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Resistant hypertension (RH) affects approximately 10-15% of treated hypertensive adults and up to 50% of individuals with chronic kidney disease (CKD). Defined by persistent elevation of blood pressure despite multidrug therapy, RH reflects inadequate therapeutic control and is associated with accelerated renal function decline, increased cardiovascular morbidity and mortality, and more than US$10 billion in excess annual healthcare costs. Growing evidence indicates that, beyond sodium retention and activation of vasoconstrictor pathways, chronic endothelial dysfunction and maladaptive microvascular remodelling - particularly in CKD-associated RH - are increasingly recognized contributors to disease progression. The vascular endothelium regulates arterial tone through three major vasodilatory systems: nitric oxide (NO), prostacyclin (PGI2), and endothelium-dependent hyperpolarization (EDH). Pharmacologic agents targeting individual pathways have demonstrated short-term vasodilatory effects but have not consistently translated into durable endothelial recovery or microvascular repair in clinical practice. Therapeutic strategies capable of coordinated engagement of all three pathways may therefore be required to modify the vascular abnormalities underlying RH. Human tissue kallikrein-1 (KLK1) and its recombinant analogue, rinvecalinase alfa (DM199), represent a promising approach. In cardiovascular and renal disease models, KLK1 supplementation restores physiological generation of kinin peptides, which, by binding vascular and renal B2 receptors, stimulate NO, PGI2, and EDH signalling pathways, thereby promoting vasorelaxation and natriuresis. Moreover, sustained KLK1 therapy has been associated with improved microvascular integrity and angiogenic signalling through both kinin-dependent and independent mechanisms. Emerging Phase II clinical evidence with DM199 in CKD populations demonstrates blood pressure reduction together with stabilization of renal function and reductions in albuminuria, suggesting potential downstream effects on microvascular structure and function. Importantly, these effects are achieved with a favourable electrolyte and safety profile, supporting investigation in CKD-associated RH where standard therapies often fail. This review integrates contemporary treatment perspectives with mechanistic and clinical evidence supporting KLK1 augmentation as a chronic, endothelial-supportive strategy targeting microvascular remodelling in CKD-associated RH.