On-Line Hemodiafiltration: The Journey and the Vision

G. Krick, C. Ronco

• Publisher: S. Karger
• Year: 2011
• ISBN:
  9783805599078
• Topic: Medicina
• Subtopic: Tecnologia e forniture mediche

On-line HDF represents a major technical development in the delivery of hemodialysis therapy: It combines the properties of increased diffusion available in current high-flux membranes with convective removal of between 6 and 30 liters per treatment and requires the use of ultrapure water and online filtration of replacement fluid. On-line HDF has been successfully introduced in Europe and Asia and is routinely prescribed for dialysis patients in these regions.The book at hand summarizes the history and achievements of on-line HDF in four parts: A report of the technological development in both machine and fiber/dialyzer is followed by a description of the challenges encountered in the evolution of on-line HDF, collecting the accounts of clinical key opinion leaders who had been involved in its early application. The third part presents a comprehensive review of the clinical results achieved with on-line HDF from its inception to the present times, in which it represents the clinical golden standard. The fourth and final part is dedicated to on-line HDF as a 'vision' for the future.

The Clinical Appraisal of On-Line Hemodiafiltration

Krick G, Ronco C (eds): On-Line Hemodiafiltration: The Journey and the Vision.
Contrib Nephrol. Basel, Karger, 2011, vol 175, pp 93-109

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The Early Years of On-Line HDF: How Did It All Start? How Did We Get Here?

Bernard Canaud

Nephrology, Dialysis & Intensive Care Unit, and Institut de Recherche et Formation en Dialyse, Montpellier, France

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Abstract

In the mid-1980s, limits and side effects of contemporary hemodialysis were basically due to short treatment time, use of low-flux membranes and employment of acetate-buffered dialysate. These were already associated with a relatively high morbidity and cardiovascular mortality as part of diaysis-related pathology. Based on these considerations, the concept of on-line hemodiafiltration (HDF) was proposed as an innovative solution. By combining diffusive and convective clearances, HDF offered the most efficient modality to clear small and middle-sized uremic toxins. Furthermore, by using ultrapure dialysis fluid and high-flux synthetic membranes, HDF also offered the most biocompatible dialysis system, thereby going a long way towards preventing inflammation. Through provision of virtually unlimited amounts of sterile dialysis fluid by cold sterilization of fresh dialysate, on-line HDF offered an economical and viable method of conducting high-efficiency HDF (high volume exchange) therapy. By keeping the hemodialysis machine with all built-in technical options (e.g. adjustable blood pump, fluid-balancing system, conductivity meter, flow and pressure monitoring, bicarbonate-buffered dialysate), HDF benefited from being associated with the use of dialysis machines with excellent technology as well as highest safety standards. Use of ultrapure water made it then possible to produce dialysis fluid of intravenous grade quality with these machines. The first on-line HDF clinical trial was performed with a modified A2008C dialysis machine in 1984-85. This confirmed the feasibility and potential of the on-line HDF method. Some 25 years later, on-line HDF has proven to be safe, efficacious and with clinical benefits that justify it becoming a new standard for high-quality care of chronic kidney patients.

Copyright © 2011 S. Karger AG, Basel

After three decades of rapid and impressive technical development in renal replacement therapy, dialysis patients were still faced with a high morbidity and mortality risk. Morbidity was reflected in frequent hospitalizations for solving vascular access dysfunction, infection-related problems, cardiovascular events and other dialysis-related pathologies, including ß₂-microglobulin amyloidosis. Mortality was high, averaging 17% per year worldwide with large inter-country variations (Japan 7%, Europe 15% and USA 25%). Causes of mortality were predominantly cardiovascular diseases (ischemic cardiac, stroke, arrhythmia, sudden death, etc.) in about 50% of patients, followed by infection, cachexia and various other causes. Several reports identified that, despite multiple adjustments for age, case-mix and comorbidity, the main source of morbidity and mortality in chronic kidney disease patients was the practice of conventional three times weekly, short sessions with low-flux hemodialyzers and acetate-buffered dialysate.

Why Was High-Efficiency Hemodiafiltration Needed in the 1980s to Complete the Armamentarium of Renal Replacement Therapy?

Several hypotheses were proposed to explain the shortfalls in renal replacement therapy. It is not our intention to review the details of the pathophysiological pathways elaborated to elucidate these findings. However, it is important to mention the putative causes and barriers of conventional hemodialysis in order understand the need for designing a more efficient and physiological renal replacement modality. Briefly, the term ‘dialysis-related pathology’ addresses five main pathophysiological features of the earlier dialysis therapy. First, the incomplete correction of uremic abnormalities by dialysis, this led to the chronic retention of particular toxic compounds [1] and was the focus of attention of the ‘uremic toxin group’. In fact, two theories were being followed at that time: the ‘small molecule hypothesis’ and the ‘middle molecule hypothesis’. The ‘small molecule hypothesis’ was supported by the US nephrology community that uniformly used the ‘dialysis dose’ concept based on urea Kt/V ratio [2-4]. The ‘middle molecule hypothesis’, on the other hand, was supported by the European nephrology community that postulated that chronic accumulation of larger molecular size toxins, which are poorly cleared by conventional hemodialysis, were implicated in the high mortality of dialysis patients [5]. The second pathophysiological feature was the ‘bioincompatibility’ of the hemodialysis system. The generation of bioactive byproducts from protein and cell activation systems led to repetitive inflammation and immune-mediated insults. In this context, two components of the hemodialysis system were identified as triggers for biologic reactions: the biochemical composition of the dialysis membrane (cellulosic versus synthetic polymers) and the microbial contamination of the dialysis fluid [6]. The third pathophysiological aspect of dialysis was the ‘hemodynamic instability’ of short treatment schedules, accounting for maltolerance in 30-40% of dialysis sessions. Hypotensive episodes induced by dialysis sessions were soon recognized as repetitive cardiac ischemic insults leading, potentially, to myocardial lesions. Apart from high ultrafiltration rate, another factor implicated was the sodium acetate buffering of the dialysate; this was finally proven to play a major role by its vasodilatory and negative inotropic roles in the maltolerance of dialysis sessions [7-9]. The fourth pathophysiological facet was the ‘unphysiology’ of intermittent therapy that maintained dialysis patients in a permanent unstable situation by creating a ‘peak-and-valley’ profile of the patient’s internal milieu [10]. Finally, the fifth characteristic was the inability to correct ‘metabolic abnormalities’ of chronic kidney patients, such as anemia, vitamin D deficiency, lipid disorders and mineral and bone disorders [11].

Following reports stressing the limits and side effects associated with short hemodialysis, several technical improvements were proposed for routine clinical practice. This time period led to an intense and fruitful research that contributed to our knowledge and substantially ameliorated outcomes of dialysis patients. In the following, major advances introduced over a short period of time in the dialysis field are briefly reviewed.

Uremic toxins benefited from particular attention. Intense research aimed at their biochemical identification and kinetic characterization, development of specific dosing assays, and proving their toxicity (either in vitro or in animal experiment models) [12]. According to the EUTOX group, uremic toxins are now best classified in three categories based on their molecular size and protein-binding affinity [13]. Although not perfect, this classification has the advantage of underlining difficulties in efficiently clearing middle sized and protein-bound uremic toxins in the clinic setting. As a result, knowledge of uremic toxins is now more comprehensive and strong links to uremic pathology were established. Furthermore, dialyzer manufacturers were prompted to increase membrane permeability and hemodialyzer performances in order to enhance removal of these toxic compounds. Subsequently, high-flux, high-performance, synthetic hemodialyzers (polyacrylnitrile, polysulfone, polyamide, etc.) were developed. Thanks to bioengineering and nanotechnological progress, their performances were optimized. Clinical results were so convincing that their use increased regularly over time so that they are now generally the more prevalent dialzer type worldwide [14-16].

Bicarbonate-buffered dialysate was introduced after the original study from Graefe et al. [17] demonstrated its clear superiority compared to acetate in terms of dialysis tolerance and incidence of hypotensive episodes. Beneficial effects of bicarbonate have been confirmed over time to the point that bicarbonate is nowadays universally the most accepted buffer for dialysate.

Systems for better control of ultrafiltration were developed simultaneously to highly permeable membranes. These systems ensured fluid volume control in dialysis patients during treatment [18]. Beneficial clinical effects were confirmed soon after implementation in hemodialysis machines. This technical option was able to achieve a precise and predictable weight loss associated with a significant improvement in hemodynamic tolerance. Ultrafiltration control systems based on volumetric or flowmetric devices were progressively implemented into the dialysate circuits of all hemodialysis machines, ensuring precise fluid volume balance during highly efficient hemodialysis sessions [19].

Microbiological contamination of water and dialysis fluids was later identified as harmful for dialysis patients. The incidence of fever reactions (pyrogenic reactions) increased significantly after the introduction of bicarbonate-buffered dialysate and high-flux membranes [20]. The link with bicarbonate was soon established and dialysis fluid filtration has since proved to be efficient in preventing fever reactions [21]. More subtly, it was also shown that even low-grade microbial contamination was implicated in monocyte/macrophage activation, resulting in cytokine production and inflammatory reactions [22]. Ultrapurity of water and dialysis fluids was proposed to prevent inflammation and related reactions during hemodialysis sessions [23, 24]. Correcting microinflammation associated with contaminated dialysate is now known to be of paramount importance in preventing the deleterious role of a ubiquitous pathogenic amplifying factor in dialysis patients.

Considering these facts, it became clear to us and others in the mid- 1980s that a more effective, gentle and economically viable dialysis...