There are many studies about the relationship between kidney injury and the occurrence of IS [22–26]. Few scholars believe that only IS can induce kidney injury [23, 24]. Many scholars have confirmed that not only IS can induce kidney injury, but also kidney injury can induce IS [25–27]. The structure and function of the microvascular system of the brain are similar to that of the kidney. Therefore, the factors that cause kidney imparirment may also damage the brain tissue. It is speculated that kidney function damage may be accompanied by brain tissue damage [7]. Therefore, some clinicians used traditional kidney function markers to predict the occurrence of IS in CKD patients. Many studies have confirmed that the decrease in eGFR and the increase in ACR are risk factors for the occurrence of non-fatal IS [7]. Other scholars have reported that the traditional kidney function markers that can be used to predict the occurrence of IS are not serological kidney function markers (including eGFR), but proteinuria-related indicators (such as ACR or 24h urinary excretion rate, etc.) [8,28 ]. Therefore, it is controversial to use traditional renal function markers as predictors for judging the occurrence of IS. For the new kidney function markers, such as CysC and NGAL, research reports have shown that the increase in CysC is a risk factor for IS [10, 11], and it is also a protective factor for patients with neurodegenerative changes [29]. There is no research showing that NGAL can predict the onset of IS. However, it has been reported that NGAL does not have the ability to predict the recurrence of IS during the recovery period for patients with IS [30]. Therefore, it is unclear which kidney function damage is a risk factor for IS, and which serum kidney function markers reflecting renal function impairment can be used to predict the occurrence of IS.
This study included four IS-related chronic diseases (hypertension, DM, CAD and hyperuricemia) and five common serum kidney function markers (Ure, Cr, CysC, NGAL and eGFR) to study whether renal function impairment can be used to predict the onset of IS, and which kidney function markers have the ability to predict the occurrence of IS. In IS patients with CKD, the five kidney function markers are more closely related to the occurrence of IS than the above diseases. This indicates that the relationship between CKD and the occurrence of IS is closer than that between the above diseases with the occurrence of IS. These results indicate that renal function impairment can predict and even participate in the development of IS.
This study further analyzed the predictive performance of five renal function markers on the occurrence of IS. In addition to the above four diseases, IS can also be seen in patients with occult atrial fibrillation and patent foramen ovale [31]. However, patients with such diseases are often regarded as healthy without obvious physical signs. Therefore, this study first conducted ROC analysis with HC, DC or no-IS (i.e., HC + DC) as controls. Compared with subjects with no-IS (HC + DC) as controls, in subjects with HC or DC alone as controls, there was no significant difference in the ability of the five renal function markers to predict the occurrence of IS. Therefore, the results of ROC analysis with no-IS as the control may be more representative. In this case, only NGAL has a good predictive ability for the occurrence of IS. However, dividing IS patients into NKF-IS and CKD-IS, we used ROC analysis to find out that only NGAL has a certain predictive value in NKF-IS patients, and CysC has the best predictive ability in CKD-IS patients. The other three kidney function markers are not outstanding in predictive ability. When the YI is maximum, the cut-off values of Ure and Cre are far lower than the upper limit of the reference values, and the cut-off value of eGFR is far higher than the medical decision. Under this cut-off value, the patient's Ure, Cre and eGFR may still be at normal levels. These three markers are not suitable for reflecting and evaluating the causal relationship between renal function impairment and IS. Therefore, NGAL and CysC can be used as kidney function markers to reflect and evaluate renal function impairment and IS, and their applicabilities are different.
NGAL has been accepted by many nephrologists as a biomarker of early acute and chronic kidney injury, and some scholars also regard it as a neuroinflammatory marker [15, 16, 32]. This study found that the level of NGAL in IS patients was higher than that of HC and DC, while the levels of the other four renal function markers were only higher than HC. It indicates that serum NGAL level may be increased in both kidney function impairment and IS occurrence. This may also indicate that the risk of IS in patients with kidney injury is extremely high, and the patients with IS may have renal function impairment for a long time. For subjects with normal renal function, among the five serum kidney function markers, only NGAL has the good predictive performance and risk assessment ability for stroke occurrence, while other markers have no or extremely low predictive value. We need to know the increase in NGAL levels in these patients is dominated by neuroinflammation, or is caused by NGAL being more sensitive to kidney damage than other markers. However, recent animal research reports have shown that in the early stage of IS, even during transient ischemic attacks, there may be potential inflammation or stress and other pathological damage in the brain tissue. This leads to an increase in its NGAL level [32]. Therefore, in IS patients with normal renal function, the influence of neuroinflammation on the serum NGAL level cannot be ignored, and it may be even more significant than the influence of kidney injury. In short, for patients with IS risk diseases with normal kidney function, as a marker of kidney injury or neuroinflammation, NGAL may be a risk factor for IS independent of DM, hypertension, CAD, and hyperuricemia.
CysC is an ideal marker for the evaluation of glomerular filtration rate published by the US Food and Drug Administration in 2002, and has the ability to reflect kidney injury more sensitively than Cre. So far, there have been many reports on the predictive ability of CysC for IS [10, 11, 33]. However, most of them are based on cardiovascular disease as the research object [11, 33]. In the process of cerebral ischemia/reperfusion injury, the increase of endogenous CysC can maintain the integrity of the lysosomal membrane, thereby playing a neuroprotective role [29]. Therefore, the occurrence of IS is usually accompanied by changes in CysC levels. This study showed that CysC may be more suitable for predicting the occurrence of IS in CKD patients, and the threshold value for the maximum YI is 1.14 mg/L. However, under this threshold, it needs to be further verified that the clinical prediction of IS occurrence is consistent with the actual results, or whether it is more reliable to predict IS occurrence by the increasing multiple of the CysC baseline level.
In contrast, when IS patients are accompanied with CKD, NGAL's ability to predict the occurrence of IS is significantly lower than other kidney function markers, and it does not have the advantage of predicting the occurrence of IS. The reason may be that NGAL is more sensitive to kidney injury than other markers. Although the increase of NGAL in CKD-IS patients is the result of both kidney injury and neuroinflammation, it is more caused by renal function impairment in patients with CKD because NGAL is extremely sensitive to renal function impairment. The influence of renal function impairment on NGAL in CKD patients largely masks the influence of neuroinflammation, which ultimately leads to the weakening of NGAL's ability to predict the occurrence of IS.
In summary, there are significant differences in the ability to predict the occurrence of IS between NGAL and CysC. CysC is suitable for predicting the occurrence of IS in CKD patients. The application of CysC to predict the occurrence of IS in CKD patients needs more in-depth exploration. The predictive value of NGAL for the occurrence of IS is more prominent in patients who have not yet significant kidney injury. In recent years, a few research reports have found that NGAL can be used to predict the recurrence of transient ischemia or stroke [34, 35]. However, how to better use NGAL to assess the risk of IS requires further research, especially in patients with stroke-related high-risk diseases and transient ischemic attacks who have no significant kidney injury. Long-term follow-up are needed to verify the level of NGAL that can be used as a warning threshold for IS occurrence.
The limitations of this study are as follows. (1) In this study, patients with AKI were excluded through the changes in Cre and urine volume within 48 h after admission. However, due to the lack of Cre baseline level in patients, AKI patients whose Cre level rises more than 1.5 times the baseline level within 7 days cannot be excluded. (2) Testing was carried out on the second day after the patient was admitted. It is impossible to eliminate the effect of the patient taking drugs for treatment of diseases within 7 d before admission. Therefore, there are confounding factors in the experimental results. However, thse experimental results suggest that NGAL may be a risk factor for the occurrence of IS in patients with normal kidney function, and CysC is a risk factor for the occurrence of IS in CKD patients. If there is an increase in NGAL levels in patients with IS-related risk diseases, and there is no clear evidence of kidney injury, we should be alert to the occurrence of IS.