CKD273, a New Proteomics Classifier Assessing CKD and Its Prognosis

Argilés, Àngel; Siwy, Justyna; Duranton, Flore; Gayrard, Nathalie; Dakna, Mohammed; Lundin, Ulrika; Osaba, L.; Delles, Christian; Mourad, Georges; Weinberger, Klaus M.; Mischak, Harald

doi:10.1371/journal.pone.0062837

Cited by 130 publications

(124 citation statements)

References 27 publications

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“…The process appears to be regulated by transforming growth factor-β1 [75] and emerging evidence suggests it exerts a renoprotective role [76] , which is possibly, at least in part, related to its capability to degrade insoluble collagen I [77] . In support of this notion, a urine peptidome study in CKD patients has demonstrated an inverse correlation between the amount of collagen I and III breakdown products and CKD progression [78,79] .…”

Section: Autophagymentioning

confidence: 89%

Acute Kidney Injury: Tubular Markers and Risk for Chronic Kidney Disease and End-Stage Kidney Failure

Tan¹,

Yap

Qian

2016

Blood Purif

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Acute kidney injury (AKI) is a common clinical syndrome directly related to patient short-term and long-term morbidity and mortality. Over the last decade, the occurrence rate of AKI has been increasing, and there has also been a growing epidemic of chronic kidney diseases (CKD) and end-stage kidney disease (ESRD) linked to severe and repeated episodes of AKIs. The detection and management of AKI are currently far from satisfactory. A large proportion of AKI patients, especially those with preexisting CKD, are at an increased risk of non-resolving AKI and progressing to CKD and ESRD. Proposed pathological processes that contribute to the transition of AKI to CKD and ESRD include severity and frequency of kidney injury, alterations of tubular cell phenotype with cells predominantly in the G2/M phase, interstitial fibrosis and microvascular rarification related to loss of endothelial-pericyte interactions and pericyte dedifferentiation. Innate immune responses, especially dendritic cell responses related to inadequate adenosine receptor (2a)-mediated signals, autophagic insufficiency and renin-angiotensin system activation have also been implicated in the progression of AKI and transitions from AKI to CKD and ESRD. Although promising advances have been made in understanding the pathophysiology of AKI and AKI consequences, much more work needs to be done in developing biomarkers for detecting early kidney injury, prognosticating kidney disease progression and developing strategies to effectively treat AKI and to minimize AKI progression to CKD and ESRD.

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Section: Autophagymentioning

confidence: 89%

Acute Kidney Injury: Tubular Markers and Risk for Chronic Kidney Disease and End-Stage Kidney Failure

Tan¹,

Yap

Qian

2016

Blood Purif

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“…This most likely confers the previously observed predictive abilities of the classifier. 19,20,28 Finally, the size of the cohort allowed the identification of urinary peptides specifically associated with mild-moderate or advanced stage CKD as well. To our knowledge, this is the first time that potential biomarkers were analyzed with respect to their association with different stages of CKD and hence may allow further stratification of patients with CKD.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

Schanstra

Zürbig

Alkhalaf

et al. 2015

Journal of the American Society of Nephrology

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197

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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 (0.303620.065; P,0.001) and integrated discrimination improvement (0.05860.014; 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.

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“…Although initially designed for the detection of CKD, employment of the classifier also allowed prediction of progression of CKD in patients with CKD derived from different aetiologies 28,29 , including patients with DN 30,31 .…”

Section: Introductionmentioning

confidence: 99%

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

Klein

Ramírez-Torres

Ericsson

et al. 2016

Kidney International

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Diabetic nephropathy (DN) is among the most frequent complications of diabetes and the first cause of end-stage renal disease. Despite being successful in animal models, the majority of clinical trials for novel drugs targeting DN failed. This lack of translational value may in part be due to an inadequate comparability of human disease and animal models that often capture only a few aspects of disease. Here we overcome this limitation by developing a multimolecular non-invasive humanized readout of DN based on urinary peptidomics. The diseasemodified urinary peptides of two type 2 diabetic (T2D) DN mouse models were identified and compared with previously validated urinary peptide markers of DN in humans to generate a classifier composed of 21 ortholog peptides. This classifier predicted the response to disease and treatment with inhibitors of the renin-angiotensin system (RASi) in mice. The humanized classifier was significantly correlated with glomerular lesions. Using a human T2D validation cohort consisting of 207 patients, the classifier also distinguished between patients with and without DN, and response to RASi. Our approach demonstrates that a combination of multiple molecular features similar in both human and animal disease could provide a step change in translational drug discovery research in T2D-DN nephropathy.

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CKD273, a New Proteomics Classifier Assessing CKD and Its Prognosis

Cited by 130 publications

References 27 publications

Acute Kidney Injury: Tubular Markers and Risk for Chronic Kidney Disease and End-Stage Kidney Failure

Acute Kidney Injury: Tubular Markers and Risk for Chronic Kidney Disease and End-Stage Kidney Failure

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

Urinary peptidomics provides a noninvasive humanized readout of diabetic nephropathy in mice

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