Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A 165 b in diabetic nephropathy. Renal expression of VEGF-A 165 b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A 165 b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A 165 b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A 165 b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A 165 b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A 165 b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.

The observation that therapeutic agents targeting vascular endothelial growth factor-A (VEGF-A) associate with renal toxicity suggests that VEGF plays a role in the maintenance of the glomerular filtration barrier. Alternative mRNA splicing produces the VEGF xxx b family, which consists of antiangiogenic peptides that reduce permeability and inhibit tumor growth; the contribution of these peptides to normal glomerular function is unknown. Here, we established and characterized heterozygous and homozygous transgenic mice that overexpress VEGF 165 b specifically in podocytes. We confirmed excess production of glomerular VEGF 165 b by reverse transcriptase-PCR, immunohistochemistry, and ELISA in both heterozygous and homozygous animals. Macroscopically, the mice seemed normal up to 18 months of age, unlike the phenotype of transgenic podocyte-specific VEGF 164 -overexpressing mice. Animals overexpressing VEGF 165 b, however, had a significantly reduced normalized glomerular ultrafiltration fraction with accompanying changes in ultrastructure of the glomerular filtration barrier on the vascular side of the glomerular basement membrane. These data highlight the contrasting properties of VEGF splice variants and their impact on glomerular function and phenotype.

ObjectiveDespite improvements in its management, infective endocarditis (IE) is associated with poor survival. The aim of this study was to evaluate the impact of a multidisciplinary endocarditis team (ET), including a cardiologist, microbiologist and a cardiac surgeon, on the outcome of patients with acute IE according to medical or surgical treatment strategies.MethodsWe conducted an observational before-and-after study of 196 consecutive patients with definite IE, who were treated at a tertiary reference centre between 2009 and 2015. The study was divided into two periods: period 1, before the formation of the ET (n=101), and period 2, after the formation of the ET (n=95). The role of the ET included regular multidisciplinary team meetings to confirm diagnosis, inform the type and duration of antibiotic therapy and recommend early surgery, when indicated, according to European guidelines.ResultsThe patient demographics and predisposing conditions for IE were comparable between the two study periods. In the time period following the introduction of the ET, there was a reduction in both the time to commencement of IE-specific antibiotic therapy (4.0±4.0 days vs 2.5±3.2 days; P=0.004) and the time from suspected IE to surgery (7.8±7.3 days vs 5.3±4.2 days; P=0.004). A 12-month Kaplan-Meier survival for patients managed medically was 42.9% in the pre-ET period and 66.7% in the post-ET period (P=0.03). The involvement of the ET was a significant independent predictor of 1-year survival in patients managed medically (HR 0.24, 95% CI 0.07 to 0.87; P=0.03).ConclusionsA standardised multidisciplinary team approach may lead to earlier diagnosis of IE, more appropriate individualised management strategies, expedited surgery, where indicated, and improved survival in those patients chosen for medical management, supporting the recent change in guidelines to recommend the use of a multidisciplinary team in the care of patients with IE.