Serum Uromodulin Research Articles

Uromodulin as a potential candidate marker for predicting the course of chronic kidney disease

Uromodulin is a nephrospecific protein that is most common in normal urine. And although it has been known for more than 70 years, the function of uromodulin remains unclear. Uromodulin is involved in regulating the transport of salts, protects against urinary tract infections, namely, the mucous membrane of the bladder, and prevents the formation of kidney stones, as well as plays a role in kidney damage and innate immunity. Serum uromodulin and uromodulin of urine, daily excretion and excretion of uromodulin per 1 milliliter of creatinine clearance are actively studied. Complete genome studies of the association have established a correlation between uromodulin gene mutations and autosomal dominant tubulointerstitial kidney disease.

Associations of Serum Uromodulin and Urinary Epidermal Growth Factor with Measured Glomerular Filtration Rate and Interstitial Fibrosis in Kidney Transplantation

Introduction: Noninvasive biomarkers that reflect tubular health and allow early recognition of accelerated graft fibrosis development are warranted. Serum uromodulin (sUmod) and urinary epidermal growth factor (uEGF) originate from kidney tubules and may reflect functional nephron mass. The aim of this study was to investigate the associations between sUmod and uEGF with measured glomerular filtration rate (mGFR) and kidney allograft interstitial fibrosis percentage (IF%) score. Methods: sUmod and uEGF measurements, mGFR by iohexol-clearance and kidney allograft biopsies were obtained from kidney transplant recipients (KTRs) included in the Omega-3 fatty acids in Renal Transplantation (ORENTRA) trial at 8 weeks (baseline) and at 1 year after transplantation (end of study). Associations were analyzed with univariable and multivariable linear regression. Results: Ninety patients at baseline and 48 patients at end of study had complete study variable assessments. uEGF normalized to urinary creatinine (uEGF/Cr) was associated with mGFR both at baseline (standardized β-coefficient [Std. β-coeff] = 0.457 [p = <0.001]) and at end of study (Std. β-coeff = 0.637 [p = <0.001]). sUmod was only associated with mGFR at end of study (Std. β-coeff = 0.443 [p = 0.002]). uEGF/Cr, sUmod, and mGFR were associated with graft IF% score both at baseline (Std. β-coeff = −0.349 [p = 0.001], −0.274 [p = 0.009] and −0.289 [p = 0.006], respectively) and at end of study (Std. β-coeff = −0.365 [p = 0.011], −0.347 [p = 0.016] and −0.405 [p = 0.004], respectively). The results remained largely unchanged in multivariable analysis. Conclusion: uEGF/Cr and sUmod were associated with mGFR and graft IF% score. Our results indicate a possible role of uEGF/Cr and sUmod in the follow-up of KTRs.

Association of serum uromodulin with adipokines in dependence of type 2 diabetes

The renal tubular glycoprotein uromodulin is associated with obesity and type 2 diabetes, but the underlying mechanisms are elusive. We investigated the association of serum uromodulin with adipokines and tested the effect modification by diabetes status. The associations of serum uromodulin with eight adipokines were assessed in 795-1080 participants of the KORA F4 study aged 62-81years using linear regression models adjusted for sex, age, BMI, estimated glomerular filtration rate and diabetes. Significant associations were assessed for effect modification by diabetes status. We further tested using logistic regression whether adjustment for the significant adipokines affected the association of uromodulin with type 2 diabetes. Serum uromodulin was inversely associated with chemerin and retinol-binding protein-4 after multivariable adjustment (p<0.001) and Bonferroni correction for multiple testing. No significant association was observed between uromodulin and the other adipokines (leptin, adiponectin, secreted frizzled-related protein 5, progranulin, omentin-1 and vaspin) after correcting for multiple testing. The association of uromodulin with chemerin and retinol-binding protein-4 was stronger in participants with type 2 diabetes than in participants without diabetes (p for interaction<0.05). However, inclusion of chemerin and retinol-binding protein-4 in logistic regression models did not attenuate the association of serum uromodulin with diabetes. Serum uromodulin was inversely associated with the predominantly pro-inflammatory adipokines chemerin and retinol-binding protein-4. The associations were stronger in participants with type 2 diabetes compared to participants without diabetes. However, the association of serum uromodulin with type 2 diabetes was independent of chemerin and retinol-binding protein-4.

Associations of Serum Uromodulin and Its Genetic Variants With Blood Pressure and Hypertension in Chinese Adults.

Background: Uromodulin, also named Tamm Horsfall protein, has been associated with renal function and regulation of sodium homeostasis. We aimed to examine the associations of serum uromodulin levels and its genetic variants with longitudinal blood pressure (BP) changes and hypertension incidence/risk.Methods: A total of 514 participants from the original Baoji Salt-Sensitive Study cohort were genotyped to examine the associations of genetic variations in uromodulin gene with the longitudinal BP changes and the incidence of hypertension over 8 years of follow-up. In addition, 2,210 subjects from the cohort of Hanzhong Adolescent Hypertension Study were used to investigate the relationships between serum uromodulin levels and the risk of hypertension.Results: SNPs rs12917707 and rs12708631 in the uromodulin gene were significantly associated with the longitudinal BP changes over 8 years of follow-up. SNP rs12708631 was significantly associated with the incidence of hypertension over 8 years. In addition, gene-based analyses supported the associations of uromodulin gene with the longitudinal BP changes and hypertension incidence in Baoji Salt-Sensitive Study cohort. Furthermore, serum uromodulin levels in the hypertensive subjects were lower than in the normotensive subjects (25.5 ± 1.1 vs. 34.7 ± 0.7 ng/mL). Serum uromodulin levels decreased gradually as BP levels increased (34.6, 33.2, 27.8, and 25.0 ng/mL for subjects with normotension, high-normal, grade 1 hypertension, and grade 2 hypertension, respectively). Serum uromodulin was significantly associated with the lower risk of hypertension [0.978 (0.972–0.984)] in Hanzhong Adolescent Hypertension Study cohort.Conclusion: This study shows that uromodulin is associated with blood pressure progression and development of hypertension.

UMOD Polymorphisms Associated with Kidney Function, Serum Uromodulin and Risk of Mortality among Patients with Chronic Kidney Disease, Results from the C-STRIDE Study.

We aimed to explore associations of several single nucleotide polymorphisms (SNPs) detected by genome-wide association studies in uromodulin (UMOD) gene with phenotypes and prognosis of chronic kidney disease (CKD) among 2731 Chinese patients with CKD stage 1–4. Polymorphisms of rs11864909, rs4293393, rs6497476, and rs13333226 were genotyped using the Sequenom MassARRAY iPLEX platform. The SNPs of rs13333226 and rs4293393 were in complete linkage disequilibrium. Based on the T dominant model, T allele of rs11864909 was associated with levels of estimated glomerular filtration rate (eGFR) and serum uromodulin with linear regression coefficients of 2.68 (95% confidence interval (CI): 0.61, 4.96) and −12.95 (95% CI: −17.59, −7.98), respectively, after adjustment for cardiovascular and kidney-specific risk factors. After a median follow-up of 4.94 years, both G allele of rs4293393/rs13333226 and C allele of rs6497476 were associated with reduced risk of all-cause mortality with multivariable-adjusted hazard ratios of 0.341 (95% CI: 0.105, 0.679) and 0.344 (95% CI: 0.104, 0.671), respectively. However, no associations were found between the variants and slope of eGFR in the linear mix effect model. In summary, the variant of rs11864909 in the UMOD gene was associated with levels of eGFR and serum uromodulin, while those of rs4293393 and rs6497476 were associated with all-cause mortality among patients with CKD.

Combined Use of Serum Uromodulin and eGFR to Estimate Mortality Risk

Serum uromodulin (sUmod) shows a strong direct correlation with eGFR in patients with impaired kidney function and an inverse association with mortality. However, there are patients in whom only one of both markers is decreased. Therefore, we aimed to investigate the effect of marker discordance on mortality risk. sUmod and eGFR were available in 3,057 participants of the Ludwigshafen Risk and Cardiovascular Health study and 529 participants of the VIVIT study. Both studies are monocentric prospective studies of patients that had been referred for coronary angiography. Participants were categorized into four groups according to the median values of sUmod (LURIC: 146 ng/ml, VIVIT: 156) and eGFR (LURIC: 84 ml/min/1.73 m2, VIVIT: 87). In 945 LURIC participants both markers were high (UHGH), in 935 both were low (ULGL), in 589 only eGFR (UHGL), and in 582 only sUmod (ULGH) was low. After balancing the groups for cardiovascular risk factors, hazard ratios (95%CI) for all-cause mortality as compared to UHGH were 2.03 (1.63–2.52), 1.43 (1.13–1.81), and 1.32 (1.03–1.69) for ULGL, UHGL, and ULGH, respectively. In VIVIT, HRs were 3.12 (1.38–7.08), 2.38 (1.01–5.61), and 2.06 (0.81–5.22). Adding uromodulin to risk prediction models that already included eGFR as a covariate slightly increased the Harrell's C and significantly improved the AUC in LURIC. In UHGL patients, hypertension, heart failure and upregulation of the renin-angiotensin-aldosterone-system seem to be the driving forces of disease development, whereas in ULGH patients metabolic disturbances might be key drivers of increased mortality. In conclusion, SUmod/eGFR subgroups mirror distinct metabolic and clinical patterns. Assessing sUmod additionally to creatinine or cystatin C has the potential to allow a more precise risk modeling and might improve risk stratification.

High Level of Uromodulin Increases the Risk of Hypertension: A Mendelian Randomization Study.

Background: The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure.Methods: We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis.Results: MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.04 (95% Confidence Interval (CI), 1.03-1.04, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 2.70E-04) in “ieu-b-38” and “ukb-b-20175”, respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, P = 4.38E-06) in “ieu-b-39” and 0.05 (SE = 0.01, P = 2.13E-10) in “ukb-b-7992”. As for the sUMOD, the OR of hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.01 (95% CI 1.01–1.02, all P < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in “ieu-b-38” and 0.01 (SE = 0.003, P = 1.04E-04) in “ukb-b-20175”. The sUMOD is causally associated with elevated DBP (“ieu-b-39”: β = 0.313, SE = 0.050, P = 3.43E-10; “ukb-b-7992”: β = 0.018, SE = 0.003, P = 8.41E-09).Conclusion: Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.

Pretransplant Serum Uromodulin and Its Association with Delayed Graft Function Following Kidney Transplantation-A Prospective Cohort Study.

Delayed graft function (DGF) following kidney transplantation is associated with increased risk of graft failure, but biomarkers to predict DGF are scarce. We evaluated serum uromodulin (sUMOD), a potential marker for tubular integrity with immunomodulatory capacities, in kidney transplant recipients and its association with DGF. We included 239 kidney transplant recipients and measured sUMOD pretransplant and on postoperative Day 1 (POD1) as independent variables. The primary outcome was DGF, defined as need for dialysis within one week after transplantation. In total, 64 patients (27%) experienced DGF. In multivariable logistic regression analysis adjusting for recipient, donor and transplant associated risk factors each 10 ng/mL higher pretransplant sUMOD was associated with 47% lower odds for DGF (odds ratio (OR) 0.53, 95% confidence interval (95%-CI) 0.30–0.82). When categorizing pretransplant sUMOD into quartiles, the quartile with the lowest values had 4.4-fold higher odds for DGF compared to the highest quartile (OR 4.41, 95%-CI 1.54–13.93). Adding pretransplant sUMOD to a model containing established risk factors for DGF in multivariable receiver-operating-characteristics (ROC) curve analysis, the area-under-the-curve improved from 0.786 [95%-CI 0.723–0.848] to 0.813 [95%-CI 0.755–0.871, p = 0.05]. SUMOD on POD1 was not associated with DGF. In conclusion, higher pretransplant sUMOD was independently associated with lower odds for DGF, potentially serving as a non-invasive marker to stratify patients according to their risk for developing DGF early in the setting of kidney transplantation.

Validity of Serum Uromodulin as Early Diagnosis Marker of Diabetic Nephropathy in T2DM

Increased prevalence of DM is accompanied by increased in its various complications include diabetic nephropathy, which can lead to end stage renal disease (ESRD). Urinary albumin-creatinine ratio (uACR) is the gold standard for diabetic nephropathy; however, it has several limitations, including the inability to early diagnose due to the absence of increased level in uACR. Uromodulin is produced by thick ascending limb (TAL) at Henle’s loop and early distal tubule of nephron. Uromodulin will decrease when tubular atrophy occurs in early stage of renal impairment with normoalbuminuria. The aim of this study was to determine the validity of serum uromodulin in type 2 diabetes mellitus (T2DM) in identifying diabetic nephropathy by comparing it with uACR as gold standard. This study was a cross-sectional analytical observational study at Dr. Hasan Sadikin (RSHS) Bandung from June to August 2020. Subjects consisted of 62 patiens with T2DM. Results showed that the serum uromodulin level had a sensitivity of 93.3%, a specificity of 88.2%, a positive predictive value of 95.5%, a negative predictive value of 83.3%, and an accuracy of 91,9% and an AUC value of 0.975. The cut-off point of serum uromodulin in this study was 47.195 ng/mL. In conclusion, serum uromodulin, when compared to the uACR as the gold standard, has good sensitivity and specificity for identifying diabetic nephropathy.

ASSOCIATION OF SERUM UROMODULIN AND GENETIC VARIANTS WITH BLOOD PRESSURE CHANGES, AND HYPERTENSION IN CHINESE ADULTS: RESULTS FROM TWO PROSPECTIVE COHORTS

Objective: Uromodulin is a novel tissue-specific biomarker for kidney function. We sought to examine the associations of serum uromodulin and genetic variants with salt sensitive and longitudinal blood pressure (BP) changes, or hypertension in humans. Design and method: Subjects (n = 514) from the Baoji Salt-Sensitive Study cohort recruited in 2004 were on the chronic salt intake intervention. We evaluated them for the development of hypertension in 2009 and 2012. In addition, a total of 2210 participants from the Hanzhong Adolescent Hypertension Study cohort were used to examine the relationships between serum uromodulin and the risk of hypertension. Results: We found that SNPs rs12708631 and rs1291770 in the uromodulin gene were significantly associated with longitudinal changes in BPs. SNP rs7198000 was significantly associated with incident hypertension over an 8-year follow-up. Several SNPs was significantly associated with diastolic BP, mean arterial pressure and pulse pressure responses to both low-salt and high-salt diets. Gene-based analyses also supported the overall association of uromodulin gene with longitudinal BP changes and hypertension incidence. In addition, hypertensive subjects have lower levels of serum uromodulin than normotensive subjects. Serum uromodulin showed a linear association with increased BP (34.6, 33.2, 27.8, 27.1 and 26.1 ng/mL for subjects with normotension, high-normal, grade 1, grade 2 and grade 3 hypertension, respectively). Serum uromodulin was significantly associated with the lower risk of hypertension in 2210 Chinese subjects. Conclusions: This study shows that uromodulin gene is associated with salt sensitive and longitudinal BP changes, or hypertension incidence, and serum uromodulin may serve as a biomarker marker for hypertension.

Role of Serum Uromodulin in the Early Diagnosis of Chronic Kidney Disease

Abstract Background: The diagnosis of chronic kidney disease (CKD) is usually delayed, when significant functional renal impairment has already occurred. The diagnosis is complex and clinical and laboratory investigations play a crucial role. There are well-established markers of CKD – serum creatinine and cystatin C. However, the search for new reliable biomarkers that aid in the assessment of kidney function and predict the evolution of the disease is still in progress. Objective: To investigate the role of serum uromodulin (sUmod) as a marker for early diagnosis of renal impairment in patients with CKD. Materials and Methods: We investigated 70 patients, 28 male and 42 female, mean age 56.53 ± 11.753, with CKD in a prospective observational study. All patients were admitted to the Clinic of Nephrology at the “St. Ivan Rilski” University Hospital between April and November 2019. After obtaining written informed consent, laboratory blood and urine tests, abdominal ultrasound and sUmod investigations were performed in all patients. Results: Plasma uromodulin levels showed decrease with the increasing of the severity of renal impairment. sUmod displayed inverse correlation with serum creatinine (r = -0.467, p &lt; 0.0001), cystatin C (r = -0.430, p &lt; 0.0001) and urea (r = -0.495, p &lt; 0.0001) and a positive correlation with eGFR (r = 0.628, p &lt; 0.0001). Conclusion: The results of our study show that sUmod levels significantly correlate with all established laboratory parameters used for the evaluation of renal impairment. It can be used as a potential early biomarker for CKD diagnosis.

Serum Level of Uromodulin as an Early Predictor Marker of Kidney Disorders

BACKGROUND: Metabolic diseases are known to be risk factors of kidney injury. The glycoprotein Uromodulin Tamm-Horsfall protein is a biochemical marker specifically synthesized and secreted by kidney tubular epithelial cells.&#x0D; AIM: The study aimed to use novel biochemical parameters to predict early changes in renal functions and to use natural food supplements to help in the prevention and management of such conditions.&#x0D; METHODS: Crossover studies comparing two interventions trials. Subjects: Seventy obese females were included in this study. They were divided in two groups, first group (34 women) with mean age 45.82 ± 1.51 and mean body mass index (BMI) 35.65 ± 0.68 kg/m2, and second group (36 women) with mean age 49.80 ± 2.27, and mean BMI 37.67 ± 1.59. Intervention: All participants have followed a low caloric balanced regimen (1000–1200 Kcal/day) of the each groups consumed a different specific nutritional supplement composed mainly of whole grains and herbs. All patients were monitored clinically, anthropometrically, dietary 24 h recall and biochemically.&#x0D; RESULTS: After intervention all the recorded anthropometric parameters showed significant decreases at p ≤ 0.05–0.01. The serum uromodulin (sUMOD) increased significantly after intervention in both groups the increments were 15.56 and 9.37%. Numerically creatinine and urea decreased, while creatinine clearance increased.&#x0D; CONCLUSION: Data revealed the importance of using dietary therapy composed of hypocaloric diet with supplements made from whole grains and special herbs in management of obesity and its metabolic disorders. sUMOD proved to be an accurate biochemical marker that showed the kidneys’ response to the management in comparison to using usual diagnostic markers.

Serum uromodulin levels, MR imaging findings, and their relationship with eGFR-based CKD staging in ADPKD patients.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease that may progress to end-stage renal disease, characterized by increased kidney volume due to cystic formations. In this study, we aimed to investigate the relationship between serum uromodulin levels, total kidney volume and estimated glomerular filtration rate (eGFR) in patients with ADPKD. This study included a total of 54 ADPKD patients and 18 healthy volunteers (control group). Total kidney volumes were calculated through magnetic resonance images using ellipsoid method. Serum uromodulin measurements were measured using an ELISA method. Serum uromodulin levels were lower in patients compared with the control group (2.47 ± 0.16 vs 2.6 ± 0.28, p = 0.021). There was no significant difference in uromodulin values among the patients in chronic kidney disease (CKD) stages 1-2, 3 and 4-5. TKV measurements of CKD stage 4-5 patients were significantly higher than the stage 1-2 patients (p = 0.015). A negative correlation was observed between TKV and eGFR (r = -0.433, p = 0.001). A positive correlation was observed between uromodulin and eGFR (r = 0.274, p = 0.02). When the serum levels of uromodulin and the level of eGFR were evaluated using simple linear regression analysis, R2 value was found to be 0.075, suggesting that 7.5% change in serum uromodulin values corresponds with the change in eGFR value. These findings are consistent with previous studies that reported that serum uromodulin may be a good biomarker for demonstrating renal function in the early stages of CKD, before eGFR levels deteriorate. Serum uromodulin level may be useful in demonstrating renal functions in the follow-up of individuals with ADPKD.

Study of Uromodulin Gene Polymorphism in Egyptian Patients with End-Stage Renal Disease.

Uromodulin (UMOD) gene polymorphism has been linked with end-stage renal disease. In this research, we studied the prevalence of UMOD rs42993393 T>C in Egyptian hemodialysis (HD) patients and the blood level of UMOD in those patients. The study was a case-control study and included 100 patients on regular HD and 100 healthy control subjects. The blood samples from the studied groups were subjected to the determination of UMOD blood level and molecular study of UMOD rs42993393 T>C genotype by polymerase chain reaction with restriction fragment length polymorphism. The serum UMOD level was significantly low in patients (38.6 7.6 ng/mL) compared to control subjects (221.3 ± 54.2, P = 0.0001). On the other hand, the UMOD rs42993393T>C was significantly increased in TC in patients (28%, odds ratio 1.3-1.0-2.0) compared to controls (22%, P = 0.03), and there was a significant increase in CC in patients (10%) compared to control subjects (3%; P = 0.0001). The T allele was significantly increased in controls compared to patients with a significant increase in C allele in patients compared to controls (P = 0.01). The present study highlights the prevalence of UMOD gene polymorphism at rs42993393T>C. There was a significant prevalence of C allele and C genotypes in HD patients. This finding may indicate that this allele may be a predisposing genotype for renal failure in susceptible patients. On the other hand, the significant reduction of serum UMOD in patients with end-stage renal disease may be attributed to the reduced functioning renal mass.

Značaj određivanja koncentracije uromodulina u serumu bolesnika sa dijabetes melitusom tip 2

Introduction: In the kidney, cells in the thick ascending limb of the loop of the Henle synthesized uromodulin (UMOD). This study aims to present the evaluation of the uromodulin serum concentration in diabetes mellitus type 2 (T2DM) patients in the early detection of kidney damage. Materials and methods: The study included 50 T2DM patients mean age of 60.75 ± 11.23 years estimated glomerular filtration rate (eGFR) 114.38 ± 22.12 ml/min and a control group of 20 healthy persons. We measured serum concentration of haemoglobin, urea, creatinine, uromodulin (ELISA method), and cystatin C (nephelometry). We determined formulas: Cockcroft-Gault# (combination Cockcroft-Gault for patients with BMI &lt; 30 kg/m2 and Cockcroft-GaultLBW for patients with BMI ≥ 30 kg/m2), CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration equation), and simple Cystatin C. Results: T2DM patients had lower hemoglobin serum concentration as well as eGFR calculated by formulas: Cockcroft-Gault# and CKD-EPI. T2DM patients had significantly higher BMI and cystatin C compared to control group. T2DM patients had significantly lower serum uromodulin concentration (136.51 ± 84.34 vs 220.50 ± 92.39 ng/ml) than in controls. Significant positive correlation between uromodulin and Cockcroft-Gault# (r = 0.432, p = 0.000), CKD-EPI (r = 0.439; p = 0.000) formulas as well as simple cystatin C (r = 0.250, p = 0.02), but negative correlation with age (r = -0.476, p = 0.000), BMI (r = -0.313, p = 0.002) and cystatin C serum concentration (r = -0.293, p = 0.015) were found. Conclusion: The role of serum uromodulin concentration is not still fortified. The results of this study showed that reduced uromodulin serum concentration indicated early kidney damage in T2DM patients.

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

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. 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. All 112 healthy living kidney donors with two kidneys revealed individual serum uromodulin concentrations between 60.1 and 450.5µg/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/1.73m2), and CKD-EPI-GFR (61.2 [53.1-69.7] vs. 88.6 [80.0-97.1] mL/min/1.73m2) 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. 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.

Serum uromodulin is a novel renal function marker in the Japanese population.

Uromodulin, also known as Tamm-Horsfall protein, is the most abundant protein in urine. It has recently been reported that uromodulin exists in a small amount in blood and that its concentration correlates with the estimated glomerular filtration rate (eGFR). First, we generated anti-human uromodulin mouse monoclonal antibodies (mAb(s)) and established a specific enzyme-linked immunosorbent assay (ELISA) for uromodulin. We then performed an observational clinical study to determine if there was a correlation between serum uromodulin concentration and estimates of kidney function and whether the serum uromodulin value could be a biomarker in clinical nephrology. The clinical study included 308 patients with and without chronic kidney disease and healthy volunteers. Serum concentrations of creatinine, cystatin C, and uromodulin were measured and correlations were sought between the eGFR calculated from the creatinine and cystatin C levels and the serum uromodulin concentration. There was a good correlation between the serum uromodulin concentration and the eGFR value calculated from the creatinine (r = 0.76) and cystatin C (r = 0.79) levels. The mean serum uromodulin level in the group with an eGFR > 90mL/min/1.73m2 calculated using cystatin C was significantly higher than that in the group with an eGFR of 80-89mL/min/1.73m2. The serum uromodulin measurement could be a useful biomarker for identification of patients with early deterioration of kidney function.

Serum uromodulin is inversely associated with biomarkers of subclinical inflammation in the population-based KORA F4 study.

BackgroundUromodulin is a kidney-specific glycoprotein synthesized in tubular cells of Henle’s loop exerting nephroprotective and immunomodulatory functions in the urinary tract. A small amount of uromodulin is also released into the systemic circulation, where its physiological role is unknown. Serum uromodulin (sUmod) has been associated with metabolic risk factors and with cardiovascular events and mortality, where these associations were partly stronger in men than in women. In this study, we investigated the associations of sUmod with biomarkers of subclinical inflammation in a population-based sample of women and men.MethodsAssociations of sUmod with 10 biomarkers of subclinical inflammation were assessed in 1065 participants of the Cooperative Health Research in the Region of Augsburg (KORA) F4 study aged 62–81 years using linear regression models adjusted for sex, age, body mass index, estimated glomerular filtration rate and diabetes. Analyses were performed in the total study sample and stratified by sex.ResultssUmod was inversely associated with white blood cell count, high-sensitive C-reactive protein, interleukin (IL)-6, tumour necrosis factor-α, myeloperoxidase, superoxide dismutase-3, IL-1 receptor antagonist and IL-22 after multivariable adjustment and correction for multiple testing (P < 0.001 for each observation). There was a trend towards a stronger association of sUmod with pro-inflammatory markers in men than in women, with a significant P for sex interaction (<0.001) regarding the relation of sUmod with IL-6.ConclusionssUmod was inversely associated with biomarkers of subclinical inflammation in older participants of the KORA F4 study. The association of sUmod with IL-6 differed between women and men. Future research should focus on whether the immunomodulatory properties of sUmod are one explanation for the association of sUmod with cardiovascular outcomes and mortality.

Serum uromodulin is inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1 in the population-based KORA F4 study.

ObjectivesUromodulin has been associated with arterial hypertension in genome-wide association studies, but data from clinical and preclinical studies are inconsistent. We here analyzed the association of serum uromodulin (sUmod) with arterial hypertension and vasoactive hormones in a population-based study.MethodsIn 1108 participants of the KORA F4 study aged 62–81 years, sUmod was measured and the association of sUmod with arterial hypertension was assessed using logistic regression models. The associations of sUmod with renin and aldosterone and with the vasoconstrictive prohormone C-terminal pro-endothelin-1 (CT-proET-1) were analyzed in 1079 participants and in 618 participants, respectively, using linear regression models.ResultsAfter multivariable adjustment including sex, age, eGFR, BMI, fasting glucose, current smoking, previous stroke and myocardial infarction, sUmod was inversely associated with arterial hypertension (OR 0.78; 95% CI 0.68–0.91; p = 0.001). SUmod was not significantly associated with renin and aldosterone after adjustment for sex, age and eGFR. However, sUmod was inversely associated with CT-proET-1 (β -0.19 ± 0.04; p < 0.001) after adjustment for sex, age, eGFR, BMI, arterial hypertension, fasting glucose, current smoking, previous stroke and myocardial infarction. The association with CT-proET-1 was stronger in participants with hypertension (β -0.22 ± 0.04) than in normotensive participants (β -0.13 ± 0.06; p for interaction hypertension = 0.003 in the model adjusted for hypertension).ConclusionsSUmod was inversely associated with arterial hypertension and the vasoconstrictive prohormone CT-proET-1, suggesting direct or indirect effects of sUmod on blood pressure regulation.

Uromodulin – biomarker of renal function with promising clinical application

Uromodulin (also known as Tamm-Horsfall protein) is a glycoprotein produced exclusively in the kidneys, mainly in the epithelial cells of the thick ascending limb of the loop of Henle. Under physiological conditions, it is the most abundant urinary protein. A small proportion is released into the renal interstitium and then into the blood, where it can be detected and used as a potential parameter of renal function. Uromodulin has numerous physiological roles and potential pathogenetic significance, including providing protection against urinary tract infections and the formation of urinary deposits, as well as being involved in the immunomodulatory functions and regulation of water and electrolyte balance by the kidneys. Unlike classic renal markers (such as creatinine), uromodulin levels decrease with progressive renal dysfunction. A significant advantage of this parameter is therefore the detectable changes in concentration at the early stages of development of chronic kidney disease. In addition, assessment in clinical materials, such as urine and blood, is relatively simple by immunoenzymatic methods. It is evident that the quantitative determination of uromodulin in blood serum is associated with a lower risk of laboratory error and has a better correlation with renal function. Based on previous studies, Tamm-Horsfall protein / uromodulin can be considered a valuable parameter for standard diagnostics of kidney function and renal diseases. It appears that no other marker is currently able to reflect the integrity and functional state of the renal tubules as sensitively as uromodulin. Due to the potential of this parameter, the article presents and overview of the current information available about uromodulin, as well as the available diagnostic tests and the frequency of their use in clinical practice.