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This study investigates the prevalence and evaluates the prognostic implications of acute kidney injury (AKI) in COVID-19 patients, with a novel emphasis on the evaluation of serum uromodulin (sUmod) as a potential kidney-specific biomarker. A cohort of hospitalised COVID-19 patients (n = 378) was examined for AKI using standard criteria. In addition to traditional urinary biomarkers, sUmod levels were analysed. Univariable and multivariable regression models were employed to evaluate the association of sUmod and AKI and in-hospital mortality. Levels of sUmod were significantly lower in patients with CKD (91.8 ± 60.7 ng/ml) compared to patients with normal kidney function (204.7 ± 91.7 ng/ml; p < 0.001). 151 patients (40.0%) presented with AKI at the time of hospital admission or developed an AKI during hospitalization. 116 patients (76.8%) had an AKI already at the time of hospital admission. COVID-19 patients with AKI had significantly lower levels of sUmod compared to patients without AKI during hospitalisation (124.8 ± 79.5 ng/ml) vs 214.6 ± 92.3 ng/ml; p < 0.001). The in-hospital mortality rate in this cohort of COVID-19 patients was 15.3%. Patients with AKI had a higher probability for in-hospital death (OR 5.6, CI 1.76 to 17.881, p = 0.004). Patients who died during hospital stay, had significantly lower sUmod levels (129.14 ± 89.56 ng/ml) compared to patients surviving hospitalisation (187.71 ± 96,64 ng/ml; p < 0.001). AKI is frequently associated with COVID-19 in hospitalized patients. Serum uromodulin may emerge as a promising biomarker for AKI in COVID-19 patients. Further research is warranted to explore its clinical application and refine risk stratification in this patient population. [ABSTRACT FROM AUTHOR]

BACKGROUND: UMOD (uromodulin) has been linked to hypertension through potential activation of Na+-K+-2Cl- cotransporter (NKCC2), a target of loop diuretics. We posited that hypertensive patients carrying the rs13333226-AA UMOD genotype would demonstrate greater blood pressure responses to loop diuretics, potentially mediated by this UMOD/NKCC2 interaction. METHODS: This prospective, multicenter, genotype-blinded trial evaluated torasemide (torsemide) efficacy on systolic blood pressure (SBP) reduction over 16 weeks in nondiabetic, hypertensive participants uncontrolled on ≥1 nondiuretic antihypertensive for >3 months. The primary end point was the change in 24-hour ambulatory SBP (ABPM SBP) and SBP response trajectories between baseline and 16 weeks by genotype (AA versus AG/GG) due to nonrandomized groups at baseline (ClinicalTrials.gov: NCT03354897). RESULTS: Of 251 enrolled participants, 222 received torasemide and 174 demonstrated satisfactory treatment adherence and had genotype data. The study participants were middle-aged (59±11 years), predominantly male (62%), obese (body mass index, 32±7 kg/m²), with normal eGFR (92±17 mL/min/1.73 m²) and an average baseline ABPM of 138/81 mm Hg. Significant reductions in mean ABPM SBP were observed in both groups after 16 weeks (AA, -6.57 mm Hg [95% CI, -8.44 to -4.69]; P<0.0001; AG/GG, -3.22 [95% CI, -5.93 to -0.51]; P=0.021). The change in mean ABPM SBP (baseline to 16 weeks) showed a difference of -3.35 mm Hg ([95% CI, -6.64 to -0.05]; P=0.048) AA versus AG/GG genotypes. The AG/GG group displayed a rebound in SBP from 8 weeks, differing from the consistent decrease in the AA group (P=0.004 for difference in trajectories). CONCLUSIONS: Our results confirm a plausible interaction between UMOD and NKCC2 and suggest a potential role for genotype-guided use of loop diuretics in hypertension management. [ABSTRACT FROM AUTHOR]

Aim: Urinary tract infections (UTIs) rank among the most prevalent infections in humans, carrying substantial implications for public health. Women experiencing recurrent UTIs are often advised to boost their fluid intake to help eliminate bacteria. In this study, we explored the impact of elevated fluid consumption during UTIs using a mouse model of pyelonephritis. Methods: UTI was induced in 8–10 w female BALB/cJ‐mice by surgically injecting Escherichia coli (O6:K13:H1) into the bladder whereafter mice were randomized to gel food (GF) or regular chow. Immune response and infection severity were determined 24‐h post‐infection. In vitro bacterial growth (OD600) was determined in urine from mice or from human volunteers. Results: Gel feeding increased urine output (1.40 ± 0.77 μL min−1, p < 0.01) and diluted the urine (668.7 ± 177 mOsmol kg−1, p < 0.0001) compared to controls on regular chow (urine output: 0.34 ± 0.27 μL min−1, osmolality: 1439 ± 473.5 mOsmol kg−1). Mice on GF had a higher risk of pyelonephritis (87.5%) and more severe infections (26.22 ± 9.88 CFU mg−1 tissue) compared to controls (43.75%; 3.87 ± 3.56 CFU mg−1, p < 0.01). Correspondingly, the growth of E. coli was markedly reduced at osmolalities above 1200 mOsmol kg−1 compared to 600 mOsmol kg−1 and GF mice had lower urine levels of uromodulin (13.70 ± 1.89 μg mL−1, p < 0.01) compared to controls (24.65 ± 2.70 μg mL−1). Conclusion: Increased water intake and urine flow in mice will markedly increase the risk of pyelonephritis. The increased risk may reflect reduced urine uromodulin combined with optimized growth conditions for E. coli. The study does not immediately support the notion that established UTIs can be eliminated by increased water intake. [ABSTRACT FROM AUTHOR]

Abstract This study investigates the prevalence and evaluates the prognostic implications of acute kidney injury (AKI) in COVID-19 patients, with a novel emphasis on the evaluation of serum uromodulin (sUmod) as a potential kidney-specific biomarker. A cohort of hospitalised COVID-19 patients (n = 378) was examined for AKI using standard criteria. In addition to traditional urinary biomarkers, sUmod levels were analysed. Univariable and multivariable regression models were employed to evaluate the association of sUmod and AKI and in-hospital mortality. Levels of sUmod were significantly lower in patients with CKD (91.8 ± 60.7 ng/ml) compared to patients with normal kidney function (204.7 ± 91.7 ng/ml; p

Objective To explore the correlation between the expression levels of serum Klotho and uromodulin （UMOD） and immunoglobulin A （IgA） nephropathy complicated with hyperuricemia. Methods From January 1, 2018 to January 1, 2022, 97 hospitalized IgA nephropathy were selected as study subjects. Based upon blood uric acid level before renal puncture, they were assigned into two groups of IgA nephropathy complicated with hyperuricemia （n=42） and normal blood uric acid （n=55）. Additionally, 97 healthy individuals during the same period were designated as control group. Serum levels of Klotho and UMOD and basic profiles of three groups were compared. Pearson’s method was applied for examining the correlation between serum levels of Klotho and UMOD, estimated glomerular filtration rate （eGFR）, uric acid and creatinine levels in patients with IgA nephropathy complicated by hyperuricemia. Multivariate Logistic regression was utilized for analyzing the influencing factors of IgA nephropathy complicated with hyperuricemia. Receiver operating characteristic （ROC） curve was employed for examining the diagnostic value of serum levels of Klotho and UMOD for IgA nephropathy complicated with hyperuricemia. Results Serum Klotho was （151.66±27.29） ng/L and serum UMOD （39.65±8.67） g/L in IgA nephropathy complicated with hyperuricemia group; serum Klotho was （185.34±38.17） ng/L and serum UMOD （51.13±12.32） g/L in normal blood uric acid group; serum Klotho was （211.53±50.63） ng/L and serum UMOD （62.39±16.86） g/L in control group. Statistically significant differences existed in serum levels of Klotho and UMOD among three groups （P＜0.05）. Systolic blood pressure was （152.62±18.82） mmHg（1mmHg=0.133 kPa）, diastolic blood pressure （98.37±13.65）mmHg, proportion of hypertension 27（64.29）, 24-hour urine protein quantification （2.55±0.69）g, blood uric acid （435.26±113.25）μmol/L, creatinine （352.55±58.62） μmol/L and eGFR （72.28±13.53）mL·min−1·（1.73m2）−1 in IgA nephropathy complicated with hyperuricemia group; systolic blood pressure was （112.58±15.97）mmHg, diastolic blood pressure （72.43±10.34）mmHg, proportion of hypertension 21（38.18）, 4-hour urine protein quantification （1.62±0.31）g, blood uric acid （342.59±84.64）μmol/L, creatinine （103.11±27.47）μmol/L and eGFR （102.96±35.68）mL·min−1·（1.73m2）−1 in normal blood uric acid group. The inter-group differences of the above parameters were statistically significant （P＜0.05）. Pearson’s correlation analysis results indicated that serum levels of Klotho and UMOD in patients with IgA nephropathy complicated by hyperuricemia were correlated negatively with blood uric acid and creatinine and positively with eGFR（P＜0.05）; hypertension, 24-hour urine protein quantification, eGFR, blood uric acid and serum levels of Klotho and UMOD were independent influencing factors for IgA nephropathy complicated with hyperuricemia （P＜0.05）. ROC curve showed that area under the curve （AUC） of serum Klotho and UMOD for diagnosing IgA nephropathy complicated by hyperuricemia alone and in combination was 0.947, 0.882 and 0.961 respectively and combined diagnostic value of the two was higher than that of single diagnosis（Zcombination-Klotho=0.887,P=0.375; Zcombination-UMOD=2.423, P=0.015）. Conclusion Serum levels of Klotho and UMOD are down-regulated in patients with IgA nephropathy complicated by hyperuricemia. Correlation exists between IgA nephropathy and hyperuricemia and a combined diagnosis has an excellent effect. Close monitoring of serum levels of Klotho and UMOD has some reference value for diagnosing IgA nephropathy complicated by hyperuricemia.

Abstract Hereditary transthyretin (ATTRv) amyloidosis is a rare, adult-onset, progressive, multisystemic condition caused by TTR pathogenic variants. Reliable biomarkers are needed to allow early diagnosis and to monitor disease severity and progression. We measured serum concentrations of growth differentiation factor-15 (GDF-15) and uromodulin (Umod) in ATTRv patients to evaluate correlations with standard markers of disease severity (FAP stage and PND score). Blood samples were collected from 16 patients diagnosed with ATTRv amyloidosis and a verified TTR variant and from 26 healthy controls. ATTRv patients were stratified by clinical phenotype (neurologic vs. mixed), genotype (V30M vs. non-V30M), and disease severity. We found significantly higher levels of serum GDF-15 in ATTRv patients compared with controls. Mean serum Umod levels were significantly lower in patients with ATTRv than controls. A positive correlation was found between serum Umod and estimated glomerular filtration rate (eGFR), while an inverse correlation was found with cystatin C levels. Conversely, GDF-15 showed a negative correlation with eGFR, and a direct correlation with cystatin C levels. No correlation was demonstrated between GDF-15 or Umod levels and traditional cardiac biomarkers. The results identify alteration of serum levels of GDF-15 and Umod in ATTRv amyloidosis.

Hereditary transthyretin (ATTRv) amyloidosis is a rare, adult-onset, progressive, multisystemic condition caused by TTR pathogenic variants. Reliable biomarkers are needed to allow early diagnosis and to monitor disease severity and progression. We measured serum concentrations of growth differentiation factor-15 (GDF-15) and uromodulin (Umod) in ATTRv patients to evaluate correlations with standard markers of disease severity (FAP stage and PND score). Blood samples were collected from 16 patients diagnosed with ATTRv amyloidosis and a verified TTR variant and from 26 healthy controls. ATTRv patients were stratified by clinical phenotype (neurologic vs. mixed), genotype (V30M vs. non-V30M), and disease severity. We found significantly higher levels of serum GDF-15 in ATTRv patients compared with controls. Mean serum Umod levels were significantly lower in patients with ATTRv than controls. A positive correlation was found between serum Umod and estimated glomerular filtration rate (eGFR), while an inverse correlation was found with cystatin C levels. Conversely, GDF-15 showed a negative correlation with eGFR, and a direct correlation with cystatin C levels. No correlation was demonstrated between GDF-15 or Umod levels and traditional cardiac biomarkers. The results identify alteration of serum levels of GDF-15 and Umod in ATTRv amyloidosis. [ABSTRACT FROM AUTHOR]

Background This study investigates the link between genetic variants associated with kidney function and immunoglobulin A (IgA) nephropathy (IgAN) progression. Methods We recruited 961 biopsy-proven IgAN patients and 651 non-IgAN end-stage renal disease (ESRD) patients from Ruijin Hospital. Clinical and renal pathological data were collected. The primary outcome was the time to ESRD. A healthy population was defined as estimated glomerular filtration rate >60 mL/min/1.73 m2 without albuminuria or hematuria. Fifteen single-nucleotide polymorphisms (SNPs) were selected from a genome-wide association study of kidney function and genotyped by the SNaPshot. Immunohistochemistry in renal tissue and ELISA in urine samples were performed to explore the potential functions of genetic variations. Results The rs77924615-G was independently associated with an increased risk for ESRD in IgAN patients after adjustments for clinical and pathologic indices, and treatment (adjusted hazard ratio 2.10; 95% confidence interval 1.14–3.88). No significant differences in ESRD-free survival time were found among different genotypes in non-IgAN ESRD patients (log-rank, P = .480). Moreover, rs77924615 exhibited allele-specific enhancer activity by dual-luciferase reporter assay. Accordingly, the urinary uromodulin–creatinine ratio (uUCR) was significantly higher in healthy individuals with rs77924615 AG or GG than in individuals with AA. Furthermore, uromodulin expression in tubular epithelial cells was higher in patients with rs77924615 AG or GG. Finally, we confirmed that an increased uUCR (P = .009) was associated with faster IgAN progression. Conclusion The SNP rs77924615, which modulates the enhancer activity of the UMOD gene, is associated with renal function deterioration in IgAN patients by increasing uromodulin levels in both the renal tubular epithelium and urine. [ABSTRACT FROM AUTHOR]

Simple Summary: Simple Summary: Uromodulin has been known for many years as a normal protein component of urine. However, in recent years, serum as well as urinary uromodulin have been investigated in relation to kidney diseases. Chronic kidney disease (CKD) is a common diagnosis, especially in old dogs, and suitable markers for the early stages of the disease are constantly being investigated. We focused on the effect of age and gender on uromodulin in serum and urine in a healthy population of dogs of the same breed, German shepherd. We compared the results with two groups of other breeds of healthy dogs. Compared with groups of patients in the early stages of CKD, we concluded that urinary uromodulin corrected to creatinine in urine seems to be the most prospective marker. Serum and urinary uromodulin are evaluated as potential biomarkers of kidney disease. The aim of our research was to select a more appropriate form of uromodulin for the diagnosis of early stages of chronic kidney disease (CKD). We also focused on the influence of age and gender in one breed on uromodulin and on the possible interbreed differences. Serum uromodulin had the lowest values in dogs younger than 2 years but no effect of gender, breed, or CKD was observed. Urinary uromodulin indexed to urinary creatinine was significantly reduced in dogs in stage 2 of CKD (p = 0.003) in contrast to uromodulin converted to urine specific gravity. Urinary uromodulin with both corrections was significantly lower in Belgian shepherds compared to German shepherds (p < 0.0001, p = 0.0054) but was not influenced by gender or age. In stage 1 of CKD, urinary uromodulin correlated with kidney disease markers SDMA (p = 0.0424, p = 0.0214) and UPC (p = 0.0050, p = 0.0024). Urinary uromodulin appears to be more associated with CKD than serum uromodulin. Further studies with a larger number of patients are needed for the suitability of urinary uromodulin as a marker of early-stage disease. [ABSTRACT FROM AUTHOR]

The histomorphological features of normal kidneys in cats and dogs have been revealed despite the high susceptibility of cats to tubulointerstitial damage. Herein, the histological characteristics of the two species were compared. Cytoplasmic lipid droplets (LDs) were abundant in the proximal convoluted tubules (PCTs) of cats aged 23–27 months but scarce in dogs aged 24–27 months. LDs were rarely observed in the distal tubules (DTs) and collecting ducts (CDs) of either species, as visualized by the expression of Tamm–Horsfall protein 1, calbindin-D28K, and aquaporin 2. The occupational area ratio of proximal tubules (PTs) in the renal cortex was higher, but that of DTs or CDs was significantly lower in adult cats than in dogs. Single PT epithelial cells were larger, but PCT, DT, and CD lumens were significantly narrower in adult cats than in dogs. Unlike adults, young cats at 6 months exhibited significantly abundant cytoplasmic LDs in proximal straight tubules, indicating lipid metabolism-related development. Histochemistry of the 21 lectins also revealed variations in glycosylation across different renal tubules and CDs in both species. Sodium-glucose cotransporter 2 was expressed only in PTs, excluding the proximal straight tubules with few LDs in adult cats or the PCTs of young cats and adult dogs. These findings are crucial for understanding species-specific characteristics of renal histomorphology and pathogenesis. [ABSTRACT FROM AUTHOR]

Uromodulin is a kidney-specific glycoprotein which is exclusively produced by the epithelial cells lining the thick ascending limb and early distal convoluted tubule. It is currently recognized as a multifaceted player in kidney physiology and disease, with discrete roles for intracellular, urinary, interstitial and serum uromodulin. Among these, uromodulin modulates renal sodium handling through the regulation of tubular sodium transporters that reabsorb sodium and are targeted by diuretics, such as the loop diuretic–sensitive Na+-K+-2Cl− cotransporter type 2 (NKCC2) and the thiazide-sensitive Na+/Cl− cotransporter (NCC). Given these roles, the contribution of uromodulin to sodium-sensitive hypertension has been proposed. However, recent studies in humans suggest a more complex interaction between dietary sodium intake, uromodulin and blood pressure. This review presents an updated overview of the uromodulin's biology and its various roles, and focuses on the interaction between uromodulin and sodium-sensitive hypertension. [ABSTRACT FROM AUTHOR]

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Introduction: The relevance of tubulo‐interstitial involvement for kidney prognosis has recently been emphasized, but validated biomarkers for predicting histology are still lacking. The aim of our study was to evaluate different serum and urinary markers of tubular damage in patients with lupus nephritis (LN) and to correlate them with kidney histopathology. Methods: A single‐center retrospective study was conducted from January 2016 to December 2021. Serum and urine samples were collected on the same day of kidney biopsy and correlated with histologic data from a cohort of 15 LN patients. We analyzed the following urinary markers, adjusted for urine creatinine: beta 2‐microglobulin, alpha 1‐microglobulin, NGAL, uKIM‐1, MCP‐1, uDKK‐3, and uUMOD. The serum markers sKIM‐1 and sUMOD were also analyzed. Results: A positive and strong correlation was observed between the degree of interstitial fibrosis (rho = 0.785, p =.001) and tubular atrophy (rho = 0.781, p =.001) and the levels of uDKK3. uUMOD also showed an inverse and moderate correlation with interstitial fibrosis (rho = −0.562, p =.037) and tubular atrophy (rho = −0.694, p =.006). Patients with >10% cortical interstitial inflammation had higher levels of uKIM‐1 [4.9 (3.9, 5.5) vs. 0.8 (0.6, 1.5) mcg/mg, p =.001], MCP‐1 [3.8 (2. 3, 4.2) vs. 0.7 (0.3, 1.2) mcg/mg, p =.001], sKIM‐1 [9.2 (5.9, 32.7) vs. 1.4 (0, 3.5) pg/mL, p =.001], and lower sUMOD [8.7 (0, 39.7) vs. 46.1 (35.7, 53) ng/mL, p =.028]. Conclusion: The use of specific urinary and serum biomarkers of tubular dysfunction or injury may help to predict certain histologic parameters in LN patients. [ABSTRACT FROM AUTHOR]

Hepatorenal syndrome (HRS) is associated with a dismal prognosis in patients with cirrhosis, and therapeutic options are limited. Biomarkers to identify patients with poor response to therapy are urgently needed. This study aimed to evaluate the predictive value of serum levels of uromodulin (sUMOD) in patients with cirrhosis and HRS treated with terlipressin and albumin (T/A). In total, 156 patients [81 patients with HRS treated with T/A, 42 patients with cirrhosis without kidney injury, and 33 patients with cirrhosis with prerenal acute kidney injury (AKI)] were included. sUMOD levels were analyzed by ELISA. Patients with HRS were prospectively followed for the composite endpoint of hemodialysis-/liver transplantation-free survival (HD/LTx-free survival). Of the 81 patients with HRS, 40 had HRS type 1 and 41 type 2. In the cohort of patients with HRS treated with T/A, median sUMOD level was 100 ng/mL (IQR 64; 144). sUMOD differed significantly between patients with HRS compared with patients without AKI (P = 0.001) but not between patients with HRS and prerenal AKI (P = 0.9). In multivariable analyses, sUMOD levels in the lowest quartile were independently associated with a lower rate of complete response to T/A (OR 0.042, P = 0.008) and a higher risk for reaching the composite endpoint of HD/LTX-free survival (HR 2.706, P = 0.013) in patients with HRS type 2 treated with T/A. In contrast, sUMOD was not significantly associated with these outcomes in patients with HRS type 1. sUMOD may be a valuable biomarker for identifying patients with HRS type 2 treated with T/A to predict response and prognosis. NEW & NOTEWORTHY: Biomarkers identifying patients with hepatorenal syndrome (HRS) and poor response to therapy are urgently needed. In this study, lower serum uromodulin (sUMOD) levels were associated with poorer response to therapy with terlipressin and albumin and consequently with poorer prognosis in patients with HRS type 2. In patients with HRS type 1, there was no association between sUMOD and poorer prognosis. [ABSTRACT FROM AUTHOR]

Background Proteinuria is not only a biomarker of chronic kidney disease (CKD) but also a driver of CKD progression. The aim of this study was to evaluate serum and urinary tubular biomarkers in patients with biopsied proteinuric kidney disease and to correlate them with histology and kidney outcomes. Methods A single-center retrospective study was conducted on a cohort of 156 patients from January 2016 to December 2021. The following urinary and serum biomarkers were analyzed on the day of kidney biopsy: beta 2 microglobulin (β2-mcg), alpha 1 microglobulin (α1-mcg), neutrophil gelatinase-associated lipocalin (NGAL), urinary kidney injury molecule-1 (uKIM-1), monocyte chemoattractant protein-1 (MCP-1), urinary Dickkopf-3 (uDKK3), uromodulin (urinary uUMOD), serum kidney injury molecule-1 (sKIM-1) and serum uromodulin (sUMOD). A composite outcome of kidney progression or death was recorded during a median follow-up period of 26 months. Results Multivariate regression analysis identified sUMOD (β–0.357, P  < .001) and uDKK3 (β 0.483, P  < .001) as independent predictors of interstitial fibrosis, adjusted for age, estimated glomerular filtration rate (eGFR) and log proteinuria. Elevated levels of MCP-1 [odds ratio 15.61, 95% confidence interval (CI) 3.52–69.20] were associated with a higher risk of cortical interstitial inflammation >10% adjusted for eGFR, log proteinuria and microhematuria. Upper tertiles of uDKK3 were associated with greater eGFR decline during follow-up. Although not a predictor of the composite outcome, doubling of uDKK3 was a predictor of kidney events (hazard ratio 2.26, 95% CI 1.04–4.94) after adjustment for interstitial fibrosis, eGFR and proteinuria. Conclusions Tubular markers may have prognostic value in proteinuric kidney disease, correlating with specific histologic parameters and identifying cases at higher risk of CKD progression. [ABSTRACT FROM AUTHOR]

The outcome for patients with sepsis-associated acute kidney injury in the intensive care unit (ICU) remains poor. Low serum uromodulin (sUMOD) protein levels have been proposed as a causal mediator of this effect. We investigated the effect of different levels of sUMOD on the risk of sepsis and severe pneumonia and outcomes in these conditions. A two-sample Mendelian randomization (MR) study was performed. Single-nucleotide polymorphisms (SNPs) associated with increased levels of sUMOD were identified and used as instrumental variables for association with outcomes. Data from different cohorts were combined based on disease severity and meta-analyzed. Five SNPs associated with increased sUMOD levels were identified and tested in six datasets from two biobanks. There was no protective effect of increased levels of sUMOD on the risk of sepsis [two cohorts, odds ratio (OR) 0.99 (95% confidence interval 0.95-1.03), P = 0.698, and OR 0.95 (0.91-1.00), P = 0.060, respectively], risk of sepsis requiring ICU admission [OR 1.04 (0.93-1.16), P = 0.467], ICU mortality in sepsis [OR 1.00 (0.74-1.37), P = 0.987], risk of pneumonia requiring ICU admission [OR 1.05 (0.98-1.14), P = 0.181], or ICU mortality in pneumonia [OR 1.17 (0.98-1.39), P = 0.079]. Meta-analysis of hospital-admitted and ICU-admitted patients separately yielded similar results [OR 0.98 (0.95-1.01), P = 0.23, and OR 1.05 (0.99-1.12), P = 0.86, respectively]. Among patients with sepsis and severe pneumonia, there was no protective effect of different levels of sUMOD. Results were consistent regardless of geographic origins and not modified by disease severity. [ABSTRACT FROM AUTHOR]

Serum creatinine levels are insensitive to real-time changes in kidney function or injury. There is a growing interest in assessing kidney injury by measuring biomarkers in body fluid. From our previous studies, we identified and reported three urinary biomarkers namely Uromodulin (UMOD), Osteopontin (OPN), and Interleukin-9 (IL-9) to be associated with kidney health. The availability of a rapid point-of-care test for these urinary biomarkers will potentially accelerate its applicability and accessibility. In this study, we aimed to develop novel lateral flow device (LFD) for UMOD, OPN and IL-9. We tested paired antibodies using Enzyme Linked Immunosorbent Assay wherein we observed functionality only for UMOD and OPN and not for IL-9. A conjugation buffer pH of 7.8 and 8.5 was found suitable at a detection antibody concentration of 15 µg/mL for LFD development. The developed LFDs were found to quantitatively measure UMOD standard (LLOD of 80,000 pg/mL) and OPN standard (LLOD of 8600 pg/mL) respectively. The LFD was also able to measure human urinary UMOD and OPN with a percent CV of 12.12 and 5.23 respectively. [ABSTRACT FROM AUTHOR]

Background: Uromodulin (Tamm-Horsfall protein), the most common protein in normal urine present in a bundant quantity, is increasingly considered as a potential biomarker relevant to kidney function and tubular reserve, chronic kidney disease and hypertension. A reduced number of tubular cells, is paralleled by reduced urinary and serum concentrations of uromodulin. Therefore, uromodulin might represent a promising biomarker for CKD. Aim: To evaluate the use of serum uromodulin as a biomarker in chronic kidney disease patients. Material and Methods: In an observational study, on 100 subjects with 50 normal healthy and 50 with CKD 1 - 5 stages patients attending Nephrology department in a tertiary care hospital for two years were enrolled. Lipid profile, Serum calcium, proteins, creatinine and serum Uromodulin along with e GFR was investigated. Data was analyzed using SPSS 16 and by using t test, ANOVA and correlation coefficients. Results: Mean age of the study participants was 47.47 ± 10.66 years. And 71% were male. On comparison between cases and controls, Serum Uromodulin, calcium, HDL was lower and other lab findings were significantly more in Cases than in controls. Serum Uromodulin was significantly decreased with severity of CKD. Conclusion: A comparative analysis of serum uromodulin with e GFR shows that eGFR is positively correlated with uromodulin. Lower serum uromodulin reflects a decline in kidney function. Thus serum uromodulin is a helpful marker in diagnosis of CKD at a nearly stage. The estimation of serum uromodulin level may aid in early diagnosis of kidney dysfunction and also in predicting the progression of disease. [ABSTRACT FROM AUTHOR]

Nephrogenic adenoma (NA) is an epithelial lesion that usually occurs in the mucosa of the urinary tract. Rare cases of deep infiltrative or perinephric lesions have also been reported. Recently, NA with characteristic fibromyxoid stroma (fibromyxoid NA) has been proposed as a distinct variant. Although shedding of distal renal tubular cells due to urinary tract rupture has been postulated as the cause of NA in general, the mechanism underlying extraurinary presentation of NA and fibromyxoid stromal change in fibromyxoid NA remains unknown. In this study, we performed mass spectrometry (MS) analysis in a case of perinephric fibromyxoid NA of an 82‐year‐old man who underwent right nephroureterectomy for distal ureteral cancer. The patient had no prior history of urinary tract injury or radiation. Periodic acid‐Schiff staining‐positive eosinophilic structureless deposits in the stroma of fibromyxoid NA were microdissected and subjected to liquid chromatography/MS. The analysis revealed the presence of a substantial amount of uromodulin (Tamm−Horsfall protein). The presence of urinary content in the stroma of perinephric fibromyxoid NA suggests that urinary tract rupture and engraftment of renal tubular epithelial cells directly cause the lesion. [ABSTRACT FROM AUTHOR]

Background. The purpose of this study was to investigate urinary uromodulin (uUMOD) excretion, reactivity of the autonomic nervous system and impaired renal blood circulation in patients with predialysis chronic kidney disease (CKD), the effect of antioxidant therapy on these parameters. Materials and methods. Ninety-one patients with CKD stage 1–5 whose average age was 47.00 ± 12.12 years took part in the ROLUNT (UROmoduLin UbiquinoNe GlutaThione) study. Thirty (32.97 %) men and 61 (67.03 %) women were divided into two groups, which were representative in terms of age and gender composition: group 1 (n = 46) — patients with CKD stage 1–5 who had a Charlson comorbidity index ≤ 2, group 2 (n = 45) — patients with CKD stage 1–5 who had a Charlson comorbidity index ≥ 3. Both groups were divided into subgroups A and B. Subgroups A included patients with impaired vegetative status, subgroups B — those without impaired vegetative status. The first A and second B subgroups took glutathione 100 mg twice a day with food for 3 months, the first B and second A subgroups took ubiquinone 100 mg once a day with food for 3 months. Results. The results of the paired t-test showed that there is a significant difference between the indicators at baseline and at the end of the study. The Pearson correlation results showed that in the group 1 (subgroup A), there is a significant average positive relationship between uUMOD and estimated glomerular filtration rate (r(21) = 0.418, p = 0.047); in the group 1 (subgroup B), there is a significant large positive relationship between uUMOD and Hb indicators (r(21) = 0.513, p = 0.012); a significant very small negative relationship between uUMOD and albumin-creatinine ratio (r(21) = 0.441, p = 0.035); in the group 2 (subgroup A), there is a significant very small negative relationship between uUMOD indicators and Kérdö index (r(20) = 0.427, p = 0.048); in the group 2 (subgroup B), there is a significant very small negative relationship between the uUMOD indicators and Yu.M. Chernov’s questionnaire (r(21) = 0.421, p = 0.045). Conclusions. Antioxidant therapy with glutathione and ubiquinone significantly affects the examination parameters in patients with CKD. Considering the safety and effectiveness of antioxidant therapy, we suggest including it in the treatment protocols for patients with CKD. Further research is recommended to develop a standard protocol. [ABSTRACT FROM AUTHOR]

Activin A is known to impede tubular repair following renal ischemia, whereas exogenous follistatin, an activin A antagonist, has been shown to ameliorate kidney damage in rats. Despite these findings, the precise role of endogenous follistatin in the kidney has yet to be elucidated. In this study, we investigated the localization of follistatin in the normal human kidney and its potential utility as a marker for acute kidney injury (AKI). In a total of 118 AKI patients and 16 healthy adults, follistatin levels in serum and urine were quantified using ELISA, and correlations with clinical parameters were analyzed. Follistatin-producing cells were positive for Na-Cl co-transporter and uromodulin, but negative for aquaporin 1 and aquaporin 2. Unlike healthy adults, urinary follistatin significantly increased in AKI patients, correlating positively with AKI severity. Urinary follistatin levels were notably higher in patients needing renal replacement therapy. Significant correlations were observed with urinary protein, α1 microglobulin, and urinary NGAL, but not with urinary KIM-1, urinary L-FABP, urinary NAG, urinary β2 microglobulin, or serum creatinine. Interestingly, no correlation between urinary and serum follistatin levels was identified, indicating a renal origin for urinary follistatin. In conclusion, follistatin, produced by distal tubules, is detectable in the urine of AKI patients, suggesting its potential as a valuable marker for monitoring acute tubular damage severity in AKI. [ABSTRACT FROM AUTHOR]

For a long time, urine has been considered sterile in physiological conditions, thanks to the particular structure of the urinary tract and the production of uromodulin or Tamm–Horsfall protein (THP) by it. More recently, thanks to the development and use of new technologies, i.e., next-generation sequencing and expanded urine culture, the identification of a microbial community in the urine, the so-called urobiota, became possible. Major phyla detected in the urine are represented by Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Particularly, the female urobiota is largely represented by Lactobacillus spp., which are very active against urinary pathogenic Escherichia (E.) coli (UPEC) strains via the generation of lactic acid and hydrogen peroxide. Gut dysbiosis accounts for recurrent urinary tract infections (UTIs), so-called gut–bladder axis syndrome with the formation of intracellular bacterial communities in the course of acute cystitis. However, other chronic urinary tract infections are caused by bacterial strains of intestinal derivation. Monomicrobial and polymicrobial infections account for the outcome of acute and chronic UTIs, even including prostatitis and chronic pelvic pain. E. coli isolates have been shown to be more invasive and resistant to antibiotics. Probiotics, fecal microbial transplantation, phage therapy, antimicrobial peptides, and immune-mediated therapies, even including vaccines for the treatment of UTIs, will be described. [ABSTRACT FROM AUTHOR]

Uromodulin, also referred to as Tamm Horsfall protein (THP), is a renal protein exclusively synthesized by the kidneys and represents the predominant urinary protein under normal physiological conditions. It assumes a pivotal role within the renal system, contributing not only to ion transport and immune modulation but also serving as a critical factor in the prevention of urinary tract infections and kidney stone formation. Emerging evidence indicates that uromodulin may serve as a potential biomarker extending beyond renal function. Recent clinical investigations and Mendelian randomization studies have unveiled a discernible association between urinary regulatory protein levels and cardiovascular events and mortality. This review primarily delineates the intricate relationship between uromodulin and cardiovascular disease, elucidates its predictive utility as a novel biomarker for cardiovascular events, and delves into its involvement in various physiological and pathophysiological facets of the cardiovascular system, incorporating recent advancements in corresponding genetics.

BackgroundMeasures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown.MethodsAmong 2377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia).ResultsAt baseline, the mean age was 73 ± 9 years and mean estimated glomerular filtration rate (eGFR) was 46 ± 11 mL/min/1.73 m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD) and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL [hazard ratio (HR) = 1.08 per 2-fold higher biomarker level, 95% confidence interval (CI) 1.03-1.13], higher MCP-1 (HR = 1.11, 95% CI 1.03-1.19) and lower UMOD (HR = 0.91, 95% CI 0.85-0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P > 0.10 for all interactions).ConclusionsAmong persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.

Sickle cell nephropathy (SCN) is a leading cause of morbidity and mortality in sickle cell disease (SCD). Early intervention is crucial for mitigating its effects. However, current diagnostic methods rely on generic tests and may not detect SCN until irreversible renal damage occurs. Therefore, specific biomarkers for early diagnosis of SCN are needed. Urinary exosomes, membrane-bound vesicles secreted by renal podocytes and epithelial cells, contain both common and cell type-specific membrane and cytosolic proteins, reflecting the physiologic and pathophysiologic states of the kidney. Using proteomics, we analyzed the proteomes of urinary exosomes from humanized SCD mice at 2 months (without albuminuria) and 4 months (with albuminuria) of age. Excretion of 164 proteins were significantly increased and 176 proteins was significantly decreased in the exosomes when mice developed albuminuria. Based on the relevance to SCD, chronic kidney disease and Western blot confirmation in mice, we analyzed protein abundance of heparanase, cathepsin C, α2-macroglobulin and sarcoplasmic endoplasmic Ca2+ ATPase-3 (SERCA3) in the urinary exosomes and urine of 18 SCD subjects without albuminuria and 12 subjects with albuminuria using Western blot analyses. Both male and female subjects increased or tended to increase the excretion of these proteins in their urinary exosomes upon developing albuminuria, but female subjects demonstrated stronger correlations between the excretion of these proteins and urine albumin creatinine ratio (UACR) compared to male subjects. In contrast, exosomal excretion of Tamm-Horsfall protein, β-actin and SHP-1 was independent of albuminuria. These findings provide a foundation for a time-course study to determine whether increases in the levels of these proteins precede the onset of albuminuria in patients, which will help determine the potential of these proteins as biomarkers for early detection of SCN. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) have been identified as promising biomarkers for the noninvasive diagnosis of various diseases. However, challenges in separating EVs from soluble proteins have resulted in variable EV recovery rates and low purities. Here, we report a high-yield (> 90%) and rapid (< 10 min) EV isolation method called FLocculation via Orbital Acoustic Trapping (FLOAT). The FLOAT approach utilizes an acoustofluidic droplet centrifuge to rotate and controllably heat liquid droplets. By adding a thermoresponsive polymer flocculant, nanoparticles as small as 20 nm can be rapidly and selectively concentrated at the center of the droplet. We demonstrate the ability of FLOAT to separate urinary EVs from the highly abundant Tamm-Horsfall protein, addressing a significant obstacle in the development of EV-based liquid biopsies. Due to its high-yield nature, FLOAT reduces biofluid starting volume requirements by a factor of 100 (from 20 mL to 200 µL), demonstrating its promising potential in point-of-care diagnostics. [ABSTRACT FROM AUTHOR]

Background: UMOD is exclusively produced by renal epithelial cells. Recent genome-wide association studies (GWAS) suggested that common variants in UMOD gene are closely connected with the risk of CKD. However, a comprehensive and objective report on the current status of UMOD research is lacking. Therefore, we aim to conduct a bibliometric analysis to quantify and identify the status quo and trending issues of UMOD research in the past. Methods: We collected data from the Web of Science Core Collection database and used the Online Analysis Platform of Literature Metrology, the Online Analysis Platform of Literature Metrology and Microsoft Excel 2019 to perform bibliometricanalysis and visualization. Results: Based on the data from the WoSCC database from 1985 to 2022, a total of 353 UMOD articles were published in 193 academic journals by 2346 authors from 50 different countries/regions and 396 institutions. The United States published the most papers. Professor Devuyst O from University of Zurich not only published the greatest number of UMOD-related papers but also is among the top 10 co-cited authors. KIDNEY INTERNATIONAL published the most necroptosis studies, and it was also the most cited journal. High-frequency keywords mainly included 'chronic kidney disease', 'Tamm Horsfall protein' and 'mutation'. Conclusions: The number of UMOD-related articles has steadily increased over the past decades Current UMOD studies focused on Biological relevance of the UMOD to kidney function and potential applications in the risk of CKD mechanisms, these might provide ideas for further research in the UMOD field. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Identifying buffaloes in estrus is crucial for enhancing the efficiency of reproduction as silent heat is a major concern in this species. Review of literature indicated the role of Tamm-Horsfall protein (THP) is associated with the physiological events around the estrus stage. Hence, the present study was aimed to quantify the expression level of THP in urine of buffaloes to ascertain its suitability as a marker for identifying buffaloes in estrus. Methods: The grouping of animals as mid-diestrus (Group-I/G-I/Control group), regular estrus (Group-II/G-II) and silent estrus (Group-III/G-III) buffaloes was done using a combinatorial approach. The expression of THP in the urine of three groups of animals was quantified by western blot. Result: The results of the present study revealed higher levels of urinary THP in G-II animals when compared to G-III and G-I animals, although it was statistically non-significant (p>0.05). The present study revealing for increased urinary expression of THP in G-II and G-III animals when compared to G-I animals probably construes the antimicrobial role of THP in the female reproductive tract and its role during estrus to prevent microbiota population beyond the physiological levels. For THP to be considered as biomarker for detecting buffaloes in silent heat there is need for further studies involving large number of animals. Nonetheless, an easy method has been developed that facilitated THP detection and quantification in urine of buffaloes by western blot. [ABSTRACT FROM AUTHOR]

The causal links between urinary uromodulin (uUMOD) and kidney stone disease (KSD) are still not clarified in general population. We assessed their relationships combining 2-sample Mendelian randomization (MR) and multivariable (MVMR) designs among general population of European ancestry. The summary information for uUMOD indexed to creatinine levels (29,315 individuals) and KSD (395,044 individuals) were from 2 independent genome-wide association studies (GWAS). The primary causal effects of exposures on outcomes were evaluated using inverse variance-weighted (IVW) regression model. Multiple sensitivity analyses were also performed. In 2-sample MR, we found that 1-unit higher genetically predicted uUMOD levels were associated with a lower risk of KSD (OR = 0.62; 95% CI 0.55–0.71; P = 2.83E−13). In reverse, we did not find the effect of KSD on uUOMD using IVW (beta = 0.00; 95% CI − 0.06–0.05; P = 0.872) and other sensitivity analyses. In MVMR, uUMOD indexed to creatinine levels were directly associated with the risk of KSD after introducing eGFR, SBP, urinary sodium or all three factors (OR = 0.71; 95% CI 0.64–0.79; P = 1.57E−09). Furthermore, our study supported that the protective effect of uUMOD on KSD may be partially mediated by eGFR (beta = − 0.09; 95% CI − 0.13 to − 0.06; mediation proportion = 20%). Our study supported that the protective effect of genetically predicted higher uUMOD levels on KSD may be partially mediated by eGFR decline, but not via SBP or urinary sodium. uUMOD might be a treatment target in preventing KSD in general population. [ABSTRACT FROM AUTHOR]

The isolation and subsequent molecular analysis of extracellular vesicles (EVs) derived from patient samples is a widely used strategy to understand vesicle biology and to facilitate biomarker discovery. Expressed prostatic secretions in urine are a tumor proximal fluid that has received significant attention as a source of potential prostate cancer (PCa) biomarkers for use in liquid biopsy protocols. Standard EV isolation methods like differential ultracentrifugation (dUC) co-isolate protein contaminants that mask lower-abundance proteins in typical mass spectrometry (MS) protocols. Further complicating the analysis of expressed prostatic secretions, uromodulin, also known as Tamm-Horsfall protein (THP), is present at high concentrations in urine. THP can form polymers that entrap EVs during purification, reducing yield. Disruption of THP polymer networks with dithiothreitol (DTT) can release trapped EVs, but smaller THP fibres co-isolate with EVs during subsequent ultracentrifugation. To resolve these challenges, we describe here a dUC method that incorporates THP polymer reduction and alkaline washing to improve EV isolation and deplete both THP and other common protein contaminants. When applied to human expressed prostatic secretions in urine, we achieved relative enrichment of known prostate and prostate cancer-associated EV-resident proteins. Our approach provides a promising strategy for global proteomic analyses of urinary EVs.

Background. The purpose of this study was to investigate urinary uromodulin (uUmod) excretion, reactivity of the autonomic nervous system and impaired renal blood circulation in patients with predialysis chronic kidney disease (CKD), and the effect of antioxidant therapy on these parameters. Materials and methods. Ninety-one patients with CKD stage 1–5 took part in the ROLUNT (UROmoduLin UbiquinoNe GlutaThione) study, their average age was 47.00 ± 12.12 years. Thirty (32.97 %) men and 61 (67.03 %) women were divided into two groups, which were representative in terms of age and gender composition: the first one (n = 46) — patients with CKD stage1–5 who had Charlson Comorbidity Index ≤ 2, the second one (n = 45) — patients with CKD stage1–5 who had Charlson Comorbidity Index ≥ 3. The first and second groups were divided into subgroups A and B. Subgroup A included patients with impaired vegetative status, subgroup B — without impaired vegetative status. Subgroups 1A and 2B took glutathione 100 mg twice a day with food for 3 months; subgroups 1B and 2A received ubiquinone 100 mg once a day with food for 3 months. In patients with CKD stage1–5, uUmod, albumin to creatinine ratio (ACR), glomerular filtration rate (GFR) were evaluated. Ninety-one ultrasound duplex color scans of the kidneys were performed and the index of resistance (IR) was determined in patients with CKD stage1–5. Results. The results of the paired t-test showed that there is a significant difference between the indicators at the beginning and at the end of the study, with the exception of the following: in subgroup 1A: hemoglobin (Hb) (T = –1.5863 [–2.0739, 2.0739] 95% confidence interval (CI) [–2.4077, 0.3207], p = 0.127); in subgroup 1B: Hb (T = –0.382 [–2.0739, 2.0739], 95% CI [–1.3977, 0.963], p = 0.706); ACR (T = –1.5899 [–2.0739, 2.0739], 95% CI [–16.7323, 2.2105], p = 0.126); systolic blood pressure (SBP) (T = –0.5625 [–2.0739, 2.0739], 95% CI [–2.2414, 1.2849], p = 0.579); diastolic blood pressure (DBP) (T = –1.7936 [–2.0739, 2.0739], 95% CI [–2.3437, 0.1698], p = 0.087); Chernov questionnaire (T = 1.5071 [–2.0739, 2.0739], 95% CI [–0.6083, 3.8431], p = 0.146); Kérdö index (T = 0.9392 [–2.0739, 2.0739], 95% CI [–1.1083, 2.9431], p = 0.358); in subgroup 2A: ACR (T = –2.0147 [–2.0796, 2.0796], 95% CI [–39.1946, 0.6219], p = 0.057); in subgroup 2B: ACR (T = –1.3328 [–2.0739, 2.0739], 95% CI [–17.4695, 3.7999], p = 0.196). The Pearson correlation results showed that in subgroup 1A, there is a significant average positive relationship between uUmod and eGFR (r(21) = 0.418, p = 0.047); a significant very small negative relationship between uUmod indicators and age (r(21) = 0.438, p = 0.037); in subgroup 1B, there is a significant large positive relationship between uUmod and Hb indicators (r(21) = 0.513, p = 0.012); a significant positive relationship between uUmod and Morisky Medication Adherence Scale-8 (MMAS-8) indicators (r(21) = 0.515, p = 0.012); a significant very small negative relationship between uUmod and ACR indicators (r(21) = 0.441, p = 0.035); in subgroup 2A, there is a significant very small negative relationship between uUmod indicators and Kérdö index (r(20) = 0.427, p = 0.048); in subgroup 2B, there is a significant very small negative relationship between the uUmod indicators and Chernov questionnaire score (r(21) = 0.421, p = 0.045); a significant very small negative relationship between uUmod indicators and Charlson Comorbidity Index (r(21) = 0.481, p = 0.020); a significant very small negative relationship between uUmod and age (r(21) = 0.471, p = 0.023). In subgroup 1A at the end of the study, the following independent variables are not significant as predictors for uUmod: IRd, IRs, SBP, DBP, Hb, ACR, age, Vein and Chernov questionnaires score, MMAS-8, Charlson Comorbidity Index and Kérdö index. In subgroup 1B at the end of the study, the following independent variables are not significant as predictors for uUmod: eGFR, IRs, SBP, DBP, Hb, Vein and Chernov questionnaires score, MMAS-8, Charlson Comorbidity Index and Kérdö index. In subgroup 2A at the end of the study, the following independent variables are not significant as predictors for uUmod: eGFR, IRd, IRs, SBP, DBP, Hb, ACR, age, Vein questionnaire score, MMAS-8, Charlson Comorbidity Index. In subgroup 2B at the end of the study, the following independent variables are not significant as predictors for uUmod: eGFR, IRd, IRs, SBP, DBP, Hb, ACR, age, Vein questionnaire score, ­MMAS-8, Kérdö index. Conclusions. Antioxidant therapy with glutathione and ubiquinone significantly affects the examination parameters of patients with CKD. Considering the safety and effectiveness of antioxidant therapy, we suggest including antioxidant therapy into the treatment protocols for patients with CKD. Further research is recommended to establish a standard protocol.

Background: Uromodulin is the most abundant protein in the urine of healthy adults, and higher urine concentrations mark better tubular health. Greater kidney size and function are predictors of higher uromodulin levels in adults. Urine uromodulin has not yet been studied in children with chronic kidney disease (CKD). Thus, we sought to determine the relationship between age and kidney function with urine uromodulin levels in children with CKD. Methods: In the CKD in Children (CKiD) cohort, we utilized multivariable linear regression to evaluate the relationship of age and eGFR with urine uromodulin levels. The primary outcome was uromodulin indexed to urine creatinine (Umod/Cr, mg/g), which was log2-transformed given its skewed distribution. Results: Among 677 CKiD participants, the median age was 11.8 years (8.2–15.3), the median eGFR was 49 ml/min/1.73 m2 (37–63), the etiology of CKD was glomerular disease in 31%, and the median Umod/Cr level was 0.114 mg/g (0.045–0.226). In the multivariable models, each one-year older age was associated with 0.18 (12%) lower log2(Umod/Cr) and 0.20 (13%) lower log2(Umod/Cr) among those with non-glomerular and glomerular disease, respectively (p < 0.001). However, we did not find a statistically significant association between eGFR and Umod/Cr in either participants with non-glomerular or glomerular disease (p = 0.13 and p = 0.58, respectively). Conclusions: Among children with CKD, older age is significantly associated with lower Umod/Cr, independent of eGFR. Further studies are needed to comprehensively evaluate age-specific reference ranges for urine uromodulin and to evaluate the longitudinal relationship of uromodulin with both age and eGFR in children with CKD. [ABSTRACT FROM AUTHOR]

Tamm–Horsfall protein (THP) is a highly N-glycosylated protein from epithelial cells of the ascending limb of Henle loop. It is secreted into the urine as part of the innate immune response against uropathogenic pathogens. As women are more likely to suffer from urinary tract infections, biomedical studies were conducted to investigate sex-differences in THP excretion, as well as differences in the THP N-glycosylation pattern. A total of 238 volunteers (92 men, 146 women, 69 with hormonal contraceptives) participated in this study, providing urine samples. Women showed a clear tendency to have higher THP concentration and excretion rates than men (p < 0.16). Regular intake of hormonal contraceptives had no significant influence on urinary THP concentration compared to no regular intake. The individual N-glycosylation pattern of THP in urine samples from randomly selected individuals (10 female, 10 male) was investigated after enzymatic release and MS analysis of the oligosaccharides. Female subjects tended to have an increased proportion of oligomannose type N-glycans and non-fucosylated glycans, whereas men had an increased proportion of fucosylated complex-type glycans. The higher level of oligomannose-type glycans in THP from women might be explained by a self-defence mechanism to overcome the higher infections pressure by the female anatomical properties. [ABSTRACT FROM AUTHOR]

Uromodulin (Umod, Tamm–Horsfall protein) is the most abundant urinary N-glycoprotein produced exclusively by the kidney. It can form filaments to antagonize the adhesion of uropathogens. However, the site-specific N-glycosylation signatures of Umod in healthy individuals and patients with IgA nephropathy (IgAN) remain poorly understood due to the lack of suitable isolation and analytical methods. In this study, we first presented a simple and fast method based on diatomaceous earth adsorption to isolate Umod. These isolated glycoproteins were digested by trypsin and/or Glu-C. Intact N-glycopeptides with or without HILIC enrichment were analyzed using our developed EThcD-sceHCD-MS/MS. Based on the optimized workflow, we identified a total of 780 unique intact N-glycopeptides (7 N-glycosites and 152 N-glycan compositions) from healthy individuals. As anticipated, these glycosites exhibited glycoform heterogeneity. Almost all N-glycosites were modified completely by the complex type, except for one N-glycosite (N275), which was nearly entirely occupied by the high-mannose type for mediating Umod's antiadhesive activity. Then, we compared the N-glycosylation of Umod between healthy controls (n = 9) and IgAN patients (n = 9). The N-glycosylation of Umod in IgAN patients will drastically decrease and be lost. Finally, we profiled the most comprehensive site-specific N-glycosylation map of Umod and revealed its alterations in IgAN patients. Our method provides a high-throughput workflow for characterizing the N-glycosylation of Umod, which can aid in understanding its roles in physiology and pathology, as well as serving as a potential diagnostic tool for evolution of renal tubular function. [ABSTRACT FROM AUTHOR]

Uromodulin, also known as Tamm-Horsfall protein, represents the predominant urinary protein in healthy individuals. Over the years, studies have revealed compelling associations between urinary and serum concentrations of uromodulin and various parameters, encompassing kidney function, graft survival, cardiovascular disease, glucose metabolism, and overall mortality. Consequently, there has been a growing interest in uromodulin as a novel and effective biomarker with potential applications in diverse clinical settings. Reduced urinary uromodulin levels have been linked to an elevated risk of acute kidney injury (AKI) following cardiac surgery. In the context of chronic kidney disease (CKD) of different etiologies, urinary uromodulin levels tend to decrease significantly and are strongly correlated with variations in estimated glomerular filtration rate. The presence of uromodulin in the serum, attributable to basolateral epithelial cell leakage in the thick ascending limb, has been observed. This serum uromodulin level is closely associated with kidney function and histological severity, suggesting its potential as a biomarker capable of reflecting disease severity across a spectrum of kidney disorders. The UMOD gene has emerged as a prominent locus linked to kidney function parameters and CKD risk within the general population. Extensive research in multiple disciplines has underscored the biological significance of the top UMOD gene variants, which have also been associated with hypertension and kidney stones, thus highlighting the diverse and significant impact of uromodulin on kidney-related conditions. UMOD gene mutations are implicated in uromodulin-associated kidney disease, while polymorphisms in the UMOD gene show a significant association with CKD. In conclusion, uromodulin holds great promise as an informative biomarker, providing valuable insights into kidney function and disease progression in various clinical scenarios. The identification of UMOD gene variants further strengthens its relevance as a potential target for better understanding kidney-related pathologies and devising novel therapeutic strategies. Future investigations into the roles of uromodulin and regulatory mechanisms are likely to yield even more profound implications for kidney disease diagnosis, risk assessment, and management. [ABSTRACT FROM AUTHOR]

BackgroundUromodulin modulates the sodium-potassium-two-chloride transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. We hypothesized that individuals with higher baseline levels of urine uromodulin would have a greater increase in systolic blood pressure (SBP) for the same increase in sodium compared with those with lower uromodulin levels.MethodsWe used data from 157 subjects randomized to the control diet of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial who were assigned to 30 days of low (1,500 mg/d), medium (2,400 mg/d), and high salt (3,300 mg/d) diets in random order. Blood pressure was measured prerandomization and then weekly during each feeding period. We evaluated the association of prerandomization urine uromodulin with change in SBP between diets, as measured at the end of each feeding period, using multivariable linear regression.ResultsBaseline urine uromodulin stratified by tertiles was ≤17.64, 17.65-31.97, and ≥31.98 µg/ml. Across the tertiles, there were no significant differences in SBP at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high, P = 0.81). After adjusting for age, sex, body mass index, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (P = 0.42).ConclusionsIn a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake.

A study published in Acta Physiologica investigates the therapeutic value of elevated fluid intake for the risk of ascending to pyelonephritis in urinary tract infection (UTI) using a mouse model. UTI is a common bacterial infection that affects women more frequently than men, with significant costs to healthcare systems. While increased fluid intake is recommended for preventing recurrent UTI, it is unclear if it reduces the risk of pyelonephritis once cystitis is established. The study found that increasing fluid intake actually augmented the occurrence and severity of pyelonephritis in the mouse model. Further research is needed to determine the transferability of these findings to humans and to evaluate the impact of various factors on fluid therapy in UTI. [Extracted from the article]

Several biophysical techniques were used to study the uromodulin isoforms in experimental models of the urine (ionic composition, osmolality, and pH) in the presence of intact uromodulin and its isoforms isolated from patients with urolithiasis. A prototype medical device for screening persons with preclinical urolithiasis was tested. A concept of targeted therapy of urolithiasis by modulating the uromodulin properties was advanced. [ABSTRACT FROM AUTHOR]

BackgroundUromodulin (UMOD) is released by renal tubular cells into the serum (sUMOD) and urine. Lower urine UMOD has been linked to mortality and cardiovascular disease but much less is known about sUMOD. We evaluated the association of sUMOD with these outcomes in community-dwelling older adults.MethodsWe measured sUMOD in a random subcohort of 933 participants enrolled in the Cardiovascular Health Study. The associations of sUMOD with all-cause mortality, incident heart failure (HF) and incident cardiovascular disease (CVD; myocardial infarction, stroke and mortality due to coronary disease or stroke) were evaluated using multivariable Cox regression, adjusting for study participants' demographics, estimated glomerular filtration rate (eGFR), albuminuria and CVD risk factors. Generalized additive models with splines were used to address the functional form of sUMOD with outcomes. Due to nonlinear associations of sUMOD with all outcomes, 2.5% of the values on either end of the sUMOD distribution were excluded from the analyses, limiting the range of sUMOD to 34.3-267.1 ng/mL.ResultsThe mean age was 78 ± 5 years, 40% were male, sUMOD level was 127 ± 64 ng/mL, eGFR was 63 mL/min/1.73 m2 and 42% had CKD defined as eGFR

Uromodulin is released into serum (sUMOD) and urine (uUMOD) exclusively by renal tubular cells. Both sUMOD and uUMOD are correlated with estimated glomerular filtration rate (eGFR), and associated with mortality and cardiovascular disease (CVD). However, no study to our knowledge has measured both sUMOD and uUMOD in the same population, thus the relationship of sUMOD with uUMOD with one another, and their respective correlates have not been evaluated simultaneously. We evaluated the correlations of sUMOD, uUMOD with eGFR in a random sub-cohort (n = 933) of the Cardiovascular Health Study and their associations with demographic and laboratory parameters and CVD risk factors using multi-variable linear regression analysis. The mean age of the cohort was 78 years, 40% were male and 15% were Black. The mean sUMOD level was 127 ng/mL, uUMOD was 30 500 ng/mL and eGFR was 63 mL/min/1.73 m2 . Correlation between sUMOD and uUMOD, adjusted for eGFR was moderate (r = 0.27 [95% confidence interval = 0.21-0.33]). The correlation of eGFR with sUMOD (r = 0.44 [0.39-0.49]) was stronger than with uUMOD (r = 0.21 [0.15-0.27]). In multi-variable analysis adjusting sUMOD for uUMOD and vice versa, sUMOD was independently associated with eGFR (β = 1.3 [1.1-1.6]), log2 C-reactive protein (β = -4.2 [-6.8 to -1.6]) and male sex (β = -13.6 [-22.7 to -4.5]). In contrast, male sex was associated with higher uUMOD (β = 3700 [400-7000]), while diabetes (β = -6400 [-10 600 to -2100]) and hypertension (-4300 [-7500 to -1100]) were associated with lower uUMOD levels. We conclude that sUMOD is more strongly associated with eGFR compared with uUMOD. Correlates of sUMOD and uUMOD differ substantially, suggesting that apical and basolateral secretion may be differentially regulated.

Biology has taught us that a protein as abundantly made and conserved among species as Tamm-Horsfall protein (THP or uromodulin) cannot just be a waste product serving no particular purpose. However, for many researchers, THP is merely a nuisance during urine proteome profiling or exosome purification and for clinicians an enigmatic entity without clear disease implications. Thanks to recent human genetic and correlative studies and animal modeling, we now have a renewed appreciation of this highly prevalent protein in not only guarding urinary homeostasis, but also serving as a critical mediator in systemic inter-organ signaling. Beyond a mere barrier that lines the tubules, or a surrogate for nephron mass, mounting evidence suggests that THP is a multifunctional protein critical for modulating renal ion channel activity, salt/water balance, renal and systemic inflammatory response, intertubular communication, mineral crystallization and bacterial adhesion. Indeed, mutations in THP cause a group of inherited kidney diseases, and altered THP expression is associated with increased risks of urinary tract infection, kidney stone, hypertension, hyperuricemia and acute and chronic kidney diseases. Despite the recent surge of information surrounding THP's physiological functions and disease involvement, our knowledge remains incomplete regarding how THP is normally regulated by external and intrinsic factors, how precisely THP deficiency leads to urinary and systemic pathophysiology and in what clinical settings THP can be used as a theranostic biomarker and a target for modulation to improve patient outcomes.

BackgroundKidney tubular atrophy on biopsy is a strong predictor of chronic kidney disease (CKD) progression, but tubular health is poorly quantified by traditional measures including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of impaired tubule function would be associated with faster eGFR declines in persons with CKD.MethodsWe measured baseline urine concentrations of uromodulin, β2-microglobulin (β2m), and α1-microglobulin (α1m) among 2,428 participants of the Systolic Blood Pressure Intervention Trial with an eGFR

Although changes in dietary sodium intake alter blood pressure (BP) in salt-sensitive individuals, pathophysiological mechanisms are still unknown. It has been reported that uromodulin is involved in sodium tubular transport, and genome-wide association studies pointed to UMOD gene as one of the most important gene candidates for arterial hypertension. Our aim was to analyze urinary uromodulin, salt intake and BP in 326 young middle-aged subjects (mean age 36±8 years, 49.4% male). In a subgroup of 175 individuals, ambulatory blood pressure monitoring and echocardiogram were performed. Uromodulin was determined by ELISA. According to the JNC-7 criteria, subjects were classified as optimal BP (n=103, men 72%), prehypertension (PHT) (n=143, men 43%) and hypertension (HT) (n= 80, men 38%). There were no differences in age, salt intake, estimated glomerular filtration rate, sodium excretion and uromodulin among BP groups. However, in PHT subjects, uromodulin was positively associated with fractional sodium excretion and negatively with 24-h sodium excretion and diastolic BP dip. These findings point to the effect of uromodulin on sodium reabsorption along the nephron and consequently circadian BP alteration in prehypertensives.

Uromodulin is a unique protein produced in the kidneys by epithelial cells of the ascending thick portion of the loop of Henle. It implements physiological mechanisms not only at the tubular level, but also participates in the coordination of general body processes. The main functions of uromodulin are an obstacle to prevent stone formation due to a violation of the aggregation of calcium salts and water reabsorption, coordination of electrolyte balance, and an obstacle to inflammatory processes locally and systemically. Moreover, the expression of uromodulin and its qualitative characteristics are under genetic control. In this regard, the pathology of the tubular apparatus or mutations in the genes encoding uromodulin lead to the development of primary or secondary tubulopathies with dysfunction of other organs and systems. At the same time, it is known that uromodulin is an incompletely studied protein both in terms of structure and features of the functions it performs. A thorough analysis of research data, including experimental work on the study of uromodulin in domestic and international literature sources, was carried out, with a presentation of the material in this manuscript.