Background
A background summary of end-stage kidney disease, dialysis treatment and a review of latest research that has compared haemodialysis and haemodiafiltration.
End-stage kidney disease
End stage kidney disease (ESKD) is among the most severe chronic, non-communicable diseases. The annual mortality rate in Europe is between 10-20% of ESKD patients treated with dialysis. This has only decreased slightly over the last 30 years despite multiple interventions. There is a clear need to assess the benefits and harms of novel interventions.
Statistics
At the end of 2013, there were around 3.2 million patients worldwide being treated for ESKD. In recent years, this number has grown c. 6% each year, which is significantly higher than the population growth rate. Of those 3.2 million patients, around 2.25 million were undergoing kidney replacement therapy in the form of dialysis.
On 31 December 2014, in Europe, 490,743 patients were on kidney replacement therapy based on collective information of national registries representing 531,690,000 population.
Kidney replacement therapy
Kidney replacement therapy, including transplantation and dialysis, is necessary for ESKD patients with kidney function below roughly 10% of the normal value. Kidney replacement therapy can be done by transplantation or dialysis, including peritoneal dialysis, low-flux and high-flux haemodialysis (HD) and haemodiafiltration (HDF).
Limited number of patients
Although kidney transplantation is the best option, this is only available to a limited number of patients. Presently, peritoneal dialysis (PD) is utilised by a minority of patients in Europe and North America. Major drawbacks to this are the loss of efficacy and peritonitis. In Europe, 30-40% of PD patients transfer to haemodialysis annually.
Most patients who cannot (yet) have kidney transplantation are therefore treated by intermittent HD. Standard treatment schedules include three 4-hour sessions per week in a dialysis centre. During HD, excess waste products of body metabolism and excess fluid are removed. Without treatment, patients will become symptomatic and ultimately die.
Despite this treatment, ESKD is associated with high risks for fatal and non-fatal cardiovascular disease and infections, as well as poor quality of life. Because of the intensive impact of treatment, this is a great burden to the patient and to society.
Patient quality of life
Despite improvements in dialysis machine and dialyzer technology, and the introduction of newer drugs, the survival of patients with kidney failure treated by dialysis remains high. Survival has not improved as much compared to other chronic conditions, including some common cancers. Many kidney dialysis patients feel tired and lack energy, which impacts on quality of life. Rates of self-reported depression are increased in kidney dialysis patients.
Dialysis
Over the past decade, an alternative to standard haemodialysis (HD) has become available ‒ haemodiafiltration (HDF). In HDF, the machine takes more fluid away from the blood as it passes through the dialyser, replacing it with dialysis water.
Comparing HD and HDF
HD removes water soluble toxic compounds that accumulate in patients with kidney failure mainly by diffusion, and a smaller amount by convection. HDF differs by increasing the amount removed by convection. Diffusion is very efficient at removing small molecules, but not so good at removing larger molecules, whereas convection is more efficient at removing larger molecules.
Although HDF improves the range of water-soluble toxic compounds removed, unlike the healthy kidney, neither HD nor HDF can offer selective removal of molecules, so both treatments can potentially lead to the loss of important molecules, such as vitamins and some proteins.
Although HDF increases the range of water-soluble toxic compounds removed, it could also lead to an increased loss of important molecules.
What studies say
Several studies have compared haemodialysis and haemodiafiltration, but many have been too small to reach any firm conclusion whether these are equivalent treatments or if either is better. Attempts to combine these studies to get enough patients for a comparison have still failed to demonstrate a difference. Equally, the studies included often differ, making comparisons difficult. Therefore, we are lacking certainty as to whether HDF offers any benefit over standard HD, or whether the treatments are equivalent, or which is better for patients.
Cochrane review
A recent Cochrane review and meta-analysis examining any form of convective therapy vs. standard HD found no convincing benefit for HDF. This confirms several, but not all, previous meta-analyses.
A specific feature of earlier meta-analyses is that any form of convective therapy (i.e. HDF or haemofiltration) was analysed, including historic studies of patients treated with low-volume convective exchanges using sterile bags.
By contrast, a more recent individual patient-level data meta-analysis of the four recent European randomised controlled trials comprised 2,753 patients with a median follow up of 2.5 years, specifically focusing on dosage of HDF. This clearly suggests that when delivered in high dose, HDF is associated with beneficial effects on relevant clinical outcome variables.
These results indicate a potential beneficial effect of HDF compared to HD in this group in terms of a 22% reduction in all-cause mortality and 31% reduction in cardiovascular mortality.
What else is needed?
Definite proof as to whether HDF when delivered in high dose is a superior treatment is still needed. A recent large observational study supports the notion that increased clinical benefit is related with higher convective volumes.
The scientific community remains critical, largely due to results that the beneficial effects might be explained by patient selection (i.e. a healthier patient receives more convection volume). Furthermore, the mechanism(s) of a possible beneficial effect is/are unproven. This also reduces the acceptance of the idea of superiority of HDF.
The current uncertainty regarding the optimal dialysis strategy for patients with ESKD in Europe results in a heterogeneous delivery of care, not driven by the best evidence base but by local physician and/or centre preference.
Convective modalities such as HDF are accepted by regulatory authorities and can be performed in the same settings and logistical framework under country specific rules. Costs differences between the two therapies may be absent or limited, although differences do exist between HDF systems, as well as between countries and deals between dialysis centres and suppliers of medical equipment.
Recent work by this consortium indicates that high dose HDF can be readily achieved in most end stage kidney disease patients, although dialysis staff may need some initial training to become aware of the specific requirements to achieve high dose HDF.
Ultimately, the combination of clinical uncertainty, heterogeneity in clinical practice between centres (physicians) and countries, the sometimes slightly higher costs and the little extra attention needed by the staff has resulted in HD being the current therapy of choice for the majority (approximately 80%) of patients in Europe. A study that could confirm proof of superiority of one treatment modality would establish treatment patterns over future decades.
However, three of these four studies were not designed to investigate the effect of the mount of convective exchange, which may have introduced some confounding as to the amount of convective exchange delivered to patients.
