What Does Uromodulin Do?

Role in the Distal Tubule: Regulation of Salt Transport and Blood Pressure

The water-impermeable thick ascending limb of Henle's loop reabsorbs approximately 30% of filtered NaCl, thereby diluting the tubular fluid and fueling the countercurrent multiplication critical for water conservation. Salt-losing tubulopathies (Bartter syndromes) and loop diuretics illustrate the importance of this segment in electrolyte, fluid, and BP homeostasis.

Phylo- and ontogenetic observations (coincidence of uromodulin immunodetection and emergence/development of the loop of Henle) and murine models suggest a functional link between uromodulin and loop of Henle activity (2,3). This nexus is at least partially explained by a positive regulation of Na⁺, K⁺, 2Cl⁻ cotransporter (NKCC2) by uromodulin (2). Furthermore, uromodulin overexpression drives salt-sensitive hypertension in mice, and there is mounting evidence for the importance of this regulatory pathway in humans (2). A case-control GWAS showed that the minor (“protective”) UMOD allele was associated with lower risk for hypertension and cardiovascular disease while also being associated with lower urinary uromodulin excretion (5), with most recent BP GWAS confirming the UMOD locus. The clinical effect of furosemide in hypertensive patients is influenced by the UMOD allelic status, suggestively linking uromodulin expression with NKCC2 activity and BP control (2). Recently, uromodulin was found to activate Na⁺, Cl⁻ cotransporter (NCC) in the early distal convoluted tubule, highlighting its broader importance in distal NaCl handling (4), even if details of the molecular regulation of NKCC2 and NCC are unsolved (Figure 1C). Clinical studies assessing whether therapeutic responses to loop diuretics are influenced by UMOD allelic status are ongoing (https://www.bhfumod.co.uk/; ClinicalTrials.gov Identifier: NCT03354897) and will hopefully guide personalized pharmacotherapy in the future.

In addition to modulating NaCl uptake, uromodulin has been shown to regulate apical Ca²⁺ and Mg²⁺ channels in the distal convoluted tubule (3). Nonetheless, it seems counterintuitive that such a massively excreted glycoprotein carries the sole purpose of regulating tubular transporters and channels. Indeed, correlation studies suggest that the ancestral (“risk”) UMOD allele, driving higher urinary uromodulin excretion, has been kept at high population frequency not because it favors salt retention, but likely because it protects against urinary tract infections (UTIs) (6).

Role in the Urine: Protection from Urinary Tract Infections

Pathogens exercise powerful selective pressure by affecting reproductive fitness. Antibacterial functions would therefore fit within an evolutionary framework explaining why most of us carry genetic determinants driving high uromodulin expression (6).

On the basis of the cryoelectron tomography–derived three-dimensional structure of native uromodulin filaments and biochemical data, a model has been proposed in which urinary uromodulin polymers act as multivalent ligands for uropathogens (via interaction between bacterial lectin and uromodulin high-mannose glycan Asn275), antagonizing uropathogen binding to bladder uroplakins and likely promoting clearance of aggregated bacteria by micturition (7) (Figure 1, B and C). In line, Umod-deficient mice display higher propensity for bladder colonization by type 1 fimbriated Escherichia coli, the most common etiology in UTI (3). Is this relevant in humans, with a plethora of urinary antimicrobial peptides? Indirect evidence stems from a population-based cohort study where urinary leukocyte counts were inversely correlated with urinary uromodulin concentrations, suggesting an “antiseptic” role (6). A prospective, longitudinal cohort study in older community-dwelling adults provided more direct proof by showing that persons in the highest urinary uromodulin concentration quartile had a significantly lower risk for UTI compared with those in the lowest quartile, independent of traditional UTI risk factors (8). These results suggest that uromodulin is an integral part of the urinary innate immune defense and hold promise for leveraging its biochemical and structural features or modulating its excretion rates to prevent or treat UTIs (3).

Role in the Circulation: Modulating Inflammation

There is increasing interest in the value of uromodulin as a biomarker for kidney and systemic outcomes. Urinary levels of uromodulin reflect tubular mass and function and are positively correlated with eGFR. In at-risk cohorts, low urinary uromodulin levels likely reflect decreased tubular mass/function and are associated with a higher risk for AKI and cardiovascular disease. Large-scale urinary uromodulin measurements, however, bear considerable analytical and interpretative challenges (3).

A fraction of uromodulin is shuttled to the basolateral thick ascending limb membrane. ELISA consistently detects uromodulin in blood at levels approximately 100× lower than in urine, suggesting basolateral release of uromodulin. Serum uromodulin levels are positively correlated with eGFR_Crea and eGFR_CysC, are negatively correlated with BUN, are undetectable in CKD stage 5, and surge after kidney transplantation, establishing their kidney source. Furthermore, higher serum uromodulin concentrations have been associated with a favorable metabolic profile, lower prevalence of cardiovascular comorbidities, and lower risk for 10-year mortality, independently of other cardiovascular risk factors including eGFR (3,9).

But what is the role of “nonurinary” uromodulin? In murine models of AKI, uromodulin translocates toward the basolateral pole and is likely released in the interstitium and systemic circulation. By crosstalking with adjacent proximal S3 tubules, uromodulin may modulate inflammatory response, accelerate recovery after AKI, and regulate bone marrow granulopoiesis via IL signaling, at least in mice (10). Recently, circulatory uromodulin was linked to systemic oxidative stress via its inhibition of TRPM2 channels. On the basis of murine and human data, the hypothesis put forward argues that AKI corresponds to a state of systemic uromodulin deficiency with correlating increase in systemic oxidative damage (11) (Figure 1C). These results provide potential clues why serum uromodulin might associate with cardiovascular outcomes. Further work will need to establish whether extrarenal outcomes associated with serum uromodulin are truly independent of kidney parameters. Indeed, serum uromodulin levels steeply drop already in CKD stage 1, not detected by conventional GFR biomarkers. Therefore, associations between serum uromodulin and cardiovascular disease should not only be adjusted for eGFR but also for additional indices of kidney and tubular damage such as proteinuria (9). More basic questions regarding the mechanisms that direct, regulate, and mediate basolateral release and prevent uromodulin polymerization in the interstitium and blood need answers as well.

Conclusion and Perspectives

Recent evidence obtained in mouse and man suggests multiple physiologic roles for uromodulin, in and outside the urine compartment, and the involvement of UMOD variants in a continuum of kidney diseases (3). Future studies should translate this knowledge on uromodulin into innovative therapies for conditions including salt-sensitive hypertension, UTI, CKD, and AKI.

Disclosures

All authors have nothing to disclose.

Funding

A. Kipp is supported by Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung grant 310030_189044. E. Olinger is supported by Kidney Research UK grant Paed_RP_001_20180925 and Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung Early Postdoc Mobility-Stipendium P2ZHP3_195181.