The vascular disease of diabetic kidney disease.

The incidence of cardiovascular disease (CVD) is increased in patients with diabetic kidney disease (DKD). Aortic stiffness is a well-accepted biomarker for cardiovascular (CV) events in all stages of CKD. The worldwide prevalence of diabetes continues to grow, as does the prevalence of DKD. Insulin resistance, hyperglycaemia, hypertension and the metabolic abnormalities of type-2 diabetes are all involved in the pathogenesis of CVD. The effect of these toxins on cardiac and vascular function is amplified by the worsening of renal function and the parallel rise of uraemic toxins. In this narrative review, we analysed why arterial stiffening can be considered a vascular mediator between diabetes and cardiac dysfunction, and we discussed the strong CV and nephroprotective effects of sodium-glucose cotransporter type 2 inhibitors (SGLT2i).

Loss of decay-accelerating factor triggers podocyte injury and glomerulosclerosis.

Kidney glomerulosclerosis commonly progresses to end-stage kidney failure, but pathogenic mechanisms are still poorly understood. Here, we show that podocyte expression of decay-accelerating factor (DAF/CD55), a complement C3 convertase regulator, crucially controls disease in murine models of adriamycin (ADR)-induced focal and segmental glomerulosclerosis (FSGS) and streptozotocin (STZ)-induced diabetic glomerulosclerosis. ADR induces enzymatic cleavage of DAF from podocyte surfaces, leading to complement activation. C3 deficiency or prevention of C3a receptor (C3aR) signaling abrogates disease despite DAF deficiency, confirming complement dependence. Mechanistic studies show that C3a/C3aR ligations on podocytes initiate an autocrine IL-1ß/IL-1R1 signaling loop that reduces nephrin expression, causing actin cytoskeleton rearrangement. Uncoupling IL-1ß/IL-1R1 signaling prevents disease, providing a causal link. Glomeruli of patients with FSGS lack DAF and stain positive for C3d, and urinary C3a positively correlates with the degree of proteinuria. Together, our data indicate that the development and progression of glomerulosclerosis involve loss of podocyte DAF, triggering local, complement-dependent, IL-1ß-induced podocyte injury, potentially identifying new therapeutic targets.

Pneumococcal Polysaccharide Vaccine Ameliorates Murine Lupus.

Current guidelines encourage administering pneumococcal vaccine Prevnar-13 to patients with lupus, but whether such vaccinations affect disease severity is unclear. To address this issue, we treated 3-month-old MRL-lpr mice, that spontaneously develop a lupus-like syndrome, with Prevnar-13 or vehicle control. After 3 months, we quantified circulating anti-Pneumococcal polysaccharide capsule (PPS) antibodies and signs of disease severity, including albuminuria, renal histology and skin severity score. We also compared immunophenotypes and function of T and B cells from treated and untreated animals. Prevnar-13 elicited the formation of anti-pneumococcal IgM and IgG. Prevnar-13 treated animals showed reduced albuminuria, renal histological lesions, and milder dermatitis compared to vehicle-treated controls. Mitigated disease severity was associated with reduced and increased T follicular helper cells (TFH) and T follicular regulatory cells (TFR), respectively, in Prevnar-treated animals. T cells from Prevnar-13 vaccinated mice showed differential cytokine production after aCD3/aCD28 stimulation, with significantly decreased IL-17 and IL-4, and increased IL-10 production compared to non-vaccinated mice. In conclusion, pneumococcal vaccination elicits anti-pneumococcal antibody response and ameliorates disease severity in MRL-lpr mice, which associates with fewer TFH and increased TFR. Together, the data support use of Prevnar vaccination in individuals with SLE.

Complement and Complement Targeting Therapies in Glomerular Diseases.

The complement cascade is part of the innate immune system whose actions protect hosts from pathogens. Recent research shows complement involvement in a wide spectrum of renal disease pathogenesis including antibody-related glomerulopathies and non-antibody-mediated kidney diseases, such as C3 glomerular disease, atypical hemolytic uremic syndrome, and focal segmental glomerulosclerosis. A pivotal role in renal pathogenesis makes targeting complement activation an attractive therapeutic strategy. Over the last decade, a growing number of anti-complement agents have been developed; some are approved for clinical use and many others are in the pipeline. Herein, we review the pathways of complement activation and regulation, illustrate its role instigating or amplifying glomerular injury, and discuss the most promising novel complement-targeting therapies.