Intra‐arterial transplantation of mesoangioblasts proved safe and partially efficacious in preclinical models of muscular dystrophy. We now report the first‐in‐human, exploratory, non‐randomized open‐label phase I–IIa clinical trial of intra‐arterial HLA‐matched donor cell transplantation in 5 Duchenne patients. We administered escalating doses of donor‐derived mesoangioblasts in limb arteries under immunosuppressive therapy (tacrolimus). Four consecutive infusions were performed at 2‐month intervals, preceded and followed by clinical, laboratory, and muscular MRI analyses. Two months after the last infusion, a muscle biopsy was performed. Safety was the primary endpoint. The study was relatively safe: One patient developed a thalamic stroke with no clinical consequences and whose correlation with mesoangioblast infusion remained unclear. MRI documented the progression of the disease in 4/5 patients. Functional measures were transiently stabilized in 2/3 ambulant patients, but no functional improvements were observed. Low level of donor DNA was detected in muscle biopsies of 4/5 patients and donor‐derived dystrophin in 1. Intra‐arterial transplantation of donor mesoangioblasts in human proved to be feasible and relatively safe. Future implementation of the protocol, together with a younger age of patients, will be needed to approach efficacy. Synopsis This study reports a safe, first‐in‐human mesoangioblast cell therapy to treat Duchenne muscular dystrophy (DMD) in 5 young patients, using a successful preclinical strategy, as an exploratory non‐randomized open‐label phase I–IIa clinical trial of intra‐arterial HLA‐matched donor cell transplantation. Five patients affected by DMD were treated by intra‐arterial infusions of escalating doses of HLA‐matched donor mesoangioblasts. The trial was overall safe but showed minimal, if any, efficacy. Data analysis suggested to treat patients at an earlier stage of the disease, optimize in in vitro models each single step of the transplantation protocol, and use genetically corrected, autologous mesoangioblasts in a future trial.

OBJECTIVE—Our aim was to evaluate the long-term effects of transplanted islets on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients. RESEARCH DESIGN AND METHODS—A total of 34 type 1 diabetic kidney-transplanted patients underwent islet transplantation and were divided into two groups: successful islet-kidney transplantation (SI-K; 21 patients, fasting C-peptide serum concentration >0.5 ng/ml for >1 year) and unsuccessful islet-kidney transplantation (UI-K; 13 patients, fasting C-peptide serum concentration <0.5 ng/ml). Patients cumulative survival, cardiovascular death rate, and atherosclerosis progression were compared in the two groups. Skin biopsies, endothelial dependent dilation (EDD), nitric oxide (NO) levels, and atherothrombotic risk factors [von Willebrand factor (vWF) and d-dimer fragment (DDF)] were studied cross-sectionally. RESULTS—The SI-K group showed a significant better patient survival rate (SI-K 100, 100, and 90% vs. UI-K 84, 74, and 51% at 1, 4, and 7 years, respectively, P = 0.04), lower cardiovascular death rate (SI-K 1/21 vs. UI-K 4/13, χ² = 3.9, P = 0.04), and lower intima-media thickness progression than the UI-K group (SI-K group: Δ1–3 years −13 ± 30 μm vs. UI-K group: Δ1–3 years 245 ± 20 μm, P = 0.03) with decreased signs of endothelial injuring at skin biopsy. Furthermore, the SI-K group showed a higher EDD than the UI-K group (EDD: SI-K 7.8 ± 4.5% vs. UI-K 0.5 ± 2.7%, P = 0.02), higher basal NO (SI-K 42.9 ± 6.5 vs. UI-K 20.2 ± 6.8 μmol/l, P = 0.02), and lower levels of vWF (SI-K 138.6 ± 15.3 vs. UI-K 180.6 ± 7.0%, P = 0.02) and DDF (SI-K 0.61 ± 0.22 vs. UI-K 3.07 ± 0.68 μg/ml, P < 0.01). C-peptide-to-creatinine ratio correlated positively with EDD and NO and negatively with vWF and DDF. CONCLUSIONS—Successful islet transplantation improves survival, cardiovascular, and endothelial function in type 1 diabetic kidney-transplanted patients.

Cardiovascular disease and the development of coronary artery disease play a pivotal role in increasing mortality in patients with type 1 diabetes. The aim of our study was to evaluate the effects of pancreas transplantation on atherosclerotic risk factors, endothelial-dependent dilation (EDD), and progression of intima media thickness (IMT) in patients with uremia and type 1 diabetes after kidney-alone (KA) or kidney-pancreas (KP) transplantation. A cross-sectional study comparing two groups of patients with type 1 diabetes was performed. Sixty patients underwent KP transplantation and 30 patients underwent KA transplantation. Age and cardiovascular risk profile were comparable in patients before transplantation. In all patients, atherosclerotic risks factors (lipid profile, fasting and postmethionine load plasma homocysteine, von Willebrand factor levels, d-dimer fragments, and fibrinogen) were assessed and Doppler echographic evaluation of IMT and endothelial function with flow-mediated and nitrate dilation of the brachial artery was performed. Twenty healthy subjects were chosen as controls (C) for EDD. Compared with patients undergoing KA transplantation, patients undergoing KP transplantation showed lower values for HbA_1c (KP = 6.2 ± 0.1% vs. KA = 8.4 ± 0.5%; P < 0.01), fasting homocysteine (KP = 14.0 ± 0.7 μmol/l vs. KA = 19.0 ± 2.0 μmol/l; P = 0.02), von Willebrand factor levels (KP = 157.9 ± 8.6% vs. KA = 212.5 ± 16.2%; P < 0.01), d-dimer fragments (KP = 0.29 ± 0.02 μg/ml vs. KA = 0.73 ± 0.11 μg/ml; P < 0.01), fibrinogen (KP = 363.0 ± 11.1 mg/dl vs. KA = 397.6 ± 19.4 mg/dl; NS), triglycerides (KP = 122.7 ± 8.6 mg/dl vs. KA = 187.0 ± 30.1 mg/dl; P = 0.01), and urinary albumin excretion rate (KP = 13.5 ± 1.9 mg/24 h vs. KA = 57.3 ± 26.3 mg/24 h; P < 0.01). Patients undergoing KP transplantation showed a normal EDD (KP = 6.21 ± 2.42%, KA = 0.65 ± 2.74%, C = 8.1 ± 2.1%; P < 0.01), whereas no differences were observed in nitrate-dependent dilation. Moreover, IMT was lower in patients undergoing KP transplantation than in patients undergoing KA transplantation (KP = 0.74 ± 0.03 mm vs. KA = 0.86 ± 0.09 mm; P = 0.04). Our study showed that patients with type 1 diabetes have a lower atherosclerotic risk profile after KP transplantation than after KA transplantation. These differences are tightly correlated with metabolic control, fasting homocysteine levels, lower d-dimer fragments, and lower von Willebrand factor levels. Normal endothelial function and reduction of IMT was observed only in patients undergoing KP transplantation.

To compare breath-hold, three-dimensional, gadolinium-enhanced magnetic resonance (MR) angiography with three-dimensional, phase-contrast MR angiography in the evaluation of renal artery stenosis. Fifty-five consecutive adult patients with clinical suspicion of renovascular disease were prospectively examined with three-dimensional, phase-contrast MR angiography and breath-hold, three-dimensional MR angiography with injection of a standard dose of gadopentetate dimeglumine to evaluate the number of renal arteries and the presence and degree of stenosis. The standard of reference was intraarterial digital subtraction angiography. Gadolinium-enhanced MR angiography depicted all 105 main renal arteries, whereas phase-contrast MR angiography depicted 104. The number of accessory renal arteries depicted was significantly higher with gadolinium-enhanced (17 of 18) than with phase-contrast (11 of 18) studies (P = .04). Both techniques depicted 27 of the 29 stenoses (sensitivity, 93%; P > .05). Sensitivities, specificities, and accuracies in the diagnosis of hemodynamically significant stenosis (> 50% narrowing) were, respectively, 94%, 96%, and 96% for phase-contrast and 100%, 97%, and 98% for gadolinium-enhanced MR angiography (P > .05). Gadolinium-enhanced MR angiography is superior to phase-contrast MR angiography in accessory renal artery depiction. No statistically significant difference in the assessment of stenosis has been found between the two techniques.

The aim of this study was to evaluate the effects of islet transplantation on patient survival and diabetic vascular complications. Thirty-seven type 1 uremic diabetic kidney transplant patients underwent islet transplantation (KI group). Uremic type 1 diabetic kidney-pancreas (KP group, n=162), kidney-alone (KD group, n=42) transplant patients, and uremic type 1 diabetic patients still on hemodialysis (HD+DM group, n=196) constituted the control groups for survival and endothelial morphology. Patient survival was similar in the KI and KP groups and higher than in the HD+DM group (P <0.05). Patients experiencing long-term islet function (KI-successful [KI-s], n=24) showed a better survival (100%, 100%, and 90%) than those in the KI group who lost islet function (KI-unsuccessful [KI-u], n=13) (84%, 75%, and 45%) at 1, 4 and 7 years, respectively (P =0.02). The cardiovascular death rate for the KI group (18%) was similar to the KD group (19%) but lower when the KI-s group is considered alone (5%), and showed a cardiovascular death rate similar to the KP group (8%). The KI-s group showed a good metabolic profile, with reduction of exogenous insulin requirement and persistent C-peptide secretion, as compared with the KI-u group. The endothelial morphology was evaluated with a skin biopsy obtained in all groups. The KI-s and the KP groups demonstrated decreased signs of endothelial injury compared with the KI-u and HD+DM groups. The KI group showed a better atherothrombotic profile than the HD+DM group, with higher levels of natural anticoagulant protein. Successful islet transplantation improves survival, atherothrombotic profile, and endothelial morphology in uremic type 1 diabetic kidney transplant patients.