Corresponding author:
Zbylut J. Twardowski M.D.
Dialysis Clinic, Inc
3300 LeMone Industrial Blvd. Columbia, MO 65201, U.S.A.
Tel.: 573.4431531 E-mail: Twardowskiz@health.missouri.edu

Hemodialysis for treatment of acute renal failure was introduced by Kolff and Berk in 1944 [1]. Their rotating drum dialyzer was difficult to operate, did not permit hydrostatic ultrafiltration, and dialysis was associated with risks of hypertension, hypotension, bleeding from wounds, fever, and electrolyte disturbances. Because of these risks, dialysis was not recommended until patients developed life threatening hyperkalemia, severe metabolic acidosis, clinical "uremia" or severe azotemia.

Kolff's dialyzer was slightly modified in Peter Bent Brigham Hospital in Boston, Massachusetts and renamed the Kolff-Brigham dialyzer. Paul Teschan, who worked with the Kolff-Brigham dialyzer during the Korean War [2], came to conclusion that waiting for the occurrence of life threatening disturbances to implement dialysis was not providing optimal therapy. The U.S. Army Surgical Research Unit of Brooke Army Medical Center in Fort Sam Houston, San Antonio, Texas, where Teschan was Chief of the Renal Branch acquired the McNeill-Collins dialyzer. This dialyzer had substantial advantages over the Kolff-Brigham rotating-drum; hydrostatic ultrafiltration was possible, only 250 ml of blood was required to fill dialyzer and lines, and no pump was necessary because of low internal resistance. This inclined Teschan to propose a paradigm shift. "If a big dialyzer used infrequently could reverse the development of uremic illness and disordered plasma chemistry then a little dialyzer [used frequently] may prevent those abnormalities" [3]. The method was named "prophylactic daily hemodialysis" and the results were dramatic [4].

Chronic hemodialysis was introduced by Scribner and his collaborators in 1960. Initially the patients were dialyzed for 24 hours every 5 - 7 days [5], but it became clear that the patients developed uremic symptoms before the next dialysis, so dialysis frequency was increased to twice weekly [6]. Ultimately the frequency of hemodialysis was established as thrice weekly at the end of the 1960's [7]. With the low efficiency dialyzers, the time of dialysis remained relatively long, up to 8 hours. Such a schedule of 8 hour, three times weekly dialysis continues to be practiced in some centers with excellent results [8].

In the late 1960's technical advances were made, particularly the introduction of the hollow fiber dialyzer [9, 10]. High efficiency dialyzers allowed delivery of increasingly larger doses of dialysis in shorter time. Thrice weekly, short dialysis became a standard in the United States. European and Japanese centers used longer dialysis time, but the frequency of three per week remained unchanged.

The first attempt of more frequent dialysis was made in Los Angeles, California , in 1967 [11]. Several patients doing poorly on three times weekly dialysis were switched to five times weekly dialysis. In all of them uremic symptoms disappeared, hypertension became manageable; hematocrit, albumin, and dry body weight increased . The program was discontinued after 3 years because the technology for frequent dialysis was not available at that time [12]. The next attempt of five times weekly dialysis was made in Bologna, Italy [13]. As before, significant clinical improvements were observed thought to be due in part to reduced osmotic fluctuations and, again, the program discontinued because of lack of appropriate technology.

A systematic study of the influences of dialysis frequency and duration was performed in the mid 1970's [14-16] Fourteen patients participated in the experiment. In six patients dialysis time was increased by 17.5% without changing flows of blood and dialysate (accordingly Kt/V also increased). In 8 patients frequency of dialysis was increased from 2 to 3 or 3 to 4, without changing weekly dialysis time. The mean follow-up time was approximately 6 months. Both goups showed improvement in many parameters, but the improvement was almost always greater in the patients who were treated more frequently. With increased frequency by one per week, hematocrit increased by 4%, albumin by 0.45 g/dl, nerve conduction velocity by 6.1%, Increased duration improved parameters only moderately; hematocrit by 1% and albumin by 0.3 g/dl, but nerve conduction velocity did not change significantly. Both increased dialysis time and frequency improved blood pressure control significantly. Systolic blood pressure dropped by 14 mm Hg, and diastolic by 6 mm Hg with increased frequency and by 14 and 7 mm Hg systolic and diastolic respectively with increased duration. A seemingly paradoxical observation was that more frequent dialyses were associated with improvement in the fistula condition. This phenomenon was attributed to improvement in uremic thrombopathy and less tendency to develop hematomas at the puncture sites.

In 1975 another attempt to implement daily dialysis was made at Maimonides Hospital in Brooklyn, New York. In 11 patients, many beneficial effects were noted. Most significantly the patients reported disappearance of all uremic symptoms and post-dialysis "washout" and fatigue Again an observation was made that fistula function was better maintained with daily dialysis. This was attributed to the absence of hypotensive episodes and improvement in immune defenses [17]. The program was abandoned, due to lack of technology and appropriate reimbursement.

The longest operating daily hemodialysis program was established in Perugia, Italy in 1982 [18]. Observations in patients on daily dialysis confirmed all previous observations and added new ones. Improvements in hemotological parameters, blood pressure control, nutrition, quality of life were again noted. Moreover, improvements were noted in myocardial function and morphology, hormonal disturbances, and sexual life [19].

Yet another Italian program, in Catanzaro, reported almost identical observations: improvements in quality of life, hypertension, myocardial function, normalization of the levels of hormones, return of normal menstrual cycles in women and good sexual function in men. One woman had a successful pregnancy while on daily dialysis [20].

In recent years several groups in Canada, Belgium, the Netherlands, France, Finland, Brazil, Germany, and several centers in the United States established daily dialysis programs [12]. There are two different forms of quotidian dialysis: short hemeral (from the Greek hemera for day asopposed to night), which is performed in 1.5 to 3.0 hour sessions, and nocturnal, where a patient dialyzes for six to ten hours while sleeping. All reports confirm beneficial effects of daily hemodialysis on blood pressure control, hematocrit, nutrition, mental health, energy, social functioning, physical activity, and vitality [21-25]. Moreover, morbidity and need of hospitalizations markedly decreases. Therefore, despite higher cost of dialysis per se, the global cost of daily dialysis treatment of patients with ESRD is lower [26].

There are no comparative studies of hemeral and nocturnal hemodialysis modalities. The efficiency of nocturnal hemodialysis is markedly higher, even to the degree that patients require phosphate supplementation instead of phosphate binders. Other deficiency states have not been described, but prophylactically the patients receive higher vitamin supplementation [25].

It is not known what weekly Kt/V is needed to provide adequate dialysis with daily hemodialysis. It may be lower than with thrice weekly dialysis, because peak concentrations are lower at the same aggregate Kt/V with more frequent dialysis sessions. Gotch introduced the concept of standard Kt/V (stdKt/V), which compares equivalent Kt/V at various hemodialysis frequencies [27]. For instance, according to this model, an equilibrated Kt/V of 1.4 per each dialysis with three times weekly sessions (weekly aggregate of 4.2) provides a weekly stdKt/V of 2.4. If six dialyses per week are performed, the same weekly std Kt/V is achieved with a per session equilibrated Kt/V of only 0.5, not 0.7 (weekly aggregate of 3.0 instead of 4.2). Results equivalent to those with thrice weekly hemodialysis may be achieved with much lower Kt/V (lower total dialysis time). On the other hand, with the efficiency potential of daily home hemodialysis, optimal (not merely adequate) dialysis may be achieved.

An update on the results with quotidian hemodialysis (hemeral and nocturnal) will be presented at the 6^th International Symposium on Home Hemodialysis in San Francisco, in February 27 - 29, 2000.

Early attempts of quotidian hemodialysis failed because of lack of suitable equipment. Today technology is better, but still not prepared for daily hemodialysis. For daily home hemodialysis the machine must be easy to operate and decrease the total time spent on dialysis related tasks. Besides dialysis, these include the setup, priming, tear down, and cleaning of the dialyzer and equipment.

In the 1980's, I came to the conclusion that daily home hemodialysis could only be practical if a new machine were built that would reduce the time required of the patient and the money required of the provider [28]. Three components seemed crucial for a small device: a built-in water treatment system; a simple, positive pressure, single pass, batch dialysate system; and a reusable extracorporeal circuit, automatically cleaned and disinfected daily. The bicarbonate-based dialysis solution, prepared mostly from dry chemicals (dextrose, sodium chloride, sodium bicarbonate) and low volume concentrates (calcium chloride, magnesium chloride, potassium chloride, and organic acid) mixed with treated water automatically in a small batch tank seemed simple and economical. Elimination of proportioning system significantly simplifies machine design and reduces its cost. Further simplification and cost reduction would be achieved by the use of positive pressure ultrafiltration that eliminates the need for a deaeration pump. Use of dry chemicals instead of concentrates lowers transportation costs, considerably decreases the need for storage space, and lessens the burden on patients. The reuse of the dialyzer and the extracorporeal blood circuit would keep treatment cost relatively low.

It took several years to begin realization of the project. In the early 1990's such a machine was designed, patented [29], and licensed to AKSYS, Ltd., a company founded by Rod Kenley for the purposes of building such a machine [30]. It took several more years to build the prototypes. The first version of the machine, called a personal hemodialysis system (PHD) has a 52 L tank connected with a four liter ultrafiltration tank. The machine prepares sterile dialysis solution. The blood path of the dialyzer with lines is filled with this solution, so no priming with the saline solution is needed. During dialysis, every 15 to 30 min, same dialysis solution is pushed back from the dialysate compartment to the blood compartment of the dialyzer to cleanse the membrane pores, thus preserving dialyzer efficiency through consecutive reuses. At the end of dialysis, same dialysis solution is pushed from the dialysate compartment to the blood compartment of the dialyzer. Consequently, the blood is returned to the patient by being pushed from the blood compartment of the dialyzer through venous and arterial lines. After disconnecting from the access, the patient connects dialyzer lines with appropriate receptacles in the dialyzer module, attaches cartridges with chemicals to the appropriate receptacles in the tank and this completes the tasks the patient has to perform. The machine automatically cleanses dialyzer and lines (sic!), performs heat disinfection using hot water (85^o C), and prepares the solution for the the next use.

Recently the machine prototypes obtained an Investigational Device Exemption (IDE) status from the Food and Drug Administration and are being tested at the Northwestern Center in Seattle (Dr. Christopher Blagg), Washington, the University of Missouri in Columbia, Missouri (Dr. Zbylut Twardowski), and University of Mississippi in Jackson, Mississippi (Dr. John Bower). The overall principal investigator of the project is Dr. Carl Kjellstrand, Vice President, Medical Affairs of Aksys, Ltd. At the University of Missouri, two machines are being tested on two patients at present. The first dialysis on the PHD machine was performed in Columbia on January 24, 2000 (Figure 1).

Preliminary data indicate, that the machines are safe. Dialyzers and lines are cleaned well (Figure 2) and there is no decrease in dialyzer clearances with consecutive uses (Figure 2). The two patients have achieved equilibrated Kt/V values of 0.88 and 0.97 (URR 0.54 and 0.57 ) per session, which yields std Kt/V values of 3.6 and 3.8 respectively.

Frequent dialyses are sometimes perceived as a risk factor for blood access malfunction and its decreased longevity. The review of the literature [31] indicates that failure rates are lower and overall fistula survival better with more frequent dialyses than with the routine dialysis frequency. The reason for this phenomenon is not clear. One of the possible explanations is that frequent dialyses improve thrombopathy and decrease rates of hematoma formation at the puncture sites. Another explanation may be the avoidance of hypotensive episodes and improvement in overall patient condition. The data on the complication rates with bridge grafts are inconclusive [31]. No comparison data are available for central vein catheters. This lack of comparisons seems to stem from the intuitive assumption by the authors that more frequent hemodialyses should not be detrimental to the catheter complication rates and survival.

In summary, more frequent than routine three times weekly dialysis is developing rapidly in many centers in the world. Most centers perform hemeral, relatively short sessions, but several centers perform nocturnal, long sessions. More frequent dialyses provide excellent clinical results. It seems that appropriate technology is developing to facilitate the widespread use of quotidian hemodialysis.

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