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Hemodialysis, peritoneal dialysis, and related therapies for renal dialysis and the elderly/technology

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Title:
Hemodialysis, peritoneal dialysis, and related therapies for renal dialysis and the elderly/technology
Creator:
Blagg, Christopher R.
Fenn, Scott
Publisher:
U.S. Congress. Office of Technology Assessment
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English
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239 pages.

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Subjects / Keywords:
Hemodialysis ( LCSH )
Peritoneal dialysis ( LCSH )
Older people --medical care ( LCSH )
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federal government publication ( marcgt )

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General Note:
This report provides the Office of Technology Assessment with an overview of some of the investment issues affecting the future of the electric power industry in support of OTA's ongoing study on competition in the industry.

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University of North Texas
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University of North Texas
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This item is a work of the U.S. federal government and not subject to copyright pursuant to 17 U.S.C. §105.
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Y 3.T 22/2:2 L 62/v.1/pt.1/hemodi. ( sudocs )

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IUF:
University of Florida
OTA:
Office of Technology Assessment

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HEMODIALYSIS, PERITONEAL DIALYSIS, AND RELATED THERAPIES FOR RENAL DIALYSIS AND THE ELDERLY/TECHNOLOGY Contract 1533-5850.0. Christopher R._Blagg, M.D. Northwest Kidney Center 700 Broadway Seattle, Washington 98122 ( 206) 292-2941

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. \ ~. OTA Manuscript A. BACKGROUND AND HISTORY 1. Heniodialysis -1 00051!J Thomas Graham, one of the early scientists to work in the area of colloid chemistry, was the first to show that crystallofds would pass through a semipeme&.,le membrane while colloids did not, and named this process "dialysis" (1). However, 1 t was not until 1913 that Abel, Rowntree, and Turner developed the first artificial '\ kidney which was used for removal of solutes from the blood of experimental animals through a semipemeable membrane (2). The membrane consisted of celloidin tubes, the dialysate was saline or artificial serum, and the animal's blood was anticoagulated with hirudin obtained by crushing the heads of leeches. It is inte resting that Abel and his co-workers suggested flattening of the celloidin tubes to increase their efficiency, reminiscent of presentday toil dialyzers, and noted that very small tubes "would undoubtedly prove valuable, 11 thus predicting hollow fiber dialyzers. Abel and -. his colleagues carried out a series of experiments, developed a number of pieces of apparatus, and were interested in the possibility of using their new invention, which they had named an "artificial kidney, 11 in humans (3). Nevertheless, the first human dialysis was not perfonned until 1924 by Georg Haas in Gennany (4) using celloidin dialyzing tubes and hirudin as anticoagulant in what was essentially a larger version of the Abel, Rowntree and Turner device (5). Over the next few years two important developments made dialysis of humans more feasible. First was the production of purified heparin as anticoagulant, and the second was development of a

PAGE 3

I OTA Manuscript -2 -conmercially available cellophane membrane. As a result, in 1937 Thalhimer constructed a dialyzer similar to the Abel dialyzer using cellophane and heparin, and used this experimentally in dogs (6). However, the surface area was not suffici-ent and he did not pursue this further. The first practical artificial kidney was developed by Kolff in Kampen, Holland, during the second world war. Kolff's dialyzer was a cylindrical drum on which was wound a 30-4Qn length of cellophane sausage tubing wh1ch was perfused with the patient's blood through a rotating coupling that was based on the Ford automobile water pump. The lower half of the rotating drum was inmersed in a stationary tank containing a large volume of dialysis fluid. Blood was pro pelled through the tubing by rotation of the drum so that a blood p1111p was not required. Kolff attempted his first human dialysis in February 1943 but the patient died (7). A nt.anber of technical difficulties had to be overcome such as membrane leaks, hemolysis, blood line disconnections and hemorrhages; but Kolff and his colleagues continued their efforts, concentrating on treating patients with acute reversible renal failure, However, it was not until their 17th patient was treated in 1945 that one survived who clearly owed their life to treatment with the artificial kidney (8). Following the second world war, Kolff rotating drum machines were sent to London, New York, Montreal, Amsterdam, and Poland. Meanwhile, Murray and co-workers in Toronto had also developed an artificial kidney which was first used in 1946 (9). The Kolff machine was

PAGE 4

000521 OTA Manuscript -3 -modified at the Peter Bent Brigham Hospital in Boston (10) and was used in a number of centers around the world to treat acute renal failure. Other dialyzers were developed following the second world war. Alwall in Sweden devised a stationary upright drum dialyzer which was the precursor of coil dialyzers (11), but the prototype of the present-day coil dialyzer was developed in 1953 by Inouye and Engleberg 1n Philadelphia (12,13). This used cellophane tubing wound in a helix around a stainless steel core, with plastic mesh acting as a spacer. The coil, w1th a surface area of 0.9m2, was placed in a pressure cooker through which dialysis fluid was recir culated from a SOL tank. Blood was circulated with or without a blood pump, and ultraf11tration was regul_ated by controlling the rate at which dialyzing fluid was drawn into the dialyzer by a water pump. This was the model for the "twin coil kidney" developed by Kolff and Watschinger (14,15) and which was eventually produced conmercially by Travenol Laboratories in the United States, gained rapid popularity, and was very widely used in the 19501s and 1960's. Its disadvantages were that it required a blood pump, had a high blood pressure in the extracorporeal circuit, required priming with blood before dialysis. and used a large open tank of dialysis fluid which could easily become contaminated. Other dialyzers were developed during these years. HacNeill and co-workers in Buffalo devised a dialyzer using short lenqths of flattened cellophane tube which was the prototype of parallel flow dialyzers (16,17), and Skeggs and Leonard at_Western Reserve developed

PAGE 5

OTA Manuscript -4 -a similar dialyzer (18,19). This latter used the countercurrent principle in which dialyzing fluid passed through the dialyzer in the opposite direction to the blood. Throughout the 1950's and early 1960's dialysis was used primarily for the treatment of acute renal failure, and while a number of units continued to use variations of the original Kolff rotating drum machine, the availability of the twin coil. artificial kidney enabled the spread of dialysis to many new centers. Interest increased because during the Korean war dialysis had proved invalu able in the management of military personnel with traumatic acute renal failure (10). Blood Access and the Developnent of Chronic Maintenance Dialysis Originally, hemodialysis required multiple arterial and venous cut-downs, one of each for each dialysis. Alwall attempted to obviate this by the use of siliconized glass tubes which were joined together between dialysis treatments by a narrow glass capillary (20). Heparin was injected into the tubing, but this approach was ab~ndoned because of frequent clotting and local infection (21). The era of modern dialysis stems from development of the teflon arteriovenous shunt by Scribner and co-workers in Seattle (22), the first of which was implanted in March 1960. Two cannulae, made from thin-walled teflon tubing with tapered ends, were inserted into the radial artery and cephalic vein near the wrist and bent through a 180 turn before passing through the skin. Between dialyses the

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OTA Manuscript -5 000523 external ends were connected to a curved teflon bypass tube using two Swagelock couplings fixed on a stainless steel ann plate. Because the rigidity of the teflon tubing caused mechanical damage to the vessel walls, this shunt was modified when flexible silastic tubing became available (23), and eventually a silastic shunt system with a single break joined by a single short teflon connector and with teflon vessel tips was developed (24). -This, the "Scribner shunt," and its various modifications became widely used throughout the world during the 1960's (25). At the same time as the development of the shunt, Scribner and his colleagues developed a new dialysis system for use with patients with chronic renal failure. This originally evolved from a system to treat acute renal failure with continuous low-flow dialysis using using a low resistance d1alyzer to make a blood pump unnecessary and a large volume of dialysis fluid which was cooled in order to minimize bacterial proliferation. Originally a Skeggs-Leonard dialyzer was used, but in 1960 a device originally developed as a blood oxygenator began to be used for dialysis, the Kiil dialyzer (26,27). The Kiil dialyzer was modified to reduce its blood volume, and a different cellophane, Cuprophan, was used as the membrane. The first patient, Clyde Shields, started treatment in March 1960 and -Hved for fl years on maintenance dialysis, dying in 1971, aged 50, from a myocardial infarction. Of the two other patients who started treatment at the same time, one is still alive 25 years later, having had a living-related donor transplant in 1968. As a result of the success of this new treatment for chronic renal failure,

PAGE 7

OTA Manuscript -6 -the Seattle Artificial Kidney Center was developed as the first outpatient conmunity dialysis center. This was the first dialysis unit to be situated outside a hospital and the first unit in which dialysis was carried out primarily by nurses and not by phys~cians (28). Further modifi_~ations of the dialysis sy~tem were made in Seattle, including the use of a single pass dialysate circuit in order to improve efficiency and re~uce bacterial counts. Efforts also led to automation of the fluid supply system based on develop0 ment of a system using a concentrated solution of electrolytes and dextrose which was diluted with tap water by means of an accurate proportioning pump _system. This conceNtrated dialysate required the substitution of acetate for bicarbonate to avoid precipitation (29). A central dialysis system based on proportioning was built in Seattle to treat 15 patients using dialysate concentrate diluted 1:34 (31). It was while these developments were occurring that the Seattle Artificial Kidney Center developed its comnittee to select patients for this expensive and unusual treatment (28,31). Home Hanodfalysis The next step in reducing the cost of hemodialysis was to move it to the home. Apparently, the first home dialysis was carried out in Japan in 1961 (32). but home dialysis as we know it today was introduced in 1964 in Boston (33), London (34), and Seattle (35). Besides being less expensive. home dialysis was also found to be

PAGE 8

OTA Manuscript -7 0005:~5 better for many patients in terms of increasing independence and the opportunity for rehabilitation (36). The Seattle group developed a modification of the proportioning system which became the standard for single patient dialysis systs (34). This system included several mnitors and alanns with the intention of making overnight dialysis in the home a safe procedure to be carried out by patient and family member. The Arteriovenous Fistula While the Scribner shunt had made ~intenance dialysis possible,. problems with clotting, infections, and the need to replace: the shunt plagued most patients. This was resolved in 1966 with the development of a surgically created arteriovenous fistula by Brescia and colleagues (37) which rapidly became the standard fonn of access for hemodialysis. Following this, for pat1ents whose own veins are not suitable for development of an arterfovenous fistula, various grafts have been developed (38,39,40), but it is still true to say in 1985 that the "native" arteriovenous fistula remains the gold standard of blood access. Consequently one of the most important measures in the management of patients with chronic renal failure before they require dialysis is preservation of the foreann vessels so these can be used for development.of a fistula when required (41).

PAGE 9

' OTA Manuscript -8 -The Square Meter-Hour and Middle Mol~cule Hypotheses The Seattle group wa$ also in11olved in the early development of 1ntennittent peritoneal dialysis (see below). nuite early on, Scribner noted that patients treated by chronic peritoneal dialysis were often underdialyzed 1n tenns of blood chemistry but nevertheless did not show evidence of peripheral neuropathy, or if this was present when they started dialysis it did not progress (42). He suggested that the peritoneal membrane was mre penneable than cellulose membranes and that peritoneal dialysis removed more of substances with a higher molecular weight than did hemodialysis. This led to the suspicion that so-called "middle molecules" might play an important role in the toxicity of uremia, and the hypothesis that for a given membrane prevention of peripheral neuropathy depends on a minimum number of hours of dfalysis per week rather than on maintenance of specific blood levels of urea and creatinine This, the square meter-hour hypothesis (43,44) and its mdification, the middle molecule hypothesis (45), suggested that inadequate removal of middle molecules (molecular weight between 300 and 2,000 daltons) may be the cause of complications such as peripheral neuropathy and pericardit1s.Since removal of middle mlecules through a conventional hemodialysis membrane is slow, the diffusion gradient remains high throughout the dialysis, unlike the situation with small molecules. Thus the net removal rate for middle molecules remains constant during a protracted dialysis, and net removal 1s proportional to the total hours per week of hemodialysis, unlike

PAGE 10

000527 OTA Manuscript -9 -small molecules which have flow-dependent removal that decreases with the decreasing plasma concentration as dialysis proceeds. These hypoth~ses had a major effect on dialysis equipment and strategies, even though the isolation, identification and toxicology of middle molecules remains clouded in uncertainty (46). However, they led to shor~ening of dialysis schedules using larger surface ar~a dialyzers or increased frequency of dialysis, usually with less total dialysis hours per week. With the development of hollow fiber dialyzers using cellophane, Cuprophan and other membranes, large surface area dialyzers have become widely used during the 19701s with shorter dialysis tis. Scribner and his colleagues also note~ the importance.of residual renal function with a short dialysis schedule1 and its contribution to the removal of middle molecules (47,48). Residual kidney function should be measured and taken into account in planning short dialysis schedul,es (49). Average dialysis time has decreased by mre than SOI between 1968 and 1978 (50). The Redy System Hemod1alysis generally uses a large volume of water which must be pretreated, and requires access to a water supply and a drain. This interferes with portability. Consequently, efforts have been made to reuse dialysis fluid, and Gordon et al (51,52) developed a system to continuously regenerate a small volume (5.5L) of dialysate using a multilayer disposable cartridge containing urease, zirconium resins, and activated carbo~. This, the Redy system, has been

PAGE 11

OTA Manuscript -10 0005;-~s available for some 15 years, and is relatively portable and can be used by dialysis patients who wish to travel. This ~teresting approach to dialysis has not been as widely used as might have been anticipated because of the large amount of supplies and accessories that have to be carried, and because the equipment itself has some disadvantages (53). Sequential Ultrafiltration During hemodialysis fluid is removed by ultrafiltration, usually in present-day machines by application of a negative pres sure to the dialysate compartment. During dialysis, episodes of hypotension, 1111scle cramps, and other symptoms are c0111110n, parti cularly when a large volume of fluid is removed during a short dialysis. Bergstrom et al (54) were the first to observe that rapid ultraf11tration was better tolerated when perfonned without simultaneous dialysis by applying negative pressure while the dialysate bypassed the dialyzer. This process, sequential ultrafiltration, allowed the removal of as 1111ch as 4L of fluid in an hour, and could be followed by dialysis without producing a significant adverse effect on blood pressure (55-57). Bicarbonate vs. Acetate As noted earlier, the development of a dialysate proportioning system required the use of sodium acetate rather than sodium bicarbonate in order to produce concentrated dialysis fluid (29). This

PAGE 12

000529 OTA Manuscript -11 -was necessary in order to prevent precipitation of calci1111 car bonate. In recent years it has become apparent that many patients with acute renal failure and same sick patients with chronic renal failure Y acc11111late acetate in the blood and tissues during rapid large surface area dialysis, leading to acetate toxicity with vascular instability and hypotension (58,59). Similar undesirable side effects occur in other chronic renal failure patients dialyzed with large surface area dialyzers, particularly those who metabolize acetate slowly (60). Not only is the rapid infusion of acetate and the inability to tabolfze ft quickly a problan, but simultaneous loss of bicarbonate occurs from the blood through the dfalyzer. It has been shown that use of bicarbonate dialysate frequently will relieve these symptoms (61) and consequently bicarbonate dialysis is being used 1110re widely, this despite the fact that the equipment is s0111eWhat more complicated and the dialysis is slightly more expensive. Dfalyzer Reuse Dialyzer reuse was first developed in 1964 by Shaldon et al who refrigerated twin coil dialyzers and their tubing sets, together with the contained blood, between dialyses (62). In 1967 Pollard et al in Seattle developed a technique for reuse of the K111 dfalyzera flat plate, nondfsposable dfalyzer (63). This technique allowed patients to put together their dfalyzer and reuse it for as many as six dialyses. After dialysis the dialyzer was rinsed, cleaned with bleach, and sterilized using fonnaldehyde. With availability of

PAGE 13

. .. -. -.... .... --.-1. -. .. .. OTA Manuscript .: 12 -0 I (\ ,, 0 .... iJ tr ~, ': ~u ., cheap disposable dialyzers, dialyzer reuse continued to be practiced at only a small number of centers, but with reduction in federal funding dialyzer reuse has again becmae important. Dialyzer reuse is a safe procedure when carried out properly (64) but has been perceived by some patients as a means by which facilities may make mney, and so during the late 1970's there was a strong patient movement against dialyzer reuse in the Uni~ed States. This continues, but nevertheless more than 601 of patients in this country now are treated with reused dialyzers. 2. PeritonHl Dialysis Peritoneal lavage was first_described by the Reverend Steven Hales in 1744 (65), but it was not until 1877 that Wegner perfused the 1bd0111inal cavity of rabbits with a cold saline solution and observed a decrease in temperature (66). He went on to note an increase in the vol&ae when concentrated sugar solutions or glycerol --' were placed in the abdominal cavity. A number of other studies on changes in outflow vol1111e with solutions of different concentrations were reported over the next 40 years, but it was not until 1918 that the ability of the per1tone1111 to absorb fluid was first used clinically to treat children with gastrointestinal problems that prevented oral intake (67). Throughout the 1920's and 1930's studies were made on the diffusion of substances across the peritoneal membrane and the effect on blood levels, the mechanism for the increased outflow vol&.1118 using hypertonic glucose, and the effect of vasodilatation and vasoconstrict1on on diffusion (68).

PAGE 14

OTA Manuscript -13 -000531 The first use of peritoneal dialysis to remove uremic toxins was by Ganter in 1923 in animals made uremic by ureteric ligation (68). He was also the first to report the use of peritoneal dialysis in the human, studying the effects of a physiological saline solu tion introduced intraperitoneally in a patient with ureteral obstruc tion due to uterine carcinoma, noting tha~ her clinical conditi_Qn showed slight improvement. Peritoneal dialysis was used clinically in a few patients during the 19301s, but the next major step was the publication of a report on the use of peritoneal dialysis in acute renal failure by Fine et al in 1946 (69). By 1950 there were reports on more than 101 patients treated by either intennittent or:. continuous peritoneal dialysis (70), and in the next 10 years peritoneal dialysis was used more widely for treatment of acute renal failure in adults and children, and to treat hypercalcemia and various poisonings. Early Peritoneal Access Devices Peritoneal access, originally achieved by means of a trochar and cannula, was a problem for repeated peritoneal dialysis. In the early 1960's there was intensive study of methods for repeated access, and various indwelling "buttons" and other devices were developed. Leakage and obstruction were serious problems, and generally these devices were not successful because of flow problems and lack of a closed dialysis system. However, in 1965 Weston and Roberts improved upon the Maxwell catheter by inserting a pointed

PAGE 15

.t 0 0 05 3 ~) OTA Manuscript -14 stylet (71). This became conmercially available as the Trocath and it simplified access for temporary peritoneal dialysis considerably. However. access continJed to be a major problem for patients on long-tenn peritoneal dialysis until the description by Palmer of a pennanently implanted silastic .catheter with a long subcutaneous tract (72). Working from this concept. Tenckhoff in Seattle attached dacron felt cuffs to the catheter just below the skin and i11111ediately ou~side the peritoneum. Tissue ingrowth into these cuffs fixed the catheter in place and provided an effective barrier against bacterial invasion of the sinus tract around the catheter. This, the Tenckhoff catheter (73), originally implanted using a special trochar, has became the standard access device for long-tenn peritoneal dialysis, and a modification with a single cuff fs widely used with acute renal failure. Oevelopnents fn Chronic Peritoneal Dialysis The modern era of peritoneal dialysis was ushered in by publi cation of the monograph by Boen in the Netherlands in 1959. This classic work, published in the United States in 1964 (74), describes studies on the kinetics of peritoneal dialysis and discusses the indications, techniques, and complications of this treatment. This. together with the report by Maxwell et al from the United States (75), established the use of peritoneal dialysis in the treatment of acute renal failure. Because of its simplicity and because hemo dialysfs was not widely available at this time, peritoneal dialysis became widely used for acute renal failure.

PAGE 16

OTA Manuscript -15 -In 1962 Scribner invited Boen to the University of Washington, Seattle, to continue his work on peritoneal dialysis and extend its application to the treatment of chronic renal failure. Equipment previously used for the experimental trertment of chronic renal failure by gastrod1alysis was modified to make the first closedsystem peritoneal dialysis cycler using dialysate sterilized in 40L .. glass bottles (76). This closed system dramatically reduced the frequency of peritonitis because it eliminated repeated connections to fresh dialysate containers during the course of the dialysis (77). In 1963 Boen started treatment of a 28-year-old woman with chronic renal failure by outpatient intermittent peritoneal dialysis (IPD), and this continued successfully for four years until the patient was transferred to home hemodialysis. This patient is alive today, having had a successful related donor transplant in in 1971. Boen and Tenckhoff continued work on development of peritoneal dialysis equipment which would eliminate the need for large containers of sterile fluid and on equipment for home IPD. The first such equipment, using heat sterilization, became available in 1970 (78) but wa-s bulky and heavy, and while successfully used by a small number of patients, was never a conmercial success. The early 1970's showed increasing interest in IPD for chronic renal failure, primarily as a result of the continuing work of Tenckhoff, supported by the National Institutes of Health. He next developed a peritoneal dialysis fluid supply system using a reverse osmosis device to produce sterile pyrogen-free water. It was this

PAGE 17

OTA Manuscript -16 -000534 equipment which made long-tenn IPD feasible (79). In the late 19701s there was renewed interest in the use of phannacologic agents to improve peritoneal clearance and so reduce the long duration of a periton~al dialysis, and the possibility of using dialysate regeneration also was explored (80,81). However, IPD was still used for less than 51 of patients in the United States, in part because of lingering suspicions based on the high infection rate associated with the use of open peritoneal dialysis systems in the 1960's. The most notable advance in peritoneal dialysis in the 1970's s the brilliant conception by Popovich, a biomedical engineer who had previously worked on hemodialysis kinetics at the University of Washington in Seattle, of the principle of continuous ambulatory peritoneal dialysis (CAPO) (82). This. technique of portable self dialysis has undergone an astonishingly rapid increase in use worldwide (83) and now accounts for about 131 of dialysis patients in the United Statas (84). The recent increased interest in peritoneal dialysis has also led to the development of another approach. In 1979 Scribner first proposed nightly automated peritoneal dialysis, together with daytime ambulatory peritoneal dialysis (85). This concept was developed by Diaz-Buxo and co-workers and has become known as continuous cycling peritoneal dialysis (CCPD). It may prove a very useful further fonn of treatment (86).

PAGE 18

OTA Manuscript -17 -00053!:> The Enhancement of Peritoneal Dialysis Efficiency Various pharmacological and physiological factors may affect peritoneal dialysis efficiency, but most of these have been studied in experimental animals and have not made a significant contribution to the illlnagement of patients. Peritoneal dialysis is inherently inefficient, and peritoneal mass transport can also be altered by both peritonitis and by generalized vascular diseases such as diabetes or sclerodenaa which affect the splanchnic blood vessels. A major factor affecting the rate of transport is the concentration gradient, but for larger molecular t~eight substances which diffuse slowly, increasing the rate of exchange beyond about 2L an hour has little effect on clearance. To improve mass transport requires either increasing peritoneal penneability or surface area, or increasing blood flow. Blood flow to the peritoneal membrane is primaril~ related to mesenteric blood flow rate, since the visceral peritoneum is much greater in area than the parietal peritone1111. Thus factors which affect the splanchnic vascular bed can affect blood flow. Phannacologic manipulations can produce vasoconstriction and vasodila tation of the vascular bed, and in particular vasoconstriction can be prevented by use of the alpha receptor blocking agent phenoxy-. benzamine. Prostaglandins have also shown to be involved in the control of vascular dynamics, again by modification of vasoconstrictor responses (87).

PAGE 19

OTA Manuscript -18 0U053G Convective transport can also be improved by increasing the osmotic activity of the dialysate or increasing capillary hydro static pressure by causing greater constriction of venules than of the arterioles, as with dopamine (88). A mnber of vasodilator agents have bee" tested. For example, isoproterenol at a concentration of 0.06mg/L in the dialysate does improve peritoneal transport, although the effect is transient (89). No systic effects were noted at this dosage. Isoproterenol Jnhibits catecholamine response and relaxes the mesenteric vascular bed. Theophylline (90) and nitroprusside (91) have also been used. D1pyridamole is interesting as it increases peritoneal transport and can be given orally. It is a smooth 1111scle relaxant and also has an antiplatelet aggregating effect which Y be helpful with systanic diseases that produce platelet thrombi 1n the mesenteric circulation (92). Other substance that have been used include dopamine (93), hydralazine (89), diazoxide (94) and tolazoline (95). Prostaglandins alter regional bl~od flow by their effect on vasoconstrictor responses (87), but studies of prostaglandin synthe tase st11111lators and inhibitors have not shown significant changes in peritoneal transport (96). Various vasodilator gastrointestinal honnones have also been investigated, and in experimental animals both glucagon and secretin can increase mesenteric blood flow (97). It has also been shown that rnethylprednisolone increases peritoneal clearance significantly (98).

PAGE 20

000537 OTA Manuscript -19 -From the foregoing, i~_is obvious that a number of drugs and honnones affect the peritoneal membrane and splanchnic blood flow, bu~ to this date these have not proved applicable to clinical practice. Further knowledge of the effects of drugs and their interactions Y eventually enable enhancement of peritoneal transport. 3. Other Technologies H11110perfusion In 1948 Muirhead and Reid found that urea was absorbed from animal blood by passing this through an exchange col1111n, so ini tiating ~he principle of using sorbents for blood purification (99). Yatzidas then described attempts to treat uremia by perfusing heparinized blood through a colmn of.activated charcoal (100). However. while activated charcoal is an effective sorbent for ,several potential uremic toxins such as creatin1ne and uric acid, it does not absorb urea or correct the water and electrolyte abnormalities associated with chronic renal failure. In addition, it soon became obvious that the charcoal had to be coated or microencapsulated to prevent particles from entering the bloodstream (101). Hemoperfusion using coated activated charcoal or Amberlite resin presently is used as treatment for severe overdosage with several hypnotic drugs including barbiturates, glu-tethamide, chlor promazine, and methaquilone (102-104). It has also been used experi mentally as an adjunct to dialysis treatment for chronic renal failure (105-107) but does not appear to be a complete alternative

PAGE 21

.. .:... .... -...-... -- ... ...,.. ___ ~'"-.. _.l----"""~ ... -.. _,...4-......_.. ... ; .._ ... .. _, .. ,._ ...... -...................... --,... ____ --.. ---.. .. .. -----. OTA Manuscript -20 -000538 to either hemodialysis or peritoneal dialysis. In addition, hemoperfusion with coated charcoal has been used to treat hepatic failure, but with inconsistent results (108,109). Hemofil tration Hanofiltration was introduced by Henderson and co-workers in 1967 (110), although the concept was originally described by Brull in 1928 (111). Ithas the advantage that it removes solutes by dif fusion, as with conventional dialysis, and ilso by convection--a process which more clearly resbles the perfonnance of the human kidney. Small and large molecules are removed at a similar rate. Introduction of the middle molecule hypothesis in the early 1970's stimulated work with hemofiltration, and a number of clinical trials have been undertaken (112-115). Different filters with different membranes can be used, including polysulfone, polyacrylonitrile, and asynnetric cellulose acetate membranes. Rather a large volume of fluid has to be ultraf11tered (20-40L 3 times weekly depending on body size), and an approximately equal amount of replacement fluid has to be added to the syst either before (predilution mode) (116) or after the filter (postd11ut1on mode) (113), and this replacement is one disadvantage of this treatment. The use of sorbent regeneration and reinfusion of ultrafiltrate has also been attempted and ay be a feasible alternative (117). Hemofiltration is an effective method to replace renal func tion, but removal of small molecules is somewhat less efficient than

PAGE 22

000539 OTA Manuscript -21 -with hemodialysis, and some loss of protein through the membrane of the ultrafilter has been described (118). On the other hand, better control of hypertension, improvement in peripheral nerve function, .and other advantages have been reported (119). Nevertheless, for the present time, hemofiltration is expensive and rather c1111bersome. Hemodiaf11tration Hemodiafiltration is a combination of hemodialysis and hano f11tration which uses both diffusion and convection. It allows use of a shorter dialysis ti, together with a smaller volume of replac~ent fluid' than with hemofiltration (120). Intradialytic morbidity is said to be. reduced, and small molecula~ weight clearances enhanced (121). Plasma Exchange Plasmapheresis was originally suggested by Abel and colleagues in 1914 ufor the relief of toxia" (3). Plasma exchange became feasible 1n the late l960's and early 1970's with developments in the technology of wrking with extracorporeal circulation. Consideration has been given to the use of plasma exchange to treat a number of very different diseases, several of them being thought to have an autoimune pathogenesis (122,123). Two methods of plasma exchange are available--one of these is continuous flow separation--plasma s~paration, and the more recent

PAGE 23

OTA Manuscript -22 Of.)01'1 I' IJ ;.,~v one is mbrane plasma separation--plasmapheresis, whic~ has become the treatment of choice since the availability of suitable mbranes (124,125). Vascular access is usually ~Y means of an arteriovenous shunt or subclavian catheter. During treatment, 4-SL of plasma are removed and replaced by fresh frozen plasma, reconstituted dried _plasma, or an alb11nin electrolyte mixtu~e (122,123). Treatment is usually carried out daily or on alternate days. Other techniques are befng developed such as use of two hollow fiber filters with different pore sizes. The first separates plasma from whole blood and the second separates filtrate from larger molecular weight substances. This filtrate is then mixed with the cell-rich residual blood from the first filter and returned to the patient (126). Other developments include selective plasma component removal (127) and plasma exchange with 1111111no-adsorption (128). Plasma exchange is frequently combined with iunosuppressive therapy for the treatment of acute hypersensitivity glomerular diseases such as Goodpasture's syndrome and rapidly progressive glomerulonephritis. It has also been used for autoinmune and other diseases including thrombotic thrombocytopenic purpura, systemic lupus erythematosus, myasthenia grav1s, Gu111ain-Barrf syndrome, rheumatoid arthritis, sclerodenna, and Raynaud's syndrome. Success has been variable, and treatment of these conditions requires further evaluation.

PAGE 24

J OTA Manuscript 4. Important Medical Issues Viral Hepatitis -23 -000541 About 1965 it was first recognized that hepatitis was a hazard in dialysis units, and in the next few years a n1111ber of serious outbreaks occurred in several centers in Europe and the United States. Both patients and staff were affected, and a number of deaths occurred (129,130). At the same time, considerable research was being carried out on viral hepatitis, and it was soon realized that after hepatitis B infection, persistent Australia antigenenia (HBsAg) could occur. Such individuals are potentially infectious to others, endangering both other patients and staff. As recently as 1984, 1n Europe there were 2,174 new cases of hepatitis in.dialysis patients, of which most were due to hepatitis B (131). There were 360 cases in dialysis staff with one death, a significant improve ment over 1980 when there were 566 staff cases and 11 deaths. Rec011111endations were developed in both the United States and Europe to help to control the spread of hepatitis in dialysis units, including isolation of affected patients, encouragement of home dialysis, and use of hyperi11111.1ne gamna globulin for protection following needle stick injury. Development of a successful vaccine for hepatitis Bis now beginning to have a significant impact on the rate of infection for staff (132). Vaccination should be considered for all staff working in dialysis units who do not have antibodies to hepatitis B, and can also be used to protect patients, also, altho~gh it may be less effective in hemodialysis patients (133).

PAGE 25

00054~ OTA Manuscript -24 -Other varieties of hepatitis also occur in dialysis patients. Hepatitis A ~Y result from transmission from acute cases but does not pose a long-tenn hazard fn dialysis units. However, with the introduction of reliable serological tests for hepatitis B infec tion. ft soon becaae obvious that apart fran a small nllllber of cases due to cytamegalovirus, Epstein-Bar virus and drugs, there was yet another cause of hepatitis in dialysis patients. This, non-A, non-B hepatitis, results rrm an agent which is transmissible from man to chimpanzees (134), and for which a new antigen-an~ibody system has been distinguished (135). Like hepatitis a, non-A, non-B hepa titis infection does result fn the carrier state and consequently can be a source of hepatitis in dialysis units. Unfortunately, non-A, non-B hepatitis is auch more likely to result in chronic liver disease than is hepatitis B (136). Specific serological tests towards a specific non-A, non-B antigen called hepatitis C antigen are being developed. In addition, a further hepatitis agent named "delta" has also been identified which is invariably_ associated with progressive liver injury in h11111n carriers. This agent has an obligatory association with hepatitis B virus and cannot replicate without the latter's presence. So far, delta agent has not become a major probl fn dialysis units, but is more c0111110nly described in intravenous drug abusers (137). Thus. while hepatitis B should be screened for on a regular basis in dialysis units and should no longer be a serious problf!ffl

PAGE 26

OTA Manuscript -25 000543 with the ava;lability of the vaccine, occasional brief outbreaks of hepatitis A my occur, and non-A, non-B hepatitis is appearing as a serious probl for some patients. Anaaia Chronic renal failure is almost always associated with anemia, except in the case of a small nllllber of the patients with polycystic kidney disease. The llljor cause for this anmia is the reduced production of erythropoietin by the kidney causing a reduction in red cell production (138). Several other mechanisms may be involved, including shortened red cell sunival (139), toxic depression of erythroid proliferation and heme synthesis by uremic inhib;tors (140,141), and blood loss occurring to a variable degree in asso ciation with the dialysis procedure (142). Ania remains one of the Jor factors fn the lack of well-befng of dialysis patients and fs important fn preventing rehabilitation of such patients. Institution of thrice-weekly dialysis in good time and a dietary protein intake of 1 to 1.5/g/kg/body weight/day helps to produce a higher hanatocrit level in patients starting dialysis (143). Transfusions, because of their potential erythropoietic suppressive effect and the risk of transaitting hepatitis, should be given only when there is clear evidence of tissue hypoxia such as angina or where required as part of a transplant program. The serllft ferritin level should be monitored regularly to check for development of iron deficiency, but unless there are unusually qreat

PAGE 27

00054~ OTA Manuscript -26 -blood losses the patient who starts dialysis with nonnal iron stores takes six 110nths to two years to develop iron deficiency. Once this occurs, ft should be treated with oral iron taken before or after a al, and without coc011111ftant ingestion of phosphate-bind1nq qels (144). For patients who cannot tolerate oral iron or in whom it does not produce iaprovement, parenteral iron-dextran can be used. However, this carries the risk of occasional systemic reactions (145) and the danger of producing iron overload. Dietary supple ntation with folic acid and histidine should also be considered (146). In patients with refractory 11111111, androgens may be of help but are associated with side effects (147). In addition, peritoneal dialysis, and in particular, CAPO, has been said to be associated with higher h11111tocrit levels. Perhaps the aost exciting recent development is the avail ability for investigation of h1111n erythropoietin produced from rec0111binant DNA. If, as is hoped, this will produce a marked improvement in the anfa of patients with renal failure, this could be one of the most significant steps fn improving the well-bein~ of patients and increasing their activity and opportunity for rehabili tation (138). Al1a1inu11 Toxicity In 1972 a new clinical syndrome was described in a number of patients who had hemodfalyzed in Denver, Colorado, for several years. This consisted of dyspraxfa, speech abnormalities, myclonus,

PAGE 28

, 000545 OTA Manuscript -27 -seizures, personality changes, and an abnonnal electroencephalogram, and progressed to death within a few months. All patients had been dialyzed with untreated Denver city Nater. Analysis of brain tissue for trace elements showed few differences from that of controls and of ur1111c patients who had died without signs of encephalopathy except for s0111 reduction in the amount of rubidillD and potassium and an increase in the content of tin (148). Alt1Din1111 was not estited at that ti. By 1976, 19 cases had been observed in Denver. and suspicion had been raised that al111in111 was responsible as tissue studies showed brain al1111inum to be four times higher than 1n dialysis patients who died fr0111 other causes and ten times higher than in nondialyzed patients, the al111in111 being localized in the gray 111tter. Al111inu11 concentrations in 1111scle and bone were also higher than in controls (149). At the saae ti, similar cases were being reported in England and in Canada froa cities with a high al111in111 content in tap water, frequently as a result of an al1a1in1111 precipitation method used to reduce any undesired color in the water (150). Further studies showed that dialysis encephalopathy had a geographical distribution which appeared to be related to the al111in1111 content of untreated or inadequately treated water used for preparing dialysate. More recently other symptoms associated with al1ainm toxicity have been described including vitamin 0-resistant osteomalacia, proximal 1111scle weakness (151), and a hypochromic microcytic anemia (152).

PAGE 29

,,,..,,. ., ..... ~\ '' -. .. r-........ o O 054G OTA Manuscript -28 -The kinetics of aluminum in dialysis patients are complex. Alumin1111 is bound to plasma protein, and uptake from dialysate may continue even when the total plas alumin1111 concentrati9n exceeds that fn the_dialysate. Transfer is also related to pH and is increased by increasing the pH of the water or by use of bicarbonate dfalysate (153). A pH below 6.5 has a similar effect. The other Jor source of aluminum which has become of increasing concern recently 1s the al1111inum-conta1n1ng' phosphate binders which are routinely administered to dialysis patient to control phosphate inqke (154,155). Efficient alumin1.111-free, and preferably mag nesium-free, phosphate binders are currently under investigation. Recently, the administration of desferrioxamine during dialysis has been shown to help remove aluminum from the body (156). Even so, because of the serious dangers associattd with aluminum intoxi cation, it is impo~tant that water be pretreated by reverse osmosis or other ans for all dialysis patients. Routine monitoring of serum aluminum levels should also be considered. Osteodystrophy Renal osteodystrophy, previously seen primarily as renal rickets 1n children, became a serious probla with the availability of ntenance dialysis. The association of hyperparathyroidism with renal disease has been known for some time (157), and calcium malabso~ption has been found in such patients and is resistant to vitamin D trnatrnent (158). However, it was found that renal

PAGE 30

000547 OTA Manuscript -29 -osteodystrophy can also be improved with large doses of vitamin Dor d1hydrotachysterol, that vitamin D increases bone resorption and there is a long delay between giving intravenous vitamin D and its physiological effects. Thus the interactions between the kidneys, the parathyroids, bone skeleton, and vitamin Dare complicated (159). Deluca and his colleagues eventually sho~ed that vitamin D had to be hydroxylated before it is physiologically effective (160), and the lag period can be shortened by giving 25-hydroxyvitamin D3 which is also active in bone cultures. The 25-hydroxylation occurs in the liver microsames and is a biofeedback-regulated process. However, 25-hydroxyvitamin D still did not appear to be the active agent. The next step was the finding that the kidney is a unique source of a potent honnone which stimulates intestinal calcium absorption and calci1111 resorption from bone. This was isolated and found to be 1,25-dihydroxyvitamin D3 (161). As a result of these findings, treatment of renal osteodystrophy and other disorders with synthetic vitamin D metabolites and analogues 1s possible. However, while vitamin D and its analogues have been shown to be effective in treating renal osteodystrophy, the osteomalacia in dialysis patients does not always respond to this treatment, and as noted above, aluminum accumulation may be the prim~ cause of osteornalacia in some of these patients. There is no doubt that this better understanding of the inter relationships between vitamin D and its metabolites, the kidneys, bones, and alimentary tract has been a major advance in the manage ment of patients with end-stage renal disease.

PAGE 31

OTA Manuscript -30 0-00548 Lipid Abnonna11ties In 1974 Scribner and co-workers reported the high morbidity and 11>rta11ty from atherosclerot1c cardiovascular disease in long-tenn dialysis patients in Seattle (162). Simi.lar data has been reported by the European Dialysis and Transplant Association (163), and it now appears that cerebrovascular and cardiovascular causes account for approximately &osof -deaths in dialysis patients. Plasma lipid abnonnalities have been shown to occur 1n dialysis patients, includ ing persistent hypertr1glyceridem1a associated with a delay of the peripheral catabolism of very low density 11poproteins, and impaired triglyceride removal from a defect in lipoprotein lipase, pres1111ably associated with the accumulation of uremic toxins (164,165). Hypertriglyeridia also may be increased by the use of dextrose in the dialysate (166) and also by use of acetate dialysate (167). The major problem affecting long-tenn survival in dialysis. patients is cardiovascular disease, and in addition to the lipid abnonnalities described, the occurrence of hypertension appears to be a major factor. This underlines the importance of blood pressure control in all dialysis patients and also in patients with renal disease.

PAGE 32

...... OTA Manuscri.pt -31 -B. DESCRIPTION OF PRESENT-DAY PROCEDURES 1. Hemodialysis 000549 Hemodialysis require~ access to the bloodstream, a hemodialyzer, equipment to provide dialy:ate to the h11110dialyzer, monitoring devices and alanas; treated water for preparation of the dialysate, and staff to carry out the treatment. Hemodialyzers More than 250 different dialyzers are available, of which about two-thirds are hollow fiber dfalyzers and the remainder are parallel plate dialyzers. Coil dialyzers, which were very important in the: past, are now used only infrequently. The Membrane There are three basic types of membrane used in dialyzers: cellulose acetate and cellulose-derived materials, Cuprophan, and mbranes of synthetic materials such as polycarbonate, polyacrylo nitr11e, and polymethylmethacrylate. The type of membrane determines various characteristics of the dialyzer such as its thrombo genicity, its activation of conaplanent, and the occurrence of allergic reactions during dialysis. Dialyzers vary in their membrane surface area from 0.31112 to 2.Sm2, and they also vary in the thickness'of the manbrane. The latter detennines the clearance and ultrafiltration characteristics of the dialyzer and nonnally ranges from 8 microns to 40 microns.

PAGE 33

.. OTA Manuscript -32 -Blood volume in the dialyzer ranges from 25-185m1 and 1s relatively fixed in a hollow fiber dialyzer. but 1n a flat plate dialyzer is influenced by tranSIIIIDbrane pressure. Clearance rates of mst dialyzers are 1n the range of 55m1/m1n to l&c.1/min creat1nine clearance, and the ultrafiltrat1on rate (UFR) usually ranges from 0.51111/hr/lllllHg to lQnl/hr/lllllHg. Newer high flux d1alyzers are becoming available which have an even higher UFR. Thus there is a very wide range of dialyzers available with different physical characteristics, and a physician has a great deal of choice in picking the most appropriate one for the individual patient. This may be particularly important for dialysis of the patient with acute renal f~11ure who is extremely sick, for other unstable patients, and for pediatric patients. Excellent s1111111r1es and tabulations of the various dialyzers are available (168,169). Hemod1alysis is most often carried out three times weekly, the duration of dialysis generally being in the range of 3 to 5 hours, although the effects of even shorter dialysis times are being studied (170). Three-times-weekly dialysis is a compromise between the increase in the ti taken to prepare and to clean up after dialysis and the advantages to be gained from more frequent dialysis. Empirical experience has shown that for most patients three times weekly 1s the optinum. Some patients elect to d1alyze more fre quently; others, particularly those who may have significant residual renal function, may d1alyze only twice weekly.

PAGE 34

000551 OTA Manuscript 33 -Dialysis fs a remarkably safe procedure, and it has been est1ted that the death rate from technical or human error is only about 1 1n 75,000 dialyses (.171). This 1s equivalent to one death every 4801ears for dialysis 3 times weekly. There are several problems which can occur with dialysis. Blood leaks due to imperfections tn the llllllbrane are extremely rare, as are blood leaks related to h11111n error. However, other problems that Y occur with d1alyzers include anaphylactic an~ allergic reactions during dialysis (172,173). These may relate to inadequate removal of sterflants from the dialyzer before use, the leaching of substances from the potting terial in hollow fiber dialyzers, or allergic reactions to the membrane itself. Most reactions have occu~ed wfthCuprophan 111111branesi they have been less COIIIIIOn with dfalyzers using regenerated cellulose or other cellulosfc membranes, and affected patients do not react to synthetic menbranes such as polyacrylonitrfle. Probably the most important single cause of an allergic reaction fs the presence of residul ethylene o~ide, and ethylene oxide-related sensitization has been found fn a proportion of hemodfalysfs patients but not in patients treated only by peritoneal dialysis (174). In addition, fn ny of the patiants who experience an acute allergic reaction ft fs possible to demonstrate the presence of IgE against human serum albumin exposed to ethylene oxide (175). Unfortunately, ethylene oxide cannot be completely removed by the usual rinsing process, but changes in the manufacturing process are already

PAGE 35

. 00055~ OTA Manuscript -34 -occurring because the rate of severe hypersensitivity reactions has declined since 1982 when it was 3.5 reactfons per 100,000 hollow fiber dialyzers sold (176). Dialysate and the Dialysate Supply Systan Currently, mst dialysis equipment uses dialysate prepared from a concentrate which is diluted with treated water and which is then delivered to the artificial kidney. Usually, the dialysate is then discarded to the drain--single pass di1ly1is. The concentrate is diluted 1:34 with water, and the concentrate 1110st c0111110nly used includes-acetate rather than bicarbonate as anion because this allows concentrate preparation without precipitation of calcium salts (29). Generally, dilution is perfonned in a proportioninq unit which is part of the dialysis equipment. Bicarbonate dialysate has also been used with greater.frequency recently, even though it r,equires somewhat 1110re c0111plex equipment and is 1110re expensive. The dialysis equipment also includes various monitors required in order to make the procedure relatively safe, and in fact, single patient dialysis equipment was developed in Seattle in order to make overnight h..,dialysis a safe procedure for patients to carry out at holle. Typical monitors include a mnftor of pressure in the blood circuit, a blood leak detector, a temperature monitor, a negative pressure monitor which pennits estimation of transmembrane pressure and may directly allow measurement of ultraffltration, and an air detector to prevent the occurrence of air embolism with breaks in the extracorporeal circuit (177). Appropriate alanns are connected

PAGE 36

. } 000563 OTA Manuscript -35 -to themnitors and can be set to specific limits. Typically the equipment jncludes a blood pump_ as, while p1111pless dialysis can be done with cannulas and a low resistance system, the pressure 1n an artertovenous fistula is generally insufficient and a blood p11np is required to achieve an adequate blood flow rate. In addition, the equipment includes a heparin p111p to nta1n anticoagulation of the patient throughout dialysis. D1alysate composition, adjusted according to the choice of the physician and the nHds of the individual patient, is generally such as~ tch normal blood electrolyte levels or to induce changes 1n the patient's blood levels to IID" closely approach nonnality. Generally, the dialysate sodiUII concentration is set between 136-147mEq/L. Jhis 1s sanewhat higher than in the early years of dialysis because it has been found that use of a higher d1alysate sod1aa concentration is associated with less dialysis morbidity, pr1s1a11bly related to prevention of a sudden fall 1n plasma osmo la11ty with dialysis (178,179). The probl with using a high dialysate sodia content is that this Y increase thirst and consequently produce greater weight gain and Y result 1n hypertension and pulnary edaa between dialyses (180). Most patients tolerate a sod1111 concentration of 135mEq/L, and only in the minority is a higher or lower sodium concentration required to control problems during dialysis. Generally, if the sodi11n concentration of acetate dialysate has to.be increased, this should be done by addition of sodium bicarbonate.

PAGE 37

.j "_..,.__,_r::-....... ,_.._ __ ., ~. --~-.. ,-.. ....... 000554 OTA Manuscript -36 -The dia1ysate potass111n concentration 1s generally 2.0nEq/L, but the patient's serum potass111n should be monitored and the dialysate concentration altered as needed. Patients with pre dialysis potassi1a levels of greater than 6.QaEq/L usually need a lower potassf1111 concentration 1n the dialysate. Contrarywise, acutely 111 patients, those with severe acidosis,_ those receiving parenieral glucose and/or bicarbonate, and particularly those using a digitalis preparation, Y require a higher dfalysate potassi1111 ~ncentration to prev1nt the occurrence of cardiac ar.rhythmias during dialysis associated with a rapid reduction in serum potassi1111 1 evel (181). The calcf1111 content of d~alysate is adjusted 1n order to result i_n a slight net flux of calci1111 into the patient during dialysis so as to help to counter the calcfa deficiency which occurs in patients wfth chronic renal failure. The rec0111111nded dialysate calc11111 concentration 1s between 3 and 3.5 mEq/L. Patients dialyzed against a lower level than this frequently develop secondary hyperparathy rofdfSDI and increasing renal osteodystrophy, whereas a higher level than 3.SmEq/L results 1n hypercalcemia (182). The rec0111111nded dialysate magnesi1111 concentration is between 0.5 and 1.0nEq/L. Higher levels 111y result in hypennagnesania which can result in abnormal mineralization, and magnes11111~free d1alysate can result in magnes11111 deficiency (183). Glucose was used in dfalysate originally 1n order to enhance fluid removal during treatment, also providing extra calories and

PAGE 38

000555 OTA Manuscript -37 -reducing symptoms. However, the usual dialysate glucose concentration of 20Qngl appears to have little impact on th~ quality of dialysis, and as glucose is one of the mre costly constituents of d1alysate its use is probably not required. The buffer base in dialysate is used to correct the metabolic acidosis and bicarbonate deficiency which occurs fn uremfc patients, and to replace bicarbonate which diffuses from blood to dialysate if bicarbonate is absent fn the dialysate. Because calcf1111 and magnesf bicarbonate are relatively insoluble, particularly ath;gher pH levels and in concentrated solutions, acetate was substituted for bicarbonate when dialysate concentrate was first developed for proportioning systlllS (29). Acetate ts a physiological buffer which ts tabolized to bicarbonate tn the body. In a relatively ineffi cient dialysis, acetate dtalysate creates no probl because acetate ts presented to the body at a rate which was easily tabolized. With development of large surface area dialyzers the rate of acetate influx and bicarbonate loss increased, and ny patients develop clinical symptoms such as headache, vomiting, nausea, cramps, and hypotension (184). Symptallls appear to relate to an increase fn organic acid and acetate levels fn the blood, and COIIIJ>arison of 1nfus1on of acetate and of other organic acids has shown that hypoxemia and decreased sen.111 potassi11n, phosphate and glucose levels occur only with acetate infusion (185). Acetate has also been shown to cause myocardial depression and vasodilatation (186, may affect lipid synthesis (187), and is more likely to cause hemodynamic tnstabi11ty and symptoms during dialysis (184).

PAGE 39

,..... -~~-. t 000556 OTA Manuscript 38 -Bicarbonate dialysate may also havelong-tenn benefits. Patients on acetate dialysis generally have a lower predialysis bicarbonate level and this chronic acidosis Y be harmful to bone afnera11zatton. Ah11fr11111 complexes are less dialyzable fn the pH range 7-7.4, and mre rigid pH control with bicarbonate Y help to reduce the influx of al111in111 from dialysate to blood (153). The effect of long-ter11 bicarbonate dialysis on the lipid profiles is still _disputed, but several studies have shown that growth honnone rele1se Y be suppressed by acetate (188,189). It has al so been suggested that pla1111 ketone levels Y increase with increase of pla-acetate levels, suggesting honnonal variations facilitating fatty acid oxidation during acetate dialysis (190). On the other hand, bicarbonate dialysate is relatively unstable, is 1110re expen sive, and 1s nonbacteriostatic, although recently use of a stabi lizer his been reported to deal with this probl. water The water used for preparation of d1alysate is usually tap water fraa the local supply, and as such, likely contalllinants include particulate tter, bacteriological contaminants, and chlllfcal contfnants. Particulate 111tter does not cross the dialysis membrane but may obstruct conduits 1n the dialysate supply system, and so an appro priate filter in the water line 1s required to protect the system fraa dallage.

PAGE 40

000557 OTA Manuscript 39 -The dialysis membrane also acts as a barrier to both bacterial and P!'rogenic terials, and so dialysate does not need to be pyrogen-free or COllll)letely sterile. However, a Jar IIN!llbrane leak with unsterile dfalysate 111y result in septicfa, althouqh 111111 leaks are not usually a cause for concern. Pyrogenfc reactions may result from use of water for dialysate with a high bacterial count because of endotoxfns passing the lllllbrane, but not all febrile reactions are related to bacterial contllllination. Nevertheless,.bacterial growth in the dialysate and water supply systelll should be controlled. Methods have included the use of filters, ultraviolet light exposure, reverse 0S110sis, use of safe and ~ndialyzable disinfectants, and various combinations of these thods. Periodic culture of the water supply and of dialysate as it leaves the dialyzer fs recamended. A colony count in the Nater of greater than 200 co)onies/ml, and 1n the postdialyzer dialysate of greater than 2,000 colonies/ml, should tr1gaer search for a source of contamination. Various chical contaminants may be present in water, and suggested IIIXf .. levels for these have been set based on EPA standards for drinking water (191). Use of appropriate wter treatnt equipment should prevent ny of the hazards associated with chanicals, but in dialysis centers which do not use water treatment the pos-sibflity of chical contamination of the water should be monitored regularly.

PAGE 41

:-_. ---~-.. ... .i 000558 OTA Mlnu~cript -40 water treatment devices include water softeners, cellular filters. reverse osaosis devices. and deionizers. Water softeners are the lust expensive but are less reliable and serve to reduce calci111. gnesf111. iron. and nganese levels. They are parti cularly useful -tn areas with hard 1111ter but have a limited spectna act1v1ty--socli1.11 ts exchanged for cations, and fluor;de and other toxic substances IIIY not be N!IIDved. The most effective -ns of chical purification include deionization, reverse 0S111Dsis. and distillation, choice dependinq on delland and the type of contllll1nation. Deionizers are effective against mst chatcal contlll1nants. while reverse 0S110sis ts good for bacteriological, organic. and pyrogenic contamination. Generally, with 111111 demand situations deionizers are mre suitable, while for larger installations reverse 0S110sis. with or without one or more deionizers, has proved better. Charcoal filters are also valuable for removal of chlor1111nes, dithylnitrosuaines, and pyrogens. Disttllation requires a bulky apparatus, is energy-inefficient and expensive, and 1s rarely used. Technique of Dialysis During haodfalys1s. aovaent of solutes and water occurs aloflCJ the concentration gradients. The process of diffusion from an area of higher concentration to one of lower concentration is a net transfer of ss as a result of randolll thennal mevement. However, the dtalyzer also has another type of transfer, the process of ultrafiltration of plasaa water along with those solutes of small

PAGE 42

000559 OTA Manuscript -41 -enough .,lecular size to cross the membrane--this is called con vective transport. The latter is independent of the concentration gradient and depends chiefly on the aechanical pressure difference between the blo sides of the llllllbrane. Both diffusive and convective processes occur during conventional heaodialysis. Diffusion of a solute depends 111inly on mlecular size rather than peraeability of the lll!lllbrane. A.~ the size of the mlecule increases. the net ss transfer decreases. -Thus S1111ler mlecular weight solutes are rapidly removed by dialysis and removal rate 1s influenced by blood and dialysate flow rates. In contrast, larger mlecular wight substances are N!IIDYed less efficiently, and the rate of n!IIDYal ts not influenced by blood or dialysate flow rates, but rather by duration of the dialysis procedure. 2. Peritoneal Dialysis (192) Peritoneal dialysis ts dependent upon acces~ to the peritoneal cavity without undue risk of bacterial contamination and the deve lopment of peritonitis. For patients with chronic renal failure a per111nent indwelling s11astic catheter 1s the only practical method for long-ter111 treataent, and the usual catheter is the Tenckhoff catheter (73). As described previously, this has one, or mre commnly blo, dacron felt cuffs, the inner of which 1s placed iaae d1ately outside the peritoneum, and the outer of which is located just below the skin exit. The catheter is inserted either at the bedside using a trochar and cannula or may be inserted surgically.

PAGE 43

... -,.... ... ,"'1~ o ,,.., ..... ':_d --- .i,, ,.,, ,: .;. ... -' ,. '. OOO5G0 OTA Manuscript -42 -Once in place the catheter must be kept clean and dry, and before and after each dialysis the catheter exit site should be cleaned with ~tadtne or hydrog..peroxide. Careful attention must.be pafd to connection and disconnection rrom the catheter. during peritoneal dialysis. Various other peritoneal dialysis catheters have been devised, the one most c0111110nly used at the present time being .the loronto Western Hospital catheter (193). Complications ~ssociated with placement of indwelling peritoneal dialysis catheters include leakage of dialysis fluid, bleed ing, reflex ileus and, rarely, bowel perforation. Th~re are a number of long-tenn complications associated with peritoneal catheters including skin exit infection, most conmonly due to staphylococcus aureus or epidennidis. Tunnel infections also occur and may extend deep into the abdominal wall and can be a cause of repeated episodes of peritonitis. Catheter cuff erosion and prolapse may occur due to pressure and necrosis of the skin at the exit site. This requires elective catheter replacement. Catheter malfunction often presents as a failure to drain the peritoneal cavity at the start of dialysis, and outflow obstruction .ts 111.1ch more c0111110n than inflow obstruction. C0111110n causes include involvement of the catheter in adhesions. catheter malposftion, catheter entanglement in the omentum and catheter obstruction by incarceration of tissue. Dye injection and X ray is often helpful in elucidating the problem. Catheter revision may be required.

PAGE 44

'--',: t ... -~, ... .. ,, .. ". -000561 OTA Manuscript -43 -Failure to drain a1$O frequently occurs as part of a functional probl and responds to bowel stimulation by an enema. This treat nt should always be tried first before looking for a mechanical cause of catheter failure. The Peritoneal Mbrane The peritoneal membrane has a surface area ofbetween 1 and 2m2. Solute removal occurs by diffusion from the-blood in the peritoneal capillar.ies to the dialyzing solution infused into the peritoneal space (194). Solutes with molecular weights of up to 30,000 daltons may cross the peritoneal membranes. Solute removal depends on. dialysate flow rate, temperature, pH, and osmolality. Fluid removal with peritoneal dialysis is carried out by osmosis, using a dialysate of higher dextrose content. Dextrose 1s poorly absorbed across the peritoneal membrana and therefore creates an osmotic gradient for fluid removal (195). Intennittent Peritoneal Dialysis (IPD) Intennittent peritoneal dialysis generally is perfonned using a machine to deliver sterile d1alysate to the peritoneal cavity. After a suitable c;twell time, the machine may pump the fluid out or siphonage may be used. Spent dialysate can be collected in a container or may be delivered to a floor drain. The simplest piece Of equipment is a cycler which operates by gravity or a pump and feeds a fixed volume of sterile peritoneal dialysate stored in several

PAGE 45

., ~........ ............................... ,, ..... --...... ,!00 .... -... --. -............ ..,_ ...... _, ........... .~ OTA Manuscript -44 -large bags through an octupus head of tubing, through a heater -. chamber, and into the patient's pe~itoneal cavity for a preset dwell time. The peritoneal cavity is then drained automatically and the cycle repeated (196). Tht second type of equipment used for IPo, which unfortunately is no longer nufactured, depends on reverse osmosis to prepare sterile, pyrogen-free water which is then mixed with sterile concentrate by a proportioning pump in order to produce sterile peritoneal d~alysate (79). The dialysate is then pumped into the peritoneal cavity and tirs are used to preset the dura tion of inflow, dwell time, and outflow. While reverse osmosis equ1Pffl'nt is more complex and more expensive than a cycler, the supplies required for each dialysis are much less expensive because the dialysate is prepared in the machine and less plastic tubinq is used. Treatment is usually carried for 10-12 hours overniqht, 3 nights weekly. While peritonitis does occur, this should be less than one episode per 2 years. The in problem with IPD is the eventual occurrence of under dialysis as the patient's residual renal function declines, so requiring either longer dialysis time than many patien~s find convenient or 1110re frequent dialysis. In addition, the mortality rate appears to be greater with IPD than with long-tenn hemodialysis (197), although this may be more a question.of patient selection. Continuous Ambulatory Peritoneal Dialysis Continuous ambulatory peritoneal dialysis (CAPO} is a form of home peritoneal dialysis in which the patient dialyzes continuously

PAGE 46

... 000563 OTA Manuscript -45 -by infusing 2 liters of sterile dialysate from a flexible plastic bag into the peritoneal cavity (198). The bag is then rolled and carried fn a pocket or belt during a dwell time of 4 to 6 hours or overnight. During the dwell time the patient can be active and carry on mc,it noraal activities. At the end of the dwell time the dialysate is drained into the empty bag. This 1s then detached and replaced by a fresh bag which is used in turn to refill the peritoneal cavity. This process of drainage, disconnection, connection, and infusion takes 30 to 45 minutes. New techniq~es which allow disconnection from the bag during dwell time are being evaluated. Various techniques and equipment for connection and disconnection areavaflable, but so far none has been shown to be superior to nonnil connection and disconnection. CAPO is simple to carry out, does not require the assistance of a second person, allows the patient greater mobility, does not require use of a machine, and is well tolerated by ny patients. Its Jar problans are its continuous nature, 7 days weekly, from which the patient has little or no re~pite, and the risk of the occurrence of peritonitis which occurs an average of slightly mre than one episode per year (199). Repeated episodes of peritonitis may lead to technique failure due to reduced efficiency of dialysis, and it is then necessary to transfer the patient to hemod1alys1s.

PAGE 47

, -' __ ..,. __ ~_ ..... ____ ,,4_, .. ... ---~----.... ----~----,."------.. --...... --......... _, .... .... _... .... ... -----. _,..,. __ .. d ,. OTA Manuscript -46 -Continuous Cycling Peritoneal Dialysis Continuous cycling peritoneal dialysis (CCPD) is a combination .of IPD and CAPO in which the patient uses 1 chine (either a cycler or reverse osmosis equipment) for peritoneal dialysis overnight while sleeping (196). Prior to disconnection fn the morning, 2 li~ers of fresh dialysate are instilled into the peritoneal cavity, and this remains 1n place until connection for the next dialysis that evening. This technique reduces the nl&Dber of connections as compared with CAPO and so may lessen therisk of peritonitis. It also avoids the need and inconvenience of making bag changes during. the day. However, it requires nightly IPD for 8 hours or more to provide adequa~e dialysis. Complications of peritoneal dialysis The cmnp11cations associated with peritoneal dialysis include mechanical probls, infections and peritonitis, metabolic effects, cardiovascular and pulmonary problems. Mechanical complications include the occurrence of pain in the rectlln or bladder area due to malposition of the catheter. In addition, pain in the shoulder may be referred from the diaphragm and associated with abdominal distention with air or excess dialysate. Bleeding may occur into the peritoneal cavity, but despite appearances this is usually not a serious problem. Leakage of dialysate may occur around the catheter, and subcutaneous dissection with dialysate can occur when one of the catheter holes is outside the

PAGE 48

Fi'~Jt,t}}'.-. if~: !f\:. Y,r' ,~. 1 -..,_,.,_,.,, ___ ~, .. ,....._~ .. -:--~--~ ...... .,_ ... _.. _.... .... -~,.-.-.~----"'- ,._..,.., __ ,._,...,., ....... ---000565 OTA Manuscript -47 -peritoneal cavity, ~r with leakage through the peritoneal membrane into the muscles and subcutaneous tissues. The mst serious mechanical complication is bowel perforation, and the risk of this can be ain1m1zed by careful attention to detail during insertion of the peritoneal catheter. Peritonitis nmains the single most important c01nplication with all fonns of peritoneal dialysis. The incidence rate varies from facility to facility, but with IPD should be less than one episode per two years of treatment. The latest United States data on CAPO shows an infection rate of slightly more than one episode per year of treatment, and this has been slowly improving for several years (199). Bacteria can gain entry into the peritoneal cavity through the lumen of the catheter or by way of the catheter tract, and meticulous sterile technique during connection and disconnection is essential. Per1ton1t1s usually presents with fever, abdominal pain, tenderness, discomfort, and/or a cloudy peritoneal fluid on outflow. A specimen of fluid should be sent for gram stain, cell count and culture, and appropriate antibiotic therapy started. Many episodes .of peritonitis can be treated at home by suitably trained patients and without admission ta hospital. Infection may also occur along the catheter tract, and this requires Mticulous local care and the use of systemic antibiotics. Catheter replacement may be required with resistant or repeated episodes of catheter tract infections. Infection with hepatitis B virus can also be a problem.for peritoneal dialysis patients. Such patients should be vaccinated

PAGE 49

... .. ... .... OTA Manuscript -48 -000566 against this and should be tested routine-ly for hepatitis B because of the rtsk associated with the presence of high concentrations of virus 1n the peritoneal fluid. Whether a similar risk applies to patients who have antibodies to KTLV-111 or who have accuired innune def1ctency syndrome r111111ns to be detenntned. Metabolic probls associated with peritoneal dialysis include protein loss, which Y be as n1ch as 9 to 10g of protein daily However, most patients eating a diet containing 1.2g of protein/ kg body weight/day probably will not have probls with this. A second connon probl ts hyperglycia and hyperltpidemia associated with absorption of glucose from the dtalysate. The pulmonary complications of peritoneal dialysis include pneumonia and atalexis as a result of abd0111inal distention and limited respir~tory 1110vements. With rkecl abdominal distention, the volume of ~he exchange can be reduced to provide relief. Pleural effusion, when it occurs, is usually right-sided, presumably due to dialysate passing through a defect in the diaphragm. Cardiovascular probls can also occur, particularly in patients with preexisting cardiac problems who become either severely overdistended or severely vol11111 depleted 3. Sequential Ultraf11tration Sequential ultraftltration is the separation in time of the ultrafiltration process and diffusion dialysis (54-57). This may be particularly helpful in patients with hanodynamic instability.

PAGE 50

1t~~tt. ~ .,r.;_ ;}jt .. : .. \,-.. .. .... : 000567 OTA Manuscript -49 -During ultraf11tration, as fluid 1s removed cardiac output and stroke vol11111 decrease but systic vascular resistance increases, and as I result, blood pressure remains stable. This is 1n contrast to the diffusion dialysis process which, if associated with ultra filtration, results in a reduction in cardiac output and stroke vol1111 associated either with a decrease or wfth no change in systic vascular resistance, so resulting in hypotensfon. Thus isolated ultrafiltration pennits easier removal of a larger volume of fluid at a faster rate wi.thou~ the development of hemodynamf c syaptallls. Hemoctynic stability during ultrafiltration may relate to the fact that protains are not r11110ved during ultraf11tration. so that the plasaa oncotic pressure rises, with consequent refilling of the pl111111 space and intenance of blood pressure. In contrast, in diffusion dialysis, as the osmotic pressure of extracellular fluid declines, fluid mves into the cells and extr~cellular fluid vol1.111e 1s lost to both d1alysate and the intracellular space, resulting in a fall in blood pressure. A combination of initial ultrafiltration followed by diffusion dialysis, so-called sequential ultrafiltra tion, is helpful in ny patients with hemodynamic instability. COIIIPlications of ultrafiltration include worsenin~ of the tabolic acidosis, possibly due to mvanent of intracellular fluid into the extracellular space, thus lowering bicarbonate concentra tioni loss of bicarbonate with ultrafiltration (200)i and development of lactic acidosis. (201). Hyperkalemia has also been reported, perhaps related to movement of intracellular fluid into the extra cellular space and the associated metabolic acidosis. Hypotension

PAGE 51

' _.. -~-... ... .. J 000568 OTA Mlnuscript -50 Y occur 1f the ultrafiltration rate exceeds 0.5m1/min/kg body weight. In the lor_ag tenn, sequential ultraftltratton may lead to hypercalct and hyperphosphatfa, together with an increased parathyroid hon1Dn1 level and a decline fn nutritional status tn saae patients (202). Hanoffltration Thfs is the process of ultraftltratton wtth associated removal of uratc toxins by the convective process, and has s0111e resemblance to gla1111rular filtration. H11110filtration depends on use of a relatively porous llllllbrane to carry out the ultraf11trat1on, and I equfP1111nt to provide a carefully 111tered volume of fluid to repla~e the pla1111 that has been ultraftltered (110). Originally called diafiltrat1on, hemof11trat1on differs fro111 ultraffltratfon fn that the ultraf11tered fluid ts replaced by an electrolyte solution similar fn COIIIPOS1tton to pla1111. The restraint offered by the lllllllbrane to passage of a solute ts measured by the stevtng coefficient. This ts the ratio of the concentrations of solute on the filtrate side and the blood side of the aad>rane. A solute which passes freely across the menbrane will have a similar concentration on both sides of the membrane and a sieving coefficient of one. On the other hand, a solute which does not pass the 111a11br1n1 at all will have a sieving coefficient of zero~ Different solutes have sieving coefficients between these two values (203). Small molecules such as urea and creatinine pass

PAGE 52

... 000569 OTA Manuscript -51 -freely through a regular dialysis membrane, and if the concentration gradient is favorable, large quantities will be cleared by diffusion. In contrast,. larger 111Dlecules will not be cleared as readily and their clearance is negatively correlated with the stze of the mlecule. Wtth convective clearance, clearance is largely size independent and is dependent on solvent drag of water movinq through the lllllllbrane under a pressure gradient resulting in bulk mvement carrying solutes with it in about the s111e concentration as plasma. Thus for solutes which pass the 11181brane clearance is approximately equal to the volume of water filtered tn unit ti. Other factors which influence the transport of solutes are the Gibbs-Donnan effect of protein and the effect of ionic charge. The viscosity of the blood, related to h1m1tocrit and protein concentration, can also affect passage of solute through the llllllbrane. The technique of h11110filtr1tfon requires passage of blood from the patient through a h1111Dftlter where ultrafiltratton of plasma occurs as a result of a pressure gradient. This can be generated either by increasing pressure on the blood side or reducing pressure on the ultrafiltrate stde. Replacement fluid containing glucose and electrolytes in similar concentrations to plasma ts infused either before the blood enters the h1111Dfflter (predilutton) or after the blood leaves the hemoftlter {postd11utfon). Predtlutton hanofiltratton ts believed to result in better clearance of solutes (116), while postdilution is less expensive and more convenient as ft uses a smaller volume of replacement fluid (113). A comb;nation of these

PAGE 53

~~j--~--.J....~i-tt::t:' -[ -: ~. 1-.., ..... 1;:_?. ~-. --~ .. ..... 0 0 0 /IW .... 1\ ~,v OTA Manuscript -52 tNO techniques can be used. The size of the equipment is related to the nead for accurate repla~SDent of fluid, and an aut01111ted system which raoves and replaces 20-120L of fluid in 4 hours has to be technically caaplu to avoid the risk of an imbalance between the vol1a1 raoved and ~t replaced. In addition, unlike dialysate for haodi1lysis, the replacaent fluid IIUSt be sterile and pyrogen free. The cost and C0111Plexity of the equipment fs one of the major reasons why helllofiltration has not gained aore popularity in the United States. Its advantages are the increased clearance of larqe aolecular weight substances, the occurrence of less morbidity durinq dialysis, and better tolerance of the procedure. Haocl1afi 1 tr1tion. Hellodiafiltration is a combination of hemocl1alysis and hemofiltration in order to obtain the advantages of both (120,121). Thus ft relies on both diffusion and convection. Hemodiafiltration requires a Slllller volaae of replacement fluid, and allows the shortening of dialysis time by as 1111ch as 401 without signs or syaptalls of underdialysfs. At the same time, small mlecular weight clurances are enhanced, including phosphate clearance, and intra d1alytic 110rb1d1ty ts reduced. Investigation of the role of this treataent is continuing. Continuous Arteriovenous Hemofiltratfon Recently continuous arteriovenous hemofiltration using a small halof11ter and without a blood pump has b9'n used in some patients

PAGE 54

GO OS 71 OTA Manuscript -53 -with acute renal failure requiring dialysis (204). Initial results have bean encouraging, and this technique ts worthy of further evaluation. 4. D1alyzer Reuse D1alyzer storage and reuse was first attempted in 1964 using _anticoagulation and refrigeration of twin cotl dialyzers, the attached blood tubing sets and the contained blood (62). In 1967 a reuse technique was developed tn Seattle to save home dialysis patients the ti and trouble of rebuilding the nondisposable Kiil d1alyzer for each dialysis (63). A similar technique was developed. for disposable flat plate d~alyzers and hollow fiber dialyzers when these were first introduced, prt111rily to reduce the cost before the enactllent of the Medicare ESRD Progr tn 1973. However, following 1973, with the relatively generous reimbursement for outpatient hemodialysts, there was little incentive to reuse dialyzers. In recent years dialyzer reuse has become much more widespread in an attempt to contain the cost of dialysis, but there has also been considerable concern on the part of some patients reqarding both the short-and long-tena safety of reused dtalyzers. TNO major studies have conclud~d that dtalyzer reuse ts safe, efficacious, and not as~octated with any increased rate of complications (64,205). Many patients in Seattle have reused each of their dialyzers 6 or more times for 5 years or more without adverse effects. Apart from the economic considerations, a reprocessed dialyzer also carries a

PAGE 55

' ,.i,._ ~-.. ......... -.. ... ,~ ,,,,...,,-f,...,..., ... R __ ,, __ .... .,._ .. -,, _......,_ ---..... ------ ,\',' f :0.:, ... I 000572 OTA Manuscript -54 -lesser risk of causing allergic reactions, is associated with a lesser degree of leukopenia during dialysis, and is generally better tolerated (206). In recent years autalllted equi1111nt has been developed for cleaning and disinfection of dialyzers, and this equipaent can also check dialyzer functions such as fiber bundle vol1111 and ultraf11tration rate. The use of fon11ldehyde as the disinfecting agent fo~ reuse of dialyzers has been one llljor cause of concern. Recently, the Center for Disease Control has reconded use of a 41 formaldehyde solu tion for dialyzer reprocessing because of seasonal variation in the risk of bacter.1al contllllination with relatively nsistant organisms such as the aycobacteri1111 species. Use of 41 formaldehyde solution requires a larger vol1111 of rinsing fluid to r1110ve formaldehyde froa the dialyzer, and testing is necessary to insure that there has been COllll)lete re1110val prior to connection to the patient. Four percent fonaaldehyde is an unpleasant substance to wrk with, and spills require special handling. Development of antinuclear-like antibodies 111y occur as a response to residual formaldehyde reachinq the patient, and these antibodies have been implicated as a cause of haolys1s in saae dialysis patients (207). Because of these and other probllllS, new disinfectants such as Alcide are being examined as possible replacements for formaldehyde. Another concern with reuse is the possibility of inadequate dialysis, either because of diminished effective membrane surface

PAGE 56

.. 000573 OTA Manuscript -55 area or because of alterations to the lllelllbrane itself. However, aost studies have shown that ultrafiltration and clearance of small aolecular 111eight substances are not impaired with reuse. A IIUlllber of substances are available to clean the lllelllbrane for dialyzr reuse before it is disinfected. Hypochlorite bleach, reverse ultraf11trat1on. wter flush, hydrogen peroxide, peracetic acid and sodi111 hydroxide have all been used. While bleach is widely used. saae lllllbranes deteriorate with thiSi and in addition, cleaning Y be so CG111Plete that bleach-cleaned dialyzers Y behave like new dialyzers tn producing the first-use syndrome and are aore likely to be as~iated with significant CQIIPlement activa tion.

PAGE 57

000574 OTA Manuscript -56 -C. DIALYSIS SETTINGS ANO PRESENT-DAY PRACTICE IN THE UNITED STATES 1. Acute Renal Failure Acute renal failure is most c0111110nly caused by acute tubular necrosis, generally following 1scha, and is 1110st often associated with cardiovascular or hepato-biliary surgery, traumatic injury, sep~is or pancreat1tis. Consequently, almost all patients with acute renal failure are hospitalized because of the underlying cause and associated complications, and treatment is by in~hospital dialysis. Generally it is preferable to use single patient dialysis machines for this purpose rather than to have a separate area set aside for dialysis of patients with acute renal failure. Sicker patients require dialysis in the intensive care unit, but with appropriate plumbing and electrical connections it is possible to dialyze other patients who are less sick fn a regular hospital room. Generally, the equipment is the same as that used for patients wit~ chronic renal failure, including the use of water treatment as may be necessary. 2. Chronic Renal Failure The dialysis of patients with chronic renal failure can be done in a hospital, in a freestanding dialysis unit, or at home. The nomenclature is somewhat confusing.

PAGE 58

OTA Manuscript -57 000575 Hospital Dialysis A hospital may perfonn two fonns of dialysis: inpatient dialysis for hospitalized patients who suffer from chronic renal failure, and outpatient dialysis for outpatients with chronic renal failure. Inpatient dialysis for hospitalized patients with chronic renal failure is often managed in the same way as described previously for hospitalized' patients with acute renl failure. However, in smaller hospitals which have an outpatient dialysis unit, patients with acute renal failure may be treated in the dialysis unit. This is not necessarily 1n the best interests of the patient and staff because the patient with acute renil failure may require much closer surveillance than the outpatient with chronic renal failure. Also, it Y be disturbing to stable patients with chronic renal failure to be treated fn proximity to a patient with acute renal failure and multiple complications. Thus, wherever possible, inpatient dialysis should be provided either in the intensive care unit or in the individual patient's room. Only the stable patient with chronic renal failure who fs an inpatient for a condition such as minor elective surgery and who has relatively little in the way of complications should be treated in a hospital outpatient dialysis unit. Hospitals also may provide outpatient dialysis for patients with chronic renal failure. The Medicare ESRD Program divides institutions that provide outpatient dialysis for chronic renal failure into two categories: dialysis centers which are hospital

PAGE 59

.. ; :-~~.ll';',~r 1,. ,r .',;;>,-'-'I,-~'-'"...,~"""' ..... ~.), .. ,,!, ---~ 000576 OTA Manuscript -58 units that also provide all the usual services provided by hospitals, and dialysis facilities which are outpatient, freestanding dialysis units (see below) which contract with a hospital to provide in-hospital services for their patients. There are 662 hospitals out of a total of 1,368 institutions approved to provide chronic dialysis services in the United States (208). In Europe, in contrast, until recently at least, the majority of outpatient dialysis was carried out in hospital units. This can create confusion in cmnparing European and American statistics, as in Europe "hospital dialysis" for chronic renal failure generally means outpatient dialysis. The major advantage of a hospital dialysis unit is that it uses the existing administrative structure of the hospital, but the disadvantage is the higher overhead and other costs associated with hospital services. Also, there is evidence that hospital units may treat a sicker patient population than outpatient dialysis units. Out-of-Hospital Dialysis As noted above, more than half the institutions providin~ outpatient dialysis in the United States are "out of hospital," and these are categorized by the Medicare ESRD Progr as dialysis facilities. They have also been called freestanding, limited care or out-of-hospital dialysis facilities. It is only recently that such facilities have been developed in Europe. Typically, an out-of-hospital dialysis facility provides staff assisted outpatient dialysis and, like a hospital dialysis unit, can

PAGE 60

.. 000577 OTA Manuscript -59 provide all modalities of treatment other than inpatient d;alysis. Freestanding units may be associated with hospitals or may be independent. They 111y be nonprofit institutions or 111y be for profit and, in the latter case, Y be owned by individuals or by a corporate chain. One such entity, National Medical Care, currently dialyzes about one quarter of the patients in the United States. Self-Care Dialysis In the early 1960's it was realized that one of the major factors contributing to the cost of dialysis was personnel. By training the patient and family or other helper to perfonn dialysis at home the cost could be reduced significantly. This requires a specific home dialysis training progr, and both hospital and freestanding dialysis units Y have such a program. Patients may be trained for hollle dialysis, or 110re recently, s01111 patients have been trained to do self-care dialysis in the dialysis unit. Home dialysis involves the patient and a family member, or in some programs a paid dialysis helper when a family member is not available, in order to assist the patient to do their dialysis at home (209). While originally developed because of its cost-saving potential, home dialysis was soon found to have other advantages, and in particular, increasing patient independence, freedom, and opportunity for rehabilitation (210). Self-care dialysis in a dialysis unit has also been used for similar reasons, usually in a

PAGE 61

r, \OTA Manuscript -60 -000578 situation where a number of patients dialyze thselves, perhaps with the assistance of f111fly lllllllbers, and with minimal assistance fraa the staff. Self-care dialysis, whether in the hallll or fn I unit, requires an organized patient training progr. Trafnfng should begin as soon as possible after the patient ts started on di~lysfs so that indepen~ence can be encouraged. The staff providing traininq should be selected for their t11ching abilities as well as their knowledge of dialysis, and trafnfng should, ff possible, be carried out in an area separate fra111 that used for regular intenance di1lysfs. Thetrafning progru should include infonnation about kidney disease and its complications, blood access, diet, tnedications, and the various procedures for the form of self-dialysis selected by the patient. Training Y be on a one-on-one basts or aay be fn groups. Written materials, slides, posters, and videotape progrus hive all been used to assist with training. Training for home IPD and for CAPO and CCPD 1s of shorter duration than for home hemodialysis. GenerallyF peritoneal dialysis training takes one to t.o weeks, and helllOdialysis training takes from three weeks to three mnths. Patient progress needs to be assessed during training, and it is important that as far as possible the patient be made responsible for their own care fn order to avoid becoming overly dependent on the spouse or other helper. The availability of a paid.home dialysis helper pennits some patients to be trained for home dialysis who do not have a family member or whose family member is not

PAGE 62

' 00057:J OTA Manuscript -61 willing to undertake this (209). Successful home dialysis requires a careful initial assessnt of patient and family and the avail ability of good social NOrk follow-up. Self-care dialysis requires blood access that 1s easy to use, lfld st patients can be taught to insert their own needles into a suitable arter1ovenous fistula or graft. The d11lyzer used, duration of dialysis, and ultrafiltrat1on rate sho~ld beselected individually for the patient so 1s to ainiize the occurrence of symptoms during dialysis. S1ilarly, hypotensive drugs should be used with care in self-care dialysis patients. Dialysis equipment and water treatment should be chosen because of re11ab111ty, ease of use, adequacy of aonitoring, and availability of repair service and intenance support. Haae dialysis requires well organized follow-up services. Generally, the patient is reviewed aonthly in the physician's office and can fn ahud a 11Dnthly predialys1s blood S1111Ple for analysis, reports being sent to the physician, the training program, and the patient. Records should be kept of each dialysis and forwarded to the training progr. Arrang-nts st be de for provision of supplies and for ntenance and repair of equipment. Ongoing social mrk support, vocational rehabtl1tat1on services, and nutri tional advice are also 1aportant. In addition to being able to contact the physician, a home dialysis patient should at all times have ready access to a nurse from the training program who can advise as to what services are required in the event of a problem or aaergency.

PAGE 63

. :" -~ 000500 OTA Manuscript -62 Selection of Patients for Various Modalities of Dialysis This ts discussed in a further section. D. MANPOWER NEEDS Ltttl1 his been published on the npower needs associated with dialysis in different sittings {211,212). Thus this section will consist of general CG11111nts on npower requirements for direct patient care and those for supporting and 1dlllintstrativ1 services. 1. Acute Renal Failure Patients with acute renal failure are hospitalized, and in many cases will be sick enough to require treatmtnt fn an intensive care setting. N1phrolo9ists and other physicians Because acute renal failure usually occurs 1s a c0111plication of another condition, ny of these patients will have an attending physician who is not a nephrologist. Nevertheless, dialysis of patients with acute renal faflure should always be supervised by a naphrologist. With th1 availability of dialysis equipaent fn ny hospitals and the growth of outside services which will provide dtalysfs equipment and dialysis nurses to ho~pftals which do not possess these, dialysis for acute renal failure fs being carried out in many hospitals which do not have a chronic dialysis program. Nevertheless, with the large number of nephrologists in the United

PAGE 64

.. .. .. : : 000581 OTA Manuscript -63 States, it should always be possible for a nephrologist to be involvacl in the care of a patient with acute renal failura. Rff1sterad nurses Dialysis for acute renal failure should always be carried out by an ~periencacl Pegistered nurse trained in provision of both h81Dd1alysis and/or peritoneal dialysis in patients with acute renal failure. Where a facility does not have nurses trained tn dtalysts and ts using dialysis services provided from elsewhere, the proce dure should always be don by a suitably trained registered nurse provided by the outside agency. Dialysis t1ehnict1ns lacause of the severity of the patient's illness, dialysis in patients with acute ranal failure generally should not be done by a licensed practical nurse or a patient care technician. Equipment technicians w111 be required to ntafn, service and repair the equipment, the nUlllber being dictated by the quantity of equipment 1v11l1ble 2. Chronic Renal Failure Inpatient hospital dialysi~ The patient with chronic renal failure who requires in-hospital dialysis has other medical problems, and so ft is important that the dialysis be carried out by an experienced registered nurse. Because all patients with chronic renal failure should already be under the

PAGE 65

.. .. .'l 00058:! OTA Manuscript 64 -care of a nephrologist, he or she should continue to be responsible for the patient's dialysis. Generally speaking, licensed practical nurses and patient care technicians should not do the dialysis of the hospitalf~ICI patient with chronic renal failure. Outpatient hospital dialysis and 1fm1ted care staff-assisted dialysis Almst all ESRD patients are followed by a nephrologist who is responsible for thefr care. In addition, units providing outpatient d~alysis, whether hospital-based or freestanding, should be under the supervision of a medical director who fs a nephrologist, and who Y or 111y not be the nephrologist caring for the individual patient. As a general rule, outpatient dialysis should be under the supervision of a registered nurse trained in hemodialysis or peri toneal dialysis as the case Y be. Nevertheless, the ~nds-on dialysis care can be given by registered nurses, licensed practical nurses, or patient care technicians, provided that all have had appropriate training. As a general rule, one staff member should be able to care for at least three dialysis patients. Because administration of drugs may be required during dialysis, ft is generally advisable to have a registered nurse available, even ff the dialyses are perfonned by patient care dialysis technicians. In some states, the law requires that a registered nurse be present to supervise dialysis fn an outpatient unit. In situations where a large n1111ber of stable patients are being dialyzed, the patient-nurse ratio may be 4:1, 5:1 or greater, -at the discretion of the unit. There are

PAGE 66

.. 000583 OTA Manuscript -65 -also units which treat a large n11Dber of unstable patients with cardiovascular 1nstabflity and other medical problans during dialysis. In these circumstances, one nurse 111y be required for each blo patients on dialysis. However, this should not be necessary for the llljority of dialysis patients. Equipment technicians are required to ntain, service, and repair the dfalysfs equipment. No information 1s available on the nllllber of chines that can be cared for by one technician, and there is a lack of good job definitions. As a general rule, all the staff involved in the care of the patient treated in an outpatient dialysis unit should be failiar with dialysis, should hive been appropriately trained, and this training should be doc1111nted. Self-care dialysis training Self-care dialysis training is best provided by staff who are experienced in dialysis and who are chosen for their abilities to teaeh patients, to allow th to learn by making mistakes, and to encourage independence. These qualities are difficult to define, but training staff need to be selected carefully if a self-care dialysis training program is to be successful. Self-care dialysis in a dialysis unit Patients trained to perfonn their own dialysis require rela tively little assistance and supervision during dialysis. Consequently, one staff member can manage five, and perhaps as many as

PAGE 67

000584 OTA Manuscript -66 ten, patients carrying out self-dialysis. Such an individual need not nacessarily be a registered nurse, but could be a suitably trai~ lic1nsecl practical nurse or patient care technician. Howev1r. as I g1neral rule, it ts still preferable to have an experienced regfstlred nurse available on the pre11ises. Holle dialysis Holle dialysis generally requires the presence of a second person durfng dialysis, with the exception of continuous ambulatory peritoneal dialysis. Generally, a p.-tfent should be trained to carry out their own dialysis, utilizing a family menber or a paid dialysis helper to provide a second pair of hands and to assist the patient in carrying out the dialysis. Such fily manbers or dialysis aides need to be trained in the same way that the home dialysis patient is trained. Occasionally, very f~ependent patients may feel they can carry out their own hollle hemodialysis or home IPD without the assistance of a second person. In the case of home hemodialysis, this is particularly inadvisable as fatalities have occurred, usually associated with a blood leak or bleeding, when the patient has become unconscious and unable to resolve the probl. Consequently, no halle h..,dialysfs patient should dfalyze without a second individual readily available who knows enough to be able to discontinue dialysis and who is trained to handle likely emerqencfes. In the case of home IPD and CCPD, this may not be necessary as the probl1111s that occur related to the dialysis are unlikely to be so

PAGE 68

000535 OTA Manuscript -67 -acute as to render the patient unable to help themselves. CAPO by its very nature is a procedure that the patient carries out themself during their daily activities, and there is no need for the assis tance of a fy aallber or paid helper. The only exception is in the case of infants and very 511111 children treated by CAPO or CCPD. The latter treatment 111y be preferable in such children because CAPO; with its need for frequent changes, becomes a Jor time ca111itaent for the mother or other fily IIN!lllber involved. Supporting and acainistrative staff Supporting and adlll1n1strat1ve staff are required for P4tients dtalyzing as outpatients, and for patients dialyz1ng at home. Again, no good information is available as to how ny patients can be supported by one such individual. Nurses For successful home hemodialysis, it is importlnt that patients have good supporting services from the home dialysis training pro gra or from the dialysis unit following the patient. A nurse should be available 24 hours daily on call by telephone and pager in order to answer the patient's questions during dialysis, to discuss problems, and to make the decision as to whether the patient requires to speak to their physician, whether they should continue the dialysis, whether the patient should be referred to other indi viduals or services such as a social worker, equipment repair

PAGE 69

~\. ..... ~-~-~----" .. --.---.... ____ ---.. ----.... _____ ,.. -----------------.... ........ --... .. 000586 OTA Manuscript 68 -technician, etc. One nurse can provide on-call support for a large IIUllber of patients, and at the Northwest Kidney Center one nurse is on call for re than 200 patients dialyzing at hollle. Similarly, patients treated by any form of peritoneal dialysis should have a nurse who can be contacted at any ti to answer questions that Y arise. In addition, the training staff or other dialysis staff 111Jst be available to see hollle dialysis patients at the unit if there are questions to be answered or ainor technical issues to be resolved. Generally thi:s 1s not a llljor need for h810dialys1s patients, but for CAPO patients a nurse 1s required for various services such as tubing changes. and one nurse can be res pons 1 b 1 e for the care of 1020 such patients. EguiJ!l!flt technicians The equipment of the hollle dialysis patient aust be 111intained, serviced, and repaired. These services can be provided by equipment technicians from the nufacturer or supplier, or may be provided directly by the facility. Because the hcllle dialysis patient is usually well dialyzed, there is no need to have a 24-hour repair s1rvice available. Arrangaents should be such that an equipment probl in the hollle can be attended to promptly the following day so as to avoid the patient having to cane to the unit for a backup dialysis. Patients should be taught the basic maintenance of their equipment, but the equipment service technicia~ should provide. routine jor servicing, as well as responding to patient problems.

PAGE 70

OTA Manuscript -69 00058? Suppliers Home dialysis patients, whatever form of home dialysis theymay be undertaking, require provision of an adequate quantity of supplies. In ny cases, _this function is delegated to the nufacturer or an outside supplier, but it behooves the facility to insure that appropriate supplies are ordered. Sane facilities 111y provide supplies directly, allowing better inventory control, but otherwise inventory nagaent and accounting should be coordinated between the unit and the supplier. Social mrkers Dialysis, whether as an outpatient or at home, puts stress on patient and fy. and ny readjustments are required at the time when a new patient first starts dialysis. At a later stage, patients and their failies Y develop problllllS requiring the services of a social worker. Medicare regulations require that all dialysis facilities have the sen1ces of a social worker, but no criteria ttave been laid down as to how many patients one social worker can follow. The social wrker 111st be fi11ar with dialysis and the probllllS of dialysis patients. Generally, it is preferable for all new patients to be interviewed by a social worker prior to the start of dialysis, and during the early 1110nths of treatment a social worker should be available to provide advice and counseling, including advice on rehabilitation services and employment. Once the patient is established on dialysis social support must continue to be

PAGE 71

,) u OTA Manuscript -70 -available, but generally is not required to the same degree. In the Northwest Kidney Center program, one social worker is responsible for approximately 100 patients, includ~ng both center and home dialysis patients. Unfortunately, some facilities do not have a social worker w~o is closely involved in patient care, but rather have a part-time social worker who serves merely to mP.et the requirements of the Medicare regulations. Financial counselors Some facilities ploy financial counselors who specialize in the finances of end-stage renal disease and who can establish the patient's _financial responsibilities, the availability of various funding sources, and counsel the patient as to the best use of their resources. Such individuals can be invaluable to both patient and facility by insuring that patients take maximum advantage of the financial services available to them. As with social work support, financial counseling is particularly important at the time that a patient conmences dialysis. It fs also helpful if the patient's financial situation is reviewed on a regular basis in order to insure that the patient continues to make the best use of available resources. Nutritionists Diet is an important part of the management of patients with chronic renal failure, and recent evidence suggests that nutrition

PAGE 72

. ''' ... ,__.,,.,.,' .,"' ~-'" -~ ....... ...... '-----"""'' .,. .... -...................... ... -~-....... 000589 OTA Manuscript -71 -may be important in delaying the onset of dialysis (213). Once a _patient starts dialysis there is an ongoing need for nutri ti ona 1 services. New patients should spend time with a nutritionist, and a careful program of nutritional advice, support and regular review should be available for all dialys~s patients. Generally, one nutritionist can support as many as 100 dialysis patients. Administrative and other staff In the case of a hospital, most of the administrative services required by the dialysis unit are provided through the hospital. Nevertheless, each unit, whether in a hospital or freestanding, must have a medical director who should be a nephrologist. Many free.standing units also have an administrator who is responsible for such services as billing and accounting, personnel functions, and the.general supporting functions required in operating a dialysis unit. In some smaller units and in units that belong to larger organizations, much of the administrative services may be provided off-site by a central administration

PAGE 73

'// ll ,. OTA Manuscript -72 -E. CURRENT-EXPERIENCE WITH DIALYSIS 1. The Present-Day Patient Population Patient demographic data from the the Health Care Financing Administration are shown in rables I through 4. The changes in the patient population which ensued with passage of the Medicare ESRD legislation and subsequent general availability of dialysis and transplantation have been described {214). This paper ex~mined the dialysis patient populatiQns in 1967 and 1976, and showed the increase in the number of elderly patients, minoritis, especially blacks, the less educated and the less well-to-do. These changes have continued~ Most striking 1s the large percentage of patients aged 65 and older are on dialysis. Such patients accounted for ~5S of all dialysis patients in 1981 (215). There has also been a marked increase in the incidence of patients with diabetic end-stage renal disease, and this now accounts for more than 251 of new patients. These changes are important for two reasons. First, until recently patients over the age of 65 have not been considered as suitable candidates for kidney transplantation, although this may change with more experience with the use of cyclosporine. Second, the increase in the number of elderly patients and diabetic patients means that a much greater portion of the ESRD patient population is likely to have vascular and other complications which affect survival and also increase morbidity. The frequency of hospitalization is greater in these patients, with consequent financial impact on the cost of the Medicare ESRD Program. It is uncertain whether all the

PAGE 74

000591 OTA Manuscript -73 -patients with diabetic end-stage renal disease and all the elderly patients who might benefit from treatment a~e being referred. However, the proportion of elderly ESRD patients will continue to increase because of aging of the general population, and the dialy sis population 1n the United States is not likely to stabilize before the year 2030 (216). Transplantation is a. factor which will affect the future number of patients on dialysis. Assuming an increased availability of cadaver kidneys, it is likely that in the future the great majority of younger patients will receive a kidney transplant. Although there will continue to be a significant failure rate for cadaver grafts, with the patients then returning to dialysis, and while some of these patients will have high levels of cytotoxic antibodies making retransplantation both less probable and less successful, nevertheless, the number of patients on dialysis aged 35 and under is likely to decline in the future (216). Consequently, the pro portion of elderly patients on dialysis is likely to increase even further. 2. Selection of Treatment for the Individual Patient Patient and physician have a n1111ber of options to select from in deciding which modality of treatment is best for the individual patient. While some general guidelines are available, there remains the problem that good comparative infonnation on the best form of

PAGE 75

0005:)~ OTA Report 74 treatment for the individual patient is sparse. Much of the sur vival infonnation available does not take into account the effect of patient selection for different modalities of treatment. Friedlllan has listed the important factors governing selection of treatlllent as patient age, cause of renal failure, physician bias, patient bias, economic realities, and the use of 1nvest1gational treatments (217). Patient age Infants and children under the age of one generally do not do well with hanodialysis, and CAPO or CCPD, which reduce the time demands on the parents, my be the preferred fonns of dialysis. Transplantation 1n very small children has been more successful with the use of adult living-related donors {218), although shorttenn results with cadaver transplants are also said to be improving (219). In older children, hanodialysis, CAPO and CCPD are all effective fonns of treatment, but in general home hemodialysis, CAPO or CCPD are to be preferred rather than outpatient dialysis in order to give the best opportunity for schooling and leisure activities. Unfortunately, growth tends to be subnonnal in children on dialysis, but may improve following transplantation. Consequently, transplantation should be considered for all children, and it also offers the best opportunity to return to school and other activities (220).

PAGE 76

0 0 05 !J:J OTA Manuscript -75 -As noted earlier, almost half the new patients starting treat nt in the United States are aged 55 or older, and almost half the patients enrolled in the Medicare ESRD progra are 55 or older. These numbers will continue ta increase. Survival is less good than 1n younger patients, but nevertheless, the results of treatment with dialysis are such as to warrant treatment of patients at 111 ages. The question remaining to be answered is the role of transplantation in patients aged 55 to 70 now that cyclosporfne 1s available. Prior. ta cyclosporine, this age group did not do well with transplantation, primarily be~ause of lesser tolerance for steroids and their side effects. Now, ff enough kidneys bec0111e available, 1110re such patients Y be transplanted. Meanwhile, for patients over the age of 55 the best treatment probably 1s hemodialysis, and home dialysis is to be preferred when practical, but CAPO or CCPD.are reasonable alternatives for some patients. For patients in the age range from adolescence to late middle age--say 55 years--survival with both dialysis and transplantation fs at fts best. Nevertheless, assessment of comparative morbidity and mortality of patients in this age group is difficult because of the need to compare equivalent subpopulations 1n tenns of age, sex, race, socioeconomic status, and diagnosis. Transplantation will depend on availability of a living-related donor or a cadaver kidney. Generally, transplantation should be encouraged, particularly in younger patients, in order to maximize independence and rehabilitation.

PAGE 77

... 0005j~ OTA Manuscript -76 Where this is not available, home hemodialysis, CAPO or CCPO are preferable, but ny patients will, by default, be treated by long tera outpatient h-,dialysis. cause of Renal Failure This is also important in considering treatment. Some diseases recur following transplantation, and so oxalosfs, focal se!Jll9ntal glomerulosclerosis, and lllllllbranoproliferative glomerulonephritis may be relative contraindications to transplantation, and cancer, either pri111ry or metastatic, is an indication for delaying or avoiding transplantation. A significant number of patients who start dialysis may recover sufficient renal function to stop dialysis for a period of time. These include some of the patients with lfgnant hypertension, gouty nephropathy, renal cortical necrosis, and also patients with renal failure due to toxic nephropathy, especially in the elderly. Patients with renal failure due to these causes should be observed on dialysis for 6-12 months before transplantation is considered to give opportunity for any improvement in residual renal function. For patients with serious cardiovascular problems, peritoneal dialysis may be the treatment of choice, and CAPO Y be preferred for patients who want home dialysis but who do not have a partner. The overall role of CAPO remains uncertain. Enthusiasts argue that this should be the primary treatment for most patients today, but some are beginning to question the long-tenn use of CAPO because

PAGE 78

000595 OTA Manuscript -77 -the peritonitis rate is not improving, even after 7 years of exoe-rience (221). For selected patients CAPO is a very satisfactory fona of treatment; but unfortunately, because of the relatively high rate of technique failure, only a ainority of patients will be able to continue on CAPO for 111Dre than 3 years. Ideally, patients who can no longer be tnated by CAPO should be encouraged to undertake hale hllllOdialysis in order to maintain their independence, but this is not alNays possible. Peritoneal dialysis is in no way a contra indication to either living-related donor or cadaver donor transplantation. Intermittent peritoneal dialysis (IPD), while rela~ively simple to undertake, is ~pensive, even when used at honle, and as residual renal function declines patients Y require prolonged hours of treatment making this unacceptable. Continuous cycling peritoneal dialysis (CCPD) Y be a reasonable alternative, but its long-tenn value has not yet been established. Thus intenance hemodialysis rB11ins the usual mde of therapy for the majority of patients, particularly the elderly. Physician Bias Exination of data from around the world shows a wide vari ation in treatment distribution from country to country. In part, at least, these differences represent physician bias (222). For example, in Canada peritoneal dialysis is used to treat 351 of the dialysis patient population, whereas in the United States this is 151. Home hemodialysis is widely used in Australia and Canada, to a

PAGE 79

.. 0005.:lti' OTA Manuscript -78 -lesser extent fn the United States and Britain, and yet in Japan it accounts for less than lS of patients. The use of 111 fonns of home dialysis varies widely in different parts of the United States, SGlllt1s rkedly fn adjacent states; for example, the home dialysis rate 1n Indiana 1s a,ch higher thin in Illinois. Individual physician biases also occur. Transplant surgeons generally favor this over dialysis, and some nephrologist~ favor home dialysis or CAPO n,ch more than others (223). Patient Bias The patient should be actively involved in selection of their treatment, and they Y ignore the best intentioned medical advice. Fear, anger and hostility may all affect patient behavior at the ti when treatment 1s started. Many patients are not seen by a nephrologist until the ti to start dialysis, and patients are influenced by the attitudes of the physicians they meet. Religious beliefs also Y affect their decision. It is important that patients have access to as much relatively unbiased infonnation as possible. One approach to this is a specific orientation program during the first two 1110nths of dialysis to give the patient a better understanding of the various options available to them (224). Economic Situation Treatment choices also may depend on economics. In western nations, politics and economics may influence use of various fonns

PAGE 80

OTA Manuscript -79 000597 of treatment, and this is illustrated by comparing the treatment of end-stage renal disease in the United States and the United Kingdom (225). New Treatments As of today, intenance hemodialysis remains the standard against-which other treatments must be judged, age for age and diagnosis for diagnosis, in tenns of survival and morbidity. Nevertheless, hamodialysis is not ideal. The complications of uremia persist, rehabilitation is often incomplete unless the pat1ent is treated at home, and treatment remains expensive. Hemofiltration and hemodiafiltration were used to treat 2,867 patients in 25 countries throughout Europe in 1983, as compared to 76,179 patients on hemodialysfs (226). Ccnparable data is not available for the United States. The drop-out rate with hemofil tration is less than one thfrc:t of that with CAPO (115), and patients naged first by hemod1alys1s appear to tolerate and even prefer hemofiltration because of fewer symptoms. However, long-term patient experienc~ with hemoffltration is still minimal, and it remains an investigational procedure. Conclusion The choice of treatment for a uremic patient is still far from an objective exercise. Only with much more statistical information, and preferably with comparative trials of age-and diagnosis-matched

PAGE 81

OTA Manuscript -80 000598 treatments, will physicians and patients be able to review the options objectively, reflect on the various pressures, and make an infonaed decision as to which treatment is best for the individual patient. 3. Major Complications Table 5 illustrates the cC111110n causes of death in the dialysis population based on data frcn the Northwest Kidney Centerr The major cause of death remains cardiovascular and cerebrovascular disease, and this Y relate to both hypertension before and after starting on dialysis, and also to the lipid abnonnalities which are c0111110n in these patients. Smoking has also shown to be a major adverse factor in mortality from cardiovascular disease 1n dialysis patients (227). With patients now surviving for 20 years or more following the start of dialysis, the importance of prevention of vascular disease is paramount. Also, apart from progression of the renal disease itself, the major cause of progression to renal failure in patients with primary kidney disease is poorly controlled hypertension (228), and the diseased kidney appears particularly prone to further damage from hypertension (229). Consequently, it is bec0111ing obvious that control of hypertension is perhaps ths single most important factor that can be manipulated to prevent progression to renal failure, and this is true whether or not dietary means can also slow the progression of renal disease. The one change in causes of death that has occurred is the increase in the number of patients in whom dialysis is discontinued,

PAGE 82

-: .. _~ _, OTA Manuscript -81 00059~ either at the patient's request or, in the case of incompetent patients, at the request of relatives. Recent data from Minneapolis (230) amt on our experience at the No~llthwest Kidney Center ts that about 101 of all deaths occur after cessation of treatment. Diabetics and elderly patients are the -,st likely to have dialysis discon tinued because the quality of their life has deteriorated. In a population which dies predominantly from complications of cardiovascular disease and hypertension, a significant proportion of the mrbtdity 1s also associated with cardiovascular disease. This accounts for 201 or more of the hospitalizations of patients with end-stage renal disease tn our progr. Another 111jor problea for patients with end-stage renal disease ts the occurrence of campltcations related to blood access. The preferred mode of blood access is the native arteriovenous fistula (231), and where this is not available a n11nber of other techniques are available, the mst connon being an arteriovenous graft of Gortex or a vein graft (232). As many patients have the potential to survive for long periods of time, circulatory access requires careful planning and great attention to detail. Problems with access often relate to events occurring long before the patient requires dialysis. Casual placanent of indwelling intravenous .catheters in foreann veins during anintercurrent illness can result in thrombosis and loss-of veins so that it is not possible to establish a native arteriovenous fistula. It is therefore essential

PAGE 83

. -OTA Manuscript -82 i1 i\ fl ,r. I'\' : \ V u ~.} V:\J ..... that pat;ents with. early renal failure be aware that they should warn medical and nursing person~el not to use forearm veins for any purpose unless absolutely necessary. A we11-funct1onin9, 111ture fistula can be used for many years; we have one patient who has now used the same arteriovenous fistula for 20 years. Access surgery, whether an arteriovenous fistula or a graft, should be performed only by vascular-surgeons who devote a considerable part of their time to access surgery and who, with the nephrologist, can assume long-tenn-respons1bi11ty for maintenance of satisfactory circulatory access to each patient (233). The c011111Dn problems with arteriovenous fistulas and grafts include thrombosis and infection. For thrombosis, percutaneous angioplasty, injection of urokinase or streptokinase, or throm bectomy may be used; and in patients who have a tendency to recur rent clotting, a 511111 dose of aspirin or other antiplatelet agent may be helpful. Thrombosis occurring in a mature fistula is usually due either to a hypotensive episode or to pressure on the fistula during an unrelated procedure. Infection in fistulas is often related to needle punctures for dialysis and usually responds to antibiotics. In a 511111 proportion of cases, aneurysmal dilatation of the fistula Y occur but can usually be corrected surgically. Other complications include venous hypertension and ischemia of the hand, and occasionally cardiac and hemodynamic complications may be associated with the high blood flow through a fistula. Endothelial hyperplasia at the anastomosis sites and consequent thrombosis is

PAGE 84

00060-1 OTA Manuscript -83 lll)re c0111110n in arteriovenous grafts than with fistulas; transluminal angioplasty Y be used to correct this problm. Access surgery is uncomfortable, and if it has to be repeated frequently 1s discouraging to the patient. Consequently cmp11ca t1ons due to access should be a1n1a1zed. Nevertheless. access probllllS raain one of the 111jor reasons for hospitalization and for morbidity in dialysis patients~ accounting for 151 of hospitali zations 1n our program.

PAGE 85

; I ,, .. 000602 OTA Manuscript 84 -F. SURVIVAL RESULTS WITH DIFFERENT MODALITIES OF TREATMENT Over the years there have been a number of reports on survival of patients with end-stage renal disease with the various modalities of treatment. These have come from individual facilities and from national registries such as the European Dialysis and Transplant Registry (131), the Canadian Registry (234), and the Australian and New Zealand Registry (235). Unfortunately at this time, there is no comparable national ESRD registry in the United States. Consequently, in order to illustrate the effects of treatment, the following results, except when stated otherwise, relate to patients treated through the regional program based on the Northwest Kidney Center in Seattle. Over the year$ this program has treated more than 2,000 patients by the various modal_ities of dialysis and by transplantation (236). What has been clearly demonstrated is that survival of patients with end-stage renal disease depends on a number of factors. A~e at the time of starting treatment is one of the most significant of these. When survival curves are drawn based on ten-year age intervals, irrespective of the fonn of treatment, there is a smooth decrease in survival with increasing age, which suggests a linear relationship (Figure 1). Linear, quadratic, and cubic models have been developed, but neither the quadratic nor the cubic model give any significant improvement in fit over the linear model for describing the effect of age on survival. In our experience the only exception to this age relationship is in patients under the age of 15, and this presumably reflects the lesser survival in the youngest patients (those under the age of 5). Similar results have

PAGE 86

000603 OTA Manuscript -85 -been found by others (237). What should be noted is that for patient~ aged 65 and over, the 5-year survival, irrespective of treatment. is approximately 251. There was no difference 1n survival between males and females. When patient survival was studied by race, there appeared to be slightly better survival in "other" patients--primarily Asians and American Indians--than in blacks or whites, but this was not of stati s tical significance (Figure 2). Another major factor affecting survival is the cause of the renal disease. This has been analyzed for the c0111110ner causes of chronic renal failure--chronic glomerulonephritis, diabetic nephropathy. congenital renal disorders, polycystic kidney disease, pyelonephritis, and primary hypertensive disease (Figure 3). Patients with renal failure secondary to congenital disorders have somewhat better survival, presumably because of their younger age. Those with renal failure due to diabetic nephropathy or primary hypertensive disease showed significantly poorer survi val, presumably related to their generalized vascular disease. A further major factor affecting survival is the presence of pre existing disease or diseases at the time of starting dialysis. Figures 4 through 7 illustrate the effect of the presence of severe hypertension, cerebrovascular disease, cancer, and coronary artery disease on survival. There are significant differences related to all these preexisting problems. Survival is also related to the number of preexisting asso ciated diseases th~ patient has at the time of starting treatment, whether or not these are comparable in severity (Figure 8).

PAGE 87

~ ,,. .. .,, 000604 OTA Manuscript -86 -The other remaining major issue ;s whether survival is comparable in patients with. the different modalities of treatment. Patient survival has been compared with related donor transplantation, cadaver donor transplantation, and hemodialysis (238). The patient population was subdivided into those with diabetes or primary hypertensive disease as the cause for their renal failure, and those with other causes. While the duration of survival was less in the diabetic and hypertensive patients, the results of comparison of the modalities of trea'bnent were similar in both population subgroups. Related donor transplantation clearly had better patient survival than the other modalities of treat ment, but patient survival with hernodialysis and cadaver transplanta~ion ~as not significantly different when account was taken of the time spent on dialysis prior to transplantation, and of the differences in age, number of associated diseases, and year of treatment in the patient populations treated by the different modalities. This analysis used the Cox proportional hazards model (239). This leaves ~nanswered the question of comparison of survival with the different forms of dialysis. Conventional wisdom is that home hemodialysis patients have a better survival than center hemodialysis patients, that survival with CAPO may or may not be similar to that with hemodialysis, and that survival with intermittent peritoneal dialysis may be inferior. However, again, the problem is the different patient populations selected for the various treatments, selection being based on both medical and nonmedical factors. Consequently, the results in the patient population treated in the Northwest Kidney Center program between 1975

PAGE 88

000605 OTA Manuscript -87 -and 1985 has been analyzed using the Cox proportional hazards model. Comparisons were made between the different modalities of dialysis and with cadaver transplantation. When known risk factors were taken into account, intennittent peritoneal dialysi$ was found to be significantly inferior in tenns of survival in comparison with cente~ hemodialysis, home hemodialysis and CAPO. Horne hemodialysis survival was somewhat better than center hemodialysis, but not significantly so, and there was no signficiant differencein survival between home hemodialysis, CAPO, and cadaver transplantation. These analyses also confinned the importance of age and number of associated diseases as factors affecting survival, and showed that patient educational level had no bearing on this. Again, the year of treatment affected survival, patients treated more recently having better results than patients treated in the early years of the last decade. Unfortunately, there were not sufficient patient numbers to examine survival with CCPO. The importance of these results is the assistance they give in selection of treatment. Rather than survival, the decision as to the fonn of dialysis for a given patient should be based on an evaluation of differences in the complications associated with the various fonns of dialysis, and the potential effects of these on the patient's lifestyle, opportunity for rehabilitation, and family and social responsibilities. These same considerations should apply in making the decision as to whether a dialysis patient should receive a cadaver transplant. In this regard, the various reports on quality of life studies with different modalities of treatment are of importance (240,241). It also is apparent

PAGE 89

'I 000606 OTA Manuscript -88 -that intennittent peritoneal dialysis, at least three times a week IPD as practiced over the last tera years, is a fonn of treatment which results 1n inferior survival, pres1111ably because of inadequate dialysis as suggested previously (197). Consequently, it becomes important to gather infonnation on CCPD to see whether results with this may more closely resable those with CAPO. These findings also suggest that an integrated program providing all modalities of dialysis and transplantation gives the greatest opportunity for optimal treatment of patients with end-stage renal disease. Unfortunately, at this time there is not enough infonnation to compare survival with transplantation and dialysis in patients over the a~e of 65, but presumably these will not differ significantly from those illustrated ftere from a population representing all ages of patients.

PAGE 90

.. .. ., 000607 REFERENCES 1. Graham T: Liquid diffusion applied to analysis. Phil Trans Roy Soc London, 151:183, 1861. 2. Abel JJ, Rowntree LG, Turner BB: On the removal of diffusible substa~ces from the circulating blood by means of dialysis. Trans Ass Am Physicians, 28:51, 1913 3. Abel JJ, Rowntree LG, Turner BB: On the removal of diffusible substances from the circulating blood of living animals by dialysis. J Phannacol Exp Ther, 5:275, 1913-1914. 4. Haas G: Versuche der Blutauswaschung am Lebenden mit Hilfe der Dialyse. 1<11 n Wochenschr, 4: 13, 1925. 5. Benedum J: George Haas (1886-1971) Pionier der Hlmodialyse. Med Hist J, 14:196, 1979. 6. Thalhimer W: Experimental exchange transfusion for reducing azotemia. Use of the artificial kidney for this purpose. Proc Soc Exp Biol Med, 37:641, 1937. 7. Thorwald J: Die Patienten. Munchen-Zurich, Droemer-Knauer Verlag, 1975, p. 99. 8. Kolff WJ: De Kunstmatige Nier. M.O. Thesis, University of Groninqen, The Netherlands, Kampen,J. H. Kok NV, 1946.

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OTA References 2 -000608 9. Murray G, Delonne E, Thomas N: Development of an artificial kidney. Arch Surg, 55:505, 1947. 10. Merrill JP: Dialysis in acute renal failure. In: Replacement of Renal Function by Dialysis, chapter 17, edited by Drukker W, Parsons FM, Maher JF, Martinus Nijhoff, Medical Division, The Hague, Boston MA, London, 1st edition, 1978, p. 322. 11. Alwall N: On the artificial kidney. I. Apparatus for dialysis of blood in vivo. Acta Med Scand, 128:317, 1947. 12. Inouye WY, Engelberg J: A simplifed artificial dialyzer and ultrafilter Surg Forum, 4:438, 1953. 13. Kolff WJ: The artificial kidney--past and future. Circulation, 15;285, 1957. 14. Watschinger 8, Kolff WJ:_ Further development of the artificial kidney of Inouye and Engleberg. Trans Am Soc Artif Intern Organs, 1:37, 1955. 15. Kolff WJ, Watchsinger 8: Further development of a coil kidney. J Lab Clin Med, 47:969, 1956. 16. MacNefll AE, Doyle JE, Anthone R, Anthone S: Technfc with a parallel flow straight tube blood dialyzer. NY State J Med, 59:4137, 1959. 9~ ,.-' ..

PAGE 92

OTA References -3 000609 17. Doyle JE, Anthone R, Anthone S, MacNeill AE: Treatment of renal failure with a parallel flow straight tubing bl~od dialyzer. NY State J Med, 59:4149, 1959. 18. Skeggs LT, Jr Leonards JR: Studies on an artificial kidney. I. Preliminary results with a new type of continuous dialyzer. Science, 108:212, 1948. 19. Skeggs LT, Jr., Leonards JR, Heisler CR: Artificial kidney. II. Construction and operation of an improved continuous dialyzer. Proc Soc Exp Biol Med, 72:539, 1949. 20. Alwall N, Bergsten BWB, Gedda PO, Norviit L, Steins AM: On the artificial kidney. IV. The technique in animal experiments. Acta Med Scand, 132:392, 1949. 21. Alwall N, Norviit L, Steins AM: On the artificial kidney. VII. Clinical experiences of dialytic treatment of uremia. Acta Med Scand, 132:587, 1949. 22. Quinton W, Dillard D, Scribner eH: Cannulation of blood vessels for prolonged hemodialysis. Trans Am Soc Artif Intern OrQans, 6:104, 1960. 23. Quinton WE, Dillard D, Cole JJ, Scribner BH: Possible improvement in the technique of long-term cannulation of blood vessels. Trans Am Soc Artif Intern Organs, 7:60, 1961.

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OTA References -4 -24. Shaldon S: Proc Working Conf on Chron Dialysis, Seattle (University of Washington), December 3-5, 1967, p. 16. 25. Wetzels E: Hlmodialyse und Peritonealdialyse. Berlin, Heidelberg, New York, Springer-Verlag, 1969, p. 127. 26. Ki11 F, (Amundsen B): Development of a parallel flow artificial kidney in plastics. Acta Chir Scand (Suppl) 253:142, 1960. 27. Pendras JP, Cole JJ, Tu WH, Scribner BH: Improved technique of continuous flow hemodialysis. Trans Pin Soc Artif Intern Organs, 7:27, 1961 28. Murray JS, Tu WH, Albers JB, Burnell JM, Scribner BH: A conmunity hemodialysis center for the treatment of chronic uremia. Trans Am Soc Artif Intern Organs, 8:315, 1962. 29. Mion CM, Hegstrom RM, Boen ST, Scribner BH: Substitution of sodium acetate for bicarbonate in the bath fluid for hemodialysis. Trans Am Soc Artif Intern Organs, 10:110, 1964. 30. Grimsrud L, Cole JJ, Lehman GA, Babb AL, Scrfbner BH: A central system for the continuous preparation and distribution of hemodialysis fluid. Trans Am Soc Artif Intern Organs, 10:107, 1964. 31. Lindholm OD, Burnell JM, Murray JS: Experience in the treatment of chronic uremia in an outpatient c011111unity hemodialysis center. Trans Am Soc Artif lntern Organs, 9:3, 1963.

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000611 OTA References -5 -32. Nose Y: Discussion. Trans Am Soc Artif Intern Organs, 11:15, 1965. 33. Merrill JP, Schupak E, Cameron E, Hampers CL: Hemodialysis in the home. JAMA, 190:466, 1964. 34. Baillod RA, Comty C, Ilahi M, Konotey-Ahulu FID, Sevitt L, Shaldon S: Overnight haemodialys1s in the home. Proc Eur Dial Transpl Assoc, 2:99, 1965. 35. Curtis FK, Cole JJ, Fellows BJ, Tyler LL, Scribner BH: Hernodialysis in the home. Trans Am Soc Artif Intern.Organs, 11:7, 1965. 36. Scribner BH: Maintenance hemodialysis in perspective--1969. Proc 4th Congr Nephrol Stockholm, 3:110, edited by Alwall N, Berqlund F, Josephson BS: Basel, Munchen, New York, Karger, 1970. 37. Brescia MJ, Cimino JE, Appel K, Hurwich BJ: Chro~ic hemodialysis using venipuncture and a surgically created arteriovenous fistula. N Enql J Med, 275:1089, 1966. 38. Girardet RE, Hackett RE, Goodwin NJ, Frieanan EA: Thirteen months experience with the saphenous vein graft arteriovenous fistula for maintenance hemodialysis. Trans Am Soc Artif Intern Organs, 16:285, 1970. 39. Tellis VA, Kohlberg WI, Bhat DJ, Driscoll B, Veith FJ: Expanded poly tetrafluoroethylene graft fistula for chronic hemodialysis. Ann Surq, 189:101, 1979.

PAGE 95

OTA References 6 000612 40. Merickel JH, Anderson RC, Knutson R, Lipschultz ML, Hitchcock CR: Bovine carotid artery shunts in vascular ~ccess surgery. Com0lications in the chronic hemodialysis patients. Arch Surg, 109:245, 1974. 41. Scribner BH: Circulatory access--still a major concern. Proc Eur Dial Transpl Assoc, 19:95, 1982. 42. Scribner BH: Discussion. Trans Am Soc Artif Intern Organs, 11:29, 19~5. 43. Babb AL, Popovich RP, Christopher TG, Scribner BH: The genesis of the square meter-hour hypothesis. Trans Am Soc Artif Intern Organs, 17:81, 1971. 44. Christopher TG, Cambi V, Harker LA, Hurst PE, Popovich RP, Babb AL, Scribner BH: A study of hemodialysis with lowered dialysate flow rate. Trans Am Soc Artif Intern Organs, 17:92, 1971. 45. Babb AL, Farrell PC, Uvelli DA, Scribner BH: Hemodialyzer evaluation by examination of solute molecular spectra. Trans Am Soc Artif Intern Organs, 18:98, 1972. 46. Middle Molecules in Uremia and Other Diseases. Proceedings of the Symposium on Present Status and Future Orientation of Middle Molecules in Uremia and Other Diseases, Avignon, France, November 28-29, 1980. Artif Organs 4, Suppl 1981. 47. Babb AL, Farrell PC, Strand MJ, Uvelli DA, Milutinovic J, Scribner BH: Residual renal function and chronic hemodialysis therapy. Proc Clin Dial Transpl Forum, 2:142, 1972.

PAGE 96

000613 OTA References 7 -48. Von Hartitzsch B: The middle molecule in present day hemodialysis. Proc Clin Dial Transpl Forum, 2:149, 1972. 49. Milutinovic J, Cutler RE, Hoover P, Meijsen B, Scribner BH; ~easurement of residual glomerular filtration rate in the patient receiving repeti tive hemodialysis. Kidney Int, 8:185, 1975. 50. Gotch FA: Progress in hemodialysis. Clin Nephr, 9:144, 1978. 51. Gordon A, Gr~enbawn MA, Marantz LB, McArthur MJ, Maxwell rti: A sorbentbased low volume recirculating dialysate system. Trans Am Soc Artif Intern Organs, 15:347, 1969. 52. Gordon A, Better OS, Greenbaum MA, Marantz LB, Gral T, Maxwell MH: Clinical maintenance hemodialysis with a sorbent-based low volume dialysate regeneration system. Trans Pm Soc Artif Intern Organs, 17:253, 1971. 53. Wing AJ, Parsons FM, Drukker W: Dialysate regeneration. In: Replacement of Renal Function by Dialysis, Chapter 17, edited by Drukker W, Parsons FM, Maher JF, Martinus Nijhoff, Boston, 2nd edition, 1983, p. 323. 54. Bergstrom J, Asaba H, Furst P, Oules R: Dialysis, ultrafiltration, and blood pressure. Proc Eur Dial Transpl Assoc, 13:293, 1976.

PAGE 97

OTA References -8 000614 55. Shaldon S: Discussion. Proc Eur Dial Transpl Assoc, 13:300, 1976. 56. Jones EO, Ward MK, Hoenich NA, Kerr DNS: Separation of dialysis and ultrafiltration--Does it really help? Proc Eur Dial Transpl Assoc, 14 :-160, 1977. 57. lvanovich P, Huang C, Stefanovic N, Del Greco F: A useful adjunct to dialysis. Proc Eur Dial Transpl Assoc, 14:605, 1977. 58. Scribner BH: Substitution of bicarbonate for acetate in the dialysate for the care of a critically 111 patient. Dial Transpl, 6(nr3):26, 1977. 59. Samar R~: Bicarbonate and acetate hemodialysis. Contemp Dial, August 1981, p. 10. 60. Tolchin DO: Acetate metabolism and high efficiency hemodialysis. Int J Artif Organs, 2:1, 1979. 61. Graefe U, Milutinovich J, Follette WC, Vizzo JE, Babb AL, Scribner BH: Less dialysis-induced morbidity and vascular instability with bicarbonate in dialysa.te. Ann Intern Med, 88:332, 1978. 62. Shaldon S, Silva H, Rosen SM: Technique of refrigerated coil preser vation haemodialysis with femoral venous catheteri.?ation. Br Med J, 2:411, 1964. I',

PAGE 98

97. OOOGJ.5 OTA References -9 -63. Pollard TL, Barnett BMS, Eschbach JW, Scribner BH: A technique for storage and multiple re-use of the Kiil dialyzer and blood tubing. Trans Am Soc Art1f Intern Organs, 13:24, 1967. 64. Kant KS, Pollak VE, Cathey M, Goertz D, Berlin R: Multiple use of d1alyzers: ~dfety and efficacy. Kidney Int, 19:728, 1981. 65. Hales S: A method of conveying liquors into the abdomen during the operation of tapping. Philos Trans R Soc Lond (Biol) 43:8, 1744-1745. 66. Wegner G: Ch1rurg1sche Bennerkungen Ober die Peritonealh8hle mit besonderer BerDcksichtigung der Ovariotomie. Langenbecks Arch Chir, 20:51, 1877. 67. Blackfan KO, Maxcy KF: The intraperitoneal injection of saline solution. Am J Dis Child, 2:1257, 1918. 68. Ganter G: Ober die Beseitigung giftiger Stoffe aus den Blute durch Dialyse. MMW, 70:1478, 1923. 69. Fine J, Frank HA, Seligman AM: The treatment of acute renal failure by peritoneal irrigation. Am Surg, 124:857, 1946. 70. Odel HM, Ferris DO, Power MH: Clinical considerations of the problem of extrarenal excretion: peritoneal lavage. Med Clin North Am, 32:989, 1948. IJ7

PAGE 99

00061.6 OTA References :10 .-71. Weston RE, Roberts M: Clinical use of stylet catheter for peritoneal dialysis. Arch Int Med, 15:659, 1965. 72. Palmer RA, Quinton WE, Gray JE: Prolonged periotneal dialysis for chronic renal failure. Lancet, 1:700, 1964. 73. Tenckhoff H, Schechter H: A bacteriologically safe peritoneal access device. Trans Am Soc Artif Intern Organs, 14:181, 1968. 74. Boen ST: Peritoneal Dialysis in Clinical Medicine. American Lecture Series, Springfield, IL, Charles C. Thomas, 1964. 75. Maxwell MH, Rockney RE, Kleeman CR, Twiss MR: Peritoneal dialysis. JAMA, 170:917, 1959. 76. Boen ST, Mulinari AS, Dillard OH, Scribner BH: Periodic peritoneal dialysis in the management of chronic uremia. Trans Am Soc Artif Intern Organs, 8:256, 1962. 77. Boen ST, Mion CM, Curtis FK, Shilipetar G: Periodic peritoneal dialysis using repeated puncture technique and an automatic cycling machine. Trans Am Soc Artif Intern Organs, 10:409, 1964. 78. Tenckhoff H, Shilipetar G, van Paasschen WH, Swanson E: A home peritoneal dialysate delivery system. Trans Am Soc Artif Intern Organs, 15:103, 1969.

PAGE 100

. 000617 OTA References -11 -79. Tenckhoff H, Meston B, Shilipetar G: A simplified automatic peritoneal dialysis system. Trans Am Soc Artif Intern Organs, 18:436, 1972. 80. Gordon A, Greenbaum M, Maxwell ffi: Sorbent regeneration of peritoneal dialysate. Trans Am Soc Artif Intern Organs, 20A:130, 1974. 81. Lewin AJ: Sorbent based regenerative peritoneal dialysis system. Dial Transpl, 7:831, 1978. 82. Popovich RP. Moncrief JW, Decherd JB, Bomar JB, Pyle WK: The definition of a novel portable/wearable equilibrium peritoneal dialysis technique. ~bstracts, Trans Am Soc Artif Intern Organs, 5:64, 1976. 83. Oreopoulos DG: The coming of age of continuous ambulatory peritoneal dialysis (CAPO). Dial Transpl, 8:460, 1979. 84. End-Stage Renal Disease Program Quarterly Statistical Study, Health Care Financing Administration, Baltimore, 1985. 85. Scribner BH: A current perspective on the role of intennittent versus continuous peritoneal dialysis in the treatment of chronic renal failure. REnal Physicians Association Northeastern Meeting Proceedings, 3:76, 1979. 86. Diaz-Buxo JA, Fanner CD, Walker PJ, Chandler JT, Holt KL: Continuous cycle peritoneal dialysis: a prelimi.nary report. Artif Organs, 5:157, 1981. 91

PAGE 101

OTA References -12 000618 87. Messina EJ, Weiner R, Kaley G: Prostaglandins and local circulatory control. Fed Proc, 35:2367, 1976. 88. Goldberg L~: Cardiovascular and renal actions of dopamine: potential clinical applications. Phannacol Rev, 24:l, 1972. 89. Nolph KO, Ghods AJ, Van Stone J, Brown PA: The effects of intraperitoneal vasodilators on peritoneal clearances. Trans Am Soc Artif Intern Organs, 22:586, 1976. 90. Maher JF, Cassetta M, Shea C, Hohnadel DC: Peritoneal dialysis in rabbits. A study of transperitoneal theophylline flux and peritoneal penneability. Nephron, 20:18, 1978. 91. Nolp~ KO, Ghods AJ, Brown PA, Twardowsk1 ZJ: Effects of intraperitoneal nitroprusside on peritoneal clearances in man with variations of dose, frequency of administration and dwell times. Nephron 24:114, 1979. 92. Maher JF, Hirszel P, Abraham JE, Galen MA, Chamberlin M, Hohnadel DC: The effect of dipyridamole on peritoneal mass transport. Trans Am Soc Art1f Intern Organs, 23:219, 1977. 93. Gutman RA, Nixon WP, McRae RL, Spencer HW: Effect of intraperitoneal and intravenous vasoactive amines on peritoneal dialysis: study in anephric dogs. Trans Am Soc Artif Intern Organs, 22:570, 1976. /dV i (i r,

PAGE 102

'0 \ 000619 OTA References -13 -94. Limido A, Cantu P, Allaria P, Colombo L, Giangrande G: Velocita di flusso ed effetto dei fannac1 nella valutazione dell efficienza della d1alis1 peritoneale. Minerva Nephrol, 26:161, 1979. 95. Maher JF: P~inciples of dialysis and dialysis of drugs. Am J Med, 62:475, 1977. 96. Maher JF, Hirszel P, Lasrich M: Modulation of peritoneal transport rates by prostaglandins. Adv Prostaglandin Thromboxane Res, 7:695, 1980. 97. Thulin L, Samneglrd H: Circulatory effects of gastrointestinal hormones and related peptides. Acta Chir Scand (Suppl) 482:73, 1978. 98. Maher JF, Hirsz~l P, LeGrow W: Enhanced peritoneal penneability with methyl prednisolone. Clin Res, 26:64A, 1978. 99. Muirhead EE, Reid AF: A resin artificial kidney. J Lab Clin Med, 33:841, 1948. 100. Yatzidis H: A convenient hemoperfusion micro-apparatus over charcoal for the treatment of endogenous and exogenous intoxications, its use as an active artificial kidney. Proc Eur Dial Transpl Assoc, 1:83, 1964.

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OTA References -14 -101. Chang TMS: Microcapsule artificial kidney in replacement of renal function: with emphasis on adsorbent hemoperfusion. In: Replacement of Renal Function by Dialysis, Chapter 12, edited by Drukker W, Parsons FM, Maher JM. Martinus N1jhoff, The Hague, Boston MA, London, 1st edition, 1978, p. 217. 102. Yatzidis H, Oreopoulos D, Tr1antophy111dis D, Voudiclare S, Tsaparas N, Gavras C, Stravroulaki A: Treatment of severe barbiturate poisoninq. Lancet, 2:216, 1965. 103. Editorial: Hemoperfusion for acute intoxication with hypnotic dru~s. Lancet, 2:1116, 1979. 104. Gelfand MC: Charcoal hemoperfusion in treatment of drug overdosage. Dial Transpl, 6(nr8):8, 1977. 105. Winchester JF, Ap111ga MT, MacKay JM, Kennedy AC: Haernod1alys1s with charcoal. haemoperfusion. Proc Eur Dial Transpl Assoc, 12:526, 1975. 106. Winchester JF, Apiliga MT, Kennedy AC: Short tenn evaluation of charcoal hemoperfusion combined with dialysis in uremic patients. Kidney Int 10 (Suppl 7):S315, 1976. 107. Winchester JF: Symposium on sorbents in uremia: Part 4. Comparison of charcoal hemoperfusion with hemodialysis. Dial Transpl, 6(nr9):46, 1977. \ (1 }_

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\ () 3. 000621 OTA References -15 -108. Chang TMS: Haemoperfusion over micro-encapsulated adsorbent in a patient with hepatic coma. Lancet, 2:1371, 1972. 109. Williams R: Approaches to the development of artificial liver support. In: Artificial Organs, edited by Kennedy RM, Courtney JM, Gaylor JDS, Gilchrist T, London and Basingstoke, Maan111an Press, 1977, p. 403. 110. Henderson LW, Besarab A, Michaels A, Bluemle LW, Jr.: Blood purification by ultrafiltration and fluid replacement (diafiltration). Trans Am Soc Artif Intern Organs, 12:216, 1967. lLl. Brull L: L'ultrafiltration in vivo. CR Soc Biol (Paris) 99:1607, 1928. 112. Henderson LW, Livoti LG, Ford CA, Kelly AB, Lysaght MJ: Clinical experience with intennittent hemodiafiltration. Trans Am Soc Artif Intern Organs, 19:119, 1973. 113. Quellhorst E, Rieger J, Doht B, Beckmann H, Jacob I, Kraft B, Mietzsch G, Scheler F: Treatment of chronic uraemia by an ultrafiltration kidney. First clinical experience. Proc Eur Dial Transpl Assoc, 13:314, 1976. 114. Baldamus CA, Schoeppe w, Koch KM: Comparison of haemodialysis (HD) and post dilution haemof11tration (HF) on an unselected dialysis population. Proc Eur Dial Transpl Assoc, 15:228, 1978. Jo~

PAGE 105

. 000622 OTA References -16 -115. Quellhorst EA, Schuenemann B, Hildebrand U: Morbidity and mortality 1n long-term hemofiltration. Amer Soc Artif Intern Organs J, 6:185, 1983 116. Henderson LW, Colton CK, Ford C: Kinetics of hemodiaf11tration. II. Clinical characterization of a new blood cleansing modality. J Lab Clin Med, 85:372, 1975. 117. Shaldon S, Beau MC, Claret G, Deschodt G, 0ules R, Ramperez P, Mion H, Mion C: Haemofiltration with sorbent regeneration of ultrafiltrate: first clinical experience in end stage renal disease. Proc Eur Dial Transpl Assoc, 15:220, 1978. 118. Bergstrom J: Ultrafiltration without dialysis for removal of fluid and solutes in uremia. Clin Nephrol, 9:156, 1978. 119. Quellhorst E, Schuenemann B, Doht B: Treatment of severe hypertension in chronic renal insufficiency (CRI) by haemofiltration. Proc Eur Dial Transpl Assoc, 14:129, 1977. 120. Leber HW, W1zemann V, Techert F: Simultaneous hemofiltration/hemo dialysis (HF/HD): Short-and long-tenn tolerance, introduction of a system for automatic fluid replacement. Artif Organs, 4:108, 1980. l n '!.

PAGE 106

000623 OTA References -17 -121. Shinzato T, Sezaki R, Usuda M, Maeda K, Ohbayashi S, Toyota T: Infusion free hemodiafiltration: simultaneous hemofiltration and dialysis with no nead for infusion fluid. Artif Organs, 6:453, 1982. 122. Peters DK, Rees AJ, Lockwood CM: Plasma exchange in glomerular and related auto-allergic diseases. Proc Eur Dial Transpl Assoc, 14:409, 1977. 123. Houwert EA, Kater L, Hene RJ, Struyvenberg A: Plasma exchange in inmune cC1Dplex disease. Proc Eur Dial Transpl Assoc, 16:520, 1979. 124. Samtleben W, Blumenstein M, Gurland HJ: Membrane plasma separation: advantages and hazards. Eur Dial Transpl Assoc Abstracts XVIIth Congress, Prague, 1980, p. 84. 125. Sprenger K, Franz HE: Membrane plasma separation (MPS): procedureal reconmendations. Proc Eur Dial Transpl Assoc, 17:353, 1980. 126. Agashi T, Kaneko I, Hauso Y, Hayasaka Y, Sanaka T, Ota K, Amemiya H, Sugino N, Abe N, Ono T, Kawai S, Yamana T: Double filtration plasmapheresis. Trans Am Soc Artif Intern Organs, 26:406, 1980. 127. Pineda AA, Taswell HF: Selective plasma component removal: alternatives to plasma exchange. Artif Organs, 5:234, 1981.

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.. .. ... 000624 OTA References -18 -128. Bensinger WI: Plasma exchange and imnunoadsorption for removal of antibodies prior to ABO incompatible bone marrow transplant. Artif Organs, 5:254, 1981 129. London WT, DiF1glia M, Sutnick AI, Blumberg OS: Hepatitis in hemodialysis units: Australia antigen and host response. N Enal J Med, -281:571, 1969 130. Drukker W, Alberts C, Ode A, ~oozendaal KH, Wilmink J: Report on regular dialysis treatment in Europe, II, 1966. Proc Eur Dial Transpl Assoc, 2:90, 1966. 131. Brunner FP, Brayer M, Brynger H, Challah S, Fassbinder W, Oules R, Rizzoni G, Selwood NH, Wing AJ: Combined report on regular dialysis and transplantation in Europe, IV, 1984. Proc Eur.Dial Transpl Assoc, 22:3, 1985. 132. Szmuness W, Stevens CE, Harley EJ, Zang EA, Alter HJ, Taylor PE, Devera A, Chen GTS, Kellner A and the Dialysis Vaccine Trail Study Group: Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection. N Engl J Med, 307:1481, 1982. 133. Stevens CE, Alter HJ, Taylor.PE, Zang EA, Harley EJ, Szmuness W, and the Dialysis Vaccine Trial Study Group: Hepatitis B vaccine in patients receiving hemodialysis: inmunogenicity and efficacy. N Engl J Med, 311:496, 1984. I r, I ..,

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OTA References. -19 000625 134. Tabor E, Drucker JA, Hoofnagle JH, Apryl M, Gerety RJ, Sieff LB, Jickson DR, Barker LF, Pineda-Tamondong G: Transmission of non-A, non-B hepatitis from man to chimpanzee. Lancet, 1:463, 1978. 135. Vitviski L, Prince AM, Trepo C, Brotman B: Detection of virus-asso c_iated antigen in serum and liver of patients with non-A, non-B hepatitis. Lancet, 2:1263, 1979. 136. Galbraith RM, Dienstag JL, Purcell RH, Gower PH, Zuckennan AJ, Williams R: Non-A, non-B hepatitis associated with chronic liver disease in a ha11110dialys1s unit. Lancet, 1:951, 1979. 137. Raimondo G, Smedile A, Gallo L, Babbo A, Ponzetto A, Rizetto M: Mult1centre study of HBV-associated delta infection and liver disease in drug addicts. Lancet, 1:249, 1982. 138. Eschbach JW, Adamson JW: Anemia of end-stage renal disease (ESRD). Kidney Int, 28:1, 1985. 139. Shaw AB: Hemolysis in chronic renal failure. Br Med J, 2:213, 1967. 140. McDennott TF, Galbraith AJ, Corlett RJ: Inhibition of cell proli feration in renal failure and its significance to the uraemic syndrome: a review. Scott Med J, 20:317, 1973.

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OTA References -20 000626 141. Wallner SF, Vautrin RM: Evidence that inhibition of erythropoiesis is important in the anemia of chronic renal failure. J Lab Clin Med, 97:170, 1981. 142. Lindsay RM, Burton JA, Dargie HJ, Prentice CRM, Kennedy AC: Dialyzer blood loss. Clin Nephrol, 1:24, 1973. 143. Eschbach JW, Adamson JW, Cook JD: Disorders of red blood cell production in uremia. Arch Intern Med, 126:812, 1970. 144. Rastogi SP, Padilla F, Boyd CM: Effect of al1111inum hydroxide on iron absorption. Abstracts Am Soc Nephrol, 8:21, 1975. 145. Hamstra RD, Block MH, Schocket AL: Intravenous iron dextran in clinical medicine. JAMA, 243:1726, 1980. 146. Kopple JD, Mercurio K, Bl11111nkrantz MJ, Jones MR, Tallas J, Roberts C, Card B, SaltzmanR, Casciato DA, Swendseid ME: Daily requirement for pyridoxine supplements in chronic renal failure. Kidney Int, 19:694, 1981. 147. Eschbach JW, Adamson JW: Improvement in the anemia of chronic renal failure with fluoxymesterone. Ann Intern Med, 78:527, 1973.

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\c,,q. OO 0627 OTA References -21 -148. Alfrey AC, Miskell JM, Burks J, Contiguglia SR, Rudolph H, Lewin E, Hols JH: Syndrome of dispraxia and multifocal seizures associated with chronic hemod1alysis. Trans M Soc Artif Intern Organs, 18:257, 1972. 149. Alfrey AC, LeGendre GR, Kaehny WD: The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med, 294:184, 1976. 150. Parkinson IS, Beckett A, Ward MK, Feest TG, Hoenich N, Stronq A, Kerr DNS: AlL111init111 removal from water supplies. Proc Eur Dial Transpl ~ssoc, 15:586, 1978. 151. Piarides AM, Edwards JWG, Cullm UX, Jr., ~cCale JT, Ellis HA: Hemod1alysis encephalopathy with osteomalacic fractures and muscle weakness. Kidney Int, 18:115, 1980. 152. Short AIK, Winney RJ, Robson JS: Reversible microcytic hypochromic anaia in dialysis patients due to 1lmini1.111 intoxication. Proc Eur Dial Transpl Assoc, 17:226, 1980. 153. Gazek EM, Babb AL, Uve111 DA, Fry DL, Scribner BH: Dialysis dementia: the role of dialysate pH in altering the dialyzability of aluminum. Trans Am Soc Artif Intern Organs, 25:409, 1979.

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0006~i8 OTA References -22 -154. Berlyne GM: Aluminum toxicity in renal failure. Int J Artif Organs, 3:60, 1980. 155. Ulmer DD: Toxicity from aluminum antacids. N Engl J Med, 294:184, 1976. 156. Brown DJ, Ham KN, Dawborn JK, Xipell JM: Treatment of dialysis osteomalacia with desferrioxamine. Lancet, 2:343, 1982. 157. Pappenhe1mer AM, W11ens SL: Enlargement of parathyroid glands in renal disease. Am J Pathol, 11:73, 1935. 158. biu SH, Chu HI: Studies of calciwn and phosphorus metabolism with special reference to pattogenesis and effects of d1hydrotachysterol (ATlO) and iron. Medicine (Baltimore). 22:103, 1943. 159. Sherrard DJ: Renal osteodystrophy. Seminars in Nephrol, 6:56, 1986. 160. Lund J, Deluca HF: Biologically active metabolite of vitamin D3 from bone, liver and blood serum. J Lipid Res, 7:739, 1966. 161. Holick MF, Schnoes HK, Deluca HF: Identification of 1,25-dihydroxy cholecalciferol: a metabolite of vitamin D active in intestine. Biochemistry, 10:2799, 1971. )Ju l \ r, J -

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. '\ I. 000629 OTA References -23 -162. Lindner A, Charra B, Sherrard OJ, Scribner BH: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med, 290:697, 1974. 163. Gurland HJ, Brunner FP, Chantler C, Jacobs C, Scharer K, Selwood NH, Wing AJ: Combined report on regular dialysis and transplantation in Europe, VI, 1975. Proc Eur Dial Transpl Assoc, 13:3, 1976. 164. Bagdade JD, Shafrir E, Wilson DE: Mechanism(s) of hyperlipidemia in ehronicuremia. Trans Am Soc Artif Intern Organs, 22:42, 1976. 165. ~avdie E, Gibso~ JC, Crawford GA, Simons LA, Mahony JF: Impaired plasma triglyceride clearan~e as a feature of both uremic and post transplant tr1glyceridia. Kidney Int, 18:774, 1980. 166. Swamy AP, Cestero RVM, Campbell RG, Freeman RB: Long tenn effect of dialysate glucose on the lipid levels of maintenance hemodialysis patients. Trans Am Soc Artif Intern Organs, 22:54, 1976. 167. Gonzalez FM, Pearson JE, Garbus SB, Holbert RD: On the effects of acetate during hemodialysis. Trans Am Soc Art1f Intern Organs, 20A:169, 1974. }II

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I .., OTA References -24 0 fl O n ,.., l', ,, ,J \)" .. 168. Hoenich NA, Kerr DNS: Dialyzers. In: Replacement of Renal Function by Dialysis, Chapter 5, edited by Drukker W, Parsons FM, Maher JF, Mart1nus Nijhoff, Boston, 2nd edition, 1983, p. 106. 169. Sh1niberger JH, Miller JH, Gardner PW: Characteristics of available dialyzers. In: Clinical Dialysis, Chapter 5, edited by Nissenson AR, Fine RN, Gentile, DE, Appleton-Centry-Crofts, Norwalk, 1984, p. 99. 170. Keshaviah P, Berkseth R, Ilstrup K, McMichael c, Collins A: Reduced treatment time: hemodialysis (HD) versus hemofiltration (HF). Trans Am Soc Artif Intern Organs, 31:176, 1985. 171. Fr1tmnln EA: Controversy in renal disease. Dialysis-induced hypotension. Amer J Kidney Dis, 2:289, 1982. 172. Key J, Nahmias M, Acchiardo S: Hypersensitivity reaction on firsttime exposure to cuprophan hollow fiber dialyzer. Am J Kidney Dis, 2:664, 1983. 173. Popli S, Ing TS, Daugirdas JT, Kheirbek AO, Viol GW, Vilbar RM, Gandhi VC: Severe reactions to Cuprophan capillary d1alyzers. Artif Organs, 6:312, 1982. 174. Marshall C, Shimizu A, Smith EK, Dolovich J: Ethylene oxide allergy in a dialysis center: prevalence in hemodialysis and peritoneal dialysis populations~ Clin Nephrol, 21:346, 1984. ( I 1

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,'' \ \. \-~' ,, 000631 OTA References -25 -175. Granmer LC, Roberts M, Nicholls AJ, Platts MM, Patterson R: IgE against ethylene oxide-altered hwnan serm alb1111in in patients who hive had acute dialysi,s reactions. J Allergy Clin Innunol, 74:544, 1984 .. 176. Villaroel F: Incidence of hypersensitivity in hemodialysis. Artif Organs, 8:278, 1984. 177. Easterling RE: Mechanical aspects of dialysis including dialysate delivery systs and water for dialysate. In: Clinical Dialysis, Chapter 4, edited by Nissenson AR,. Fine RN, Gentile DE, AppletonCentury-Crofts, Norwalk, 1984, p. 53. 178. Ogden DA: A double blind crossover c0111J)arison of high and low sodium dialysis. Proc Clin Dial Transplant Forum, 8:157, 1978 179. Wehle B, Asaba H, Castenfors J, Furst P, Grahn A, Gunnarsson B, Shaldon S, Bergstrom J: The influence of dialysis fluid composition on the blood pressure response during dialysis. Clin Nephrol, 10:62, 1978. 180. Robson M, Oren H, Ravid M: Dialysate sodium concentration, hypertension and pulmonary edema in hemodialysis patients. Dial Transpl, 6:78, 1978.

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.. .. 000632 OTA References -26 -181. Wiegand CF, Davin TD, RaJi _L, Kjellstrand CM: Severe hypokalemfa induced by hemodialysis. Arch Intern Med, 141:167, 1981. 182. Regan RJ, Peacock M, Rosen SM, Robinson PJ, Horsman A: Effect of dialysate calc11a concentration on bone disease in patients on hemo dialysis. Kidney Int, 10:246, 1976. 183. Burnell JM, Teubner E: Effects of decreasing dialysate magnesium in patients with chronic renal failure. Proc Dial Transplan~ Forum, 6:191, 1976. 184. Pagel MD, Ahmad S, Vizza JE, Scribner BH: Acetate and bicarbonate fluctuations and acetate intolerance during dialysis. Kidney Int, 21:513, 1982. 185. K1rkendol PI, Devia CJ, Bower JD, Holbert RD: A comparison of the cardiovascular effects of sodium acetate, sodium bicarbonate, and other potential sources of.fixed base in hemodialysate solutions. Trans M Soc Artif Intern Organs, 23:399, 1977. 186. A1zawa Y, Ohmori T, Imai K, Nara Y, Matsuoko M, Hirasawa Y: Depressant action of acetate upon the human cardiovascular system. Clin Nephrol, 8:477, 1977. 187. Ahmad S, Haas L, Pagel M, Sherrard D: Improved lipid profiles with bicarbonate dialysis. Proc Clin Dial Transplant Forum, 10:186, 1980. }\ 1

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000633 OTA References -27 -188. Orskov H, Hansen AP, Hansen HE, Alberti KG, Noy GA, Nosadini R: Acetate: inhibitor of growth honnone hypersecretion in diabetic and non-diabetic uraem;c subjects. Acta Endocrinol, 99:551, 1982. 189. Schmitz O, Hansen AP, Hansen HE, Orskov H, Alberti KG: Acetate suppresses growth honnone secretion in uraic patients: hemodialysis and acetate infusion experiments. Artif Organs, 6:132, 1982. 190. Desch G, Polito C, Descomps B, Mion CM, Crastes de Paulet A: Effect of acetate on ketogenes1s during hemodialysis. J Lab Clin Med, 99:98, 1982 191. Renal-Disease and Detoxification Conmittee: American National Standards for Hemodialysis Systems. Arlington, Virginia, Association for the Advancement of Medical Instrumentation, 1982. 192. Nolph KO: Peritoneal Dialysis, 2nd Edition, Martinus Nijhoff Publishers, Boston, 1985. 193. Ponce SP, Pierratos A, Izatt S, Mathews R, Khanna R, Zellennan G, Oreopoulos DG: Comparison of the survival and complications of three pennanent peritoneal dialysis catheters. PD Bulletin, 2:82, 1982. 194. Nolph KO, Twardowski ZJ: The peritoneal dialysis system. In: Peritoneal Dialysis, Chapter 2, edited by Nolph KO, Martinus Nijhoff, Boston, 2nd edition, 1985, p. 23. 11.1"

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. 000634 OTA Report -28 \ 195. Henderson L: Ultrafiltration with peritoneal dialysis. In: Peritoneal Dialysis, Chapter 6, edited by Nolph KO, Martinus Nijhoff, Boston, 2nd edition, 1985, p 159. 196. Diaz-auxo JA: Continuous cyclic peritoneal dialysis In: Peritoneal Dialysis, Chapter 9, edited by Nolph KD, Martinus Nijhoff, Boston, 2nd edition, 1985, p. 247. 197. Ahmad S, ~allagher N, Shen F: Intermittent peritoneal dialysis: status reassessed. Trans P.111 Soc Artif Intern Organs, 25:86, 1979. 198. !40ncrief JW, P~pov1ch RP: Continuous ambulatcry peritoneal dialysis. In: Peritoneal Dialysis, Chapter 8, edited by Nolph KO, Mart1nus Nijhoff, Boston, 2nd Edition, 1985, p. 209. 199. Steinberg SM, Cutler SJ, Novak JW, Nolph KD: Report of the National CAPO Registry of the National Institutes of Health: Characteristics of Participants and Selected Outcome Measures for the Period January 1, 1981, through August 31, 1984. Potomac, Bl4ES Corporation, 1985. 200. Bosch JP, Saccaggi A, Glabman S: Alternatives in extracorporeal uria therapy. In: Clinical Dialysis, Chapter 28, edited by Nissenson AR, Fine RN, Gentile DE, Appleton-Century-Crofts, Norwalk, 1984, p. 681.

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. : 000635 OTA References -29 -201. Ing TS, Vilbar RM, Shin KO, Viol GW, Bansal VK, Geis WP, Hano JE: Predialytic isolated ultrafiltration. Dial Transplant, 7:557, 1978. 202. Glabman S, Geronemus R, von Albertini B, Kahn T, Moutousfs G, Bosch JP: Clinical trial of intenance sequential ultrafiltratfon on dialysis (UFD). Trans Am Soc Artff Intern Organs, 25:394, 1979. 203. Henderson LW: Biophysics of ultraffltratfon and hemofiltration. In: Replacement of Renal Function by Dialysis, Chapt~r 12, edited by Drukker W, Parsons FM, Maher JF, Martinus Nijhoff, Boston, 2nd edition, 1983, p. 242. 204. Lauer A, Saccaggi A, Ronco C, Belledonne EM, Glabman S, Bosch JP: Continuous arteriovenous hemofiltration 1n the critically 111 patient: clinical use and operational characteristics. Ann Int Med, 99:,ss, 1983. 205. Pollak VE, Kant KS, Parnell SL, Levin NW: Repeated use of dialyzers is safe: long-tenn observations on morbidity and mortality fn patients with end-stage renal disease. Nehpron, 42:217, 1986. 206. Chenoweth DE, Cheung AK, Ward DM, Henderson LW: Anaphylatoxin ~onnation during hemodialysis.: comparison of nfl:i arid re-used dialyzers. Kidney Int, 24:770, 1983. I I J

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r' ; 000636 OTA References -30 -207. Fassbinder W, Koch KM: A specific hemolytic anemia indced by fonnaldehyde sterilization of dialyzers. Contr Nephrol, 36:51, 1983. 208. Health Care Financing Aaninistration: End-Stage Renal Disease Program Highlights, 1984. 209. Clark MF: Experience with paid dialysis helpers. J Amer Assoc Nephrol Nurses and Technicians, 4 (suppl):39, 1977. 210. Blagg CR, Hickman RO, Eschbach JW, Scribner BH: Home hemodialysis: six years' experience. N Engl J Med, 283:1126, 1970. 211. Orrell FL, Butts ES, Barbour BH: Nephrology Manpower Study: Final Report. A Report to the California C~ittee on Regional Medical Programs, Project #XFV-11. Professional Staff Association, Inc., of Los Angeles County/University of Southern California Medical Center, Los Angeles. CA, 1973. 212. Mapes D, Hoppers. Jones v. Johnson J, Fannell NA: Project to Develop a Staffing Guideline Systan in ESRD Network #3. ESRD Network Coordi nating Council 13, Sausalito, CA, 1981 213. Mitch WE: The influence of the diet on the progression of renal insufficiency. Ann Rev Med, 35:249, 1984. 'Ir, rt

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..I .... OTA References -31 -214. Evans RW, Blagg CR, Bryan FA: Implications for health care policy: a social and demographic profile of hemodialysis patients in the United States. JAMA, 245:487, 1981. 215. Eggers PW, Connerton R, McMullan M: The Medicare experience with endstage renal disease: Trends in incidence, prevalence, and survival Health Care Financing Review, 5:69, 1984. 216. Krakauer H: Technical report on inmunosuppressants in renal trans plantation prepared for the Task Force on Organ Transplantation and ti.,e Office of Organ Transplantation, HSRSA, PHS, 1985. 217. Frin EA: Choosing uremia therapy in the mid-19801s. Transplantation Proc, 17:23, 1985. 218. Miller LC, Bock GH, Lum CT, Mauer SM: Transplantation of the adult kidney into the very small child: Long-tenn outcome. J Pediatr 100:675, 1982. 219. Arbus GS, Hardy BE, Balfe JW, Churchill BM, Steele BT, Baumal R, Curtis RN: Cadaver1c renal transplants in children under six years of age. Kidney Int, in press. 220. Fine RN: Renal transplantation for chi14ren -the only realistic choice. Kidney Int, Suppl 17:S-15, 1985. I I'

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, I ,, 1 000638 OTA References -32 -221. Fenton S, Pei Y, Delmore T, Cattran D, Bo\ttfflan C, JohnstonN, Campbell \ I, Richardson R: The peritonitis rate (P) is not improving with time. Abstracts Amer Soc Artif Intern Organs, p. 37, 1986. 222. Porter GA, Lawson L, Buss J: Bias in selecting treatment for end-stage renal disease. Kidney Int Suppl 17:S-34, 1985. 223. Friedman EA: Physician bias in uria therapy. Kidney Int, Suppl 17, S-38, 1985, 224. Eschbach JW, Seymour M, Potts A, Clark M, Blagg CR: A hemodialysis orientation unit. Nephron, 33:106, 1983. 225. Rennie D, Rettig RA, Wing AJ: Limited resources and the treatment of end-stage renal failure in Britain and the United States. Quart J Med, 56:321, 1985. 226. Kramer P, Broyer M, Brunner FP, Brynger H, Challah S, Oules R, Rizzoni f G, Selwood NH, Wing AJ, Balas EA: Ccnbined report on regular dialysis and transplantation in Europe, XIV, 1983. Proc Eur Dial Transpl Assoc, 21:5, 1984. 227. Haire HM, Sherrard DJ, Scardapang D: Smoking, hypertension, and mortality ina maintenance dialysis population. Cardiovasc Med, 3:1163, 1978. ,~o

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\ ) .. ~. t--OTA References -33 000639 228. Parving H, Anderson AR, Smidt UN, Sevendsen PA: Early aggressive antihypertensive treatment reduces rate of dec11n in kidney function in diabetic nephropathy. Lancet, 1:1175, 19~ 229. Baldwin OS: Chronic glomerulonephritis: non-iunologic mechanisms of progressive glomerular damage. Kidney Int, 21:109, 1982. 230. Neu S, l(jellstrand CM: Stopping long-tenn dialysis: an pirical study of withdrawal of life-supporting treatment.' N Engl J Med, 314:14, 1986. 231. ~ole JJ, Hickma~ RO, Dennis MB, Jr., Jensen W, Scribner BH: Pennanent circulatory access--past, present and future. In: Access Surgery, edited by Kootstra G, Jorning PJG, NTP Press, Ltd., Boston, 1982., p. 1. 232. Haimov N, Burrows L, Schanzer H, Neff M, Baez A, Kwun K, Slifkin R: Experience with arterial substitutes in the construction of vascular access for hemodialysis. J Cardiovasc Surg, 21:149, 1980. 233. Clnadian Renal Failure Register--1984 Report, Kidney Foundation of Canada, Ontario, Canada, 1985. 234. Disney APS: Eighth Report of the Australia and New Zealand Combined Dialysis and Transplant Registry (ANZDATA). The Queen Elizabeth Hospital, Woodville, South Australia, 1985. I~\ I

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' t~ I ,, ~. OTA References -34 00064~ 235. Blagg CR, Wahl PW, Lamers JY: Treatment of chronic renal failure at the Northwest Kidney Center, Seattle, from 1960 to 1982. Amer Soc Artif Intern Organs J, 6:170, 1983. 236. Hutchinson TA, Thomas DC, Lieux JC, Harvey CE: Prognostically controlled comparison of dialysis and renal transplantation. Kidney Int, 26:44, 1984. 237. Vollmer WM, Wahl PW, Blagg CR: Survival with dialysis and trans plantation in patients with end-stage renal disease. N Engl J Med, 308:1553, 1983. 238. Cox DR: Regression models and life tables (with d~scussion). JR Stat Soc (B), 34:187, 1972. 239. Johnson JP, McCauley CR, Copley JB: The quality of life of hemod1alysis and transplant patients. Kidney Int, 22:286, 1982. 240. Evans RW, Manninen DL, Garrison LP, Jr., Hart LG, Blagg CR, Gutman RA, Hull AR, Lowrie EG: The quality of life of patients with end-stage renal disease. N Engl J Med, 312:553, 1985

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000641 TABLE 1 Medicare ESRO Program incidence rates per million population, by age, sex, and race: 1978-80 Percent Age, su, and r.ace 1978 1979 1980 change 1978-80 Total 71 78 82 15 ASE 0-14 years 6 6 7 17 15-24 years 26 26 24 -8 25-34 years 53 54 58 9 35-44 years 85 84 86 1 45-54 years 120 135 136 13 55-64 years 173 193 204 18 65-74 years 208 230 241 16 75 years and over 96 134 153 59 SEX Male 82 90 95 16 Female 61 67 70 15 RACE White 59 63 67 15 Black 159 184 185 16 All other 118 131 140 19 Reprinted fraa HCFA Review 5:69, 1984 ......

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\ ; ; 000642 TABLE 2 Medicare ESRD program incidence rates per million population, by age, sex, and race: 1978-80 average. Race ~11 Persons AFit te A11 lltiier Total Ra1e Female Total Aa1e Fema1e Tota1 Aa1e Fema1e .. TOTAL 77 66 63 74 52 169 186 154 04 years 3 3 2 3 4 3 2 3 2 5-9 years 6 7 6 6 7 6 6 1 5 10-14 years 13 13 12 12 13 12 14 16 13 l&-19 years 21 23 19 1"9 21 17 30 32 27 20-24 years 32 37 28 28 31 24 57 70 46 25-29 years 46 55 37 38 44 31 94 122 70 30-34 years 61 75 47 48 58 39 143 196 99 35-39 years 76 95 58 59 72 46 196 266 138 40-44 years 95 116 75 71 86 56 263 340 199 45-49 years 119 140 99 88 105 72 345 413 286 50-54 years 145 164 127 107 125 91 440 492 396 55 59 years 174 197 153 130 153 109 547 586 514 60-64 years 204 234 177 157 .190 129 616 639 597 65-69 years 220 265 183 175 224 135 633 646 623 70-74 years 218 279 173 179 243 132 591 609 576 75-79 years 183 256 136 154 228 107 496 532 469 a>-84 years 128 201 87 111 183 72 310 372 268 85 years and over 43 84 25 40 82 21 71 99 56 Reprinted from HCFA Review 5:69, 1984. -~--

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tiX' ;),I {f\ ~!:, I ; \ ijt .. :. r,; '<" TABLE 3 Prtaary dtagnosts for newly entitled ESRD persons: 1973-80 1973 and prior 1974 1975 1976 1977 1978 1979 1980 NUIIIER CF PERSClfS 13,320 6,553 6,805 6,245 7,226 7,505 8,315 9,310 Percent distrtbutton All CAUSES 100 100 100 100 100 100 100 100 &laaerulonephrttts 36.4 29.2 27.1 24. 7 23.5 21. 7 21.0 19.7 Prtaary hypertensive disease 13.2 13.9 15.0 15.8 20.4 22.2 22.1 23.4 Dtlbettc nephropathy 7.0 11.9 12.2 14.0 15.8 18.0 18. 7 21.8 Polycysttc kidney disease 8.7 7.5 6.5 7.0 6.7 6.4 6.1 5.9 Collagen vascular disease 1.5 2.0 1.8 1.8 1.3 1.7 1. 4 1.4 lntesttttal nephritis, heredtt1ry 1.5 1.4 1.0 1.6 1.2 .1 1.0 1.0 lntersttttal nephrttts, other 1215 10.4 1010 9.4 7.2 6.6 6. 7 6.4 Analgesic abuse nephropathy ( ) .1 ( ) .2 1.0 1.0 1 ., 1.1 Obstructive uropathy, acquired .3 .2 .1 .4 2.2 2.5 2.5 2.4 Obstructive uropathy, congenital 1 1 1 .5 1.5 1.3 1. 5 1.1 Alflotdosts (1) ,1, (l) .1 .5 .6 .4 .5 Multiple MyelClla 1 (1) 1 1 .8 1.0 1. 0 1.0 Gouty nephropathy cl> (1) ,1) I cl, .3 .3 .3 .5 Other, unspectfted 9.4 12.5 13.3 I 12.1 7.8 6.5 6.1 5.0 Etiology unknown 9.0 11.0 12.8 12.4 9.6 9.5 10.1 8.8 1 Less than 1 percent. Reprinted f ran tl:FA Review 5:69, 1984. ..

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I .. '.'';, {iJ "" ~T TABLE 4 Medicare ESRD progra tnctdence, by diagnosis and age: 1980 o-14 15-24 25-34 35-44 45-54 55-64 65-74 75 years lears tears lears lears lears lears tears and over NUIIIER CF PERSONS 137 472 1,060 1,113 1,530 2,126 2,065 807 Percent distribution ALL CAUSES 100 100 100 100 100 100 100 100 GlG111rulonephritts 37.2 40.0 30. 7 24.0 17.6 15.2 14.6 12.6 Prtaary hypertensive disease o.o 5.9 11.9 20.0 24.4 25.0 29.1 36.7 Dtabettc nephropathy 0.7 5.5 3).8 28.1 24.3 25.9 17.4 10.4 Pollcysttc kidney disease 6.6 1.1 2.3 7.5 10. 7 7.4 4.5 2.0 Col agen vascular disease 2.2 4.7 2.5 2.1 1.4 0.6 0.8 0.4 lntesttttal nephrttts, hereditary 2.9 4.4 2.2 0.9 0.5 0.7 0.3 0.4 lntersttt1a1 nephritis, other 4.4 8.1 5.1 4.1 5.6 6.6 7.1 9.3 Analgesic abuse nepbropathy o.o 0.2 0.1 1.3 1.2 1.7 1.3 0.2 Obstructtve urop1thy1 acquired 0.7 1.1 0.7 0.4 1.4 2.4 4.2 5.8 Obstructive uropathy, congenital 18.2 9.1 2.0 0.6 0.1 0.1 0.1 o.o -lotdosts o.o o.o o.o 0.4 0.7 0.7 0.8 0.5 Multiple ayelona o.o o.o o.o 0.4 0.6 1.3 1. 9 2.1 6e11ty nephropathy 0.1 0.2 0.2 0.2 0.7 0.5 0.6 0.7 Other, unspecified 20.4 13.1 6.4 3.6 3.5 4.3 12. 7 4.2 ~ttology unknown 5.8 6.6 5.2 6.5 7.2 7.7 4.4 14.6 Reprinted fran 11:FA ~evtew 5:69, 1984.

PAGE 128

\ : .. 'r' TABLE 5 Cause of death. 1n patients in the f1 rst to years of treatment and thereafter .. Ear1y--F1rst Two Years ~,ter Two Years Card10Yascular 50.51 48.& CYA 9.41 9.01 Hellorrhage 1.51 3.71 Infection 13.51 13.71 Stap Treatment 12.71 t.71 Ccer 2.91 2.01 Fraa Blagg CR, Wahl PW, Lamers JY: ASAIO J, 6:170, 1984. /J-,1 I I 000645

PAGE 129

l: I '.,;,t Figure 1 Patient survival by age. too i I Ftgure 2 Patient survival by race. too > -s .. z I IO DAVS 00 IOO IIOQ "., .. 1:i, I.It 111M Stat I.OIO l: o 20 7IIO 0 soo IO IO 000646

PAGE 130

:,.~'' '\' ,_,.,,,\..' Figure 3 Patient survival by renal failure diagnosis. 100 > ... I I 100 10 IO ao II Figure 4 Patient survival with and without preexfst1ng sevire hypertension. too IO ... .._ I .. .. Ill IO IO ...... I ,. -r ... _,. o I r-:1 .. IO 0 DAYS O O 100 SIOO 1700 IIOO eot l.00 UGO 7IOO ISOO C I LIIINO -Lit-Mn .-......... 1 .. .. !IJ!PP!M!JI! I 000647

PAGE 131

.. '" I [!1lrf~ ;:>~ f:' r ., .. .. ... .. ,\, :,' 000648 Figure 5 Patient survival 1n patients with and without preexisting cerebrovascular disease soo i i soo IO IO I .... ~. -. ,0 I II I 'l .a. I t IO Figure 6 Patient survival 1n patients wfth and without.a history of cancer. soo > IO I IO ... .... I 40 ... .,. .. f. j ,0 ,-IO I l IO DAYS IOIO IIIO o QIO 1400 ... 0 7IIO 0 p C I ,~ ......... l&at ..... ---~ ... l .?, ,.

PAGE 132

,' Figura 7 Patient survi-val 1n patients with and without preexisting coronary artery disease. II soo ,. > IO I I : 100 10 ,. 10 I,. ,. Ill r .II. r I O .L r Figure 8 Patient survival based on number of associated diseases. \31 000649


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