UMOD Polymorphisms Associated with Kidney Function, Serum Uromodulin and Risk of Mortality among Patients with Chronic Kidney Disease, Results from the C-STRIDE Study.
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SUBMITTER: Wang J
PROVIDER: S-EPMC8620616 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Uromodulin, the most abundant protein in urine, is synthesized in the thick ascending loop of Henle and distal convoluted tubules. Patients with chronic kidney disease (CKD) have reduced urinary uromodulin levels secondary to tubular damage. Genome wide association studies identified significant single nucleotide polymorphism (SNP) associations with CKD at the uromodulin (UMOD) locus. We examined the association of urinary uromodulin concentrations with CKD and with SNP rs1333226 in the UMOD gene. The study included 71 black South Africans with hypertension-attributed CKD with an eGFR ≤ 60ml/min/1.73m2, 52 first-degree relatives, and 58 unrelated controls. Urinary uromodulin concentration was measured using Luminex® multiplex kits. After DNA extraction from blood using the Maxwell® automated platform, genotyping of rs13333226 was performed using real-time PCR using TaqMan® genotyping assays. Urinary uromodulin levels were significantly lower in CKD cases compared to both controls and first-degree relatives and correlated negatively with age, serum uric acid, serum creatinine, and systolic BP and positively with CKD-EPI eGFR. For each 1-standard deviation increase in uromodulin level, the multivariable-adjusted odds ratio for CKD was 0.6 (95% CI [0.48 to 0.81]; p <0.01). There were no significant differences in the minor allele frequency between CKD cases and controls (p = 0.59) nor between first-degree relatives and controls (p = 0.98). There were no significant associations between genotype at rs13333226 and urine uromodulin levels (p = 0.43). Higher levels of urinary uromodulin are associated with lower odds of hypertension-attributed CKD. We did not detect associations of genotype at rs13333226 with urinary uromodulin levels in our sample population. Larger sample size studies from ethnically disparate populations are essential to further categorize this association.
| S-EPMC6466913 | biostudies-literature
Project description:BackgroundUromodulin is specifically synthesized and secreted by kidney tubular epithelial cells. Studies on the association of serum uromodulin and outcomes of chronic kidney disease (CKD) are lacking. This study aimed to evaluate whether serum uromodulin was associated with outcomes of patients with CKD.MethodsWe measured serum uromodulin concentrations by ELISA in 2652 CKD patients from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) and investigated the association of serum uromodulin with outcomes of CKD patients, including end-stage kidney disease (ESKD) receiving kidney replacement therapy, cardiovascular events and mortality by Cox proportional hazards regression model.ResultsA total of 2652 CKD patients were enrolled in this study, with an age of 48.7?±?13.8 years and the baseline eGFR of 49.6?±?29.4 mL/min/1.73 m2, of whom 58.4% were male. The median level of urinary albumin/creatinine ratio and serum uromodulin was 473.7 mg/g (IQR 134.1-1046.6 mg/g) and 77.2 ng/mL (IQR 48.3-125.9 ng/mL), respectively. Altogether, 404 ESKD, 189 cardiovascular events, and 69 deaths occurred during the median follow-up of 53.6 (IQR 44.0-64.0) months. Lower levels of serum uromodulin were independently associated with higher risk of incident ESKD after adjusting for traditional cardiovascular risk factors, with the hazard ratios (HRs) of 3.23 (95% confidence intervals [CIs] 2.15-4.85) for the middle tertile and 7.47 (95% CI 5.06-11.03) for the bottom tertile, compared with top tertile and 0.31 (95% CI 0.25-0.38) per every standard deviation increase. After further adjustment for the baseline eGFR, the association was greatly attenuated, but still significant, with HRs of 1.92 (95% CI 1.26-2.90) for the bottom tertile compared with top tertile and 0.69 (95% CI 0.55-0.86) per every standard deviation increase.ConclusionsSerum uromodulin is independently associated with an increased risk of incident ESKD in CKD patients.
| S-EPMC6245763 | biostudies-literature
Project description:An ELISA to analyse uromodulin in human serum (sUmod) was developed, validated and tested for clinical applications.We assessed sUmod, a very stable antigen, in controls, patients with chronic kidney disease (CKD) stages 1-5, persons with autoimmune kidney diseases and recipients of a renal allograft by ELISA.Median sUmod in 190 blood donors was 207?ng/mL (women: men, median 230 versus 188?ng/mL, P?=?0.006). sUmod levels in 443 children were 193?ng/mL (median). sUmod was correlated with cystatin C (rs?=?-0.862), creatinine (rs?=?-0.802), blood urea nitrogen (BUN) (rs?=?-0.645) and estimated glomerular filtration rate (eGFR)-cystatin C (rs ?= ?0.862). sUmod was lower in systemic lupus erythematosus-nephritis (median 101?ng/mL), phospholipase-A2 receptor- positive glomerulonephritis (median 83?ng/mL) and anti-glomerular basement membrane positive pulmorenal syndromes (median 37?ng/mL). Declining sUmod concentrations paralleled the loss of kidney function in 165 patients with CKD stages 1-5 with prominent changes in sUmod within the 'creatinine blind range' (71-106 µmol/L). Receiver-operating characteristic analysis between non-CKD and CKD-1 was superior for sUmod (AUC 0.90) compared with eGFR (AUC 0.39), cystatin C (AUC 0.39) and creatinine (AUC 0.27). sUmod rapidly recovered from 0 to 62?ng/mL (median) after renal transplantation in cases with immediate graft function and remained low in delayed graft function (21?ng/mL, median; day 5-9: relative risk 1.5-2.9, odds ratio 1.5-6.4). Immunogold labelling disclosed that Umod is transferred within cytoplasmic vesicles to both the apical and basolateral plasma membrane. Umod revealed a disturbed intracellular location in kidney injury.We conclude that sUmod is a novel sensitive kidney-specific biomarker linked to the structural integrity of the distal nephron and to renal function.
| S-EPMC5837243 | biostudies-other
Project description:Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.
| S-EPMC3856354 | biostudies-literature
Project description:Uromodulin (UMOD) mutations are responsible for three autosomal dominant tubulo-interstitial nephropathies including medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Symptoms include renal salt wasting, hyperuricemia, gout, hypertension and end-stage renal disease. MCKD is part of the 'nephronophthisis-MCKD complex', a group of cystic kidney diseases. Both disorders have an indistinguishable histology and renal cysts are observed in either. For most genes mutated in cystic kidney disease, their proteins are expressed in the primary cilia/basal body complex. We identified seven novel UMOD mutations and were interested if UMOD protein was expressed in the primary renal cilia of human renal biopsies and if mutant UMOD would show a different expression pattern compared with that seen in control individuals. We demonstrate that UMOD is expressed in the primary cilia of renal tubules, using immunofluorescent studies in human kidney biopsy samples. The number of UMOD-positive primary cilia in UMOD patients is significantly decreased when compared with control samples. Additional immunofluorescence studies confirm ciliary expression of UMOD in cell culture. Ciliary expression of UMOD is also confirmed by electron microscopy. UMOD localization at the mitotic spindle poles and colocalization with other ciliary proteins such as nephrocystin-1 and kinesin family member 3A is demonstrated. Our data add UMOD to the group of proteins expressed in primary cilia, where mutations of the gene lead to cystic kidney disease.
| S-EPMC2860893 | biostudies-literature
Project description: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.
| S-EPMC6754623 | biostudies-literature
Project description:Background It is unclear whether short-term blood pressure variability is associated with renal outcomes in patients with chronic kidney disease. Methods and Results This study analyzed data from participants in the C-STRIDE (Chinese Cohort Study of Chronic Kidney Disease) who had chronic kidney disease stages 1 to 4. Short-term blood pressure variability was measured by calculating the weighted SD (w-SD) of systolic blood pressure (SBP). Renal outcomes were defined as dialysis initiation and/or transplantation. Risk factors associated with w-SD of SBP were evaluated by linear regression. Associations of short-term SBP variability with renal outcomes were evaluated by Cox regression. In total, 1421 patients with chronic kidney disease were included in this study (mean age, 49.4±13.6 years; 56.2% men; estimated glomerular filtration rate, 50.5±29.3 mL/min per 1.73 m2; proteinuria, 0.9 [0.3-2.0] g/d). Mean w-SD of SBP was 12.6±4.4 mm Hg. w-SD of SBP was independently associated with older age, 24-hour SBP, blood pressure circadian pattern, and angiotensin II receptor blocker treatment. During a median follow-up of 4.9 years, 237 patients developed renal outcomes (37.01 per 1000 patient-years). The incidence rate increased across the quartiles of w-SD (log-rank P=0.005). w-SD of SBP was associated with an increased risk of renal outcomes, both as a continuous variable (hazard ratio [HR], 1.47; 95% CI, 1.09-1.99) and as a categorical variable (quartile 4 versus quartile 1: HR, 1.60; 95% CI, 1.08-2.36), independent of 24-hour SBP, daytime SBP, and nighttime SBP. Conclusions Short-term SBP was independently associated with the risk of dialysis initiation and/or transplantation in patients with chronic kidney disease.
| S-EPMC7429039 | biostudies-literature
Project description: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.
| S-EPMC7460670 | biostudies-literature
Project description:The mucoprotein uromodulin is the most abundant protein in mammalian urine and has important roles in ion transport, maintenance of water and electrolyte balance, and clearance of bacteria from the urinary tract. Low urinary uromodulin concentrations have been associated with increased mortality risk. However, measuring uromodulin in urine has several preanalytic drawbacks, and sensitive assays for the detection of uromodulin in blood have become available. In this study, we investigated the association of serum uromodulin concentration with cardiovascular biomarkers and mortality risk in a large cohort of patients referred for coronary angiography. Uromodulin concentrations were available in 3057 of 3316 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Higher serum uromodulin concentration associated with a favorable metabolic profile, lower prevalence rates of comorbidities (arterial hypertension, diabetes mellitus, and heart failure), and a lower risk for 10-year mortality, with hazard ratios (95% confidence intervals) of 0.65 (0.54 to 0.78), 0.71 (0.58 to 0.88), and 0.57 (0.45 to 0.73) in the second, third, and fourth quartiles, respectively, compared with the first quartile. The association with reduced mortality was independent of other cardiovascular risk factors, including eGFR, and stronger after adjustment for the genotype of the rs12917707 polymorphism at the UMOD locus. Adding serum uromodulin concentration to established cardiovascular risk prediction scores improved risk prediction. Uromodulin may, therefore, be a useful marker for cardiovascular and renal health.
| S-EPMC5491294 | biostudies-literature
Project description:Rationale & objectiveUromodulin is released by tubular epithelial cells into the serum and lower levels are associated with more severe interstitial fibrosis and tubular atrophy. Low serum uromodulin (sUMOD) levels are associated with mortality and cardiovascular disease. However, little is known about the association of sUMOD levels with long-term kidney outcomes in older adults, a population with a high prevalence of interstitial fibrosis and tubular atrophy.Study designCase-cohort study and case-control study.Setting & participantsRandom subcohort (n=933) and additional cases of end-stage kidney disease (ESKD) and kidney function decline (≥30% decline in estimated glomerular filtration rate [eGFR]) during follow-up of the Cardiovascular Health Study (CHS).PredictorsUMOD level.OutcomesESKD (n=14) from the random subcohort and all additional ESKD cases from outside the random subcohort (n=39) during follow-up (10 years, case-cohort study); kidney function decline of≥30% eGFR at 9 years of follow-up in individuals with repeated eGFR assessments from the random subcohort (n=56) and additional cases (n=123). 224 participants from the random subcohort served as controls (case-control study).Analytical approachModified multivariable Cox regression for ESKD and multivariable logistic regression for kidney function decline. Both analyses adjusted for demographics, eGFR, urinary albumin-creatinine ratio, and other kidney disease progression risk factors.ResultsMean age of the random subcohort was 78 years, 40% were men, 15% were black. Mean sUMOD level was 127±64ng/mL and eGFR was 63±19mL/min/1.73m2. In multivariable analysis, each 1-SD higher sUMOD level was associated with 63% lower risk for ESKD (HR, 0.37; 95% CI, 0.14-0.95). In demographic-adjusted analyses of kidney function decline, each 1-SD higher sUMOD level was associated with 25% lower odds of kidney function decline (OR, 0.75; 95% CI, 0.60-0.95); after multivariable adjustment, the association was attenuated and no longer significant (OR, 0.88; 95% CI, 0.68-1.14).LimitationsPossibility of survival bias in the kidney function decline analysis.ConclusionsHigher sUMOD levels may identify elderly persons at reduced risk for ESKD.
| S-EPMC7188359 | biostudies-literature