Dialysis
a meta-analysis evaluating RCTs on all-cause mortality was published.77 Eighteen randomised trials were considered eligible for scrutiny, yielding a total of 588 patients: 326 HDF versus HD, 21 HDF versus acetate-free biofiltration (AFB) and 91 AFB versus HD. Unexpectedly, the highest mortality rate was observed in HDF patients. However, given the quality of and variability between the trials, the authors could not recommend the use of one modality over the other. Other concerns included the variability of the convection volumes applied,78,79 negative effects of dialysate contamination on outcome,79
potential short
duration of follow-up, relatively low mortality rates and the use of both biocompatible and bio-incompatible (cellulose) dialysers.80
After publication of this meta-analysis, several prospective
observational studies were published. The Dialysis Outcomes and Practice Patterns Study (DOPPS) database provided information on a large cohort of European patients (n=2,165) treated with different dialysis techniques.81
Ninety-seven patients were treated with high-
efficiency HDF, arbitrarily defined as ≥15 litres of substitution fluid per treatment. In this patient group, mortality risk was 35% lower than in patients treated with low-flux HD (1,366 patients). Similar findings were obtained from the EuCLiD database, encompassing 2,564 patients, of whom 394 were treated with HDF. Unfortunately, this study was only published as a letter, without crucial information on residual renal function, dilution mode and convection volumes.82 In the RISchio CArdiovascolare nei pazienti afferenti all Area Vasta In Dialisi (RISCAVID) cohort, 757 patients were followed for 30 months during treatment with either HD (n=424), HDF with sterile bags (n=204, substitution volume 10–15 litres/session) or ol-HDF (n=129, 22–25 litres/session).83
In this observational study, mortality in ol-HDF
patients was 22% lower than in the other groups. Finally, a 34% reduction of mortality risk was observed in 232 patients who were, over a period of 18 years, predominantly treated with HDF, compared with 626 patients predominantly treated with HD.84
Although observational studies often provide stimulating results, their design may suffer from biased allocation of therapy and hence almost certainly an influence of the factors determining therapy allocation on outcome (so-called confounding by indication). Obviously, the only way to omit confounding by indication is to perform well-designed RCTs with sufficient power to detect clinically relevant differences. So far, the only RCT published after the meta-analysis mentioned before was too small (64 patients) to detect significant differences in cardiovascular or all-cause mortality rates between low-flux HD and ol-HDF.85
Although mortality was 41% lower in HDF patients,
significance disappeared after correction for 23 patients who dropped out of the study during the three years of follow-up.86
Ongoing Studies
In the coming years, the results of several RCTs on the effect of ol-HDF on clinical end-points will become available. First, the results of two studies on the effect of HDF on haemodynamic stability are awaited. In a French RCT, 600 patients over 65 years of age have been randomised to ol-HDF or high-flux HD.87
In Italy, treatment with
convective therapies (pre-dilution HDF or HF) is being compared with low-flux HD in 250 chronic HD patients.88
Follow-up in both studies
is two years. As none of these studies seems adequately powered to detect an effect on survival, mortality is a secondary end-point.
Currently, three RCTs have been designed, and most likely are sufficiently powered to evaluate the effects of HDF on survival and
72
EUROPEAN NEPHROLOGY
Conclusions
Today, post-dilution ol-HDF is the most commonly used convective renal replacement therapy in clinical practice. Results from various studies indicate that ol-HDF is an efficient, safe and well-tolerated long-term treatment modality for patients with ESRD. Favourable effects of ol-HDF may result from enhanced convective transport of uraemic retention products. Furthermore, ol-HDF combines the potential benefits of high-flux synthetic membranes and a high quality of dialysis fluid purity, thereby improving the biocompatibility of the procedure. Finally, the thermal balance of ol-HDF may help prevent HD-induced hypotensive periods. As a result of these potential benefits, ol-HDF may reduce cardiovascular instability, attenuate the micro-inflammatory state that is frequently observed in HD patients and ameliorate quality of life, mineral metabolism, EPO sensitivity and survival in selected patient groups. On the other hand, increased platelet activation and coagulation may partly counteract these beneficial effects. Potential limitations of the reported evidence in this review are the small number of patients included in many of the studies cited, the absence of randomisation in various comparative studies, confounding by indication in observational studies, the lack of data on the purity of dialysis water in control groups and the absence of data on convective volumes. Therefore, results from prospective RCTs of sufficient power to detect significant differences in morbidity and mortality are mandatory. Currently, three studies comparing HDF with HD meeting these requirements are in progress, the results being expected in the upcoming years. n
Muriel PC Grooteman is a Consultant Nephrologist at the VU Medical Centre in Amsterdam. Her main research topics include clinical research and bio-incompatibility of haemodialysis therapy and cardiovascular disease in patients treated with dialysis.
cardiovascular morbidity. In the Dutch CONvective TRAnsport STudy (CONTRAST, NCT00205556),46
715 patients, enrolled since 2003, will be
followed until December 2010. In this study, patients are randomised to post-dilution ol-HDF or low-flux HD. Primary end-points are all- cause mortality and cardiovascular morbidity. In the Turkish HDF study (NCT00411177), 780 patients are enrolled, comparing high-flux HD with post-dilution ol-HDF, and being followed for two years. The primary end-point is a composite of overall mortality and new cardiovascular events. Recently, a Spanish study (NCT00694031) was initiated, comparing ‘conventional HD’ with ol-HDF in 750 patients. The expected follow-up in this study is three years and the primary end- point is overall survival. The results of these trials are eagerly awaited, and their individual results may give rise to a meta-analysis using either aggregated data or individual patient records. The latter is more desirable since it allows, given a sufficient sample size, subgroup analyses with adequate adjustment for potential confounding.
Menso J Nubé is a Professor of Nephrology at the VU Medical Centre in Amsterdam. His line of investigation concentrates on clinical research. His main areas of interest are bio-incompatibility of haemodialysis and cardiovascular disease in patients with end-stage renal disease.
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