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 Table of Contents    
RESEARCH ARTICLE
Year : 2021  |  Volume : 53  |  Issue : 3  |  Page : 198-206
 

Nephroprotective effects of ethanolic root extract of Azima tetracantha lam in adenine-induced chronic kidney failure in Wistar rats


1 Department of Pharmacology, Chettinad Hospital and Research Institute, Chennai, Tamil Nadu, India
2 Former Professor of Pharmacology, Chettinad Hospital and Research Intitute, Chennai, Associate Professor and Incharge Head, Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Bibinagar, Hyderabad, Telangana, India
3 Senior Veterinary Medical Officer, Central Animal House, Chettinad Hospital and Research Institute, Chennai, Tamil Nadu, India

Date of Submission11-Oct-2019
Date of Decision29-Sep-2020
Date of Acceptance17-May-2021
Date of Web Publication22-Jun-2021

Correspondence Address:
Dr. Venu Gopala Rao Konda
Former Associate Professor, Department of Pharmacology, Chettinad Hospital and Research Institute, Kelambakkam, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_552_19

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 » Abstract 


OBJECTIVES:

  1. To evaluate the effects of ethanolic root Ethanolic extract of Azima tetracantha. Lam roots (EEATR) in adenine-induced chronic kidney failure in Wistar albino rats
  2. To assess the antioxidant activity of EEATR.

MATERIALS AND METHODS: Thirty rats were selected and allocated to five groups with six animals in each group. Group 1 was given normal saline (control), Group 2 – adenine, 0.75% 40 mg/kg, Group 3 – adenine and 250 mg/kg of EEATR, Group 4 – adenine and 500 mg/kg EEATR, and Group 5 – EEATR 500 mg/kg. Saline, adenine, and EEATR were given orally once daily for 28 days. EEATR was given 60 min before adenine administration. Urine output, blood urea nitrogen (BUN), creatinine, albumin, and total proteins were estimated. The histopathological changes in the kidneys were examined, and antioxidant property of the extract was assessed in the renal tissue.
RESULTS: Adenine treated rats had a reduction in urine output (‒45%), food intake (‒46%), body weight (‒28%), total proteins (‒66%) and albumin (‒59%) and an increase in creatinine (950%), BUN (73.6%), and kidney weight (43.75%). Histological examination of the kidneys showed capillary congestion, tubular damage, glomerular distortion, and many oxalate crystals. Rats co-administered with EEATR 250 and 500 mg/kg had marked improvement (P ≤ 0.0001%) in all the above parameters with a marked reduction in size and number of oxalate crystals in the kidney. In the anti-oxidant assays, EEATR exhibited significant antioxidant activity.
CONCLUSION: EEATR was found to be an effective nephroprotective agent in adenine-induced chronic renal failure in Wistar albino rats.


Keywords: Adenine, azimaroot extract, nephroprotective, oxalate crystals, renal failure


How to cite this article:
Arunachalam R, Rao Konda VG, Eerike M, Radhakrishnan AK, Devi S. Nephroprotective effects of ethanolic root extract of Azima tetracantha lam in adenine-induced chronic kidney failure in Wistar rats. Indian J Pharmacol 2021;53:198-206

How to cite this URL:
Arunachalam R, Rao Konda VG, Eerike M, Radhakrishnan AK, Devi S. Nephroprotective effects of ethanolic root extract of Azima tetracantha lam in adenine-induced chronic kidney failure in Wistar rats. Indian J Pharmacol [serial online] 2021 [cited 2021 Jul 24];53:198-206. Available from: https://www.ijp-online.com/text.asp?2021/53/3/198/318974





 » Introduction Top


Chronic renal failure (CRF) is currently known as chronic kidney disease (CKD). “CKD is defined as either kidney damage or glomerular filtration rate <60 mL/min/1.73 m2 for ≥3 months.”[1]

CKD is a serious life-threatening disease characterized by chronic, progressive, and irreparable loss of kidney function. According to the WHO, kidney disease is responsible for nearly 850,000 deaths that occur annually, of which CKD is found as the 12th leading cause of death. Globally, it affects 800 per million populations (pmp). The annual incidence of CKD in India is approximately 150–200 pmp.[2]

The main feature of CKD is a progressive loss of renal mass resulting in gross reduction in the number of active nephrons. The loss of nephrons is compensated to some extent by the hypertrophy of the existing nephrons. This hypertrophy is due to the upregulation of growth factors especially transforming growth factor beta.[3]

Hypertrophy of nephrons leads to hyper filtration and improved urine output but eventually these compensatory mechanisms fail and nephrosclerosis occurs. Hence, the protection of the existing nephrons from further damage is the objective of treatment of CKD.

The management of CRF includes primarily the treatment of the underlying cause, withdrawal of the medications that could contribute to the development of CKD, dietary restriction of proteins, correction of fluid and electrolyte changes, diuresis, dialysis, and finally renal replacement therapy (RRT).

RRT helps mainly in the removal of waste such as excessive fluid, electrolytes, and end products of metabolism. Although these conservative treatments improve the symptoms and discomfort to the patients, the clinical outcome of CKD is not satisfactory and patients have to be on lifelong dialysis or undergo renal transplantation. Hence, the aims of the treatment are to root out the cause for CKD, prevent further progression of disease and protect the renal tissue. There is no treatment available at present to achieve all these aims.

As the cost of lifelong dialysis/renal transplantation is not affordable for all, an alternative equally effective, life-saving therapy is mandatory to save these patients.

In the traditional systems of medicine, many medicinal plants (both terrestrial and aquatic), metals and minerals are used in the treatment of CKD.

Azima tetracantha Lam (AT) is also known as needle bush and bee sting bush. It is used in the native medical systems in India, Africa, and Madagascar.[4]

AT has been used traditionally for the treatment of kidney disease.[5] It is found to have anti-inflammatory, antipyretic, analgesic, antioxidant, antimicrobial, antifungal, anticancer, antiulcer, diuretic, anti-snake venom, and hepatoprotective effects.[6]

In Ayurveda and Siddha systems, AT has been used for its powerful diuretic and anti-inflammatory actions. Ethanolic extract of AT root has been found to protect the kidneys from damage in acute kidney failure induced with glycerol in rats.[7] However, whether it would have the protective effect in CRF is not known. Hence, this study was done to evaluate the beneficial effects of the root extract of A. tetracantha in rat model of chronic kidney failure.

Aim

The aim of this study is to study the effects of ethanolic extract of A. tetracantha Lam. Root (EEATR) in chronic kidney failure in rats induced by adenine.

Objectives

  • To induce CRF in Wistar albino rats by giving adenine orally
  • To study the effects of EEATR in adenine-induced CRF in rats
  • To assess the antioxidant activity of EEATR in renal tissue.



 » Materials and Methods Top


The experiment was started after getting approval Institutional Animal Ethics Committee and conducted following the Committee for the Purpose of Control and Superviion of experiments on animals (CPCSEA) guidelines, India.

Chemicals

Adenine and the chemicals required for this study were procured from the Sigma Aldrich company, in New Delhi, India.

Preparation of average true range extract

A. tetracantha plant material was obtained from the town, Vandhavasi, located at about 115 Km south of Chennai. The plant specimen was authenticated by botanist Dr. Narasimhanin Chennai, Tamil Nadu and submitted to the Botanical Survey of India, Bengaluru. The specimen number is FRLH 120171.

One kilogram of average true range (ATR) was thoroughly cleaned using water and then dried in shade for 30 days in the room temperature. The dried roots were ground to get a coarse powder. Extraction was done with the coarse powder using Soxhlet apparatus for 15 cycles with 95% v/v ethanol. The extract was then dried using a flash evaporator. The final extract of 56.01 g was obtained which was green in color, thick and sticky in nature.

Animals

Thirty healthy Wistar albino rats (male) with the body weight ranging between 150 and 200 g were received from the animal house of the Institute.

CRF was induced with administration of oral adenine.

Adenine administration

Adenine (0.75%) was dissolved in water and administered orally (40 mg/kg) once a day for 4 weeks. However, adenine had been administered to rats by mixing with pellet diet in previous studies.[8]

Experimental design

A total of 30 rats were allocated to five groups with each group containing six animals. Group 1 was treated with normal saline (10 ml/kg), Group 2 with 0.75% adenine 40 mg/kg, Group 3 with adenine 40 mg/kg and EEATR extract 250 mg/kg, Group 4 with adenine 40 mg/kg and 500 mg/kg of EEATR extract, and Group 5 with 500 mg/kg of EEATR extract alone. All the groups received the respective treatment through oral tubing once a day for 28 days. EEATR extract was given 60 min before adenine administration.

The rats were examined once a week for 4 weeks. Food intake (g in 24 h), water intake (ml in 24 h), body weight (g), urine output (ml in 24 h),[9] blood urea nitrogen (BUN), serum creatinine, serum total proteins, and albumin[10] were assessed weekly once for 4 weeks according to the methods followed in previous studies.

Twenty-four hour urine output was measured using metabolic cage. Retro-orbital sinus puncture was done under halothane anesthesia to collect the blood samples on day 28.

After collecting the blood samples, all the rats except those in Group 5 were sacrificed by giving a high dose of halothane. The abdomen was opened, and the kidneys were isolated. The weight of the kidneys in each group was measured and average calculated.

The morphological characteristics, the size, color, and texture were noted and histopathological changes examined. The number and intensity of oxalate crystals in the kidney tissue were examined in all the groups.

Estimation of antioxidant enzymes

Lipid peroxidase (LPO), superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPx), and catalase (CAT)[11] were estimated in renal tissue using enzyme-linked immunosorbent assay kits.

Statistical analysis

The data were summarized as mean ± standard error of the mean. The statistical significance among the groups was estimated using the one-way analysis of variance followed by Tukey-Kramer Multiple Comparisons Test. P < 0.05 was considered statistically significant.

Study results

CRF was successfully induced in rats treated with direct oral adenine administration.

Food, water intake, body weight, urine output, BUN, serum creatinine, serum albumin and total proteins, morphology of kidney, kidney weight, antioxidant enzymes, and histopathological changes did not show significant change from day 1 to day 28 in the saline-treated control (Group 1) and ATR extract-treated groups.

Food intake

Food intake was reduced by 46% in adenine-treated Group 2 rats, whereas in EEATR-treated Group 3, it was reduced by 7%, and in Group 4, the reduction was nil. The improvement in food intake in Group 3 and 4 was found to be highly significant (P < 0.0001). There was no significant change in food intake in both the saline and EEATR-treated groups [Graph 1].



Water intake

Forty percent reduction in water consumption in Group 2, 21% reduction in Group 3, and no reduction was seen in Group 4. The improvement in water intake seen in Group 3 and 4 was highly significant (P < 0.001) [Graph 2].



Body weight

CRF-induced untreated rats had 28% reduction in baseline body weight, whereas in rats treated with EEATR, the reduction was 12% in Group 3 and 0.5% in Group 4.The reduction in weight loss observed in EEATR groups was found highly significant (P < 0.01) [Graph 3].



Urine output

The urine output was measured at baseline, weekly once and on day 28. On day 28, it was decreased to 4.9 ml (45%) in untreated CRF rats from the baseline value of 7.6 ml. In Group 3, the urine output was 6.1 ml (19.7%), whereas in Group 4, it was 7.5 ml (1.3%). The extent to which urine output was reduced in Group 3 and 4 was significantly low compared to Group 2 (P < 0.001) [Graph 4].



Serum creatinine

Serum creatinine increased rapidly from 0.92 mg at baseline every week and at week 4 it increased to nearly 10 times, 9.66 mg in Group 2 rats. In Group 3, it was 6.13 and in Group 4, it was 1.55 mg. The reduction in creatinine level in Group 4 was 83.95%. The improvement in creatinine level was highly significant (P < 0.001) [Graph 5].



Blood urea nitrogen

There was a progressive increase in BUN from the baseline level of 19.4 mg to 33.5 mg at the end of 4 weeks and the increase was 73.6%in Group 2 rats. The BUN level was 24.7 in Group 3 and 18.6 mg in Group 4 which was lower than the baseline value. The BUN level at 4 weeks in Group 4 was similar to that of the saline and EEATR control groups. The difference among Group 2, 3, and 4 was statistically highly significant (P < 0.001) [Graph 6].



Serum total proteins and albumin

Group 2 rats had a progressive decrease in serum total proteins from 5.92 g/dl to 2 g/dl (66% reduction) and albumin from 4.35 g/dl to 1.78 g/dl (59%). Group 3 had shown increase in serum albumin and total proteins when compared to Group 2. Serum total proteins and albumin levels were not affected in Group 4 from baseline value. The increase in serum proteins was highly significant in the groups treated with extract (P < 0.0001) [Graph 7] and [Graph 8].



Morphology of kidney

Kidney in the control group was found to be smooth in consistency and pink in color, whereas in CRF-induced rats, the kidney was rough, enlarged, and brown in color. The kidneys in the group treated with EEATR alone were smooth in consistency and appearance [Figure 1].
Figure 1: Morphology of kidney

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Kidney weight

The average kidney weight was 848 mg in the control group and 1219 mg in adenine treated group. Concurrent administration of EEATR resulted in reduction in renal weight to 959 mg in Group 3 and 922 mg in Group 4 (P < 0.0001) [Graph 9].



Antioxidant levels in kidney tissue

Level of LPO increased and GPx, GSH, SOD, and CAT levels decreased in Group 2. LPO levels decreased in Groups 3 and 4 and the levels of GSH, SOD, CAT, and GPX increased in Groups 3 and 4. The difference among Groups 2, 3, and 4 was found to be highly significant (P < 0.0001) [Graph 10], [Graph 11], [Graph 12], [Graph 13], [Graph 14].



The F values calculated for all the above parameters have shown that the difference among the groups is highly significant [F value [Table 1]].
Table 1: Comparison of parameters among the groups

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Histopathology

Kidney tissues were stained with eosin and hematoxylin and examined. In Group 1, the renal glomeruli were normal with unaltered Bowman's capsule. The proximal and distal convoluted tubules were normal without capillary congestion/hemorrhage. Group 2, adenine treated rats showed distorted glomeruli, apical blebbing, capillary congestion, hemorrhages, interstitial damage, and formation of many oxalate crystals. In Group 3 rats, the number of normal glomeruli increased, proximal and distal convoluted tubules were well-defined with a decrease incapillary congestion, interstitial damage, oxalate crystals, and hemorrhages were seen. Animals in Group 4 rats had many intact glomeruli and tubules, resolution of the interstitial damages, marked reduction in number and size of the oxalate crystals. The difference in histopathological changes was marked in Group 4 [[Figure 2] in × 10].
Figure 2: Histopathology. Kidneys are stained with haematoxylin and eosin and figures were in ×10 magnification

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 » Discussion Top


”CKD” refers to kidney damage that can become severe over time. When the damage is severe, kidney function fails and this stage is called end-stage renal disease or kidney failure. The prevalence of CKD ranges from <1% to 13%, in different regions of India and a prevalence of 17% has been reported by the International Society of Nephrology's Kidney Disease Data Center.[12]

CKD is a debilitating disease, causing severe morbidity as well as mortality. The current treatment includes the management of the risk factors such as diabetes mellitus and hypertension and providing supportive measures. The medical management prolongs life but the patients have to be on lifelong RRT. RRT refers to renal dialysis (peritoneal/hemodialysis) hemofiltration and/or renal transplantation. Renal dialysis has saved the lives of many patients with renal failure. However, the cost of frequent renal dialysis, discomfort, and the compromised quality of life experienced by the patients make them opt for alternative systems of therapy.

In traditional systems, many medicinal plant products are used for renal failure treatment. Among the medicinal plants, A. tetracantha has been used by various ethnic groups in the treatment of diseases such as rheumatism, venereal diseases, stomach disorders, chronic diarrhea, chronic dysentery, headache, fever, toothache, cough, sprain, cold, snake bite and also as an appetizer and a diuretic. A. tetracantha root extract was found to be effective in acute kidney failure induced by glycerol in Wistar rats.[7] Hence, this study was conducted to find its effect in adenine-induced chronic kidney failure in Wistar rats.

Adenine and chronic renal failure

Adenine is normally converted to adenosine monophosphate by the enzyme 5-phosphoribosyl-1-pyrophosphate. This enzyme becomes insufficient to metabolize adenine when adenine is administered continuously. Hence, adenine is metabolized through a different metabolic pathway and gets oxidized by xanthine dehydrogenase to 2, 8 dihydroxyadenine. As 2, 8 dihydroxyadenine is poorly soluble, it gets precipitated in the renal tubules, resulting in the formation of crystals leading to tubular injury and inflammation, tubular obstruction, and marked fibrosis.[13] In addition, there are associated biochemical changes characteristic of CRF, like elevated creatinine level and BUN, reduced urine output and body weight resembling human CRF. Hence, adenine-induced renal failure in rats is a common model for the study of CKD.

In the conventional model, adenine is mixed with rats' pellet diet. However, the limitation of this method is that the animal may not consume the whole quantity of the pellet diet. Hence, in this study, adenine was dissolved in water and fed through direct oral tubing.

At the end of 4 weeks, Group 2 rats ingested with adenine showed reduction in food intake (‒46%), water consumption (‒40%), body weight (‒28%), urine output (‒45%), total proteins (‒66%), and albumin (‒59%). The blood urea level increased 10 times that of the basal value and BUN increased by 73.6% [Graph 1], [Graph 2], [Graph 3], [Graph 4], [Graph 5], [Graph 6]. Histopathological examination of kidneys showed changes suggestive of interstitial nephritis with marked distortion of glomeruli, tubular damage with the development oxalate crystals, capillary congestion, hemorrhages, and apical blebbing. There were many large oxalate crystals [Figure 2] and [Figure 3]. All these changes confirmed renal damage.
Figure 3: Oxalate crystals are seen under fluorescent dye

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Treatment with EEATR extract (250 and 500 mg/kg) reduced the renal damage significantly. It caused highly significant reduction in creatinine, BUN, renal weight, P = 0.0001% [Graph 6], [Graph 7], [Graph 8], [Graph 9] as well as elevation of the serum proteins. EEATR administration also improved the food and water intake, body weight, and urine output (P < 0.0001) [Graph 1], [Graph 2], [Graph 3], [Graph 4]. In addition, EEATR markedly reduced the number and size of oxalate crystals [Figure 2] and [Figure 3].

Adenine administration caused reduction in the levels of the antioxidants, CAT, GSH, SOD and GSHPx, and elevation in LPO. EEATR extract, when co-administered with adenine, normalized the levels of the antioxidants [Graph 10], [Graph 12], [Graph 13], [Graph 14].

The difference in the levels of all the parameters between Group 2 and 3, between Groups 2 and 4, and those of Groups 3 and 4 was highly significant (P = 0.0001). The results showed that both 250 and 500 mg/kg doses were protective to the kidney against adenine-induced damage. The property of the extract to reduce the oxalate crystal formation denotes its anti lithotropic property which can contribute to reducing the inflammatory reaction as well as free radical formation. However, it remains to be studied whether a dose higher than 500 mg will be more protective to the kidneys. EEATR thus normalized the various altered parameters at the given two doses. Although both the doses prevented renal damage significantly, the effect was greater with 500 mg than 250 mg EEATR and this is the first report of the nephroprotective effect of ATR extract in chronic kidney failure induced in rats.

El-Habibi and El-Sayed evaluated the effects of the juice of pomegranate (PJ) and pomegranate peel methanolic extract (PPME) in chronic kidney failure induced with adenine. In their study, the renal parameters did not return to normal at the end of 4 weeks. The percentage reduction in creatinine was 30% and 42% with PJ and PPME, respectively. Whereas, in our study, the reduction in creatinine was 83.95% with 500 mg of EEATR, and with 250 mg, it was 36%. At a dose of 500 mg, EEATR extract is found to be better than PJ juice and the peel extract for protecting the kidney.[14]

The effect of Gum Arabic and its mechanism of action in adenine-induced chronic kidney damage were evaluated by Ali et al. They estimated the inflammatory markers, CRP and IL10 and assessed the antioxidant activity and concluded that the anti-inflammatory and antioxidant activities of gum Arabic contributed to its protective effect in adenine-induced CRF.[15] In our study also, EEATR extract exhibited significant antioxidant activity. The protective effect of the antioxidant quercetin in preventing chronic kidney damage reported by Yang et al.[16] also supports our finding that antioxidant activity can offer renal protection. Further phytochemical studies are needed to find out the nature of antioxidant chemicals present in ATR.

The effect of total saponin fraction of Sun Ginseng was tested against adenine-induced CRF in rats and the authors observed that ginseng saponin ameliorated the changes produced by adenine.[17]

The root extract is to found to contain flavonoids, tannins, terpinoids, alkaloids, saponins, and glucosinolates. Saponins have actions similar to glucocorticoid. They inhibit the release of inflammatory mediators, production of enzyme involved in inflammation and vascular permeability.[18],[19]

Saponins present in AT root can contribute to the protective effect of EEATR.

Oxalate crystals are the common type of renal crystals. These aggregate together to form stones with the help of mucoproteins. Inhibition of mucoproteins will result in disintegration of stones. Saponins have been found to have litholytic effect by causing disaggregation of mucoproteins.[20] Saponins present in ATR could be responsible for the reduction in the size of the stone.

AT is used in traditional medicine mainly for its diuretic activity. Diuretics will be of use in renal failure in for removing the metabolic wastes. According to NKF KDOQI guidelines, the use of thiazide, loop, and potassium diuretics is recommended.

The ethanolic extract of A. tetracantha L. leaves had shown significant diuretic activity.[21] The increased urine output following the administration of EEATR extract denotes its diuretic activity. However, the diuretic activity of AT root extract has to be studied separately in future.

Glucosinolates, especially N-hydroxy - 3 -indolylmethyl -glucosinolate was detected in A. tetracantha root.[4] Glucosinolates found in vegetables such as mustard, cauliflower, cabbage, horseradish, and broccoli have antioxidant, anti-inflammatory, and antimicrobial properties.[22] Similarly, glucosinolates present in the root can contribute to the antioxidant activity along with other phytochemicals.

Based on the observations of this study showing highly significant protective effects of EEATR on the renal and nonrenal parameters associated with adenine-induced renal damage and the supportive evidences for the role of the antioxidant and anti-inflammatory activities contributing to renal protection, it can be stated that EEATR has a promising nephro protective effect and it is safe. Future studies with doses higher than 500 mg and mechanistic studies are needed to decide the optimum dose and the mechanism of protection of EEATR.


 » Conclusion Top


Ethanolic root extract of A. tetracantha was found to be an effective nephroprotective and anti lithotropic agent in adenine-induced chronic kidney failure in Wistar albino rats. Its effect was greater at 500 mg/kg than 250 mg/kg of the extract.

Values expressed as mean ± standard error of the mean, n = 6

Note: G-Group, D - Day

G-1 Control, G-2 Adenine, G-3 Adenine + EEATR 250 mg/kg, G-4 Adenine + EEATR 500 mg/kg, G-5 EEATR 500 mg/kg.

Statistics: G 1-8 (Intergroup Comparison, one-way analysis of variance, ***P < 0.0001, highly significant), Tukey Kramer multiple comparison “test- versus 2 (*P< 0.001), 1 versus 3 (*P < 0.001), 1 versus 4 (*P < 0.001), 1 versus 5 (ns P > 0.05), 2 versus 3 (*P < 0.001), 2 versus 4 (*P < 0.001), 2 versus 5 (*P < 0.001), 3 versus 4 (*P < 0.001), 3 versus 5 (*P < 0.001), 4 versus 5 (*P < 0.05)”

Graph 9-14 Day 28 (Intergroup Comparison, one-way analysis of variance, ***P < 0.0001, highly significant), Tukey Kramer multiple comparison “test-1 versus 2 (*P < 0.001), 1 versus 3 (*P < 0.001), 1 versus 4 (*P < 0.01), 2 versus 3 (*P < 0.001), 2 versus 4 (*P < 0.001), 3 versus 4 (*P < 0.001)”

Financial support and sponsorship

This study was financially supported by Chettiand Hospital and Research Institute for providing facilities, to carry out this work.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

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