Technological Advances in Renal Replacement Therapy: Five Years and Beyond

Anjay Rastogi* and Allen R. Nissenson† *Division of Nephrology, Department of Medicine, University of California, Los Angeles, Los Angeles, California; and †Office of the Chief Medical Officer, DaVita Inc., El Segundo, California

The worldwide epidemic of chronic kidney disease shows no signs of abating in the near future. Current dialysis forms of renal replacement therapy (RRT), even though successful in sustaining life and improving quality of life somewhat for patients with ESRD, have many limitations that result in still unacceptably high morbidity and mortality. Transplantation is an excellent option but is limited by the scarcity of organs. An ideal form of RRT would mimic the functions of natural kidneys and be transparent to the patient, as well as affordable to society. Recent advances in technology, although generally in early stages of development, might achieve these goals. The application of nanotechnology, microfluidics, bioreactors with kidney cells, and miniaturized sorbent systems to regenerate dialysate makes clinical reality seem closer than ever before. Finally, stem cells hold much promise, both for kidney disease and as a source of tissues and organs. In summary, nephrology is at an exciting crossroad with the application of innovative and novel technologies to RRT that hold considerable promise for the near future. Clin J Am Soc Nephrol 4: S132–S136, 2009. doi: 10.2215/CJN.02860409

he ongoing worldwide epidemic of chronic kidney dis- more user-friendly delivery systems. In PD, introduction of ease (CKD) includes ESRD. According to recent US automated cyclers has improved convenience of the technique T Renal Data System estimates, more than 900,000 pa- for some patients, increased the practical volume of dialysate, tients worldwide have ESRD and are on renal replacement and, therefore, increased solute clearance and ultrafiltration therapy (RRT) (1). The majority of these patients are on inter- capacity; however, none of these advances has had a substantial mittent, diffusion-based hemodialysis (HD), with only a rela- impact on patient outcomes. tively small fraction able to receive kidney transplants because An ideal form of RRT would mimic the kidneys completely. of the scarcity of available donor organs. It would be continuously operating; would remove solutes Even though dialysis is touted as the only currently available with a molecular weight spectrum similar to that of the kid- successful therapy that replaces the functions of an organ ex neys; would remove water and solutes on the basis of individ- vivo, it has several limitations. The advent of clinical dialysis in ual patient needs; and would be biocompatible, wearable, and the 1950s has had a huge impact on the way in which ESRD and ideally implantable. It would also be low cost, reliable, and safe. acute kidney failure are managed, but several decades later, the A few years ago, these goals would have seemed impossible to morbidity and mortality in patients with ESRD remain unac- achieve, but with advances in the sciences of nanotechnology ceptably high (1). One possible reason is that the equivalent and microfluidics, renal replacement of the future may come clearance provided by three-times-a-week conventional HD or closer to this ideal (3–5). typical continuous ambulatory peritoneal dialysis (PD) is barely 15 to 20 ml/min, and the treatment by any criterion is unphysiologic (2). At the same time, the quality of life of Nanotechnology Applications patients who are on dialysis has remained suboptimal, and the Nanotechnology, as defined by Drexler (6), refers to atomi- cost of these procedures has remained high. cally precise functional machine systems developed on the Several attempts have been made to prove intramuscularly scale of the nanometer (i.e., one-billionth of a meter). This the efficiency of dialysis and outcomes in patients. In HD, these technology is an area of intense research, with a national com- attempts include more biocompatible membranes, high-flux and high-efficiency membranes, more frequent and longer du- mitment by the US government to promote research in this ration of dialysis, use of convective forms of therapy, and use of field. The precision provided by nanotechnology will make possible the design of tools that will operate at the molecular level. Nanomedicine is the application of nanotechnology for the advancements of biomedical research and is defined as the Portions of this article are reprinted with permission of the publisher (Elsevier) monitoring, repair, construction, and control of human biologic from Advances in Chronic Kidney Disease 14, 2007, pp 14–27. systems at the molecular level by use of engineered nanode- Correspondence: Dr. Anjay Rastogi, University of California, Los Angeles (UCLA), 7-155 Factor Building, 10833 Le Conte Avenue, Los Angeles, CA 90095. vices and nanostructures. The number of potential applications Phone: 310-206-6741; Fax: 310-825-6309; E-mail: [email protected] to RRT is many, and a few major ones are discussed next.

Human Nephron Filter To compare conventional HD with RRT that uses the HNF, Nissenson and colleagues (7,8) have proposed the human we modeled dialysis with a 4-h treatment three times a week nephron filter (HNF) as a novel mode of RRT for patients with (Monday, Wednesday, and Friday), no residual kidney func- ESRD. The HNF consists of two membranes that operate in tion, and a dialyzer with a urea clearance of 277 ml/min at a Qb series within one cartridge. The first membrane is called the G of 300 ml/min and a Qd of 500 ml/min. For the HNF model, membrane and is analogous to the glomerular membrane in the the assumption was no residual kidney function, a 12-h treat- nephron. It mimics the functions of the glomerulus by using ment 7 d/wk, a blood flow of 100 ml/min, and a 100% rejection convective transport to generate plasma ultrafiltrate that con- of urea by the T membrane as noted previously. Simulating 30 tains solutes that approach the molecular weight of albumin. ml/min GFR would result in a time-averaged urea concentra- The second membrane is called the T membrane and mimics tion (TAC) in the HNF-modeled patient of approximately 27 the functions of the tubule. It is molecularly engineered and mg/dl, with minimal fluctuations of blood urea nitrogen selectively reclaims convectively the designated solutes to throughout a weekly cycle. By contrast, the thrice-weekly dial- maintain homeostasis. No dialysate is used in the system. ysis simulation yields a TAC of 67.3 mg/ml, with wide excur- The blood is pumped at approximately 100 ml/min across sions of blood urea nitrogen reflecting the intermittent nature the G membrane after access is obtained. The entire thickness of of the treatment. If the HNF were to run continuously, then the the membrane is approximately 1 mm, with the total surface TAC would fall to normal levels. area needed just over one tenth of a square meter. Operating 12 Similar simulations were performed for ␤2-microglobulin, h/d, 7 d/wk, it can provide the equivalent of 30 ml/min GFR. assuming free passage of ␤2-microglobulin through the G The T membrane is supported on a substrate and contains membrane and 100% rejection by the T membrane. For the molecularly engineered pores that make it unique. Total surface ␤2-microglobulin studies, the rate of ␤2-microglobulin produc- area needed is just over one-hundredth of a square meter. The tion was assumed to be 0.17 mg/min, and the rate of clearance membrane contains approximately 1.6 ϫ 1016 pores, 1 to 5 nm for the Fresenius dialyzer was assumed to be 78 ml/ min. The apart. The pores will come in different sizes and shapes, and HNF system can reduce and sustain low levels of ␤2-micro- eventually a pore library will be available to permit custom globulin compared with other dialytic approaches. With 12-h, membranes to be produced to meet individual needs. There are 7-d/wk treatment, levels of ␤2-microglobulin are predicted to key differences between molecularly engineered membranes approach normal. and conventional polymer membranes: Molecularly engineered Modeling was also done to assess the removal of some of the membranes contain a predetermined number and size of pores other key substances, including sodium, potassium, calcium, that are atomically engineered and have specific interactions magnesium, phosphorus, and bicarbonate, under a variety of with solutes that provide selective transport characteristics to clinical conditions. In a 70-kg patient on a normal diet, the the membrane. The active filtration layer is ultrathin—approx- initial HNF system is capable of maintaining balance for all of imately 2.5 nm—approaching the size of a single molecule. In these substances, except bicarbonate, which may need addi- contrast to these molecularly engineered membranes, the con- tional supplementation. Other solutes of various molecular size ventional polymer membranes are thick, have unselective will also be removed, many of which are not commonly mea- transport of solutes, and have a wide distribution of pore sizes sured; thus, patients will need close monitoring. The experience and numbers that are difficult to control. to date with daily, overnight diffusion dialysis would suggest The G membrane discriminates between solutes on the basis that this monitoring is unlikely, but careful consideration of this of molecular size. The ultrafiltrate formed after blood passes possibility will be necessary when clinical trials with the HNF through the G membrane contains both desirable and undesir- are conducted. The combined use of sensors in the device (e.g., able solutes. The ultrafiltrate passes over the T membrane, pH, ion-selective electrodes), preclinical evaluation, and em- which reclaims most of the desirable solutes and rejects the piric observation is expected to allow us to formulate appro- undesirable ones. The T membrane is able to differentiate be- priate usage variables. cause each of its pores is a designed discriminator and is made An additional challenge with the proposed system will be the up of multiple unique pores. The pores were designed to reab- approach to anticoagulation when the device is in use, because sorb all of the desirable solutes and reject the undesirable ones. continuous contact with the circulation will be obtained. Ini- Pores with similar radii can be designed to have very different tially low-level systemic anticoagulation will be achieved with and selective transport properties. warfarin or heparin. The surfaces of the pores in the T mem- Modeling studies of the performance of the HNF for urea, brane, however, were designed to have the ability to bond ␤2-microglobulin, and a variety of other solutes have been covalently to anticoagulant substances, such as heparin and performed. The amount of water passed to waste could be thrombomodulin. This approach may minimize or eliminate varied, depending on the volume status of the patient, and a the need for administration of anticoagulants. very high efficiency of water recovery (more than 99%, as with the native kidney) is assumed to be achieved. The efficiency of Silicone Nanopore Membranes urea removal is assumed to be 100% in this model, with com- The conventional membranes currently in use are character- plete rejection of urea reabsorption by the T membrane. With ized by variation in both pore size and distribution and are an assumed blood flow of 100 ml/min, urea clearance is calcu- relatively thick. In addition, the pores at the end of the cylin- lated to be 62.8 ml/min. drical fibers tend to be round. The pores in these membranes S134 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: S132–S136, 2009 are formed by extrusion and solvent-casting techniques, and proved survival (18–20). Of particular interest is the potential their geometry and surface chemistry are determined by the differential beneficial effect in patients with acute kidney injury chemistry of the polymers used in the synthesis and the fluid associated with sepsis (21–25). dynamics of the casting process; however, this geometry and surface chemistry do not provide the optimal filtration function Nanoelectronics for several reasons. Large molecular weight molecules are re- For creation of a fully automated, implantable dialysis sys- tained because of the dispersion of pore size. Such dispersion tem, accurate real-time assessment of fluid/electrolyte/acid- can be corrected for but at the cost of hydraulic permeability. base status is needed. In addition, this detection system must be The hydraulic permeability of a round pore will depend on the miniature in size. MEMS technology is a miniature component 4th power of the radius of that pore; however, if a pore is slit system that integrates sensors, actuators, and electronics and is shaped rather than round, then the hydraulic permeability will proposed as a more accurate, reliable, and yet miniature depend on the long dimension of the pore. At the same time, method of assessing fluid status and other critical variables. the steric hindrance will still be determined by the smallest Applying MEMS to dialysis systems might provide the analyt- dimension of the pore. The glomerular membrane provides ical platform needed (26,27). electrostatic hindrance in addition to the steric hindrance. Many substrates have an anionic surface charge at physiologic Wearable Artificial Kidney pH. This net charge density on a microfluidic substrate in Gura and colleagues (28,29) have been developing a wearable contact with an aqueous solution gives rise to an electric double artificial kidney (WAK) that uses existing technology coupled layer called the Debye layer (9), which has thickness that can be with miniaturization. This HD system uses a sorbent system on the same scale as the nanopore size and can contribute to the that regenerates dialysate, reminiscent of the peritoneal-based selective property of these membranes by rejecting charged wearable system developed by Lee and Roberts (30). The WAK solutes. Recently, Fissell et al. (10) described in vitro results with is the first of the wearable HD concepts that has undergone such a membrane. clinical trials. Preliminary results suggest that adequate small Leonard and colleagues (11–13) proposed membraneless di- solute and water removal can be accomplished with this device. alysis by application of the principles of microfluidics. This Most recently, Gura et al. (30) reported on removal of phosphate approach is based on the principle that at low Reynolds num- and ␤2-microglobulin using the WAK in eight long-term HD ber, two miscible liquids can flow in parallel in direct contact patients. Patients were fitted with a wearable HD device for 4 to with each other without significant mixing. This property per- 8 h with excellent tolerance to the treatment. On average, 99.8 Ϯ mits diffusive transport to take place as in conventional dialysis 63.1 mg of ␤2-microglobulin was removed, with a mean clear- but without the presence of a dialysis membrane. Elimination ance of 11.3 Ϯ 2.3 ml/min, and an average of 445.2 Ϯ 326 mg of of the dialysis membrane and its limiting features offers many phosphate was removed, with mean plasma phosphate clear- potential advantages to solute removal. This theoretical con- ance of 21.7 Ϯ 4.5 ml/min. These clearances compared favor- struct holds promise for future dialysis devices. An initial ap- ably with mean urea and creatinine plasma clearances (21.8 Ϯ plication focused on ultrafiltration, packaged in a wearable 1.6 and 20.0 Ϯ 0.8 ml/min, respectively). These results confirm device, has been proposed by these investigators as a starting that such a device not only is well tolerated by patients but also point (14). can achieve adequate removal of larger as well as smaller solutes. Living Membranes and Bioartificial Kidney Ronco et al. (31) described a new wearable system for con- A major limitation of current membranes is the tendency to tinuous PD called Vicenza WAK (ViWAK). The system uses a occlude over time because of protein deposition and thrombus cartridge that contains polystyrenic resin that completely re- formation. This tendency limits the life of the cartridge and the moves ␤2-microglobulin and ion exchange resin that removes efficiency of the process. A technique that uses endothelial urea and creatinine. Circulating 12 L of exhausted PD solution cell–lined conduits with microelectromechanical systems through the experimental adsorption unit at the rate of 20 (MEMS) has made advances in this field. Another limitation of ml/min provided 11.2 L of net solute clearance. ViWAK is current technology is the lack of the biologic functions of the designed to be used 10 h during the day, can potentially reduce tubule, including metabolic, reclamation, and endocrine func- the number of exchanges compared with continuous ambula- tions. Humes and colleagues (15–17) proposed living mem- tory PD, and uses less fluid than ambulatory PD. REDY sorbent branes that incorporate renal tubule cells to overcome this cartridge has been used by other investigators to regenerate problem. This technique depends on the ability to isolate and dialysate similar to the composition of commercially available grow adult tubular cells in culture. These cells are subsequently peritoneal dialysate using spent dialysate (32). Although WAK grown along the inner surface of the fibers of the standard has the potential to become the preferred from of treatment for hemofiltration cartridge. This tubule cell cartridge is then ESRD, many improvements are still required. placed in series with a conventional hemofilter, constituting a bioartificial kidney called a renal assist device. In vitro and ex Stem Cells vivo tests of renal assist devices have been conducted of animals Stem cells are characterized by their ability to self-replicate and critically ill patients, with promising results that include and undergo multilineage differentiation to produce functional better cardiovascular and hemodynamic parameters and im- tissue. The stems cells are broadly divided into embryonic and Clin J Am Soc Nephrol 4: S132–S136, 2009 Technological Advances in RRT S135 adult categories, depending on their source, with subtle differ- 13. Leonard EF, Cortell S, Vitale NG: Membraneless dialysis: Is ences in the two categories. Stem cells hold promise in multiple it possible? Contrib Nephrol 149: 343–353, 2005 gelds, including acute and chronic renal disease, and as a 14. Leonard EF: Technical approaches toward ambulatory potential source of tissues and organs (33); however, ethical ESRD therapy. Semin Dial 2009, in press concerns surrounding their use may require much to be done 15. Fissell WH, Manley S, Westover A, Humes HD, Fleisch- man AJ, Roy S: Differentiated growth of human renal before stem cells can live up to their full potential. tubule cells on thin-film and nanostructured materials. ASAIO J 52: 221–227, 2006 Conclusions 16. Humes HD, Fissell WH, Weitzel WF, Buffington DA, For patients with ESRD, the past four decades have provided Westover AJ, MacKay SM, Gutierrez JM: Metabolic re- many miracles. Countless millions throughout the world placement of kidney function in uremic animals with a would have died if not for the availability of RRT. Unfortu- bioartificial kidney containing human cells. Am J Kidney Dis 39: 1078–1087, 2002 nately, however, mortality, morbidity, and quality of life re- 17. 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