Introduction
General anesthesia is a medically-induced loss of consciousness with loss of protective reflexes due to the administration of one or more anesthetic agents [1]. One of these agents is ketamine which can provide short-term pain relief [2]. It is a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. This drug is derived from phencyclidine and is an injectable or inhalational anesthetic or an illegally abused drug with sedative and antidepressant effects [3]. Ketamine is eliminated by the liver and kidneys [4]. The use of this drug in humans can be accompanied by mild or acute side effects such as increased saliva secretion, increased heart rate, systemic arterial pressure, and intracranial pressure [5]. If this drug is used on pregnant humans or animals, it may cause side effects on their fetuses and newborns. 
Some pregnant women need surgery due to problems related to their pregnancy or other diseases, where ketamine is a common anesthetic drug [6]. Considering the importance of the kidney, which is the main organ for maintaining the homeostasis of the body [7], we aim to investigate the effect of ketamine on the kidney tissue of rats born from exposed mothers.

Methods
This study was carried out in a laboratory on 15 Wistar female rats with almost similar weights in compliance with the medical ethics. The housing conditions were the same for all rates. After one week of adaptation to the environment, the rats were randomly divided into three groups of 5 including control, long-term anesthesia, and short-term anesthesia. To create pregnancy in rats, two male rats were used in each group. Pregnancy was confirmed after observing the vaginal plaque [8]. Pregnant rats in the long-term anesthesia group were anesthetized with ketamine at a dose of 75 mg/kg once a week, while pregnant rats in the short-term anesthesia group were anesthetized with ketamine at a dose of 25 mg/kg three times a week. The ketamine injection was done weekly and regularly from one week before pregnancy to one week after pregnancy [9].
After giving birth and during the lactation period, 10 rat newborns from each group (a total of 30 neonatal rats) were randomly selected for tissue sampling. With a surgical blade, their abdominal area was cut by scissors and fixed by forceps. Then, the kidney was separated and weighed by a digital scale. The samples were fixed with formalin and evaluated by optical microscope.

Results
The histological results obtained from the samples of all neonatal rats in the control group were normal in the cortical and central areas. The glomeruli in the cortical area had adequate number and normal size along with healthy cell characteristics and the Bowman’s capsule in the outer layer composed of normal squamous cells. Under the capsule, the urinary space had a normal size. Proximal complex tubules with relatively large and acidophilic cells, normal nuclei, and small lumen space as well as distal complex tubules with higher number of cells in cross-sections and larger lumen space were observed. In the central area of the tissue, the collecting tubules and different areas of Henle’s arch were healthy and there were no signs of hyperemia, inflammation, or cysts.
In the kidney samples prepared from the short-term anesthesia group, the number of glomeruli in the cortical areas was adequate mostly with normal tissue characteristics; only some of them were disorganized and irregular. Also, in a small number of them, a shrinkage was observed which reduced the urinary space. The Bowman’s capsule was visible with normal cells, appropriate cell spacing, and appropriate sizes. Proximal complex and distal complex tubules had proper lumen characteristics, normal cells and nuclei, and normal structure. The tubules in the center of the kidney were also normal.
In the kidney samples prepared from the long-term anesthesia group, the number and distribution of glomeruli were different compared to the control group; some of them had different sizes and shapes. The urinary space showed a very small decline. The Bowman’s capsule had squamous and wide cells with a clear and normal nucleus. Proximal complex and distal complex tubules had also normal cell number and shape and appropriate lumen size in all areas. The characteristics of the tubules in the central area of kidney were also normal.

Conclusion 
Anesthetic drugs, including ketamine, can have a toxic effect on vertebrate and human fetuses [5]. According to the hematological, biochemical and histopathological evaluations in this study, the long-term administration of ketamine in rats, showed the degeneration of the epithelial cells of the tubules, tubular epithelial cell necrosis, glomerulus atrophy, and infiltration of inflammatory cells were observed in the kidney. The results of our study related to the histological evaluation of the group received short-term administration of ketamine, showed that only some glomeruli were disorganized and irregular and shrinkage associated with reduced urinary space was observed in a small number of them. In the long-term administration group, the number and distribution of glomeruli in the kidney tissue were inappropriate and some of them had irregular size and shape, while in the control group, the characteristics of cortical and central areas, Bowman’s capsule, urinary tubes and urinary spaces were normal. Therefore, it can be said that ketamine causes negative changes in the kidney tissue of the fetus born from the mother exposed to ketamine, but these changes were not significant in two ketamine groups compared to the control group. Hence, it can be concluded that ketamine does not cause any acute and important kidney damage in the newborns of rats exposed to ketamine. However, it is better to conduct more comprehensive studies to further investigate this effect to know more about the histological effects of ketamine and plan for its safer use in medical cases.

Ethical Considerations
Compliance with ethical guidelines
This study was approved by the Ethics Committee of Islamic Azad University, Shahrood Branch (Code: IR.IAU.SHAHROOD.REC.1398.049).

Funding
This study was funded by the Student Research Committee of Islamic Azad University, Shahrood Branch.

Authors' contributions
Study concept, design, and supervision: Behrooz Yahyaei and Leila Khojasteh; Acquisition, analysis, or interpretation of data: Behrooz Yahyaei, Aref Arminfar, Ali Jorjani; Drafting of the manuscript: Aref Arminfar, Hesammedin Babaei, Alireza Avazzadeh, Kimia Jannati Toupkanloo; Critical revision: Hesammedin Babaei and Ali Jorjani; funding acquisition: Behrooz Yahyaei, Aref Arminfar. 

Conflicts of interest
According to the authors, there is no conflict of interest.

Acknowledgments
The authors would like to thank the Student Research Committee of the Islamic Azad University, Shahrood Branch for their financial support in this research.


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