Individual uromodulin serum concentration is independent of glomerular filtration rate in healthy kidney donors

Abstract Objectives The mucoprotein uromodulin is considered to correlate with glomerular filtration rates (GFR) in patients with chronic kidney disease (CKD). Here we investigated how serum uromodulin is associated with measured GFR using inulin-clearance and GFR estimated by CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation in healthy subjects. Methods We assessed possible correlations between uromodulin serum concentrations, inulin-GFR and CKD-EPI-GFR in a well characterized study cohort of 112 healthy living kidney donors with two kidneys before and 64 with one kidney after kidney donation. A subgroup of 32 individuals, which presented data before and after nephrectomy, was assessed separately. Results All 112 healthy living kidney donors with two kidneys revealed individual serum uromodulin concentrations between 60.1 and 450.5 µg/L. Sixty-four healthy kidney donors after nephrectomy had significantly lower median (interquartile range) serum uromodulin concentrations (124 [101–166] vs. 185 [152–238] µg/L), inulin-GFR (67.3 [60.6–74.6] vs. 93.5 [82.1–104.4] mL/min/1.73 m2), and CKD-EPI-GFR (61.2 [53.1–69.7] vs. 88.6 [80.0–97.1] mL/min/1.73 m2) as compared to the 112 donors before donation (p<0.001). The subgroup of 32 subjects, which presented data before and after nephrectomy, showed almost the same pattern of kidney function. No statistically relevant associations were found between serum uromodulin and inulin-GFR or CKD-EPI-GFR regarding this healthy population. Conclusions These novel findings indicate that – in contrast to patients with CKD – serum uromodulin concentrations are not correlated with measured and estimated GFR in healthy individuals.

[1]  F. Lang,et al.  Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signaling. , 2020, Cardiovascular research.

[2]  Henry J González-Torres,et al.  The Importance of Tubular Function in Chronic Kidney Disease , 2019, International journal of nephrology and renovascular disease.

[3]  D. Stolz,et al.  Tubular injury triggers podocyte dysfunction by β-catenin-driven release of MMP7. , 2019, JCI insight.

[4]  Frank A. Witzmann,et al.  Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel , 2019, Science Translational Medicine.

[5]  N. Bansal,et al.  Association of Serum Uromodulin With ESKD and Kidney Function Decline in the Elderly: The Cardiovascular Health Study. , 2019, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[6]  B. Müller-Stich,et al.  Serum uromodulin and Roux-en-Y gastric bypass: improvement of a marker reflecting nephron mass. , 2019, Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery.

[7]  M. Rewers,et al.  The relationships between markers of tubular injury and intrarenal haemodynamic function in adults with and without type 1 diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes , 2018, Diabetes, obesity & metabolism.

[8]  O. Devuyst,et al.  Uromodulin is expressed in the distal convoluted tubule, where it is critical for regulation of the sodium chloride cotransporter NCC. , 2018, Kidney international.

[9]  M. Burnier,et al.  Uromodulin and Nephron Mass. , 2018, Clinical journal of the American Society of Nephrology : CJASN.

[10]  L. Lv,et al.  Renal tubule injury: a driving force toward chronic kidney disease. , 2018, Kidney international.

[11]  E. Christensen,et al.  Serum uromodulin—a marker of kidney function and renal parenchymal integrity , 2017, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[12]  P. Fraunberger,et al.  The value of uromodulin as a new serum marker to predict decline in renal function , 2018, Journal of hypertension.

[13]  W. März,et al.  Serum Uromodulin and Mortality Risk in Patients Undergoing Coronary Angiography. , 2017, Journal of the American Society of Nephrology : JASN.

[14]  T. Bartz,et al.  Urinary Uromodulin and Risk of Urinary Tract Infections: The Cardiovascular Health Study. , 2017, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[15]  A. Pozzi,et al.  Progression of chronic kidney disease: too much cellular talk causes damage. , 2017, Kidney international.

[16]  L. Renders,et al.  Plasma Uromodulin Correlates With Kidney Function and Identifies Early Stages in Chronic Kidney Disease Patients , 2016, Medicine.

[17]  P. Awadalla,et al.  Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion. , 2016, Clinical journal of the American Society of Nephrology : CJASN.

[18]  F. Paccaud,et al.  Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population. , 2016, Clinical journal of the American Society of Nephrology : CJASN.

[19]  L. Risch,et al.  The serum uromodulin level is associated with kidney function , 2014, Clinical chemistry and laboratory medicine.

[20]  N. Tsuboi,et al.  Clinicopathological assessment of the nephron number , 2014, Clinical kidney journal.

[21]  G. Reibnegger,et al.  Glomerular Filtration Rate (GFR) determination via individual kinetics of the inulin-like polyfructosan sinistrin versus creatinine-based population-derived regression formulae , 2013, BMC Nephrology.

[22]  Harold I Feldman,et al.  Estimating glomerular filtration rate from serum creatinine and cystatin C. , 2012, The New England journal of medicine.

[23]  Z. Al-Aly,et al.  Tamm-Horsfall protein-deficient thick ascending limbs promote injury to neighboring S3 segments in an MIP-2-dependent mechanism. , 2011, American journal of physiology. Renal physiology.

[24]  S. Kmoch,et al.  Uromodulin Biology and Pathophysiology – An Update , 2010, Kidney and Blood Pressure Research.

[25]  C. Schmid,et al.  A new equation to estimate glomerular filtration rate. , 2009, Annals of internal medicine.

[26]  Tom Greene,et al.  Assessing kidney function--measured and estimated glomerular filtration rate. , 2006, The New England journal of medicine.

[27]  Hong-ying Huang,et al.  Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. , 2004, Kidney international.

[28]  W. Solbach,et al.  Polarized Expression of Tamm-Horsfall Protein by Renal Tubular Epithelial Cells Activates Human Granulocytes , 2002, Infection and Immunity.

[29]  E. Lentjes,et al.  Glomerular filtration rate measurement by "single-shot" injection of inulin. , 1994, Kidney international.

[30]  S. Povey,et al.  Localization of the Tamm‐Horsfall glycoprotein (unomodulin) gene to chromosome 16p12.3‐16p13.11 , 1993, Annals of human genetics.

[31]  T. Hoops,et al.  Uromodulin (Tamm-Horsfall glycoprotein/uromucoid) is a phosphatidylinositol-linked membrane protein. , 1990, The Journal of biological chemistry.