Efficacy of Islet After Kidney Transplantation

This is an interventional treatment trial for Type 1 Diabetes Mellitus focused on measuring Hypoglycemia, Kidney Transplant, Insulin independence, Islet Transplantation, Intensive Insulin Therapy Read More

Inclusion Criteria:

• Mentally stable and able to comply with study procedures;
• Clinical history compatible with type 1 diabetes with onset of disease at less than 40 years of age, insulin dependence for at least 5 years at study entry, and a sum of age and insulin dependent diabetes duration of at least 28;
• Absent stimulated C-peptide (defined as less than 0.3 ng/ml) 60 and 90 minutes post-mixed-meal tolerance test;
• Received kidney transplant for ESRD and are taking appropriate calcineurin inhibitor (CNI) based maintenance immunosuppressive therapy;
• Stable renal function as defined as 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;
• Intensive diabetes management followed by reduced awareness of hypoglycemia or an HbA1c ≥ 7.5%.

Exclusion Criteria:

• Body mass index (BMI) greater than 30 kg/m2 or weight more than 90 kg;
• Insulin requirement of >1.0 IU/kg/day or <15 U/day;
• 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 and the pancreas transplant occurred more than 6 months prior to enrollment;
• Untreated proliferative diabetic retinopathy;
• Systolic blood pressure higher than 160 mmHg or diastolic blood pressure higher than 100 mmHg;
• Calculated glomerular filtration rate of less than 40 ml/min/1.73meter-squared. More information about this criterion is in the protocol;
• Proteinuria (albumin/creatinine ratio or ACr > 300 mg/g) of new onset since kidney transplantation;

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

  1. Positive cross match;
  2. Islet donor-directed anti-HLA antibodies detected my Luminex Single Antigen/specificity bead assay, including weakly reactive antibodies that would not be detected by a flow cross-match; or
  3. Antibodies to the renal donor (i.e. presumed de novo).
• Pregnant, breastfeeding, or unwilling to use effective contraception throughout the study and 4 months after study completion;
• Active infection, including hepatitis B, hepatitis C, HIV, or tuberculosis. More information about this criterion is in the protocol.
• Negative for Epstein-Barr virus (EBV) by (VCA) IgG determination;
• Invasive aspergillus infection, histoplasmosis, and coccidioidomycosis infection one year prior to study enrollment;
• History of malignancy except for completely resected squamous or basal cell carcinoma of the skin;
• Known active alcohol or substance abuse;
• History of Factor V Leiden mutation;
• Any coagulopathy or medical condition requiring long-term anticoagulant therapy after transplantation or individuals with an INR greater than 1.5;

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

  1. Recent MI (within past 6 months);
  2. Evidence of ischemia on functional cardiac exam within the last year;
  3. Left ventricular ejection fraction < 30%; or
  4. Valvular disease requiring replacement with prosthetic valve.
• 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;
• Active infections (except mild skin and nail fungal infections);
• Acute or chronic pancreatitis;
• Active peptic ulcer disease, symptomatic gallstones, or portal hypertension;
• Treatment with any anti-diabetic medication other than insulin within the past 4 weeks;
• Use of any investigational agents within the past 4 weeks;
• Received live attenuated vaccine(s) within the past 2 months;
• Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial;
• Male participants with elevation of prostate specific antigen (PSA) of more than 4 unless cancer has been excluded;
• Any condition other than T1D as the primary cause of end stage renal disease (ESRD) in the native kidney;
• Positive screen for BK virus by polymerase chain reaction (PCR) determination at time of screening;
• A previous islet transplant;
• A kidney transplant recipient with T1D who has an HbA1c < 7.5% and no history of severe hypoglycemia.