Renalase is a small molecule that should be easily filtered by the kidney, however, there is still no consensus regarding the mechanism on which renalase regulation and action is based. As with many other factors, its accumulation may be caused by abnormal production and secretion of this protein, together with limited filtration capacity or impaired filtration due to structural or functional abnormalities of the kidney. Due to the potentially protective effect of renalase, this filtration may be also limited physiologically, or renalase could be reabsorbed under conditions of increased demand for this protein. As already shown in many studies, the elevation of renalase is observed e.g. after acute exercise, when its expression in skeletal muscles increases, and decreases in other tissues indicating that it is a reaction to oxidative stress (16). A similar observation was made in another study in which renalase blood concentration increased by 3-fold 30 minutes after epinephrine infusion with a suggestion, that this is due to potential renalase enzymatic properties (17). Results of some of the scientific research also point out that renalase might be a cytokine related to kidney dysfunction and inflammatory processes affecting CKD patients. As was further shown, an elevation in catecholamines concentration, especially epinephrine, accompanying kidney diseases due to nervous system hyperactivity, stimulates expression of renalase (18). Many known cytokines are rather poorly excreted in conditions of their much higher production, which is one of the mechanisms involved in higher mortality among patients with acute kidney injury. Elevation of serum renalase may be a defense mechanism against further injury of the kidney. It has been proven that blood renalase might activate Akt kinase, and therefore MAPK kinases pathway, preventing or reducing kidney damage, what was observed in vitro on tissue model of acute kidney injury (8). What is more, renalase-dependent MAPK signaling and cytoprotection was described as mediated by PMCA4b receptor (20). PMCA4b gene is expressed in many tissues, mainly in endometrium, fat, and skin, but also in heart, urinary bladder, and kidney tissues (21). This receptor is a Ca2+-ATPase, responsible for maintaining the electrolyte concentration, but its role in Ca2+ handling in the kidney was not discernible, and its function in renal tissues remains an open question (22). As our results indicate, serum renalase differs significantly between healthy adults and CKD patients and is much higher in the latter group, and that there is a significant difference in the StUR ratio. At the same time, there is no correlation between serum and urine renalase in healthy individuals, and the multivariate analysis in CKD group shows, that serum renalase is the only significant independent factor strongly positively associated with urinary renalase concentration. Therefore, in physiological conditions this molecule, like creatinine, is continuously produced and filtered. This finding is supported by fact, that the urinary renalase/Cr ratio is very similar between control and CKD group (medians 53.7 and 44, respectively; p=0.99) indicating, that they are both removed in a balanced proportion. In renal patients, RNLS probably undergoes a "recycling" mechanism in the kidney or there is a barrier preventing from excess loss of this particular protein, even in patients with proteinuria, as it does not have an influence on urinary renalase concentration.
The elevation in serum renalase has been also repeatedly associated with heart and circulatory dysfunctions, very common in CKD, since heart seems to be another very important source of RNLS. Low concentration of renalase is considered as one of the predictive factors of coronary artery disease (CAD) (8, 12, 23), and an increase in serum renalase is associated with significantly greater hazards of all-cause mortality and adverse renal outcomes (24). In our study, the presence of hypertension or any of cardiovascular disease had no impact on renalase concentration. What is more, none of the renalase parameters (its concentration in serum and urine, FE, StURR, urinary renalase/Cr) were related to systolic or diastolic blood pressure, nor to heart rate. What is interesting, blood pressure in the control group was higher than in the CKD group, and this association reached the statistical significance in the case of diastolic pressure. Despite this, renalase concentration in serum of healthy adults was significantly lower, what strongly suggests and indicates that renalase does not have a general antihypertensive effect, described in many scientific reports. It does not mean, that RNLS does not have such properties at all, but probably possess them only under certain conditions.
The urinary renalase/Cr (ng/mg) ratio was firstly described in 2014 and only for healthy children and adolescents (13). The authors established the reference values and percentiles for urinary renalase excretion showing, that in the youngest children (<3y.o.) concentration of renalase is significantly higher than in other age groups (3-5.9, 6-8.9, 9-11.9, 12-14.9 and 15-17.9). Urinary renalase/Cr median for the <3 y.o. children was 245.46 ng/mg, while in the adolescents – 99.51 ng/mg. In our study, this ratio was 53.7 ng/mg in control (age median 48) and 44 ng/mg in CKD group (age median 52), what is consistent with the assumption that this coefficient decreases with age, although in our research no significant association between age and renalase/Cr was observed.