ARTIFICIAL KIDNEY

Eda ÇELİK, January, 2004

Table of Contents

1. Introduction…………………………………………………………………………...	1
1.1 Structure and Function of the Kidney ……………………………………………	1
1.2 Renal Failure……………………………………………………………………...	2
2. Treatment of Renal Failure …………………………………………………………..	2
2.1 Historical Development …………………………………………………………	2
2.2 Peritoneal Dialysis …………………………………………………………........	4
2.3 Hemodialysis ………………………………………………………….................	5
2.3.1. The Hemodialysis Circuit ………………………………………………...	5
2.3.2. Types of Hemodialyzers ………………………………………………….	7
2.3.3. Hemodialysis Membranes ………………………………………………...	8
2.3.3.1 Cellulosic Membranes …………………………………………....	8
2.3.3.2 Synthetic Membranes …………………………………………......	9
2.3.3.3 Recent studies on Hemodialysis Membranes ……………………..	11
2.3.4. Vascullar access for Hemodialysis ………………………………………	12
2.3.5. Blood-Material Interactions in Hemodialysis …………………………….	12
2.4 Tissue Engineering the Kidney …………………………………………............	14
2.4.1 Bioartificial Kidney …………………………………………......................	14
3. Conclusion …………………………………………...………………………………	15

1.      Introduction

1.1  Structure and Function of the Kidney

	Figure1. Human Kidney [2]

 

The kidneys (Figure 1) serve a tremendously  important role in the human body, as 180 liters of blood plasma are cleaned and filtered every single day. The kidneys are both regulatory and excretory organs. The kidneys have several major functions, including the following:

1. Regulation of body fluid osmolality and volume by excretion of water or NaCl
2. Regulation of electrolyte balance by carefully matching the daily excretion of the electrolytes by the kidneys with the daily intake.  The concentrations of Na⁺, K⁺, Cl^-, HCO₃^-, Ca²⁺, Mg²⁺ and PO₄^3- are strictly regulated.
3. Regulation of acid-base balance. The body maintains a constant pH via several buffering mechanisms. The kidney plays a major role in this by the net excretion of hydrogen ions when the blood is too acidic and the net excretion of bicarbonate ion when the blood is too alkaline.
4. Excretion of metabolic products such as urea, uric acid, creatinine, and foreign substances such as drugs.
5. Production and secretion of hormones such as renin, erythropoietin, prostoglandins, kinins and 1,25-dihydroxyvitamin D₃ [1].

	Figure 2. The nephron [2]

 

The basic functioning unit of the kidney is called the nephron (Fig.  2). Each human kidney contains approximately 1.2 million nephrons, which are hollow tubes composed of a single cell layer. The nephron consists of a glomerulus, a proximal tube, a loop of Henle, a distal tubule and a collecting duct system [1]. Kidney function is served by two major mechanisms: ultrafiltration (the estimated mean pressure in the glomerulus is about 60 mm Hg) which results in the separation of large amounts of extracellular fluid through plasma filtration in the glomeruli, and a combination of passive and active tubular transport of electrolytes and other solutes, together with the water in which they are dissolved, in the complex system provided in the rest of the nephron. Kidney function is estimated using the glomerular filtration rate or GFR. The normal GFR averages 120 ml/min [3].

1.2  Renal Failure

There are two types of renal failure: acute and chronic. Acute renal failure is typically associated with ischema (reduction in blood flow), acute glomerulonephritis, tubular necrosis or poisining with nephrotoxins. The kidney function may be recovered if the kidney is not severely damaged. Chronic renal failure is usually caused by chronic glomerulonephritis, infection of the urinary tract, hypertension or vascular disease [3]. People who are diagnosed with chronic renal disease (about 1 in 5000 to 10000) have a GFR below 25 ml/min. End stage renal disease (ESRD) is diagnosed when GFR is less than 5 ml/min.

2. Treatment of Renal Failure 

All ESRD patients must choose some forms of renal replacement therapy in order to sustain their lives, such as hemodialysis (artificial kidney), peritoneal dialysis or kidney transplant. Considering the recent transplantation technology, as with all organs, the availability of healthy donor is very low compared to the number of people who need them. So even today, there are a large number of people who are dependent on the artificial kidneys.

2.1 Historical Development

The term dialysis was coined in 1854 by Thomas Graham to refer to the separation of substances from solution based on their different diffusion through a semipermeable membrane. Graham performed a variety of in vitro experiments of the movements of various solutes through dialysis membranes. D.W. Richardson made the first in vitro dialysis of human blood in 1889. He coined the term "crystalloid" to refer to solutes of the blood which readily passed through the membrane and "colloid" for those which did not. Abel, Rowntree and Turner, performed the first in vivo dialysis, but only in animals. Hass is credited with performing the first dialysis in humans [4].

Figure 3. Kolff’s original Dialysis machine [5].

The first workable artificial kidney, a hemodialyzer apparatus, was developed during World War II in 1944-1945 by Dr. Willem Kolff. This device resembled a drum barrel made of slats with open spaces between the slats. Cellophane  “sausage"  casing was wound around the drum. The lower portion of the drum, which was suspended length-wise in a half barrel reservoir, was lowered in a dialysis bath. This procedure required a large volume of blood circulation outside the body during dialysis and required priming with blood transfusions. Either metal tubes or glass tubing was used to create a blood access, in an artery and a vein, and could be used only once per pair of blood vessels. Neither blood pumps nor plastic tubing was used to connect the blood accesses to the cellulose sausage casing. Rotating Ford water pumps permitted the drums to rotate at either end, enabling the blood to flow through. Blood was "pumped" using the patient's heart and blood pressure into the cellulose casing, and was propelled from one end of the drum to the other, by the turning of the drum. Blood was then collected in a glass cylinder with an open nipple at the lower end. This was connected by rubber tubing to the patient's venous access. By alternating lowering and raising the cylinder, blood was collected and drained back into the patient's vein [6]. To simplify the equipment, Inouye and Engelberg, in 1953, devised a coiled cellophane tube arrangement that was stationary and disposable, and shortly thereafter Kolff and Watschinger reported a variant of this design, the Twin Coil, that became the standard for clinical practice for a number of years [3].

At the end of the Second World War, Kolff sent some of his artificial kidneys as a gift to several countries; one of these kidneys came to The Mount Sinai Hospital, where in 1948 it was first utilized to perform hemodialysis in a patient with bichloride of mercury poisoning [4]. In 1954, the feasibility of renal transplantation was first demonstrated by Murray and coworkers [3].

While the technical capacity to perform dialysis was already available to treat patients with acute renal failure before 1960, the lack of an acceptable long-term vascular access limited the use of dialysis for the prolonged treatment of chronic renal failure. Frequent cannulation of peripheral veins led to inadequate flow, inflammation, thrombosis and eventual loss of these veins. Thus, the single most important contribution to the establishment of chronic hemodialysis was the creation of the Quinton-Scribner shunt in 1960.  Unfortunately, this external arteriovenous shunt was plagued by infection and thrombosis. A major advance in the vascular access problem took place in 1966 with the creation of an arteriovenous fistula in the forearm by Brescia et al. The endogenous arteriovenous fistula immediately became, and still remains, the gold standard of vascular access for chronic hemodialysis [4].

At the end of 1950’s, Kiil first reported results with a flat plate dialyzer design in which blood was made to flow between two sheets of cellophane supported by solid mats with grooves for the circulation of dialysate. Also, in 1959, Maxwell and colleagues described the intermittent peritoneal dialysis (IPD). By 1965, the first home dialysate preparation and control units were produced industrially. Home dialysis programs based on twin coil or flat plate dialyzers were soon underway. In 1967, Lipps and colleagues reported the initial clinical experience with hollow fiber dialyzers, which have since become the mainstay of hemodialysis technology. In parallel developments, Hendorson and coworkers, in 1967, proposed the process which is known as hemofiltration today. In 1976, Popovich and Moncrief described continuous ambulatory peritoneal dialysis (CAPD) [3]. In 1985, a portable hemodialysis system with sorbent regeneration of dialysate was described [7].

Advancements in peritoneal catheters, devices to decrease contamination during exchanges, and development of automated equipment, continued into the 1990's to make peritoneal dialysis more efficient. In the 1980s-1990s, computerized hemodialysis machines, better dialyzers, and improved monitoring and safety devices reduced treatment times, gave doctors better ways to monitor treatment, and made possible a more normal life for patients. In 1989, a major breakthrough was the introduction of a drug to combat anemia in dialysis patients [6]. In 1999, Humes used tissue engineering to develop a device called the Renal Tubule Assists Device (RAD), which is to be a portion of the “bioartificial kidney”.

Apperantly, today hemodialysis and peritoneal dialysis are the widemost applications. 

2.2 Peritoneal Dialysis

Peritoneal dialysis is carried out in the peritoneal cavity of the patient. The peritoneum is a thin membrane lining the abdominal organs. It forms a closed sac. Through a cannula placed through the skin or a catheter permanently implanted, dialysate solution (about 2 liters in an adult) is infused, allowed to dwell for a designated time period, and drained. This semipermiable membrane permits transfer of solutes from the blood to the dialysate [8].

The efficiency of the process is strongly dependent upon the blood flow through the peritoneal membrane, the permeability of the peritoneal membrane, and the dialysate conditions of flow, volume, temperature, and net concentration gradient. Peritoneal dialysis may be performed intermittently (IPD) or continuously (CAPD) [8].

An advantage of peritoneal dialysis over hemodialysis is that direct blood contact with foreign surfaces is not required, eliminating the need for anticoagulation [8]. Other advantages and disadvantages of peritoneal dialysis in comparison with hemodialysis are given in Table 1.

Table 1. Advantages and disadvantages of peritoneal dialysis [4,9]

 

Advantages

Home dialysis therapy

Easier to travel

Cheaper than hemodialysis

Continuous process maintains steady-state blood chemistry values

More freedom in food and fluid intake

Longer preservation of residual renal function

Disadvantages

Infections, metabolic and mechanical complications

Risk of inadequate dialysis

Malnutrition

Psychological problems related to indwelling catheter

Significant daily glucose load

 

2.3 Hemodialysis

Hemodialysis literally means dialysis of the blood. It is based on extra-corporeal exchanges between blood and a dialysis solution through a semi-permeable membrane in a dialyser (artificial kidney). This is an intermittent therapy with patients typically having thrice-weekly treatments of from 2.5 to 4 hours. Although most hemodialysis is performed in free-standing treatment centers, it may also be provided in a hospital or performed by the patient at home    [10].

2.3.1. The Hemodialysis Circuit         

The hemodialysis circuit (Figure 4) consists of two fluid pathways. The blood side is entirely disposable, though many centers re-use some or all circuit components in order to reduce costs. It comprises a 16-gauge needle for access to the circulation (usually through a fistula created in the patient's forearm), lengths of dioctyl phthalate plasticized poly(vinyl chloride) tubing including a special tubing segment adapted to fit into a peristaltic blood pump, the hemodialyzer itself (Figure 5), a venous bubble trap and an open mesh screen filter, various ports for samples and gauge connections, and a return cannula. Components of the blood-side circuit are supplied in sterile and nonpyrogenic condition; ethylene oxide is the most common sterilant, although both radiation and steam sterilization are rapidly gaining favor. The dialysate side is essentially a machine capable of proportioning out glucose and electrolyte concentrates with water to provide dialysate of appropriate composition, pumping dialysate past a restrictor valve and through the hemodialyzer at subatmospheric pressure, and monitoring temperature, circuit pressures, and flow rates. During treatment the patient's blood is anticoagulated with heparin. Typical blood flow rates are 200–350 mL/min; dialysate flow rates are usually 500 mL/min. Straightforward techniques have been developed to prime the blood side with sterile saline prior to use and to rinse back nearly all the formed elements after treatment. Although most mass transport occurs by diffusion, circuits are operated with pressure on the blood side controlled to 13.3 to 66.7 kPa (100 to 500 mm Hg) higher than on the dialysate side. This provides an opportunity to remove 2 to 4 liters of fluid along with the solute; higher rates of fluid removal are technically possible but physiologically unacceptable. Hemodialyzers must be designed with high enough hydraulic permeabilities to provide adequate fluid removal at the upper pressure range, but not so high that excessive dewatering  will occur at the lower pressure ranges [10].

Figure 4. The hemodialysis circuit [11]

2.3.2. Types of Hemodialyzers

Mainly three types of hemodialysis apparatus are worth mentioning.  The first commercial dialysers were in the form of coiled cellulose tubing. The coil design did not produce uniform dialysate flow distribution across the membrane. Later developments were of large, flat polypropylene plates sandwiching a blood compartment of copper-cellulose sheets (which had to be changed manually), then compact, factory-made, flat-plate filters [12].

Some advantages to the use of flat plate dialyzer are its low resistance to blood flow. Because of this fact, there is not as much need for the use of an anti-blood clotting solution. Another advantage of this dialyzer is that its filtration rate is controllable and predictable. Furthermore, the amount of blood contained within the dialyzer is relatively low. The less blood that is out of the body at one point in time, the better the dialyzer. The final advantage of the parallel plate dialyzer is that it is inexpensive [13].  

Nowadays, the most commonly used hemodialysers consist of small units made up of bundles of finely extruded hollow fibers [12]. This is the most effective design for providing low-volume high efficiency devices with low resistance to flow. The fibers are potted in polyurethane at each end of the fiber bundle in the tube sheet, which serves as the membrane support [14] (Figure 6).

            Figure 5. The hemodialyzer [15]

                                                                                      

 Figure 6. Hollow fiber dialyzer [16]

2.3.3. Hemodialysis Membranes

The central element of a hemodialysis unit is the semipermeable membrane, and it represents the largest foreign surface with which the blood is in contact during treatment. Hemodialysis membranes vary in composition, transport properties and biocompatibility [3]. Hemodialysis membranes are fabricated from two classes of materials: cellulosic and synthetic (Table 2). Cellulosic membranes can be further divided into regenerated cellulosics and modified cellulosics.

2.3.3.1 Cellulosic Membranes

Cellulosic membranes are typically more hydrophilic than synthetic membranes with the exception of polyethylene-polyvinyl alcohol copolymer due to the interaction of hydroxyl groups with water by hydrogen bonding. This is an advantage because the adsorption of proteins decreases as the hydrophilicity increases. Asymmetry allows high diffusion, thus, asymmetric membranes are better for passing small solutes, therefore, this is a disadvantage of cellulosic membranes, which are typically symmetric. However, the symmetry of a membrane is determined by the ease manufacturing of the membrane one way or the other, therefore any membrane can be symmetric or asymmetric. The thickness of a membrane also affects the permeability of the membrane. The general rule is that increasing thickness corresponds with decreasing diffusive permeability. This is an advantage to cellulosic membranes, which are typically thicker than synthetic membranes. Although, there are conflicting viewpoints, cellulosic and synthetic membranes have similar biocompatibility [17]. 

 Regenerated Cellulose Membranes (Cuprophanes)

Regenerated cellulose membranes are most commonly prepared by the cuproamonium process, macroscopically homogenous, and hydrophilic. A popular regenerated cellulose membrane is the trademarked membrane Cuprophan^â. In the presence of water, these cuprophane membranes form hydrogels. The solute diffusion occurs through the highly water-swollen amorphous regions. The primary advantages to cuprophane membranes are their low cost, ability to be cut thin, high mechanical strength, and effective diffusive transport properties of small solutes (e.g. urea and sodium chloride). Some disadvantages with cuprophane membranes are their limited transport of middle molecules and the presence of unstable nucleophilic groups, which initiate complement activation and transient leukopenia during the first hour of contact with blood. Some toxicological considerations involving allergic reactions are known: cuprophan hypersensitivity and the release of trace metals [17].

Modified Cellulose Membranes

Some modified cellulose membranes are cellulose acetate and derivatized cellulose (Hemophan^â). Cellulose acetate membranes are made from cellulose diacetate polymers and has the advantage of being more permeable to water and larger solutes than that of the cuprophane membranes. Derivatized cellulose or Hemophan^â was initially fabricated to improve biocompatibility. Both cellulose acetate and Hemophane are morphologically homogeneous or symmetric, meaning that the membrane porosity is similar throughout the entire thickness of the membrane [17].

2.3.3.2 Synthetic Membranes

At the opposite end of the spectrum are membranes prepared from synthetic engineered thermplastics, such as polysulfones, polyamides, and polyacylonitrile-polyvinylchloride copolymers. These hydrophobic materials, which account for about 10 % of the hemodialyzer market, form asymmetric and anisotropic membranes with solid structures and open void spaces. These membranes are characterized by a skin on one surface, typically a fraction of a micron thick, which contains very fine pores and constitutes the discriminating barrier determining the hyraulic permeability and solute retention properties of the membrane. The bulk of the membrane is composed of a spongy region, with interstices that cover a wide size range and with a structure ranging from open to closed cell foam. The primary purpose of the spongy region is to provide mechanical strength; the diffusive permeability of the membrane is usually determined by the properties of this matrix. These materials are usually less activating to the complement cascade than are cellulosic membranes. The materials are also less restrictive to the transport of middle and large molecules. Drawbacks are increased cost and such high hydraulic permeability as to require special control mechanisms to avoid excess fluid loss and to raise concerns over the biologic quality of dialysate fluid because of the possibility of back filtration carrying pyrogenic substances to the blood stream [3].

Table 2. Polymeric Materials for Dialysis Membranes [10]

Material   Manufacturer Regenerated cellulosics Cuprophan   Akzo cuprammonium cellulose   Asahi     Terumo SCEa   Teijn     Althin Synthetically modified cellulose Hemophan   Akzo cellulose acetate   Akzo     Toyobo     Althin     Teijin cellulose triacetate   Toyobo SMCb   Akzo Synthetics polysulfone   Akzo     Fresenius     NMC     Kurary     Kawasumi polycarbonate   Gambro polyamide   Gambro polyacrylonitrile   Hospal     Asahi SPANc   Akzo EVALd   Kawasumi/Kuraray PMMAe   Torray

a SCE = saponified cellulose ester.   b SMC = specially modified cellulose.   c SPAN = sulfonated polyacrylonitrile.   d EVAL is a poly(vinyl alcohol), a copolymer of ethylene and vinyl alcohol.   e PMMA = poly(methyl methacrylate).

2.3.3.3 Recent studies on Hemodialysis Membranes

The membrane, being the central element of a hemodialysis unit, is also in the center of studies to improve the artificial kidneys.

Experts agree that the two areas that need the most improvement are diffusion properties and biocompatibility. To improve diffusion properties of hemodialysis membranes there is a continuing search for membranes with better characteristics either by alteration in chemical constitution of existing membranes or by synthesis of new membranes. To reduce symptoms associated with biocompatibility, the interactions of hemodialysis membranes with blood cells and plasma proteins need to be minimized. This implies less activation of complement, leukocytes and kininogens, and thrombogenesis. To accomplish this, much more research is needed in this area [17].

In a recent study [18] for example, Chitosan (CS)/heparin (HEP) polyelectrolyte complex (PEC) was covalently immobilized onto the surface of polyacrylonitrile (PAN) membrane. PAN is one of the most important polymeric materials used in the biomedical field due to its excellent properties, such as good thermal, mechanical stability and biocompatibility. However, the hemocompatibility of the PAN membrane is still insufficient and thus the injection of anticoagulant is required during hemodialysis. The results of the study showed that PEC-immobilization can endow the PAN membrane hemocompatibility and antibacterial activity while retaining the original permeability.

Another example is the cellulose membrane, which is widely used for hemodialysis throughout world, but its blood compatibility must be improved. In a study [19], two kinds of betaine (sulfobetaine and carboxybetaine) were grafted onto cellulose membranes. The platelet adhesion test showed that membranes-grafted betaines have excellent blood compatibility feature by the low platelet adhesion.

In another study [20], urease was immobilized onto the outer surface of polyacrylonitrile (PAN) hollow fiber by covalent linkage. The intention of enzyme immobilization onto synthetic matrixes is not only to achieve higher operational stability, faster response and lower cost, but also to improve the number of reuse and storage stability. The advantage of immobilized urease was that it can be reused for more than 8 and 15 times while retaining 80% of the activity. Urea was removed from the blood side 2 times faster than a regular dialyzer. Furthermore, the concentration of urea in the dialysate side was also reduced due to the catalysis of urease. This suggests that a dialyzer immobilized with urease may greatly shorten the time required for the dialysis.

2.3.4. Vascullar access for Hemodialysis

Initially, repeated access to the circulation was achieved by the insertion of rigid Teflon tubes into an adjacent forearm vein and artery; the tubes were connected on the forearm surface by flexible tubes that could be separated and connected to the filter at each dialysis (Quinton-Scribner shunt). This arrangement was superseded by an arteriovenous fistula (AV fistula or Cimino-Brescia fistula) created in the forearm, into which needles are inserted for access at each dialysis. When this fistula cannot be formed, several options are available, including the placement of synthetic grafts subcutaneously, or of a long central line into a great vein [21]. The graft, which may be either straight or looped, is placed close to the surface under the skin. The graft may be of an artificial material such as polytetrafluoroethylene (PTFE) or Gortex, or can be obtained from the patient's own vein e.g. the vein in the thigh [2].

2.3.5. Blood-Material Interactions in Hemodialysis

Major foreign body contact takes place with the dialyser membrane that has an area of (1–1.5m²). This contact results in the activation of the body’s humoral and cellular processes. Requirements for the hemodialysis membrane are good mechanical strength, permeability for water and solutes, and blood compatibility [22]. Membrane biocompatibility has many determinants, including the polymers used, the hydrophilic or hydrophobic character, polarity, the architecture of the device ( hollow fiber, flat plate, etc.) and the method of sterilization (ethylene oxide, gamma irradiation, steam) [23].

Interaction of blood with the material surface results in the adsorption of proteins to the surface, the adhesion and activation of cells. Increase in permeability coefficient could either be due to an increase in the hydrophilicity or the high porosity of the membranes. Limitation of protein and cell interaction with artificial surfaces can be approached by copolymerisation and blending of hydrophobic and hydrophilic polymers. A microdomain surface structure formed by hydrophilic patches in a hydrophobic matrix limited the blood–membrane interactions, and in that way increased the blood compatibility [22].

Formation of platelet–leukocyte microaggregates has been observed during hemodialysis. These microaggregates can mediate some pathophysiologic abnormalities. For example: once attached to neutrophils, activated platelets induce a functional activation of those cells resulting in increased highly reactive oxygen species (ROS), mainly superoxide anion and hydrogen peroxide. These oxygen radicals may play an important role in the pathogenesis of atherosclerosis. This pathophysiological event occurs in the early phase of the hemodialysis procedure and can be observed with membranes of different polymer composition. Although the formation of platelet–leukocyte aggregates appears to be a universal phenomenon in hemodialysis, subtypes of this phenomenon consisting of activated platelets and fibrinogen binding maybe membrane dependent: only Cuprophan induced an increase in anti-CD62 binding to neutrophils, suggesting that the aggregated platelets linked to neutrophils were activated [22].

Another undesirable side effect on hemostasis during hemodialysis is caused by heparin. This polysaccharide is generally used as anticoagulant during dialysis. Several authors reported the occurrence of major hemorrhagic effects in patients on chronic intermittent hemodialysis. The incidence of such effects like subdural hematoma, major gastrointestinal tract- or retroperitoneal bleeding is low. However, when they occur, these problems maybe devastating. No studies are available which distinguish between intrinsically present abnormalities of platelets and the effects of heparin administration. In patients, with heparin-associated antiplatelet antibodies (HAAbs) other anticoagulants are used, such as danaparoid (antifactor Xa) or lepirudin (antitrombin) [22]. Citrate anti-coagulation was shown to reduce the hemodialysis-induced release of granulocyte degranulation products almost completely, if compared with heparin. These results suggest that the mode of anti-coagulation has a profound influence on bioincompatibility [23].

Sometimes antiplatelet agents are used during hemodialysis to prevent thrombosis. Several studies report that clopidogrel or ticlopidine reduced platelet aggregation in patients receiving chronic maintenance hemodialysis, although it was not always completely prevented [22].

2.4 Tissue Engineering the Kidney

Dialytic therapies are lifesaving, but not always highly tolerated. Transplantation of human kidneys is limited by the availability of donor organs. During the past decades, a number of different approaches have been applied toward tissue engineering the kidney as a means to replace renal function. Main approaches are:

1. integration of new nephrons into the kidney
2. growing new kidneys in situ
3. use of stem cells
4. generation of histocompatible tissues using transplantation
5. bioengineering of an articial kidney

Only the bioengineered artificial kidney is currently being evaluated in patients, and then only for short-term use in the setting of severe acute renal failure [24].

2.4.1 Bioartificial Kidney

Hemodialysis replaces some filtration functions of the kidney, but does not recapitulate endocrine/metabolic activities of renal cells. To adress this deficiency, Humes et al. have developed a synthetic hemofiltration cartridge and a renal tubule cell-assist device (RAD) containing porcine or human cells in an extracorporeal circuit.

Figure 7. Renal Assist Device (RAD) [25]

The RAD (Figure 7) replaces both renal filtration and endocrine/metabolic activity. Cells are grown as confluent monolayers along the inner surface of hollow fibers within a standard hemofiltration cartridge. The non-biodegradability and the pore size of the hollowfibers permit the membranes to act as both scaffolds for the cells and as an immunoprotective barrier. The isolated/expanded renal cells show differential renal transport, metabolic, and endocrine activity. The RAD placed in series to a standard hollow fiber hemofiltration cartridge with ultrafiltrate and postfiltrated blood connections can reproduce functional relationship between the glomerulus and tubule. Its use in the treatment of acutely uremic dogs increases excretion of ammonia and enhances glutathione metabolism and 1.25(OH)₂D₃ production during 24 hours of treatment. The evaluation of this device in the treatment of severely ill patients with acute renal failure has been initiated [24].

3. Conclusion

Kidney was the first organ whose function was substituted by an artificial device, and the first organ to be succesfully transplanted [26]. From the first workable artificial kidney of Dr. Kolff, many improvements were achieved. The successful implementation of hemodialysis required paralell advences in anticoagulation therapy, artificial membrane technology and the development of vascular access. Still, diffusional limitations of the membranes and biocompatibility problems remains and to date, there is no totally implantable artificial or bioartificial kidney available. We can not rely on advancements in renal transplantation, either, because there will always be a lack of donors. However, in the future, success will come with the tissue engineered kidneys.

And for the near future, industrial plans are on wearable artificial kidney, which was introduced by Willem Kolff in 1975. US-based National Quality Care Inc. believes that there is a serious need for a portable, artificial kidney, which can be used continually, 24 hours a day, seven days a week [27].

References

1. Schmidt, R.F. and Thews, G., 1983. “Human Physiology”, Springer-Verlag, Berlin.
2. http://www.kdf.org.sg/kidneyfunction.htm
3. Bronzino, J.D., 1995. “The Biomedical Engineering Handbook”, CRC Pres, USA.
4. Uribarri J., 1999. “Past, Present and Future of End-Stage Renal Disease Therapy in the United States”, Mount Sinai Journal of Medicine, 66, 14-19.
5. http://www.nd.edu/~aostafin/benl/2003/page28.html
6. http://www.kidneyetn.org/zframes-nkfethistdial.html
7. Mourad G, Issautier R, Mion C.  A portable hemodialysis system with sorbent regeneration of dialysate: preliminary results.  Trans Amer Soc Artif Intern Organs  1985; 31: 568-571.
8. Ratner B.D., Hoffman A.S., Schoen F.J., Lemons J.E., “Biomaterials Science”, Academic Press, 1996, USA.
9. Gokal, R. and Mallick, N.P., 1999. “Peritoneal Dialysis”, The Lancet, 353, 823-828.
10. Lysaght, M.J. 1993. “Dialysis” in Kirk Othmer Encyclopedia of Chemical Technology, John Wiley& Sons Inc.
11. http://diabetes.about.com/library/blimagegallery/blNIDDKhemodialysis.htm
12. Grinval’d, V.M., 2001. “Analysis of Structure of Hemodialysis Apparatuses”, Biomedical Engineering, 35, 4, 197-204.
13. http://www.shodor.org/master/biomed/physio/dialysis/hemodialysis/sixa.htm
14. http://classes.kumc.edu/cahe/respcared/cybercas/dialysis/frantype.html
15. Ratner, B.D., ed., et. al., 1996. “Biomaterials Science, An Introduction to Materials in Medicine”, Academic Press.
16. http://diabetes.about.com/library/blimagegallery/blNIDDKfiber_dialyzer.htm
17. Nou, L.K, 2000. “Hemodialysis Membranes: Characteristics of Ideal Membranes, Characteristics of Available Membranes, and the Future of Hemodialysis Membranes”, Biomaterials-BME 430, Pharmacy 601.
18. Lin W.,C., Liu, T.,Y., Yang, M.,C., 2003. “Hemocompatibility of polyacrylonitrile dialysis membrane immobilized with chitosan and heparin conjugate” Biomaterials, Article in Pres.

19. Yuan, J., Zhang, J., Zang, X., Shen, J., Lin S. 2003. “Improvement of blood compatibility on cellulose membrane surface by grafting betaines”, Colloids and Surfaces B: Biointerfaces, 30, 147-155.
20. Lin, C., C., Yang, M.C., 2003. “Urea permeation and hydrolysis through hollow .ber dialyzer immobilized with urease: storage and operation properties” Biomaterials, 24,1989–1994.
21. Mallick, N.P., Gokal, R., 1999. “Haemodialysis”, The Lancet, 353, 737-742.
22. Spijker, H.T., Graaff, R., Boonstra, P.W., Busscher, H.J., van Oeveren, W., 2003. “On the influence of flow conditions and wettability on blood material interactions”, Biomaterials, 24, 826, 4717-4727.
23. Grooteman, M.P.C. and Nube, M.J., 1998. “Haemodialysis-related bioincompatibility: fundamental aspects and clinical relevance”, The Netherlands Journal of Medicine”, 52, 169-178.
24. Hammerman M.R., 2003. “Tissue Engineering the Kidney”, Kidney International, 63, 1195-1204.
25. http://www.nephrostherapeutics.com/products/rad.htm
26. Lamprecht, F.F.L., Groth, T., Albrecht, W., Paul, D., Gross, U. 2000. “Development of membranes for the cultivation of kidney epithelial cells” Biomaterials, 21, 183-192.
27. “US company focuses on wearable artificial kidney”, Membrane Technology, 10, October 2003.