The Edmonton Protocol

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A new protocol was developed in Edmonton, Canada in 1999 that radically changed the face of clinical islet transplantation. The first seven patients treated under the Edmonton Protocol all achieved and maintained insulin independence beyond one year, demonstrating for the first time that islet transplantation could achieve insulin independence with rates similar to whole pancreas transplantation, but without a need for a major inter-ventional surgery.32 The success of this protocol has been attributed to a number of key modifications from previous clinical trials (Fig. 3). Of note, patients were given an adequate number of high-grade islets prepared from an average of two donor organs. Furthermore, a more potent but less diabetogenic, steroid-free anti-rejection therapy was developed using sirolimus, low-dose tacrolimus and an anti-interleukin-2 receptor monoclonal antibody (anti-IL-2R mAb).

Since the release of the early Edmonton results, considerably more experience has been accrued both in Edmonton and at other centers worldwide. At the University of Alberta, a total of 70 patients have now received islet-alone transplants. (Tables 1,2 and 3) Most patients continue to require two islet infusions in order to provide adequate engraft mass (approximately 12 000 IE/kg islet mass, based on the recipient body weight), but approximately 10% become insulin-free after just one islet infusion. Of patients undergoing completed islet transplants, 82% remain insulin-free by the

Edmonton Protocol

AB O-compatible Adequate islet cell mass

More potent, steroid-tree, less diabetogenic immunosuppression

Insulin Independence

Refined islet isolation:

- no cufturc

- no xenoproteins

' no cryopreservBtion

Immediate infusion through percutaneous portal access

Figure 3. Key components and concepts behind the Edmonton Protocol.

Table 1. Product Release Criteria Prior to Clinical Islet Transplantation

Islet count

Islet mass per kg

Tissue packed cell volume

Islet Viability

Gram stain on final prep

Endotoxin content

Negative

< 5 EU /kg (based on recipient weight)

> 4000 IE /kg (based on recipient weight) < 5.0cc

Table 2. Indications for Clinical Islet Transplantation

1. Islet-alone transplantation a. Type 1 diabetes (C-peptide negative) for more than 5 years b. Evidence for compliance with intensive and optimal insulin and monitoring regimen c. Evidence for failure of optimal insulin therapy, with severe hypoglycemia, hypoglycemic unawareness or glycemic instability, as measured by:

ii. Lability Index > 400

2. Islet-after kidney transplantation a. Type 1 diabetes and stable kidney allograft function b. Immunosuppression with "islet-friendly," steroid free, sirolimus/tacrolimus based

3. Other a. Type 1 diabetes and stable other solid organ allograft function (e.g. heart, lung, liver, etc.)

b. Immunosuppression with "islet-friendly," steroid free, sirolimus/tacrolimus based end of one year. There is some fall off in insulin independence, with 70% remaining insulin-free at two years and 50% free at three years post transplant. Most patients who return to insulin continue to secrete endogenous insulin (and C-peptide) in sufficient amounts to continue to stabilize risk of hypoglycemic reactions or of glycemic lability, and 88% of patients continue to demonstrate islet function as long as five years post transplant. Islet transplantation has proven to be remarkably successful in stabilizing glucose control to a degree that is vastly superior to even intensive insulin therapy, and patients typically demonstrate normalization of HbAlC.33 As a result of this high level of success, a number of Provinces in Canada therapy therapy

Table 3. Current Contraindications to Clinical Islet Transplantation

1. Severe co-existing, uncorrectable cardiac disease

2. Active alcohol or substance abuse

3. Psychiatric disorder if it makes the subject non-compliant with therapy

4. History of non-adherence to prescribed regimens

5. Active infection, including hepatitis C, hepatitis B, HIV

6. Any history of or current malignancies except squamous or basal skin cancer

7. Age less than 18 or greater than 65 years

8. Creatinine clearance < 65mL/min/1.73m2

9. Serum creatinine > 150|mol/L(1.7mg/dL)

10. Macroalbuminuria (urinary albumin excretion rate > 300 mg/24 h)

11. Positive pregnancy test, intent for future pregnancy or failure to follow effective contraceptive measures, or presently breast feeding now regard islet transplantation as a "non-experimental" alternative standard of care for selected patients with unstable forms of type 1 diabetes. An international multicentre trial of the Edmonton Protocol was recently completed by the Immune Tolerance Network in nine sites, and this study demonstrated that the original Edmonton findings could be replicated at times to a very high level of success, depending on the experience of the site.34 Worldwide, there have now been over 400 patients treated since 1999, and increasing momentum and focus on the remaining challenges of islet isolation, alternative insulin-secreting regulated sources, better immuno-suppression with less side effects, and the possibility of immunological tolerance continue to drive the field forward.

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