The quest to find the best form of kidney dialysis

Celestina Manzoni, Andrea Cavalli, 
Monica Limardo, 
Sara Viganò and Francesco Locatelli

Department of Nephrology, Dialysis and Renal Transplant, 
Alessandro Manzoni Hospital, Lecco, Italy

Uremia is a pathological condition caused by the retention of toxins that are normally excreted by the kidneys. The aim of hemodialysis (HD), besides to correct hydrosodic retention and electrolytic and acid-base disequilibrium, is to remove these toxins. Urea, a small molecule, is assumed as a marker for these toxins and the kinetic modelling of urea is universally accepted as the best way to prescribe and verify the delivered dialytic therapy.

Despite the fact that dialysis therapy is undoubtedly essential to save the lives of millions of people and while enormous technological progresses have been achieved during the last years, standard low-flux HD still seems very limited in effect, since morbidity and mortality of dialysis patients remain extremely high compared with non-HD subjects with similar demographics, and is estimated between 14 and 26% per year in Europe and at 24% in USA.1 It must be considered that nowadays there are no greater numbers of selection criteria for patients to be admitted for the treatment, so that more and more old patients with severe co-morbidities are starting HD.

Advent of high-flux hemodialysis
However, the main raison for the high morbidity and mortality of hemodialysis patients is generally attributed to the inadequate removal of so-called ‘middle molecules’ (MM). This hypothesis lead to the introduction, more than 20 years ago, of an alternative dialysis method to standard HD called high-flux HD.2

High-flux HD characteristic is in the use of membranes of high permeability that increase the in vitro clearance of vitamin B12 (molecular weight 1,355 Daltons, considered a marker of middle molecules). Moreover, they remove solutes of higher molecular weight as the beta2-microglobulin (11.8 KDa).

Another important characteristic of high-flux membranes is the high biocompatibility. During conventional HD with ‘bioincompatible’ membranes, several cellular mechanisms and biological systems are activated. This reaction, secondary to interactions between the blood and the ‘foreign’ artificial material of the hemodialysis system, can be defined as an ‘inflammatory response.’ From the clinical point of view, chronic inflammation is a common feature among dialysis patients. Furthermore, a strong relation between malnutrition, chronic inflammation, and atherosclerosis (MIA syndrome) has been documented in this population.

Therefore, theoretical advantages of high-flux HD are both related to the higher toxins removal and to the better biocompatibility of 
the treatment.

A confirmation of the importance of MM in uremic toxicity is in the results of a large retrospective study performed by Leypoldt et al on a data subset from the United States Renal Data System showing a clear correlation between the death rate and the in vitro B12 dialyzer clearance.3

The HEMO and MPO studies
With the introduction of high-flux HD, many observational studies have shown that high-flux treatments were associated with positive effects on the morbidity and survival of dialysis patients. However, the results of the HEMO study4 – a prospective, randomised study aimed at verifying the advantages of high-flux HD over low-flux HD – were very surprising and in some way disappointing, insofar as they showed, at primary analysis, that high-flux HD was associated with a non-significant reduction of mortality of 8%, although secondary analyses pointed to an advantage for high-flux HD in subgroups of patients.5

During the course of the HEMO study, the impact of high-flux HD on mortality was addressed in another prospective, randomised study, the MPO study.6 This was specifically designed to include a sicker patient population that could possibly take more advantage from high-flux HD, in order to provide sufficient statistical power to possibly demonstrate differences in patient survival. Serum albumin equal or less than 4g/dl was considered an indicator for increased morbidity and mortality risk.

Besides, whereas the HEMO study included incident and prevalent patients, who were on dialysis an average of 3.7 years and 60% of them were treated with high-flux HD before entry in the study, the MPO study enrolled only incident patients, to avoid early mortality bias (so-called selection of survivors) and a carry-over effect of the previous treatment to the actual intervention phase. Moreover, the reuse of the dialyzer was not allowed. Seven hundred and thirty-eight patients were enrolled in 59 European centres and randomised to two parallel groups, according to the high or low-flux, and have been observed for 3–7.5 years.

No significant effect of membrane permeability on survival was found in the population as a whole. However, high-flux HD showed a significant survival benefit in patients at risk for worse outcome, defined by serum albumin < 4g/dl. The relative risk reduction of mortality in this patient population, after adjustment for confounding factors, was 37%.

Significant survival benefit
Moreover, a secondary analyses of the HEMO study, namely of patients who were on renal replacement therapy for more than 3.7 years, showed a significant survival benefit in the high-flux group with a reduction of the relative mortality risk by 32%.5 In a secondary analysis of the MPO study, it was found a higher survival rate in diabetic population as a whole treated with high-flux compared with low-flux dialysis, with an adjusted relative risk reduction of 38%.

The general applicability of the MPO study results found in patients with relatively low albumin plasma levels and diabetic patients should be seen against the background of an increasing proportion of dialysis patients with inflammation and/or malnutrition and of diabetic nephropathy as primary renal disease or diabetes as comorbidity.

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Serum albumin is a strong predictor of mortality7 and related to nutritional and inflammatory status. Epidemiologic studies have confirmed that low serum albumin levels are frequent in HD patients. Owen et al8 reported 60% of the patients with serum albumin less than 4.0g/dl, which is similar to the more recent figures from the DOPPS study, with 57 to 86% of the patients with serum albumin below this level.9 Thus the potential general applicability of the MPO results is impressive.

The causal relation between treatment with high-flux HD and survival could lie in the eliminative capacity of high-flux membranes. As shown previously and also in the MPO study, high-flux membranes have a significant removal capacity for beta2-microglobulin and positively affect serum levels in the long term, which in turn are related to mortality.10

Guideline recommendations
The current European Best Practice Guidelines (EBPG) on dialysis strategies, published in 2007, contain the following recommendation: Guideline 2.1: “The use of synthetic high-flux membranes should be considered to delay long-term complications of hemodialysis therapy.” Specific indications include: to reduce dialysis-related amyloidosis (evidence level III); to improve control of hyperphosphataemia (level II); to reduce the increased cardiovascular risk (level II); to improve control of anaemia (level III).11

The European Renal Best Practice (ERBP) Advisory Board, in the light of the MPO results, published a position statement to change existing guideline 2.1. The board considers that the MPO study provides sufficient evidence to upgrade the strength of the guidance to a level 1A (strong recommendation, based on high-quality evidence) that high-flux HD should be used in the case of high-risk patients (comparable to the low-albumin group of the MPO study). Because the substantial improvement in an intermediate marker (beta2-microglobulin) in the high-flux group of the MPO study, the ERBP Advisory Board considers that synthetic high-flux membranes should be recommended even in low-risk patients.12

A further improvement in convective treatments is represented by the online treatments. Online preparation from fresh dialysate by a cold-sterilising filtration process is a cost-effective method of providing large volumes of infusion solution. By making fluid volume no longer a limiting factor, it allows to perform blood-cleansing techniques characterised by the removal of solutes by high convective transfer: hemofiltration (HF) and hemodiafiltration (HDF).
Some data from clinical studies suggest that HDF could give clinical advantages compared to HD by correcting several factors possibly related to the high mortality rate of HD patients. These advantages include:

• Better control of hyperphosphatemia
• 
Better correction of anemia with lower 
dosages of erythropoietin,
• 
More effective removal of advanced 
glycation end products (AGEs)
• Less cardiovascular instability
• Lower levels of beta2-microglobulin.

It is matter of fact that survival, together with quality of life, are the most important outcomes.

The DOPPS study
In 2006, characteristics and outcomes of patients receiving HDF versus HD in five European countries in the Dialysis Outcomes and Practice Patterns Study13 were published. The study analysed 2,165 patients from 1998 to 2001, stratified into four groups: low- and high-flux HD (respectively 63.1% and 25.2% of all patients), and low- and high-efficiency HDF (respectively 7.2% and 4.5% of all patients).

High-efficiency HDF patients were associated with a significant 35% lower mortality relative risk (RR= 0.65 P= 0.01) than those receiving low-flux HD, while patients receiving low-efficiency HDF were associated with a non-significant 7% lower mortality relative risk (RR= 0.93 P= 0.68) compared to those receiving low-flux HD. It must be observed, however, that the number of patients treated by HDF was quite small and so there is the risk of statistic fluctuation.

Lack of gold-standard trials
While these results are apparently very impressive, they show only an association and not a demonstration. A selection bias by indication could not be ruled out. As the authors themselves acknowledged, the benefits of HDF must be tested by randomised controlled clinical trials before recommendations can be made for clinical practice.

That is particularly true, when considering the discrepancies between the results of observational studies and the randomised controlled trials. As yet, since the number of randomised prospective trials comparing HDF with standard HD is very limited, no conclusive data is available on the effect of HDF on survival and morbidity in HD patients. Further studies are exploring the potential beneficial effect of convection.

The Italian prospective multicentre study14 compared on-line convective treatments (HF and HDF) with standard low-flux HD, assuming as primary end point cardiovascular stability and blood pressure control and as secondary aims the impact on symptoms, morbidity and mortality. The results show that, compared with conventional HD, convective therapies (HDF and HF) reduce intradialytic symptomatic hypotension in long-term dialysis patients.15

The Convective Transport Study (CONTRAST) was initiated in the second quarter of 2004.16 This is a prospective randomised international study conducted in more than 25 centres (mainly in the Netherlands, also in Norway and Canada) and approximately 800 incident and prevalent HD patients are randomised to either low-flux HD or on-line HDF and will be followed for three years to investigate the effect of increased convective transport by online HDF on all-cause mortality and cardiovascular morbidity and mortality in chronic HD patients. Unfortunately, this study is not comparing high-flux HD with online HDF, thus leaving still open the key question whether online HDF is superior using hard outcomes (such as survival) in comparison with high-flux HD.

At present, considering the results of HEMO and of MPO and Italian studies,15 there are strong evidence-based data favouring high-flux treatments, and suggestions supporting online HDF including the use of ultrapure dialysate. 
A large randomised controlled study is needed 
to definitively prove the clinical advantages of 
on-line HDF on uremic patients.

References

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