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During the last few years, the incidence of microvascular complications in diabetes mellitus has rapidly increased as a consequence of both an increase in incidence of type 2 and type 1 diabetes mellitus. The pathogenesis of diabetic microvascular complications is still largely unknown. Among the many hypotheses, a dysfunction in angiogenesis has been suggested as a common origin for retinopathy, nephropathy, and neuropathy. Based on this hypothesis, inhibition of vascular endothelial growth factor (VEGF) has been tested as a potential therapeutic approach to prevent and cure diabetic microvascular complications. Several VEGF inhibitors are currently under evaluation or are approved for the treatment of wet age-related macular degeneration and macular edema. These include inhibitors of intracellular transcription of VEGF (e.g. bevasiranib), inhibitors of extracellular VEGF (e.g. pegaptanib), inhibitors of VEGF receptor expression (e.g. aflibercept [VEGF-TRAP]) and inhibitors of the intracellular signaling cascade activating VEGF (e.g. midostaurin). According to the existing evidence base, although inhibition of VEGF results in a better outcome in the case of diabetic retinopathy and also, despite some discrepant results, in the case of diabetic nephropathy, there is no final confirmation that VEGF inhibition is a valid approach for diabetic neuropathy. The latter complication actually, in line with other chronic neuropathies, seems to improve with stimulation of angiogenesis through increased expression of VEGF.

End-stage renal disease (ESRD) is characterized by several atherothrombotic abnormalities, and kidney transplant seems to improve most of them. However, because it is not clear which mechanism is responsible for such improvement, our purpose was to clarify that point.We conducted a cross sectional study involving 30 ESRD patients, 30 ESRD kidney-transplanted patients (Ktx) and 30 healthy controls (C) to evaluate platelet morphology and function, atherothrombotic profile, endothelial abnormalities and cytokine levels involved in the insulin resistance/endothelial dysfunction. (i) Platelet morphology: The ESRD group showed platelet size similar to the other two groups (ESRD=3518x10(3)+/-549x10(3) nm2, C=3075x10(3)+/-197x10(3) nm2, Ktx=2862x10(3)+/-205x10(3) nm2) with similar platelet granules and number. (ii) Platelet surface glycoprotein: The CD41 and P-Selectin were similar between groups. (iii) Platelet intracellular calcium: Resting intracellular calcium was statistically higher in ESRD compared to the C group (ESRD=182.1+/-34.5, Ktx=126.7+/-14.1, C=72.0+/-11.0 nM, P<0.01). (iv) Hypercoagulability markers and natural anticoagulants: The Ktx and ESRD groups showed higher levels of hypercoagulability markers compared to the C group. A reduction in antithrombin activity was evident in ESRD compared to the Ktx group (P=0.03). (v) Endothelial morphology: The ESRD group showed a thickened vessel basal membrane compared to the Ktx and C groups with more endothelial sufference. (vi) Insulin resistance and pro-inflammatory cytokine profile: The ESRD showed a higher homeostasis model assessment provided equations for estimating insulin resistance (HOMA-IR) compared to the Ktx and C groups (ESRD=2.6+/-0.3, Ktx=1.8+/-0.2, C=1.1+/-0.1, P=0.005) and increased soluble tumor neurosis factor alpha (sTNFalpha) (P<0.05) and soluble vascular cell adhesion molecule (sVCAM) levels (P<0.01). Positive correlations were evident among HOMA-IR and sTNFalpha (P<0.001) and sVCAM (P=0.01), respectively. In a small subgroup of ESRD who underwent Ktx (five pts), our findings were confirmed at 1 year of follow-up, suggesting an improvement of almost haemostatic abnormalities. Kidney transplant is associated with a better atherothrombotic profile in ESRD, platelet intracellular calcium and cytokines seem to be most influenced by the transplant, while most morphological abnormalities are retained.

Objective: In uremic type 1 diabetic patients, kidney and pancreas transplantation (KP) and kidney-alone transplantation (KD) provide full restoration of normal renal function; however, only KP, i.e., curing diabetes, is expected to prevent endothelial damages. Our aim was to study L-arginine-induced vasodilation of the renal vasculature in uremic type 1 diabetic patients after KP or KD using magnetic resonance (MR)., Research Design and Methods: MR quantitative flow measurements were performed in 15 KP patients (mean age 39.0 +/- 1.7 years, 10 men and 5 women), in 11 KD patients (mean age 47.3 +/- 1.9 years, 7 men and 4 women), and in 8 nondiabetic kidney transplant patients (mean age 44.0 +/- 4.8 years, 7 men and 1 woman), who were used as control subjects, to measure renal blood flow and velocity and renal vascular resistance before and immediately after infusion of L-arginine., Results: Renal blood flow and velocity were not different at baseline in KP, KD, and control subjects. In contrast, during L-arginine administration renal blood flow increased significantly in KP subjects (basal 8.4 +/- 0.6 vs. post 9.6 +/- 0.8 ml/s, Delta 14.3 +/- 4.4%, P < 0.05) and in control subjects (basal 9.3 +/- 0.8 vs. post 9.1 +/- 0.8 ml/s, Delta 17.3 +/- 6.2%, P < 0.01), while it remained unchanged in KD subjects (basal 10.0 +/- 0.8 vs. post 11.6 +/- 0.9 ml/s, Delta -1.36 +/- 6.9%, NS). Parallel results have been achieved for renal blood velocity (KP subjects: 20.1 +/- 4.9%, P < 0.01; control subjects: 23.0 +/- 7.99%, P < 0.01; and KD subjects: -0.3 +/- 6.5%; NS). A reduction in renal vascular resistance in response to L-arginine was evident in KP and control subjects but not in KD patients., Conclusions: L-Arginine vasodilatory response was successfully assessed with MR quantitative flow measurements. KP patients and control subjects, but not those with KD, showed a preserved L-arginine-induced vasodilation of the renal vasculature.