The use of cell cycle arrest biomarkers in the early detection of acute kidney injury. Is this the new renal troponin?

Abstract

Acute kidney injury (AKI) has a high prevalence in critical care patients. Early detection might prevent patients from developing chronic kidney disease and requirement for renal replacement therapy. If we compare AKI with acute coronary syndrome, in which an increase in cardiac troponin may trigger early diagnosis and therapeutic intervention, we could extrapolate a similar technique in patients with early AKI without changes in urinary frequency or serum creatinine. The objective is to identify biomarker-positive, creatinine-negative patients that would allow therapeutic interventions to be initiated before finding changes in serum creatinine, preventing kidney damage. Tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 are cell cycle arrest biomarkers that have demonstrated, in recent clinical trials, to have good sensitivity and specificity for early detection of AKI. Other recent studies have shown that the joint use of these biomarkers with serum creatinine and urine production could improve the prognosis of AKI in critical patients. The application of these biomarkers in clinical practice would enable the early identification of patients at risk of AKI, establishing interventions that would improve the survival of renal function.

<p>Evaluating Nephrocheck^® as a Predictive Tool for Acute Kidney Injury</p>

“…During renal injury in the early phases of AKI, several tumor suppressor proteins like p53, p27 and p21 can be activated, and they upregulate different proteins. 11 IGFBP-7 directly increases the expression of p53 and p21, while TIMP-2 enhances p27 expression. These effects are carried in an autocrine and paracrine pattern through IGFBP-7 and TIMP-2 receptors.…”

“…Some authors postulated that these proteins cause cell-cycle arrest during the very early phase of cellular damage leading the cell-cycle arrest in G1 phase in response to various insults (eg oxidative stress, toxins, ischemia, sepsis, inflammation). 11,12 Cells react to injury by repairing while entering and exiting different phases of proliferation assisted by kinases. G1 cell-cycle arrest prevents division of cells with damaged DNA, allowing an adequate repair ( Figure 1).…”

“…14 Markers of cell-cycle arrest such as TIMP-2 and IGFBP7 may act as a signal warning that the tubular cells have been stressed and have to shut down their functions in the aim of preserve energy. TIMP-2 and IGFBP7 appear to be able to signal in autocrine and paracrine fashions, spreading the alarm from the site of injury 11 to other sites. In Kashani et al 15 prospective, multicentre investigation conducted in 2013, IGFBP-7 and TIMP-2 were validated using a clinical assay and compared to existing markers of AKI in a cohort of heterogeneous critically ill patients without evidence of AKI at the enrolment.…”

Roles Played by Biomarkers of Kidney Injury in Patients with Upper Urinary Tract Obstruction

“…TIMP-2 has a molecular weight of approximately 24 kDa and IGFBP7 has a molecular mass of 29 kDa [ 110 ]. Both of them are expressed and secreted by renal tubular cells, and involved in G1 cell cycle arrest during the early phases of cellular stress or injury caused by various insults (e.g., sepsis, ischemia, oxidative stress, and toxins) [ 111 ]. TIMP-2/ IGFBP7 shows the best accuracy among AKI biomarkers in patients with various types of AKI condition including AKI after kidney transplantation and AKI in critical care settings, sepsis and platinum-based chemotherapy, and chronic kidney damage induced by diabetes mellitus and congestive heart failure [ 112 , 113 ].…”

Biomarkers in acute kidney injury

“…TIMP-2 and IGFBP-7 are expressed and secreted in the kidneys as well as other tissues. Some authors postulated that these proteins halt the G1 phase of the cell cycle in response to different factors (for example, oxidative stress, toxins, ischemia, sepsis, and in lammation); their signaling pathways also have an autocrine and paracrine pattern [51,52]. Hence, markers of cellular cycle detention like TIMP-2 and IGFBP-7 act as a warning sign that tubular cells have been a subject of stress and have to shut down their function to preserve energy.…”