Kidney international最新文献

IgA nephropathy (IgAN), the world's most common primary glomerular disease, carries a significant lifetime risk for kidney failure as well as an enormous socioeconomic burden. In the past, studies in patients with IgAN largely focused on optimizing so-called supportive care, that is, blockade of the renin-angiotensin system, blood pressure control, and lifestyle modifications. The effectiveness of immunosuppressive measures, particularly high-dose corticosteroid therapy, has been reported variably, but there is considerable evidence for an increase in serious adverse effects with such therapies. This disappointing situation has changed dramatically with a better understanding of the pathogenesis of IgAN, and with regulatory agencies accepting changes in proteinuria and the estimated glomerular filtration rate loss or slope over 2 to 3 years as surrogate outcome markers. A multitude of new therapies are now being evaluated in IgAN, and several drugs, such as sodium-glucose transporter-2 inhibitors, sparsentan (a dual endothelin-1 and angiotensin II receptor blocker), nefecon (a targeted release formulation of budesonide), and iptacopan (a complement factor B inhibitor), have been approved, with more to come in the next few years. In this review, we propose a new treatment paradigm that combines therapies with different mechanisms of action to target the immune components and the chronic kidney disease components of IgAN in parallel to preserve long-term kidney survival.

Melanocortin therapeutics, exemplified by adrenocorticotropic hormone, have a proven steroidogenic-independent anti-proteinuric and glomerular protective effect. The biological functions of melanocortins are mediated by melanocortin receptors (MCR), including MC1R, which recent studies have shown to protect against glomerular disease. However, the role of other MCRs like MC5R is unknown. Here, MC5R knockout exacerbated glomerulopathy in mice injured by adriamycin (ADR) or nephrotoxic serum (NTS), as demonstrated by increased albuminuria and podocyte injury. Conversely, selective MC5R agonism using a peptidomimetic agonist improved outcomes of glomerulopathies. Mechanistically, MC5R is expressed in glomerular podocytes. Reconstitution of MC5R in podocytes attenuated glomerular injury and proteinuria in MC5R knockout mouse models of glomerulopathies, indicating a direct podocyte protective effect. In vitro, MC5R agonism in primary wild-type podocytes attenuated ADR-elicited cytoskeleton disruption, hypermotility and apoptosis, associated with restored inhibitory phosphorylation of glycogen synthases kinase 3b (GSK3β), a signaling transducer downstream of MC5R and at the nexus of multiple podocytopathic pathways. In parallel, ADR-induced phosphorylation and activation of GSK3β substrates, such as paxillin and NF-κB RelA/p65, were abrogated, leading to improved actin cytoskeleton integrity and diminished expression of mediators of podocyte injury, like MCP-1, B7-1 and Cathepsin L. This protective effect of MC5R agonism was blunted in wild-type podocytes expressing constitutively active GSK3β and was mimicked in MC5R knockout podocytes by ectopic expression of dominant negative GSK3β. Consistently in ADR-injured MC5R knockout mice, worsened podocytopathy was associated with enhanced GSK3β hyperactivity. These findings suggest that MC5R signaling protects against podocyte injury and may serve as a novel therapeutic target for glomerular diseases.

Stenosis within the arteriovenous fistula (AVF) of hemodialysis patients leads to vascular access dysfunction and inadequate hemodialysis. Percutaneous transluminal angioplasty (PTA) is the standard therapy for stenosis. However, rates of restenosis and loss of access patency remain high. Outcomes of a novel cell-impermeable endoprosthesis (CIE) have not been investigated in this setting. Therefore, our study was designed to address this as a prospective, international, multicenter pivotal trial (NCT04540302) with 245 patients with stenosis in their venous outflow circuit randomized to treatment: 122 receiving CIE and 123 receiving PTA across 43 international centers. Primary endpoints included target lesion primary patency (TLPP) at six months (freedom from clinically driven target lesion revascularization or target lesion thrombosis) and freedom from safety events through 30 days post-index procedure that affected the access circuit and resulted in reintervention, hospitalization, or death. Access circuit primary patency (ACPP) was evaluated as a secondary efficacy endpoint. Six-month TLPP and ACPP were significantly higher for the CIE cohort versus PTA (TLPP: 89.6% vs. 62.3%; ACPP: 72.2% vs. 57.0%). Thirty days post-index procedure, there was no statistically significant difference in the freedom from safety events for the CIE versus PTA (96.6 vs. 95.0%). No differences were observed in adverse events between either cohort. Our study shows that among patients with stenosis in their AVF, the CIE was superior to PTA with respect to six-month TLPP and ACPP with no observed difference in 30-day primary safety events.

Kidney replacement therapy is one of the most energy-consuming and waste-producing medical treatments. Reducing the need of dialysis is therefore an environmentally friendly choice. However, preferring prevention, lifestyle-related interventions and patient education to drugs is time consuming, and most physicians are already overburdened by the many demands of routine clinical practice. In this mini review, we discuss the role that could be played by prevention, diet, and nonpharmacologic interventions in reducing the impact of care of chronic kidney disease and kidney replacement therapy. Although evaluating the environmental impact of chronic kidney disease and kidney replacement therapy is extremely complicated, the need for rethinking all the steps in current nephrology practice to preserve our planet's health is urgent, and shifting from a "drug prescription" model to a "time prescription" one would benefit both our patients and the environment.