04-11-2010, 02:11 PM
From Medscape.com
Posted: 11/21/2008; Nat Clin Pract Nephrol. 2008;4(11):604-605. © 2008 Nature Publishing Group
"For years, dialysis has been the standard treatment for uremia. However, regular, long-lasting therapy sessions tethered to an essentially unmovable machine are not ideal for patients. After continuous ambulatory peritoneal dialysis was introduced in the early 1980s,[1] interest has focused on developing a truly wearable or portable dialysis system.[2] Early examples of wearable hemodialysis devices reported in the literature were excessively large and heavy, performed inefficiently and, most problematic of all, lacked effective safety controls.[3,4] Only recently have some interesting papers describing innovative and truly wearable devices deservedly spurred interest in the field.[5-7] Although the idea of a wearable artificial kidney (WAK) is not new, it is only the advent of nanotechnology and miniaturization that has made the vital qualities of efficiency and safety achievable on a small scale.
The reasons for developing a WAK can be categorized as clinical, technical and/or socioeconomic. The outcomes of patients on chronic renal replacement therapy remain dismal with respect to quality of life, morbidity and mortality. However, a growing body of literature indicates that both prolonged and more-frequent dialysis sessions are associated with strikingly improved outcomes.[8] Switching patients from the typical thrice-weekly regimen to one of daily dialysis leads to considerable improvements in the quality of life (e.g. liberalization of diet and fluid restrictions) and to substantial reductions in complications (such as anemia and hypertension), psychological symptoms, hospitalizations and need for medications (e.g. phosphate binders and antihypertensives).[9] Daily dialysis is also reported to increase appetite (leading to improved nutrition and increased serum albumin levels), enhance volume control, eliminate metabolic acidosis and electrolyte abnormalities (e.g. sodium retention, hyperkalemia, hyperphosphatemia), and also potentially decrease the risk of morbidity and mortality from cardiovascular disease and stroke by improving blood pressure control and preventing repeated cardiac stunning due to intradialytic hypotension. Extending this approach to a therapy that, like the human kidney, works not just daily, but continuously, seems logical. Although continuous ambulatory peritoneal dialysis does achieve this goal, no more than 10% of patients on dialysis use this modality worldwide. Furthermore, despite improvements in connectology, peritonitis remains the most common problem encountered by these patients, who are carefully selected for this treatment. Once residual renal function is lost, patients on peritoneal dialysis often rely on an increasing number of hypertonic glucose exchanges, whose implementation is associated with the risk of developing life-threatening encapsulating peritoneal sclerosis. Therefore, alternative solutions, such as WAKs, should be pursued.
Technologies that are available today were not even imaginable a few years ago, and we should take advantage of recent advances to make a quantum leap in the treatment of uremia. The miniaturization and weight reduction of WAKs has been made possible by the development of new materials and production processes. Such technological advances are also likely to drive progress in conventional dialysis.
Following these technological breakthroughs, the major question that will determine the success of this process is whether society wishes to invest in radically new approaches to uremia treatment or to maintain the status quo and continue to bear the morbidity, mortality and cost of treating patients with chronic kidney disease (CKD). In the US alone, the number of patients with CKD is growing steadily and currently approaches 400,000. The total cost of treating these patients exceeds US$30 billion a year. The cost of CKD to society during the current decade is estimated to be $1 trillion worldwide.[10] Furthermore, the mortality rate of patients with CKD currently remains unacceptably high, reaching that of metastatic carcinoma of the breast, colon or prostate. WAKs would enable patients with end-stage renal disease to receive substantially higher doses of dialysis, while lowering the overall cost and manpower burden associated with conventional renal replacement therapy by reducing the need to build and staff hemodialysis centers.
The reasons for developing a WAK are clearly compelling and several systems are currently under development. Some use extracorporeal blood cleansing to achieve blood purification, others are based on peritoneal dialysis. To enable patient mobility, these devices rely on the regeneration of effluent ultrafiltrate and/or dialysate, typically by use of charcoal and other sorbents. In the early pioneering days, patients were treated for 3-4 months with these devices, but the cartridges had to be changed three to four times daily.[3] Improvement in sorbent technology has enabled patients to be treated for longer intervals, as shown in animal and human pilot studies.[5-7] However, we are actively investigating novel sorbent compounds that would enable patients to use a WAK for 7 days without changing sorbent cartridges. The most recent human clinical trials of WAKs centered on patient safety and device performance and reliability. These trials were successful in terms of delivering accurate controlled ultrafiltration[6] and predicted solute clearances.[7] Most importantly, the devices proved to be safe.[7]
Several challenges must be overcome to enable the rapid development and widespread application of WAKs. In order to be truly wearable, the device must be small, light and capable of operating independently of an electrical outlet; it must also be affordable. Minimal amounts of dialysate should be used and regenerated by an effective, cheap and safe sorbent-based process. The design must be ergonomic and combine a user-friendly interface[8] with a small, easy-to-wear device. Improving vascular access is probably the most important challenge in the development of WAKs, because the catheters and percutaneous types of vascular access used for conventional hemodialysis are associated with high morbidity, including infection and central venous stenosis. In order to reduce the risk of infection, a new way of drawing blood from the circulation and returning it to the patient must be developed. Use of grafts based on new, nonthrombogenic biomaterials, or biomaterials coated with anticoagulants, or implanted with DNA or RNA constructs designed to minimize thrombosis, might help to maintain patency of the dialysis circuit for several hours or days with little or no need for anticoagulation. Alternatively, the recent development of newer oral anticoagulants, based on direct inhibition of factor Xa or thrombin, could enable WAKs to operate effectively without recourse to additional anticoagulation.
Recent experiments have demonstrated the feasibility of the WAK concept and the potential for innovations in the near future.[5-7] Many improvements and refinements to the current devices are still needed, but, unless this challenge is confronted directly, most patients on dialysis will continue to experience the poor outcomes associated with thrice-weekly treatment. A paradigm shift is required in renal replacement therapy, and the artificial kidney could, like other once-unthinkable devices such as computers, pacemakers and telephones, bring about a revolution. Whether this dream comes true now, next year or never is up to society at large."
Authors and Disclosures:
Claudio Ronco,1 Andrew Davenport,2 Victor Gura 3
1Department of Nephrology, Dialysis and Transplantation, St Bortolo Hospital, Vicenza, Italy
2Royal Free & University College Medical School, London, UK
3Xcorporeal Inc., Los Angeles, CA
Posted: 11/21/2008; Nat Clin Pract Nephrol. 2008;4(11):604-605. © 2008 Nature Publishing Group
"For years, dialysis has been the standard treatment for uremia. However, regular, long-lasting therapy sessions tethered to an essentially unmovable machine are not ideal for patients. After continuous ambulatory peritoneal dialysis was introduced in the early 1980s,[1] interest has focused on developing a truly wearable or portable dialysis system.[2] Early examples of wearable hemodialysis devices reported in the literature were excessively large and heavy, performed inefficiently and, most problematic of all, lacked effective safety controls.[3,4] Only recently have some interesting papers describing innovative and truly wearable devices deservedly spurred interest in the field.[5-7] Although the idea of a wearable artificial kidney (WAK) is not new, it is only the advent of nanotechnology and miniaturization that has made the vital qualities of efficiency and safety achievable on a small scale.
The reasons for developing a WAK can be categorized as clinical, technical and/or socioeconomic. The outcomes of patients on chronic renal replacement therapy remain dismal with respect to quality of life, morbidity and mortality. However, a growing body of literature indicates that both prolonged and more-frequent dialysis sessions are associated with strikingly improved outcomes.[8] Switching patients from the typical thrice-weekly regimen to one of daily dialysis leads to considerable improvements in the quality of life (e.g. liberalization of diet and fluid restrictions) and to substantial reductions in complications (such as anemia and hypertension), psychological symptoms, hospitalizations and need for medications (e.g. phosphate binders and antihypertensives).[9] Daily dialysis is also reported to increase appetite (leading to improved nutrition and increased serum albumin levels), enhance volume control, eliminate metabolic acidosis and electrolyte abnormalities (e.g. sodium retention, hyperkalemia, hyperphosphatemia), and also potentially decrease the risk of morbidity and mortality from cardiovascular disease and stroke by improving blood pressure control and preventing repeated cardiac stunning due to intradialytic hypotension. Extending this approach to a therapy that, like the human kidney, works not just daily, but continuously, seems logical. Although continuous ambulatory peritoneal dialysis does achieve this goal, no more than 10% of patients on dialysis use this modality worldwide. Furthermore, despite improvements in connectology, peritonitis remains the most common problem encountered by these patients, who are carefully selected for this treatment. Once residual renal function is lost, patients on peritoneal dialysis often rely on an increasing number of hypertonic glucose exchanges, whose implementation is associated with the risk of developing life-threatening encapsulating peritoneal sclerosis. Therefore, alternative solutions, such as WAKs, should be pursued.
Technologies that are available today were not even imaginable a few years ago, and we should take advantage of recent advances to make a quantum leap in the treatment of uremia. The miniaturization and weight reduction of WAKs has been made possible by the development of new materials and production processes. Such technological advances are also likely to drive progress in conventional dialysis.
Following these technological breakthroughs, the major question that will determine the success of this process is whether society wishes to invest in radically new approaches to uremia treatment or to maintain the status quo and continue to bear the morbidity, mortality and cost of treating patients with chronic kidney disease (CKD). In the US alone, the number of patients with CKD is growing steadily and currently approaches 400,000. The total cost of treating these patients exceeds US$30 billion a year. The cost of CKD to society during the current decade is estimated to be $1 trillion worldwide.[10] Furthermore, the mortality rate of patients with CKD currently remains unacceptably high, reaching that of metastatic carcinoma of the breast, colon or prostate. WAKs would enable patients with end-stage renal disease to receive substantially higher doses of dialysis, while lowering the overall cost and manpower burden associated with conventional renal replacement therapy by reducing the need to build and staff hemodialysis centers.
The reasons for developing a WAK are clearly compelling and several systems are currently under development. Some use extracorporeal blood cleansing to achieve blood purification, others are based on peritoneal dialysis. To enable patient mobility, these devices rely on the regeneration of effluent ultrafiltrate and/or dialysate, typically by use of charcoal and other sorbents. In the early pioneering days, patients were treated for 3-4 months with these devices, but the cartridges had to be changed three to four times daily.[3] Improvement in sorbent technology has enabled patients to be treated for longer intervals, as shown in animal and human pilot studies.[5-7] However, we are actively investigating novel sorbent compounds that would enable patients to use a WAK for 7 days without changing sorbent cartridges. The most recent human clinical trials of WAKs centered on patient safety and device performance and reliability. These trials were successful in terms of delivering accurate controlled ultrafiltration[6] and predicted solute clearances.[7] Most importantly, the devices proved to be safe.[7]
Several challenges must be overcome to enable the rapid development and widespread application of WAKs. In order to be truly wearable, the device must be small, light and capable of operating independently of an electrical outlet; it must also be affordable. Minimal amounts of dialysate should be used and regenerated by an effective, cheap and safe sorbent-based process. The design must be ergonomic and combine a user-friendly interface[8] with a small, easy-to-wear device. Improving vascular access is probably the most important challenge in the development of WAKs, because the catheters and percutaneous types of vascular access used for conventional hemodialysis are associated with high morbidity, including infection and central venous stenosis. In order to reduce the risk of infection, a new way of drawing blood from the circulation and returning it to the patient must be developed. Use of grafts based on new, nonthrombogenic biomaterials, or biomaterials coated with anticoagulants, or implanted with DNA or RNA constructs designed to minimize thrombosis, might help to maintain patency of the dialysis circuit for several hours or days with little or no need for anticoagulation. Alternatively, the recent development of newer oral anticoagulants, based on direct inhibition of factor Xa or thrombin, could enable WAKs to operate effectively without recourse to additional anticoagulation.
Recent experiments have demonstrated the feasibility of the WAK concept and the potential for innovations in the near future.[5-7] Many improvements and refinements to the current devices are still needed, but, unless this challenge is confronted directly, most patients on dialysis will continue to experience the poor outcomes associated with thrice-weekly treatment. A paradigm shift is required in renal replacement therapy, and the artificial kidney could, like other once-unthinkable devices such as computers, pacemakers and telephones, bring about a revolution. Whether this dream comes true now, next year or never is up to society at large."
Authors and Disclosures:
Claudio Ronco,1 Andrew Davenport,2 Victor Gura 3
1Department of Nephrology, Dialysis and Transplantation, St Bortolo Hospital, Vicenza, Italy
2Royal Free & University College Medical School, London, UK
3Xcorporeal Inc., Los Angeles, CA