INTRODUCTION:

Urinary system plays a vital role in our body for the maintaining and regulating endocrine glands functions, body blood pressure, acid-base balance and erythropoiesis. Nephrotoxicity is one of the leading causes for the kidney problems in the form of acute and chronic renal failure which intern causes anaemia, bone disorders, CVS risk, and dyslipidaemia, nephritis when body is exposed to a drug or toxic substances.^1.2 The kidneys are considered as a major target organ for exogenous toxicants, because they are essential organ required to perform several important body functions including the maintenance of homeostasis, regulation of the extracellular environment such as detoxification, and excretion of toxic metabolites as well as drugs.³ when kidney get damage resulting in the dysfunction or impairment of urinary system, then body is unable to get rid of excess of formed urine and waste metabolites from body, elevation of blood electrolytes were also seen (K, Na and Mg).⁴

In India, over 2/3^rd cases of hypertension and diabetes accounts for 40-60% cases of kidney related disorder especially chronic kidney disorder (CKD).⁵

Acute renal failure and chronic renal failure are quite different from each other, in case of ARF there will be rapid and reversible loss of renal function over a period of days to weeks or more. The reported causes for ARF in acute tubular necrosis which occurs due to toxin or ischemia. Chronic renal failure is an irreversible state of renal function deterioration over a period of year’s leads to rapid loss of excretory metabolites and depletion of endocrine functions. Medicinal plants serve as a vital source of potentially useful agents for developing effective therapy to prevent a variety of kidney problems. A variety of medicinal plants and plant extracts have been reported for their significant Nephroprotective activity in animal models.⁶

Plant organs such as leave, stems, bark, roots, flowers, seeds and fruits has been used as alternative and complementary therapy. Medicinal herbs contain mixture of active components or phytochemicals like flavonoids, alkaloids, saponin, terpenoids, isoprenoids, polyphenols and tannins etc. herbs which are rich in antioxidants also have Nephroprotective properties. Nephroprotective are the agents which shows protective activity towards to nephrotoxicity which is caused by the drugs such as Cisplatin, gentamicin and acetaminophen etc.⁷ This review gives a brief idea regarding drug causes nephrotoxicity and overview of therapeutic choice with some important, popular plant-derived medicinal herbs act as Nephroprotective agents.

Agents Which Inducing Nephrotoxicity:

Number of chemical agents, therapeutic drugs and diagnosing agents are responsible for clinically inducing significant nephrotoxicity. Hence, agents which causes nephrotoxicity are well known to be nephrotoxic in nature. Drugs which responsible for inducing nephrotoxicity are classified in Table no 1 as below. ^6.8

Table 1: drugs which causes nephrotoxicity

Drugs	Example
analgesic	Acetaminophen, Aspirin
Anti-depressant	Amitriptyline, Fluoxetine, Doxepin
Anti-microbial	Amphotericin-B, Acyclovir, Foscarnet, Ganciclovir, Trimethoprim, Rifampicin
Anti-retroviral	Adefovir, Tenofovir, Indinavir
Chemotherapeutic	Carmustine, Cisplatin, Cyclophosphamide
Proton pump inhibitor	Omeprazole, Pantoprazole
Aminoglycosides	Gentamycin, Amikacin, Kanamycin, Streptomycin
Biological agents	Recombinant leucocyte and Interferon

Mechanism of Some Important Drug Induced Nephrotoxicity:

Cisplatin Induced Nephrotoxicity:

Cisplatin is chemotherapeutic agent responsible for high prevalence of nephrotoxicity. Clinically cisplatin nephrotoxicity was seen after 10 days of drug administration, which causes decrease in the GFR rate, elevation of serum creatinine level and decrease serum Mg and K ions.

When cisplatin diffuses into kidney cells via passive or facilitated transport mechanism, renal tubular cells get exposed to cisplatin results in the activation of some important signalling pathways, such as MAPK, p⁵³, ROS and SO or p²¹ which are involved in renal cell death. Mainly cisplatin induces TNF-α production in renal tubular cell, which intern triggers the tissue inflammatory response and further contributes to cell injury and renal cell death. Or cisplatin also cause injury to renal vasculature leads to ischemia of tubular cells cause decrease GFR. Together of these cascade pathway leads to acute renal failure (ARF). ⁹

Gentamicin Induced Nephrotoxicity:

Gentamicin belongs to the category aminoglycosides antibiotic, widely used in the treatment of Gram Negative bacterial infection. Despite of this nephroprotective is a deleterious adverse effect of aminoglycoside therapy.¹⁰

Patient with gentamicin therapy having renal impairment but exact mechanism involved in gentamicin induced nephrotoxicity till now not yet cleared. Renal proximal tubule cells are primary target for aminoglycosides antibiotic where accumulation and cause nephrotoxicity via specific transporter, other mechanism may also contribute for gentamicin induced nephrotoxicity like excess production of ROS, hydroxyl radical, superoxide anions and RNS, also inhibition of Na K⁺ATPase inhibition and also mitochondrial oxidative phosphorylation. Accumulation of gentamicin also suggest that cell apoptosis, necrosis and oxidative stress.¹¹

Acetaminophen Induced Nephrotoxicity:

Acetaminophen is commonly used analgesic or anti-pyretic, overdosing of this drug might cause potentially inducing hepatorenal damage in experimental animals and human. Nephrotoxicity of acetaminophen depends on its metabolic profile, at therapeutic dose acetaminophen get conjugated in liver with Glucuronide or sulphate results in formation of water soluble, non-toxic compound that is easily excreted via bile. Small amount of acetaminophen metabolised into highly reactive and toxic metabolite called N-acetyl-p-benzoquinone-imine (NAPQI) by microsomal enzyme P-450. Intracellular GSH conjugate with NAPQI, result in the formation of mercapturic acid, which eliminate via kidney. Hence its plays crucial role in detoxification of acetaminophen. So overdose of acetaminophen, the active amount of NAPQI exceeds binding capacity of GSH result in the accumulation of NAPQI, active NAPQI binds with intracellular macromolecule lead to tissue damage. Then consequent activation of lysosomal enzyme induce tissue necrosis and organ dysfunction. Proximal renal tubules are primary target for acetaminophen toxicity.¹²

Figure no 1: nephrotoxicity pathway of acetaminophen

Medicinal herbs with Nephroprotective effects:

1) Alstonia scholaris Linn:

Alstonia scholaris Linn also called as devils tree or dita bark belongs to the family Apocynaceae. Traditionally this plant has been used to treat various aliment like asthma, anti-microbial, anti-bacterial, anti-diabetic and anti-arthritis etc.¹³

Dichloromethane extract of Alstonia scholaris shows Nephroprotective activity on gentamycin (80 mg/kg) induced experimental rats at a dose of 200 and 400 mg/kg. animals treated with gentamycin prone for severe nephrotoxic due to high levels of serum urea, creatinine, uric acid, total protein and urine urea, uric acid and creatinine concentration, but animals treated with extract of Alstonia scholaris linn shows significant reduction in creatinine, uric acid, urea in both serum and urine sample due to presence of terpenoids, alkaloids or flavonoids in herb.¹⁴

2) Abelmoschus esculentus L:

Abelmoschus esculentus commonly known as Okra Pods, its vegetable crop belongs to the family Malvaceae. Various parts of this herb used in the treatment of dysentery, diarrhoea, demulcent, spermatorrhoea and laxative.¹⁵

Animals treated with sodium nitrate shows that increase in the level of BUN, creatinine and decrease in activity of SOD, CAT. Sodium nitrate also causes necrosis of kidney tubules but okra pods treated animal shows significant reduction in kidney necrosis. Decreases level of BUN, creatinine and increase activity of SOD, CAT. Hence drug shows effective Nephroprotective actions on animal model.¹⁶

3) Corallocarpus epigaea:

Corallocarpus epigaea is medicinal herb belongs to the family Cucurbitaceae. Traditionally this herb used to treat syphilitic rheumatism and dysentery. It also possesses laxative properties. Herb is also effective remedy for the treatment for diabetes, snake bite, anthelmintic and herpes, powder of this root extract beneficial for chronic mucous enteritis.^17.18

Hydroalcoholic extract of Corallocarpus epigaea shows Renoprotective effect against Cisplatin induced nephrotoxicity at a dose of 100, 200 and 400 mg/kg. Elevation of serum creatinine and urea, decrease serum albumin was observed in Cisplatin treated group while, in case of extract treated group along with Vit-E (100 mg/kg) as a standard Nephroprotective agent reveals that increased in SOD, decrease in malondialdehyde level. Histopathological studies shows amelioration of cisplatin induced tubular necrosis of the kidney.¹⁹

4) Biophytum sensitivum (Linn):

Biophytum sensitivum commonly known as lajjalu, it is an annual herb used against diabetes mellitus (madhumeha) belongs to the family oxalidaceae. Traditionally drug used in the treatment of tonic, stimulant, stomach ache, asthma, insomnia and cramps etc.²⁰

Ethanol extract of whole plant Biophytum sensitivum (linn) shows nephroprotective properties against cisplatin induced nephrotoxicity in wistar albino rats. In this study several kidney functional tests and injury marker such as water intake, urine volume, and body weight, urine p^H. Urine level of total protein, sodium, potassium, calcium and magnesium are analysed. Co-administration of the whole plant extract shows marked reduction in urine excretion of total protein, calcium, low level of serum BUN, creatinine concentration and significant increase in the body weight, urine p^H, serum level of protein, calcium and sodium was observed, hence plant shows its ethno-medicinal useful in nephrotoxicity.²¹

5) Descurania sophia:

Descurania sophia is a dicot annual weed belongs to the family called cruciferae (brassiaceae). It is a traditional Chinese medicine used to cure different aliments. Seeds of this used to relives cough, asthma, reduces edema, promote urine (diuresis) and it has some pharmacological benefits due to rich in phytoconstituents.²²

Hydroalcoholic extract of Descurania sophia shows protective effect against gentamicin induced nephrotoxicity in experimental animals. Hence there is significant and dose dependent reduction in serum level of BUN, creatinine, cholesterol, triglycerides, Na excretion and cell death rate (apoptosis) was observed.²³

6) Sphaeranthus amaranthoides:

Sphaeranthus amaranthoides commonly known as sivakaranthai, it is procumbent herb belongs to the family Asteraseae. This herb is folklore medicine used to treat skin disease, eczema, blood disorder, stomach worms, filarial and fever.^24.25

Aqueous extract Sphaeranthus amaranthoides burm f. is effective in protecting kidney damage from gentamicin induced nephrotoxicity and useful for treating acute kidney injury (AKI). Animals which are pre-treated with different concentration of Sphaeranthus amaranthoides shows normal level of LDH, GGT, creatinine, BUN and electrolyte in both serum and urine but in gentamicin treated group elevated in above parameters was observed.²⁶

7) Eurycoma longifolia:

Eurycoma longifolia Jack is an herbal medicinal plant, popularly known as ‘Tongkat Ali.’ Belongs to the family Simaroubaceae. The plant have been traditionally used for its antimalarial, aphrodisiac, anti-diabetic, antimicrobial and anti-pyretic activities.²⁷

Herbal extract Eurycoma longifolia (EL) shows nephroprotective activity against paracetamol-induced nephrotoxicity in experimental animals. On the 15th day, serum creatinine, BUN, total protein and albumin were measured in serum and creatinine clearance was measured in urine. Histopathological analysis of all groups has done. There was a significant (p<0.05) elevation in serum creatinine and blood urea levels in the paracetamol alone group compared to the treatment groups due to nephrotoxicity. In the herbal extract treated groups, dose-dependent renal protection against paracetamol-induced nephrotoxicity was observed in serum total protein, albumin, and urea. Both serum and urine biochemical results and histopathological analysis of the kidney indicates that nephroprotective potential of EL extract against paracetamol-induced nephrotoxicity.²⁸

8) Combretum micranthum:

Combretum micranthum is medicinal plant belongs to the family Combretaceae. Nephrotoxicity was reported in glucose on human embryonic kidney cells (HEK-293) as an in vitro model for diabetic nephropathy. The final results showed that exposure of kidney cells to high glucose (100 mM) for period of 72 h significantly reduced the cell viability resulting in morphological alteration such as cell shrinkage, rounded cell shape and cytoplasmic vacuolation. Treatment with CM extract at 10 and 25 μg/mL shows that there is significant improvement in cell viability from 10 to 23% compared to the high glucose control. Hence study shows that potential nephroprotective properties of C. micranthum.²⁹

9) Tamarindus indica Linn:

Tamarindus indica is essential drug belongs to the family Fabaceae, found mainly in tropical countries. Drug used in unani system and it is effective in treating dysentery, cardiac tonic, stomachic, laxative, digestant and as an anti-septic.³⁰

The ethanolic extract of fruit pulp of Tamarindus indica Linn shows Nephroprotective activity on cisplatin induced nephrotoxicity in experimental rats. The evaluation of renal parameters on nephrotoxic rats with EETI showed significantly elevated the attenuated body weight, urine volume, creatinine clearance and significant reduction in elevated serum creatinine level, histopathological studies also shows reversal of kidney damage and restore the normal kidney structure which supports its Nephroprotective activity due to presence of flavonoids.³¹

10) Plectranthus amboinicus:

Plectranthus amboinicus is a popular medicinal plant belongs to the family called lamiaceae. Medicinal plant which found in all over India and it is used as folkloric medicine in the treatment of flu, bronchitis and epilepsy.³²

The aqueous leaf extract of P. amboinicus possesses significant nephroprotective activity against Adriamycin induced acute nephrotoxicity. Co-administration of the aqueous leaf extract of P. ambonicus at dose of 400 mg/kg shows significant reduction in the elevated levels of serum creatinine concentration in extract treated group compared to the nephrotoxic control group. Histopathological analysis of kidney tissues shows attenuation of acute tubular necrosis in the plant extract treated group compared to ADR induced control group.³³

CONCLUSION:

Drug induced nephrotoxicity is associated with acute renal damage as well as with chronic kidney diseases. There are numerous types of nephrotoxic agents leads to progression of renal damage and necrosis. Hence, observing the therapeutic efficacy of various medicinal plants in the treatment of drug induced nephrotoxicity in animal models, Herbal plants plays a vital role as nephroprotective agents. This nephroprotection may be due to presence of some chemical constituents in these medicinal herbs. Biomarkers are also make a significant contributions to new drug development because they facilitate the process of toxicity assessment of drugs This review article provide support for exploration of these medicinal plants for researchers to develop cost-effective poly-herbal formulation for the future prospective.

CONFLICTS OF INTEREST:

We do not have conflicts of interest with publication of this manuscript.

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Received on 18.05.2021 Modified on 21.10.2021

Asian J. Res. Pharm. Sci. 2022; 12(1):52-56.

DOI: 10.52711/2231-5659.2022.00010