**3. Extracorporeal dialysis therapy**

figures showing 50% survival at 5.8 years in the 55–64 years group [4], it is not hard to see why this comparison is made. Clearly, one of the key challenges for the nephrology community is to change this unacceptably high mortality rate. In addition to this, there are many other factors that make a large difference to the patient in front of us, and arguably, these are as impor‐

The aim of haemodialysis is to replicate normal physiology as much as possible. Although this may sound straightforward initially, there are a vast array of factors to consider. The ideal treatment should give good survival rates, prevent cardiovascular events and hospitalizations, effectively manage fluid and salt balance and address the anaemia and mineral‐bone disorder associated with chronic kidney disease (CKD). Patient well‐being, cognition, sleep, the ability to work and nutritional status are also hugely important factors which need addressing and the list could continue. For a treatment, which for the majority of patients is performed for 12 hours of the week (just 7% of the week in terms of time), this is an incredibly tall order and it

Conventional haemodialysis (CHD) is the most common treatment schedule and lasts for 3–4 hours thrice weekly. This treatment mainly takes place in a hospital or in a dedicated dialysis unit. Other treatment regimes include short daily haemodialysis (SDHD), which is performed for 1.5–3 hours 5–7 times per week, long nocturnal daily haemodialysis (LNDHD) which is performed for 6–8 hours 5–7 times per week and long conventional haemodialysis (LHD),

Although CHD is the most common treatment regime now, LHD was the most common treatment initially in the 1960s [5]. This treatment came about purely by convention. Home haemodialysis in the United Kingdom was started in London in 1964 by Shaldon and his team [6] and expanded following this. Home haemodialysis was necessary as hospital facilities were sparse, treatment times were lengthy and home dialysis offered both financial and logistical benefit. Prevalence in the United Kingdom peaked in 1982 when 62% of HD patients were at home [3]. As dialysis treatment time shortened and patient numbers increased, haemodialysis practice changed from a predominantly home‐based therapy to a predominantly hospital‐

The National Cooperative Dialysis Study (NCDS) (*n* = 151) [7] was published in 1981. It showed no difference between the shorter and longer duration dialysis groups (2.5–3.5 hours three times per week vs. 4.5–5 hours three times per week). This further paved the way to the adoption of CHD. Data from this study were later used to develop a method for calculating

at small molecule clearance as a marker of dialysis adequacy. There is an association between dialysis dose and mortality [9]; however, the benefit (from the NCDS data) was seen up until

/*V* of 1.2 with no survival advantage with doses above this. This was later echoed in the much larger HEMO study (involving 1846 patients) and again showed no advantage in

/*V*) which is now used worldwide. *K*<sup>t</sup>

/*V* exclusively looks

/*V*urea (*K*<sup>t</sup>

tant to address and considerably improve.

is not entirely surprising that outcomes remain poor.

which is typically 8 hours 3 times per week.

**2. Background**

102 Advances in Hemodiafiltration

based therapy.

a *K*<sup>t</sup>

haemodialysis adequacy [8] *K*<sup>t</sup>

The basic principle behind dialysis is the removal of solutes across a semipermeable mem‐ brane. Haemodialysis relies on the process of diffusion where solutes move from an area of high concentration to an area of low concentration. Solutes pass from the patients' blood to the dialysis fluid across the dialysis membrane in this manner. The concentration gradient is maintained by the countercurrent flow of dialysate and blood and the maintenance of adequate blood and dialysate flow.

Haemofiltration allows the clearance of larger molecules through the process of convection. A hydrostatic pressure gradient is used to pass the patient's blood across a membrane with a large pore size. Solutes follow water through a process called "solvent drag" [12]. Large volumes of fluid are typically filtered and a replacement fluid is required, which enters the dialysis circuit and is mixed with the patient's blood before it is returned.

Haemodiafiltration (HDF) combines the techniques of both haemodialysis and haemofiltra‐ tion. Solutes are cleared by both diffusion and convection, thus allowing more efficient clearance of both small and middle molecules. The replacement fluid can either be obtained from pre‐prepared bags or prepared "online" by the machine (OL‐HDF), which is able to produce ultrapure fluid. This dialysis therapy has a number of potential advantages, which are discussed in more detail later in this chapter.

#### **3.1. Clearance in extracorporeal dialysis**

*K*t /*V* is widely used to give us information on dialysis adequacy; however, it is solely dependent on the clearance of urea. Urea has the advantage of being easy to measure; however, it may not be directly toxic and many of the identified uraemic toxins are larger in size and are not cleared efficiently by conventional haemodialysis [13]. In general, molecules are classified as small molecular weight (MW) molecules (<500 Da), middle MW molecules (>500 Da) and 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 of B2M which can lead to dialysis‐related amyloidosis [15].

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 to the patient.

#### **3.2. Biocompatibilty in dialysis**

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 considerably.

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, haemoglobin and ferritin [29].
