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ENGINEERING A NEW APPROACH TO SEPTIC SHOCK
ANN
ARBOR, MICH—In
gram-negative sepsis, the progression to septic shock and
multiorgan failure increases the mortality rate to more
than 50%. Plasma levels of two proinflammatory cytokines—tumor
necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6)—appear
to predict patient outcome, but pharmacologic attempts to
interrupt the inflammatory process or reduce the burden
of inflammatory mediators have proved disappointing. A nonpharmacologic
approach may provide better results, though.
Researchers at the University of Michigan have developed an extracorporeal renal assist device (RAD) that uses renal tubule cells and is incorporated with a hemofiltration cartridge to form a tissue-engineered bioartificial kidney. In previous animal studies, the device successfully replaced the filtration, transport, metabolic, and endocrine functions of the kidney. It has the potential to alter cytokine concentrations and change the natural history of septic shock and multiorgan failure.[1]
BETTER CARDIAC OUTPUT, LONGER SURVIVAL
“Acute kidney failure in the ICU continues to have a mortality rate of about 70%, and it has not improved over the last 20 or 30 years with dialysis or renal substitution,” said H. David Humes, MD, Professor of Medicine at the University of Michigan in Ann Arbor. “It is due to the injury or death of the renal tubule cells. Perhaps the missing component of renal substitution therapy is … the metabolic component.” Dr. Humes and his colleagues found that using tubule cells protected against sepsis in animals with acute renal failure.
In their latest published
study, they used pigs in which septic shock was induced
via infusion of Escherichia coli into the peritoneal
cavity. A RAD containing porcine tubule renal cells or an
identical sham dialysis cartridge was introduced into the
extracorporeal circuit. Serum chemistry levels and endotoxin
and cytokine concentrations were measured.
The induction of E coli
resulted in a rapid and profound drop in arterial blood
pressure. Blood pressure was similar in both groups. However,
cardiac output was significantly higher in the RAD group
than in the control group for the duration of the experiment.
This difference in cardiac output conferred a significant
survival advantage in the RAD group, which lived for nine
hours, compared to the 4.5-hour survival time in the control
group.
Septic shock also caused a rapid decline in renal function in both groups. Although no differences in hepatic blood flow were observed between the groups, renal blood flow was significantly better maintained in the RAD group. The improved renal blood flow was due to lower renal vascular resistance in the RAD group than in the control group.
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THE
MAKING OF A TISSUE-ENGINEERED KIDNEY
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ANN
ARBOR, MICH—In an interview, H. David Humes,
MD, Professor of Medicine at the University of Michigan,
explained how the renal tubule assist device (RAD)
was developed and how it became a component of the
tissue-engineered kidney.
Dr.
Humes and his colleagues started out with a hemofiltration
cartridge, similar to a dialysis cartridge. Human
(or other mammalian) stem or progenitor cells were
then placed into the cartridge, which has about 5,000
to 6,000 small straw-like fibers inside.
“You
can seed the cells into the openings of the straw-like
fibers,” said Dr. Humes. “It’s sort of like a bioreactor
where you can grow the cells to form bioartificial
tubule constructs with kidney tubule cells on the
inside and—if you are treating a patient or animal—blood
on the outside.” The fibers are not only a scaffold
for the cells to grow on but they are also immunoprotective
against rejection.
“After
you tissue engineer a bioartificial tubule component,
it is attached to a pure synthetic membrane that clears
the blood—similar to the first step of kidney filtration,”
Dr. Humes continued. “If you put these two devices
or cartridges together you have a filtering unit and
a tubular unit that reabsorbs and produces metabolic
substrate and metabolic products to be returned to
the patient.” Finally, these units are hooked up outside
the body in an extracorporeal pump system similar
to that used in the ICU for dialysis or hemofiltration,
“and you’ve got a bioartificial kidney that’s been
tissue engineered,” Dr. Humes said.
What
is the time factor involved in the development of
these components? After obtaining a kidney—for example,
a donor organ that can’t be used for transplantation
because of excessive scarring or anatomical abnormalities—renal
tubule cells are isolated and allowed to propagate.
“It may take several weeks to get from a few hundred
thousand cells to billions of cells,” said Dr. Humes.
“Cells are seeded into the hemofiltration cartridge,
and then it takes about two weeks for the device to
mature. So, from kidney tissue to tissue-engineered
construct,” Dr. Humes estimated, “it takes about eight
weeks.“
—Gale Jurasek
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LOWER
LEVELS OF INFLAMMATORY CYTOKINES
There
were significant differences between the two groups in plasma
levels of IL-6 and interferon-gamma (INF-gamma), with the
RAD group having significantly lower concentrations of both
cytokines. To see whether the lower values for IL-6 and
INF-gamma were due to changes in cellular cytokine processes,
peripheral blood mononuclear cells were tested. The ratio
of endotoxin-stimulated to unstimulated concentrations of
IL-6 was significantly higher in the RAD group.
In this study and in studies with ICU patients, said Dr. Humes, his group “saw that cells in patients with acute kidney failure were basically changing the systemic inflammatory response. This was in patients who not only had acute kidney failure but also multiorgan failure and severe sepsis.” They theorized that perhaps early in septic shock, the kidneys were being damaged by shock as well as by the toxins that bacteria were producing. If the kidney and its tubule cells are being injured early in septic shock, said Dr. Humes, and if tubule cell metabolic performance can be restored by replacing the cells, it might change the course of that process.
The role of the kidneys in septic shock has not been clinically recognized, Dr. Humes observed. “Kidney failure is only recognized three or four days after it happens, when the blood elements that are normally filtered and cleared by the kidneys begin to accumulate.”
The difference in IL-6 levels in RAD-treated animals was remarkable because plasma elevations of proinflammatory cytokines correlate directly with clinical outcomes in patients with systemic inflammatory response syndrome. “This was an unanticipated effect of tubule cells and indicates that the kidney provides other important functions than just clearing the blood of uremic toxins,” pointed out Dr. Humes.
“We went into this study not expecting the peripheral events that became central to the mechanism by which renal tubule cells may be immunoregulators,” Dr. Humes admitted. “[Our findings] open the way for a cascade of interesting scientific queries and can also be translated into an innovative approach to septic shock, which still has a very high mortality rate.”
—Gale Jurasek
Reference
1. Humes HD, Buffington DA, Lou L, et al. Cell therapy with a tissue-engineered kidney reduces the multiple-organ consequences of septic shock. Crit Care Med. 2003;31:2421-2428.
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