Bioartificial Kidney Ameliorates Gram-Negative Bacteria-Induced Septic Shock in Uremic Animals

Abstract

Abstract. The bioartificial kidney (BAK) consists of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10 9 porcine renal proximal tubule cells. BAK replaces filtration, transport, and metabolic and endocrinologic activities of a kidney. Previous work in an acutely uremic dog model demonstrated that BAK ameliorated endotoxin (lipopolysaccharide [LPS])-induced hypotension and altered plasma cytokine levels. To further assess the role of BAK in sepsis in acute renal failure, dogs were nephrectomized and 48 h later administered intraperitoneally with 30 ϫ 10 10 bacteria/kg of E. coli. One hour after bacterial administration, animals were placed in a continuous venovenous hemofiltration circuit with either a sham RAD without cells (n ϭ 6) or a RAD with cells (n ϭ 6). BP, cardiac output, heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance were measured throughout the study. All animals tested were in renal failure, with blood urea nitrogen and serum creatinine concentrations greater than 60 and 6 mg/dl, respectively. RAD treatment maintained significantly better cardiovascular performance, as determined by arterial BP (P Ͻ 0.05) and cardiac output (P Ͻ 0.02), for longer periods than sham RAD therapy. Consistently, all sham RAD-treated animals, except one, expired within 2 to 9 h after bacterial administration, whereas all RAD-treated animals survived more than 10 h. Plasma levels of TNF-␣, IL-10, and C-reactive protein (CRP) were measured during cell RAD and sham RAD treatment. IL-10 levels were significantly higher (P Ͻ 0.01) during the entire treatment interval in the RAD animals compared with sham controls. These data demonstrated in a pilot large animal experiment that the BAK with RAD altered plasma cytokine levels in acutely uremic animals with septic shock. This change was associated with improved cardiovascular performance and increased survival time. These results demonstrate that the addition of cell therapy to hemofiltration in an acutely uremic animal model with septic shock ameliorates cardiovascular dysfunction, alters systemic cytokine balance, and improves survival time.

Technological Advances in Renal Replacement Therapy

“…In vitro and ex vivo tests of renal assist devices have been conducted of animals and critically ill patients, with promising results that include better cardiovascular and hemodynamic parameters and improved survival (18 -20). Of particular interest is the potential differential beneficial effect in patients with acute kidney injury associated with sepsis (21)(22)(23)(24)(25).…”

The Bioartificial Kidney and Bioengineered Membranes in Acute Kidney Injury

“…A series of additional animal experiments investigated the impact of treatment with this device on the high mortality of sepsis complicated by AKI. Studies in both dogs and pigs have demonstrated that RAD treatment in a bioartificial kidney circuit improves cardiovascular performance associated with changes in cytokine profiles and confers a significant survival advantage in septic or endotoxin animal models [13,14,15]. …”

Developmental approaches to kidney tissue engineering

“…In terms of augmentation of traditional hemodialysis, a "renal assist device," which is composed of a membrane coated with cultured porcine proximal tubule cells, has been developed (14,15). These cells support unidirectional transport, and when added in series to a traditional hemofiltration circuit, the resultant bioartificial kidney appears to significantly improve outcomes of acutely uremic dogs in models of endotoxin-mediated sepsis (10). Human trials are in progress.…”