The main results of this prospective study indicated that the occurrence of AKI is common after an IS also in a Brazilian cohort of patients and underscored that the development of AKI is an important complication after IS and an independent predictor of short-term mortality. Together with the baseline severity, assessed by NIHSS, the AKI correctly classified 83.6% of cases. Moreover, the sVCAM-1 showed a potential useful for the prediction of AKI after IS. This result may highlight the increased levels of sVCAM-1 in patients with AKI after IS and that the sVCAM-1 may be an important biomarker to predict AKI in these patients.
Data from the literature show that the onset of AKI in patients after IS is a common complication. However, the reported incidence varies widely and might be underestimated using coding definitions. In a meta-analysis, the authors reported that rates of AKI after IS varied with a range of 0.82–26.68% [32]. Another meta-analysis with 12 studies and more than 5 million patients revealed a prevalence of 11.6% of AKI in patients with ischemic or hemorrhagic stroke, and its occurrence was associated with higher mortality in patients with IS than those without AKI [2]. In a cohort of 40 Hispanic patients, 90.0% of them with IS, the onset of AKI reached 62.5% of the subjects [33]. In a prospective study with 2,155 first IS patients, AKI during hospitalization occurred in 27.0% of them and was associated with a significant increase in mortality after 10 years [7]. AKI has been previously reported in patients with different types of cardiovascular diseases including subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral infarctions 7, 8, 34–37]. The NIHSS score has been established as a very important predictor of short and long-term mortality after IS [38–40]. However, our study showed that patients with high plasma levels of sVCAM-1 showed higher chance to death than those with high baseline severity. Therefore, sVCAM-1 showed to be a good predictor of mortality after IS.
The exact mechanisms underlying AKI after IS are unknown and must be explored. In general, the association between two disease states could be due to chance association: shared risk factors for the two disease states, or the presence of common pathophysiological mechanisms underlying both conditions [41]. Renal failure in IS patients appears to be only a sign of end-organ damage caused by long-term arterial stiffness of small and major arteries caused by atherosclerosis and its associated vascular risk factors, such as aging, smoking, SAH, T2DM, and cardiovascular diseases [42] or independent of other risk factors for atherosclerosis.
Moreover, VCAM-1 is also expressed in normal kidneys, but levels increase many-fold in diseased states [43–45]. Systemic inflammation and immune responses mediated by cytokines, reactive oxygen species (ROS), cell adhesion molecules (CAM) likely play a central role in promoting kidney dysfunction after brain injury [11, 46–48]. CAM play pivotal roles in forming and maintaining cell-cell and cell-substrate contacts in the various segments of the nephron and that perturbations in the functioning of these molecules can have profound effects on renal function. Molecules such as intracellular adhesion molecule-1 (ICAM-1), the integrins and selectins play important roles in the recruitment of leukocytes and inflammatory responses that are associated with nephrotoxic injury [49]. In a study that evaluated the role of microvascular endothelial injury and endothelial glycocalyx dysfunction in the pathogenesis of AKI, the VCAM-1, but not ICAM-1, appeared to be related to kidney injury in a Bayesian model [50]. Therefore, it is plausible that CAM may be an important factor triggering kidney disfunction.
Injury to the brain increases the expression of inflammatory factors such as C-reactive protein (CRP), IL-6, IL-1β, ROS, tumor necrosis factor-α (TNF-α), matrix metalloproteinase-9 [11]. Baseline IL-6 at admission predicted AKI in patients with severe sepsis [51]. Moreover, in vitro studies show that IL-6 can lead to cell damage and apoptosis, increased mesangial proliferation and infiltration and increased leukocyte proliferation, which are all associated in pathophysiology of kidney disease. Finally, IL-6 is directly involved in inflammatory pathways in experimental models of glomerulonephritis [52]. Elevated circulating MMP-9 is associated with resistant albuminuria and chronic kidney disease (CKD) progression in patients [53]. Therefore, it is possible that MMP-9 also contributes to CKD following brain injury. Th17 cytokines can drive renal inflammation partly by increasing TNF-α expression and upregulating chemokines which cause the infiltration of immune cells into the renal tissue [54]. However, our results did not show correlation of the occurrence of AKI with levels of these biomarkers.
The incidence of AKI was significantly elevated in elderly patients after IS. However, the risk of AKI after IS did not differ between elderly men and women [7]. Our results are not in agreement with previous studies that showed the association between comorbidities such as SAH and T2DM, age and sex with AKI, suggesting that these factors may affect brain–kidney interaction [11].
Although the IS subtypes did not differ among the IS patients without and with AKI, the LAC subtype was more frequent among the patients with AKI. This finding contrasts with data from other studies, where lacunar infarction is less associated with AKI than the other subtypes of ischemic stroke [55, 56].
Studies regarding the association between inflammatory biomarkers and AKI after IS are scarce [57]. Previous studies evaluated the occurrence of AKI and the possible biomarkers in different setting especially in hospitalized patients and particularly in the intensive care unit (ICU) due to major surgery, cardiac surgery, cardiorenal and hepatorenal syndromes, iatrogenic interventions, critical illness, renal transplant, and sepsis [58–60].
The discrepancies in results between studies of sVCAM-1 and other biomarkers evaluated in the present study could be due to differences in patient inclusion and exclusion criteria, control group definitions, time between IS ictus and sample collection, or laboratory methods. Some previous studies[61, 62] determined the CAMs levels with ELISA, a less sensitive method compared to immunofluorimetry which is used by the present study. Moreover, pharmacologic treatments can also affect soluble CAMs levels, such as angiotensin-converting enzyme inhibitor, enalapril, and angiotensin receptor II blocker, and losartan, decreased sVCAM-1, but not sICAM-1 [63]. Other studies showed that three months of simvastatin therapy was able to significantly decrease both sICAM-1 and sVCAM-1 levels[64] and antiplatelet agents, including aspirin, have been found to decrease serum sICAM-1 level [65].
Despite the importance of our results, some limitations must be discussed as follow. Firstly, this study included a relatively small cohort of IS patients. Several IS patients were excluded due to the rigid inclusion and exclusion criteria allowing an analysis with fewer confounding factors. Secondly, the renal function was only assessed during hospitalization, and we did not have data concerning renal function after 72 h and during the three-month follow-up, as well as whether AKI was reversible. However, some strengths may be highlighted, such as the controlled of possible confounding variables, and the evaluation of predictive models with a broad panel of clinical and inflammatory biomarkers involved in the pathophysiological mechanisms of IS.
Understanding the bidirectional nature of interaction between the brain and kidney after cerebral injury would have clinical implications for the treatment of IS and overall patient outcome. While the use of biomarkers in nephrology has gained considerable traction, significant progress must still be made before they can be considered for clinical application. As the same way that individuals with diabetic nephropathy driven by high levels of TNF-α receptor (TNFR)-1 and TNFR2 may indicate that anti-inflammatory agents could be repurposed to treat these conditions [60], the high levels of sVCAM-1 in patients in the acute phase of IS may be useful in the clinical practice to an early prediction of the occurrence of AKI as well as the short-term mortality after IS.