Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock.
OBJECTIVE
Gram-negative septic shock has a clinical mortality rate approaching 50%. The cause of death is secondary to a systemic inflammatory response syndrome with resulting cardiovascular collapse, ischemic damage to vital organs, and multiple-organ systems failure. Renal tubule cell injury occurs early in septic shock but is not clinically appreciated. Since renal tubule cells appear to play a critical role in the immunoregulation of stress states, renal cell therapy during septic shock may alter the detrimental multiple-organ consequences of systemic Gram-negative infection. The development of a tissue-engineered bioartificial kidney consisting of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 109 renal proximal tubule cells may be a new therapeutic approach to this clinical disorder.


METHODS
Laboratory study.


METHODS
University medical school.


METHODS
Pigs weighing 30-35 kg.


METHODS
To assess the effect of the bioartificial kidney and the RAD in septic shock, pigs were administered 30 x 10(10) bacteria/kg body weight of Escherichia coli into the peritoneal cavity and within 1 hr were immediately placed in a continuous venovenous hemofiltration extracorporeal circuit with either a sham RAD without cells or a RAD with cells.


RESULTS
In this animal model, septic shock resulted within hours in acute tubule necrosis in the kidneys of all animals. Renal cell therapy resulted in significantly higher cardiac outputs and renal blood flow rates in treated animals compared with sham controls. RAD treatment also was associated with significantly lower plasma circulating concentrations of interleukin-6 and interferon-gamma compared with sham-treated animals. IL-6 release rates from peripheral blood mononuclear cells isolated from RAD-treated animals were significantly higher after endotoxin stimulation than those isolated from control animals. These physiologic and molecular alterations were associated with nearly a doubling of the average survival time in the RAD-treated group compared with the sham control group.


CONCLUSIONS
These results demonstrate that renal cell therapy ameliorates cardiac and vascular dysfunction, alters systemic cytokine abnormalities, and improves survival time in a large animal model of Gram-negative septic shock. A cell therapeutic approach with a tissue-engineered bioartificial kidney may be a new treatment modality for this current unmet medical need.
Humes
H David
HD
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109-0726, USA. dhumes@umich.edu
Buffington
Deborah A
DA
Lou
Liandi
L
Abrishami
Simin
S
Wang
Min
M
Xia
Jun
J
Fissell
William H
WH
D058186:Acute Kidney Injury / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D017690:Cell Transplantation / Q000379:methods*; D004195:Disease Models, Animal; D006439:Hemodynamics; D006440:Hemofiltration; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007684:Kidney Tubules / Q000166:cytology; D007688:Kidneys, Artificial; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control; D012079:Renal Circulation; D012772:Shock, Septic / Q000150:complications / Q000628:therapy*; D013552:Swine; D023822:Tissue Engineering
D015850:Interleukin-6; D007371:Interferon-gamma