Nature’s Cure for the Management of Drug Induced Nephrotoxicity
Umme Salma Durbar
Bachelor of Dental Surgery, Saveetha Dental College and Hospital, Chennai.
*Corresponding Author E-mail: ummesalmadurbar@gmail.com
ABSTRACT:
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. Drugs are a common source of acute kidney injury. Drugs shown to cause nephrotoxicity exert their toxic effects by one or more common pathogenic mechanisms. Nephrotoxic drugs include Antimicrobials, Amphotericin B, Betalactam antibiotics, Cidofovir, Zoledronate, NSAIDs, Cyclosporins, ACE Inhibitors, Methotrexate. A number of herbs are traditionally used in different countries for treating drug- or toxin-induced hepatic and renal disorders. Various fruits, plant extracts, spices, essential oils are also used in treating drug induced nephrotoxicity. The actions of the above mentioned natural sources will be discussed in this review article.
KEYWORDS: Nephrotoxicity, Antimicrobials, Amphotericin B, Cyclosporins, Methotrexate
INTRODUCTION:
The kidney is required by the body to perform several important functions including the maintenance of homeostasis, regulation of the extracellular environment, such as detoxification, and excretion of toxic metabolites and drugs. Nephrotoxicity is defined as renal dysfunction that arises as result of exposure to external agents such as drugs and environmental chemicals1. The complex nature of critical illness often necessitates the use of multiple therapeutic agents, many of which may individually or in combination have the potential to cause renal injury.2 Drugs cause approximately 20 percent of community- and hospital acquired episodes of acute renal failure3-,6. Among older adults, the incidence of drug-induced nephrotoxicity may be as high as 66 percent3,7.
The 3 clinical syndromes that can be recognised in drug-induced nephropathy are acute renal failure, chronic interstitial nephritis and the nephrotic syndrome.
The first can be caused by prerenal problems, acute interstitial nephritis, acute tubular necrosis and intratubular obstruction. The important drugs that cause prerenal failure are NSAIDs, captopril and cyclosporin. The drugs most likely to cause acute interstitial nephritis are antibiotics and NSAIDs. Important causal agents of acute tubular necrosis are aminoglycosides, amphotericin B, radio contrast agents and cyclosporin. Intratubular obstruction is often associated with chemotherapy. Chronic interstitial nephritis was formerly caused by phenacetin; paracetamol (acetaminophen), particularly in combination with other analgesics. Drug-induced nephrotic syndrome is mostly immunologically mediated8.
General preventive measures include using alternative non-nephrotoxic drugs whenever possible; correcting risk factors, if possible; assessing baseline renal function before initiation of therapy, followed by adjusting the dosage; monitoring renal function and vital signs during therapy; and avoiding nephrotoxic drug combinations3. Nephroprotective agents are the substances which possess protective activity against Nephrotoxicity. Medicinal plants have curative properties due to the presence of various complex chemical substances. Fruits and essential oils may also serve as a source against drug induced nephrotoxicity. Many herbs have been proven to be effectual as nephroprotective agents9.
Drugs inducing nephrotoxicity:
Agents which cause nephrotoxicity are well known to be nephrotoxic. Many therapeutic drugs, diagnostic agents & chemical agents have been shown to induce clinically significant nephrotoxicity.
Analgesics-acetaminophen, aspirin
Antidepressants-amitriptyline, doxepin, flouxetin
Antihistamines-doxylamine, diphenhydramine
Antimicrobials- acyclovir, ganciclovir, amphotericinb , beta lactams, foscarnet
Antiretroviral-adefovir, tenofovir, indinavir
Benzodiazepines
Cardiovascular agents-angiotensin converting enzyme inhibitor, clopidogrel
Chemotherapeutics-carmustine, semustine, cisplatin
Diuretics- loops, thiazides
Drug of abuse- cocaine, heroin, ketamine
Proton pump inhibitors- omeprazole, pantoprazole
Others-allopurinol, haloperidol3
Mechanism of action:
The kidney is particularly prone to the actions of nephrotoxins. High levels of toxin can be delivered to the kidney secondary to the large blood supply in this organ. There is also an enormous surface area of the renal tubular epithelium providing sites for toxin interaction and uptake. It is also to be noted that tubular cells have a high metabolite rate and this can be subject to perturbations induced by toxins. Toxins may alter membrane phospholipid metabolism as lysophospholipids and free fatty acids have toxic detergent properties. Nephrotoxins could be accumulated in lysosomes and thus have the potential to alter lysosomal functions10.
Nephroprotective agents in nature:
Plants
Plants with diverse medicinal properties have come under extensive study in the light of their antioxidant, antimutagenic, and anticarcinogenic effects.
Gentamicin (GM) is an aminoglycoside antibiotic which is commonly used for the treatment of infections caused by gram-negative bacteria11.The plant Casuarina equisetifolia Forst belongs to the family Casuarinaceae. Phytochemical analysis of methanolic extract of Casuarina equisetifolia leaves revealed the presence of tannins, flavonoids, alkaloids, phenolics, terpenoids and steroids. Casuarina equisetifolia leaves extract significantly enhanced antioxidant defense against GM induced oxidative damage in renal tissues. This may be attributed to free radical scavenging property of extract as well as direct antioxidant action12.
Alqasoumi et al., 13,14 investigated the possible protective effect of water spinach Ipomea aquatica ethanol extract against GM-induced nephrotoxicity. The author found that concomitant administration of Ipomea aquatica extract attenuated the harmful effects of GM both by inhibiting free-radical formation and/or by restoration of the antioxidant systems.
Shirwaikar et al., 13,15 studied the protective activity of ethanolic extract of Aerva lanata in cisplatin and GM-induced nephrotoxicity. The author found that the ethanol extract of Aerva lanata was found to normalize the raised blood urea, serum creatinine and bring about marked recovery in kidneys.
Cisplatin an antineoplastic drug used in the treatment of many solid-tissue cancers has its chief side effect in nephrotoxicity. Dried calyx of H. sabdariffa is rich in various phytochemicals such as anthocyannins, tannins, phenolic acids, phytosterols and policosanols 16. H. sabdariffa calyx dye could be used in therapy and management of nephrotoxicity due to it antioxidant properties. H. sabdariffa calyx contains natural antioxidants like ascorbic acid which exhibits good nephroprotective properties17,18.
The alcoholic extract of Craaeva nurvala 250 and 500 mg/kg for 10 days showed protective activity against cisplatin 5 mg/kg induced nephrotoxicicty. The results suggested, that the alcoholic extract has significantly altered the dysfunction of renal proximal tubule cells by decreasing the concentration of blood urea nitrogen, creatinine, lipid peroxidation, glutathione and catalase19,20.
Strychnos potatorum Linn commonly referred to as clearing nut belongs to the family Loganiaceae. The seeds of Strychnos potatorum possess marked nephroprotective activity and could have a promising role in the treatment of acute renal injury induced by nephrotoxins, especially gentamicin.21
Aerva javanica is medicinal plant belonging to the family Amaranthaceae. The aqueous extracts of Aerva javanica roots were studied for the scientific evaluation of nephroprotective activity. The aqueous extract at the dose level of 400 mg/kg body weight was found to normalize the elevated biochemical markers and bring about a marked recovery in kidneys as evidenced by using microscopy 22.
Ficus religiosa (L.), commonly known as pepal, belongs to the family Moraceae. The results concluded that methanolic extract of Ficus religiosa L. latex may have nephroprotective and curative activity against nephrotoxicity induced by cisplatin due oxidative stress23.
Vernonia cinere belongs to family Asteraceae. The alcoholic extract showed pronounced curative activity and the ethyl acetate extract has exhibited good prophylactic activity and petroleum ether extract showed moderate protection for both curative and prophylactic models against cisplatin-induced toxicity 24.
Fruits:
Benincasa hispida belongs to cucurbitaceae family. Administration of hydroalcoholic extract of Benincasa hispida (HABH) concurrent with paracetamol exposure prevented paracetamol induced nephrotoxicity. The HABH possess alkaloids, flavonoids, saponins, terpenoids and tannins. Upon treatment with 200 mg/kg and 400 mg/kg of HABH demonstrated significant dose dependant increase in depleted tissue GSH and reduction in lipid peroxidation caused by paracetamol induced nephrotoxicity and all the physical and biochemical markers brought back to the normal in a dose dependent manner.25
The ethanol extract of Momordica dioica fruit extract (200 mg kg (-1)) was studied for nephroprotective and curative activities. The study suggested that the nephroprotective and curative activities of M. dioica fruit extract against cisplantin induced nephrotoxicity are due to its antioxidant activity. It is further concluded that this antioxidant activity may be attributed to the phenolics, flavonoids and amino acids present in the extract.26
Fruits from the plant Tribulus terrestris was found to have protective action against drug induced nephrotoxicity 27.
Dates (Phoenix dactylifera) are one of the members of the palm family Arecaceae, or Palmae. An important report of extracts of the flesh and pits of Phoenix dactylifera in gentamycin treated nephrotoxicity rat model showed significantly reduced the increase in plasma creatinine and urea concentrations induced and ameliorated the proximal tubular damage.28
Studies have revealed nephroprotective activity of Solanum xanthocarpum fruit extract against gentamycin-induced nephrotoxicity and renal dysfunction. Solanum xanthocarpum extract lessened the negative effects of GM-induced nephrotoxicity possibly by inhibiting free radical mediated process 29.
Essential oils:
Ginger essential oil presents many biological activities, such as anti-inflammatory, antiemetic, and antineoplastic effects, some studies have demonstrated the renoprotective effect. GEO treatment has beneficial effects in an experimental mice model of cisplatin-induced nephrotoxicity, as reflected by decreased creatinine levels and increase in the protein : creatinine ratio. GEO also inhibits the expression of pro-inflammatory TNF-α cytokine levels and protects against ischemic injury by increasing BMP-7 expression.30
Badary and collaborators investigated the effects of thymoquinone on cisplatin-induced nephrotoxicity, and results revealed that thymoquinone induced amelioration of cisplatin nephrotoxicity and potentiated its antitumor activity. This natural product is also capable of improving the therapeutic efficacy of ifosfamide by decreasing ifosfamide-induced nephrotoxicity 31.
Treatment with N.sativa oil produced a dose dependent amelioration of the biochemical and histological indices of GM nephrotoxicity32.
Spices:
Antunes et al. 33 reported curcumin administration (8 mg/kg before and after cisplatin injection) provided protection against cisplatin induced neurotoxicity, ototoxicity and nephrotoxicity. Also curcumin treatment (200 mg/kg/day for 10 days) ameliorated the gentamicin-induced nephrotoxicity 34. Curcumin treatment prevents chloroquine-induced nephrotoxicity.
(E)-β-caryophyllene (BCP) is a natural sequiterpene found in many essential oils of spice (e.g. cinnamon, origanum, black pepper, basil and cloves) and food/medicinal plants. Studies have shown that β-caryophyllene (BCP) is able to markedly attenuate the cisplatin-induced decline in kidney function and ameliorate the observed histological damage, and that this protective effect is mediated through CB2 receptors 35.
Mentha piperita L. belongs to family Lamiaceae. It can be concluded that concurrent administration M. piperita successfully prevented renal damage associated with gentamicin, explored by various biochemical and histological examinations. Alteration in mean body weight, blood urea nitrogen, creatinine, creatinine clearance, uric acid, urinary protein and enzymes excretion associated with gentamicin were reduced by treating animals simultaneously with crude extract of M. piperita. Further, the study also shows that concomitant use of M. piperita does not decline the efficacy of gentamicin with respect to its antibacterial activities 36.
Herbs:
Euphorbia hirta (L.) (Euphorbiaceae) is a very popular herb. It has been suggested that the ethanol extract of E. hirta can prevent the toxic effects of nitrobenzene and can be used in the treatment of nephrotoxicity. The protective action of the ethanol extract of E. hirta was probably due its antioxidant nature which protects the kidney against nephrotoxicity induced by nitrobenzene 37.
Orthosiphon stamineus Benth. is a medicinal herb belonging to the family Lamiaceae. The methanolic extract of Orthosiphon stamineus benth was evaluated for its nephroprotective activity against gentamycin induced nephrotoxicity 19.
Pimpinella tirupatiensis (Apiaceae) is a herbaceous medicinal plant. Administration of P. tirupatiensis extract helped to uplift the GSH depletion induced by Acetaminophen. The findings suggest the potential use of the ethanolic extract of Pimpinella tirupatiensis as a novel therapeutically useful nephroprotective agent 38.
Tea:
An extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A 39.
CONCLUSION:
This review attempts to portray the discovery and development of various natural agents in treating drug induced nephrotoxicity. Thus various plants, fruits, essential oil, herbs, tea can be potentially used for the development of effective therapy to combat drug induced nephrotoxicity. This article provides few natural sources which are scientifically proved in treating renal disorders caused by various drugs.
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38. Therapeutic efficacy of Pimpinella tirupatiensis (Apiaceae) on acetaminophen induced nephrotoxicity and oxidative stress in male albino rats S. Palani, S. Raja , R. Praveen Kumar , Soumya Jayakumar, B. Senthil Kumar. International Journal of PharmTech Research .Vol.1, No.3, pp 925-934, July-Sept 2009
Received on 22.06.2015 Modified on 15.08.2015
Accepted on 30.09.2015 © RJPT All right reserved
Research J. Pharm. and Tech. 8(11): Nov., 2015; Page 1593-1597
DOI: 10.5958/0974-360X.2015.00284.X