Urinary peptide-based classifier CKD273: towards clinical application in chronic kidney disease - PubMed (original) (raw)

Urinary peptide-based classifier CKD273: towards clinical application in chronic kidney disease

Claudia Pontillo et al. Clin Kidney J. 2017 Apr.

Abstract

Capillary electrophoresis coupled with mass spectrometry (CE-MS) has been used as a platform for discovery and validation of urinary peptides associated with chronic kidney disease (CKD). CKD affects ∼ 10% of the population, with high associated costs for treatments. A urinary proteome-based classifier (CKD273) has been discovered and validated in cross-sectional and longitudinal studies to assess and predict the progression of CKD. It has been implemented in studies employing cohorts of > 1000 patients. CKD273 is commercially available as an in vitro diagnostic test for early detection of CKD and is currently being used for patient stratification in a multicentre randomized clinical trial (PRIORITY). The validity of the CKD273 classifier has recently been evaluated applying the Oxford Evidence-Based Medicine and Southampton Oxford Retrieval Team guidelines and a letter of support for CKD273 was issued by the US Food and Drug Administration. In this article we review the current evidence published on CKD273 and the challenges associated with implementation. Definition of a possible surrogate early endpoint combined with CKD273 as a biomarker for patient stratification currently appears as the most promising strategy to enable the development of effective drugs to be used at an early time point when intervention can still be effective.

Keywords: CKD progression; chronic kidney disease (CKD); peptides-based classifiers; proteomics; urinary biomarkers.

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Figures

Fig. 1

Fig. 1

Early diagnosis and/or prognosis of diseases improves chances for a better outcome for the patient. The initiation of molecular processes that result in (chronic) diseases can be detected based on molecular changes, using proteomic technologies, prior to advanced organ damage. This could allow earlier intervention where drugs are most effective. The figure is adapted from Stepczynska et al. [10].

Fig. 2

Fig. 2

Representation of urinary CE-MS workflow. Urinary proteins are detected by CE-MS, where the mass and relative abundance of each protein is analysed. All the detected peptides are stored in a database, which allows further evaluation of the peptides to be used for diagnostic purposes.

Fig. 3

Fig. 3

Major milestones on the path towards implementation of CKD273. Shown are the main milestones and developments from the initial discovery until the issuing of the FDA Letter of Support.

Fig. 4

Fig. 4

Biological processes generally accepted to be involved in CKD onset and progression. The processes are indicated in the boxes. Outside, peptides found significantly changes in CKD are indicated, at the respective step in the disease development. [36].

Fig. 5

Fig. 5

Representation of the studies evaluating the performance of the CKD273-classifier in the diagnosis and prognosis of CKD according to disease stage. The bars show the CKD stages in which the classifier was used. The Figure is adapted from Critselis and Lambers Heerspink [36].

Fig. 6

Fig. 6

Schematic concept of CKD onset and progression. The kidney contains ∼1 million filtration units (glomeruli). From the initially healthy status (a), some glomeruli experience pathological molecular changes (yellow) reversibly compromising their function. Without treatment, additional glomeruli will be damaged (c), a few also beyond the point where effective treatment may be possible (red). As pressure on the remaining intact glomeruli increases, damage of individual glomeruli is further accelerated (d), with now detectable impact on kidney functional parameters (albuminuria and/or eGFR), and the first glomeruli are lost (black). The molecular mechanisms are identical at this later stage to the beginning, but irreversible damage has occurred to multiple glomeruli, which cannot be repaired. Progression from (d) to (e) (established CKD, most glomeruli damaged, many beyond repair or completely lost) and then to (f) (ESRD, very few glomeruli still functional) cannot be prevented because of the too high burden on the few remaining glomeruli. Prevention would have been possible with intervention at (b) or (c), stages where molecular changes displayed by CKD273 are evident but functional parameters are not yet affected.

Fig. 7

Fig. 7

Humanized model concept. Improving the translatability of animal models of disease with the development of a multimolecular humanized readout. The analysis of multiple urinary proteomic changes in the animal model allows identifying, similar (ortholog) changes in human disease and animal models, leading to a humanized readout, which will more efficiently translate the effects of new drugs in preclinical models to the clinic.

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