OC 09.3 - Direct oral anticoagulants improve podocyte health and reverse hypercoagulopathy in an experimental model of glomerular disease

Background: Thromboembolic comorbidities in nephrotic syndrome (NS) are driven by an acquired hypercoagulopathy. Antiproteinuric therapy is known to alleviate hypercoagulopathy. We recently demonstrated that thrombin knockdown was antiproteinuric and alleviated glomerular podocyte injury in a rat NS model.

Aims: To study the combined effects of direct oral anticoagulant (DOAC)-mediated thrombin inhibition on hypercoagulopathy and proteinuria in rat NS models.

Methods: The well-established podocin-DTR transgenic rat NS model was utilized. NS was induced with diphtheria toxin (DT) injection on day 0. Dabigatran and rivaroxaban were administered daily for 10 days. Day 10 urine was collected for urine protein-to-creatinine ratio analysis. Thrombin generation was performed with and without DOAC-Stop, a DOAC adsorbent reagent, to differentiate direct anticoagulant from indirect antiproteinuric effects on hypercoagulapathy. Terminal podocyte injury was determined by TUNEL using flow cytometry. IVC ligation experiments were performed on day 10 to investigate in vivo effects of DOAC treatment with or without ciraparantag, an investigational DOAC antidote.

Results: Both DOACs significantly improved proteinuria, decreased podocyte injury, and reduced ETP. DOAC-Stop reversed 30% of the dabigatran effect on ETP, suggesting that 70% of the effect was due to its antiproteinuric effect. Similarly, rivaroxaban had both a direct anticoagulant and an indirect antiproteinuric effect on ETP (49% and 51% of total effect, respectively). Preliminary IVC ligation data reveal that untreated NS had significantly larger clots after IVC ligation versus controls. Both DOACs improved clot burden in comparison to untreated pDTR NS. Ciraparantag partially reversed the beneficial effect of both DOACs on clot size, suggesting an antiproteinuric effect on in vivo thrombosis.

Conclusion(s): Dabigatran and rivaroxaban improve proteinuria, podocyte health, and reverse hypercoagulopathy in the rat pDTR NS model. Both DOACs ameliorated hypercoagulopathy via direct anticoagulant and indirect antiproteinuric effects. These data suggest that DOACs may represent a novel approach to simultaneously improve glomerulopathy and provide thromboprophylaxis in nephrotic syndrome.