Hypertension in diabetes.

Diabetes mellitus, a disease that affects hundreds of millions of people worldwide, is increasing in prevalence in all age groups, including children and adolescents. Much of the morbidity and mortality associated with diabetes is closely related to hypertension, often coincident with diabetes. Comorbid hypertension and diabetes often worsen the outcomes of each other, likely rooted in some overlapping pathogenic mechanisms. In this educational review, we will discuss the shared pathophysiology of diabetes and hypertension, particularly in regard to inflammation and oxidative stress, the sympathetic nervous system, vascular remodeling, and the renin-angiotensin-aldosterone system (RAAS). We will also review current hypertension diagnosis and management guidelines from many international jurisdictions for both adult and paediatric populations in the setting of diabetes. Many of these guidelines highlight the use and utility of RAAS blockers in this clinical scenario; however, on review of the evidence for their use, several meta-analyses and systematic reviews fail to demonstrate superiority of RAAS blockers over other anti-hypertensive medications. Finally, we discuss several new anti-hypertensive medications, review their mechanisms of action, and highlight some of the evidence for their use in the setting of hypertension and diabetes.

Drugs in treating paediatric acute kidney injury.

Acute kidney injury (AKI) is a complex syndrome which affects a significant proportion of hospitalized children. The breadth and impact of AKI on health outcomes in both adults and children have come to the fore in recent years with increasing awareness encouraging research advancement. Despite this, management strategies for most types of AKI remain heavily reliant on fluid and electrolyte management, hemodynamic optimization, nephrotoxin avoidance and appropriate initiation of kidney replacement therapy. Specific drugs targeting the mechanisms involved in AKI remain elusive. Recent improvement in appreciation of the complexity of AKI pathophysiology has allowed for greater opportunity to consider novel therapeutic agents. A number of drugs specifically targeting AKI are in various stages of development. This review will consider some novel and repurposed agents; interrogate the plausibility of the proposed mechanisms of action, as they relate to what we know about the pathophysiology of AKI; and review the level of existing literature supporting their efficacy. The evidence base, particularly in children, is limited.

Von Willebrand factor regulates complement on endothelial cells.

Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have traditionally been considered separate entities. Defects in the regulation of the complement alternative pathway occur in atypical hemolytic uremic syndrome, and defects in the cleavage of von Willebrand factor (VWF)-multimers arise in thrombotic thrombocytopenic purpura. However, recent studies suggest that both entities are related as defects in the disease-causing pathways overlap or show functional interactions. Here we investigate the possible functional link of VWF-multimers and the complement system on endothelial cells. Blood outgrowth endothelial cells (BOECs) were obtained from 3 healthy individuals and 2 patients with Type 3 von Willebrand disease lacking VWF. Cells were exposed to a standardized complement challenge via the combination of classical and alternative pathway activation and 50% normal human serum resulting in complement fixation to the endothelial surface. Under these conditions we found the expected release of VWF-multimers causing platelet adhesion onto BOECs from healthy individuals. Importantly, in BOECs derived from patients with von Willebrand disease complement C3c deposition and cytotoxicity were more pronounced than on BOECs derived from normal individuals. This is of particular importance as primary glomerular endothelial cells display a heterogeneous expression pattern of VWF with overall reduced VWF abundance. Thus, our results support a mechanistic link between VWF-multimers and the complement system. However, our findings also identify VWF as a new complement regulator on vascular endothelial cells and suggest that VWF has a protective effect on endothelial cells and complement-mediated injury.