ABSTRACT The U.S. recently reached a historic milestone, surpassing one million life-saving organ transplants. For these patients, tacrolimus—a calcineurin inhibitor (CNI)—is the cornerstone of immunosuppression, prescribed to over 90% of transplant recipients due to its proven efficacy and tolerability. However, tacrolimus is associated with a distinctive triad of kidney-centered adverse effects: hypertension, hyperkalemia, and metabolic acidosis. Intriguingly, this triad resembles the rare Mendelian disorder Familial Hyperkalemia and Hypertension (FHHt), which results from over-activation of the NaCl-cotransporter (NCC) in the distal convoluted tubule. NCC activity is regulated by the WNK/SPAK (With-no-lysine and Ste20/ SPS-1 -related- proline- alanine- rich protein kinase) signaling pathway. In the distal convoluted tubule, kidney-specific WNK1 (KS-WNK1) is essential for activation of the WNK/SPAK/NCC cascade. Mice carrying human gain-of-function mutations in KS-WNK1 have over- activation of this pathway, thereby mimicking both the CNI- and FHHt-associated phenotypes. We propose that KS-WNK1 acts as a scaffold, recruiting WNK/SPAK components into biomolecular condensates known as WNK bodies, thereby amplifying NCC signaling. Biomolecular condensates are membraneless compartments that concentrate macromolecules through phase separation, creating localized environments that regulate specific biochemical reactions. The study of condensate biology has reshaped our understanding of intracellular organization and has sparked growing interest in pharmacologic strategies to target these structures. Our preliminary data indicate that tacrolimus increases the abundance of WNK bodies, suggesting a direct mechanistic link between CNIs, condensates, and NCC overactivation. The goal of this R01 is to use CNIs as both an experimental tool and clinical model to manipulate WNK body composition, dynamics, and function, while concurrently testing how CNIs alter kidney physiology th