In patients with diabetes receiving chronic haemodialysis, both very high and low glucose levels are associated with poor outcomes, including mortality. Conditions that are associated with an increased risk of hypoglycaemia in these patients include decreased gluconeogenesis in the remnant kidneys, deranged metabolic pathways, inadequate nutrition, decreased insulin clearance, glucose loss to the dialysate and diffusion of glucose into erythrocytes during haemodialysis. Haemodialysis-induced hypoglycaemia is common during treatments with glucose-free dialysate, which engenders a catabolic status similar to fasting; this state can also occur with 5.55 mmol/l glucose-containing dialysate. Haemodialysis-induced hypoglycaemia occurs more frequently in patients with diabetes than in those without. Insulin therapy and oral hypoglycaemic agents should, therefore, be used with caution in patients on dialysis. Several hours after completion of haemodialysis treatment a paradoxical rebound hyperglycaemia may occur via a similar mechanism as the Somogyi effect, together with insulin resistance. Appropriate glycaemic control tailored for patients on haemodialysis is needed to avoid haemodialysis-induced hypoglycaemia and other glycaemic disarrays. In this Review we summarize the pathophysiology and current management of glycaemic disarrays in patients on haemodialysis.

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.

Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1β (IL-1β) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1β signaling, we demonstrate that IL-1β lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1β pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.