Uromodulin Concentrations Research Articles

O39 IMPACT OF UROMODULIN CONCENTRATION ON RENAL AND HAEMODYNAMIC PARAMETERS IN A BLACK AFRICAN COMMUNITY WITH A HIGH PREVALENCE OF HYPERTENSION

Background and Objective: The burden of hypertension (HTN) and related comorbidities disproportionately affects developing countries like South Africa, particularly in urban populations of African ancestry. This demographic exhibits a volume-dependent form of HTN that is resistant to antihypertensive drugs that target the renin-angiotensin-aldosterone system. Renal fluid retention or abnormalities may cause HTN in this group, thus the need to investigate various nephron components for a better understanding. Uromodulin is a potential biomarker for renal function and tubular reserve. However, the relationship with renal function, haemodynamic parameters and HTN in a Black African population is unknown. Therefore, the aim of this study was to explore the relationship between urinary uromodulin concentration and renal as well as haemodynamic parameters in a Black African community with a high prevalence of volume-dependent HTN. Methods: Systemic haemodynamics (central pressures [SphygmoCor] and echocardiographic aortic velocity and diameter measurements in the outflow tract), urinary uromodulin concentrations (ELISA assay) and renal function (creatinine clearance from 24-hour urine collections [n=370]) were determined in a Black African community (n=397). Results: No relationships between urinary uromodulin concentrations and age, body mass index, blood pressure or hypertension were noted. However, urinary uromodulin concentrations were higher in females than males, even after adjusting for several confounders (p=0.0007). Although urinary uromodulin concentrations were unrelated to renal function, an inverse relationship with stroke volume (SV) was observed (p=0.0023). The inverse relationship between SV and urinary uromodulin concentration was independent of confounders and present in hypertensives (p=0.007) but not normotensives (p=0.43). The hypertensives were noted to have a higher SV than the normotensives (p=0.047). Conclusion: In a Black African community sample with a high prevalence of volume-dependent primary hypertension, urinary uromodulin was inversely related to SV, particularly in participants with hypertension. These data suggest the need to investigate the mechanisms linking urinary uromodulin to haemodynamic parameters to identify novel pathways to target for better treatment strategies in hypertension.

Association of serum copeptin and urinary uromodulin with kidney function, blood pressure and albuminuria at 6 weeks post-partum in pre-eclampsia.

Preeclampsia (PE) is associated with subsequent higher risk of cardiovascular and kidney disease. Serum copeptin, as a proxy for vasopressin, and urinary uromodulin, were associated with PE physiopathology and kidney functional mass respectively. We describe concentrations of these proteins in the post-partum period and characterize their association with persistent hypertension (HTN) or albuminuria. Patients with PE and healthy controls with uncomplicated pregnancy were prospectively included at two teaching hospitals in Switzerland. Clinical parameters along with serum copeptin and urinary uromodulin were measured at 6 weeks post-partum. PE patients were further characterized based on presence of HTN (defined as either systolic BP (SBP) ≥140 mmHg or diastolic (BP) ≥90 mmHg) or albuminuria [defined as urinary albumin to creatinine ratio (ACR) ≥3 mg/mmol]. We included 226 patients with 35 controls, 120 (62.8%) PE with persistent HTN/albuminuria and 71 (37.1%) PE without persistent HTN/albuminuria. Median serum copeptin concentration was 4.27 (2.9-6.2) pmol/L without differences between study groups (p > 0.05). Higher copeptin levels were associated with higher SBP in controls (p = 0.039), but not in PE (p > 0.05). Median urinary uromodulin concentration was 17.5 (7.8-28.7) mg/g with lower levels in PE patients as compared to healthy controls (p < 0.001), but comparable levels between PE patients with or without HTN/albuminuria (p > 0.05). Higher uromodulin levels were associated with lower albuminuria in PE as well as control patients (p = 0.040). Serum copeptin levels at 6 weeks post-partum are similar between PE patients and healthy controls and cannot distinguish between PE with or without residual kidney damage. This would argue against a significant pathophysiological role of the vasopressin pathway in mediating organ damage in the post-partum period. On the opposite, post-partum urinary uromodulin levels are markedly lower in PE patients as compared to healthy controls, potentially reflecting an increased susceptibility to vascular and kidney damage that could associate with adverse long-term cardiovascular and kidney outcomes.

Diagnosing Polyomavirus Nephropathy without a Biopsy: Validation of the Urinary PyV-Haufen-Test in a Proof-of-Concept Study including Uromodulin Knock-out-Mice.

Polyomavirus nephropathy (PyVN) leads to kidney transplant dysfunction and loss. Since a definitive diagnosis requires an invasive kidney biopsy, a timely diagnosis is often hampered. In this clinical dilemma the PyV-haufen-test, centering around the detection of three-dimensional PyV aggregates in the urine, might provide crucial diagnostic information. A multistep experimental design. Hypothesis: PyV-haufen form within the kidneys under high concentrations of uromodulin, a kidney specific protein; PyV-haufen are kidney-specific-disease-markers. Investigative step A showed colocalization of uromodulin with aggregated PyV (i) in ten kidneys with PyVN by immunohistochemistry, (ii) in urine samples containing PyV-haufen by electron microscopy/immunogold labeling (n = 3), and (iii) in urine samples containing PyV-haufen by immunoprecipitation assays (n = 4). Investigative step B: In in-vitro experiments only high uromodulin concentrations of ≥ 1.25 mg/mL aggregated PyV, as is expected to occur within injured nephrons. In contrast, in voided urine samples (n = 59) uromodulin concentrations were below aggregation concentrations (1.2 -19.6 µg/mL). Investigative step C: 0/11 (0%) uromodulin KO-/- mice with histologic signs of PyVN showed urinary PyV-haufen shedding compared to 10/14 (71%) WT+/+ mice. PyV-haufen form within kidneys under high uromodulin concentrations. Thus, PyV-haufen detected in the urine are specific biomarkers for intra-renal disease, i.e. definitive PyVN.

Label-Free, Impedance-Based Biosensor for Kidney Disease Biomarker Uromodulin.

We demonstrate the development of a label-free, impedance-based biosensor by using a passivation layer of 50-nm tantalum pentoxide (Ta2O5) on interdigitated electrodes (IDE). This layer was fabricated by atomic layer deposition (ALD) and has a high dielectric constant (high-κ), which improves the capacitive property of the IDE. We validate the biosensor's performance by measuring uromodulin, a urine biomarker for kidney tubular damage, from artificial urine samples. The passivation layer is functionalized with uromodulin antibodies for selective binding. The passivated IDE enables the non-faradaic impedance measurement of uromodulin concentrations with a measurement range from 0.5 ng/mL to 8 ng/mL and with a relative change in impedance of 15 % per ng/mL at a frequency of 150 Hz (log scale). This work presents a concept for point-of-care biosensing applications for disease biomarkers.

Association the allelic variation and SNP rs12917707 genotyping with UMOD serum level among Iraqi patients infected with uropathogenic Escherichia coli

: The current study included 90 samples collected and divided into (45) Urinary tract infections of E. coli patients and (45) controls with different ages of both genders. Patient samples were collected from UTI patients admitted to ALYarmouk Teaching Hospital, AL-Karama Teaching Hospital and Al Kidney Teaching Hospital from November 2020 to March 2021. The current study measured Tamm Horsfall protein (THP) concentration in patients with Urinary tract infections and healthy groups. The study also included the Relationship of Umod rs12917707 genotype and Uromodulin level in patients and control using Nested T-ARMS PCR. Our study had two objectives: First, to address whether urinary uromodulin concentration is associated with urinary tract infection with E. coli in a community-based study, and second, to determine whether a single-nucleotide polymorphism (SNP) in the UMOD region, rs12917707, is associated with urinary uromodulin concentrations. After statistical analysis, the results showed that there could be an association between having mutant homozygous GG polymorphism in the UMOD gene and having UTI of E. coli. At the same time, the mutant homozygous TT represents a risk factor compared to other genotypes (ORs: 0.4, 95% CI (0.17 - 0.93 and ORs: 4.4, 95% CI (1.47-13.26) respectively. The results also showed a significant decrease at P≤0.01 in the patients group with Urinary tract infection (1.38 ± 0.03) Ng/ml compared with the control sample, which was (1.83 ± 0.04) Ng/ml. Keywords: urinary tract infection, UPEC, UMOD-promoter region, SNPs, Nested T-ARMS PCR

Water Loading and Uromodulin Secretion in Healthy Individuals and Idiopathic Calcium Stone Formers.

Uromodulin is a protein made only by the kidney and released in urine, circulating in polymerizing and nonpolymerizing forms. This protein's multiple functions include inhibition of stone formation in the urine. The physiological determinants of uromodulin production are incompletely understood. We investigated changes in uromodulin levels and key factors governing its production and release in urine and serum. We performed an experiment to determine whether water loading, a common intervention to prevent stone formation, will alter the rate of uromodulin production. During a 2-day period, 17 stone forming participants and 14 control participants were subjected to water loading (day 1) and normal fluid intake (day 2). Uromodulin levels were measured on timed hourly collections in urine and plasma during the period of the study. Water loading increased urinary uromodulin secretion (33±4 versus 10±4 μ g/min at baseline, P < 0.0001) in stone formers and control participants. Despite high urine volumes, most participants maintained relatively stable urinary uromodulin concentrations. Native Western blots for polymerizing and nonpolymerizing uromodulin suggest that polymerizing uromodulin was the predominant form at higher urinary flow volumes. Urine flow rates and sodium excretion were significant correlates of urinary uromodulin production. Water loading did not affect serum uromodulin levels, which were also not associated with urinary uromodulin. Water loading increases the secretion of polymerizing urinary uromodulin. This increased secretion reduces the variability of urinary uromodulin concentrations despite high urine volumes. Serum uromodulin levels were not affected by this treatment.

Serum Uromodulin and All-Cause Mortality in Peritoneal Dialysis Patients: A Chinese Cohort Study

Serum Uromodulin and All-Cause Mortality in Peritoneal Dialysis Patients: A Chinese Cohort Study

Urine acute kidney injury biomarkers in extremely low gestational age neonates: a nested case control study of 21 candidate urine biomarkers.

Acute kidney injury (AKI) is common and is associated with poor clinical outcomes in premature neonates. Urine biomarkers hold the promise to improve our understanding and care of patients with kidney disease. Because kidney maturation and gender can impact urine biomarker values in extremely low gestational age neonates (ELGANs), careful control of gestational age (GA) and time is critical to any urine biomarker studies in neonates. To improve our understanding of the potential use of urine biomarkers to detect AKI during the first postnatal weeks, we performed a nested case-control study to evaluate 21 candidate urine AKI biomarkers. Cases include 20 ELGANs with severe AKI. Each case was matched with 2 controls for the same GA week (rounded down to the nearest week), gender, and birth weight (BW) (± 50g). Urine cystatin C, creatinine, ghrelin, fibroblast growth factor-23 (FGF23), tissue metalloproteinase 2 (TIMP2) and vascular endothelial growth factor A (VEGFa) concentrations were higher in ELGANs with early severe AKI compared to matchedcontrol subjects without AKI. Urine epidermal growth factor (EGF) and uromodulin (UMOD) concentrations are lower in cases than controls. Interleukin (IL)-15 was lower on day 1, but higher on day 8 in cases than controls; while VEGFa was lower on day 1, but higher on day 5 in cases than controls. Urine biomarkers hold the promise to improve our ability to reliably detect kidney injury. Interventional studies are needed to determine the biomarkers' ability to predict outcomes, enhance AKI phenotypes, and improve timely interventions which can prevent the sequalae of AKI in ELGANs. A higher resolution version of the Graphical abstract is available as Supplementary information.

Uromodulin and its association with urinary metabolites: the German Chronic Kidney Disease Study.

The progression of chronic kidney disease (CKD), a global public health burden, is accompanied by a declining number of functional nephrons. Estimation of remaining nephron mass may improve assessment of CKD progression. Uromodulin has been suggested as a marker of tubular mass. We aimed to identify metabolites associated with uromodulin concentrations in urine and serum to characterize pathophysiologic alterations of metabolic pathways to generate new hypotheses regarding CKD pathophysiology. We measured urinary and serum uromodulin levels (uUMOD, sUMOD) and 607 urinary metabolites and performed cross-sectional analyses within the German Chronic Kidney Disease study (N=4628), a prospective observational study. Urinary metabolites significantly associated with uUMOD and sUMOD were used to build weighted metabolite scores for urine (uMS) and serum uromodulin (sMS) and evaluated for time to adverse kidney events over 6.5 years. Metabolites cross-sectionally associated with uromodulin included amino acids of the tryptophan metabolism, lipids and nucleotides. Higher levels of the sMS [hazard ratio (HR)=0.73 (95% confidence interval 0.64; 0.82), P=7.45e-07] and sUMOD [HR=0.74 (95% confidence interval 0.63; 0.87), P=2.32e-04] were associated with a lower risk of adverse kidney events over time, whereas uUMOD and uMS showed the same direction of association but were not significant. We identified urinary metabolites associated with urinary and serum uromodulin. The sUMOD and the sMS were associated with lower risk of adverse kidney events among CKD patients. Higher levels of sUMOD and sMS may reflect a higher number of functional nephrons and therefore a reduced risk of adverse kidney outcomes.

Abstract P232: Pregnancy Induced Changes In Urinary Uromodulin Excretion In Normotensive And Chronic Hypertensive Rodent Models

Hypertensive disorders complicate 1-4% of pregnancies and are the leading cause of maternal death. Pregnancy involves major adaptions in renal hemodynamics, tubular and endocrine functions. Uromodulin (UMOD) is a renal protein that plays a role in renal sodium and divalent cation transport and is associated with hypertension and kidney diseases. We aimed to understand the role of blood pressure (BP) in urinary UMOD excretion during pregnancy. Pregnant Wistar Kyoto (WKY) and Stroke Prone Spontaneously Hypertensive (SHRSP) rats (n=8) were studied for 18.5 gestational days (GD). A group of pregnant SHRSP were treated with the beta-blocker propranolol (100mg/kgBW/day; n=8) and the calcium channel blocker nifedipine (25mg/kgBW/day; n=7) from GD 0.5. Systolic BP (SBP; tail cuff plethysmography), urine and plasma characteristic were monitored at baseline, GD3.5, GD12.5 and GD 18.5. UMOD concentration were measured in 24hr urine with ELISA. Pregnant SHRSP were hypertensive throughout the gestation compared to WKY (delta SBP 22.6 ± 3.6 mmHg, p&lt;0.0001). At baseline (pre-pregnancy), urinary UMOD levels were 2-fold higher in WKY compared to SHRSP (p&lt;0.05). During pregnancy, the urinary UMOD gradually decreased in WKY (2-fold decrease, p&lt;0.05), whereas a 1.5-fold increase (p&lt;0.05) was observed in hypertensive SHRSP compared to pre-pregnancy. The changes observed in urinary levels corresponded to total kidney UMOD levels at GD18.5, wherein SHRSP kidney shows 1.3-fold (p&lt;0.01) greater expression of UMOD compared to WKY. Nifedipine reduced BP in pregnant SHRSP (delta SBP between GD18.5 and baseline: 44.3 ± 7.4 mmHg, p&lt;0.0001) while propranolol did not affect BP. However, neither nifedipine nor propranolol changed urinary UMOD excretion in pregnant SHRSP. BP was not significantly correlated with urinary uromodulin levels in pregnant WKY (Pearson, r=-0.01, p 0.95) and SHRSP without (r=-0.16, p 0.46) or with (nifedipine r=0.26, p 0.31; propranolol r=0.17, p 0.45) antihypertensive treatment. We demonstrate differences in UMOD excretion between hypertensive and normotensive pregnancy and changes during pregnancy that are at least in part BP independent. Our data provide novel insights into molecular changes associated with hypertensive pregnancy.

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.

Association of Serum Uromodulin with Death, Cardiovascular Events, and Kidney Failure in CKD.

Uromodulin is exclusively produced by tubular epithelial cells and released into urine and serum. Higher serum uromodulin has been associated with lower risk for kidney failure in Chinese patients with CKD and with lower risk for mortality in the elderly and in patients undergoing coronary angiography. We hypothesized that lower serum uromodulin is associated with mortality, cardiovascular events, and kidney failure in white patients with CKD. We measured serum uromodulin in 5143 participants enrolled in the German CKD (GCKD) study. The associations of baseline serum uromodulin with all-cause mortality, major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, nonfatal myocardial infarction or stroke, or incident peripheral vascular disease), and kidney failure (dialysis or transplantation) were evaluated using multivariable Cox proportional hazard regression analyses in a cohort study design, adjusting for demographics, eGFR, albuminuria, cardiovascular risk factors, and medication. The mean age of participants was 60±12 years, 60% were male. Mean serum uromodulin concentration was 98±60 ng/ml, eGFR was 49±18 ml/min per 1.73 m2, and 78% had eGFR <60 ml/min per 1.73 m2. Participants in lower serum uromodulin quartiles had lower eGFR and higher albuminuria, prevalence of diabetes, hypertension, coronary artery disease, and more frequent history of stroke at baseline. During a follow-up of 4 years, 335 participants died, 417 developed MACE, and 229 developed kidney failure. In multivariable analysis, the highest serum uromodulin quartile was associated with lower hazard for mortality (hazard ratio [HR], 0.57; 95% CI, 0.38 to 0.87), MACE (HR, 0.63; 95% CI, 0.45 to 0.90), and kidney failure (HR, 0.24; 95% CI, 0.10 to 0.55) compared with the lowest quartile. Higher serum uromodulin is independently associated with lower risk for mortality, cardiovascular events, and kidney failure in white patients with CKD. Deutsches Register für Klinische Studien (DRKS; German national database of clinical studies), DRKS00003971.

Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling.

Uromodulin is produced exclusively in the kidney and secreted into both urine and blood. Serum levels of uromodulin are correlated with kidney function and reduced in chronic kidney disease (CKD) patients, but physiological functions of serum uromodulin are still elusive. This study investigated the role of uromodulin in medial vascular calcification, a key factor associated with cardiovascular events and mortality in CKD patients. Experiments were performed in primary human (HAoSMCs) and mouse (MOVAS) aortic smooth muscle cells, cholecalciferol overload and subtotal nephrectomy mouse models and serum from CKD patients. In three independent cohorts of CKD patients, serum uromodulin concentrations were inversely correlated with serum calcification propensity. Uromodulin supplementation reduced phosphate-induced osteo-/chondrogenic transdifferentiation and calcification of HAoSMCs. In human serum, pro-inflammatory cytokines tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) co-immunoprecipitated with uromodulin. Uromodulin inhibited TNFα and IL-1β-induced osteo-/chondrogenic signalling and activation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated β cells (NF-kB) as well as phosphate-induced NF-kB-dependent transcriptional activity in HAoSMCs. In vivo, adeno-associated virus (AAV)-mediated overexpression of uromodulin ameliorated vascular calcification in mice with cholecalciferol overload. Conversely, cholecalciferol overload-induced vascular calcification was aggravated in uromodulin-deficient mice. In contrast, uromodulin overexpression failed to reduce vascular calcification during renal failure in mice. Carbamylated uromodulin was detected in serum of CKD patients and uromodulin carbamylation inhibited its anti-calcific properties in vitro. Uromodulin counteracts vascular osteo-/chondrogenic transdifferentiation and calcification, at least in part, through interference with cytokine-dependent pro-calcific signalling. In CKD, reduction and carbamylation of uromodulin may contribute to vascular pathology.

SUN-195 URINARY UROMODULIN LEVELS AND UROMODULIN GENE IN BLACK SOUTH AFRICANS WITH HYPERTENSION-ATTRIBUTED CHRONIC KIDNEY DISEASE

Uromodulin, the most abundant protein in urine, is synthesized in the thick ascending loop of Henle. Patients with chronic kidney disease (CKD) have reduced urinary uromodulin levels secondary to tubular damage. Genome wide association studies identified significant single nucleotide polymorphism (SNP) associations with CKD at the uromodulin (UMOD) locus. We examined the association of urinary uromodulin concentrations with CKD and with the SNP rs1333226 in the UMOD gene.

LOWER URINE UROMODULIN IS ASSOCIATED WITH TREND TO LOWER SODIUM EXCRETION IN MIDDLE-AGED SUBJECTS

Objective: Recent GWAS studies found uromodulin gene polymorphisms to be associated with increased risk for hypertension (HT) and chronic kidney disease. It was hypothesized that relation of uromodulin with HT might be through effects on sodium renal excretion. Our aim was to analyse association of urinary uromodulin concentrations (uUMc) with blood pressure (BP) and sodium excretion in a group of untreated middle-aged subjects. Design and method: In this cross-sectional study 175 apparently healthy untreated subjects without a history for CV and with eGFR > 60 ml/min/1.73 m2 were enrolled. Fasting blood and urine 24-hour urine sample were obtained and BP was measured following ESH/ESC guidelines in office (Omron M6) and during regular working (ABPM: Mobile-O-Graph). Based on office BP subjects were divided according to the JNC-7 classification. Uromodulin was determined by Enzyme Linked Immunosorbent Assay (ELISA). Sodium and potassium excretion were analysed in 24-hour urine samples. Fractional sodium excretion (FENa) was calculated. Results: Optimal BP (OBP), prehypertension (PHT) and HT were diagnosed in 47 subjects (43% m, mean age 37), 68 subjects (74% m, mean age 30), and 60 subjects (72% m, mean age 39), respectively. Nonsignificant trend to higher uUMc was found in HT compared to PHT/OBP (52 vs 40/42, respectively). In multivariate linear regression analyses (F = 3.1; p = 0.002) uUMc was positively associated with waist circumference (β = 0.502, p = 0.01), creatinine clearance (β = 0.391, p = 0.03), urinary potassium (β = 0.378, p = 0.001), urinary sodium/potassium ratio (β = 0.413, p = 0.004), and negatively with sodium excretion (β = −0.479, p = 0.003) with a trend to lower FENA. In adjusted multivariate logistic regression analyses, uUMc was not predictor for either for HT or for PHT Conclusions: In our group lower uUMC was associated with lower natriuresis and FENa what is in line with previous observations indicating that decreased salt intake is related to lower uUMc. However, as some other authors found that lower uUMc is related to increased sodium reabsorption in proximal tubule we also observed trend to lower FENa.

Urinary Uromodulin Levels and UMOD Variants in Black South Africans with Hypertension-Attributed Chronic Kidney Disease.

Uromodulin, the most abundant protein in urine, is synthesized in the thick ascending loop of Henle and distal convoluted tubules. Patients with chronic kidney disease (CKD) have reduced urinary uromodulin levels secondary to tubular damage. Genome wide association studies identified significant single nucleotide polymorphism (SNP) associations with CKD at the uromodulin (UMOD) locus. We examined the association of urinary uromodulin concentrations with CKD and with SNP rs1333226 in the UMOD gene. The study included 71 black South Africans with hypertension-attributed CKD with an eGFR ≤ 60ml/min/1.73m2, 52 first-degree relatives, and 58 unrelated controls. Urinary uromodulin concentration was measured using Luminex® multiplex kits. After DNA extraction from blood using the Maxwell® automated platform, genotyping of rs13333226 was performed using real-time PCR using TaqMan® genotyping assays. Urinary uromodulin levels were significantly lower in CKD cases compared to both controls and first-degree relatives and correlated negatively with age, serum uric acid, serum creatinine, and systolic BP and positively with CKD-EPI eGFR. For each 1-standard deviation increase in uromodulin level, the multivariable-adjusted odds ratio for CKD was 0.6 (95% CI [0.48 to 0.81]; p <0.01). There were no significant differences in the minor allele frequency between CKD cases and controls (p = 0.59) nor between first-degree relatives and controls (p = 0.98). There were no significant associations between genotype at rs13333226 and urine uromodulin levels (p = 0.43). Higher levels of urinary uromodulin are associated with lower odds of hypertension-attributed CKD. We did not detect associations of genotype at rs13333226 with urinary uromodulin levels in our sample population. Larger sample size studies from ethnically disparate populations are essential to further categorize this association.

Serum uromodulin and progression of kidney disease in patients with chronic kidney disease

BackgroundUromodulin is specifically synthesized and secreted by kidney tubular epithelial cells. Studies on the association of serum uromodulin and outcomes of chronic kidney disease (CKD) are lacking. This study aimed to evaluate whether serum uromodulin was associated with outcomes of patients with CKD.MethodsWe measured serum uromodulin concentrations by ELISA in 2652 CKD patients from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) and investigated the association of serum uromodulin with outcomes of CKD patients, including end-stage kidney disease (ESKD) receiving kidney replacement therapy, cardiovascular events and mortality by Cox proportional hazards regression model.ResultsA total of 2652 CKD patients were enrolled in this study, with an age of 48.7 ± 13.8 years and the baseline eGFR of 49.6 ± 29.4 mL/min/1.73 m2, of whom 58.4% were male. The median level of urinary albumin/creatinine ratio and serum uromodulin was 473.7 mg/g (IQR 134.1–1046.6 mg/g) and 77.2 ng/mL (IQR 48.3–125.9 ng/mL), respectively. Altogether, 404 ESKD, 189 cardiovascular events, and 69 deaths occurred during the median follow-up of 53.6 (IQR 44.0–64.0) months. Lower levels of serum uromodulin were independently associated with higher risk of incident ESKD after adjusting for traditional cardiovascular risk factors, with the hazard ratios (HRs) of 3.23 (95% confidence intervals [CIs] 2.15–4.85) for the middle tertile and 7.47 (95% CI 5.06–11.03) for the bottom tertile, compared with top tertile and 0.31 (95% CI 0.25–0.38) per every standard deviation increase. After further adjustment for the baseline eGFR, the association was greatly attenuated, but still significant, with HRs of 1.92 (95% CI 1.26–2.90) for the bottom tertile compared with top tertile and 0.69 (95% CI 0.55–0.86) per every standard deviation increase.ConclusionsSerum uromodulin is independently associated with an increased risk of incident ESKD in CKD patients.

Serum uromodulin as an early biomarker of tubular atrophy and interstitial fibrosis in patients with glomerulopathies

To assess the significance of the serum uromodulin (Tamm-Horsfall protein - THP) concentration (Sumo) as an early biomarker of tubular atrophy (TA) and interstitial renal fibrosis (IF) in patients with glomerulopathies. 84 patients with glomerulopathy and 11 practically healthy persons (control) were examined. Uromodulin concentrations in serum and urine (Uumo) were measured, renal excretion of this protein and the estimated glomerular filtration rate (eGFR) were established. A semi-quantitative assessment of nephrobioptates was performed. Sumo decreases with a minimum expression of tubular atrophy (TA) or interstitial fibrosis (IF), when the values of eGFR still remain normal. Variations of such excretory parameters of THP as Uumo, daily excretion, and ratio: urinary uromodulin / urinary creatinine, did not manifest a similar trend. Sumo is promising as an early biomarker of fibrotic and atrophic renal damage. The parameters of renal excretion of THP do not seem to have this property. The reason for the delay in the decline of Uumo in the progression of CKD as compared to the decrease in Sumo seems to be the need to maintain a sufficient Uumo to counteract urinary tract infection and stone formation.