Cell-cycle arrest and acute kidney injury: the light and the dark sides

Abstract

Acute kidney injury (AKI) is a common consequence of systemic illness or injury and it complicates several forms of major surgery. Two major difficulties have hampered progress in AKI research and clinical management. AKI is difficult to detect early and its pathogenesis is still poorly understood. We recently reported results from multi-center studies where two urinary markers of cell-cycle arrest, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) were validated for development of AKI well ahead of clinical manifestations--azotemia and oliguria. Cell-cycle arrest is known to be involved in the pathogenesis of AKI and this 'dark side' may also involve progression to chronic kidney disease. However, cell-cycle arrest has a 'light side' as well, since this mechanism can protect cells from the disastrous consequences of entering cell division with damaged DNA or insufficient bioenergetic resources during injury or stress. Whether we can use the light side to help prevent AKI remains to be seen, but there is already evidence that cell-cycle arrest biomarkers are indicators of both sides of this complex physiology.

Keywords: acute kidney injury; cell-cycle arrest; insulin-like growth factor-binding protein 7; tissue inhibitor of metalloproteinases-2.

FIGURE 1:

Stage-based management of AKI. Shading of boxes indicates priority of action—solid shading indicates actions that are equally appropriate at all stages whereas graded shading indicates increasing priority as intensity increases. AKI, acute kidney injury; ICU, intensive care unit. Source: www.KDIGO.org.

FIGURE 2:

Top: [TIMP-2]•[IGFBP7] ROC curves for the Opal (solid), Sapphire (short dash) and Topaz (long dash) cohorts. Closed circles and triangles indicate [TIMP-2]•[IGFBP7] cutoffs of 0.3 and 2.0, respectively. Area under the ROC curve (95% CI) = 0.79 (0.69–0.88), 0.80 (0.74–0.84) and 0.82 (0.76–0.88) for Opal, Sapphire and Topaz, respectively. Bottom: Relative risk of AKI stage 2 or 3 within 12 h in the Opal (light gray), Sapphire (medium gray) and Topaz (dark gray) cohort.

FIGURE 3:

Proposed mechanistic involvement of the novel biomarkers in AKI: Initial tubular cells sustain injury by various insults. In response to DNA and possibly other forms of damage IGFBP7 and TIMP-2 are expressed in the tubular cells. IGFBP7 directly increases the expression of p53 and p21 and TIMP2 stimulates p27 expression. These effects are conducted in an autocrine and paracrine manner via IGFBP7 and TIMP-2 receptors. The p proteins in turn, block the effect of the cyclin-dependent protein kinase complexes (CyclD-CDK4 and CyclE-CDK2) on the cell-cycle promotion, thereby resulting in G1 cell-cycle arrest for short periods of time presumably to avoid cells with possible damage from dividing. Source: [14].

FIGURE 4:

Proposed clinical application of risk assessment for patients immediately after cardiac surgery. STS, Society of Thoracic Surgery; I/O, input and output; sCr, serum creatinine; CVP, central venous pressure; NSAIDS, Non-steroidal anti-inflammatory drug; ACE, Angiotenson converting enzyme inhibitor; SCVO2, central verous oxygen saturation; h/o, history of; LV Fx, Left ventricular function; PA, pulmonary artery; CI, cardiac index.