Pathophysiology of the cortico-sympathoadrenal system in the postoperative period of partial nephrectomy

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Abstract


Introduction. Organ-preserving kidney surgeries are widespread in urological practice. Any surgical intervention triggers a cascade of reactions in the body that are characteristic of stressful situations, which adversely affects blood flow volume in the parenchymal organs, worsens microcirculation, and reduces the trophic and reparative abilities of organs. The application of anti-ischemic protection is an essential part of patient rehabilitation to maintain renal function.

Objective. To investigate the nephroprotective properties of α-tocopherol acetate (a-TA) and its effect on α-tocopherol acetate (a-TA) parameters of the cortico-sympathoadrenal system following organ-preserving kidney surgery.

Material and methods. An experimental study was performed on 70 white laboratory rats, 10 of which were not subjected to surgical treatment. Sixty rats underwent lower pole left kidney superimposition with Z-joints. Postoperatively, 30 rats were intramuscularly injected with a 10% oil solution of 0.2 mL a-TA twice a day for 5 days. The cortico-sympathoadrenal system parameters were determined on the 7th, 14th, and 28th days. Results. Postoperative administration of a-TA resulted in early normalization of the cortico-sympathoadrenal system.

Conclusion. The studied indices regar ding the tissue of the operated kidney are responsible for regulating vascular tone, severity of the inflammatory response, microcirculation, and reparative processes. The use of a-TA accelerates recovery from organ-preserving surgery and biochemical abnormalities.


Introduction

Acute renal injury caused by ischemia/reperfusion during organ-preserving surgical treatment of the kidney is an independent risk factor for chronic kidney disease [1]. Kidney disease not only can exacerbate renal dysfunction but can also adversely affect systemic processes, most often in older patients [2]. Because of the urgency of this problem, an active search is under way for various agents that protect the kidneys against intraoperative trauma. At present, there are many ways to prevent ischemia, such as different variants of pharmacological preconditioning and control of the margin of resection [1, 3–7]. Unfortunately, these methods depend not only on the surgeon’s experience but also on equipment available. The classical method of organ preservation in surgical treatment of the kidney is the application of “thermal” ischemia, which is considered safe for up to 20 min. Technically, it is not always possible to keep within this time interval or to avoid blood loss [8], which can affect future function of kidney tissue and lead to the development of renal failure [9]. Therefore, the development of methods for postoperative rehabilitation is an urgent task.

Lipid peroxidation processes are involved in the pathogenesis of acute ischemic renal injury during organ-preserving surgical treatment; thus, the use of antioxidants is a reasonable method of correcting the consequences of intraoperative trauma [3]. α-Tocopherol acetate (α-TA) is a natural fat-soluble antioxidant. In the body, it is located mainly in cell membranes. Numerous studies have proved that α-TA influences the redistribution of metabolic reactions in many adaptive processes that prepare cells for oxygen deprivation conditions: for example, it stimulates intracellular increases in the level of cyclic adenosine monophosphate (c-AMP), it supports reserve pathways for the formation of adenosine triphosphate (ATP) during glycolysis, and it activates the synthesis of protein and nucleic acids. α-TA also significantly improves the function of ischemic kidneys, normalizes sodium reabsorption, improves creatinine clearance, reduces the accumulation of malondialdehyde without affecting significantly the activity of antioxidant enzymes, and lowers the oxygen tension in the cortex of the kidney. The use of α-TA as a means of ischemic preconditioning to increase the antioxidant reserve in tissues has increased the rate of survival among experimental animals to 50% [10–23].

Materials and methods

The study was performed with 70 white laboratory rats weighing 200 to 300 g. The work with animals was conducted in accordance with the current Rules for Conducting Works Using Experimental Animals and the Guiding Principles for Biomedical Research Involving Animals. Ten animals were not subjected to surgical treatment and served as an intact group for determining reference values. The other 60 rats underwent organ-preserving surgical treatment of the kidney (resection of the lower pole of the left kidney with the application of Z-shaped sutures to the resection area). In the postoperative period, the 60 animals that underwent surgery were divided into two groups: the control group (n = 30), in which only surgical treatment was performed, and the study group (n = 30), in which 0.2 mL of 10% α-TA oil solution was injected intramuscularly twice a day for 5 days. The levels of creatinine and the hormones of the corticosympathetic adrenal system (CSAS) (adrenaline, noradrenaline, dopamine, serotonin, histamine, and 11-oxycorticosteroid) in the blood and the operated kidney were measured in all laboratory animals on days 7, 14, and 28. The CSAS indices were studied with the Hitachi MPF-4 spectrophotometer (Hitachi High Technologies, Tokyo). The concentration of test substances in the blood was expressed in micrograms per milliliter, whereas that in the kidney was expressed in micrograms per gram. The levels of adrenaline, noradrenaline, and dopamine were determined by a differential fluorometric methodaccording to Osinskaya (1977), on the basis of their oxidation by iodine with the formationoffluorescentproducts. Thehistaminecontent in the blood was determined by a method based on the measurement of the fluorescence of the condensation products of histamine with ortho-phthaldehyde (the Shore method in the modification of Meshcheryakova, 1987), and that of serotonin was determined with ninhydrin (Proshina, 1981; Menshikova, 1987). The concentration of 11-oxycorticosteroids was determined according to the method of Pankova and Usvatova (1973) with a standard sample.

The rats were sacrificed in compliance withthe Guiding Principles for Biomedical Research Involving Animals and the rules set forth in the Declaration of Helsinki.

Results

Changes in the studied indicators of CSAS are presented in Table 1. The level of adrenaline in the animals of the control group increased on day 7 after the surgery in the blood by 26% (p > 0.05) and by 40% in the kidneys (p < 0.05). By day 14 after surgery, adrenaline levels had decreased sharply by 53% in the blood (p < 0.05), which was 41% lower than the preoperative level, and by 59% in the kidneys (p < 0.05), which was 43% lower than before surgery. By day 7 after surgery, the level of adrenaline in the blood in the study group had increased by 41% (p < 0.05). By day 14, this indicator, in both the study group and the control group, had decreased by 50% and had fallen to 29% below normal values (p < 0.05). In the kidneys, on postoperative day 7, in animals that received α-TA, the increase was 26% (p > 0.05). By day 14, the adrenaline level in the study group had decreased by 45% (p < 0.05), which was 31% (p < 0.05) below normal. By day 28, the level of adrenaline had normalized both in the blood and in the kidneys in both experimental groups.

 

Table 1. Changes in the indices of the cortico–sympathetic–adrenal system in white rats with a resected kidney in the study and control groups.

Indicator

Group

Before the surgery (n = 10)

Day 7

(n = 60)

Day 14

(n = 60)

Day 28

(n = 60)

 

Adrenaline

Blood (μg/mL)

Control group

0.094 ± 0.007

0.118 ± 0.015

0.055 ± 0.009*

0.080 ± 0.006

Study group

0.094 ± 0.007

0.133 ± 0.016*

0.067 ± 0.008*

0.100 ± 0.009

Kidney (μg/g)

Control group

0.562 ± 0.052

0.788 ± 0.084*

0.321 ± 0.039*

0.540 ± 0.033

Study group

0.562 ± 0.052

0.706 ± 0.066

0.388 ± 0.042*

0.525 ± 0.040

 

Noradrenaline

Blood (μg/mL)

Control group

0.114 ± 0.008

0.135 ± 0.010

0.162 ± 0.011*

0.122 ± 0.014

Study group

0.114 ± 0.008

0.144 ± 0.013

0.172 ± 0.016*

0.158 ± 0.013*

Kidney (μg/g)

Control group

3.186 ± 0.198

3.764 ± 0.194*

4.077 ± 0.232*

3.433 ± 0.230

Study group

3.186 ± 0.198

3.705 ± 0.172

3.865 ± 0.288

3.222 ± 0.221

 

Dopamine

Blood (μg/mL)

Control group

0.111 ± 0.007

0.068 ± 0.011*

0.055 ± 0.008*

0.082 ± 0.006*

Study group

0.111 ± 0.007

0.060 ± 0.010*

0.085 ± 0.007*/**

0.165 ± 0.020 */**

Kidney (μg/g)

Control group

1.230 ± 0.126

0.408 ± 0.049*

0.653 ± 0.075*

0.780 ± 0.099*

Study group

1.230 ± 0.126

0.544 ± 0.077*

0.690 ± 0.098*

0.842 ± 0.087*

 

11-oxycorticosteroid

Blood (μg/mL)

Control group

0.65 ± 0.06

0.98 ± 0.11*

0.86 ± 0.10

1.18 ± 0.12*

Study group

0.65 ± 0.06

0.98 ± 0.11*

0.86 ± 0.10

0.48 ± 0.10**

 

Histamine

Blood (μg/mL)

Control group

0.102 ± 0.003

0.137 ± 0.011*

0.184 ± 0.013*

0.109 ± 0.004

Study group

0.102 ± 0.003

0.112 ± 0.014

0.155 ± 0.015*

0.104 ± 0.007

Kidney (μg/g)

Control group

0.502 ± 0.045

0.901 ± 0.088*

1.100 ± 0.132*

0.736 ± 0.077*

Study group

0.502 ± 0.045

0.728 ± 0.084*

0.789 ± 0.100*

0.461 ± 0.033**

 

Serotonin

Blood (μg/mL)

Control group

0.068 ± 0.003

0.137 ± 0.010*

0.184 ± 0.013*

0.109 ± 0.004*

Study group

0.068 ± 0.005

0.096 ± 0.008*/**

0.101 ± 0.010*/**

0.077 ± 0.011**

Kidney (μg/g)

Control group

0.418 ± 0.032

0.633 ± 0.055*

0.750 ± 0.061*

0.580 ± 0.052*

Study group

0.418 ± 0.032

0.580 ± 0.039*

0.660 ± 0.060*

0.404 ± 0.030**

*Significant difference (p < 0.05) between experimental and intact animals. **Significant difference (p < 0.05) between groups of control animals and groups of animals treated.

 

After the surgical intervention in the animals of the control group, the concentration of noradrenaline in the blood had increased significantly (42%) by day 14 and subsequently normalized. In the study group, similar dynamics of the indicator were evident: namely, an increase to 51% (p < 0.05) by day 14, followed by a decrease. At the end of the experiment, the level of noradrenaline remained 39% higher than preoperative values (p < 0.05). In the kidneys in the control group, the level of noradrenaline had increased by 18% on day 7 (p < 0.05) and by 30% on day 14 (p < 0.05), and the levels subsequently normalized by the end of the experiment (p > 0.05). Changes in noradrenaline in the kidneys in the study group were not significant.

The level of dopamine in the control group decreased progressively in the blood until day 14 (by 39% by day 7 and by 50% by day 14). By the end of the experiment, its content tended to increase (26%) but did not reach the baseline level. In the kidneys, the maximum (to one third of normal levels) decrease in dopamine (p < 0.05) was observed on day 7, and then dopamine content gradually increased; however, by day 28, it remained below the preoperative level by 37% (p < 0.05). On day 7 after the surgery, in the study group, levels of dopamine had decreased by 46% in the blood (p < 0.05) and by 56% in the kidneys (p < 0.05). After α-TA was administered, the concentration of dopamine increased from day 14 and exceeded the baseline level by 49% in the blood by the end of the experiment (p < 0.05); in the kidneys, in contrast, it exceeded the baseline level by only 32% (p < 0.05). In the study group, there was a significant increase by 55% in the level of dopamine by day 14 of the experiment and a significant increase by 101% by the end of the experiment. There were no statistically significant changes in the kidneys in the control group.

Glucocorticoid activity in the blood of control group animals was 51% higher on day 7 (p < 0.05) and decreased by 12% on day 14; values remained higher (by 32%) in relation to the reference level (p < 0.05) and again increased by the end of the experiment to 82% of the baseline level (p < 0.05). In the study group, the indices on days 7 and 14 were identical to those in the control group, and on day 28, there was a decrease in the level of glucocorticoid activity by 44%; this index reached the preoperative level (p > 0.05) and was 2.5 times lower than the reference values.

The level of histamine in the blood and in the kidneys of control animals were significantly higher on day 7 (43% and 79%, respectively) and on day 14 (80% and 119%, respectively) and then decreased (became normalized in the blood but remained 47% above the norm [p < 0.05] in the kidneys). With the administration of α-TA, in the blood a significant increase in the index (52%) occurred only on day 14. In the kidneys of study group animals, the histamine level significantly increased on days 7 and 14 after the surgery by 45% and 57%, respectively, with the normalization of the index by day 28 (p > 0.05) and was 37% lower than the level of histamine in the kidneys of the control group animals (p < 0.05).

The level of serotonin in the blood of control group animals doubled by the end of the first week (p < 0.05) and increased by 2.7 times by the end of the second week (p < 0.05). By the last day of the experiment, the level of serotonin had decreased but remained 1.6 times (p < 0.05) higher than the preoperational level. In the study group, a significant increase in serotonin concentration was observed only on days 7 and 14 of the experiment (by 41% and 49%, respectively, in blood and by 39% and 59%, respectively, in the kidneys). On day 28 of the experiment, serotonin levels in the study group had returned to normal (p > 0.05). In comparison with the control group, the use of α-TA produced a significant decrease in serotonin levels in the blood throughout the postoperative period (by 43%, 82%, and 42%, respectively). In comparison with control group indices, the changes produced by α-TA in the kidneys remained statistically insignificant on days 7 and 14, and at the end of the experiment, the serotonin level was below the control level by 30% (p < 0.05).

Fluctuations in the level of blood creatinine throughout the experiment in both groups were within the normal range and were statistically insignificant.

Discussion

The kidney is the most important excretory and endocrine organ [24]. Any surgical intervention involving the kidneys affects the activity of the sympathoadrenal and renin–angiotensin–aldosterone systems and the metabolism of catecholamines in the body, which are closely related [25, 26]. Catecholamines, serotonin, histamine, and kinins from the source of ischemic injury play an important role in the occurrence of primary microcirculatory and rheological disorders in the renal parenchyma and trigger disorders of systemic hemodynamics [27, 28]. To assess the severity of biochemical abnormalities in the parenchyma of the operated kidney, we monitored the levels of CSAS indices responsible for the regulation of vascular tone, the severity of the inflammatory

response, the microcirculation, and reparative processes. Resection of the lower pole of the left kidney with preservation of the contralateral organ led to a hormonal-mediator imbalance, which was manifested by an increase in vasoconstrictive monoamines (adrenaline, noradrenaline, and serotonin) and in 11-oxycorticosteroid, which potentiated them, and by a decrease in vasodilatory monoamines (dopamine). The blood creatinine indices in both groups were not much affected by the surgery performed and did not differ from the similar blood values of the intact rats, which, in our opinion, reflected sufficient total renal function. The mechanism of the protective effect of α-TA as a natural antioxidant is based not only on its antioxidant properties but also on its membrane- stabilizing action: the ability to influence the adaptation of cellular metabolism to the conditions of ischemia. Its use in the postoperative period led to an early recovery of the CSAS indices in the experiment.

Conclusion

The dynamics of the levels of adrenaline, noradrenaline, dopamine, serotonin, histamine, and 11-oxycorticosteroid in the blood and tissue of the kidneys of laboratory animals were affected by the use of α-TA in the postoperative period. These changes are a prerequisite for improving microcirculation, reducing the intensity of inflammatory reactions, and increasing reparative processes in the surgical site; these findings confirm the nephroprotective properties of α-TA.

Igor S. Shormanov

Yaroslavl State Medical University

Author for correspondence.
Email: i-s-shormanov@yandex.ru

Russian Federation, Yaroslavl

Doctor of Medical Science, Professor, Head of the Department of Urology and Nephrology

Marina S. Los

Yaroslavl Regional Clinical Hospital

Email: 922099@mail.ru

Russian Federation, Yaroslavl

Candidate of Medical Science, Urologist

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