Islet Transplantation in Type 1 Diabetic Kidney Allograft

Inclusion Criteria:

• Male and female subjects age 18 to 68 years.

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

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

• Absent stimulated c-peptide (< 0.3 ng/mL) in response to a MMTT [Boost® 6 mL/kg bodyweight (BW) to a maximum of 360 mL; another product with equivalent caloric andnutrient content may be substituted for Boost®] measured at 60 and 90 min afterstart of consumption.

• Subjects who are > or at 3 months post-renal transplant who are taking appropriatecalcineurin inhibitor (CNI) based maintenance immunosuppression ([tacrolimus aloneor 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 72hoursafter kidney transplantation (islets and kidney are from the same donor)

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

Exclusion Criteria:

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

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

• Other (non-kidney) organ transplants except prior failed pancreatic graft where thegraft failed within the first two weeks due to thrombosis, followed bypancreatectomy; with the pancreas transplant occurring more than 6 months prior toenrollment.

• Untreated or unstable proliferative diabetic retinopathy.

• Blood Pressure: SBP > 160 mmHg or DBP >100 mmHg despite treatment withantihypertensive agents.

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

• Proteinuria (albumin/ creatinine ratio or ACr > 300mg/g) of new onset since kidneytransplantation.

• Either Class I or Class II panel-reactive anti-HLA antibodies > 50%. Subjects witheither Class I or Class II panel reactive anti-HLA antibodies >50% will be excludedif any of the following are detected: Positive cross-match, Islet donor-directedanti-HLA antibodies detected by Luminex Single Antigen/specificity bead assayincluding weakly reactive antibodies that would not be detected by a flowcross-match, or Antibodies to the renal donor (i.e. presumed de novo).

• For female subjects: Positive pregnancy test, presently breast-feeding, desires tobe pregnant at any time point in the future, which includes during or after thecompletion of the study even if study participation is ended early, or unwillingnessto use effective contraceptive measures for the duration of the study and 4 monthsafter discontinuation. For male subjects: intent to procreate during the duration ofthe study or within 4 months after discontinuation or unwillingness to use effectivemeasures of contraception. Oral contraceptives, Norplant®, Depo-Provera®, andbarrier devices with spermicide are acceptable contraceptive methods; condoms usedalone are not acceptable.

• Presence or history of active infection including hepatitis B, hepatitis C, HIV, ortuberculosis (TB). Subjects with laboratory evidence of active infection areexcluded even in the absence of clinical evidence of active infection.