Rational selection of a biomarker panel targeting unmet clinical needs in kidney injury

Abstract

The pipeline of biomarker translation from bench to bedside is challenging and limited biomarkers have been adopted to routine clinical care. Ideally, biomarker research and development should be driven by unmet clinical needs in health care. To guide researchers, clinical chemists and clinicians in their biomarker research, the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) has developed a structured questionnaire in which the clinical gaps in current clinical pathways are identified and desirable performance specifications are predefined. In kidney injury, the high prevalence of the syndrome acute kidney injury (AKI) in the hospital setting has a significant impact on morbidity, patient survival and health care costs, but the use of biomarkers indicating early kidney injury in daily patient care remains limited. Routinely, medical labs measure serum creatinine, which is a functional biomarker, insensitive for detecting early kidney damage and cannot distinguish between renal and prerenal AKI. The perceived unmet clinical needs in kidney injury were identified through the EFLM questionnaire. Nephrologists within our tertiary care hospital emphasized that biomarkers are needed for (1) early diagnosis of in-hospital AKI after a medical insult and in critically ill patients, (2) risk stratification for kidney injury prior to a scheduled (elective) intervention, (3) kidney injury monitoring in patients scheduled to receive nephrotoxic medication and after kidney transplantation and (4) differentiation between prerenal AKI and structural kidney damage. The biomarker search and selection strategy resulted in a rational selection of an eleven-protein urinary panel for kidney injury that target these clinical needs. To assess the clinical utility of the proposed biomarker panel in kidney injury, a multiplexed LC-MS test is now in development for the intended translational research.

Keywords: Acute kidney injury; Biomarkers; Clinical needs; Urinalysis; Urine proteomics.

Fig. 1

Strategy for the rational biomarker selection and test development driven by unmet clinical needs in kidney injury. Clinical needs were identified by nephrologists using a peer reviewed EFLM Test Evaluation questionnaire. Subsequently, desirable test roles, test purposes and clinical performance specifications in the clinical pathway were defined. Through a literature study a candidate biomarker panel is proposed that could meet existing gaps in current practice and aims to improve clinical practice and outcome. A multiplex test is in development to enable precision diagnostics in kidney injury

Fig. 2

Paradigm shift from current practice to desirable clinical practice by targeting suboptimal detection of kidney injury using a kidney injury biomarker panel. Test purposes and test roles of individual panel proteins in the clinical care pathway are driven by the identified unmet clinical needs. Early optimised treatment may prevent conversion to irreversible structural kidney damage and would improve patient outcome

Fig. 3

Desirable time kinetics of kidney injury biomarkers. The four unmet clinical needs in kidney injury all require specific biomarker rise and fall patterns. For early diagnosis, early rises within hours are essential whereas for late diagnosis a protracted time kinetic is needed. For risk stratification the biomarker concentration should be altered prior to the intervention. For kidney injury monitoring, a close relation to structural damage is needed

Fig. 4

Proposed kidney injury biomarker panel targeting the unmet clinical needs in kidney injury at the Departments of Nephrology and Clinical and Laboratory Medicine, Leiden, The Netherlands. Four major clinical gaps were identified in kidney injury testing using a questionnaire. After verification of the needs, a literature search was performed and eleven candidate biomarkers were selected for a mass spectrometry-based test to address the unmet clinical needs