It is not derived from blood plasma but is produced by the thick ascending limb of the loop of Henle of the mammalian kidney.

While the monomeric molecule has a MW of approximately 85 kDa, it is physiologically present in urine in large aggregates of up to several million Da.

[10][12][13][14] Uromodulin excretion in urine follows proteolytic cleavage of the ectodomain of its glycophosphatidylinositol-anchored counterpart that is situated on the luminal cell surface of the loop of Henle.

[16] Uropontin, nephrocalcin and uromodulin (this protein) are the three known urinary glycoproteins that affect the formation of calcium-containing kidney stones or calculus.

Tamm–Horsfall protein is part of the matrix in renal calculi but a role in kidney stone formation remains debatable.

[6] Antibodies to Tamm–Horsfall protein have been seen in various forms of nephritis (e.g., Balkan nephropathy), however, it remains unclear whether there is any pathophysiologic relevance to these findings.