Succesful transplantation of human islets in recipients bearing a kidney graft

Abstract

Refinements in procedures of pancreas enzymatic digestion, and new immunosuppression strategies have allowed clinical trials of islet transplantation in patients with Type I (insulin-dependent) diabetes mellitus [1]. Until recently, the majority of transplants were done in patients who also receive kidney allografts [2]. Clinical results in these patients have not been satisfactory, with a 12 month survival of islet allografts (as defined by basal C-peptide > 0.17 nmol/l) being achieved in less than 40 % of recipients, and insulin independence in only 13 % of recipients [2]. The number of recipients who become insulin independent after transplantation is low and so the procedure has also been considered successful when recipients maintained detectable serum C-peptide during follow-up [3±4] or HbA 1 c was normalized [5]. Regardless of which outcome measure is used, around 30 % of the cases reported in the International Registry of Transplantation (ITR) showed the absence of islet function af- Diabetologia (2002) Abstract Aims/hypothesis. Islet transplantation is a minimally invasive approach to curing Type I (insulin-dependent) diabetes mellitus. Success has recently been reported in patients receiving solitary islet transplants but the outcome in patients receiving islets together with, or after, kidney transplants has been limited and unpredictable. Methods. Here we report successful islet transplantation in a cohort of 15 patients with Type I diabetes who were followed for at least 1 year after islet transplantation, after having already received kidney allografts because of end-stage nephropathy. Results. C-peptide after transplantation was higher than 0.17 nmol/l in all 15 recipients, reflecting the absence of primary non-function. Insulin requirement was reduced by over 50 % in all but one patient, and insulin independence was achieved in 10 (66 %) recipients, five of whom now have stable, prolonged insulin independence, well controlled fasting glycaemia, a substantial first-phase and normal secondphase response to glucose, normal insulin sensitivity (HOMA analyses) and HbA 1 c of under 6.2 % (33, 26, 18, 13 and 12 months after transplantation respectively). Of importance for patient management, an assessment of fasting blood glucose and proinsulin values following overnight withdrawal of insulin administration one month after transplantation was a potent predictor of insulin independence, and could be used to decide patients who should have further islet preparations. Conclusion/interpretation. These findings support the use of islet transplantation as a cure for Type I diabetes in patients with severe complications. [Diabetologia (2002) 45: 77±84]

Islet isolation for allotransplantation: variables associated with successful islet yield and graft function

“…Islet quality tests were performed on material processed shortly before transplant. Preparations were considered adequate for transplantation according to the following criteria: (1) NE (>5,000 per kg bodyweight); (2) purity >20% (dithizone-staining determination of islet/total mass); and (3) islet sterility [16]. Purification was defined to be 20% or greater, because in our experience this limit maintains the tissue volume for transplant to less than 10 ml.…”

Prediction of Clinical Outcome in Islet Allotransplantation

“…Considering that the true expectation of recipients of islet transplantation is independence from exogenous insulin administration, the transplant outcome has often been quantified through reaching insulin independence (1,2,17,18) or, when this is impossible, through the decrease of insulin requirement as percentage of initial need or reduction of absolute values of insulin units (12,19). However, this parameter too may not adequately represent the transplanted ␤-cell mass, especially the in case of multiple infusions, where it is necessary to discriminate the effects of various preparations.…”

“…Indeed, data in this regard are contrasting and inconclusive (3,26,27), even though the first step of insulin response to an arginine test or the first and the second step to a test for intravenous charge of glucose have been described to correlate with the functioning ␤-cell mass in several studies (17,19,28,29). In particular, the first phase and the area under the curve for insulin in response to intravenous glucose administration were closely related to glycemic control (29), but inversely correlated with the posttransplant insulin requirement and proinsulin levels (17), thus representing a useful test for islet graft function follow-up.…”

“…It is known that islet transplant function is variable with the passing of time, with a slow and progressive decrease of secretive reserve (17,30,31). Therefore, it is very important to decide at which time of follow-up islet function should be evaluated.…”

Kidney Function After Islet Transplant Alone in Type 1 Diabetes

“…Several studies have reported a high rate of insulin independence and normalization of blood glucose and A1C levels after either pancreas or islet transplantation (3)(4)(5)(6)(7). In patients with type 1 diabetes, pancreas or islet transplantation has improved kidney graft survival (8,9), whereas the positive impact of pancreas transplantation on the native kidney has been counterbalanced by the nephrotoxicity of immunosuppressants, namely calcineurin inhibitors (10,11).…”