UROMODULIN PROFILE AS AN INNOVATIVE MARKER OF EARLY TUBULAR DYSFUNCTION AND CKD PROGRESSION

Tubulointerstitial injury is one of key drivers of CKD progression. Traditional biomarkers such as estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (uACR) do not allow timely detection of early tubular dysfunction in chronic kidney disease (CKD). The measurement of urinary uromodulin (uUmod) concentration and the calculation of uromodulin indices (Umod) may serve as additional, more sensitive predictors of disease progression, while digital tools can optimize risk assessment and standardize interpretation.

Ninety-one patients with CKD stages 1–3 and 32 healthy controls were examined. The eGFR change was assessed after six months. Rapid progression was defined as a decline in eGFR (CKD-EPI) ≥5 mL/min/1.73 m² and/or an increase in serum creatinine (sCrea) ≥10%. Serum uromodulin (sUmod) and urinary uromodulin (uUmod) were measured by ELISA. Derived indices included fractional excretion of Umod (FeUmod), fractional secretion of Umod (FsUmod), sUmod/sCrea, urinary albumin (uAlb)/uUmod, and uUmod/sUmod. Diagnostic performance was assessed by ROC analysis.

In healthy individuals, urinary uromodulin (uUmod) concentration ranged from 20 to 50 µg/L, consistent with normal tubular secretion by cells of the thick ascending limb of the loop of Henle. In patients with CKD, including those at stages 1 to 3, a decrease in urinary uromodulin excretion (<20 µg/L) was observed in a substantial proportion of cases, indicating that tubular dysfunction may occur even at the earliest stages of the disease, though not uniformly across all patients. Calculation of the uUmod/sUmod ratio improved the accuracy of tubular function assessment and reduced the influence of interindividual differences in Umod production and analytical assay variability. This index serves as an integrated biomarker of reduced tubular Umod excretion relative to its serum pool. Its application enhances interpretive precision, especially when uUmod levels are close to threshold values or when inter-laboratory differences exist. A cutoff value of uUmod/sUmod = 414.95 demonstrated 93.3% sensitivity and 98.6% specificity for identifying low tubular Umod excretion. An elevated uAlb/uUmod ratio (>0.94) was associated with an increased risk of CKD progression (defined as a ≥5 mL/min/1.73 m² eGFR decline and/or ≥10% rise in sCrea over six months). This association remained significant after multivariable adjustment for major covariates, confirming the independent prognostic value of uAlb/uUmod as a marker of combined glomerular and tubular injury. Implementation of the developed desktop calculator for Umod-index computation reduced calculation time from 15–20 minutes to <1 minute, minimized arithmetic errors, and improved inter-observer agreement (κ = 0.82 vs 0.61 without the tool).

The degree of tubular injury varies within the same CKD stage, and conventional stratification based on albuminuria and eGFR does not fully reflect the heterogeneity of tubulointerstitial damage. In such cases, derived biomarkers of tubulointerstitial injury have greater prognostic value than absolute concentrations. The indices uUmod/sUmod and uAlb/uUmod may be incorporated into CKD risk-stratification algorithms for the detection of tubular injury and additional assessment of progression risk. The desktop calculator for Umod-profile analysis streamlines clinician workflow, standardizes risk stratification, and facilitates integration of digital technologies into nephrology practice.