How has urinary proteomics contributed to the discovery of early biomarkers of acute kidney injury?

Abstract

In the past decade, analysis of the urinary proteome (urinary proteomics) has intensified in response to the need for novel biomarkers that support early diagnosis of kidney diseases. In particular, this also applies to acute kidney injury, which is a heterogeneous complex syndrome with a still-increasing incidence at the intensive care unit. Unfortunately, this major need remains largely unmet to date. The current report aims to explain why attempts to implement urinary proteomic-discovered acute kidney injury diagnostic candidates in the intensive care unit setting have not yet led to success. Subsequently, some key notes are provided that should enhance the chance of translating selected urinary proteomic candidates to valuable tools for the nephrologist and intensivist in the near future.

Keywords::

• acute kidney injury
• animal model
• diagnostic biomarker
• early detection
• intensive care unit
• urinary proteomics

Acknowledgement

J De Loor is supported by Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Research Foundation-Flanders).

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Acute kidney injury (AKI) or, according to its novel nomenclature, ‘kidney attack’ represents a very heterogeneous syndrome, with often a multifactorial etiology including several injurious hits in time.

• Within the relatively young field of urinary proteomics, the discovery of early diagnostic AKI biomarkers is a hot topic.

• Relatively few original urinary proteomics papers have been published within the specific field of AKI during the past decade.

• The majority of the AKI urinary proteomic studies have been carried out in human patients.

• The current preclinical AKI models – mostly in rodents – do not reflect the complexity of the AKI syndrome, nor do they exactly reflect its pathophysiology, just like preclinical sepsis models do not replicate the complexity of human sepsis. Nevertheless, novel diagnostic AKI biomarkers discovered by urinary proteomics in such simplified too homogeneous models warrant proof-of-concept evaluation in different patient cohorts, as specific urinary biomarkers might perform superior in one group whilst inferior in another group of patients (stratification).

• Based on either the biological function, or both the function and (renal) origin of a biomarker, a cautious prediction may be made regarding its diagnostic potential in specific cohorts. Besides the predominant AKI etiology and pathophysiology, age and sex must also be considered as important determinant factors.

• The successful clinical translation of novel urinary proteomic-discovered AKI biomarkers remains remarkably poor, while the need for relevant biomarkers has sharply increased together with the incidence of hospital-acquired AKI in the intensive care unit.

• There is a growing consensus that the heterogeneous AKI syndrome requests multiple biomarkers for its early diagnosis, and that hence a panel of such biomarkers rather than a single biomarker should be used to increase accuracy. Nevertheless, this implicates both financial and practical considerations.

• Major hurdles in evaluating urinary biomarkers’ performances are the lack of an accurate gold standard for AKI diagnosis, the issue of correcting for variation in urine volume by normalization to urinary creatinine or otherwise and the inherent underestimation of the diagnostic value when using the same cut-off in all types of patients.

• Results obtained from the current urinary proteomic studies typically show disappointing clinical value upon their validation, which is however often a biased conclusion based on the following arguments. First, claiming of a biomarker to be the ‘renal troponin’ suited for use in all AKI settings is setting the expectations too high. Second, laboratory tests that measure the biomarker concentration may be imperfect. Essentially, in clinical practice, no substantial progress has been made in the last decade in sharp contrast to the efforts performed, and serum creatinine together with urine output remain the clinician’s tools to date.

Notes