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Rationale & Objective: Uromodulin (UMOD) is the most abundant protein found in urine and has emerged as a promising biomarker of tubule health. Circulating UMOD is also detectable, but at lower levels. We evaluated whether serum UMOD levels were associated with the risks of incident kidney failure with replacement therapy (KFRT) and mortality., Study Design: Prospective cohort., Setting & Participants: Participants in AASK (the African American Study of Kidney Disease and Hypertension) with available stored serum samples from the 0-, 12-, and 24-month visits for biomarker measurement., Predictors: Baseline log-transformed UMOD and change in UMOD over 2 years., Outcomes: KFRT and mortality., Analytical Approach: Cox proportional hazards and mixed-effects models., Results: Among 500 participants with baseline serum UMOD levels (mean age, 54y; 37% female), 161 KFRT events occurred during a median of 8.5 years. After adjusting for baseline demographic factors, clinical factors, glomerular filtration rate, log-transformed urine protein-creatinine ratio, and randomized treatment groups, a 50% lower baseline UMOD level was independently associated with a 35% higher risk of KFRT (adjusted HR, 1.35; 95% CI, 1.07-1.70). For annual UMOD change, each 1-standard deviation lower change was associated with a 67% higher risk of KFRT (adjusted HR, 1.67; 95% CI, 1.41-1.99). Baseline UMOD and UMOD change were not associated with mortality. UMOD levels declined more steeply for metoprolol versus ramipril (P<0.001) as well as for intensive versus standard blood pressure goals (P = 0.002)., Limitations: Small sample size and limited generalizability., Conclusions: Lower UMOD levels at baseline and steeper declines in UMOD over time were associated with a higher risk of subsequent KFRT in a cohort of African American adults with chronic kidney disease and hypertension., Plain-Language Summary: Prior studies of uromodulin (UMOD), the most abundant protein in urine, and kidney disease have focused primarily on urinary UMOD levels. The present study evaluated associations of serum UMOD levels with the risks of kidney failure with replacement therapy (KFRT) and mortality in a cohort of African American adults with hypertension and chronic kidney disease. It found that participants with lower levels of UMOD at baseline were more likely to experience KFRT even after accounting for baseline kidney measures. Similarly, participants who experienced steeper annual declines in UMOD also had a heightened risk of kidney failure. Neither baseline nor annual change in UMOD was associated with mortality. Serum UMOD is a promising biomarker of kidney health., (Published by Elsevier Inc.)

Background: Uromodulin (UMOD), also known as Tamm-Horsfall protein, is a kidney-specific protein expressed by epithelial cells lining the thick ascending limb of the loop of Henle. In the current study, we aimed to clarify the clinical significance of UMOD in ANCA-associated glomerulonephritis (AAG). Materials and methods: Sixty-one biopsy-proven AAG patients were included in this study. UMOD was measured using ELISA. The relationships between serum UMOD (sUMOD) levels and various clinicopathological findings were evaluated. Results: AAG was classified into four categories (focal, crescentic, mixed, and sclerotic). In addition, tubulointerstitial lesions were classified as mild, moderate, and severe. The levels of sUMOD and urinary UMOD (uUMOD) were correlated with each other. A negative correlation between sUMOD levels and serum Cr levels, and positive correlation between sUMOD levels and eGFR were found. Patients in the high sUMOD group were associated with low serum Cr levels, focal classification, and mild tubulointerstitial injury compared to the low sUMOD group. Comparing the characteristics among histopathological classes, patients in the focal class had the best renal function and the highest levels of uUMOD/Cr and sUMOD. The focal class had significantly better renal survival compared with the severe histopathological classes (crescentic, mixed, and sclerotic). In univariate logistic regression analyses, prognostic factors for severe histopathological classes were low uUMOD/Cr, high serum Cr, and low sUMOD. Multivariate analyses revealed that low sUMOD predicted severe histopathological classes independent of serum Cr. The mean levels of sUMOD were significantly different between the focal class and severe histopathological classes, with a sensitivity of 70.6% and specificity of 90.0% (cut-off 143 ng/ml, AUC 0.80) by ROC curves. Conclusion: Low sUMOD levels were associated with severe clinicopathological findings and might be considered as a risk factor for end stage renal disease in AAG. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a common complication in hospitalized patients with cirrhosis. Uromodulin, a protein uniquely produced by the kidney and released both in the urine and circulation, has been shown to regulate AKI and is linked to tubular reserve. Although low levels of urine uromodulin are associated with AKI after cardiac surgery, it is unclear whether circulating uromodulin can stratify the risk of AKI, particularly in a susceptible population such as hospitalized patients with cirrhosis. Thus, we investigated whether plasma uromodulin measured at the time of admission is associated with subsequent hospital-acquired AKI (defined by a rise in serum creatinine >0.3mg/dL within 48 h or ≥ 1.5 times baseline) in patients with cirrhosis. A total of 98 patients [mean age 54 yr, Model for Endstage Liver Disease Sodium (MELD-Na) score 19, and baseline creatinine of 0.95 mg/dL] were included, of which 13% (n = 13) developed AKI. Median uromodulin levels were significantly lower in patients who developed AKI compared with patients who did not (9.30 vs. 13.35 ng/mL, P = 0.02). After adjusting for age, sex, diabetes, hypertension, albumin, and MELD-Na score as covariates on multivariable logistic regression, uromodulin was independently associated with AKI [odd ratios of 1.19 (95% confidence interval 1.02, 1.37; P = 0.02)]. Lower uromodulin levels on admission are associated with increased odds of subsequent AKI in hospitalized patients with cirrhosis. Further studies are needed to better understand the role of uromodulin in the pathogenesis and as a predictive biomarker of AKI in this population. NEW & NOTEWORTHY In this study, we found that admission plasma uromodulin levels are significantly lower in patients who developed subsequent acute kidney injury (AKI) during their hospital stay compared with patients who did not. Additionally, uromodulin is independently associated with AKI development after adjusting for clinically relevant parameters such as age, sex, diabetes, hypertension, severity of cirrhosis, and kidney function. To our knowledge, this is the first study linking plasma uromodulin with AKI development in patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Human urinary extracellular vesicles (uEVs) contain proteins from all nephron segments. An assumption for years has been that uEVs might provide a noninvasive liquid biopsy that reflect physiological regulation of transporter protein expression in humans. We hypothesized that protein abundance in human kidney tissue and uEVs are directly related and tested this in paired collections of nephrectomy tissue and urine sample from 12 patients. Kidney tissue was fractioned into total kidney protein, crude membrane (plasma membrane and large intracellular vesicles)-enriched, and intracellular vesicle-enriched fractions as well as sections for immunolabeling. uEVs were isolated from spot urine samples. Antibodies were used to quantify six segment-specific proteins [proximal tubule-expressed Na+-phosphate cotransporters (NaPi-2a), thick ascending limb-expressed Tamm-Horsfall protein and renal outer medullary K+ channels, distal convoluted tubule-expressed NaCl cotransporters, intercalated cell-expressed V-type H+-ATPase subunit G3 (ATP6V1G3), and principal cell-expressed aquaporin 2] and three uEV markers (exosomal CD63, microvesicle marker vesicle-associated membrane protein 3, and β-actin) in each fraction. By Western blot analysis and immunofluorescence labeling, we found significant positive correlations between the abundance of CD63, NaCl cotransporters, aquaporin 2, and ATP6V1G3, respectively, within the different kidney-derived fractions. We detected all nine proteins in uEVs, but their level did not correlate with kidney tissue protein abundance. uEV protein levels showed higher interpatient variability than kidneyderived fractions, indicating that factors, besides kidney protein abundance, contribute to the uEV protein level. Our data suggest that, in a random sample of nephrectomy patients, uEV protein level is not a predictor of kidney protein abundance. [ABSTRACT FROM AUTHOR]

Hypertension disease characterize an intense health issue for improving countries. grant to the studies of the world health organization (WHO), that about 40% of adults Iraqi suffered from hypertension. Some causes of infrequent monogenic lead to hypertension, but the predominance of hypertension is likely to be multifactorial disorder, due to interference of environmental and genetic factors. Outcome of PCR-SSCP for uromodulin promoter gene illustrated that two several haplotypes confer to the numbers of the bands in the uromodulin promoter gene containing bands 4 and 5. But, these haplotype was reveal among two groups; in hypertension patient groups and control, results appear that was related among bands4 and 5 in patients as contrast with group control. [ABSTRACT FROM AUTHOR]

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Objective: Recent studies have reported that reduced excretion of urinary uromodulin is associated with renal tubular function and risks of progressive kidney disease. Gouty nephropathy is usually seen in patients with gout. Patients with chronic gouty nephropathy are characterized by the deposition of monosodium urate crystals primarily involving the collecting ducts in the medulla. We postulated that this correlation may be specific to gout and may serve as a useful biomarker for chronic kidney disease (CKD).Materials and Methods: A total of 114 Taiwanese patients diagnosed with gout (n = 72), CKD (n = 26), or healthy volunteers (n = 16) were prospectively enrolled for this study from the Rheumatology and Nephrology Outpatient Clinics of our institution. We obtained urine and blood samples on patient visits to the outpatient clinics. Demographic data were obtained from medical records.Results: In patients with gout, the spot urinary uromodulin/creatinine ratio (uUMCR; mg/g) in patients with CKD was significantly lower than that in those without CKD (CKD group: 2.2; non-CKD group: 5.6, p = 0.005). Multivariate analysis revealed that patients with CKD and gout had a lower uUMCR than those with gout alone (p = 0.028). A significant association was not observed in our non-gout cohort.Conclusion: The association of decreased uUMCR with CKD status was identified only in patients with gout in the present study. We believe that uUMCR might serve as an indicator of differential CKD in patients with gout. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the correlation between uromodulin (THP) protein levels in serum and in urine with albuminuria and other renal function biomarkers in patients with type-2 diabetes mellitus. A case-control study design was employed to enroll 120 subjects, where 30 diabetic patients with normo-albuminuria (as first case group), 30 diabetic patients with microalbuminuria (as second case group), 30 diabetic patients with macroalbuminuria (as third case group) as well as 30 healthy subjects (as control group). Blood and urine samples were collected from the patients during their visits to diabetic clinics. Age, gender and BMI were assessed for each participant. Serum and urine uromodulin level were measured by ELISA technique, fasting serum glucose, serum creatinine and blood urea were measured by spectrophotometer, serum cystatin-c by ELISA technique, HbA1c measured by the CLOVER A1c system, urinary albumin was measured by turbidimetric end-point method, urinary uromodulin creatinine ratio (uromodulin index) and urinary albumin creatinine ratio (UACR) were estimated. Also, eGFR was calculated. The results show that the serum uromodulin was significantly and inversely correlated with FSG, also with HbA1c. A uromodulin indexwas significantly decline in macroalbuminuria group as compared with control group, also a uromodulin index was significantly decline in macroalbuminuria group as compared with normal bumiuria group. Uromodulin (Tamm-Horsful protein), which was specifically secreted from kidney, may considered as a marker changed in parallel with the change in renal function in patients with type-2 diabetic patients. [ABSTRACT FROM AUTHOR]

Uromodulin-related autosomal-dominant tubulointerstitial kidney disease (ADTKD-UMOD) is a rare monogenic disorder that is characterized by tubulointerstitial fibrosis and progression of kidney function loss, and may progress to end-stage renal disease. It is usually accompanied by hyperuricaemia and gout. Mutations in the uromodulin gene (UMOD) resulting in malfunctioning of UMOD are known to be the cause of ADTKD-UMOD, which is assumed to be an endoplasmatic reticulum (ER) storage disease. As a case vignette, we report a 29-year-old female with a suspicious family history of chronic kidney disease presenting with progressive loss of renal function, hyperuricaemia and frequent urinary tract infections. Urinary tract infections and pyelonephritides may represent a clinical feature of uromodulin malfunction as it plays a protective role against urinary tract infections despite only sporadic data on this topic. ADTKD-UMOD was diagnosed after genetic testing revealing a missense mutation in the UMOD gene. Light microscopy showed excessive tubular interstitial fibrosis and tubular atrophy together with signs of glomerular sclerosis. Electron microscopic findings could identify electron dense storage deposits in the ER of tubular epithelial cells of the thick ascending loop. Immunohistological staining with KDEL (lysine, aspartic acid, glutamic acid, leucine) showed positivity in the tubular cells, which likely represents ER expansion upon accumulation of misfolded UMOD which could trigger the unfolded protein response and ER stress. This review highlights pathophysiological mechanisms that are subject to ADTKD-UMOD. [ABSTRACT FROM AUTHOR]

BACKGROUND The mechanism explaining the inverse association between renal urate and albumin excretion remains unclear. First, we evaluated the impact of candidate variants in the main urate transporter genes (i.e. SLC2A9, SLC22A12, ABCG2) on the association between fractional excretion of uric acid (FEUA) and urinary albumin/creatinine ratio (uACR). Second, we examined uromodulin and sodium excretion as mediators of the association between FEUA and uACR. METHODS We performed cross-sectional analysis of 737 French Canadians from the CARTaGENE cohort, a random sample of the Quebec population aged 40–69 years (a total of 20,004 individuals). Individuals with available genotyping and urinary data were obtained from a sub-study including gender-matched pairs with high and low Framingham Risk Score and vascular rigidity index. We further excluded individuals with an estimated glomerular filtration rate <60 ml/min/1.73 m2, glycosuria, and use of confounding medication. A spot urine sample was analyzed. Genotyping was performed using the Illumina Omni2.5–8 BeadChips. Genetic variants were analyzed using an additive model. RESULTS Final analyses included 593 individuals (45.5% of men; mean age 54.3 ± 8.6). We observed an antagonistic interaction between rs13129697 variant of the SLC2A9 gene and FEUA tertiles on uACR (P = 0.002). Using the mediation analysis, uromodulin explained 32%, fractional excretion of sodium (FENa) 44%, and uromodulin together with FENa explained 70% of the inverse relationship between FEUA and uACR. Bootstrapping process confirmed the role of both mediators. CONCLUSIONS Our data suggest that the association of albuminuria with decreased renal urate excretion may be modified by the transporter SLC2A9, and mediated by uromodulin and sodium handling. [ABSTRACT FROM AUTHOR]

Aim: Serum uromodulin (sURO) was recently found as a sensitive tubular marker in early chronic kidney disease stages. Thus far, mainly early uromodulin urinary excretion was tested in kidney recipients. The aim of our study was to conduct a long-lastinlong-term assessment of sURO in kidney graft function monitoring. Material/Methods: Forty-one stable kidney recipients (aged 47 (13.7)) were studied around the 3rd month (3m) and the 2nd year (2y) after kidney transplantation. Sera were tested for sURO, creatinine and tacrolimus levels. Kidney biopsy was scored according to revised Banff 97 classification. Results: sURO level (mean 66.06ng/ml at 3m; 77.81 at 2y) increased borderline significantly (P = 0.051) in time and significantly correlated with eGFR (3m RS = 0.46; 2y RS = 0.58), creatinine levels (RS respectively -0.55 and -0.56) and donor age (3m Rs = -0.33; 2y RS = -0.41). We observed borderline correlations between sURO and Banff biopsy scoring: 3m-sURO with arteriolar hyalinosis-ah (RS = -0.3, P = 0.06) and 2y-sURO with peritubular capillaritis-ptc (RS = 0.45, P = 0.07). Correlations of sURO with 3m tacrolimus levels (Rs = 0.3, P = 0.08) were borderline, however patients with CNI toxicity lesions in biopsy had sURO significantly lower (mean 3m-sURO 52.7 vs 83.1 ng/ml; 2y-sURO 61.9 vs 98.1 ng/ml). Conclusions: sURO can reflect kidney graft quality and function. sURO correlated with ptc, which is considered to be an early marker of a chronic antibody-mediated graft injury. Tacrolimus doesn't influence sURO levels directly, but sURO is lower in patients with toxic kidney injury in biopsy. sURO can reflect kidney graft quality and function. sURO correlated with ptc, which is considered to be an early marker of a chronic antibody-mediated graft injury. Tacrolimus doesn't influence sURO levels directly, but sURO is lower in patients with toxic kidney injury in biopsy. [ABSTRACT FROM AUTHOR]

BACKGROUND Uromodulin 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. METHODS We 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. RESULTS Baseline 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). CONCLUSIONS In 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. [ABSTRACT FROM AUTHOR]

Uromodulin and microRNAs (miRNAs) have recently been investigated as potential biomarkers for kidney graft associated pathology and outcome, with a special focus on biomarkers indicating specific disease processes and kidney graft survival. The study’s aim was to determine whether expression of serum uromodulin concentration and selected miRNAs might be related to renal function in kidney transplant recipients (KTRs). The uromodulin concentration and expression of six selected miRNAs (miR-29c, miR-126, miR-146a, miR-150, miR-155, and miR-223) were determined in the serum of 100 KTRs with stable graft function and chronic kidney disease of all five stages. Kidney graft function was estimated with routine parameters (creatinine, urea, cystatin C, and Chronic Kidney Disease Epidemiology Collaboration study equations) and precisely measured using chromium-51 labelled ethylenediaminetetraacetic-acid clearance. The selected miRNAs were shown to be independent of kidney graft function, indicating their potential as biomarkers of associated kidney graft disease processes. In contrast, the serum uromodulin level depended entirely on kidney graft function and thus reflected functioning tubules rather than any specific kidney graft injury. However, decreased concentrations of serum uromodulin can be observed in the early course of tubulointerstitial injury, thereby suggesting its useful role as an accurate, noninvasive biomarker of early (subclinical) kidney graft injury.

Background: Transient proteinuria during febrile illness is a common phenomenon. Recent studies have re-examined the pathophysiology of proteinuria and new urinary markers to characterize it, including B7-1 (CD80), which is expressed also in glomerular podocytes and influences the glomerular barrier.Aim: To investigate the pattern of proteinuria in febrile non-renal diseases, including B7-1.Methods: We prospectively analyzed urine samples of 44 febrile children and 28 afebrile controls for different protein components: albumin (glomerular marker), β2-microglobulin (tubular marker), uromodulin (Tamm Horsfall protein-THP, a renal endogenous protein) and B7-1. Febrile illness was characterized as focal bacterial vs. viral. Exclusion criteria were underlying renal disease, steroid treatment or urinary tract infection.Results: Elevated urine albumin (64.5 ± 10.3 vs. 17.8 ± 4 mg/g, mean ± S.E.M., p = 0.0009) and β2-microglobulin (1.44 ± 0.34 vs. 0.182 ± 0.03 mg/g, mean ± S.E.M., p = 0.005] and decreased uromodulin (10.5 ± 1 vs. 26.7 ± 2.2 Arbitrary units, mean ± S.E.M., p = 0.0001) excretion were found during febrile illness vs. controls. Urine B7-1 was also increased in the febrile group (0.27 ± 0.05 vs. 0.07 ± 0.01 ng/ml, mean ± S.E.M., p = 0.001), and was the only marker which was significantly higher in bacterial vs. viral disease.Conclusions: Febrile proteinuria is not generalized: while proteins of both glomerular and tubular origin increase, uromodulin decreases. Urine B7-1 is increased during fever, more significantly in bacterial infections. Thus, urinary B7-1 may be used as an additional marker to differentiate between febrile states of bacterial vs. viral origin.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is characterized by autosomal dominant inheritance, progressive chronic kidney disease, and a bland urinary sediment. ADTKD is most commonly caused by mutations in the UMOD gene encoding uromodulin (ADTKD-UMOD). We herein report the first confirmed case of a multi-generational Brazilian family with ADTKD-UMOD, caused by a novel heterozygous mutation (c.163G>A, GGC→AGC, p.Gly55Ser) in the UMOD gene. Of 41 family members, 22 underwent genetic analysis, with 11 individuals found to have this mutation. Three affected individuals underwent hemodialysis, one peritoneal dialysis, and one patient received a kidney transplant from a family member later found to be genetically affected. Several younger individuals affected with the mutation were also identified. Clinical characteristics included a bland urinary sediment in all tested individuals and a kidney biopsy in one individual showing tubulointerstitial fibrosis. Unlike most other reported families with ADTKD-UMOD, neither gout nor hyperuricemia was found in affected individuals. In summary, we report a novel UMOD mutation in a Brazilian family with 11 affected members, and we discuss the importance of performing genetic testing in families with inherited kidney disease of unknown cause.

Keywords: albuminuria; proteinuria; urinalysis EN albuminuria proteinuria urinalysis e1 e2 2 11/28/22 20230101 NES 230101 To the Editor, With interest, we read the recent publication on estimating urinary albumin to creatinine ratio (ACR) from proteinuria to creatinine ratio (PCR) using same-day measurements [[1]]. In conclusion, care should be taken when estimating albuminuria out of proteinuria data, in particular in the case of low-range proteinuria or in patients presenting with Bence Jones proteinuria. When using economic arguments to avoid testing for albuminuria (proteinuria tests are less expensive than immunochemical albuminuria tests), it should be noted that quantitative albuminuria can be achieved using inexpensive common urine test strips in conjunction with a sensitive urine test reader [[8]]. [Extracted from the article]

The article presents several researches that were published in different periodicals on topics including the role of uromodulin in flushing out bacteria; and calibrating mitochondrial DNA (mtDNA) mutations through age. It mentions T follicular helper (TFH) cells are CD4+ T cells that facilitate B cell antibody production and B cell memory responses in germinal centers of lymphoid organs; and diagnosing cancer with body's immune response.

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 log 2 -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 m 2 (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 log 2 (Umod/Cr) and 0.20 (13%) lower log 2 (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. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

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.

Graphical abstract Highlights • For urine peptidomics, the individucal difference of healthy samples maybe very huge. • The results of peptidomics were more stable at protein ranther than peptides level. • Much inter-individual urine peptidome variance appears to be inevitable and not indicative of any abnormality. • The urine peptidome should be divided into physiology-related and disease-related components. Abstract Biomarkers are routinely discovered by comparing the signal intensity of mixture samples from healthy and disease, which defaults to the most obvious difference between the two groups are associated with the disease. Actually, there also may be huge differences among healthy individual samples, so elucidation of individual differences of healthy samples can help to determine the screening criteria for biomarkers. The urine sample of a 12 healthy people and 3 mixed urine samples were analyzed by using nano-liquid chromatography-high-resolution tandem mass spectrometry. The number of identified peptides and proteins as well as peptide sequence was compared to explore the compositional features and inter-individual differences in the urine peptidome. The numbers of peptides detected ranged from 80 to 1715 per sample, with the number of proteins of origin ranging from 18 to 146. Despite this very large variance, some peptides were detected in all 15 samples, includes peptides from uromodulin, hemoglobin, fibrinogen, and collagen alpha-2(I) chain. We have found that the results of peptidomics were more stable at protein level, peptides from proteins such as uromodulin, hemoglobin and fibrinogen were detected with high frequency and huge difference of signal intensity in urine of health person, which suggested that selecting these peptides as disease biomarkers may be compromised by insufficient specificity. [ABSTRACT FROM AUTHOR]

Previously, our comprehensive cardiovascular characterization study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesized at the thick ascending limb of the loop of Henle and is encoded by the Umod gene. Umod−/− mice have significantly lower blood pressure than Umod+/+ mice, are resistant to salt-induced changes in blood pressure, and show a leftward shift in pressure-natriuresis curves reflecting changes of sodium reabsorption. Salt stress triggers transcription factors and genes that alter renal sodium reabsorption. To date there are no studies on renal transcriptome responses to salt stress. Here we aimed use RNA-Seq to delineate salt stress pathways in tubules isolated from Umod+/+ mice (a model of sodium retention) and Umod−/− mice (a model of sodium depletion) ± 300 mosmol sodium chloride (n = 3 per group). In response to salt stress, the tubules of Umod+/+ mice displayed an upregulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, P = 2.48 e−12) and Hspa1b (Log2 fold change 4.05, P = 2.48 e−12). This response was absent in tubules of Umod−/− mice. Interestingly, seven of the genes discordantly expressed in the Umod−/− tubules were electrolyte transporters. Our results are the first to show that salt stress in renal tubules alters the transcriptome, increasing the expression of heat shock genes. This direction of effect in Umod+/+ tubules suggest the difference is due to the presence of Umod facilitating greater sodium entry into the tubule cell reflecting a specific response to salt stress. [ABSTRACT FROM AUTHOR]

Cell-culture methods that simplify the inherent complexities of the kidney have not sufficiently reproduced its true characteristics. Although reports indicate that organoid methodology surpasses traditional cell culture in terms of reproducing the nature of organs, the study of human kidney organoids have been confined to pluripotent stem cells. Furthermore, it has not yet progressed beyond the developmental state of embryonic kidney even after complicate additional differentiation processes. We here describe the kidney organotypic culture method that uses adult whole kidney tissues but mainly differentiates into tubular cells. This model was validated based on the retention of key kidney organotypic-specific features: 1) expression of Tamm-Horsfall protein; 2) dome-like organoid configurations, implying directed transport of solutes and water influx; and 3) organoid expression of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in response to nephrotoxic injury (i.e., gentamicin and cisplatin exposure). This 3D-structured organoid prototype of the human renal tubule may have applications in developing patient-specific treatments for kidney diseases. [ABSTRACT FROM AUTHOR]

Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. Umod-knockout (Umod-/-) mice excreted more urinary magnesium thanWTmice and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in theUmod-/- mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical Trpm6 staining in the DCT of Umod-/- mice. Applying biotinylation assays and whole-cell patch-clamp recordings, we found that UMOD enhances TRPM6 cell-surface abundance and current density from the extracellular space. UMOD physically interacted with TRPM6 and thereby impaired dynamindependent TRPM6 endocytosis.WTmice fed a low-magnesium diet had an increased urinary UMOD secretion compared with the same mice on a regular diet. Our results suggest that increased urinary UMOD secretion in low-magnesium states reduces TRPM6 endocytosis and thereby up-regulates TRPM6 cell-surface abundance to defend against further urinary magnesium losses. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the study was assessment of four selected macromolecules level: osteopontin, calgranulin, uromodulin and bikunin in fresh morning urine sample in children with nephrolithiasis in the course of idiopathic hypercalciuria. Materials and Methods: The study included 90 subjects aged from 12 months to 18 years. The study group comprised 57 subjects- children with urinary tract lithiasis in the course of idiopathic hypercalciuria and the control group - 33 healthy children with no history of urolithiasis. Determinations of osteopontin, calgranulin, uromodulin and bikunin levels in the first morning urine were performed. Results: The study group had a significantly decreased osteopontin excretion and significantly increased bikunin excretion, and increased, however statistically nonsignificant, calgranulin excretion in comparison with the control group. Uromodulin excretion did not differ between groups. In both groups a statistically significant positive correlation was observed between uromodulin and bikunin levels. Conclusion: Children with urinary tract lithiasis in the course of idiopathic hypercalciuria reveal a different distribution of the study proteins than a healthy population. [ABSTRACT FROM AUTHOR]

A main feature of Fabry disease is nephropathy, with polyuria an early manifestation; however, the mechanism that underlies polyuria and affected tubules is unknown. To increase globotriaosylceramide (Gb3) levels, we previously crossbred asymptomatic Glatm mice with transgenic mice that expressed human Gb3 synthase (A4GALT) and generated the GlatmTg(CAG-A4GALT) symptomatic Fabry model mice. Additional analyses revealed that these mice exhibit polyuria and renal dysfunction without remarkable glomerular damage. In the present study, we investigated the mechanism of polyuria and renal dysfunction in these mice. Gb3 accumulation was mostly detected in the medulla; medullary thick ascending limbs (mTALs) were the most vacuolated tubules. mTAL cells contained lamellar bodies and had lost their characteristic structure (i.e., extensive infolding and numerous elongated mitochondria). Decreased expression of the major molecules--Na+-K+-ATPase, uromodulin, and Na+-K+-2Cl- cotransporter--that are involved in Na+ reabsorption in mTALs and the associated loss of urine-concentrating ability resulted in progressive water- and salt-loss phenotypes. GlatmTg(CAG-A4GALT) mice exhibited fibrosis around mTALs and renal dysfunction. These and other features were consistent with pathologic findings in patients with Fabry disease. Results demonstrate that mTAL dysfunction causes polyuria and renal impairment and contributes to the pathophysiology of Fabry nephropathy. [ABSTRACT FROM AUTHOR]

Expression of Tamm-Horsfall protein (THP or uromodulin) is highly restricted to the kidney thick ascending limb (TAL) of loop of Henle. Despite the unique location and recent association of THP gene mutations with hereditary uromodulin-associated kidney disease and THP single nucleotide polymorphisms with chronic kidney disease and hypertension, the physiological function(s) of THP and its pathological involvement remain incompletely understood. By studying age-dependent changes of THP knockout (KO) mice, we show here that young KO mice had significant salt and water wasting but were partially responsive to furosemide, due to decreased luminal translocation of Na-K-Cl cotransporter 2 (NKCC2) in the TAL. Aged THP KO mice were, however, markedly oliguric and unresponsive to furosemide, and their NKCC2 was localized primarily in the cytoplasm as evidenced by lipid raft floatation assay, cell fractionation, and confocal and immunoelectron microscopy. These aged KO mice responded to metolazone and acetazolamide, known to target distal and proximal tubules, respectively. They also had marked upregulation of renin in juxtaglomerular apparatus and serum, and they were hypertensive. Finally, the aged THP KO mice had significant upregulation of Na-coupled urate transporters Slc5a8 and Slc22a12 as well as sodiumhydrogen exchanger 3 (NHE3) in the proximal tubule and elevated serum uric acid and allantoin. Collectively, our results suggest that THP deficiency can cause progressive disturbances in renal functions via initially NKCC2 dysfunction and later compensatory responses, resulting in prolonged activation of the renin-angiotensin-aldosterone axis and hyperuricemia. [ABSTRACT FROM AUTHOR]

Our previous study has shown that lime powder (LP) had an inhibitory effect against calcium oxalate stone formation. However, the precise mechanisms underlying such beneficial effect remained unclear. Our present study thus aimed to address the effect of LP on excretory level and compositions of urinary proteins using a proteomics approach. From a total of 80 calcium oxalate stone formers recruited into our 2-year randomized clinical trial of LP effect, 10 patients with comparable age and clinical parameters were selected for this proteomic study. 24-h urine specimens were collected from all subjects, at baseline (before) and after LP treatment for 6 months, and then subjected to quantitative proteomics analysis and subsequent validation by ELISA. Total urinary protein excretion was significantly decreased by LP treatment, but unaffected by placebo. Nanoflow liquid chromatography coupled to tandem mass spectrometry (nanoLC-MS/MS) followed by quantitative analysis revealed 17 proteins whose levels were significantly altered (16 decreased and 1 increased) exclusively by LP treatment. Among these, the decrease of transferrin and increase of uromodulin were validated by ELISA. Moreover, there was a significant correlation between microalbuminuria and urinary transferrin level by Pearson’s correlation test. In summary, LP treatment caused significant reduction in total urinary protein excretion and changes in urinary protein compositions that could be linked to stone inhibitory effects and might be relevant mechanisms responsible for the beneficial effects of LP to prevent kidney stone formation and recurrence. [ABSTRACT FROM AUTHOR]

Background: Extracellular vesicles (EVs) enclose mRNA derived from their cell of origin and are considered a source of potential biomarkers. We examined urinary EV mRNA from individuals with diabetic kidney disease (DKD), chronic kidney disease, type 2 diabetes (T2DM), and obese and healthy controls to determine if such biomarkers had the potential to classify kidney disease and predict patients at higher risk of renal function decline.Methods: A total of 242 participants enrolled in this study. Urinary EV mRNA from all subjects were isolated by a filter-based platform, and the expression of 8 target genes were determined by quantitative polymerase chain reaction (qPCR). Changes in estimated glomerular filtration rate (eGFR) in 161 T2DM patients were evaluated for 2 consecutive years and compared with EV RNA profiles at baseline.Results: We observe that mild and severe DKD groups show a significant 3.2- and -4.4-fold increase in UMOD compared to healthy controls and expression increases linearly from healthy, diabetic, and DKD subjects. UMOD expression is significantly correlated to albumin creatinine ratio (ACR), eGFR, and HbA1c. Using linear discriminant analyses with mRNA from severe DKD and T2DM as training data, a multi-gene signature classified DKD and -non-DKD with a sensitivity of 93% and specificity of 73% with area under the receiver operating characteristic (ROC) curve (AUC) = 0.90. Although 6% of T2DM were determined to have a > 80% posterior probability of developing DKD based on this mRNA profile, eGFR changes observed within the 2-year follow-up did not reveal a decline in kidney function.Conclusion: Urinary EV UMOD mRNA levels are progressively elevated from T2DM to DKD groups and correlate with widely used eGFR and ACR diagnostic criteria. An EV mRNA signature could identify DKD with greater than 90% sensitivity and 70% specificity. [ABSTRACT FROM AUTHOR]

Background: Uromodulin is a kidney-derived glycoprotein and putative tubular function index. Lower serum uromodulin was recently associated with increased risk for kidney allograft failure in a preliminary, longitudinal single-center -European study involving 91 kidney transplant recipients (KTRs).Methods: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial is a completed, large, multiethnic controlled clinical trial cohort, which studied chronic, stable KTRs. We conducted a case cohort analysis using a randomly selected subset of patients (random subcohort, n = 433), and all individuals who developed kidney allograft failure (cases, n = 226) during follow-up. Serum uromodulin was determined in this total of n = 613 FAVORIT trial participants at randomization. Death-censored kidney allograft failure was the study outcome.Results: The 226 kidney allograft failures occurred during a median surveillance of 3.2 years. Unadjusted, weighted Cox proportional hazards modeling revealed that lower serum uromodulin, tertile 1 vs. tertile 3, was associated with a threefold greater risk for kidney allograft failure (hazards ratio [HR], 95% CI 3.20 [2.05-5.01]). This association was attenuated but persisted at twofold greater risk for allograft failure, after adjustment for age, sex, smoking, allograft type and vintage, prevalent diabetes mellitus and cardiovascular disease (CVD), total/high-density lipoprotein cholesterol ratio, systolic blood pressure, estimated glomerular filtration rate, and natural log urinary albumin/creatinine: HR 2.00, 95% CI (1.06-3.77).Conclusions: Lower serum uromodulin, a possible indicator of less well-preserved renal tubular function, remained associated with greater risk for kidney allograft failure, after adjustment for major, established clinical kidney allograft failure and CVD risk factors, in a large, multiethnic cohort of long-term, stable KTRs. [ABSTRACT FROM AUTHOR]