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

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

Autosomal dominant tubulointerstitial kidney disease genotype and phenotype correlation in a Chinese cohort.

Genes of UMOD, HNF1B, MUC1, REN and SEC61A1 were reported to be associated with autosomal dominant tubulointerstitial kidney disease (ADTKD). 48 probands and their family members (N = 27) were enrolled in this genetic screening study. A combination of methods was employed for comprehensive molecular analysis of both copy number variations (CNVs) and single nucleotide variants (SNVs). 35 probands were followed for years. The phenotype-genotype and genotype-outcome correlation were inferred from these datasets. In this cohort, 18 probands were diagnosed with ADTKD, according to Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Moreover, 11 probands were diagnosed with ADTKD-UMOD, one with ADTKD-REN and one with ADTKD-HNF1B, based on molecularly confirmed pathogenic variants. The 11 UMOD variants were mainly located in codons 28 to 289 and half of the variants were found to change the cysteine amino acid. According to the follow-up data, suspected ADTKD individuals had a better prognosis compared to ADTKD individuals (p = 0.029). Individuals with a cysteine substitution in the UMOD gene appeared to have a better prognosis than individuals with other amino acid substitutions (p = 0.015).

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

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

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

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

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

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

Correlation of serum uromodulin levels with renal fibrosis and renal function progression in patients with CKD.

To explore the relationship of serum uromodulin levels with renal function progression and renal fibrosis in chronic kidney disease (CKD) patients. Totally 168 CKD patients treated in Department of Nephrology of the present hospital between June 2017 and June 2019 were recruited. These patients were allocated to the deterioration and control groups according to the estimated glomerular filtration rate (eGFR). Multi-factor Logistic regression analysis was utilized for the correlation factors influencing renal function progression and the correlation between serum uromodulin and renal fibrosis was also compared. Number of patients receiving ARB or ACEI drugs intervention was lower in the deterioration group than that in the control group (P<0.05). 24-hour urine protein quantification and HA were higher, while eGFR and uromodulin were lower in the deterioration group compared with the control group (both P<0.05). eGFR (OR=0.373) and uromodulin (OR=0.717) were the protective factors for renal function progression. The risk of renal fibrosis was higher in the deterioration group compared with the control group (P<0.05). Uromodulin was significantly higher in the fibrosis group compared with the normal group (P<0.05). Serum uromodulin is an independent risk factor for renal function progression, and is remarkably correlated with renal fibrosis, which deserves clinical promotion.

Uromodulin and microRNAs in Kidney Transplantation-Association with Kidney Graft Function.

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.

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

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

Age appropriate reference intervals for eight kidney function and injury markers in infants, children and adolescents.

Objectives: The use of kidney function and injury markers for early detection of drug-related glomerular or tubular kidney injury in infants, children and adolescents requires age-specific data on reference intervals in a pediatric healthy population. This study characterizes serum values for eight kidney function and injury markers in healthy infants, children and adolescents. Methods: A single center prospective observational study was conducted between December 2018 and June 2019. Serum samples from 142 healthy infants, children and adolescents aged between 0 and ≤15 years were collected. Statistical analyses for eight markers (albumin (ALB), ß2-microglobulin (B2M), ß-trace protein (BTP), creatinine (SCR), cystatin C (CYSC), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), uromodulin (URO)) were performed to obtain reference intervals and associations with age, sex and weight were investigated (Pearson correlation, linear and piecewise regression). Results: ALB and SCR increased with age (p<0.01), whereas B2M, BTP and KIM-1 values decreased with advancing age (p<0.05) in this healthy pediatric study population. CYSC showed dependency on sex (lower concentration in females) and decreased with age until reaching approximately 1.8 years; thereafter an increase with age was seen. NGAL and URO did not show any age-dependency. Conclusions: This study provides age appropriate reference intervals for key serum kidney function and injury markers determined in healthy infants, children and adolescents. Such reference intervals facilitate the interpretation of changes in kidney function and injury markers in daily practice, and allow early detection of glomerular and tubular injury in infancy, childhood and adolescence.

Annexin V in children with idiopathic nephrotic syndrome treated with cyclosporine A.

BACKGROUND: Treatment with cyclosporine A (CsA), a calcineurin inhibitor, is effective in children with difficult idiopathic nephrotic syndrome (INS). Prolonged CsA treatment can result in several adverse effects, the most significant being nephrotoxicity (CsAN). The plasma and urine levels of the proteins annexin V (AnV) and uromodulin (UM) were investigated in order to assess their usefulness as indicators of early-stage CsAN. Uromodulin is considered a distal tubular damage marker. Annnexin V is present in the distal tubules. OBJECTIVES: To measure AnV in children with INS receiving CsA treatment and to assess the usefulness of this biomarker for monitoring CsAN and as an indicator of changes in the distal tubules of the nephron. MATERIAL AND METHODS: The prospective study included 30 patients with INS and 22 controls. Plasma and urinary AnV levels were measured 3 times: before CsA treatment, and after 6 and 12 months of therapy. The AnV levels were compared to those of UM. RESULTS: The urinary AnV and UM levels were significantly higher in the INS patients before CsA therapy in comparison to the reference group. A progressive increase of urinary AnV was observed after 6 and 12 months of therapy. Urinary UM only increased after 6 months. No significant correlations were found between plasma and urinary concentrations of the proteins studied. CONCLUSIONS: The increased urinary excretion of AnV in children with INS receiving CsA treatment may suggest its usefulness as an early marker of subclinical CsAN. Annexin V seems to be a more sensitive indicator of tubular damage in the course of CsA therapy than UM, though large, multicenter studies are needed.

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

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

Serum uromodulin and risk for cardiovascular morbidity and mortality in the community-based KORA F4 study.

BACKGROUND AND AIMS: Serum uromodulin, a novel biomarker of kidney function and tubular integrity, has been linked to cardiovascular events and total mortality in patients at high cardiovascular risk. Here, we analyze the association of serum uromodulin with cardiovascular morbidity and cardiovascular as well as total mortality in the population-based KORA F4 study stratified by sex. METHODS: Baseline serum uromodulin was measured in 1079 participants of the KORA F4 study (age 62-81 years). Using multivariable adjusted Cox proportional hazards models, the associations of serum uromodulin with total mortality and cardiovascular mortality were analyzed after a median follow-up period of 8.6 years, and with non-fatal and fatal stroke and myocardial infarction/coronary death after a median follow-up time of 8.4 years. RESULTS: Serum uromodulin was significantly inversely associated with total mortality (HR 0.65; 95% CI 0.53-0.79 per standard deviation of logarithmized serum uromodulin; p < 0.001) and cardiovascular mortality (HR 0.70; 95% CI 0.52-0.93) in men, but not in women (HR for all-cause mortality in women 0.98; 95% CI 0.77-1.25, HR for cardiovascular mortality 0.78; 95% CI 0.56-1.11) after adjustment for age, BMI, diabetes and eGFR. In addition, serum uromodulin was significantly inversely associated with incident stroke in men (HR 0.68; 95% CI 0.50-0.92), but not in women (HR 0.96; 95% CI 0.68-1.38) after multivariable adjustment. The association of serum uromodulin with incident myocardial infarction was attenuated and lost significance after multivariable adjustment in both sexes. CONCLUSIONS: Serum uromodulin is an independent biomarker for total and cardiovascular mortality in men from the general community aged 62 years or older.

Association of serum uromodulin with mortality and cardiovascular disease in the elderly-the Cardiovascular Health Study.

BACKGROUND: Uromodulin (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. METHODS: We 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. RESULTS: The 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 <60 mL/min/1.73 m2. Patients in the lower sUMOD quartiles had lower eGFR and higher albuminuria (P < 0.01, respectively). During a median follow-up of 9.9 years, 805 patients died, 283 developed HF and 274 developed CVD. In multivariable analysis, higher sUMOD was significantly associated with a lower hazard for mortality {hazard ratio [HR] 0.89 [95% confidence interval (CI) 0.80-0.99] per 1 standard deviation (SD) higher sUMOD}, CVD [HR 0.80 (95% CI 0.67-0.96)] and the composite endpoint [HR 0.88 (95% CI 0.78-0.99)]; the association with HF was not statistically significant [HR 0.84 (95% CI 0.70-1.01)]. CONCLUSION: Higher sUMOD is independently associated with a lower risk for mortality and CVD in older adults.

Association of serum and urinary uromodulin and their correlates in older adults-The Cardiovascular Health Study.

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 (ß = 1.3 [1.1-1.6]), log2 C-reactive protein (ß = -4.2 [-6.8 to -1.6]) and male sex (ß = -13.6 [-22.7 to -4.5]). In contrast, male sex was associated with higher uUMOD (ß = 3700 [400-7000]), while diabetes (ß = -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.

Serum uromodulin is associated with the severity of clinicopathological findings in ANCA-associated glomerulonephritis.

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.

Circulating uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel.

High serum concentrations of kidney-derived protein uromodulin [Tamm-Horsfall protein (THP)] have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with postsurgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity, and our findings might help explain how circulating THP deficiency is linked with poor outcomes and increased mortality.

Admission plasma uromodulin and the risk of acute kidney injury in hospitalized patients with cirrhosis: a pilot study.

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.

Uromodulin in mineral metabolism.

PURPOSE OF REVIEW: Uromodulin (UMOD), also known as Tamm-Horsfall protein, is the most abundant protein in human urine. UMOD has multiple functions such as protection against urinary tract infections and nephrolithiasis. This review outlines recent progress made in UMOD's role in renal physiology, tubular transport, and mineral metabolism. RECENT FINDINGS: UMOD is mostly secreted in the thick ascending limb (TAL) and to a lesser degree in the distal convoluted tubule (DCT). UMOD secretion is regulated by the calcium-sensing receptor. UMOD upregulates ion channels [e.g., renal outer medullary potassium channel, transient receptor potential cation channel subfamily V member 5, and transient receptor potential melastatin 6 (TRPM6)] and cotransporters [e.g., Na,K,2Cl cotransporter (NKCC2) and sodium-chloride cotransporter (NCC)] in the TAL and DCT. Higher serum UMOD concentrations have been associated with higher renal function and preserved renal reserve. Higher serum UMOD has also been linked to a lower risk of cardiovascular disease and diabetes mellitus. SUMMARY: With better serum UMOD detection assays the extent of different functions for UMOD is still expanding. Urinary UMOD regulates different tubular ion channels and cotransporters. Variations of urinary UMOD secretion can so contribute to common disorders such as hypertension or nephrolithiasis.

Serum uromodulin is associated with urinary albumin excretion in adolescents with type 1 diabetes.

Early diabetic kidney disease (DKD) occurs in adolescents with type 1 diabetes (T1D). Lower serum uromodulin (SUMOD) predicts DKD progression in adults with T1D. In this study, we demonstrate that lower SUMOD is associated with urinary albumin excretion in adolescents with T1D, suggesting a potential relationship between SUMOD and early kidney dysfunction in T1D youth.