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1.
PLoS One ; 17(7): e0270018, 2022.
Article in English | MEDLINE | ID: mdl-35834547

ABSTRACT

IMPORTANCE: Extracellular matrix proteins and enzymes involved in degradation have been found to be associated with tissue fibrosis and ureteropelvic junction obstruction (UPJO). In this study we developed a promising urinary biomarker model which can identify reduced renal function in UPJ obstruction patients. This can potentially serve as a non-invasive way to enhance surgical decision making for patients and urologists. OBJECTIVE: We sought to develop a predictive model to identify UPJO patients at risk for reduced renal function. DESIGN: Prospective cohort study. SETTING: Pre-operative urine samples were collected in a prospectively enrolled UPJO biomarker registry at our institution. Urinary MMP-2, MMP-7, TIMP-2, and NGAL were measured as well as clinical characteristics including hydronephrosis grade, differential renal function, t1/2, and UPJO etiology. PARTICIPANTS: Children who underwent pyeloplasty for UPJO. MAIN OUTCOME MEASUREMENT: Primary outcome was reduced renal function defined as MAG3 function <40%. Multivariable logistic regression was applied to identify the independent predictive biomarkers in the original Training cohort. Model validation and generalizability were evaluated in a new UPJO Testing cohort. RESULTS: We included 71 patients with UPJO in the original training cohort and 39 in the validation cohort. Median age was 3.3 years (70% male). By univariate analysis, reduced renal function was associated with higher MMP-2 (p = 0.064), MMP-7 (p = 0.047), NGAL (p = 0.001), and lower TIMP-2 (p = 0.033). Combining MMP-7 with TIMP-2, the multivariable logistic regression model predicted reduced renal function with good performance (AUC = 0.830; 95% CI: 0.722-0.938). The independent testing dataset validated the results with good predictive performance (AUC = 0.738). CONCLUSIONS AND RELEVANCE: Combination of urinary MMP-7 and TIMP-2 can identify reduced renal function in UPJO patients. With the high sensitivity cutoffs, patients can be categorized into high risk (aggressive management) versus lower risk (observation).


Subject(s)
Hydronephrosis , Matrix Metalloproteinase 7 , Tissue Inhibitor of Metalloproteinase-2 , Ureteral Obstruction , Biomarkers/urine , Child , Child, Preschool , Female , Humans , Hydronephrosis/etiology , Hydronephrosis/urine , Kidney/physiopathology , Kidney Pelvis/physiopathology , Lipocalin-2/urine , Male , Matrix Metalloproteinase 2/urine , Matrix Metalloproteinase 7/urine , Prospective Studies , Tissue Inhibitor of Metalloproteinase-2/urine , Ureteral Obstruction/complications , Ureteral Obstruction/surgery , Ureteral Obstruction/urine
2.
J Proteome Res ; 20(5): 2662-2672, 2021 05 07.
Article in English | MEDLINE | ID: mdl-33650863

ABSTRACT

The glycoprotein uromodulin (UMOD) is the most abundant protein in urine, and N-glycans are critical for many biological functions of UMOD. Comprehensive glycan profiling of UMOD provides valuable information to understand the exact mechanisms of glycan-regulated functions. To perform comprehensive glycosylation analysis of UMOD from urine samples with limited volumes, we developed a streamlined workflow that included UMOD isolation from 5 mL of urine from 6 healthy adult donors (3 males and 3 females) and a glycosylation analysis using a highly sensitive and reproducible nanoLC-MS/MS based glycomics approach. In total, 212 N-glycan compositions were identified from the purified UMOD, and 17% were high-mannose glycans, 2% were afucosylated/asialylated, 3% were neutral fucosylated, 28% were sialylated (with no fucose), 46% were fucosylated and sialylated, and 4% were sulfated. We found that isolation of UMOD resulted in a significant decrease in the relative quantity of high-mannose and sulfated glycans with a significant increase of neutral fucosylated glycans in the UMOD-depleted urine relative to the undepleted urine, but depletion had little impact on the sialylated glycans. To our knowledge, this is the first study to perform comprehensive N-glycan profiling of UMOD using nanoLC-MS/MS. This analytical workflow would be very beneficial for studies with limited sample size, such as pediatric studies, and can be applied to larger patient cohorts not only for UMOD interrogation but also for global glycan analysis.


Subject(s)
Glycomics , Tandem Mass Spectrometry , Adult , Child , Female , Glycosylation , Humans , Male , Polysaccharides , Uromodulin
3.
Mol Cell Proteomics ; 19(3): 456-466, 2020 03.
Article in English | MEDLINE | ID: mdl-31896675

ABSTRACT

Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage. Improving diagnostic modalities to identify UTI risk factors would significantly alter the clinical management of children with VUR. We profiled the urinary proteomes of 22 VUR patients with low grade VUR (1-3 out of 5), a history of recurrent UTIs, and renal scarring, comparing them to those obtained from 22 age-matched controls. Urinary proteins were analyzed by mass spectrometry followed by protein quantitation based on spectral counting. Of the 2,551 proteins identified across both cohorts, 964 were robustly quantified, as defined by meeting criteria with spectral count (SC) ≥2 in at least 7 patients in either VUR or control cohort. Eighty proteins had differential expression between the two cohorts, with 44 proteins significantly up-regulated and 36 downregulated (q <0.075, FC ≥1.2). Urinary proteins involved in inflammation, acute phase response (APR), modulation of extracellular matrix (ECM), and carbohydrate metabolism were altered among the study cohort.


Subject(s)
Proteome , Urinary Tract Infections/urine , Vesico-Ureteral Reflux/urine , Female , Humans , Male , Peptides/urine , Pilot Projects , Recurrence , Urinary Tract Infections/metabolism , Urine/chemistry , Vesico-Ureteral Reflux/metabolism
4.
Mol Cell Proteomics ; 15(8): 2607-15, 2016 08.
Article in English | MEDLINE | ID: mdl-27215552

ABSTRACT

Prenatal hydronephrosis is a common condition that may spontaneously resolve after birth. However, this condition can result in renal damage and requires surgical correction in a number of cases. Preventing renal damage is paramount, but existing diagnostic technology is invasive, exposes infants to radiation, is costly, and is often indeterminate. A better understanding of the pathophysiology of renal obstruction as reflected in the urinary proteome may provide new insights into the disease that could potentially alter the clinical management of hydronephrosis. We performed a quantitative proteomics study of urine that was surgically obtained from eight clinically significant, unilaterally obstructed infants versus eight healthy controls, with the goal of identifying quantitatively varying proteins and the biological networks associated with them. Notably, urine was obtained from both the obstructed kidney and the bladder. Over 1100 proteins were identified, and a total of 76 quantitatively varying proteins were identified. Proteins involved in oxidative stress, inflammation, and renal disease pathways showed the most significant abundance differences. This study gives a deeper understanding of the critical proteomic changes associated with renal obstruction and represents the deepest proteomic profile of renal obstruction to date.


Subject(s)
Biomarkers/urine , Kidney/metabolism , Proteomics/methods , Ureteral Obstruction/metabolism , Urinary Bladder/metabolism , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Male , Protein Interaction Maps
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