Analysis of the safety evaluation for premarketing clinical trials of hemodialyzer and of postmarketing safety reports of hemodialyzer in Japan and the US: insights into the construction of a sophisticated premarketing evaluation.

Our aim was to conduct a scoping review of the regulations for hemodialyzers in the safety evaluation in Japan and the United States, and to evaluate the criteria for premarketing clinical trials and postmarketing safety reports to inform the development of a sophisticated premarketing evaluation in Japan. Regulations for approval of hemodialyzers were identified from the databases of the Ministry of Health, Labor and Welfare in Japan and the Federal Drug Agency (FDA) in the United States (US). The criteria for premarket clinical trials and postmarketing safety reports were evaluated for both countries. Standards in Japan required evaluation of blood compatibility and reporting of acute adverse effects by a premarketing clinical trial in 6 of 86 applications with semipermeable membrane materials deemed to be different to those of previously approved devices from 1983 to 31 August 2015. By comparison, the clinical trial was required in one of 545 approvals in the US from 1976 to 29 January 2016, but blood compatibility was not the point. All postmarketing adverse effects identified in Japan were included in the set of 'warnings'. The more stringent requirements for evaluation of blood compatibility and acute adverse effects in Japan seemed to be related to differences in the history of quality management systems for medical devices between the two countries. This study revealed that there were differences between Japan and the US in requiring the premarketing clinical trials for the hemodialyzers. Our findings could be useful for constructing sophisticated premarketing safety evaluation.

Removal of free light chains in hemodialysis patients without multiple myeloma: a crossover comparison of three different dialyzers.

BACKGROUND: Immunoglobulin light chains are classified as middle molecule uremic toxins able to interact with B lymphocyte membranes leading to the activation of transmembrane signaling. The ensuing impairment of neutrophil function can contribute to the chronic inflammation state of uremic patients, and the increased risk of bacterial infections or vascular calcifications. The aim of this crossover observational study was to assess the difference in free light chain removal by three different hemodialysis filters in patients not affected by multiple myeloma. METHODS: Free light chain removal was compared in the polymethylmethacrylate (PMMA) membrane Filtryzer BK-F, the polyphenylene HFR17 filter and the conventional polysulfone filter F7HPS. Twenty chronic hemodialysis patients were enrolled: mean age was 67.7 ± 17.0 years, M/F = 14/6, dialysis vintage (months) 25.5 ± 32.0. The patients were randomized into two groups of treatment lasting 6 weeks each. The dialysis sessions checked were the midweek sessions and the blood was drawn at times 0, 120' and 240'. Kappa (k) and lambda (λ) light chain levels, ß2microglobulin (ß2M), C reactive protein (CRP) and albumin were checked. RESULTS: K light chain levels were 345.0 ± 100.0 mg/L, λ light chains were 121.4 ± 27.0 mg/L. The values of k light chains at times 120' and 240' were significantly lower with PMMA and HFR17 than those obtained with F7. The reduction ratio per session (RRs) for k light chains was 44.1 ± 4.3% with HFR17, 55.3 ± 3.4% with PMMA, 25.7 ± 8.3% with F7 (p = 0.018). The RRs for λ light chains was 30.3 ± 2.9% with HFR17, 37.8 ± 17.3% with PMMA, 14.0 ± 3.9% with F7 (p = 0.032). As to ß2M, RRs was 42.4 ± 3.2% with HFR17 vs. 33.9 ± 2.8% with PMMA vs. 6.3 ± 1.9% with F7 (p = 0.022). The three filters tested showed no differences in CRP or albumin levels. CONCLUSION: In terms of light chain and ß2M removal, the PMMA and on-line HFR filters are similar and both are significantly more effective than the F7 filter in chronic dialysis patients. TRIAL REGISTRATION: The present trial was registered retrospectively ( NCT02950389 , 31/10/2016).

Multifunctions of Excited Gold Nanoparticles Decorated Artificial Kidney with Efficient Hemodialysis and Therapeutic Potential.

Chronic kidney disease (CKD) is inflammation-related. Patients with chronic renal failure who undergo hemodialysis (HD) have some acute adverse effects caused by dialysis-induced oxidative stress, protein adsorption, platelet adhesion, and activation of coagulation and inflammation. Here, resonantly illuminated gold nanoparticles-modified artificial kidney (AuNPs@AK) for achieving high efficiency accompanying therapeutic strategy for CKD during HD is proposed. The efficiency in removing uremic toxins increased obviously, especially in the presence of protein (closer to the real blood). The excited AuNPs@AK expressed negatively charged surface reduced some acute adverse effects caused by dialysis-induced protein adsorption, platelet adhesion, and activation of coagulation, thus avoiding thrombosis during HD. Unlike to traditional HD which provides only one function of removing uremic toxins, the solution collected from the outlet of the sample channel of excited AuNPs@AK showed an efficient free radical scavenger that could decrease dialysis-induced oxidative stress. In the CKD mouse model, this antioxidative solution from excited AuNPs@AK further decreased fibronectin expression and attenuated renal fibrosis, suggesting a reduced inflammatory response. These successful in vitro and in vivo approaches suggest that resonantly illuminated AuNPs@AK in HD take multiadvantages in shortening treatment time and reducing risk of adverse effects, which promise trailblazing therapeutic strategies for CKD.

Artificial organs 2014: a year in review.

In this Editor's Review, articles published in 2014 are organized by category and briefly summarized. We aim to provide a brief reflection of the currently available worldwide knowledge that is intended to advance and better human life while providing insight for continued application of technologies and methods of organ Replacement, Recovery, and Regeneration. As the official journal of the International Federation for Artificial Organs, the International Faculty for Artificial Organs, the International Society for Rotary Blood Pumps, the International Society for Pediatric Mechanical Cardiopulmonary Support, and the Vienna International Workshop on Functional Electrical Stimulation, Artificial Organs continues in the original mission of its founders "to foster communications in the field of artificial organs on an international level." Artificial Organs continues to publish developments and clinical applications of artificial organ technologies in this broad and expanding field of organ Replacement, Recovery, and Regeneration from all over the world. We take this time also to express our gratitude to our authors for offering their work to this journal. We offer our very special thanks to our reviewers who give so generously of time and expertise to review, critique, and especially provide meaningful suggestions to the author's work whether eventually accepted or rejected. Without these excellent and dedicated reviewers, the quality expected from such a journal could not be possible. We also express our special thanks to our Publisher, John Wiley & Sons, for their expert attention and support in the production and marketing of Artificial Organs. We look forward to reporting further advances in the coming years.

Unexpected triggering of the dialysate blood leak detector by haemolysis.

This case showed that it is possible for haemoglobin released by haemolysis in the extracorporeal circuit to pass through a high permeability (albumin retaining) dialyser membrane. In the incident described, the blood leak detector of the dialysis machine was activated before the patient became symptomatic. Haemolysis should be considered as a possible cause of blood leak alarms during dialysis with high flux membranes.

The basic, quantifiable parameter of dialysis prescription is Kt/V urea; treatment time is determined by the ultrafiltration requirement; all three parameters are of equal importance.

There have only been two randomized controlled trials studying outcome as a function of dose in hemodialysis (HD). The first was the National Cooperative Dialysis Study which showed that adequate dialysis was achieved with spKt/V >1.00. The second study was HEMO which was originally designed to study spKt/V 1.2 compared to spKt/V 1.45. Unfortunately by the time HEMO was started, observational studies (OS) had convinced the nephrology community that the minimum adequate dose of spKt/V was 1.40, so the lower target was increased to 1.4 and the upper target to 1.7. The study showed no difference in outcome, although OS have now demonstrated that outcome improves up to spKt/v 2.00. Analysis of HEMO as treated showed that there is a fundamental flaw in dose-targeted OS in that the optimal dose always, but spuriously, increases as the studied dose increases due to dose-targeting bias. Similar flaws exist in the association of treatment time to outcome.

Renal cell therapy is associated with dynamic and individualized responses in patients with acute renal failure.

BACKGROUND: Renal cell therapy in conjunction with continuous hemofiltration techniques may provide important cellular metabolic activities to patients with acute renal failure (ARF) and may thereby change the natural history of this disorder. The development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) human renal proximal tubule cells provides an opportunity to evaluate this form of therapy in patients with ARF in the intensive care unit. METHODS: Nine patients with ARF and multi-organ systems failure (MOSF) have been treated so far with a tissue-engineered kidney in an FDA-approved Phase I/II clinical study currently underway. Acute physiologic parameters and serum cytokine levels were assessed before, during and after treatment with a bioartificial kidney. RESULTS: Use of the RAD in this clinical setting demonstrates maintenance of cell viability and functionality. Cardiovascular stability appears to be maintained during RAD treatment. Human tubule cells in the RAD demonstrated differentiated metabolic and endocrinologic activity. Acute physiologic and plasma cytokine data demonstrate that renal cell therapy is associated with rapid and variable responses in patients with ARF and MOSF. CONCLUSION: The initial clinical experience with the bioartificial kidney and the RAD suggests that renal tubule cell therapy may provide a dynamic and individualized treatment program as assessed by acute physiologic and biochemical indices.

Metabolic replacement of kidney function in uremic animals with a bioartificial kidney containing human cells.

Current renal substitution therapy with hemodialysis or hemofiltration has been an important life-sustaining technology, but it still has suboptimal clinical outcomes in patients with end-stage renal disease or acute renal failure. This therapy replaces the small solute clearance function of the glomerulus but does not replace the metabolic and endocrinologic functions of the tubular cells. This article shows that the combination of a synthetic hemofiltration cartridge and a renal tubule cell assist device (RAD) containing human cells in an extracorporeal circuit replaces filtration, metabolic, and endocrinologic functions in acutely uremic dogs. The RAD maintained excellent performance and durability characteristics for 24 hours of continuous use in the uremic animals. The RAD increased ammonia excretion, glutathione metabolism, and 1,25-dihydroxyvitamin D3 production. Cardiovascular stability in the animals was documented in these studies during this extracorporeal treatment. With these results, clinical evaluation of this device in the treatment of severely ill patients with acute renal failure in an intensive care unit has been initiated.

Bioartificial kidney alters cytokine response and hemodynamics in endotoxin-challenged uremic animals.

The mortality from sepsis complicated by renal failure remains extremely high despite the application of modern renal replacement therapy. This study investigated whether treatment with a bioartificial kidney consisting of a hemofilter in a continuous venovenous hemofiltration circuit (CVVH) with a cartridge containing renal proximal tubule cells, also called the Renal Tubule Assist Device (RAD), would alter the course of sepsis in an animal model. The RAD has been previously characterized in vitro and ex vivo and provides transport, metabolic and endocrine activity. Mongrel dogs (n = 10) underwent surgical nephrectomy and 48 h later were treated with CVVH and either a RAD containing cells (n = 5) or an identically prepared sham cartridge (n = 5). After 4 h of therapy, intravenous endotoxin 2 mg/kg was infused over 1 h to simulate gram-negative septic shock. Data on blood pressure, cardiac output and systemic markers of inflammation were collected. Mean peak levels of an anti- inflammatory cytokine, IL-10, were significantly higher in cell-treated animals (15.25 vs. 6.29 ng/ml; p = 0.037), and mean arterial pressures were higher in cell-treated versus sham-treated animals (p < 0.04). We have demonstrated that treatment of an animal model of endotoxin shock and renal failure with a bioartificial kidney has measurable effects on circulating mediators of inflammation and on hemodynamic stability of the challenged animal.

Artificial organs and vanishing boundaries.

With the first clinical use of the artificial kidney over 5 decades ago, we entered into a new era of medicine-that of substitutive and replacement therapy. Yet it took nearly another 15 years until chronic treatment was possible and nearly another 15 years until widespread treatment was possible due to government support. The history of development and clinical use of other artificial organ technologies such as the artificial heart and heart valves, the artificial lung, artificial blood, joint replacements, the artificial liver, the artificial pancreas, immunologic, metabolic, and neurologic support, neurocontrol, and tissue substitutes have followed similar long development paths. Despite their relatively long time to be put into clinical use, the contributions of artificial organ technologies to the betterment of mankind have been unquestionably a major success. For example, modern day surgery would not be possible without heart-lung support, and the technologies for heart support have led to the development of various minimally invasive technologies. The powerful impact that artificial organ technologies presently has on our lives is seen through the statistic that in the U.S.A. nearly 1 in 10 persons is living with an implanted medical device. With the aging of our population and the improvements in technologies, these numbers will only increase.

Problems and solutions for artificial kidney.

The uremic syndrome is the prototype of a slowly progressive endogenous intoxication, when a detoxifying organ (in this case the kidney) fails. It is characterized by the gradual retention of a host of metabolites, which is in part corrected by dialysis, allowing survival with an acceptable quality of life. This paper reviews the main problems of hemodialysis today, and possible solutions. Adequacy of dialysis is estimated currently from the concentration of urea, which is used as a marker molecule. The problem is that urea is not really toxic by itself. Other markers with known toxicity, such as middle molecules (300-12,000 D) and protein bound compounds should be considered. The question then arises whether the classical dialytic concept based on diffusion should be modified. Adsorptive systems may be strong binders of protein bound solutes. Other concepts that are now arising, and that may add to toxin removal, are slow and daily dialysis. Another question that could be raised is whether it would not be possible to support toxin removal, by administering peroral sorbants. Dialysis patients are prone to vascular disease and die early from cardio-vascular complications. One of the solutions for this problem could be to bring the blood of dialyzed patients into contact with antioxidants (e.g. vitamin C or E). The risk for perdialytic hemodynamic instability is increased in many dialysis patients. The ideal solution would be to develop an "intelligent" dialysis system, whereby blood volume and plasma osmolality are sensed continuously, and ultrafiltration and dialysate sodium concentration are adapted in function of this evolution. An adequate vascular access is indispensable to perform adequate dialysis, but thrombotic/stenotic complications are frequent. This could be prevented by molecular biological modification of vascular grafts, whereby genetic information is entered into the cells, blocking the natural chain of events that otherwise unavoidably leads to neointimal hyperplasia and atherosclerosis. Another old dream is to develop a wearable artificial kidney, whereby patients can move around, and be treated 24 hours per 24 hours, in stead of being treated intermittently at a specific location by the dialysis machine. According to some authors, part of the natural renal function could be replaced by cultured renal tubular cells, which are brought in contact with the blood of the patients. It is concluded that thrilling improvements lie ahead in the future, but the following questions arise: 1) What is the cost of all these improvements? 2) Will it remain possible to reimburse all this? 3) What is going to happen in transplantation, mainly regarding improvements in immunosuppression and the development of xenotransplantation?

The design of an optimized portable artificial kidney system using recirculation and regeneration of dialysate.

This paper is intended as an overview of the research carried out at Coventry University in the design of a portable artificial kidney system. It was seen that the key to the problem was the reduction in dialysate volume, and so it was decided to develop a prototype that would utilize the regeneration and recirculation of a small volume of dialysate. A prototype system has been produced and used to simulate a dialysis session. Activated carbon was used as a sorbent for the regeneration of the dialysate, circulating in a closed loop. For the purpose of this work, the adsorption of urea was investigated as this is, volumetrically, the major solute to be removed. Peltier effect cooling was used to vary the dialysate temperature down to 2 degrees C, as activated carbon will adsorb greater amounts of urea at lower temperatures. A series of tests was then carried out to investigate the effect of dialysate temperature, flowrate and volume on the amount of urea that could be dialysed. From the experimental results, a model of the system was derived, which made it possible to determine the implications of different operating conditions on the overall mass and size of a portable dialysis system. The output of this model was then used to establish a design specification and produce an optimum design solution for the system.

Effect of dialyzer reuse on survival of patients treated with hemodialysis.

OBJECTIVE: To evaluate the impact of dialyzer reuse on the survival of US hemodialysis patients. STUDY DESIGN AND PARTICIPANTS: Nonconcurrent cohort study of 27938 patients beginning hemodialysis in the United States in 1986 and 1987. MAIN OUTCOME MEASURE: Patient survival. RESULTS: Dialysis in freestanding facilities reprocessing dialyzers with the combination of peracetic and acetic acids was associated with greater mortality than treatment in facilities not reprocessing dialyzers (rate ratio [RR],1.10, 95% confidence interval [CI], 1.02-1.18; P=.02) In contrast, there was no significant difference between survival in freestanding facilities reprocessing dialyzers with either formaldehyde (RR,1.03, 95% CI, 0.96-1.10; P=.45) or glutaraldehyde (RR, 1.13, 95% CI, 0.95-1.35, P=.18) and survival in freestanding facilities not reprocessing dialyzers. Among freestanding facilities reprocessing dialyzers, use of peracetic/acetic acid was associated with a higher rate of death than use of formaldehyde (RR = 1.08, 95% CI, 1.01-1.14; P=.02). There was no statistical difference between survival in hospital-based facilities reprocessing dialyzers with either peracetic/acetic acid (RR=0.95, 95% CI, 0.85-1.06; P=.40), formaldehyde (RR=1.06, 95% CI, 0.98-1.15; P=.12), or glutaraldehyde (RR=1.09, 95% CI, 0.71-1.67; P=.70) and survival in hospital-based facilities not reprocessing dialyzers. In addition, choice of sterilant was not associated with a statistically significant difference in survival among hospital-based facilities reprocessing dialyzers. CONCLUSIONS: Dialysis in freestanding facilities reprocessing dialyzers with peracetic/acetic acid may be associated with worse survival than dialysis in free-standing facilities not reprocessing dialyzers or in those reprocessing with formaldehyde. We were unable to determine whether these relationships arose from greater comorbidity among patients treated in facilities using peracetic/acetic acid, poor quality of dialysis procedures in these facilities, or direct toxicity of peracetic/acetic acid. These findings raise important concerns about potentially avoidable mortality among US hemodialysis patients treated in dialysis facilities reprocessing hemodialyzers.