Multicenter Trial of the Effect of AAT on Islet Transplant Engraftment and Durability After Renal Transplant

Exclusion Criteria

• •Weight more than 100 kg or body mass index (BMI) \> 33 kg/m2.
• •Insulin requirement of \>1.0 U/kg/day or, \> 60 U/day total, or \<15 U/day.
• •Other (non-kidney) organ transplants except prior failed pancreatic graft where graft failure is attributed to thrombosis within the first 4 weeks or to other technical reasons that require graft pancreatectomy; with the graft pancreatectomy occurring more than 6 months ago.
• •Untreated or unstable proliferative diabetic retinopathy.
• •Blood Pressure: SBP \> 160 mmHg or DBP \>100 mmHg despite treatment with antihypertensive agents.
• •Calculated GFR of ≤ 40 mL/min/1.73 m2 using the subject's measured serum creatinine and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation1. Strict vegetarians (vegans) will be excluded only if their estimated GFR is ≤ 35 mL/min/1.73 m2.
• •7\. Proteinuria (albumin/creatinine ratio or ACr \> 300mg/g) of new onset since kidney transplantation.
• •Calculated panel-reactive anti-HLA antibodies \> 50%. Subjects with calculated panel reactive anti-HLA antibodies ≤ 50% will be excluded if any of the following are detected:
• •* Positive cross-match,
• •* 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
• •* Antibodies to the renal donor (i.e. presumed de novo).
• •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.
• •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.
• •Negative screen for Epstein-Barr virus (EBV) by IgG determination at time of screening or previous kidney transplant.
• •Invasive aspergillus, histoplasmosis, and coccidoidomycosis infection within the last year.
• •Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
• •Known active alcohol or substance abuse.
• •Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g. warfarin) after islet transplantation (low-dose aspirin treatment \[325 mg PO\] is allowed) or subjects with international normalized ratio (INR) \> 1.5. The use of Plavix is allowed only in conjunction with mini- laparotomy procedure at the time of islet transplant.
• •Severe co-existing cardiac disease, characterized by any one of these conditions:
• •* Recent MI (within past 6 months);
• •* Evidence of ischemia on functional cardiac exam within the last year;
• •* Left ventricular ejection fraction \< 30%; or
• •* Valvular disease requiring replacement with prosthetic valve.
• •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.
• •Use of any investigational agents within 4 weeks of enrollment.
• •Administration of live attenuated vaccine(s) within 2 months of enrollment.
• •Any medical condition that, in the opinion of the investigator, will interfere with the safe participation in the trial. (Cancer screenings should be performed per current American Cancer Society guidelines).
• •Positive screen for BK virus by polymerase chain reaction (PCR) performed at time of screening.
• •A kidney transplant patient with type 1 diabetes who has an HbA1c \< 7.5 and no history of severe hypoglycemia.
• •Selective or severe IgA deficiency (levels \< 5-7 mg/dL)
• •AAT deficiency (defined as \< 1.0ng/mg AAT)