Skip to main content

Effect of renal replacement therapy on selected arachidonic acid derivatives concentration

Abstract

Background

Platelet activation is an important side effect of dialysis, resulted in a subsequent release of arachidonic acid (AA) from activated platelets. AA is involved in many pathologic conditions, such as inflammation, asthma, cancer, diabetes, hypertension, and the pathogenesis of kidney disease. The aim of this study was to define whether the dialysis type affects the concentration of AA derivatives in patients with chronic kidney disease.

Methods

117 patients were qualified to the study group. Based on the type of renal replacement therapy, patients were divided into the following groups: hemodialysis (HD A – before/HD B - after hemodialysis), peritoneal dialysis (PD), kidney transplant patients (TE - before/TE A – after transplantation) and conservative treatment (CT) (30; 30; 27; 30 patients, respectively). The control group consisted of 30 healthy volunteers (NK). The ELISA methods were used to measure the concentrations of TXB2, 5-HETE, 12-HETE, and 15-HETE in the blood serum.

Results

Renal replacement therapy significantly influences the concentration of TXB2 (mean ± SD [ng/mL]: HD A- 34.6 ± 9; HD B- 28.3 ± 15.2; PD- 28.3 ± 15.2; CT- 34.2 ± 8.0; TE- 36.7 ± 42.9; TE A- 27.9 ± 8.8; NK– 19.6 ± 15; p = 0.010), 5-HETE (mean ± SD [ng/mL]: HD A- 284.2 ± 428.4; HD B- 304.8 ± 516.2; PD – 530.0 ± 553.3; CT- 318.7 ± 366.0; TE- 525.6 ± 358.0; TE A – 409.8 ± 377.1; NK 838.1 ± 497.8; p < 0.001) and 15-HETE (HD A—18.1 ± 8.7; HD B- 42.2 ± 14; PD – 36.3 ± 13.8; CT- 33.7 ± 14.0; TE- 19.5 ± 10.2; TE A – 34.4 ± 16.3; NK 22.2 ± 17.8; p < 0,001). There was a significant relationship between the type of renal replacement therapy and the duration of dialysis, and the concentration of TXB2, 12-HETE acid, and 15-HETE.

Conclusions

The type of renal replacement therapy significantly affects the concentration of AA derivatives. Peritoneal dialysis is the best method of dialysis, taking into account the concentration of arachidonic acid derivatives.

Peer Review reports

Background

Chronic kidney disease (CKD) is one of the most frequently occurring diseases that affects 6–15% of the world’s population [1, 2]. Progression of renal failure aggravates ongoing inflammation and increases oxidative stress [3]. Chronic inflammation leads to activation of the endothelium, increased synthesis of adhesion molecules, penetration of monocytes into the intima of the vessels, as well as stimulation of thrombotic processes [4].

Conservative treatment is used in the initial stages of CKD, and dialysis or renal transplantation is necessary at the end-stage. One of the side effects of dialysis is the synthesis of pro-inflammatory factors and increased oxidative stress as a result of the blood contact with artificial materials of dialyzers and the creation of vascular access, which is necessary for dialysis. Consequences of this include transient leukopenia, activation of platelets and cells of the immune and complement systems, and an increase in interleukin-1 concentration [5].

Platelets also play a crucial role during organ transplantation. Many cell-derived blood-borne factors regulate their activation, and to a large extent, depend on the pro-oxidative-antioxidant balance. Healthy endothelium synthesizes prostacyclin (PGI2) and nitric oxide to prevent adhesion and activation of platelets. During ischemia and reperfusion of organs undergoing transplantation, there is excessive adhesion of platelets and leukocytes, leading to inflammation and tissue damage. As a result, it can strongly stimulate the immune response, as well as cause an increase in organ alloreactivity [6].

Arachidonic acid (AA) derivatives released from activated platelets are involved in many physical processes. Notably, they take part in the development of inflammation, asthma, cancer, diabetes, hypertension, and the pathogenesis of kidney diseases.

Activated platelets mainly synthesize thromboxane A2 (TXA2) in response to platelet aggregation and vasoconstriction. In solutions, unstable TXA2 rapidly degraded to an inactive but more stable form TXB2 [7,8,9]. Although TXA2 appears to be of minor importance in maintaining renal function under physiological conditions, increased TXA2 biosynthesis in the kidney was observed in various animal models of kidney disease. Unfortunately, one of the inherent and most important aspects of organ transplantation that occur in the transplanted organ is ischemia-reperfusion injury (I/R) [10]. Several authors have already reported that during I/R injury and allograft rejection, there is increased production of thromboxane synthase and consequently increased thromboxane B2 (TXB2) concentration. Inhibition of TXA2 synthesis during reperfusion significantly improves graft function in animal models of kidney transplantation [11, 12].

The 5-, 12-, and 15- hydroxyeicosatetraenoic (HETE) acids are formed from arachidonic acid by the lipoxygenase pathway [13]. 12-HETE activity is found in platelets as a result of platelet activation by agonists such as thrombin or collagen. The role of the 12-HETE isoform in platelets is not entirely clear, and the role in the direct regulation of platelet function is undocumented. The relationship between HETE acids, chronic kidney disease, platelet activation, and the type of renal replacement therapy used is not yet fully understood. Studies show that lipoxygenases are involved in kidney damage in the course of diabetic nephropathy, and it has been demonstrated that the urine concentration of 12-HETE significantly increases in this group of patients [14, 15]. Besides, 12-HETE, together with 15-HETE, induces the synthesis of TGF-β1 (transforming growth factor β1) in mesangial cells, where its action stimulates the synthesis of extracellular matrix proteins that lead to kidney fibrosis.

Knowledge of the relationship between the type of renal replacement therapy used and the level of circulating arachidonic acid derivatives can be extremely important. It has been shown that during peritoneal dialysis, increased eicosanoids are synthesized by macrophages and peritoneal mesenchymal cells due to the properties of dialysis fluids, which are generally not biocompatible [16]. Understanding the relationship between the level of arachidonic acid derivatives and the type of renal replacement therapy used may inform us on the chances of patient survival post-kidney transplantation, whether dialysis is still providing effective treatment for a patient, or which type of renal replacement therapy is appropriate for a given patient.

Methods

Samples

Blood samples (K2EDTA) (7,5 ml) and serum (7,5 ml) were drawn from all study participants. Blood was drawn from hemodialysis patients via their arteriovenous fistula, and peripheral venipuncture was used for all other participants (from hemodialysis patients immediately before and after the dialysis and from transplant patient before transplantation and 5–7 days after surgery. K2EDTA samples were centrifuged at 2600 rpm for 10 min at 20 °C to obtain plasma, respectively [17]. Serum samples were centrifuged at 6000 rpm for 10 min at 20 °C to obtain serum, respectively.

Concentrations of arachidonic acid derivatives

The concentrations of TXB2, 5-HETE, 12-HETE, 15-HETE were determined by an ELISA (Quantikine® Colorimetric Sandwich ELISAs, R&D Systems, USA, Quantikine® Colorimetric Sandwich ELISAs, My BioSource, USA; Quantikine® Colorimetric Sandwich ELISAs, Cayman Chemical Company, USA).

Statistical analysis

The Schapiro Wilk test was used to evaluate data distributions, which in the case of some variables (5-HETE concentrations), showed a non-parametric distribution. The Exact Fisher and Chi-square tests were used to analyze quantitative data. A T-test and ANOVA were used for univariate systems, the differences between associated (paired) and unrelated (unpaired) (parametric distribution). The Kruskal-Wallis ANOVA was used to evaluate differences, as well as the U - Test for unpaired data or the Wilcoxon test for paired data (non-parametric distributions). A linear multiple regression model was used to determine the multifactor evaluation of relationships between the parameters studied. Statistical analysis of the results was carried out using Statistica PL 12 Trial (StatSoft) [17].

Results

The study involved 147 participants, including 117 patients qualified. Based on the type of renal replacement therapy used, patients were divided into the following groups: before (HD A) and after (HD B) hemodialysis (blood was collected from patients immediately before and after dialysis peritoneal dialysis (PD), patients before (TE) and after (TE A) kidney transplantation (5–7 days after the surgery), and conservative treatment (CT) (CKD stages 2–5) (30, 30, 27, and 30 patients, respectively). Patients recruited into the TE group did not simultaneously belong to the group of hemodialysis or peritoneal dialysis patients. The control group consisted of 30 healthy volunteers [17]. Persons belonging to the control group did not have any chronic diseases. In order to qualify for this group, it was to show the basic blood tests such as blood count, biochemistry including, in particular, the concentration of creatinine, albumin, total protein, cholesterol, triglyceride, and glucose levels. Detailed information regarding the study and control can be found in Tables 1 and 2.

Table 1 General characteristics of hemodialyzed patients (HD), peritoneal dialysis (PD) treated conservatively (CT), kidney transplantation (TE) and control group (NK) participating in the study (mean ± OS)
Table 2 General characteristics of hemodialysis patients (A - before, B - after HD), peritoneal dialysis (PD) treated conservatively (CT) before and after kidney transplantation (TE and TE A) and control group (NK) taking partin the study (mean ± OS)

Statistically significant relationship between the concentration of TXB2 and the studied groups (HD A- 34.6; HD B- 28.3; PD- 28.3; CT- 34.2 ± 8.0; TE- 36.7; TE A- 27.9; NK − 19.6 [ng/mL]; p = 0.01) (Table 3) was observed. The lowest TXB2 concentration was found in the control group and the highest in patients before kidney transplantation (Fig. 1). Statistically significant differences in the concentration of thromboxane were also demonstrated in the serum of patients before hemodialysis (HD A) and before kidney transplantation (TE), as well as the control group (NK). An association was also found between serum TXB2 concentrations in group HD B and TE A and HD B and NK. The relationship between the concentration of thromboxane in the serum of patients treated conservatively, before kidney transplantation, and in the control group, as well as between the peritoneal dialysis and control groups, was also demonstrated. Statistically significant differences were also observed between the concentration of TXB2 in the TE and NK groups, and TE A and NK (Table 4).

Table 3 Concentration of platelet-derived growth factors of patients with chronic renal disease hemodialysed (before and after HD A, HD B), peritoneal dialysis (PD), conservative treatment (CT), before and after kidney transplantation (TE, TE A) and in the control group (NK) (mean ± OS, median – lower and upper quartile)
Fig. 1
figure1

Relationship between the type of renal replacement therapy and the concentration of TXB2. TXB2 concentration - differences between NK groups, CT, HD A, HD B, PD, TE, TE A (p = 0.010). NK- control group CT - treated conservatively; HD A - before hemodialysis; HD B - after hemodialysis; PD - peritoneal dialysis; TE- before kidney transplantation: TE A - after kidney transplantation

Table 4 Statistical differences in the concentration of arachidnonic acid derivatives, between the studied groups (p-value)

There were statistically significant differences between the concentrations of 5-HETE acid in the blood serum of patients in different study groups (p < 0.001; (HD A- 284.2; HD B- 304.8;PD - 530.0; CT- 318.7; TE- 525.6; TE A - 409.8; NK- 838.1 [ng/mL]; p < 0.001) (Table 3). The lowest concentration of 5-HETE was obtained in patients before hemodialysis, and the highest was in the control group (Fig. 2). Differences in the concentration of 5-HETE acid between HD A and PD groups, and TE and NK groups were observed, as well as between HD B and PD groups, TE and TE A groups, and between HD B and NK groups. There was also a relationship between the concentration of 5-HETE acid in the blood serum of patients with peritoneal dialysis and control group, and before and after kidney transplantation with the control group, as well as between patients treated conservatively (CT) and before kidney transplantation (TE) and the control group (NK) (Table 4).

Fig. 2
figure2

Relationship between the type renal replacement therapy and the concentration of 5-HETE. 5-HETE concentration - differences between CT, HD A, HD B, PD, TE, TE A, NK groups (p < 0,001). NK - control group CT - treated conservatively; HD A - before hemodialysis; HD B - after hemodialysis; PD - peritoneal dialysis; TE - before kidney transplantation: TE A - after kidney transplantation

There was no relationship between serum 12-HETE concentrations between the study groups (HD A- 3.0; HD B- 3.1; PD- 3.1; CT- 3.0; TE- 3.7; TE A- 2.8; NK 3.3 [ng/mL]; p > 0.05) (Table 3). Statistically significant differences occurred between the concentration of 12-HETE in blood serum of patients treated conservatively (CT) and after renal transplantation (TE A) (Table 4), and between the group of patients after transplantation and control group (Table 4).

We found a statistically significant differences between the concentrations of 15-HETE acid in the blood serum of patients in different study groups (HD A- 18.1; HD B- 42.2; PD- 36.3; CT- 33.7; TE- 19.5; TE A- 34.4; NK- 22.2 [ng/mL]; p < 0.001) (Table 3). The lowest concentrations of 15-HETE acid were observed in patients before hemodialysis and in the control group, and the highest concentration was in the group of patients after hemodialysis (Fig. 3). There were also statistically significant differences between the concentration of 15-HETE in the serum of patients before hemodialysis (HD A) and peritoneal dialysis (PD), treated conservatively, and after renal transplantation (TE A). The analysis shows a relationship between 15-HETE acid concentration in HD B and CT, HD B and TE, and HD B and NK groups. Significant differences in the concentration of 15-HETE acid occurred in patients on peritoneal dialysis, before kidney transplantation, and in the control group, as well as between transplant patients and the control group. There were significant differences in the concentration of 15-HETE acid in the blood serum of patients before and after hemodialysis, and before and after renal transplantation (Table 4).

Fig. 3
figure3

Relationship between the type of renal replacement therapy and the concentration of 15-HETE. 15-HETE concentration - differences between NK groups, CT, HD A, HD B, PD, TE, TE A (p < 0,001). NK- control group CT - treated conservatively; HD A - before hemodialysis; HD B - after hemodialysis; PD - peritoneal dialysis; TE- before kidney transplantation: TE A - after kidney transplantation

The concentration of arachidonic acid derivatives is influenced by sex, duration of dialysis, and the cause and severity of CKD.

We found a correlation between TXB2, 12-HETE acid, and 15-HETE acid concentrations, the type of renal replacement therapy used, and the duration of dialysis (p < 0.001). There were also statistically significant differences between the concentration of the examined parameters, the type of renal replacement therapy, and the age of the patient (p < 0.001) (Table 5). We also observed a relationship between the concentration of 5-HETE acid in the blood serum of patients and the stage of chronic kidney disease (p = 0.003) (Table 5). 5-HETE concentration was highest in patients in the second stage of CKD, and lowest in patients in the fifth stage.

Table 5 The influence of particular parameters on concentrations of arachidonic acid derivatives

Based on multivariate regression analysis, it was found that parameters such as the type of renal replacement therapy, age of patients, duration of dialysis, causes, and stage of CKD had an effect on thromboxane concentration at approximately 37% (Table 6).

Table 6 Analysis of the impact of the tested parameters on the concentration and activity values ​​of the tested parameters - multifactorial regression analysis

Discussion

In patients with chronic kidney disease, platelets are activated as a consequence of dialysis, increased inflammation, and oxidative stress, which results in an increased production of thromboxane and HETE acids [5]. It has also been shown that peritoneal dialysis leads to an increased synthesis of eicosanoids by peritoneal macrophages and mesenchymal cells due to the properties of the dialysis fluid, which are generally not biocompatible [16]. Therefore, knowledge of the relationship between the type of renal replacement therapy and the level of arachidonic acid derivatives is extremely important. According to the literature, it is possible to use this knowledge to gain insights into the chances of survival of a patient following kidney transplantation, whether dialysis is still providing effective treatment, or which type of renal replacement therapy is suitable for a given patient.

Activated platelets mainly synthesize thromboxane A2 in response to platelet aggregation and vasoconstriction. Thromboxane A2 is characterized by very short half-life (about 30 s). In aqueous solutions, TXA2 is unstable and rapidly degraded to an inactive but more stable form of TXB2. Although TXA2 appears to be of minor importance in maintaining renal function under physiological conditions, increased TXA2 biosynthesis in the kidney is confirmed in various animal models of kidney disease. One of the most important events that occur in a transplanted organ is ischemia-reperfusion injury (I/R), which, unfortunately is an inherent aspect of transplantation. The mechanism of I/R damage includes activation of the inflammatory response, formation of reactive oxygen species, and microcirculation disorders. In addition, several mediators such as TNF-α, endothelin, and arachidonic acid eicosanoid metabolites contribute to such mechanisms, including hydroxyeicosatetraenoic (HETE) acids and thromboxane [10]. Several authors have already reported that during I/R injury and allograft rejection, there is increased production of thromboxane synthase and consequently increased TXB2 concentration. Inhibition of TXA2 synthesis during reperfusion significantly improves graft function in animal models of kidney transplantation [10, 12].

TXA2 is synthesized by mesangial cells and podocytes. Decrease of renal blood flow to afferent and efferent arterioles caused by glomerulonephritis, cyclosporin overdose, or renal transplant rejection. As a consequence, there is a decrease in the number of mesangial cells, increase in the activity of the plasminogen activator inhibitor-1 (PAI-1), decrease in the activity of the tissue plasminogen activator (t -PA) and increase in the level of TGF-β. This leads to the deposition of fibrin and matrix proteins in the glomeruli and the mesangial matrix, which leads to worsening of renal failure [18, 19].

In our study, a statistically significant relationship was found between the concentration of thromboxane B2 and the groups studied. The lowest concentration of TXB2 was found in the control group and the highest in patients before renal transplantation. Statistically significant differences were also observed between the concentration of TXB2 in the TE and NK groups and TE A and NK. In patients after kidney transplantation, a not statistically significant decrease in thromboxane concentration was observed. There was no statistically significant difference between TXB2 concentration in patients before or after hemodialysis. On the other hand, there were significant differences between the concentration of thromboxane in hemodialysis patients and peritoneal dialysis, with a lower concentration of TBX2 in the PD group.

In the literature, there are many reports on the concentration of thromboxane in patients with different types of renal replacement therapy. Dołęgowska et al. (2009) showed that kidney transplantation is associated with changes in TXB2 concentration and that thromboxane alone may be a marker of organ function. In addition, after kidney transplant patients were divided into three groups: early graft function (EGF), slow graft function (SGF), and delayed graft function (DGF), the authors showed that the concentration of thromboxane increased within the first 5 min after transplantation in each of these groups [10]. However, our own studies showed a decrease in TXB2 concentration within a few days after kidney transplantation. Averna et al. (2001) showed that the administration of drugs that reduce or eliminate thromboxane-dependent activation of platelets in vivo might reduce the risk of cardiovascular events but may also prevent the long-term survival of patients with kidney transplantation [20]. Considering that an increase in thromboxane concentration may be indicative of transplant rejection and may lead to an increase in TGF-β concentration, which is also a sign of poor functioning of the transplanted kidney [18, 19], together with the results obtained in our own studies, it can be suggested that the decrease in TXB2 and TGF-β after kidney transplantation may be a sign of good prognosis for this group of patients. The relationship between the concentration of thromboxane and TGF-β is also confirmed by correlations obtained in our own studies. A positive correlation was found between the concentrations of thromboxane and TGF-β and platelet-derived growth factor-B (PDGF-B) in patients treated conservatively, as well as the positive correlation between PDGF-B and TXB2 concentrations after renal transplantation, and a strong positive correlation between the concentration of thromboxane and TGF-β in the control group. Orlińska et al. (1995) showed that both exogenous and endogenous transforming growth factor (TGF) regulates the production of thromboxane, And elevated levels of TGF-β lead to the increased production of TXB2 [21].

The data also supports the hypothesis that a lower concentration of TXB2 and TGF-β after transplantation is a good prognosis for these patients because no significant correlation was found between TXB2 and TGF-β after kidney transplantation. Stępniewska et al. (2019) observed a significantly lower concentration of thromboxane in hemodialysis patients than in peritoneal dialyzes patients and in those treated conservatively (stage 3–5). They also showed that the type of renal replacement therapy affects the concentration of arachidonic acid metabolites, and the concentrations of thromboxane Moreover, they showed that the levels of 20-HETE and 15-HETE acids can be indicators of kidney damage and possible cardiovascular diseases [18]. Zhao et al. (2015), in turn, found that in patients on peritoneal dialysis, there was an increased synthesis of eicosanoids by macrophages and peritoneal mesenchymal cells due to the properties of dialysis fluids, which are generally not biocompatible [16].

In other studies, however, the platelets of patients undergoing regular hemodialysis have been shown to be exposed to increased oxidative stress due to endothelial damage and carbohydrate and lipid metabolism disorders. They are activated excessively because their function is weakened due to ineffective antioxidant activity [22, 23]. Platelets are the main source of TXB2, and so the excessive activation of platelets may lead to an increased release of TXB2.

In our own studies, thromboxane concentrations were low in the PD group and significantly higher in the groups before and after hemodialysis, as well as in patients treated conservatively. This may support the thesis that platelets are excessively activated during hemodialysis and that these patients are more exposed to oxidative stress than PD patients.

The 5-, 12-, and 15-HETE acids are formed from arachidonic acid on the lipoxygenase pathway [13]. The relationship between HETE acids, chronic kidney disease, and platelet activation and the type of renal replacement therapy is not yet fully understood. Studies show that lipoxygenases are involved in kidney damage in the course of diabetic nephropathy, and the concentration of 12-HETE acid in urine significantly increases in this group of patients. Higher expression of 12/15 LOX (12/15 lipoxygenase) is associated with an increase in fibronectin and other mediators of diabetic nephropathy [14, 15].

According to the latest research, HETE acids can have a strong influence on the intensity of the inflammatory process. For example, the levels of 12-HETE, 15-HETE stimulate the overexpression of pro-inflammatory genes in macrophages, while the levels of 5-HETE promote the production of T cells. Moreover, 12-HETE together with 15-HETE induces the synthesis of TGF-β1 in mesangial cells, where it stimulates the synthesis of proteins of the extracellular matrix, thus leading to renal fibrosis. Due to the very short half-life of HETE acids and its unstable nature, the activities of HETE acids only occur in an autocrine or paracrine manner [24,25,26,27,28].

AA lipoxygenase derivatives are also involved in the regulation of blood pressure. Increased urinary excretion of 12-HETE was found in patients with essential arterial hypertension [11]. HETE acids may also affect early kidney transplantation as evidenced by significant changes in 5-HETE, 12-HETE and 15-HETE levels after kidney transplantation [24, 29]. Matsuyama et al. (2004) reported that the activity of AA derivatives formed on the cyclooxygenase and lipoxygenase pathway correlates with the intensity of I/R [24, 30]. In addition, several other authors report that elevated HETE levels in animals were detected during allograft rejection. These observations clearly justify the need to study this pathway of AA metabolism during human kidney transplantation [16, 24, 31, 32].

Wang et al. [33] have shown that free fatty acids (FFA) are best removed during low flow hemodialysis. As much as 60% of FFA is removed from the plasma after 4 h of hemodialysis. Lipids with a higher molecular weight, such as triglycerides and sphingomyelin, are not effectively removed. The concentration of FFA and SFA (saturated fatty acids) is increased between successive hemodialysis procedures, which is crucial to prevent the risk of cardiovascular events [33]. During peritoneal dialysis, however, there is an increased synthesis of eicosanoids by macrophages and peritoneal mesenchymal cells due to the properties of dialysis fluids, which are generally not biocompatible. The volume and nutritional status of peritoneal dialysis patients also affect the plasma lipid profile and are associated with inflammatory biomarkers (e.g., isoprostanes) and oxidative stress [22]. In our own studies, confirmation was obtained in the form of significantly higher concentrations of 5-HETE and 15-HETE in the group PD than in the group before hemodialysis, and also after hemodialysis in the case of 5-HETE.

Stępniewska et al. (2017) did not demonstrate a relationship between the concentration of 5- and 15-HETE acids and the type of renal replacement therapy used [18]. In the studies described in this work, however, this relationship was found. The lowest concentration of 5-HETE was observed in patients before hemodialysis and the highest in the control group. In the case of 15-HETE acid, the lowest concentration was observed in patients before hemodialysis and in the control group, and the highest concentration in the group of patients after hemodialysis. Reinhold et al. (2013) studied the relationship between concentrations 12- and 15-HETE and the function of a transplanted kidney. In this study, they observed a correlation between the concentration of HETE acids and kidney function 2 weeks post-transplantation but did not find a relationship between 12- and 15-HETE concentrations and acute transplant rejection [34, 35].

Dołęgowska et al. (2010) showed significant perioperative changes in the metabolism of AA derivatives arising in the LOX pathway, expressed as changes in 5-, 12- and 15-HETE concentrations, accompany kidney transplants in humans. These changes relate to early renal function after transplantation (EGF). Moreover, concentrations of 5-, 12- and 15-HETE decreased in the first 5 min after transplantation in the EGF and DGF groups with the exception of the SGF group [24]. HETE acids may, in the future, serve as a new perioperative predictor of early organ function after transplantation. Dołęgowska et al. (2010), however, confirmed the results obtained by Reinhard et al. (2013) showing no relationship between HETE concentration and acute rejection of the transplant. This study also updates the hypothesis previously suggested by other scientists, which is that knowledge of AA metabolism in the early phase of allograft reperfusion may offer an entirely new way to attenuate reperfusion injury during organ transplantation in humans [16].

In our study, there was a significant relationship between 5-HETE concentration before and after kidney transplantation and the control group. The concentration of 5-HETE was highest in the control group and lowest after kidney transplantation. There was also a significant difference between 15-HETE concentration before and after kidney transplantation, with an increase in the concentration of 15-HETE acid after kidney transplantation. There was no relationship between serum 12-HETE concentrations between the groups. However, a significantly lower concentration of 12-HETE acid after renal transplantation was demonstrated compared to the control group and patients treated conservatively. Considering the results obtained by other scientists, and taking into account the high importance of these acids in the body’s inflammatory response, an increase in the concentration of HETE acids after transplantation may indicate poor functioning of a transplanted kidney.

Based on our results, it is difficult to state clearly whether the concentration of HETE acids can indicate the possibility of graft rejection or not, due to the increase in 15-HETE acid concentration and decrease in 5-HETE acid concentration after kidney transplantation, and the lower concentration of 12-HETE compared, for example, compared with patients treated conservatively or the control group. Long-term observation of patients after kidney transplantation would be necessary to fully understand the importance of HETE acids in predicting graft rejection.

It should also be pointed out that eicosanoids are mediators of inflammation, and can also influence the metabolism of fibroblasts in wound healing processes and the reorganization of connective tissue [35]. The creation of vascular access in hemodialysis patients would also explain the increase in systemic compounds whose function is the chemotaxis of fibroblasts and the stimulation of healing processes.

The present study describes the relationship between the thromboxane, 12-HETE, and 15-HETE concentration and the duration of dialysis and the type of therapy used. It has been shown that the longer the dialysis takes, the lower concentration of TXB2 and 15-HETE acid. In the case of 12-HETE acid, its highest concentration occurred in patients before kidney transplantation, who, on average, had the most prolonged duration of dialysis. Also, based on a multivariate regression analysis, it was found that parameters such as the type of renal replacement therapy, age of patients, duration of dialysis, cause, and stage of CKD affected thromboxane concentration in 37%. The type of renal replacement therapy (p = 0.042) and dialysis duration (p = 0.004) both had a significant effect on the concentration of thromboxane.

The results obtained in this study do not confirm those obtained by other scientists, except the concentration of 12-HETE, which indicates increased activation of platelets in patients undergoing long-term dialysis. Because increased production of thromboxane leads to the deposition of fibrin and matrix proteins in the glomeruli and mesangium, and subsequently leads to the worsening of renal failure [18, 19], a lower thromboxane concentration is an indicator of good prognosis for patients on long-term dialysis. A decreasing concentration of 15-HETE might indicate a lower chance of graft rejection after transplantation.

There are no reports on the dependence of 5-HETE on the subject of chronic disease and the stage of chronic kidney disease. It has been shown, however, that supplementation with polyunsaturated fatty acids (PUFA) over 8 weeks results in a decrease in the pro-inflammatory leukotriene-B4 (LTB4) and 5-HETE, and increases the synthesis of less inflammatory leukotriene, LTB5 and 5-hydroperoxyeicosatetraenoic (5-HPETE) in patients with CKD stages 2–5 [36]. In our research, the concentration of 5-HETE decreased as kidney disease progressed. This may indicate less pro-inflammatory processes and a good prognosis for patients in the fifth stage of CKD.

Conclusions

The type of renal replacement therapy used significantly affects the level of arachidonic acid derivatives (TXB2, 5-HETE, and 15-HETE). Apart from the type of therapy used in CKD patients, the factors significantly affecting the release of arachidonic acid derivatives were the age of patients, the duration of dialysis, the cause of CKD, and the stage of its advancement. Considering the concentration of arachidonic acid derivatives, peritoneal dialysis is the best method of dialysis. Concentrations of arachidonic acid derivatives in patients with CKD may be helpful in the selection of appropriate renal replacement therapy, prognosis of patients after kidney transplantation or long-term dialysis.

Availability of data and materials

The datasets generated and/or analysed during the current study are not publicly available due [these are sensitive data owned by the Pomeranian Medical University in Szczecin] but are available from the corresponding author on reasonable request.

Abbreviations

12/15 LOX:

12/15 lipoxygenase

12-HETE:

12- hydroxyeicosatetraenoic acid

15-HETE:

15- hydroxyeicosatetraenoic acid

5-HETE:

5-hydroxyeicosatetraenoic acid

AA:

Arachidonic acid

CKD:

Chronic kidney disease

CT:

Conservative treatment

DGF:

Delayed graft function

EGF:

Early graft function

FFA:

Fatty acids

HD A:

Before hemodialysis group

HD B:

After hemodialysis group

I/R:

Ischemia-reperfusion injury

LOX:

Lipoxygenase

LTB4:

Pro-inflammatory leukotriene-B4

NK:

Control group

PAI-1:

Plasminogen activator inhibitor-1

PD:

Peritoneal dialysis

PGI2 :

Prostacyclin I2

PUFA:

Polyunsaturated fatty acids

SGF:

Slow graft function

TE:

Before transplantation group

TE A:

After transplantation group

TGF-β1:

Transforming growth factor β1

t-PA:

Tissue plasminogen activator

TXA2 :

Thromboxane A2

TXB2 :

Thromboxane B2

References

  1. 1.

    Szczeklik A. (red), Diseases of the kidneys of the urinary tract. Acute in the kidney and chronic kidney disease. Kraków: Interna Szczeklika, Medycyna Praktyczna; 2017. p. 1443–61.

    Google Scholar 

  2. 2.

    Jha V, Garcia-Garcia H, Isek K, Li Z, Naicker S, et al. Chronic kidney disease global dimension and perspectives. Lancet. 2013;382:260–72.

    Article  Google Scholar 

  3. 3.

    Silverstein DM. Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease. Pediatr Nephrol. 2009;24:1445–52.

    Article  Google Scholar 

  4. 4.

    Dudzik M, Deeg P, Raczak G. The influence of the inflammatory process on changes in the circulatory system of patients with chronic kidney disease. Cardiol Poland. 2009;67:10.

    Google Scholar 

  5. 5.

    Vazzana N, Santilli F, Lattanzio S, Liani M, Giacci L, et al. Determinants of thromboxane biosynthesis in patients with moderate to severe chronic kidney disease. Eur J Intern Med. 2016;33:74–80.

    CAS  Article  Google Scholar 

  6. 6.

    Dołęgowska B. Predictors of delayed transplanted kidney function - analysis of prooxidation-antioxidant balance and arachidonic acid metabolism in blood platelets and plasma during ischemia-reperfusion period. Wydawnictwo Pomorskiej Akademii Medycznej: Schin Martin; 2009.

    Google Scholar 

  7. 7.

    Hannun YA, Obeid LM. Principles of bioactive lipid signaling lessons from sphingolipids. Nat Rev Mol Cell Biol. 2008;9:139–50.

    CAS  Article  Google Scholar 

  8. 8.

    Sałata D, Dołęgowska B. Bioactive lipids in physiology and renal pathophysiology. Post Hig Med Dośw. 2014;68:73–83.

    Article  Google Scholar 

  9. 9.

    Bieberich RR. It’s lipid’s world: Bioactive lipid metabolism and signaling in neural stem cell differentiation. Neurochem Res. 2012;37:1208–29.

    CAS  Article  Google Scholar 

  10. 10.

    Dołegowska B, Błogowski W, Domański L. Dynamics of thromboxane level changes during early phase of allograft reperfusion. Clin Transpl. 2009;23:716–22.

    Article  Google Scholar 

  11. 11.

    Dołęgowska B, Błogowski W, Kędzierska K, Safranow K, Jakubowska K, et al. Platelets arachidonic acid metabolism in patients with essential hypertension. Platelets. 2009;20:242–9.

    Article  Google Scholar 

  12. 12.

    Bellido-Reyes YA, Akamatsu H, Kojima K, Arai H, Tanaka H, et al. Cytosolic phospholipase A2 inhibition attenuates ischemia-reperfusion injury in an isolated rat lung model. Transplantation. 2006;81:1700–7.

    CAS  Article  Google Scholar 

  13. 13.

    Hammond VJ, O'Donnell VB. Esterified eicosanoids: generation, characterization and function. Biochim Biophys Acta. 1818;2012:2403–12.

    Google Scholar 

  14. 14.

    Kang SW, Adler SG, Nast CC, Lapage J, Gu JL, et al. 12-Lipoxygenase is increased in glucose-stimulated mesangial cells and in experimental diabetic nephropathy. Kidney Int. 2001;59:1354–62.

    CAS  Article  Google Scholar 

  15. 15.

    Hatley ME, Srinivasan S, Reilly KB, Bolick DT, Hedrick CC. Increased production of 12/15 lipoxygenase eicosanoids accelerates monocyte/endothelial interactions in diabetic db/db mice. J Biol Chem. 2003;278:25369–75.

    CAS  Article  Google Scholar 

  16. 16.

    Zhao YY, Vaziri ND, Lin RC. Lipidomics: new insight into kidney disease. Adv Clin Chem. 2015;68:153–75.

    CAS  Article  Google Scholar 

  17. 17.

    Cecerska-Heryć E, Heryć R, Wiśniewska M, Michalczyk A, Dołęgowska B. Regenerative potential of platelets in patients with chronic kidney disease. Int Urol Nephrol. 2019;51:1831–40.

    Article  Google Scholar 

  18. 18.

    Stępniewska J, Dołęgowska B, Puchałowicz K, Gołembiewska E, Ciechanowski K. Bioactive lipids derived from arachidonic acid metabolism in different types of renal replacement therapy. Chem Phys Lipids. 2017;206:71–7.

    Article  Google Scholar 

  19. 19.

    Ponnuchamy B, Khalil RA. Cellular mediators of renal vascular dysfunction in hypertension. Am J Physiol Regul Integr Comp Physiol. 2009;296:R1001–18.

    CAS  Article  Google Scholar 

  20. 20.

    Averna M, Barbagallo CM, Ganci A, Giammarresi C, Cefalù AB, et al. Determinants of enhanced thromboxane biosynthesis in renal transplantation. Kidney Int. 2001 Apr;59(4):1574–9.

    CAS  Article  Google Scholar 

  21. 21.

    Orlinska U, Kuhn DC. Regulation of TXB (2) and PGE (2) production by TGF-beta (1) in in vitro silica dust-exposed rat alveolar macrophage. Mediat Inflamm. 1995;4:413–6.

    CAS  Article  Google Scholar 

  22. 22.

    Stępniewska J, Dołęgowska B, Cecerska-Heryć E, Gołembiewska E, Malinowska-Jędraszczyk A, et al. The activity of antioxidant enzymes in blood platelets in different types of renal replacement therapy: a cross-sectional study. Int Urol Nephrol. 2016;48:593–9.

    Article  Google Scholar 

  23. 23.

    Stępniewska J, Gołembiewska E, Dołęgowska B, Domański M, Ciechanowski K, et al. Oxidative stress and antioxidative enzyme activities in chronic kidney disease and different types of renal replacement therapy. Curr Protein Pept Sci. 2015;16:243–8.

    Article  Google Scholar 

  24. 24.

    Dołęgowska B, Błogowski W, Safranow K, Domański L, Jakubowska K, et al. Lipoxygenase-derived hydroxyeicosatetraenoic acids—novel perioperative markers of early post-transplant allograft function? Nephrol Dialysis Transplantation. 2010;25:4061–7.

    Article  Google Scholar 

  25. 25.

    Petrich K, Ludwig P, Kühn H, Schewe T. The suppression of 5-lipoxygenation of arachidonic acid in human polymorphonuclear leucocytes by the 15-lipoxygenase product (15S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid: structure-activity relationship and mechanism of action. Biochem J. 1996;314:911–6.

    CAS  Article  Google Scholar 

  26. 26.

    Wen Y, Gu J, Chakrabarti SK, Aylor K, Marshall J. The role of 12/15-lipoxygenase in the expression of interleukin-6 and tumor necrosis factor-alpha in macrophages. Endocrinology. 2007;148:1313–22.

    CAS  Article  Google Scholar 

  27. 27.

    Douthwaite JA, Johnson TS, Haylor JL, Watson P, El Nahas AM. Effects of transforming growth factor-beta1 on renal extracellular matrix components and their regulating proteins. J Am Soc Nephrol. 1999;10:2109–19.

    CAS  PubMed  Google Scholar 

  28. 28.

    Kim YS, Xu ZG, Reddy MA, Li SL, Lanting L, et al. Novel interactions between TGF-β1 actions and the 12/15-lipoxygenase pathway in mesangial cells. J Am Soc Nephrol. 2005;16:352–62.

    CAS  Article  Google Scholar 

  29. 29.

    Dołęgowska B, Błogowski W, Domański L. Association between the Perioperative Antioxidative Ability of Platelets and Early Post-Transplant Function of Kidney Allografts: A Pilot Study. PLoS. 2012;7:e29779.

    Article  Google Scholar 

  30. 30.

    Matsuyama M, Nakatani T, Hase T, Kawahito Y, Sano H, et al. The expression of cyclooxygenases and lipoxygenases in renal ischemia-reperfusion injury. Transplant Proc. 2004;36:1939–42.

    CAS  Article  Google Scholar 

  31. 31.

    Mangino MJ, Anderson CB, Deschryver K, Turk J. Arachidonate lipoxygenase products and renal allograft rejection in dogs. Transplantation. 1987;44:805–8.

    CAS  Article  Google Scholar 

  32. 32.

    Goulet JL, Griffiths RC, Ruiz P, Mannon RB, Flannery P, et al. Deficiency of 5-lipoxygenase accelerates renal allograft rejection in mice. J Immunol. 2001;167:6631–6.

    CAS  Article  Google Scholar 

  33. 33.

    Wang L, Hu C, Liu S, Chang M, Gao P, et al. Plasma Lipidomics investigation of hemodialysis effects by using liquid chromatography-mass spectrometry. J Proteome Res. 2016;15:1986–94.

    CAS  Article  Google Scholar 

  34. 34.

    Rieger GM, Hein R, Adelmann-Grill BC, Ruzicka T, Krieg T. Influence of eicosanoids on fibroblast chemotaxis and protein synthesis in vitro. J Dermatol Sci. 1990 Sep;1:347–54.

    CAS  Article  Google Scholar 

  35. 35.

    Reinhold SW, Scherl T, Stölcker B, Bergler T, Hoffmann U, et al. Lipoxygenase products in the urine correlate with renal function and body temperature but not with acute transplant rejection. Lipids. 2013;48:167–75.

    CAS  Article  Google Scholar 

  36. 36.

    Maaløe T, Schmidt EB, Svensson M, Aardestrup IV, Christensen JH, et al. The effect of n-3 polyunsaturated fatty acids on leukotriene B4 and leukotriene B5 production from stimulated neutrophil granulocytes in patients with chronic kidney disease. Prostaglandins Leukot Essent Fatty Acids. 2011;85:37–41.

    Article  Google Scholar 

Download references

Acknowledgments

Not applicable.

Funding

The paper was funded by National Science Centre Poland grant no. 2011/01/B/NZ5/04235, and by Pomeranian Medical University in Szczecin grant no. MB-134-141/15. The funding body covered the costs of material collection and the purchase of reagents and data analysis.

Author information

Affiliations

Authors

Contributions

ECH - Writing -Original Draft Preparation, Methodology. RH – Visualization. MW – Investigation Resources. NS – Formal Analysis. BG – Writing-Review& Editing. BD – Conceptualization. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Elżbieta Cecerska-Heryć.

Ethics declarations

Ethics approval and consent to participate

The Bioethical Commission at the Pomeranian Medical University in Szczecin approved the research carried out (no KB-0012/36/11) - consent in writing. All participants, including the healthy volunteers in the control group, were informed about the purpose and scope of the study and gave their consent to donate samples and for the resulting data to be published.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent for publication

Written informed consent was obtained from the patient for publication of this study.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Cecerska-Heryć, E., Heryć, R., Wiśniewska, M. et al. Effect of renal replacement therapy on selected arachidonic acid derivatives concentration. BMC Nephrol 21, 394 (2020). https://doi.org/10.1186/s12882-020-02053-8

Download citation

Keywords

  • Thromboxane B2
  • 5-HETE
  • 12-HETE
  • 15-HETE
  • Renal replacement therapy
  • Chronic kidney disease
  • Kidney transplantation