ISLET AFTER KIDNEY TRANSPLANTATION

Description of Study

Patient Selection Criteria

Open Sites

Study Purpose

The purpose of this study is to determine if islet transplantation is a safe and effective treatment for patients with type 1 diabetes who have received a kidney transplant. The study will also assess how an islet transplant affects a patient's quality of life. To qualify for the study, patients must have type 1 diabetes, be between the ages of 18 and 65, have a stable kidney transplant for at least 3 months, and meet the patient selection criteria

What to Expect Before Islet Transplant After Kidney Transplantation (IAK)

Because islet after kidney transplantation remains an experimental procedure, criteria for study participation are very strict. To participate in this research study, the candidate must have type 1 diabetes and must have already received a successful kidney transplant for diabetic kidney disease 3 or more months ago. Patients must be under the continuing care of a kidney transplant doctor and be on a combination of any of the following anti-rejection medications: sirolimus, tacrolimus, MMF and prednisone (5mg a day or less) to prevent rejection of the kidney transplant. Interested study candidates on anti-rejection medications other than sirolimus, tacrolimus, MMF and/or prednisone SHOULD NOT make any changes to their anti-rejection medication regimen on their own. Switching anti-rejection medications may increase the risk of rejecting the kidney transplant and should only be done under the supervision of the patient's treating kidney transplant doctor. Patients who are on anti-rejection medications other than sirolimus, tacrolimus, MMF or low-dose prednisone and/or patients with a kidney transplant that is not working well, are not be eligible to be subjects for islet transplantation on this study.

Before being accepted onto the IAK study, patients must undergo a detailed physical exam, blood tests, and other tests to ensure that they (and their kidney transplant) are healthy enough to receive islet transplant and that they meet the study eligibility criteria. Patients cannot participate in this research study if they have diseases of the heart, liver, gallbladder, and/or kidney, of if they have cancer, infections or other chronic illnesses.

Qualified patients will be placed on the United Network of Organ Sharing (UNOS) waiting list for islet transplantation. When islets from a donor with a matching blood type become available, the islet transplant candidate is brought in for a blood draw to perform a more advanced matching test (called a crossmatch test) that will determine if it is safe for the patient to receive the donor islets. A physical exam and other tests will also be done. If these tests indicate that the patient is in good condition, preparation for islet transplant begins.

Medications Given for Islet Transplant

Patients will be given several medications before and after islet transplantation to protect the islet cells and prevent infection. These include:

Patients will continue to take anti-rejection medicines as prescribed by the kidney transplant doctors to protect the kidney and to also help prevent the body from rejecting the islets. Additional anti-rejection drugs used for the IAK study are:

• Basiliximab (ba·si·lix·i·mab) or Daclizumab (dac·liz·u·mab) - given into a vein before and after islet transplantation for extra protection of the newly transplanted islet cells
• Etanercept (e·tan·er·cept) - given into a vein approximately 1 hour before transplantation and as a shot underneath the skin twice a week for 2 weeks after transplantation to prevent inflammation

Patients also receive the following antibiotics and anti-viral drugs to prevent infection:

• Vancomycin (van·co·my·cin) and Imipenem (im·i·pe·nem) - antibiotics given through the vein before transplant to prevent general infections
• Bactrim (bac·trim) SS - given by mouth three times per week for 6 months after transplant to prevent pneumonia
• Valganciclovir (val·gan·ci·clo·vir ) or Acyclovir (a·cy·clo·vir) - anti-viral medicines given to prevent viral infections after transplant

The following medications are given after transplant to prevent blood from clotting at the transplant site:

• Enoxaparin (e·nox·a·pa·rin) - given as two injections under the skin per day for 10 days after transplant
• Aspirin (as·pi·rin) - give once a day by mouth for 14 days after transplant

The following vitamins and other supplements will be taken by mouth after transplant to protect the transplanted islets, promote islet health, and keep islet transplant patients healthy:

• Vitamin C
• Vitamin E
• Nicotinamide (nic·o·tin·a·mide)
• Pravastatin (pra·va·sta·tin)
• Iron

Islet Transplant

Islets contain the cells that make insulin. Islet transplantation is an experimental procedure that involves taking islet cells from the pancreas organ of a person who has died and then transplanting the islets into patients with diabetes to try to help them control their blood sugar and possibly stop taking insulin. The islet transplantation is performed by a specially trained radiologist. Patients are awake for the procedure, but are sedated for comfort. The radiologist inserts a needle into portal vein in the liver. Once in the portal vein, the islets are infused through the needle over approximately 30 minutes. After the islets are infused, the needle is removed and the opening in the vein is sealed to prevent bleeding. The patient is then taken to the recovery room. It is important to note that because it is difficult to isolate all the islets from a pancreas, most people will need two to three transplant procedures to receive enough islets to potentially stop using insulin.

What to Expect After Transplant

Following islet transplantation, patients are monitored in the hospital for 24 hours to watch for bleeding or complications . Patients continue to test their blood sugar levels frequently (before and after meals and at bedtime). Adjustments to insulin doses are made over several weeks as the islets settle into their new home in the liver.

During the 2-year follow-up, patients are seen frequently in clinic to 1) monitor for safety, 2) track how well the islets are working, 3) determine how the body's immune system is reacting to the transplanted islets, and 4) monitor for changes in quality of life, as described below. Study patients will also continue to be followed by their own kidney transplant doctor.

After the transplant, patients are seen frequently to monitor for potential side effects. The frequency of these visits range from a few times per week immediately after transplant to once per month in long-term follow-up.

Anti-rejection drug levels

The levels of the anti-rejection medications will be measured with a blood test at least once per month after islet transplant.

Kidney transplant function monitoring

The following tests will be done to make sure your kidney transplant continues to work well:

• Blood (approximately 1 teaspoon) will be taken to measure serum creatinine levels twice a week for the first month, once a week during the second month, every two weeks in Month 3, monthly through month 6, and every 3 months thereafter.
• A small urine sample at the clinic once a week in the first month and then at Month 3 and every 6 months thereafter to measure the amount of protein and creatinine in the urine.
• A 24-hour urine collection will be done every 6 months for more advanced kidney function tests.

Blood sugar monitoring

Islet transplant recipients will need to continue to test blood sugar frequently (seven times per day: before and after each meal and at bedtime) and maintain a log of blood sugar and insulin doses. The logs will be reviewed by the research doctors to track blood sugar control and adjust insulin doses as needed.

Regular safety check-ups in the clinic

Regular safety monitoring clinic visits are held weekly intervals for the first month and then at Month 3 and every 3 months after that for 2 years after transplant to assess for complications. On these outpatient visits, the following will be done:

• Review blood sugar and insulin logs and medication logs.
• Review patient symptoms
• Vital signs (blood pressure, pulse, body temperature) and weight are measured.
• Blood tests to monitor patient health and islet, kidney, and liver function.
• Physical exam by a research doctor

Diabetes complications

Islet recipients will also be assessed every 6 months to watch for changes in diabetes-related complications using the following tests:

• Retinopathy screen - This involves putting drops in your eyes to widen the pupils so the doctor can look at the back of the eye (the retina) and assess for blood vessel damage.
• Neuropathy screen - This test checks for nerve damage in the feet and involves touching the patient's feet lightly with fibers (monfilaments).

Several specialized tests are done to measure how well the transplanted islets are working.

• Hemoglogin A1c: This test is done every 3 months to measure blood sugar control.
• Glucagon stimulation: This test involves taking two blood samples, one before and one after a glucagon injection is given to measure blood sugar and insulin levels. Glucagon should stimulate the islets to make insulin.
• Continuous glucose monitoring: This test involves placing a GlucoseSensor (MiniMed®), which consists of a small pager-like device connected by a cable to a tiny cable that is inserted just under the skin. The sensor measures sugar levels continuously for 3 days and results are downloaded to a computer as a way of showing how well the islets are working.
• Intravenous (through the vein) glucose tolerance test (IVGTT): This test involves measuring the amount of insulin produced by the islets in response to a sugar (glucose) injection. Blood samples will be taken before and for 30 minutes after the sugar injection to measure changes in blood sugar and insulin levels.
• Arginine stimulation test (AST):This is done after each IVGTT study. Arginine is another factor that stimulates insulin production by the islets. Arginine is injected into a vein and blood samples are drawn over 30 minutes to measure how much insulin the islets are able to produce.
• Oral glucose tolerance test (OGTT): This test involves monitoring insulin production and blood sugar levels over 2 hours after drinking a sugary solution. This test is similar to the IVGTT described above.
• Glucose clamp study: This test involves injecting both sugar and insulin to measure how sensitive the body is to insulin. Blood samples are taken repeatedly over 3.5 hours to measure sugar and insulin levels. This test helps determine how sensitive your body is to insulin.
• Mini-IVGTT: This test is similar to the IVGTT, but uses a smaller injection of sugar to look for subtle changes in how much insulin the islets are able to produce. This test may help predict islet cell rejection.

The immune system consists of organs, tissues, and cells that normally fight off infections or other foreign substances. Several biological markers can be measured in blood samples to monitor for possible signs of rejection after transplantation. Blood is drawn several times during the 2-year follow-up period to measure immune system factors.

To find out how quality of life is affected after islet transplant, patients will be asked to complete a set of questionnaires before islet transplantation and at 6, 12, and 24 months after islet transplantation. You will be asked to answer approximately 100 questions each time. The questions ask you to rank your feelings about your overall health, diabetes, diabetes treatment, the impact diabetes has on your work, relationships and life, and the frequency with which you experience potential diabetes-related symptoms and how much they bother you.

Possible Complications

Islet transplantation is an experimental procedure and may have side-effects related to the transplant itself and the anti-rejection medications.

Islet transplantation may cause bleeding at the site of islet infusion, infection, blood clot in the veins of the liver, and abdominal pain. Islet transplant may also cause the immune system to make antibodies to donor tissue. This could increase the risk of rejecting the kidney transplant and may make it difficult to find a matching donor should a future organ transplantation become necessary.

Anti-rejection medications can have several side effects. Some of the most common include mouth ulcers, anemia (low red blood cells that cause symptoms of tiredness), nausea, vomiting, diarrhea, high cholesterol or fat levels in the blood, liver problems, high blood pressure, fatigue, kidney problems, abnormal menstrual periods in women, and an increased risk of infection. Anti-rejection medications may also increase the risk of developing cancer.