PMMA is a fundamental and major choice for improving PROs in patient-centered dialysis care.

Introduction

In recent decades, high-efficiency dialysis modalities such as online hemodiafiltration (HDF) and the expanded hemodialysis [1] with medium-cutoff dialyzer have been widely performed to improve the survival rate of dialysis patients. The advantages or disadvantages of these therapies have been evaluated by the survival rate parameters, the onset of a cardiovascular event, and other adverse events, which became the basis of evidence-based medicine (EBM). Even with improvements in the technology and quality of dialysis, the average life expectancy of dialysis patients of all ages is still only about half that of the general population [2]. In many developed countries, the dialysis population is getting older every year, with the average age of dialysis patients exceeding 70 years. Amid these changes in chronic dialysis therapy, the paradigm in clinical practice and research in dialysis needs to change to patient-reported outcomes (PROs) rather than EBM outcomes [3]. Polymethyl methacrylate (PMMA) is one of the synthetic materials for dialysis membranes with unique properties. Several clinical benefits of PMMA for dialysis patients are reported, such as ameliorating uremic pruritus [4, 5] and the inflammatory status [6]. These benefits are due to the PMMA's unique protein adsorption and biocompatibility properties. In this article, we introduce daily practice and the clinical results of our patient-centered care and propose the role of the PMMA in the patient-centered dialysis care.

The Trend of Patient-Centered Dialysis Care

The main concept of 21st-century medicine addresses three essential elements: patient-centeredness, patient and family engagement, and shared decision-making [7]. “Patient-centeredness” is the symbolic phrase of this concept and the most important topic we must review in our daily clinical practices. In clinical practice and research, we have put most of our attention to the outcomes or targets from randomized controlled trials and/or cohort studies as the basis for making decisions. This decision-making system, EBM, is a reasonable basis for most medical workers. However, it may occasionally be challenging to reflect the patients' priorities or favors to make decisions within the EBM. Based on a new concept, we have to set up the outcomes of daily clinical practice and research primarily according to the patients' priorities, benefits, and preferences.

Tong et al. [8] have developed patient-centered care in nephrology as the Standardized Outcome in Nephrology (SONG) initiative. The SONG initiative has established several working groups for different areas of nephrology, including SONG-HD (hemodialysis), SONG-PD (peritoneal dialysis), SONG-Kids, and SONG-CKD (non-dialytic chronic kidney disease). Both EBM and patient outcomes were divided into three categories according to their importance in clinical practice and research: core outcomes, middle tier, and outer tier [8]. In the SONG-HD initiative, which is the main topic of this paper, “fatigue” was highlighted as one of the core outcomes along with other EBM outcomes such as cardiovascular disease, vascular access patency, and mortality [8]. The patient outcomes in the middle and outer tiers include most of the symptoms, claims, and problems reported from patients in daily practice in our dialysis centers. Unfortunately, it can be difficult to solve these problems completely. There is an urgent need to develop a practice pattern to achieve these outcomes (goals), but this has not yet been proposed by the SONG-HD initiative or other studies.

Chronic kidney disease (CKD) patients are known to have high rates of malnutrition, which is the most potent mortality risk factor [9]. Malnutrition observed in CKD, especially in CKD-5D, is caused by pathophysiological factors in uremia, inflammation, and nutrient loss during a dialysis session, the physical and mental condition of the patient, and many other factors [9]. Malnutrition inflammation atherosclerosis syndrome was proposed by Stenvinkel et al. [10] in 1999, as they highlighted the inflammatory aspect of pathophysiology and dialysis therapy for accelerating atherosclerosis in dialysis patients. The International Society of Renal Nutrition and Metabolism proposed Protein Energy Wasting, a guide that focuses on the dialysis patients' physical deterioration caused by uremia and dialysis therapy [11]. However, there is no significant difference between these two concepts for overviewing the CKD patients' nutritional problems. In recent years, the dialysis population in developed countries has been aging, and physical decline known as frailty or sarcopenia has become the most urgent problem we have to face. Physical activity in dialysis patients is essential for enjoying daily life and achieving outcomes such as “ability to move and work” and “mobility.” These are addressed in the SONG-HD initiative, and are closely related to the most important PRO for dialysis patients: “fatigue” [8]. Therefore, maintaining a good nutritional status is essential for patient-centered dialysis care.

Daily Practice Pattern in Dialysis Based on PROs and Nutritional Assessment

Based on the trend of patient-centered dialysis care, we must establish a routine practice pattern of dialysis prescription to achieve PROs and maintain a nutritional status. So far, the dialysis prescription, such as dialysis schedule, dialysis efficacy, usage of online HDF, and membrane choice, has been adjusted for each patient based on EBM, and only a few practice patterns center around the dialysis patients' PROs. In 2005, we initiated the concept of “patient-oriented dialysis (POD).” This concept includes two basic components: first, adjusting dialysis prescriptions based on PROs; and second, providing nutritional interventions based on a global nutritional assessment [12, 13, 14, 15].

The original assessment sheet called “Ai-POD sheet” has been used for assessing the patient's symptom burden, which contains 20 questions for dialysis-related symptoms and feelings in our facilities shown in Table 1. Each symptom was evaluated by a 5-graded face scale (0: none – 4: extreme), and the overall Ai-POD score was calculated [14, 15]. After the routine examination with the Ai-POD sheet performed every 6 months, a meeting was held to identify patients needing interventions and discuss the treatment. We made an improvement plan when the patient's symptom was greater than score 2 as shown in Figure 1. We have been doing this clinical pattern for almost 15 years, and found that some PROs respond well to dialysis prescription interventions. These include fatigue, intradialytic hypotension, muscle cramp, skin itchiness, irritable state, restless legs syndrome, skin pigmentation, appetite, and nutritional status [14]. We found that the length of time needed to determine the effect varies by the outcome. For example, only a short period was required to ameliorate post-dialysis fatigue or intradialytic hypotension, while an extended period was required for improving skin pigmentation and nutritional status. If a patient has severe symptoms such as restless legs syndrome or itchiness, initially, we recommend increasing the dialysis dose by extending dialysis time without changing dialysis modality or membranes. If a patient does not accept the suggestion to extend the dialysis time, we start protein permeable dialysis by protein adsorptive membrane or online HDF with mild albumin leakage as 1–3 g/session, while monitoring changes in the targeted symptom. If the symptom did not improve, we intensified the albumin leakage by changing membranes, increasing the convection volume, or switching the dilution mode of HDF from pre-dilution to post-dilution. The albumin leakage was attenuated again when obvious hypoalbuminemia occurred, or the patient complained of fatigue as shown in Figure 2 [14]. The allowance level of albumin leakage during a dialysis session is thought to be around 3 g but more leakage can be acceptable depend on the patient's condition [14, 16].

Table 1.

Questionnaire items in Ai-POD sheet

Questions		Grading (score)
Symptoms in daily life
1	Do you have any pains on your joints?	No (0) < Somewhat (1) < Moderate (2) < Very much (3) < Extreme (4)
2	Do you have skin itchiness?	No (0) < Somewhat (1) < Moderate (2) < Very much (3) < Extreme (4)
3	Do you have irritability?	No (0) < Somewhat (1) < Moderate (2) < Very much (3) < Extreme (4)
4	Do you have fatigue?	No (0) < Somewhat (1) < Moderate (2) < Very much (3) < Extreme (4)
5	Do you have palpitation or shortness of breath?	No (0) < Somewhat (1) < Moderate (2) < Very much (3) < Extreme (4)
6	Are you constipated?	No (0) < Somewhat (1) < Moderate (2) < Very much (3) < Extreme (4)
7	Do you fall asleep just after you go to bed?	Always (0) < Frequently (1) < Sometimes (2) < Rarely (3) < No (4)
8	Do you have comfortable sleep until the morning?	Always (0) < Frequently (1) < Sometimes (2) < Rarely (3) < No (4)
Symptoms related to dialysis
9	Do you have any pains during cannulation?	No (0) < Somewhat (1) < Moderate (2) < Very much (3) < Extreme (4)
10	Do you get headache around your dialysis session?	No (0) < Rarely (1) < Sometimes (2) < Frequently (3) < Always (4)
11	Do you have painful hypotension during dialysis session?	No (0) < Rarely (1) < Sometimes (2) < Frequently (3) < Always (4)
12	Do you have muscle cramps during dialysis session?	No (0) < Rarely (1) < Sometimes (2) < Frequently (3) < Always (4)
13	Can you get up from your bed just after dialysis session?	Quickly possible (0) < (1) < (2) < (3) < Need a long time (4)
Dietary life 14	Do you have appetite?	Always (0) < Frequently (1) < Sometimes (2) < Rarely (3) < No (4)
15	Do you enjoy your meals?	Always (0) < Frequently (1) < Sometimes (2) < Rarely (3) < No (4)
16	Do you have thirsty?	No (0) < Somewhat (1) < Moderate (2) < Very much (3) < Extreme (4)
17	Do you have any difficulties with your dietary life?	No (0) < Somewhat (1) < Moderate (2) < Very much (3) < Extreme (4)
Feelings
18	Do you have depressive feelings?	No (0), Yes (4)
19	Are you motivated?	Yes (0), No (4)
20	Are you satisfied with life?	Very much (0) < (1) < (2) < (3) < Not at all (4)

Fig. 1.

Flow chart of patient-centered dialysis care by Ai-patient-oriented dialysis sheet. PROs, patient-reported outcomes; POD, patient-oriented dialysis.

Fig. 2.

Daily practice pattern based on patient-reported outcomes. HD, hemodialysis; HDF, (online) hemodiafiltration; PROs, patient-reported outcomes; RRF, residual renal function; HF-HD, high-flux hemodilysis.

We reported that the severity of symptoms in hemodialysis patients, as measured by the Ai-POD score, is closely related to mortality risk [15]. Ten dialysis-related symptoms and feelings were identified as independent mortality risk factors: irritable feeling, fatigue, constipation, intradialytic hypotension, muscle cramp, difficulty getting up after dialysis, poor appetite, enjoyment of a meal, thirst, and dissatisfied feelings [15]. Some of them have already been reported as independent mortality risk factors, while others have not yet been reported. As this was a retrospective study, a well-designed randomized trial is needed to prove the effects of interventions on the symptoms. However, patients need to know that they will have to endure their symptoms until the end of the study, and that improvement in their symptoms will be beneficial to them even if the results are not statistically significant.

Modified Malnutrition Inflammation Score (MIS) sheet shown in Table 2 has been used for assessing the nutritional status of all dialysis patients every 6 months in our facilities. The original MIS sheet was composed by Kalanter-Zadeh et al. [17] and contained ten nutritional parameters, seven parameters from the Dialysis Nutrition Score (DNS) [18], and three parameters were added specifically for dialysis patients. Furthermore, we added three parameters to assess the cause for malnutrition and make intervention plans: normalized protein catabolic rate for predicting dietary intake, serum C-reactive protein for evaluating inflammatory focus, and dialysis prescription (shown in Table 2). After malnutrition screening using the modified MIS sheet, Nutrition Support Team (NST) meetings were held with doctors, dietitians, nurses, and clinical engineers shown in Figure 3. Patients were classified into the following three groups by the total score of MIS; the no risk group as the total MIS <5, the mild risk group as 5∼7, and the moderate/high risk group as ≥8 [19]. In the NST meeting, we considered the cause of malnutrition to make nutritional interventions for the patients of the moderate/high risk group and the patients with more than 5-point worsening of the total MIS. If there is an unexplained nutritional deterioration or unexplained inflammation, the dialysis prescription may be changed, such as transition from HD to HDF or vice versa, or transition to biocompatible membranes.

Table 2.

Modified MIS sheet

Name	Sex	Age	Date	Checked by
Height, cm	DW, kg	Dialysis starting date		Diabetes (+, -)
Patients’ related medical history
1. Change in end dialysis DW (overall change in past 3–6 months)
0		1	2	3
No decrease in DW or weight loss <0.5 kg		Minor weight loss (≥0.5 kg but <1.0 kg)	Weight loss more than 1.0 kg but <5%	Weight loss >5%
2. Dietary intake
0		1	2	3
Good appetite and no deterioration of the dietary intake pattern		Somewhat sub-optimal solid diet intake	Moderate overall decrease to full liquid diet	Hypo-caloric liquid to starvation
3. GI symptoms (nausea, vomiting, diarrhea, poor appetite)
0		1	2	3
No symptoms with good appetite		Mild symptoms, poor appetite or nauseated occasionally	Occasional vomiting or moderate GI symptoms	Frequent diarrhea or vomiting or severe anorexia
4. Functional capacity (nutritionally related functional impairment)
0		1	2	3
Normal to improved functional capacity, feeling fine		Occasional difficulty with baseline ambulation, or feeling tired frequently	Difficulty with otherwise independent activities (e.g., going to bathroom)	Bed/chair-ridden, or little to no physical activity
5. Comorbidity including number of years on dialysis
0		1	2	3
On dialysis less than 1 year and healthy otherwise		Dialyzed for 1–4 years, or mild comorbidity (excluding MCC)	Dialyzed >4 years, or moderate comorbidity (including MCC)	Any severe comorbidity (2 or more MCC)
MCC: CHD class III or IV, AIDS, severe CAD, moderate to severe COPD, stroke, malignant tumor
Physical Exam (BIA or direct measurement)
6. Decreased fat stores (BIA or direct measurement) TSF, mm (%), AMC, cm
0		1	2	3
Normal %TSF >91%		Mild decrease %TSF: 81˜90%.	Moderate decrease %TSF: 61˜80%	Severe decrease %TSF <60%
7. Signs of muscle wasting (BIA or direct measurement) AMC, cm (%)
0		1	2	3
Normal %AMC >91%		Mild decrease %AMC: 81˜90%	Moderate decrease %AMC: 61˜80%	Severe decrease %AMC <60%
BMI
8. BMI = wt (kg)/Ht2 (m) (kg/m2)
0		1	2	3
BMI ≥20 kg/m2		BMI: 18˜19.99 kg/m2	BMI: 16˜17.99 kg/m2	BMI <16 kg/m2
Laboratory parameters
9. Serum albumin (g/dL)
0		1	2	3
Albumin ≥4.0 g/dL		Albumin: 3.5˜3.9 g/dL	Albumin: 3.0˜3.4 g/dL	Albumin <3.0 g/dL
10. Serum TIBC (µg/dL)
0		1	2	3
TIBC ≥250 mg/dL		TIBC: 200˜249 g/dL	TIBC: 150˜199 g/dL	TIBC <150 mg/dL
Total score		Good (0˜5), mild risk (6˜10), moderate ˜ severe risk (11 ˜)
Others
CRP (mg/dL)		nPCR (g/kg/day)	Dialysis modality HD, HDF (pre-, post-)	Membrane material
Previous Total score		Comments to you
				NST meeting, Yabuki Hospital

DW, dry weight; GI, gastrointestinal; MCC, major cormobid conditions; CHF, congestive heart failure; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; BIA, bioimpedence analysis; TSF, triceps skinfold thickness; AMC, arm muscle circumference; SGA, subjective global assessment; BMI, body mass index; TIBC, total iron binding capacity; CRP, C-reacting protein; nPCR, normalized protein catabolic rate; HD, hemodialysis; HDF, hemodiafiltration.

Fig. 3.

Flow chart of nutritional support team meeting with the malnutrition inflammation score sheet. MIS, malnutrition inflammation score; CRP, C-reactive protein; nPCR, normalized protein catabolic rate.

We believe that a patient-centered approach, in which PROs and nutritional parameters are essential, can improve the quality of life of dialysis patients and ultimately lead to good survival rates. However, there is no golden prescription that can be applied to all dialysis patients, and we must find the appropriate dialysis prescription through trial and error.

Dialysis Quality Evaluation

Historically, the quality of dialysis has been evaluated from two major perspectives (except for variations in dialysis schedule): solute removal property and biocompatibility. In the last two decades, high-efficiency and high-filtration therapies such as online HDF have become the mainstream of renal replacement therapy, and these therapies have been developed to achieve aggressive middle-molecule removal and higher biocompatibility. The removal characteristics were evaluated by the removal rate and the removed amount of various middle molecules and their pre-dialysis values. Biocompatibility was initially evaluated experimentally and then by biological responses such as complement activation, effects on blood cells, and induction of inflammatory reactions. Finally, their clinical impact is estimated by patient mortality or the incidence of adverse effects and hospitalization. However, with the recent trend of patient-centered dialysis care, we believe that the quality of dialysis should be reviewed from the perspective of PROs. We need to evaluate whether different dialysis modalities and membrane materials have different effects on PROs and nutritional status. If we find significant differences between modalities and membranes, we need to consider the mechanisms of these differences in relation to solute removal properties and biocompatibility. Recently, several published studies have examined the relationship between dialysis modalities and PROs.

Sakurai et al. [16] reported that the removal rate of alpha-1 microglobulin has distinctive features for ameliorating intradialytic hypotension, itchiness, bone pain, and restless legs syndrome compared to the removal rate of beta-2 microglobulin (B2MG). They also reported that refilling online HDF with a removal rate of more than 35% of alpha-1 microglobulin significantly improved restless legs syndrome in dialysis patients. However, these studies did not evaluate differences in membrane materials.

Recovery time is one of the semi-quantitative parameters for assessing health-related quality of life (QoL), and is an independent risk factor of mortality and hospitalization [20]. In a previous report, longer recovery time was associated with age, sex, diabetes, intradialytic weight loss, lower dialysate sodium concentration, and longer dialysis time; Kt/V was not significant [20]. However, these factors may vary among dialysis centers because the concept and prescription of dialysis may differ from one facility to another. At our dialysis center, recovery time was not affected by any factors highlighted in previous studies (Nawano, by personal communication). In general, long and slow dialysis is reported to effectively avoid hypotension and crashes during dialysis and normalize extracellular fluid volume. Nocturnal home hemodialysis is a typical prescription for slow and prolonged dialysis, and it has been reported that it significantly reduces recovery time [21]. Recently, Bolton et al. [22] observed improved recovery times after switching from regular HD/HDF to the expanded hemodialysis.

Pruritus is one of the discomfort symptoms of dialysis patients, and severe pruritus was reported as a mortality risk factor by Narita et al. [23]. In their study, Kt/V was not significantly related to severe pruritus, but serum concentration of B2MG was identified as an independent risk factor. This study did not evaluate the removal rate of B2MG, membrane material, or use of HDF. While these studies suggest that the removal of middle molecules in dialysis therapy may have some effect on PROs, a recent systematic review reported that MCO membranes improve several important outcomes for patients, including pruritus, symptom severity, recovery time, and restless leg syndrome [24]. More studies will evaluate the impact of solute removal, especially middle molecules removal, on PROs in hemodialysis patients. The CONVINCE trial is an ongoing randomized control trial to demonstrate the benefits of online HDF on the survival of hemodialysis patients. Several PROs were included in the trial as secondary outcomes [25].

The biocompatibility of dialysis therapy is another important aspect of assessing the quality of dialysis, an issue that is both old and still new. Traditionally, “biocompatibility of dialysis” focused on the phenomena that occur on the surface of the artificial membrane due to the interaction of blood components. The biochemical and bio-physiological properties of the membrane surface have been assessed by the activation of blood cells, the complement system, and the blood coagulation system. However, it is still unclear how the biocompatibility of membranes is reflected in clinical manifestations other than anaphylaxis. In high-flux, high-convective therapies, membrane materials must be strong enough to maintain membrane pore integrity and resist high transmembrane pressures due to high convection volumes. Membrane materials that meet these requirements are synthetic membranes such as polysulfone (PS), polyether sulfone (PES), and polyether polymer alloy. In recent years, it has been reported that some of the chemical components essential for the construction of these membranes can adversely affect the quality of dialysis therapy. Polyvinyl pyrrolidone (PVP) is a chemical that provides hydrophilicity to hydrophobic materials and is frequently used in beverages and pharmaceuticals to make them more soluble in water. PVP is an essential component to make membranes such as PS, which is originally a hydrophobic material, hydrophilic, and biocompatible. PVP, however, has been linked to anaphylaxis, thrombocytopenia, and inflammatory reactions that were sometimes seen in dialysis treatments using PS [26, 27]. Bisphenol A (BPA) is a well-known hormone-disrupting chemical. BPA is also an indispensable component to make plastics, but its use is prohibited for tableware, especially baby bottles, in many countries. It has been reported that BPA accumulates in the serum of dialysis patients using membranes containing BPA in higher concentrations than those using membranes without BPA [28]. It has also been reported that membranes with BPA cause inflammatory reactions in dialysis patients. There are also membrane materials that do not contain PVP or BPA, such as PMMA, cellulose triacetate, and polyacrylonitrile, as shown in Table 3 [12]. According to these reports, it must be noted how the biocompatibility of dialysis membranes has a significant impact on PROs in dialysis patients, and a new research field should examine the impact of treatment biocompatibility on PROs.

Table 3.

PVP and BPA by membrane and housing material

Membrane material	Provider	Housing material	PVP	BPA
				membrane	housing
CTA	Company A	Polypropylene	–	–	–
PAN	Company B	ABS copolymer	–	–	–
PAES/PVP/PAN	Company B	Polycarbonate	+	-	+
PAES/PVP	Company B	Polycarbonate	+	–	+
PES	Company A	Polypropylene	+	–	–
PEPA	Company C	Polycarbonate	+	+	+
PEPA	Company C	Polycarbonate	–	+	+
PMMA	Company D	Polystyrene	–	–	–
PS + PVP	Company E	Styrene-butadiene copolymer resin	+	+	–
PS + PVP	Company D	Polycarbonate	+	+	+
PS + PVP	Company F	Polypropylene	+	+	–
PS + PVP	Company G	Polycarbonate	+	+	+

CTA, cellulose triacetate; PAN, polyacrylonitrile; ABS, acrylonitrile butadiene styrene; PAES, polyarylethersulfone; PVP, polyvinyl pyrrolidone; PES, polyethersulfone; PEPA, polyether polymer alloy; PMMA, polymethyl methacrylate; PS, polysulfone; BPA, bisphenol A.

Characteristics of PMMA Membrane

PMMA membranes are composed of two types of polymers with different structures: isotactic PMMA polymer and syndiotactic PMMA polymer [29]. These membranes are characterized by excellent biocompatibility because PMMA does not contain PVP or BPA and has excellent protein adsorption and a homogenized pore structure. PMMA, due to its symmetrical homogeneous structure and protein adsorption properties, cannot be used in high-convective dialysis mode, and the removal rate of MMs is relatively low compared to other synthetic membranes with asymmetric structure such as PS. However, PMMA has been reported to have various benefits such as an anti-inflammatory effect and improvement of anemia [30], itchiness [5, 31], nutrition status [5], and immune response [32, 33] in dialysis patients. Since the solute removal performance of PMMA is lower than that of PS, these effects may be mainly attributed to its biocompatibility.

Toray developed the new PMMA Filtryzer NF (NF-type PMMA) to improve the hemocompatibility of the previous type of PMMA (BG-type PMMA) [29]. As previously addressed, since PMMA is a protein-adsorbing membrane, a protein adsorption layer is formed on the inner surface of the membrane during the dialysis session. This protein layer functions as a protein coat consisting of its own serum proteins, leading to better biocompatibility. On the other hand, if the adsorbed proteins lose their native properties and deteriorate, they may trigger a consequent coagulation cascade or inflammatory process. Clinicians and technicians sometimes noted blood clotting when treating patients with increased coagulation systems after surgery or inflammation by PMMA. The membrane surface of NF-type PMMA was modulated by titrating adsorbed water on the membrane surface to avoid the deterioration of the adsorptive protein (mainly albumin) and the adhesion of platelets to the membrane surface [29]. It has been experimentally proven that the adsorbed albumin has not lost its original properties [29]. We reported that the reduction of blood platelet count and adhered platelet count on the membrane surface was significantly lower in NF-type PMMA compared to BG-type PMMA [34]. Nevertheless, there was no difference in the amount of protein adsorbed between the NF-type and BG-type. The skin perfusion pressure was well maintained during dialysis in the NF-type PMMA but decreased in the BG-type PMMA. Therefore, it was suggested that less stimulation of platelets in the NF-type PMMA was advantageous in maintaining peripheral circulation during the dialysis session [34].

Clinical Advantages of PMMA on PROs

As previously addressed, even though the removal performance of PMMA for MMs is not as high as other synthetic membranes such as PS, various advantages of PMMA have been reported. In this manuscript, we have reviewed the clinical advantages of PMMA in PROs and related topics. Most notably, Abe et al. [35] reported the clinical advantage of PMMA. Using Japanese mega data, the risk of mortality in dialysis patients was evaluated by dialysis membrane material used. Two-year mortality rates for patients undergoing dialysis with PMMA and PES membranes were significantly lower than those using PS membranes [35]. It was hypothesized that the higher biocompatibility of both membranes than PS, due to the absence of both PVP and BPA in PMMA and the absence of BPA in PES, may have lowered inflammation-related risks [12, 29]. One more possible mechanism of the survival advantage of PMMA could be associated with improving PROs and health-related QoL. Indeed, there are several reports of PMMA improving some of the PROs, and we already reported that the lower satisfied PROs were associated with a lower survival rate [15].

Uremic pruritus is one of the uncomfortable symptoms, and the prevalence of pruritus was reported as 40–50% of chronic dialysis patients [36, 37]. Although pruritus was not identified as an independent mortality risk factor in the DOPPS study, it is considered to deteriorate sleep quality and QoL, ultimately leading to poor outcomes [37]. Similar to DOPPS, our experience also demonstrated that the total PROs score was a risk factor for mortality, but itchy skin was not identified as an independent risk factor [15]. Aucella et al. [38] reported that BG ameliorated skin itchiness in a preliminary study. Uchiumi et al. [5] also reported that uremic skin itchiness was significantly improved by NF but not by PS in a multicenter randomized control trial. We examined the clinical effects of NF on eight PROs, including itchiness, in a randomized study. The results showed an improvement in the total QoL score but no significant change in the itchiness score [39]. Uremic itchiness is an important outcome for patients, and is an appropriate parameter that responds well to therapeutic interventions and helps to personalize dialysis prescriptions. PMMA and online HDF are effective options in our routine practice to treat uremic pruritus, resulting in a prevalence of pruritus of about 15%, which is one-third of previous studies.

Fatigue is listed as one of the core outcomes in the SONG-HD initiative [8]. Like pruritus in our practice pattern, fatigue is also an appropriate parameter to individualize dialysis prescription, and has been identified as an independent mortality risk factor [15]. Recovery time has been regarded as one of the parameters to assess the severity of dialysis-related fatigue [20]. However, only a few studies have evaluated the effects of membrane material on fatigue and recovery time, especially for PMMA. Sklar et al. [40] evaluated the effects of BG on post-dialysis fatigue and inflammatory cytokine kinetics compared to cellulose membranes. BG significantly reduced serum tumor necrosis factor-alpha but did not improve the fatigue score. In our study, NF significantly improved the total PRO score but did not improve fatigue specifically [39]. However, in another preliminary study, NF improved fatigue and total symptom score in older dialysis patients [41]. It is easy to imagine that dialysis-related fatigue can strongly impact a patient's physical activity, appetite, and QoL, so it is essential to customize the dialysis prescription for each patient to avoid fatigue.

Nutritional status, including maintenance of appetite, is one of the strongest prognostic factors closely related to the QoL in dialysis patients. Inflammation is regarded as one of the mechanisms of malnutrition observed in dialysis patients. Several studies suggested that PMMA may improve the inflammatory state of dialysis patients by adsorbing high-molecular-weight solutes. Uchiumi et al. [5] reported that patients treated with NF-type PMMA rather than PS had better-preserved muscle mass as estimated from the creatinine generation rate. Chida et al. [41] reported that NF improved the creatinine generation rate and geriatric nutrition risk index.

Role of PMMA in Patient-Centered Dialysis Care

In recent years, high-efficient therapy such as high-volume online HDF has been performed worldwide to improve the survival of dialysis patients. In most papers, a high substitution volume greater than 20 L/session in the post-dilution mode is desirable to get a better outcome, but the mechanism of the better outcome and the meaning of larger substitution volume have been still unclear. Most online HDF has been performed in the pre-dilution mode in Japan, and the average substitution volume is around 40 L/session. Kikuchi et al. [42] reported that the Japanese style of online HDF had a better survival rate than high-flux HD and online HDF with less convection volume. As previously addressed, in Japan, the clinical effects of the online HDF are evaluated by the removal rates of middle molecules and the PROs [14, 16]. Online HDF is one of the most effective modalities to ameliorate PROs. However, online HDF cannot always ameliorate all PROs from dialysis patients. As mentioned earlier, as we change dialysis prescriptions by trial and error while addressing the PROs [13, 14], the final distribution of online HDF and each membrane material suggests the “preferred prescription” in patient-centered dialysis care. Our facility provides online HDF to 55% of dialysis patients and HD to 45% as shown in Figure 4, and PMMA is the most used membrane material for HD patients at 35% as shown in Figure 5. Recently, Maduell et al. [43] reported that NF could be used for post-dilution online HDF and its solute removal property was with good efficiency and complete safety. However, in Japan hemodialyzers are permitted only for HD therapy, and online HDF should be performed with a hemodiafilter [14]. PMMA had been used only for hemodialyzers, but TORAY launched a PMMA hemodiafilter that was composed with NF-type PMMA in 2021. In a few years, we could know new possibilities of online HDF with PMMA hemodiafilter.

Fig. 4.

Distribution of online HDF by age. The distributions of hemodialysis and online HDF were calculated from 660 patients in 4 dialysis centers in the Seiei Medical Group as of December 2021. HD, hemodialysis; HDF, (online) hemodiafiltration.

Fig. 5.

Distribution of membrane material by dialysis mode. The center panel shows the distribution of hemodialysis, predilution online hemodiafiltration and post-dilution online HDF on 660 patients in 4 dialysis centers in the Seiei Medical Group as of December 2021. The distributions of each membrane material are sown in the left panel (HDF) and in the right panel (hemodialysis). ATA, asymmetric cellulose triacetate; HD, hemodialysis; HDF, (online) hemodiafiltration; PAN, polyacrylonitrile; PEPA, polyether polymer alloy; PES, polyether sulfone; PMMA, polymethyl methacrylate; PS, polysulfone.

Conclusion

With the aging of the dialysis population in many countries, the goal of chronic dialysis therapy is shifting from prolonging life to achieving the PROs for each patient. In patient-centered dialysis care, it is imperative to set appropriate outcomes for each patient, as the primary outcome is different for each patient. It is also important to know that changing dialysis prescriptions can improve some of the patients' symptoms. Nutritional status and physical fitness are fundamental factors in achieving the outcomes, and “fatigue” is the most reliable clinical parameter to support these factors and assess the effectiveness of interventions. The dialysis method and dialysis membrane should be selected based on the patient's fatigue level, and PMMA is one of the effective options to achieve this outcome and patient-centered dialysis care.

Conflict of Interest Statement

Ikuto Masakane is the director of Yabuki Hospital. He received a lecture fee from Toray Medical, NIPRO, Nikkiso, Baxter, Medtronic, Terumo, Kyowa-Kirin, Chugai Pharma., Torii Pharma., Kissei Pharma., Novel Pharma, Fuso Pharma., Astra Zeneca, TAKEDA Pharma., Ono Pharma., Astellas Pharma., Tanabe-Mitsubishi Pharma., JCR Pharma., Novartis Japan, MSD, and Dainihon-Sumitomo Pharma. Minoru Ito is the vice director of Yabuki Hospital. He received a lecture fee from Baxter, Kyowa-Kirin, Kissei Pharma., Tanabe-Mitsubishi Pharma., Ono Pharma., Astellas Pharma., Fuso Pharma., Chugai Pharma., Dainihon-Sumitomo Pharma., Otsuka Pharma., Bayer Pharma., and Eli Lilly Japan. Hideki Tanida is the director of the dialysis center of Yabuki Hospital. He has no conflict of interest to declare. Takaaki Nawano is a nephrologist in the 1st Department of Internal Medicine, Yamagata University Hospital. He has no conflict of interest to declare.

Funding Sources

We have no funding.

Author Contributions

Ikuto Masakane organized the concept of “POD” and published several studies about the patient-centered dialysis care, which is included in the paper. He composed most of the paper body and related documents. Minoru Ito analyzed the relationship between symptom burdens and survival of dialysis patients. He checked the contents and conclusion of the paper and has approved them. Hideki Tanida had the responsibility for Ai-POD survey and MIS survey in the dialysis center. He checked the contents and conclusion of the paper and has approved them. Takaaki Nawano performed a structural analysis of the dialysis-related fatigue and recovery time. He checked the contents and conclusion of the paper and has approved them.

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Funding Statement

We have no funding.