Inhibition of Interleukin-33 to Reduce Glomerular Endothelial Inflammation in Diabetic Kidney Disease

BackgroundInflammation is a significant contributor to cardiorenal morbidity and mortality in diabetic kidney disease (DKD). The pathophysiological mechanisms linking systemic, sub-acute inflammation and local, kidney injury-initiated immune maladaptation is partially understood.MethodsHere, we explored the expression of pro-inflammatory cytokines in patients with DKD; investigated mouse models of type 1 diabetes (T1D) and type 2 diabetes (T2D); evaluated glomerular signaling in vitro; performed post hoc analyses of systemic and urinary markers of inflammation; and initiated a phase 2b clinical study (FRONTIER-1; NCT04170543).ResultsTranscriptomic profiling of kidney biopsies from patients with DKD revealed significant glomerular upregulation of IL-33. Inhibition of IL-33 signaling reduced glomerular damage and albuminuria in the uninephrectomized db/db mouse model (T2D/DKD). On a cellular level, inhibiting IL-33 improved glomerular endothelial health by decreasing cellular inflammation and reducing release of pro-inflammatory cytokines. Therefore, FRONTIER-1 was designed to test the safety and efficacy of the IL-33-targeted monoclonal antibody tozorakimab in patients with DKD. So far, 578 patients are enrolled in FRONTIER-1. The baseline inflammation status of participants (N > 146) was assessed in blood and urine. Comparison to independent reference cohorts (N > 200) validated the distribution of urinary TNFR-1 and CCL2. Treatment with dapagliflozin for 6 weeks did not alter these biomarkers significantly. Complete FRONTIER-1 results are expected by spring of 2024.ConclusionsWe show that blocking the IL-33 pathway may mitigate glomerular endothelial inflammation in DKD. The findings from the FRONTIER-1 study will provide valuable insights into the therapeutic potential of IL-33 inhibition in DKD.