Molecular Basis of Rare Inherited Tubulopathies of the Kidney: A Primer for Clinicians

Hereditary renal tubulopathies are rare monogenic disorders caused by defects in tubular transport mechanisms that impair the handling of electrolytes, water, and acid-base balance along the nephron. While each tubulopathy is individually uncommon, their collective burden is clinically relevant, as these disorders can severely affect quality of life and predispose to nephrolithiasis, dehydration episodes, and progression to chronic kidney disease. Advances in molecular genetics have identified more than 70 genes involved in renal tubular physiology; however, a substantial proportion of these cases remain genetically unresolved, and marked phenotypic heterogeneity complicates diagnosis and management. This narrative review provides an integrated overview of the main transport systems operating in the different tubular segments of the nephron-proximal tubule, thick ascending limb of the loop of Henle, distal convoluted tubule and collecting duct-summarizing the tubulopathies associated with each segment and discussing in greater detail representative inherited disorders that illustrate the clinical consequences of their dysfunction. We highlight current diagnostic challenges and limitations of existing therapeutic strategies and discuss novel diagnostic approaches as well as emerging treatment options. Improved genetic diagnosis, validation of candidate biomarkers, and the development of novel therapeutic strategies will be essential to advance precision medicine and improve outcomes for patients with inherited renal tubulopathies.