(A) Bae et al. (12) show that in wild-type pigs, intestine, liver, and muscle primarily secrete metabolites, while other organs such as the lung and heart primarily take up metabolites. The healthy kidney plays a key role in metabolite homeostasis, taking up amino acids (AA) and other metabolites when concentrations are high and releasing them when concentrations are low. Metabolite loss to the urine is minimized by the absorption of filtered metabolites in proximal tubular segments of the nephron. This process is maintained by numerous Na⁺-dependent (or H⁺- dependent) transporters on the apical surface of proximal tubular cells. (B) In CFTR^–/– pigs, the inter-organ balance of metabolites is disturbed. The CF kidney presumably has disrupted ion balance across the tubular epithelium due to loss of the CFTR chloride transporter. Hypothetically, activation of a yet-to-be identified Na solute (solute X) cotransporter, or downregulation of the Na K-ATPase, leads to an increase in the intracellular Na⁺ concentration in proximal tubular segments of CF kidneys and disrupts the transport of amino acids and other metabolites. As a result, CF kidneys would have disordered metabolite homeostasis, which increases metabolite loss to the urine.