Dataset Information

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

ABSTRACT: Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

SUBMITTER: Schanstra JP

PROVIDER: S-EPMC4520165 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

Schanstra Joost P JP Zürbig Petra P Alkhalaf Alaa A Argiles Angel A Bakker Stephan J L SJ Beige Joachim J Bilo Henk J G HJ Chatzikyrkou Christos C Dakna Mohammed M Dawson Jesse J Delles Christian C Haller Hermann H Haubitz Marion M Husi Holger H Jankowski Joachim J Jerums George G Kleefstra Nanne N Kuznetsova Tatiana T Maahs David M DM Menne Jan J Mullen William W Ortiz Alberto A Persson Frederik F Rossing Peter P Ruggenenti Piero P Rychlik Ivan I Serra Andreas L AL Siwy Justyna J Snell-Bergeon Janet J Spasovski Goce G Staessen Jan A JA Vlahou Antonia A Mischak Harald H Vanholder Raymond R

Journal of the American Society of Nephrology : JASN 20150114 8

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and pr ...[more]

PMID: 25589610

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Project description:Introduction:Chronic kidney disease of uncertain etiology (CKDu), an emerging chronic kidney disease (CKD) subtype, contributes to significant morbidity and mortality in certain tropical countries. Although several indicators of CKDu have been previously suggested, sensitive and specific tests to detect early disease or predict disease progression are currently unavailable. This study focused on evaluating 8 renal urinary markers, namely neutrophil gelatinase-associated lipocalin (NGAL), Kidney Injury Molecule-1 (KIM1), cystatin C (CST3), beta 2 microglobulin (B2M), osteopontin (OPN), alpha 1 microglobulin (A1M), tissue inhibitor of metalloproteinase 1 (TIMP1), and retinol binding protein 4 (RBP4), with the hypothesis that these have distinct expression patterns in patients with CKDu. Methods:A cross-sectional study was conducted with 5 study groups comprising subjects from CKDu, endemic CKD, nonendemic CKD, and endemic healthy and nonendemic healthy controls. The urinary levels of the 8 selected renal biomarkers were quantified using multiplex biomarker assay, and the data were subjected to systematic analysis using logistic regression algorithm aiming to extract the best marker combination that could distinctly identify the disease groups noninvasively from the healthy controls. Results:A 3-marker signature panel comprising A1M, KIM1, and RBP4 was identified to represent the best minimum marker combination for differentiating all CKD categories, including CKDu, from healthy controls with an overall sensitivity of ?0.867 and specificity ?0.765. The marker combination comprising OPN, KIM1, and RBP4 showed high predictive performance for distinguishing patients with CKDu from patients with CKD with both sensitivity and specificity ?0.93, which was superior to any existing noninvasive indicator. Conclusion:In all, our systematic evaluation of urinary markers previously linked to CKD, in general, allowed identification of exclusive marker panel combination for early diagnosis and confirmation of CKDu.

Project description:Rationale & Objective Chronic kidney disease (CKD) is a major cause of morbidity and mortality. To date, there are no widely used machine-learning models that can predict progressive CKD across the entire disease spectrum, including the earliest stages. The objective of this study was to use readily available demographic and laboratory data from Sonic Healthcare USA laboratories to train and test the performance of machine learning-based predictive risk models for CKD progression. Study Design Retrospective observational study Setting & Participants The study population was composed of deidentified laboratory information services data procured from a large US outpatient laboratory network. The retrospective data set included 110,264 adult patients over a 5-year period with initial estimated glomerular filtration rate (eGFR) values between 15-89 mL/min/1.73 m2. Predictors Patient demographic and laboratory characteristics. Outcomes Accelerated (ie, >30%) eGFR decline associated with CKD progression within 5 years. Analytical Approach Machine-learning models were developed using random forest survival methods, with laboratory-based risk factors analyzed as potential predictors of significant eGFR decline. Results The 7-variable risk classifier model accurately predicted an eGFR decline of >30% within 5 years and achieved an area under the curve receiver-operator characteristic of 0.85. The most important predictor of progressive decline in kidney function was the eGFR slope. Other key contributors to the model included initial eGFR, urine albumin-creatinine ratio, serum albumin (initial and slope), age, and sex. Limitations The cohort study did not evaluate the role of clinical variables (eg, blood pressure) on the performance of the model. Conclusions Our progressive CKD classifier accurately predicts significant eGFR decline in patients with early, mid, and advanced disease using readily obtainable laboratory data. Although prospective studies are warranted, our results support the clinical utility of the model to improve timely recognition and optimal management for patients at risk for CKD progression. Plain-Language Summary Defined by a significant decrease in estimated glomerular filtration rate (eGFR), chronic kidney disease (CKD) progression is strongly associated with kidney failure. However, to date, there are no broadly used resources that can predict this clinically significant event. Using machine-learning techniques on a diverse US population, this cohort study aimed to address this deficiency and found that a 5-year risk prediction model for CKD progression was accurate. The most important predictor of progressive decline in kidney function was the eGFR slope, followed by the urine albumin-creatinine ratio and serum albumin slope. Although further study is warranted, the results showed that a machine-learning model using readily obtainable laboratory information accurately predicts CKD progression, which may inform clinical diagnosis and management for this at-risk population. Graphical abstract

Dataset Information

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

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Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

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