Lower Uromodulin Research Articles

Decreased urinary uromodulin is potentially associated with acute kidney injury: a systematic review and meta-analysis

BackgroundUrinary uromodulin (uUMOD) is one of the novel biomarkers for predicting AKI. However, currently available publications showed inconsistent results. We designed this meta-analysis to evaluate the potential association between uUMOD and AKI.MethodsWe searched research articles with no language restriction in Medline, Web of Science, Cochrane Library, Embase, and 3 Chinese datasets from inception to February 2021. We used random-effects models to estimate the standardized mean difference (SMD) between patients with AKI or not, while the leave-one-out method and random-effects meta-regression to evaluate the sensitivity and the impact of potential confounders such as age and surgery.ResultsThe meta-analysis comprising 3148 subjects from 11 studies showed that the uUMOD of the AKI group is significantly lower than the non-AKI group (SMD: − 0.71; 95% confidence interval (CI), − 1.00, − 0.42, P < 0. 001, I2 = 78.8%). Subgroup analysis revealed the difference is also significant in a different age, surgery condition, and assay time but not acute rejection (AR) group, especially in children (SMD: − 1.21, 95% CI: − 1.80, − 0.61; P < 0.001) and patients undergoing surgery (SMD: − 1.03, 95% CI: − 1.75, − 0.30; P < 0.001). Lower uromodulin is associated with higher odds for AKI incidence (odds ratio = 2.47, 95% CI: 1.12, 5.47; P < 0.001, I2 = 89%). Meta-reggression found that age was associated with the SMD of uUMOD. The study outcome was reliably confirmed by the sensitivity analysis.ConclusionThe present study suggested a negative association between uUMOD and AKI especially in children and surgical patients.

Abstract 08: Functional Characterisation Of Uromodulin Promoter Risk Variants Associated With Blood Pressure

Using a genome wide association study (GWAS), we identified a locus on the promoter of the human uromodulin (UMOD) gene associating with primary hypertension. In this study we aimed to identify genotype-differential protein binding partners which influence UMOD expression and to examine pathways linking UMOD expression to blood pressure variability in humans.We examined a variant on this locus, by incubating 50mer oligonucleotides featuring alternate alleles (C/G) with HEK-293 nuclear protein extract. Subsequently, we performed an electrophoretic mobility shift assay (EMSA) and purified protein complexes to analyse by Tandem-mass-spectroscopy (MS2). Filtering for peptide matches &gt;20, we interpreted these data by Ingenuity Pathway Analysis (IPA). From a bank of 98 human renal biopsy samples, we assessed UMOD expression by qRT-PCR. RNA-seq was performed using the NextSeq-500 system on a subset of high and low UMOD expressors (n=3/ group). Differentially expressed (false-discovery-rate (FDR) &lt;0.05) genes were identified, with strong correlations in these data validated by qRT-PCR. Implicated pathways were interpreted using both IPA and gene set enrichment analysis (GSEA).The C allele at our risk variant displayed greater binding affinity versus the G allele; 0.77 (0.13, 1.40, 95%CI). In contrast no difference in binding affinity was observed between the T and C alleles of our control variant, 0.08 ( -1.22, 1.39, 95%CI). Mass spectroscopy of EMSA complexes identified PARP1 binding at this target. By IPA we identified a complex between PARP1 and HNF1β as driving expression of UMOD. RNA-sequencing identified positive correlation in expression of UMOD and the Na-K-Cl cotransporter (NKCC2) (FDR=2.58e-9, log2-fold-change [L2FC]= 3.3), the renal outer medullary potassium channel (ROMK) (FDR=3.69e-2, L2FC= 2.79) and the epithelial sodium channel (ENaC) (FDR=1.83e-2, L2FC= 1.25). We validated this coexpression between UMOD and NKCC2 by qRT-PCR and show a significant correlation (p=2.2e-16, R2= 0.844, n=84).Together these data suggest our risk variant contributes to differences in UMOD expression via a PARP1:HNF1β transcriptional complex and these differences associate with blood pressure through sodium homeostasis in the human kidney.

Associations of CKD risk factors and longitudinal changes in urine biomarkers of kidney tubules among women living with HIV

BackgroundNovel urine biomarkers have enabled the characterization of kidney tubular dysfunction and injury among persons living with HIV, a population at an increased risk of kidney disease. Even though several urine biomarkers predict progressive kidney function decline, antiretroviral toxicity, and mortality in the setting of HIV infection, the relationships among the risk factors for chronic kidney disease (CKD) and urine biomarkers are unclear.MethodsWe assessed traditional and infection-related CKD risk factors and measured 14 urine biomarkers at baseline and at follow-up among women living with HIV in the Women’s Interagency Health Study (WIHS). We then used simultaneously adjusted multivariable linear regression models to evaluate the associations of CKD risk factors with longitudinal changes in biomarker levels.ResultsOf the 647 women living with HIV in this analysis, the majority (67%) were Black, the median age was 45 years and median follow-up time was 2.5 years. Each traditional and infection-related CKD risk factor was associated with a unique set of changes in urine biomarkers. For example, baseline hemoglobin a1c was associated with worse tubular injury (higher interleukin [IL]-18), proximal tubular reabsorptive dysfunction (higher α1-microglobulin), tubular reserve (lower uromodulin) and immune response to injury (higher chitinase-3-like protein-1 [YKL-40]). Furthermore, increasing hemoglobin a1c at follow-up was associated with further worsening of tubular injury (higher kidney injury molecule-1 [KIM-1] and IL-18), as well as higher YKL-40. HCV co-infection was associated with worsening proximal tubular reabsorptive dysfunction (higher β2-microglobulin [β2m]), and higher YKL-40, whereas HIV viremia was associated with worsening markers of tubular and glomerular injury (higher KIM-1 and albuminuria, respectively).ConclusionsCKD risk factors are associated with unique patterns of biomarker changes among women living with HIV, suggesting that serial measurements of multiple biomarkers may help in detecting and monitoring kidney disease in this setting.

MO101ASSESSING EARLY RENAL INVOLVEMENT IN ESSENTIAL HYPERTENSION BY MEASURING URINARY ALBUMIN AND UROMODULIN EXCRETION

Abstract Background and Aims Kidneys are target organs in hypertension. Hypertensive damage results in glomerular as well as tubular dysfunction. Albuminuria is a known marker of glomerular damage. Whereas, urinary uromodulin is increasingly considered as potential biomarker of early tubular dysfunction. The aim of this study was to identify the pattern of early renal involvement based on glomerular and tubular function assessment by measuring urinary albumin and uromodulin in hypertensive patients Method In this cross-sectional study 122 hypertensive subjects with age&amp;gt;30 years, duration of hypertension &amp;lt;5years, without accelerated or malignant BP, absence of dipstick proteinuria and eGFR&amp;gt;60ml/min. Subjects with possibility of secondary hypertension were excluded. There were also 33 normotensive volunteers included as healthy referents. Morning spot urine for albumin-creatinine ratio (ACR mg/g), urine uromodulin-creatinine ratio (urUMODµg/g), urinary sodium-creatinine ratio (mEq/g) and potassium-creatinine ratio (mEq/g) were measured in single urine sample. Urine uromodulin was measured by ELISA method. Results The hypertensive and healthy subjects were matched for age 48±11 vs. 47±11, years (P=NS). The systolic BP was 145±15 vs. 112±12 mmHg and diastolic BP 86±9 vs. 70±8 mmHg; (p&amp;lt;0.001) and the mean ACR was 29±65 vs. 5.6±2.7 mg/g, (p&amp;lt;0.001) respectively. Around 20% hypertensives had albuminuria. Urinary potassium excretion was lower in hypertensives (51±31 vs. 69±31, mEq/g; p&amp;lt;0.02). The median urUMOD in hypertensive subjects was 3.38 (1.73-9.06) and in normotensives 3.85(2.28-5.69) µg/g (P=NS).Multivariate analysis showed significant inverse association between diastolic blood pressure and urinary uromodulin excretion. An urURMOD cut-off of 2.9 (25th percentile in normotensives) showed eGFR, urinary sodium &amp; potassium excretions were significantly lower at low uromodulin cut-off and this was seen in38%subjects. Conclusion The glomerular involvement was found in 20% hypertensives as evidenced by albuminuria. In general urinary uromodulin level was not different between hypertensive and normotensive subjects. Association of low uromodulin cut-off with lower eGFR, Na+ and K+ excretion indicates simultaneous tubule glomerular involvement in 38%.

Abstract P332: Urine Uromodulin Does Not Alter the Relationship Between Salt Intake and Blood Pressure: The DASH-Sodium Trial

Introduction: Genome-wide association studies have revealed susceptibility variants for hypertension in the UMOD gene. The encoded protein, uromodulin, modulates NKCC2 transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. Hypothesis: Individuals with higher levels of urine uromodulin will have a greater increase in systolic blood pressure compared to those with lower uromodulin levels. Methods: We used data from 157 subjects in the control diet of the DASH-Sodium trial assigned to 30 days of low (1500 mg/d), medium (2400 mg/d), and high salt (3300 mg/d) diets in random order. Blood pressure was measured at baseline and at 5 visits during the last 9 days of each feeding period. We evaluated the association of urine uromodulin with change in systolic blood pressure between diets, as measured by the average at the end of each feeding period, using multivariable linear regression. Results: Baseline urine uromodulin stratified by tertiles was less than or equal to 17.64, 17.65 - 31.97, and greater than or equal to 31.98 μg/mL (overall mean 30.0 μg/mL, SEM 1.85 μg/mL). Across the tertiles, there were no significant differences in systolic blood pressure (SBP) at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high p = 0.81, Figure). After adjusting for age, sex, BMI, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (β = -0.68 per 10 μg/mL increase in urine uromodulin, p = 0.28). Conclusion: 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. Further human studies are needed to evaluate the findings seen in animal models, where the expression of higher levels of urine uromodulin has been associated with salt sensitive hypertension.

ASSOCIATION OF URINARY LEVELS OF UROMODULIN AND UMOD RS1333226 WITH SERUM URIC ACID

Objective: It was reported that low uromodulin is associated with increased uric acid reabsorption in proximal tubule but also tubular uric acid affect uromodulin excretion. On the other hand, UMOD mutations have been identified in patients with familial juvenile hyperuricemia nephropathy and similar diseases characterized by increased levels of serum uric acid (SUA). Our objective was to find out whether urine uromodulin levels depending on UMOD polymorphism rs1333226 are associated with differences in SUA concentrations. Design and method: A group of 350 untreated subjects (men 45,9 %, mean age 40 years), subgroup of larger cohort from the ENAH study (random sample of rural population) were enrolled into the study. Subjects were divided into 3 groups based on the 33th and 77th percentiles of SUA (Median SUA levels were 210, 299, and 410 mmol/L, respectively). Urinary uromodulin levels were measured by Enzyme Linked Immunosorbent Assay (ELISA) and genotyping for UMOD rs1333226 by RT-PCR with the fluorescence-based TaqMan system. Only samples with urine creatinine in normal ranges were included in analyses. Uromodulin was indexed to urine creatinine. Results: Negative correlation between urine uromodulin and serum uric acid levels was observed (44, 36, and 30 mmol/g in the 1st, 2nd, and 3rd SUA groups (p = 0.01). There were no significant differences among GFR CKD-EPI values among groups. There was a positive correlation between BMI and SUA as well as between waist circumference and SUA. We found no difference in rs1333226 allele frequencies across 3 groups; allele A 82% and allele G 18%. Conclusions: Our findings showed a negative correlation between urinary uromodulin and SUA therefore being in agreement with previous studies reporting that uromodulin affects uric acid kidney excretion. On the other hand we did not find difference in rs1333226 allele frequencies across SUA groups which could mean that this UMOD SNP is not associated with UA reabsorption. However, this should be proven on larger number of patients.

The SPRINT trial suggests that markers of tubule cell function in the urine associate with risk of subsequent acute kidney injury while injury markers elevate after the injury

Urine markers can quantify tubular function including reabsorption (α-1 microglobulin [α1m]) and β-2-microglobulin [β2m]) and protein synthesis (uromodulin). Individuals with tubular dysfunction may be less able to compensate to insults than those without, despite similar estimated glomerular filtration rate (eGFR) and albuminuria. Among Systolic Blood Pressure Intervention Trial (SPRINT) participants with an eGFR under 60 ml/min/1.73m2, we measured urine markers of tubular function and injury (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], interleukin-18 [IL-18], monocyte chemoattractant protein-1, and chitinase-3-like protein [YKL-40]) at baseline. Cox models evaluated associations with subsequent acute kidney injury (AKI) risk, adjusting for clinical risk factors, baseline eGFR and albuminuria, and the tubular function and injury markers. In a random subset, we remeasured biomarkers after four years, and compared changes in biomarkers in those with and without intervening AKI. Among 2351 participants, 184 experienced AKI during 3.8 years mean follow-up. Lower uromodulin (hazard ratio per two-fold higher (0.68, 95% confidence interval [0.56, 0.83]) and higher α1m (1.20; [1.01, 1.44]) were associated with subsequent AKI, independent of eGFR and albuminuria. None of the five injury markers were associated with eventual AKI. In the random subset of 947 patients with repeated measurements, the 59 patients with intervening AKI versus without had longitudinal increases in urine NGAL, IL-19, and YKL-40 and only 1 marker of tubule function (α1m). Thus, joint evaluation of tubule function and injury provided novel insights to factors predisposing to AKI, and responses to kidney injury.

The value of uromodulin as a new serum marker to predict decline in renal function.

Uromodulin is the most abundant protein in urine. Low uromodulin has been found associated with diabetes as well as with chronic kidney disease (CKD). Whether it also predicts a future decline in kidney function is not known. We evaluated the association between serum uromodulin and kidney function in 529 patients and performed a genome-wide association study. Clinical parameters including renal function were determined at baseline and reassessed at a 4-year follow-up visit. Patients' serum uromodulin levels were highest associated with a polymorphism in the UMOD coding region and were significantly correlated with estimated glomerular filtration rate (eGFR) (r = 0.242, P < 0.001) and, in an inverse way, with the albumin-creatinine ratio (r = -0.120, P = 0.012). Serum uromodulin concentrations were significantly lower in patients with CKD (eGFR < 60 ml/min per 1.73 m) than in patients with normal kidney function (71.9 ± 29.0 vs. 169.1 ± 76.1 ng/ml, P < 0.001) and the same applied to patients with albuminuria (148.7 ± 72.2 vs. 167.9 ± 77.6 ng/ml, P = 0.008) or hypertension (160.9 ± 74.0 vs. 181.8 ± 87.8 ng/ml, P = 0.037). Prospectively, patients who developed CKD during the follow-up had significantly less uromodulin in serum than those who did not (126.8 ± 42.3 vs. 180.2 ± 79.1 ng/ml, P = 0.003). Serum uromodulin concentration was inversely associated with the development of CKD, even after adjustment for patients age, sex, genotype of the identified polymorphism, hypertension and diabetes status, and eGFR (odds ratio = 0.263, P = 0.019), and it significantly increased the performance of a prediction model for CKD (C-statistics 0.844 vs. 0.804, P = 0.049). The current study is the first evaluating the value of uromodulin in serum as a novel predictive biomarker for renal function and for the incidence of CKD.

Association of Preoperative Urinary Uromodulin with AKI after Cardiac Surgery.

AKI is a serious complication after cardiac surgery. Although high urinary concentrations of the tubular protein uromodulin, a marker of tubular health, are associated with less AKI in animal models, its relationship in humans is unknown. A post hoc analysis of a prospective cohort study of 218 adults undergoing on-pump cardiac surgery between 2004 and 2011 was conducted. Multivariable logistic and linear regression analyses were used to evaluate the associations of preoperative urinary uromodulin-to-creatinine ratio with postoperative AKI (defined as a rise in serum creatinine of >0.3 mg/dl or >1.5 times baseline); severe AKI (doubling of creatinine or need for dialysis) and peak postoperative serum creatinine over the first 72 hours. Mean age was 68 years, 27% were women, 95% were white, and the median uromodulin-to-creatinine ratio was 10.0 μg/g. AKI developed in 64 (29%) patients. Lower urinary uromodulin-to-creatinine ratio was associated with higher odds for AKI (odds ratio, 1.49 per 1-SD lower uromodulin; 95% confidence interval, 1.04 to 2.13), which was marginally attenuated after multivariable adjustment (odds ratio, 1.43; 95% confidence interval, 0.99 to 2.07). The lowest uromodulin-to-creatinine ratio quartile was also associated with higher odds for AKI relative to the highest quartile (odds ratio, 2.94; 95% confidence interval, 1.19 to 7.26), which was slightly attenuated after multivariable adjustment (odds ratio, 2.43; 95% confidence interval, 0.91 to 6.48). A uromodulin-to-creatinine ratio below the median was associated with higher adjusted odds for severe AKI, although this did not reach statistical significance (odds ratio, 4.03; 95% confidence interval, 0.87 to 18.70). Each 1-SD lower uromodulin-to-creatinine ratio was associated with a higher adjusted mean peak serum creatinine (0.07 mg/dl per SD; 95% confidence interval, 0.02 to 0.13). Lower uromodulin-to-creatinine ratio is associated with higher odds of AKI and higher peak serum creatinine after cardiac surgery. Additional studies are needed to confirm these preliminary results.