Marco Formica MD
S.C. Nefrologia e Dialisi, Azienda Ospedaliera S. Croce e Carle, Cuneo, Italy
Since the start of regular dialysis treatment of terminal, irreversible renal failure in 1960 (1) many attempts have been made to improve a complex and heavy workload system designed to replace kidney function.
Initially efforts were addressed at changing the dialysis system with a recirculating tank into a single pass circuit, with the goal to improve dialysis efficiency by means of maintaining a relatively high concentration gradient available for diffusion, and to move from acetate to bicarbonate as a buffer in the dialysis fluid, in order to improve acid-base balance and hemodynamics.
So bicarbonate dialysis became the standard reference and in 1965 as many as 160 chronic uremic patients in Europe were on regular treatment in 40 centres (2).
Notwithstanding the pathogenesis of the uremic syndrome was still not clearly understood, although the concept that dialysis clears the blood of waste products provided the grounds for such chronic therapy.
In this contest, correlation of uremic symptoms to blood levels of multiple toxins with low molecular weight (mainly urea, widely distributed in total body water) have not been demonstrated and this led some researchers to hypothesize that larger molecules (with a molecular weight ranging from 500 to 2000 daltons: the so-called “middle molecules”) could be responsible for the uremic syndrome (3). In fact the cellulosic, low-flux, membranes used for blood purification in the 1970s were able to clear low molecular weight substances but, due to their small pores, to retain larger molecules which could account not only for symptoms but also for outcomes.
Larger solutes removal in conjunction with ultrafiltration, which would be defined as convective mass transfer taking place in a new technique called hemofiltration (4,5), was carried out as an alternative to diffusion to move away waste products from the bloodstream. In this setting, high hydraulic permeability synthetic membranes (allowing ultrafiltration rates as high as 120-150 ml/min) were employed, underlining the technological involvement of those years.
In 1978 (6) hemodiafiltration was proposed, which combined the advantages of diffusion (able to achieve a high clearance of low molecular weight substances) and convection (tied to a high volume, solvent-drag removal of middle molecules without hemodynamic impairment). From then on, this technique spread out in dialysis centres also if some concerns raised about the negative interferences of diffusion and convection applied at the same time.
In the following years other extracorporeal, mixed techniques have been proposed with some peculiar features.
The issue of the deleterious effects of acetate in the dialysate, mainly addressed to impair the contractile cardiac function and the systemic vascular resistances, beyond oxidative stress, was taken into consideration with the proposal of Acetate Free Biofiltration (AFB), where the plasma levels of acetate remain within the normal range by means of a buffer-free dialysate and a post-dilution reinfusion of a low-volume, bicarbonate-containing, substitution fluid (7).
Another blood purification approach was to split convection from diffusion by means of two different in series dialysers: the Paired Filtration Dialysis (so-called double-chamber system) (PFD), where the first filter was devoted to achieve convection and the following to diffusion, the reinfusion fluid being administered between. More recently this technique evolved towards HemodiaFiltration with on-line Reinfusion (HFR), where a sorbent cartridge is employed to regenerate the endogenous ultrafiltrate, in a closed loop circuit, in order to spare constitutional nutrients (aminoacids, vitamins, etc.) as well as to halt any possible contamination from the external environment (8). Beyond other scarcely used techniques, such as mixed-hemodiafiltration or push-pull hemodiafiltration, mid-dilution has been proposed (9) in order to overcome the limitations of the infusion sites, by means of a peculiar filter whose internal fibres are divided in two bundles, one devoted to post-dilution the other to process the blood in a pre-dilutional fashion.
More recently on-line techniques had been proposed with new dialysis monitors in the attempt to overcome the limitations of the amount of fluid available in a reliable setting of clinical safety (10). These procedures should then fully exploit the expected advantages of convective mechanism and improve patient well-being and survival (11).
As a matter of fact, considering the interplay between different transport mechanisms, it’s noteworthy that convection influences diffusion by reducing the regional blood flow, thus increasing viscosity and shear-rate, mostly in the distal part of the filter where the ultrafiltration rate approaches zero: this finding supports the need for adequate filter surface for diffusive performances in hemodiafiltration. At the same time diffusion affects convection by decreasing the concentration gradient and so the instant solute clearance; moreover in the proximal part of the dialyser, where the ultrafiltration rate is quite high, backdiffusion of buffers from the dialysate is hampered.
This means that high-flux membranes display a peculiar filtration-backfiltration profile, the water flux being null in both directions just in the middle side of the filter (12) due to the volume-control system of the available devices and the low mean transmembrane pressure usually required.
In mixed/convective techniques, the solute mass transfer may be influenced by the site of reinfusion that can take place in pre-dilution as well as in post-dilution. In fact, pre-dilution reduces the concentration-polarization phenomenon at the blood-membrane interface, the hemoconcentration, the viscosity and the shear-rate because there is a “relative” blood flow reduction, typical of convective exchanges. Still pre-dilution improves the filtration fraction, which is critical not only for solute removal but also for extracorporeal circuit patency and increases removal of protein-bound solutes, probably by shifting solutes to their unbound fraction. On the other hand, post-dilution works downstream of the convective exchange site, thus restoring physiological volumes. It allows better clearances with less volume of fluid to be exchanged, but requires high blood flows. Nevertheless it is associated with the need for high transmembrane pressure with albumin leakage and failure of constant ultrafiltration, due to thickening of secondary membrane layer on the blood side, with fibres clotting.
While low-flux membranes exploit diffusion as a solute transport mechanism and have limited solute sieving properties, for high-flux dialysers (characterized by high permeability to water and solutes with a molecular weight up to 12000 daltons), convection represents the main physical force, additional to diffusion which is poor due to the predominant hydrophobic nature of the polymers.
Of course differences in convective solute transport are obtained, for example, in high-flux dialysis, where just internal filtration occurs, as compared to hemodiafiltration, where higher rates of fluid exchange are applied and clearances of middle molecules, such as â2-microglobulin, are about 4-fold higher than in the former treatment (13).
Some observational studies reported an improved survival in patients using high-flux membranes, compared to low-flux (14-16), supporting beneficial effects that have still to be confirmed in larger, prospective, randomized trials.
It has to be considered that effects of flux may also be jeopardized by residual renal function, still present in some patients at the beginning of dialysis treatment.
Convective treatments (such as high-flux hemodialysis, hemofiltration and hemodiafiltration) had been demonstrated to offer some clinical advantages in terms of physiological outcomes in epidemiological studies (17-20), but they are still not convincing in improving major end-points, such as morbidity and mortality, in comparison with standard hemodialysis. Furthermore, it is very difficult to split the effect of convection per se to those peculiar to membrane biocompatibility, since convective treatments are performed mainly with synthetic, biocompatible membranes that are able to hamper the inflammatory response triggered by the contact between blood and artificial surfaces.
Indeed another issue that contributes to this very complex scenario is the availability of ultrapure dialysate which, in turn, may mask some of the advantages attributed to convection, reducing the inflammatory stimuli coming from the dialysate in conventional dialysis (21).
Lastly, the delivered dialysis dose may also affect the outcome, when the matched treatments are not comparable for this parameter (22).
Convective therapies also show some drawbacks, such as protein loss or energy balance impairment, that have to be kept into account.
Concerning the former, it has been demonstrated that albumin loss, negligible in four hour low-flux and high-flux hemodialysis, during on-line hemodiafiltration with “conventional” high-permeability membranes ranges from 1 to 3 gr per session (23). This loss may be huge when using protein-leaking membranes, accounting for up to 8 gr albumin loss in pre-dilution and 25 gr in post-dilution hemodiafiltration (24). In any case, however, the maximum level of albumin loss that could be tolerated has yet to be established, also referring to the patients’ nutritional state and to the possibility to increase their rate of albumin synthesis.
Temperature may also influence the clinical responses in conventional hemodialysis and convective or mixed techniques. In fact, hemodynamic behaviours during extracorporeal treatments are also related to different losses of thermal energy. In on-line, post-dilutional hemodiafiltration the rate of hypotensive episodes, which are lower with respect to conventional hemodialysis, are quoted at the same rate when an isothermic dialysis is run (25). The increase in body temperature detected during dialysis may be explained by peripheral vasoconstriction that takes place in response to ultrafiltration (26); this phenomenon is more likely to occur in pre-dilutional than in post-dilutional on-line techniques, due to different heat gain according to the volume of reinfusion fluids employed.
In order to address the relationships among these factors and their impact on patient survival and morbidities, two large studies have been planned in the mid-late 90s: the HEMO (Hemodialysis) (27) and the MPO (Membrane Permeability Outcome) (28), the results of the latter, referred only to incident patients with no dialyser reuse, being still awaited.
The HEMO study was designed to evaluate patient outcome in relation to two different dialysis doses (eKT/V of 1.05 or 1.45) and two different levels of convection (low or high-permeability, according to â2-microglobulin clearance and with an ultrafiltration coefficient above 14 ml/h/mmHg).
High dose and high-flux dialysis showed only little (respectively 4% and 8%), not statistically significant, advantages, although in patients with more than 3.7 years of vintage the relative risk of death was reduced by 32% in the high-flux group (p=0.005), and by 19% in the global group of women treated with high doses (p=0.01).
Beyond these crude data, however it is important to underline the positive trend of improving survival in high dose and high-flux dialysis, that, albeit not statistically significant in this study, might have a clinical relevance especially in patients undergoing long-term dialysis.
Other data coming from the DOPPS (Dialysis and Outcome Practice Pattern Study) study show that patients receiving hemodiafiltration had 23% higher survival than subjects on conventional hemodialysis (29), but when adjusted for KT/V the difference no longer exists, thus leading to the conclusion that hemodiafiltration affords a lower mortality rate due to delivery of a higher dialysis dose. Interestingly, different results have been pointed out by a large database network (30), where outcomes in on-line hemodiafiltration are better than in standard hemodialysis (Odds ratio 0.626; 95% C.I. 0.426-0.921; p=0.017) and are not influenced by variations in treatment adequacy.
It is acknowledged that patient’s age, coexisting diseases and nutritional status initially affects survival on dialysis, while treatment-related factors might play an important role in long-term survival (27,31).
But do we have evidence that convective or mixed treatments reduce short and long-term complications in hemodialysis patients ?
As far as cardiovascular stability is concerned, the absence of randomized studies does not allow us to draw any conclusions about acute intradialytic clinical symptoms, also if some interesting issues had been pointed out (32) regarding a possible, beneficial effect of increased convective clearances in improving blood pressure in hypotension-prone patients and stabilizing hypertensive subjects. These preliminary results need to be confirmed with a strict control of patients’ fluid state, accurate blood pressure monitoring and sodium balance in long-term evaluations.
Anemia is another field where different dialysis strategies may be challenged: recently, on-line techniques seem intriguing for their capacity to achieve higher hematocrit levels, with reduced use of rh-EPO (18), by means of two mechanisms: reduced microbiological and pyrogenic contamination of dialysate and more efficient removal of solutes in a large spectrum of molecular weights. But also in this setting, conflicting results are obtained (21) so it is still questionable if the advantages, where present, can be related to the technique, to different dialysis doses or to a reduced inflammatory trigger from standard dialysate.
Small improvements in nutritional state are reported during on-line hemofiltration, but the running mechanisms are further to be elucidated. They are referred as an increase in lean body mass along time, which could reflect an increase in cell body mass (33). Also in this case, the presence of ultra-pure dialysate might support an optional contribution of convection (34). To note that other authors were not previously able to find any correlation between convection and several variables related to the nutritional status (body weight, serum albumin and transferrin, subscapular and triceps skinfolds, mid-arm circumference, plasma cholesterol and triglycerides) (35).
Regarding the quality of life there is general agreement on possible advantages offered by convective techniques in terms of improved physical well-being (32,33). Still, in these studies, some methodological drawbacks need to be overcome with better designed clinical trials.
Referring to uremic toxicity profile, â2-microglobulin levels are reported to be lower in on-line hemofiltration/hemodiafiltration (33,36) with respect to low/high-flux hemodialysis, the reduction rate increasing from 58% to 73% due to the higher clearances. Of course these results, may, at least in part, be influenced by the quality of water in conventional/high-flux dialysis on the amount of â2-microglobulin production through the generation of inflammatory mediators triggered by endotoxins and pyrogens. These data are relevant from a clinical point of view: in fact, it has been reported that patients undergoing hemofiltration or hemodiafiltration have a risk for tunnel carpal syndrome that is 44% lower than those on standard dialysis (RR=0.56; 95% C.I. 0.34-0.92; p=0.02) (20). The relationship between the amount of substitution fluids and the risk of developing dialysis-related amyloidosis has been further confirmed by the Japanese Registry, where it was found to be progressively lower (the risk for conventional dialysis being equal to 1) for high-flux hemodialysis (RR=0.489), off-line hemodiafiltration (RR=0.117) and on-line hemodiafiltration (RR=0.013) (37).
Concerning homocysteine, which is a low-molecular weight substance, 80% protein bound, well-known risk factor for cardiovascular diseases, the differences among various extracorporeal techniques seem to be attributed to the removal of uremic toxins with inhibitory effects on enzymes involved in extrarenal homocysteine metabolism, more than on the pore size of the membrane or the quantity of exchanged fluids (38).
Worldwide, but obviously mainly in western countries, extracorporeal blood purification techniques for chronic renal failure patients are still expanding (an annual growth about 6% is reported) and emerging trends along time are representative of what is changing fuelled by practices, outcomes and technological improvements.
From data recently published (39) concerning an extensive international network gathering end stage renal disease (ESRD) patients from 122 countries, two main trends have been pointed out. The first is the tendency towards a wider use of synthetic (e.g. polysulphone, polyacrylonitrile, poliamide, polymethylmethacrylate, etc.) membranes (in 2004 up 16% in respect to 2003) and the second is the increased preference for high-flux dialyzers (up 14% in comparison to the previous year). But while in Europe there is a trend to use more synthetics membranes (83%) and a small percentage of high-flux dialysis (44%), in Japan there is the opposite behaviour, with a huge employment of high-flux (96%) and a lower consumption of synthetic dialyzers.
Both these features are relevant also for an increased prevalence of convective/mixed treatments (at year-end 2004, 10% in Europe and 5% in Japan), provided new monitors and related tools are available and reliable quality of water is achieved.
Unfortunately, at the moment no conclusion can be drawn about which is the best renal replacement therapy: in fact, relying upon effectiveness criteria provided by systematic reviews on randomized clinical trials, no significant differences in clinically important outcomes have been pointed out so far (40). Indeed new or renewed schedules, such as daily or nocturnal or long-lasting dialysis, have to be taken into account in order to define the reference “better dialysis” achievable today.
Moreover it can be further speculated that convection might offer over-protection on high-flux , beyond conventional diffusive techniques, regarding specific clinical pictures such as carpal tunnel syndrome (14,20); however, up to now, no clear evidence has been shown about the relationship between exchanged volumes and survival.
In conclusion there are intriguing and stimulating issues that drive our attention to move from renal replacement therapies based upon diffusive solute transport towards convective or mixed treatments that yield significant performances in terms of the removal of waste products in accordance with safe behaviour during dialysis (41), with the expectation to also improve long-term survival of ESRD patients.
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