**4. Increasing haemodialysis frequency and length with home haemodialysis**

protein‐bound molecules. β2‐microglobulin (B2M), which is commonly used as a marker of middle molecules, has a molecular weight of around 11,800 Da. It has been demonstrated that outcomes are improved when middle molecular clearance (1000–50,000 Da in the study) are enhanced [14]. There has been much interest in increasing middle MW molecule clearance, and it is clear that accumulation of middle MW molecules can be harmful such as in the case

β‐Trace protein, cystatin‐C and B2M are all middle MW molecules that are freely filtered, resorbed and catabolized in the tubular cells. A study by Lindström et al. [16] has shown clear differences in the clearance of these molecules by different dialysis modalities—CHD did not change the concentrations of any of these proteins while in HDF both cystatin C and B2M were reduced and β‐trace protein was only reduced in HDF. This demonstrates a clear difference between dialysis modalities in terms of clearance and a clear biomarker that could be meas‐ ured. Moreover, β‐trace protein had been found to be an independent predictor of both death and cardiovascular mortality in haemodialysis patients [17]. The use of such molecules could be part of the way that we assess haemodialysis adequacy in the future and tailor treatment

The specifications of dialysis membranes have improved considerably. The use of cellulose‐ based membranes were common initially; however, they were associated with complement and leucocyte activation [18] resulting in dialyser reactions. The majority of dialysis mem‐ branes in use now are synthetic and are more biocompatible—reactions can still occur however and anaphylactoid reactions have been reported, particularly in patients on ACE inhibitors [19]. More recently, dialysis membranes have been manufactured with larger pore sizes to allow a higher ultrafiltration rate and allow clearance of larger molecules. Membranes can be classified as high flux or low flux and for the purposes of the HEMO study [20] were defined as B2M clearances of <10 ml/min for low flux and >20 ml/min for high flux. High‐flux mem‐ branes have been found to lower pre‐dialysis B2M concentrations [21] and may prevent dialysis‐related amyloidosis [22]. Several observational studies have identified a survival benefit with high‐flux dialysers [23, 24]. Although the HEMO study showed no benefit from high‐flux membranes, the study may not have been sufficiently powered to detect a significant benefit [25]. The subsequent European study, the MPO Study [26], showed survival benefit to those patients with a serum albumin of <40 g/l. Several guidelines now recommend high‐flux dialysers including the European Renal Association [27] and practice has also changed

The production of a high‐quality infusion fluid is of paramount importance in HDF. More than 20 litres of infusion fluid can be administered to the patient during a typical HDF session and thus ultrapure water and dialysis fluid are required. Ultrapure water is defined by the standard for replacement fluid requiring <0.1 colony‐forming units (CFU)/ml and an endotoxin concentration <0.03 endotoxin unit (EU)/ml [28]. The use of ultrapure dialysis fluid is associ‐ ated with a reduction in inflammatory markers and an improvement in serum albumin,

of B2M which can lead to dialysis‐related amyloidosis [15].

to the patient.

104 Advances in Hemodiafiltration

considerably.

haemoglobin and ferritin [29].

**3.2. Biocompatibilty in dialysis**

The seminal paper in 1992 by Bernard Charra and his group in Tassin, France, showed hugely impressive survival rates of their haemodialysis patients of 87% at 5 years and 43% at 20 years, which far surpassed matched patients on both European and US registries. All patients received 8 hours of haemodialysis three times per week (LHD). It is likely that the survival association is related to achieving good blood pressure control (antihypertensives were seldom required in the group) through optimized ultrafiltration and the enhanced clearance of uraemic toxins provided by the longer treatment. Their publication sparked interest once again in extended haemodialysis. With the continued increasing demand for renal replacement therapy and limited resources in hospitals, novel ways of providing haemodialysis were required. Home haemodialysis seemed an attractive option and could also accommodate more frequent and extended schedules. The first daily nocturnal haemodialysis programme was set up in Toronto in 1994 [30].

The prescription of home haemodialysis in the United Kingdom remains very variable; however, the most common prescription in 2009 was still 4 hours thrice weekly (51.9% of home HD patients), followed by alternate day dialysis (20.5%), short daily (17.4%) and nocturnal (2.9%) [31]. This is a surprising finding given the benefits of more frequent and extended haemodialysis (which we will now expand on). This does however reflect patient choice and the comfort of both patients and clinicians with a CHD schedule.

#### **4.1. The benefits of extended and more frequent haemodialysis**

Several benefits have come to light from more frequent and extended haemodialysis and these will be outlined in this section.

### *4.1.1. Survival, cardiovascular outcomes and hospitalizations*

Observational studies show a significant mortality benefit associated with home haemodial‐ ysis, even when adjustments are made for age and comorbidity [32]. These findings are also apparent in studies in Australia and New Zealand [33], which have a higher uptake of home haemodialysis. Figures of 90% survival at 5 years and 45% at 20 years have been quoted [34]. **Figure 1** shows a clear survival advantage to home haemodialysis over both peritoneal dialysis and facility‐based HD. These data have to be interpreted with care given the high number of confounders. Patients selected for home haemodialysis are generally younger with a low comorbidity burden. They are usually highly motivated and take an interest in their healthcare.

The frequent haemodialysis network (FHN) trials were setup to give a more definitive answer to the benefits of more frequent and extended haemodialysis [35, 36]. The SDHD arm of the trial randomized 245 patients to either frequent (6 times per week) or conventional haemo‐ dialysis and the nocturnal arm randomized 87 patients to either CHD or LDNHD. Two coprimary composite endpoints were used—death or change in LV mass or death or change in physical‐health composite score. There was a favourable outcome with regard to both coprimary endpoints for the SDHD trial but not with the LNDHD trial. Looking purely at survival, there was no significant benefit from either trial. With a 12‐month follow‐up period and the numbers involved with the trials, they were not powered to detect an effect on mortality. The question therefore still remains unanswered as to whether more frequent and extended haemodialysis does have a favourable effect on survival.

**Figure 1.** The survival of home HD patients in New Zealand compared with facility HD and peritoneal dialysis (PD). Image adapted from Marshall et al. [35].

There is an associated reduction in cardiovascular‐related admissions in converting patients from CHD to LDNHD [37]. There are also fewer cardiovascular‐associated hospital admissions associated with SDHD compared with matched CHD; however, all‐cause hospitalizations remain unchanged [38]. The FHN studies once again showed no change in the rate of hospi‐ talizations.

#### *4.1.2. Ultrafiltration and blood pressure control*

There is a strong association between a high ultrafiltration rate (>10 ml/kg/hour) and mortality [39, 40]. Chronic fluid overload contributes to an increased LV mass and congestive cardiac failure [41] and this is likely to be highly significant in terms of cardiovascular morbidity and mortality. Increasing haemodialysis treatment time improves the tolerance of ultrafiltration [42, 43]. There are also many reports of improved blood pressure control both in LNHD and in SDH [44–46] and a regression of left ventricular hypertrophy [47]. It has also been shown that ejection fraction, in those with heart failure, can be improved through more frequent haemodialysis and ultrafiltration [48]. With CHD, it often the case that dry weight is not achieved. Patients that experience hypotension during haemodialysis often have their ultrafiltration stopped, receive saline infusions and thus never achieve their dry weight and in fact can exacerbate the situation further. Extended dialysis allows much lower ultrafiltration rates and thus less haemodynamic disturbance. It is likely the effect that extended dialysis has on blood pressure goes beyond the optimization of volume status. When compared to patients on CHD, some patients with a high extracellular volume (measured by bioimpedance) but on extended haemodialysis achieve normotension [49]. A theory put forward for this phenom‐ enon is that extended haemodialysis may lead to efficient removal of vasoactive factors that contribute to hypertension.

#### *4.1.3. Small molecule clearance*

coprimary endpoints for the SDHD trial but not with the LNDHD trial. Looking purely at survival, there was no significant benefit from either trial. With a 12‐month follow‐up period and the numbers involved with the trials, they were not powered to detect an effect on mortality. The question therefore still remains unanswered as to whether more frequent and

**Figure 1.** The survival of home HD patients in New Zealand compared with facility HD and peritoneal dialysis (PD).

There is an associated reduction in cardiovascular‐related admissions in converting patients from CHD to LDNHD [37]. There are also fewer cardiovascular‐associated hospital admissions associated with SDHD compared with matched CHD; however, all‐cause hospitalizations remain unchanged [38]. The FHN studies once again showed no change in the rate of hospi‐

There is a strong association between a high ultrafiltration rate (>10 ml/kg/hour) and mortality [39, 40]. Chronic fluid overload contributes to an increased LV mass and congestive cardiac failure [41] and this is likely to be highly significant in terms of cardiovascular morbidity and mortality. Increasing haemodialysis treatment time improves the tolerance of ultrafiltration [42, 43]. There are also many reports of improved blood pressure control both in LNHD and in SDH [44–46] and a regression of left ventricular hypertrophy [47]. It has also been shown that ejection fraction, in those with heart failure, can be improved through more frequent haemodialysis and ultrafiltration [48]. With CHD, it often the case that dry weight is not achieved. Patients that experience hypotension during haemodialysis often have their

extended haemodialysis does have a favourable effect on survival.

Image adapted from Marshall et al. [35].

106 Advances in Hemodiafiltration

*4.1.2. Ultrafiltration and blood pressure control*

talizations.

Increasing haemodialysis frequency provides more efficient clearance of small MW molecules. It provides a lower peak urea, lower mean urea and less fluctuation [50]. This provides a lower time‐averaged concentration (TAC). Looking purely at *K*<sup>t</sup> /*V* would, however, be misleading as this would remain the same despite the enhanced clearance.

#### *4.1.4. Phosphate balance*

There is a clear association between raised serum phosphate and adverse cardiovascular outcomes in patients with CKD [51, 52]. Conventional haemodialysis does provide sufficient phosphate removal for western diets, and as a result, there is a net phosphate gain [53]. As a result of this, multiple phosphate binder tablets are often required to reduce the absorption of phosphate from the gut. On average, haemodialysis patients have an average pill burden of 19 pills per day and many of these are phosphate binders [54]. A higher pill burden in this setting is associated with lower quality of life scores [54].

Phosphate removal on haemodialysis has been found to be time dependent [55] and thus is significantly enhanced in NHD. Phosphate removal is also increased by SDHD but not to the same extent as NHD [56]. In LNDHD, many patients will discontinue their phosphate binders [57] and some require supplementation that can be added to the dialysate [58].

#### *4.1.5. Anaemia*

Reports are mixed when it comes to more frequent haemodialysis and anaemia management. Reduced erythropoietin doses have been reported when patients switch to SDHD from CHD [59] and in NHD [60]. One of the theories put forward for this change is the control of inflam‐ mation and reduction in IL‐6 levels which improve erythropoietin responsiveness [61]. The exact effect that more frequent or extended dialysis has on anaemia, however, is still unclear. Again both FHN studies showed no effect on erythropoietin dose.

#### *4.1.6. Quality‐of‐life measures and carer burden*

Home haemodialysis allows patients the independence to fit their dialysis treatment around their lifestyles. One may expect this to bring significantly improvements to quality of life; however, this may be offset by the burden of having to perform the treatment so frequently, which can lead to burnout or the increased burden on carers. While there are many reports of improvements in quality‐of‐life measures from switching to NHD [62] or SDHD [63], some show only small improvements in kidney‐specific measure of quality of life [64], while others show no difference. Larger studies have shown a reduction in depressive symptoms related to increased dialysis frequency [65].

Data from the recent FHN daily trial showed a significant increase in quality‐of‐life score in the SDHD group [35] with no specific benefit from NHD over CHD at home. In the FHN NHD arm, however, both groups had an increase in their quality‐of‐life score showing the positive effect that the setting of the haemodialysis treatment has on this outcome [36] regardless of prescription. Perceived burden on unpaid carers is high among HD patients [66]; however, the FHN trials did not show a higher perceived burden with either SDHD or LDNHD [67].

The patient‐reported experience on both LDNHD and SDHD has been positive in terms of physical, psychological and lifestyle aspects [68]. There is also an associated faster recovery time with home haemodialysis [69]. Once again, it is fair to say once again that the jury is still with regard to whether these treatments truly impact on quality of life. In general, the effect seems to be positive with a paucity of data suggesting a negative impact.

#### *4.1.7. Pregnancy*

Intensive dialysis has been used very successfully in pregnancy. A case series from Canada [70] shows a markedly improved live birth rate and duration of pregnancy with a dose response between dialysis and pregnancy outcomes. Women who had >36 hours of dialysis per week had significantly improved live birth rates (85 vs. 45% in those who had <20 hours of dialysis per week), which again demonstrates and gives strength to high‐dose dialysis.

#### **4.2. Disadvantages of more frequent and home haemodialysis**

While there are many advantages of home haemodialysis, the treatment is not suitable for all patients and it is not a treatment without disadvantages. Although exceedingly rare, there is always the possibility that human error can occur resulting in significant blood loss through a variety of mechanisms. There are reports of patient deaths from exsanguination while on home haemodialysis [71]. The sophistication of safety mechanisms is continually improving to make this event less likely with blood leak detectors, pressure monitoring and line discon‐ nect detectors featuring on newer machines.

A clear finding from the FHN trial was an increase in interventions needed for vascular access with 47% of the frequent dialysis group requiring intervention compared with 29% in the CHD group. Interventions to fistulas were required much more often than in catheters. This was not an entirely surprising finding given the considerably increased use of vascular access form more frequent haemodialysis. A solution to this could be the use of a buttonhole technique for fistula cannulation or using single‐needle haemodialysis to reduce the number of needling events. The evidence, however, is not there to support this practice and a systematic review of buttonhole cannulation in home haemodialysis patients found an increase in infectious events, an increase in staff support required and no reduction in surgical interventions compared with the "rope ladder" technique [72]. The FHN nocturnal trial used single‐needle haemodialysis, and despite this, there was still a trend towards increased vascular interventions in this group.

Finally, globally, the uptake of extended higher frequency haemodialysis remains low, despite a range of benefits and favourable health economics. There can be major patient and clinical factors driving modality uptake. A key determinant, however, is patient motivation and choice. Extended time or frequency on home HD may add to patient and carer burden and is therefore often perceived as a barrier limiting its uptake.
