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Background: Of 5 clinical trials testing dose response of continuous renal replacement therapy (CRRT) in acute kidney injury, 2 showed a benefit, 2 showed none, and 1 appeared equivocal. However, blood-membrane interactions may dominate macromolecule transport in continuous venovenous hemodiafiltration, reducing the impact of dose adjustment. The dosing arms in the Acute Renal Failure Trial Network (ATN) study may have delivered similar clearances for middle molecules., Methods: We simulated the 2 CRRT doses in the ATN study using a synthetic polydisperse macromolecular probe in bovine blood. Clearance of tracers between 10 and 100 kDa molecular weight was measured during 6 h of therapy., Results: Middle-molecule clearance differed by less than 2 ml/min between the 2 dosing arms., Conclusion: The CRRT prescription used in the ATN study appears to have achieved dose separation for small molecules while holding middle-molecule clearance nearly constant. This may explain the outcome difference between the ATN study and earlier studies, and suggests subsequent trial designs., (Copyright 2009 S. Karger AG, Basel.)

Nanotechnology, defined as the science of material features between 10(-9) and 10(-7) of a meter, has received extensive attention in the popular press as proof-of-concept experiments in the laboratory are published. The inevitable delay between feature articles and clinical endpoints has led to unwarranted skepticism about the applicability of the technology to current medical therapy. The theoretic advantages of micro- and nanometer scale engineering to renal replacement include the manufacture of high-hydraulic permeability membranes with implanted sensing and control structures. Recent data in membrane design and testing is presented, with a review of the challenges remaining in implementation of this technology., (Copyright (c) 2007 S. Karger AG, Basel.)

Hemodialysis and hemofiltration have been important technologies in saving the lives of patients with acute (ARF) and chronic renal failure by clearing small solutes from plasma and thereby preventing death from acidemia, hyperkalemia, volume overload, and uremia. These therapeutic approaches, however, are still suboptimal, as patients with ARF have mortality rates exceeding 50%, and patients with end-stage renal disease (ESRD) have, on average, a life expectancy of 4-5 years. The preeminent cause of death in patients with ARF is the development of sepsis or the systemic inflammatory response syndrome with resulting systemic vasodilation, hypotension, ischemic injury to solid organs, multi-organ failure, and death. This vasodilation is due to persistent and excessive pro-inflammation. Similarly, the reduced survival times of patients with ESRD on chronic dialysis have been associated with a persistent and chronic systemic pro-inflammatory state. We have hypothesized that the loss of renal tubule cell mass acutely in acute tubule necrosis and chronically in ESRD results in an immunologically dysregulated state leading to excessive pro-inflammation. The replacement of renal tubule cell function may thus change the current dismal prognosis of patients with these disorders. In this regard, this report presents the first patient ever treated with a bioartificial kidney consisting of a synthetic hemofilter in series with a renal tubule assist device (RAD) containing approximately 10(9) human renal tubule cells. This treatment in a critically ill patient with multi-organ failure and ARF in the intensive care unit was associated temporally with improved cardiovascular parameters and enhanced native kidney function. Multiple systemic plasma cytokine levels and gene expression profiles of peripheral white blood cells were also temporally changed with cell therapy. Clinical trials in patients suffering from either ARF or ESRD are currently ongoing to evaluate the influence of the RAD on the inflammatory response in these groups of patients., (Copyright 2004 S. Karger AG, Basel)

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., (Copyright 2002 S. Karger AG, Basel)