Brief Description for Transplant Centers 

 

 

What do we  offer?

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Patients with poor controlled type 1 diabetes end up with ESRD. Simultaneous kidney and pancreas transplantation remains the best therapeutic option for them. Those, who received kidney alone from a live or decease donor, may benefit from Pancreas after Kidney Transplantation (PAK). 

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However, there is still a group of patients with kidney transplant alone, who are compliant with immunosuppression therapy but suffering from progressive complications driven by poorly controlled diabetes, who are not candidate for a whole pancreas transplant. 

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We offer those patients participation in our clinical trial and receiving Islet after Kidney Transplantation (IAK). 

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Inclusion criteria:​

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Subjects who meet all of the following criteria are eligible for enrollment:

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1. Male and female subjects age 18 to 68 years.

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2. Subjects who are able to provide written informed consent and to comply with the procedures of the study protocol.

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3. Clinical history compatible with T1D with disease onset < 40 years of age and insulin-dependence for ≥ 5 years at the time of enrollment, and a sum of subject age and insulin dependent diabetes duration of ≥ 28.

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4. Absent stimulated c-peptide (< 0.3 ng/mL) in response to a MMTT [Boost® 6 mL/kg body weight (BW) to a maximum of 360 mL; another product with equivalent caloric and nutrient content may be substituted for Boost®] measured at 60 and 90 min after start of consumtion.

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5. Subjects who are ≥ 3 months post-renal transplant who are taking appropriate calcineurin inhibitor (CNI) based maintenance immunosuppression ([tacrolimus alone or in conjunction with sirolimus, mycophenolate mofetil, myfortic, or azathioprine; or cyclosporine in conjunction with sirolimus, mycophenolate mofetil, or myfortic] ± Prednisone ≤ 10 mg/day) or subject will receive islets transplant within 72 hours after kidney transplantation (islets and kidney are from the same donor)

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6. Stable renal function as defined by a creatinine of no more than one third greater than the average creatinine determination performed in the 3 previous months prior to islet transplantation, until rejection, obstruction or infection is ruled out.

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Subjects who meet one of the options in the following criterion are eligible for transplantation:

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7. Reduced awareness of hypoglycemia manifested by a Clarke score of 4 or more measured upon study enrollment and at least one episode of severe hypoglycemia in the 12 months prior to study enrollment. This criterion requires that there has been involvement in intensive diabetes management. Such management must be under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the 12 months prior to study enrollment;

 

OR

 

After enrollment followed by at least 4 months of IIT, a subject must have a reduced awareness of hypoglycemia manifested by a Clarke score of 4 or more and at least 1 episode of severe hypoglycemia;

 

OR

 

Any subject not meeting the hypoglycemia option must receive intensive insulin therapy (IIT) for a minimum of 12 months under the care of an experienced diabetes specialist. At the end of this period s/he must have both an HbA1c > 7.5% and a value for HBA1c within the 95% confidence interval for the HbA1c in the preceding month of IIT. If the HbA1c has fallen below this 95% confidence interval , the patient must be followed for at least one more month of IIT to achieve a stable HbA1c above 7.5%, as per the above definition;

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OR

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Any subject not meeting one of the above options in this criterion may continue IIT beyond the required 12 months. The subject will be eligible for islet transplantation if the second or third option is met after 12 months of IIT.

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Exclusion criteria:​

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• History or current ancer or neoplasm or PTLD after kidney transplant

• any active chronic infection (BK, HBV, HCV, HIV, TB etc) 

• legally blind

• uncontrolled psychiatric disorder

 

Subjects who meet any of these criteria are not eligible for enrollment:

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1. Weight more than 90 kg or body mass index (BMI) > 30 kg/m2.

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2. Insulin requirement of >1.0 IU/kg/day or <15 U/day.

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3. Other (non kidney) organ transplants except prior failed pancreatic graft where the graft failed within the first two weeks due to thrombosis, followed by pancreatectomy; with the pancreas transplant occurring more than 6 months prior to enrollment.

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4. Untreated or unstable proliferative diabetic retinopathy.

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5. Blood Pressure: SBP > 160 mmHg or DBP > 100 mmHg despite treatment with antihypertensive agents.

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6. Calculated GFR < 40 mL/min/1.73 m2 using the subject's measured serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [1]. Strict vegetarians (vegans) will be excluded only if their estimated GFR is ≤ 35 mL/min/1.73 m2

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7. Proteinuria (albumin/creatinine ratio or ACr > 300 mg/g) of new onset since kidney transplantation.

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8. Either Class I or Class II panel-reactive anti-HLA antibodies > 50%.

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Subjects with either Class I or Class II panel reactive anti-HLA antibodies > 50% will be excluded if any of the following are detected:

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a. Positive cross-match,

b. Islet donor-directed anti-HLA antibodies detected by Luminex Single Antigen/specificity bead assay including weakly reactive antibodies that would not be detected by a flow cross-match, or

c. Antibodies to the renal donor (i.e. presumed de novo).

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9. For female subjects: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 4 months after discontinuation. For male subjects: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.

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10. Presence or history of active infection including hepatitis B, hepatitis C, HIV, or tuberculosis (TB). Subjects with laboratory evidence of active infection are excluded even in the absence of clinical evidence of active infection.

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11. Negative screen for Epstein-Barr virus (EBV) by IgG determination at time of screening or previous kidney transplant.

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12. Invasive aspergillus, histoplasmosis, and coccidoidomycosis infection within one year prior to study enrollment.

 

13. Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.

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14. Known active alcohol or substance abuse.

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15. Evidence of Factor V Leiden mutation.

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16. Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g. warfarin) after transplantation (low-dose aspirin treatment [81 mg PO] is allowed) or subjects with international normalized ratio (INR) > 1.5.

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17. Severe co-existing cardiac disease, characterized by any one of these conditions: 

 

a. Recent MI (within 6 months);

b. Evidence of ischemia on functional cardiac exam within the last year;

c. Left ventricular ejection fraction < 30%; or

d. Valvular disease requiring replacement with prosthetic valve.

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18. Persistent elevation of liver function tests at the time of study entry. Persistent serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvate transaminase (SGPT [ALT]), alkaline phosphatase or total bilirubin, with values > 1.5 times normal upper limits will exclude a subject.

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19. Active infections (except mild skin and nail fungal infections).

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20. Acute or chronic pancreatitis.

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21. Active peptic ulcer disease, symptomatic gallstones, or portal hypertension.

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22. Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.

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23. Use of any investigational agents within 4 weeks of enrollment.

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24. Administration of live attenuated vaccine(s) within 2 months of enrollment.

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25. Any medical condition that, in the opinion of the investigator, will interfere with the safe participation in the trial.

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26. Male subjects with elevation of prostate specific antigen (PSA) > 4 unless malignancy has been excluded.

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27. Any condition other than T1DM as the primary cause of end stage renal disease (ESRD) in the native kidney.

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28. Positive screen for BK virus by polymerase chain reaction (PCR) performed at time of screening.

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29. A previous islet transplant.

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30. A kidney transplant patient with type 1 diabetes who has an HbA1c < 7.5 and no hx of severe hypoglycemia.