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For other articles and previous issues click here. February 13, 2006 Islet
Cell Transplant Interventional radiologists are investigating techniques for transplanting islets in people with type 1 diabetes, using ultrasound guidance plus a unique coil-and-gelfoam methodology that virtually eliminates previous bleeding risks. With so much media attention given to this country’s burgeoning diabetes rate, it’s no surprise that medical researchers pursue new therapies for this American scourge. In the past decade, procedures for transplanting pancreases (and sometimes kidneys) from deceased donors into people with type 1 diabetes have been refined to the point where this complex operation is well recognized as a major step forward in helping these patients. The survival rate for patients who have a pancreas transplant, with or without a kidney transplant, is now greater than 95%, according to experts at the University of Minnesota (UMN), which forged many of today’s techniques. Of course, no matter how successful, serious risks always accompany such major open surgeries. Today, continuing research is targeting the real crux of diabetes—the body’s failure to produce the insulin necessary to take up and circulate its own glucose. The key players in that natural system are the beta cells produced within the islets of the pancreas. Since 1974, researchers have experimented with harvesting and transplanting just the islets, infusing them into the diabetic patient where (with luck) they will thrive and reproduce like the patient’s own, secreting insulin directly into the circulatory system and helping regulate blood sugar levels more normally. Improving
Success Rates Then in 1999, researchers at the University of Alberta in Edmonton, Canada, developed a specific protocol for islet transplantation that met with repeated success. In 2000, eight more teaching and research centers around the world were selected to reproduce and continue study trials on the Edmonton Protocol: UMN, University of Miami, Harvard Medical School, St. Louis’s Washington University, and Seattle’s Pacific Northwest Research Institute, along with Germany’s Justis-Liebig University, Italy’s Universita Vita-Salute, and Switzerland’s University Hospital of Geneva. While dozens more sites now perform islet transplantations using the Edmonton Protocol, these institutions continue to refine the original technique. Each site is testing slightly different surgical approaches and drug regimens, all of which have continuously reported fewer side effects as well as longer-lasting insulin independence in their test patients. Now the UMN Medical School, which annually performs approximately 10% of all pancreas and islet transplants conducted worldwide, reports that its advance on the Edmonton Protocol has reduced the incidence of traumatic bleeding while also almost uniformly helping patients achieve insulin independence one year out. (UMN is also one of 10 U.S. institutions designated by the National Institutes of Health as islet resource centers that produce and distribute transplant-grade pancreatic islets.) Two UMN researchers, Saravanan Krishnamoorthy, MD, and Siobhan Flanagan, described their team’s procedural innovations and accomplishments to November’s RSNA meeting in a session entitled “Percutaneous Intrahepatic Islet Transplantation: Technique and Sandwich Closure.” Type
1 Diabetes Risks The first line of defense once a diagnosis of diabetes is confirmed still remains external-supplied (exogenous) insulin—but, the UMN researchers stress, even with insulin therapy, many type 1 patients find it nearly impossible to achieve and maintain the perfect balance. As Krishnamoorthy points out, “It requires very strict follow-up with a physician or nurse practitioner to be sure that there aren’t any side effects, and that the patient understands how to manage their diabetes and is taking the medicine properly. Logically, replacing the body’s own insulin with injections seems to make sense, but [in actual practice] it requires at least three injections a day. Some people have a pump implanted, which acts like an injection, but [even then] the patient has to check glucose frequently.… [The patient has to] be very organized about the system because it is difficult to [juggle] the combination of food, activity, and insulin.” Physicians treating diabetes are already well aware that, as the disease progresses, even strict control of insulin can’t guarantee sugar stabilization, although it can help minimize the chances of the worst affects. Says Krishnamoorthy, “While the idea of controlling glucose [with insulin supplementation] sounds simple, in reality type 1 diabetes is hard to manage.” Islets
vs. Pancreas Islets are actually clusters of cells within the pancreas. Only 1% to 2% of the pancreas is made up of islets, but in those with diabetes the beta cells within the islets no longer produce insulin. However, with proper immunosuppressant medication, donor islets from another person can be transplanted to live in the patient with diabetes, where they reestablish themselves and begin to make and release insulin again. The ultimate goal is to free the patient from any form of insulin dependence—and, essentially, halt the disease progression—without the use of immunosuppressant medications. To isolate islets from a deceased donor, researchers inject the pancreas with collagenase enzymes, which break down the connective tissues. The organ is then placed in a Ricordi Chamber, a device specifically developed to separate and filter islets. Once collected and isolated, the islets are assessed for quantity, quality, and purity. Finally, they are cultured in a medium in preparation for transplanting. The usual transplantation requires approximately 1 million islets for the average-sized (defined as 155 pounds) patient. It usually requires the equivalent of two donor organs to produce the 1 million islets. Recently, the team led by Bernhard Hering, MD, at UMN’s Diabetes Institute for Immunology and Transplantation (DIIT) has been able to use islets from a single donor to achieve insulin independence in some clinical trial participants. The greatest benefit of pancreas transplantation has been organ lifespan. To date, most transplanted pancreases have outlived many of the transplanted islets. That longevity means researchers know with some certainty that a pancreas transplant helps fend off the worst common diabetic complications, including retinopathy, kidney disease, and blood vessel atrophy. Pancreas transplants are also proven to improve patient survival rates as well as quality of life. However, the inherent surgical risks mean that many researchers, clinicians, and patients are pinning their hopes on the potential offered by new advances in islet transplantation. The
Edmonton Protocol As with a full organ surgical transplant, donor and recipient are matched by blood type. Physicians use ultrasound to visualize the liver and help target that organ’s portal vein. The islets are injected into a catheter inserted into the portal vein via a small abdominal incision. The liver is selected because of its ability to regenerate itself after damage; the transplanted islets usually begin to respond immediately and, with the support of immunosuppressants, new blood vessels usually form around the transfused islets within one month, ensuring that their insulin can easily reach the bloodstream for circulation throughout the patient’s body. “The reason the liver works best is the portal vein has blood in it to provide oxygen and nutrients, and so these islets are able to stay alive,” says Krishnamoorthy. “[Once they are established], they sense the glucose in the blood, they produce insulin, and they help the patient regulate [blood sugar levels], without the patient having to give himself injections.” The procedure is considered minimally invasive, and, although most recipients receive two injections over a one-month interim, virtually all transplant patients stay in the hospital no more than one or two days at a time. Indeed, Krishnamoorthy foresees a time when ultrasound-guided islet transplantation could become an outpatient procedure. UMN’s
Innovation Although a similar coil technique had been tried before, Krishnamoorthy points out that even so, bleeding was common and sometimes excessive. So the UMN researchers decided to test the use of materials specifically designed to stanch blood flow. “We developed a method to close the access site through the parenchyma [organ tissues], where the islets are injected. We call it the ‘sandwich technique’ because of the layered applications of gelfoam and coil,” explains Krishnamoorthy. “The coil is metal, and it slows blood, so once you’ve got the needle in … as you pull it out, you put in the coil. [That ensures] that any blood that squirts out of the portal vein will be slowed down.” Flanagan adds, “The layers of coil and gelfoam are deposited until the liver capsule is reached. As the coil slows the blood as it comes out, the gelfoam acts like a plug and blocks it off. And so, we just keep repeating that combination until the needle reaches the liver capsule.” The researchers note that the coil measures only 1 or 2 millimeters. “It doesn’t fully fit in artery, [it’s just large enough that] as the needle is pulled out, you can insert the coil and the gelfoam into that [injection site] space within the liver tissue where the needle was,” Krishnamoorthy explains. Adds Flanagan, “We don’t want it in the artery or the vein because that would block off those vessels and lead to complications such as portal vein thrombosis.” Promising
Results Almost as importantly, he adds, “what we found is that with that technique, we only had one complication that involved bleeding. The rest of the patients didn’t have any bleeding complications. That was the breakthrough of this technique.” All the clinicians in Krishnamoorthy’s group were interventional radiologists. “Remember, in an open transplant operation to transplant a kidney or pancreas, you have to make a cut through the patient’s abdomen. The transplant surgeon observing us does open procedures … [and] was pretty impressed to see us do this minimally invasively,” he notes. “Even though percutaneous islet transplantation is currently an experimental procedure, the sandwich closure is a safe method that prevents many of the complications common to previous techniques used to transplant islets.” Continuing
Learning Curve In theory, ultrasound seems the ideal modality for the procedure, enabling the physician to select the needle pathway that will present the fewest complications; for example, allowing the clinician to avoid major vessels and bile ducts. It has long been used to visualize organ structures because it images soft tissue and muscles well, even demarcating solid from fluid-filled areas. It also allows the user to actively choose among real-time views. In practice, using ultrasound effectively takes time, repeated experience, and perhaps even a natural aptitude. As Krishnamoorthy notes, “During one procedure, we had to insert the transfusion needle multiple times until we found the right place, and this did cause bleeding problems.” In fact, two patients each underwent two procedures to achieve correct needle placement. This learning curve involved in ultrasound, he says, “does [currently] confine the technique to major research centers. It requires physicians specifically trained in the technique.” He adds, however, “[Percutaneous ultrasound guided islet transplantation] should be able to broaden out, because there are probably far more radiologists who could do this. Going into the portal vein is something that interventional radiology already does now, for other medical conditions, in procedures that are almost identical.” Even with the advances the percutaneous sandwich technique offers, Krishnamoorthy acknowledges that islet transplantation currently remains available only in clinical trials. “The idea sounds great, and it’s been tried for about a decade, so you might ask, Why haven’t we cured diabetes? There is a whole host of factors. The function of the islets depends on the number, quality, and purity of islets isolated from the donor pancreas—the more high-quality islets that are transplanted into the clinical trial participant, the better the chances that patient will become insulin-independent after the transplant.” “This is still an area of active research at DIIT,” he concludes. “But we’re one of the top centers in the world researching islet transplantation, and we’re continually making advances. [The UMN technique] is a safe method of transplantation that could potentially become a same-day procedure.” Looking
Ahead But that issue is another day’s struggle. Today’s challenge—undertaken at UMN and other institutions—is building on the incredible promise of islet cell transplantation. — J. K. Bucsko is a freelance healthcare and technical writer based in Westville, N.J.
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