Advances in uromodulin biology and potential clinical applications

Uromodulin (also known as Tamm–Horsfall protein) is a kidney-specific glycoprotein secreted bidirectionally into urine and into the circulation, and it is the most abundant protein in normal urine. Although the discovery of uromodulin predates modern medicine, its significance in health and disease has been rather enigmatic. Research studies have gradually revealed that uromodulin exists in multiple forms and has important roles in urinary and systemic homeostasis. Most uromodulin in urine is polymerized into highly organized filaments, whereas non-polymeric uromodulin is detected both in urine and in the circulation, and can have distinct roles. The interactions of uromodulin with the immune system, which were initially reported to be a key role of this protein, are now better understood. Moreover, the discovery that uromodulin is associated with a spectrum of kidney diseases, including acute kidney injury, chronic kidney disease and autosomal-dominant tubulointerstitial kidney disease, has further accelerated investigations into the role of this protein. These discoveries have prompted new questions and ushered in a new era in uromodulin research. Here, we delineate the latest discoveries in uromodulin biology and its emerging roles in modulating kidney and systemic diseases, and consider future directions, including its potential clinical applications. In this Review, the authors examine advances in uromodulin biology, including the existence of non-polymeric forms of the protein, its versatile functions, crosstalk with the immune system, its potential as a biomarker and its role in kidney disease, as well as considering how uromodulin might be targeted therapeutically. Key points Most urinary uromodulin undergoes polymerization into filaments and has important roles in maintaining urinary homeostasis. This polymerization occurs on the apical membrane and is highly organized. Non-polymeric uromodulin, an increasingly recognized form, has distinct kidney and systemic roles. Recognizing the specific form and site of action is crucial to understanding the function of uromodulin. Acute kidney injury is characterized by uromodulin deficiency. Non-polymerizing uromodulin supplementation might improve the course of acute kidney injury and prevent the transition to chronic kidney disease. Single-nucleotide polymorphisms in UMOD and PDILT are strongly linked to the risk and progression of chronic kidney disease. Whether this effect depends on expression of a spe