Dataset Information

Identification of Biomarkers for PKD1 Using Urinary Exosomes.

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of ESRD. Affected individuals inherit a defective copy of either PKD1 or PKD2, which encode polycystin-1 (PC1) or polycystin-2 (PC2), respectively. PC1 and PC2 are secreted on urinary exosome-like vesicles (ELVs) (100-nm diameter vesicles), in which PC1 is present in a cleaved form and may be complexed with PC2. Here, label-free quantitative proteomic studies of urine ELVs in an initial discovery cohort (13 individuals with PKD1 mutations and 18 normal controls) revealed that of 2008 ELV proteins, 9 (0.32%) were expressed at significantly different levels in samples from individuals with PKD1 mutations compared to controls (P<0.03). In samples from individuals with PKD1 mutations, levels of PC1 and PC2 were reduced to 54% (P<0.02) and 53% (P<0.001), respectively. Transmembrane protein 2 (TMEM2), a protein with homology to fibrocystin, was 2.1-fold higher in individuals with PKD1 mutations (P<0.03). The PC1/TMEM2 ratio correlated inversely with height-adjusted total kidney volume in the discovery cohort, and the ratio of PC1/TMEM2 or PC2/TMEM2 could be used to distinguish individuals with PKD1 mutations from controls in a confirmation cohort. In summary, results of this study suggest that a test measuring the urine exosomal PC1/TMEM2 or PC2/TMEM2 ratio may have utility in diagnosis and monitoring of polycystic kidney disease. Future studies will focus on increasing sample size and confirming these studies. The data were deposited in the ProteomeXchange (identifier PXD001075).

SUBMITTER: Hogan MC

PROVIDER: S-EPMC4483583 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Identification of Biomarkers for PKD1 Using Urinary Exosomes.

Hogan Marie C MC Bakeberg Jason L JL Gainullin Vladimir G VG Irazabal Maria V MV Harmon Amber J AJ Lieske John C JC Charlesworth M Cristine MC Johnson Kenneth L KL Madden Benjamin J BJ Zenka Roman M RM McCormick Daniel J DJ Sundsbak Jamie L JL Heyer Christina M CM Torres Vicente E VE Harris Peter C PC Ward Christopher J CJ

Journal of the American Society of Nephrology : JASN 20141204 7

Autosomal dominant polycystic kidney disease (ADPKD) is a common cause of ESRD. Affected individuals inherit a defective copy of either PKD1 or PKD2, which encode polycystin-1 (PC1) or polycystin-2 (PC2), respectively. PC1 and PC2 are secreted on urinary exosome-like vesicles (ELVs) (100-nm diameter vesicles), in which PC1 is present in a cleaved form and may be complexed with PC2. Here, label-free quantitative proteomic studies of urine ELVs in an initial discovery cohort (13 individuals with P ...[more]

PMID: 25475747

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Project description:BackgroundChronic renal disease (CKD) is a common and irreversible loss of renal function. Renal fibrosis reflected the degree of renal dysfunction. However, the current biomarkers only characterize the renal function instead of indicating the fibrosis degree. The potential diagnostic value of urinary exosomes derived circRNAs for renal fibrosis needs to be further studied.MethodsUrine exosomes from 3 chronic kidney disease (CKD) patients without renal fibrosis and 3 renal fibrotic patients were collected and human circRNAs microarray analysis were performed to detect the circRNAs expression profile. 110 biopsy-proven CKD patients and 54 healthy controls were enrolled and urine exosomes derived RNA was isolated. The expression of hsa_circ_0036649 was measured and the correlation with renal function parameter and pathological indicators was performed. The receiver operating characteristic (ROC) curve for the diagnosis of renal fibrosis was calculated.ResultsHuman circRNAs microarray showed 365 circRNAs up expressed and 195 circRNAs down expressed in renal fibrotic patients compared to none fibrosis CKD patients. The expression of hsa_circ_0036649 was decreased in renal fibrotic patients according to RT-PCR and correlated with serum creatinine, blood urea nitrogen (BUN), estimated glomerular filtration rate and cystatin c. Further, the expression of hsa_circ_0036649 was correlated with the score of tubulointerstitial fibrosis (TIF) and the score of glomerular sclerosis. The ROC curve showed that hsa_circ_0036649 may predict renal fibrosis at a cut-off value of 0.597 with a sensitivity of 45.5% and specificity of 87.9%.ConclusionExpression of urinary exosomes derived hsa_circ_0036649 associated with the degree of renal fibrosis. Its potential role as a biomarker in CKD remained to be supported by further follow-up studies.Key MessagescircRNAs profile in urine exosomes in renal fibrosis patients was revealed.The expression of urine exosomes derived hsa_circ_0036649 was correlated to renal function and fibrosis degree.circRNAs derived from urinary exosomes may become a new research direction for biomarkers of renal fibrosis.

Project description:Background and study aims Bowel cancer is diagnosed in 40,000 people each year in the UK. Early detection and treatment of bowel cancer is important as it improves survival. This has led to a “fast-track” system to speed up waiting times and access to hospital tests. Deciding who to test is a hard for GPs and hospital doctors because bowel symptoms are common and are not usually due to cancer. In addition, not all people with a bowel cancer develop symptoms. Therefore, at present the vast majority of patients are required to undergo testing. An internal camera examination of the large bowel (colonoscopy) is the best way to look at the large bowel. This is invasive, can be uncomfortable and needs strong laxatives to prepare the bowel. There is a risk of unplanned admission to hospital and surgery. This test is also expensive and the demand is increasing in the NHS. In the UK, 300,000 people a year are referred through the fast-track system for suspected bowel cancer. Over 90% of these have normal results, meaning they have undergone unpleasant testing that did not help them. It is now possible to look at natural chemicals, produced by normal bacteria that live in everybody’s bowel, to help diagnose bowel conditions. Bowel cancer alters the chemical “signature”. The aim of this study is to test the urine of 600 people referred by their GP to the fast-track pathway for these chemicals to see how good they are at predicting bowel cancer. Who can participate? Patients aged 18 and over, referred by their GP for fast-track assessment due to symptoms of colorectal cancer What does the study involve? Participants provide a urine sample when they attend the hospital for colonoscopy or CT scanning. Participants are also asked to complete a short questionnaire collecting demographic information and some data about lifestyle including smoking status, alcohol use and dietary habit (meat eating, vegetarian or vegan diet). From that point on their clinical pathway is unaffected by participation in the study and the results of the volatile compound testing are not be available to the clinical team. At the end of their investigations (maximum of 63 days), a member of the research team accesses patient notes to collect disease outcome data coded as cancer, polyp or normal. The participants receive treatment as normal judged on the clinical data available to the clinicians caring for them. The urine samples are sent for analysis at the University of the West of England. They are analysed using three separate machines to identify which of these machines is the best for use in a clinical setting, to take forward into a larger study. Data from the testing are then analysed along with the data about disease status in order to assess the sensitivity and reliability of the testing for the identification of patients at high risk of having colon cancer.

Dataset Information

Identification of Biomarkers for PKD1 Using Urinary Exosomes.

Publications

Identification of Biomarkers for PKD1 Using Urinary Exosomes.

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