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order to prospectively validate the lower (0.3) biomarker cutoff of KDIGO-recommended interventions [10] and might also
value for risk assessment of AKI. This was the rst study to enable interventional studies for the treatment of AKI in the
FULL REVIEW
evaluate urinary [TIMP-2][IGFBP7] where the end point not-so-distant future [13].
was determined by clinical adjudication by AKI experts blinded Importantly, both TIMP-2 and IGFBP7 may increase in re-
to the results of the test. We found that the urinary [TIMP-2] sponse to a wide variety of insults (inammation, oxidative
[IGFBP7] test signicantly improved risk assessment by strati- stress, ultraviolet radiation, drugs and toxins) [2123]. This
fying patients into distinct risk categories, with a 7-fold increase may help explain why they correspond to risk for AKI, a syn-
in risk for patients with a [TIMP-2][IGFBP7] test value >0.3 drome known for its multiple etiologies even in the same pa-
compared with those 0.3. When two cutoffs are used, relative tient. However, these insults may not actually destroy cells
risk for >0.32.0 was 5, and >2.0 relative risk was 17 (P < 0.002). and these molecules appear to be able to signal in autocrine
Furthermore, using a multivariate model including clinical in- and paracrine fashions [23, 24] thus behaving more like an
formation, urinary [TIMP-2][IGFBP7] remained statistically alarm spreading to adjacent cells (Figure 3). In terms of tim-
signicant and a strong predictor of AKI. The clinical model ing, this signal could represent the earliest point of cellular
alone exhibited an AUC 0.70, 95% CI 0.630.76 while the stress. Biomarkers that can detect cellular stress (or conversely
AUC was 0.86, 95% CI 0.800.90 for clinical variables plus cell health) may be more useful than markers of injury or cell
[TIMP-2][IGFBP7]). death [13].
Thus, urinary [TIMP-2][IGFBP7] has now been shown to As urinary [TIMP-2][IGFBP7] can aid in the risk assess-
provide early risk stratication for imminent AKI in over 1200 ment for AKI, it is important to recognize that, like all diagnos-
critically ill patients in three multi-center studies enrolling di- tic tests, it does not take the place of clinical judgment.
verse groups of patients (Table 1) with the prevalence of major Furthermore, while the test was designed to risk assess for
exposures for AKI, such as sepsis, similar to other reports in the stage 23 AKI, the biomarker concentrations correspond to se-
literature [19, 20]. verity of AKI across all three stages [17]. Thus, clinical applica-
tions may vary depending on the clinical question. However,
the markers do not appear to persist in the urine for long
C L I N I C A L A P P L I C AT I O N O F A K I after AKI has occurred and thus they may be normal in patients
BIOMARKERS who have already manifest AKI by functional criteria (e.g. sCr).
Finally, the cutoffs for the test are based on overall behavior of
Taken together the results of these studies of urinary [TIMP-2] the biomarkers in the majority of patients. While this perform-
[IGFBP7] should enable early triage and risk stratication in a ance appears to be very consistent across various exposures and
wide range of critically ill patients from the emergency room, susceptibilities for AKI, specic groups of patients may require
acute admission areas and intensive care. Specic approaches more ne-tuning. For example, Meersch et al. examined sensi-
might also be used in settings such as cardiac surgery. Early tivity and specicity of [TIMP-2][IGFBP7] for AKI (stage 1 or
identication of these at-risk patients should improve delivery greater) in a high-severity group of patients undergoing cardiac
surgery [25]. These investigators found a sensitivity of 0.92 Each phase of the cell cycle has a specic function that is re-
and specicity of 0.81 for a cutoff value of 0.5 (AUC 0.90) quired for appropriate cell proliferation. Quiescent cells are
using the maximum urinary [TIMP-2][IGFBP7] concentra- normally in G0. In order for cells to divide and begin the process
tion achieved in the rst 24 h following surgery (composite of repair, they must enter and exit each phase of the cell cycle on
time point). schedule [26]. If the cell exits a phase too soon, or stays in a
Taking the cardiac surgery example, we propose a set of phase too long, the normal repair and recovery process can be-
actions based on pre-test assessment of risk and the urinary come maladaptive [26]. For instance, if epithelial cells remain
[TIMP-2][IGFBP7] test result (Figure 4). Low, moderate and arrested in G1 or G2, it favors a hypertrophic and bro-
high risk are based on a combination of (i) underlying clinical tic phenotype [27, 28]. Conversely, exit from cell cycle in late
predisposition (susceptibility) which includes most of the same G1 leads to apoptosis [29]. Cyclins and cyclin-dependent
kinases, and inhibitors control each phase of the cell cycle Interestingly, the various sub-types of TIMP proteins may
[26]. The cell uses cell-cycle arrest as a protective mechanism play different roles in the kidney. Wang et al. have shown that
to avoid cell-division when potentially damaged [30]. By initi- TIMP-3 protects the cells from damage, whereas TIMP-2
ating cell-cycle arrest, cells can thus avoid cell division during appears to promote injury through matrix metalloproteinase
stress and injury, which is protective. However, if the cells do activation [32]. Similarly, research studies in renal transplant
not re-initiate the cell-cycle and remain arrested at G1 or G2 allografts show that matrix metalloproteinase activity is import-
(or possibly other phases of cell cycle), a brotic phenotype ant in mediating scarring in chronic allograft nephropathy [33].
can ensue. Indeed there is already evidence that urinary [TIMP-2]
Both TIMP2 and IGFBP7 have been implicated in the G1 [IGFBP7] is strongly associated with a composite end point
cell-cycle arrest phase noted to occur during the very early of death or need for dialysis. We found that [TIMP-2]
phases of cellular stress (Figure 3) [2123]. Specically, it has [IGFBP7] >2.0 (ng/mL)2/1000 was associated with increased
also been shown that renal tubular cells also go through this risk for mortality or receipt of RRT over the next 9 months (haz-
G1 cell-cycle arrest phase following stress due to a variety of in- ard ratio [HR], 2.11; 95% condence interval [95% CI], 1.37 to
sults [31]. Induction of cell-cycle arrest is not only associated 3.23; P,0.001). Interestingly, in a multivariate analysis adjusted
with increased risk for AKI but may also serve as a mechanistic for the clinical model, [TIMP-2][IGFBP7] >0.3 (ng/mL)2/
link between AKI and CKD [28]. Sustained cell-cycle arrest 1000 were associated with death or RRT only in subjects who
will result in a senescent cell phenotype and lead to brosis. developed AKI (P = 0.002) [34]. Additionally, Aregger et al.
F I G U R E 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-inammatory 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.
recently demonstrated that IGFBP7 levels predicted mortality, growing appreciation for the concept of secondary injury to the
renal recovery and severity/duration of AKI in a small cohort of kidney as danger signaling molecules (damage and pathogen-
critically ill adults [35]. associated molecular patterns) are delivered to the renal tubule
As discussed above, cell-cycle arrest is nonetheless a pro- via both glomerular ltration and the blood stream [39]. These
tective mechanism to avoid the cell entering the cell-cycle molecules are detected by pattern recognition receptors on the
when it is injured or even in an adverse environment [36]. tubular cell surface where they initiate a cascade leading to in-
Thus, temporary G1 cell-cycle arrest should reduce kidney ammation and/or apoptosis. In essence, the available data sug-
damage. Using an animal model of septic AKI secondary to gest that cell-cycle arrest signaling is a protective response, but
cecal ligation and puncture we hypothesized that a pharmaco- when engaged by multiple cells such that increases in markers
logically induced early cell-cycle arrest would be associated like TIMP-2 and IGFBP7 can be detected in the urine, it is often
with less AKI [37]. We used cyclosporine A, a known inducer followed by AKI. Furthermore, if cell-cycle arrest persists the re-
of cell-cycle arrest and previously shown to attenuate kidney sult can become maladaptive and lead to a brosis phenotype.
damage in the setting of folic acid-induced AKI [38], and Early protection of cells might be achievable by supporting the
found that a single dose given 18 h after cecal ligation and cells own self-preservation mechanisms including cell-cycle ar-
puncture and along with initial antibiotics was successful in rest. Conversely, once the danger is past, it may be important to
reducing AKI [37]. Thus manipulation of cell-cycle may re- rapidly reverse this process so that the adverse consequences in-
present a new therapeutic strategy in the prevention and treat- cluding cell senescence and brosis are avoided. Thus, cell-cycle
ment of AKI. arrest activation and deactivation at critical clinical time points
These results are also important because they have implica- for a patient may prove to be targets of therapeutic intervention
tions for how we understand the pathogenesis of AKI. There is a in the future.
FULL REVIEW
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study. Crit Care 2014; 18: 716 Received for publication: 9.12.2014; Accepted in revised form: 4.4.2015