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Kidney Function Restoration Program

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immunotoxicity and hematotoxicity, result in immunosuppression and hypersensitivity reactions. Genotoxicity of certain drugs is also known, which leads to mutagenesis, carcinogenesis, and teratogenesis owing to the interaction of drugs or their reactive metabolites with the genetic machinery (DNA, transcription, and translation). Drugs undergo metabolic detoxification in the body for effective elimination (clearance) of the drug from the body in the form of metabolites to minimize or abolish the adverse actions of drugs. An imbalance between the formation of reactive metabolites of a drug and their detoxification results in drug toxicity. Hypersensitivity and subsequent tissue damage result if the metabolite acts as a hapten and transforms into a neoanti-gen. The reactive metabolites of drugs uncouple selective biochemical processes, interfere with the structure and function of various macromolecules like proteins, DNA and RNA, and cause a multitude of adverse actions of drugs. A drug may directly or indirectly cause adverse actions of a drug. Again, it should be emphasized that such adverse actions of drugs may be individual-specific involving sudden death, cancer, and inheritable mutations.

Hypersensitivity reaction, one of the major adverse actions arise from drug tox-icity, is recognized to be associated with significant morbidity and mortality among the human subjects.1,2 The major adverse actions of drugs include thrombocytopenia, hemolytic anemia, toxic erythema, and toxic epidermal necrolysis. A substantial body of evidence currently available indicates that the adverse actions of drugs are often caused by the drug metabolites rather than by the parent drug itself. For example, the primary amines (j3-naphthylamine, aminobiphenyl), the acetyl derivatives of primary amines (2-acetylaminofluorene), and the secondary amines (N-methyl-4-aminoazobenzene) are N-hydroxylated by either cytochrome P-450 enzymes or amine N-oxidase. Under certain conditions, the metabolites are further activated by their metabolic conversion to N-O-sulfate esters.3,4 Owing to the variations in inherent metabolic nature among different individuals of a population (apparently determined by their genetic makeup), the drug toxicity mainly depends upon the body's ability to protect itself against such toxicity through the upregulation of defense or repair mechanisms and the involvement of immune system. However, the clinical use of protective drugs to combat severe toxicity caused by drugs and toxicants has been limited.5-7

Drug-Induced Nephrotoxicity

Kidney is the major site of action in the removal of toxic drugs and their reactive metabolites from the body through urinary excretion. As a result of this, the kidney is routinely exposed to high concentrations of these drugs and their active metabolites, leading to the manifestation of nephrotoxicity. Kidney, rich in vasculature, is capable of accumulating nephrotoxins.8-10 As most of the drugs cause nephrotox-icity directly or indirectly, the clinical use of several important life-saving drugs has been limited. Some of the important drugs such as antibiotics, nonsteroidal antiinflammatory drugs (NSAIDS), angiotensin converting enzyme (ACE) inhibitors, anticancer agents, immunosuppressants, and radiographic contrast agents are known to cause nephrotoxicity.11-14 Antibiotics like aminoglycosides, amphotericin B, tetracyclines, acyclovir, and pentamidine have been reported to cause renal failure through different mechanisms including direct toxicity to the renal tubules, allergic interstitial nephritis, and crystallization of the antibiotic within the renal tubules.11'12 NSAIDS (aspirin and COX-2 inhibitors) have been identified to cause hypertension, congestive heart failure (CHF), and acute or chronic renal failure.13 Certain ACE inhibitors have been shown to cause uremia, hyperkalemia, decreased glomerular filtration rate (GFR, an index of kidney function), and dialysis dependence.15

Cisplatin, a heavy metal chemotherapeutic drug, is effective in treating a variety of malignancies in the experimental animals and humans. However, cisplatin is a potent nephrotoxin causing renal failure in 25-36% of patients after a single dose of administration.16-18 Lithium, used for therapy against bipolar disorder in patients, has been known to cause renal abnormalities such as nephrogenic diabetes insipidus, chronic interstitial nephritis, and minimal change glomerulonephropathy.19 Cyclosporine (CsA) and tacrolimus (FK-506 or Fujimycin) have been widely used as immunosuppressive drugs to prevent allograft rejection in heart, liver, and kidney transplantation and to treat autoimmune diseases. CsA and tacrolimus therapies have been known to lead to thrombotic microangiopathy and functional and structural changes in the kidney of the experimental animals and transplant patients, ultimately causing renal dysfunction.20,21 Radiographic contrast dye has been shown to cause severe vasospasm in the afferent arteriole and acute renal failure in individuals with risk factors including diabetes, chronic renal failure, diuretic therapy, myeloma, and CHF.14,22 Drugs of abuse such as cocaine have been reported to induce renal damage including the acute tubular necrosis due to rhabdomyolsis and allergic interstitial nephritis.23

Apart from the administration of nephrotoxic drugs, prolonged use of Chinese herbs as alternative medicines has been implicated in the manifestation of 35% of all the cases of acute renal failure in some countries.24 Several reports have been made on the progressive kidney failure leading to the end-state renal disease among women taking diet pills containing Chinese herbs. Aristolochic acid has been identified as the toxicant in the Chinese herbs, and the resulting nephropathy due to the consumption of those Chinese herbs was characterized by an extensive fibrosis of the renal inter-stitium. Toxic metals such as mercury, lead, arsenic, and bismuth present in certain drugs and herbal medicines have been shown to cause renal dysfunction. The combined use of more than one nephrotoxic drug tends to cause possible additive toxic effects. Acute tubular necrosis results due to the administration of statins in combination with immunosuppressive agents such as cyclosporine. Similarly, nephrotoxicity arising from the combined treatment of cisplatin and aminoglycosides may be more severe than that induced by either of the agents alone.

Therapeutic Options to Prevent and Treat Drug-Induced Nephrotoxicity

In most cases, the ability of hydration pretreatment to reduce the nephrotoxicity of many drugs has been recognized. Fluid volume replacement, dialysis therapy, drug dosage adjustment, and steroid usage in the treatment of acute interstitial nephritis, while avoiding the repeated administration of the same drug(s), have been recognized as the important strategies to prevent or attenuate the nephrotoxicity of some routinely used drugs in clinical practice. Nephrotoxicity of cisplatin can be attenuated by intravenous saline administration at a dose of 150-250 mL/h before, during, and after cisplatin chemotherapy. Discontinuation of administration of the nephrotoxic drug, introduction of oral prednisone therapy (1-2 mg/kg/day for 4-6 weeks), and plasmapheresis appear to be beneficial to patients with the drug-induced acute allergic interstitial nephritis and thrombotic microangiopathy. Hydration therapy with the intravenous saline infusion and prophylactic mucomyst has been shown to reduce the contrast agent-induced nephrotoxicity.22,25 Correction of hyperkalemia and acidosis and supplementation with insulin-like and hepatocyte-type growth factors have been shown to offer recovery among the patients with intrinsic acute renal failure. In patients with acute renal failure, the use of osmotic agent, mannitol, which induces hypervolemia, is avoided.26

Cisplatin-Induced Nephrotoxicity

Cisplatin is a water-soluble planar member of the platinum coordination complex class of anticancer drugs. Structurally, the drug consists of an atom of platinum surrounded by chloride and ammonium atoms in the cis position of a horizontal plane. Cisplatin still remains as a preferred antineoplastic drug for the treatment of a variety of solid tumors such as metastatic bladder and testicular and ovarian carcinomas.27 In circulation, cisplatin binds to serum proteins up to 90%, gets distributed to most of the tissues, and is cleared in the intact parent form by the kidney.28 Cisplatin and their analogs have been shown to interact with the thiols and macromolecules.29 The nephrotoxicity of cisplatin is associated with the actions of reactive oxygen species (ROS). Glutathione (GSH) detoxifies cisplatin by rapid complexation (binding) as the reactivity (affinity) of platinum complexes is greater with the cysteine residue of GSH.30 The enhanced production of tumor necrosis factor-a (TNF-a) has been suggested to mediate the cisplatin nephrotoxicity31 through the activation of p38 mitogen-activated protein kinase (p38 MAPK).32 Light microscopic and ultrastructural studies have shown that the cisplatin-induced kidney injury and necrosis in rat are predominantly confined to the S3 segment of proximal tubules in the corticomedullary region without or with accompaniment of distal changes.33 Recent studies have shown that nedaplatin, a second generation platinum complex, is less nephrotoxic than cisplatin.10,34 Despite the intensive prophylactic measures, irreversible renal damage is encountered among nearly one-third of the cisplatin-treated patients.27,35 Cisplatin treatment also induces extensive cell death in the proximal and distal tubules and loop of henle.27,36 Deoxyribonuclease I has been shown to be involved in the cisplatin nephrotoxicity.37 Multiple studies have demonstrated that cisplatin nephro-toxicity is associated with DNA fragmentation, activation of the MAPK cascade, and molecular responses typical to stress responses.9 Increased Bax and decreased senescence marker protein-30 (SMP)-30 gene expression has been observed during the cisplatin-induced nephrotoxicity as analyzed by the Microarray Technology38 indicating apoptosis and perturbation of the intracellular calcium homeostasis. Oxidative stress has emerged as one of the crucial mechanisms of cisplatin-induced nephro-toxicity as it is associated with the elevated generation of ROS and induction of lipid peroxidation in the kidney as a result of decline in the antioxidant levels and antioxidant enzyme activities.39,40 Cisplatin treatment also has been shown to cause significant oxidant generation in the kidney through both the xanthine oxidase activation and impaired antioxidant defense system, thus contributing to the accelerated oxidative stress-mediated reactions in the tissue.41

Nephroprotective Agents

Several strategies have been sought after to alleviate the nephrotoxic effects of cisplatin during the anticancer therapy including the use of less intensive treatment and replacement with less toxic analog of cisplatin, carboplatin. Identification of specific cytochrome P450 isoenzymes in the human renal tubular cells and the development of specific inhibitors appear to be promising in either the protection or amelioration of cisplatin nephrotoxicity. Several studies have demonstrated that dietary antioxidants apparently detoxify the ROS and also enhance the anticancer efficacy of chemotherapy while minimizing certain adverse effects (reviewed by Conklin, 2000).42 Various antioxidants also have been shown to protect against cisplatin-induced nephrotoxicity.43'44 Radical scavengers and antioxidants such as vitamin E, vitamin C,45 manganese superoxide dismutase (SOD),44 selenium,46 caffeic acid phenylethylester,47 melatonin,48 N-acetyl cysteine,49 erdosteine,50 edarabone,51 have been reported to attenuate cisplatin-induced nephrotoxicity. Recent studies have suggested that the combination of tomato juice and dried black grapes ameliorate the cisplatin nephrotoxicity.41 Agents such as amifostine (a cytoprotector),52 recombinant human erythropoietin,53 quercitin,54 and desferrioxamine (iron chelator)55 have also been reported to attenuate the drug-induced toxicity.

Nitric Oxide (NO) plays a crucial role in maintaining normal renal function.56 The nitric oxide synthase (NOS) inhibitors (NG-nitro-L-arginine methyl ester and 2-amino-4-methylpyridine) have been shown to effectively mitigate lipid peroxidation and other biochemical alterations associated with the cisplatin nephrotoxicity.57 On the other hand, the NOS inhibition has been observed to aggravate the cisplatin-induced nephrotoxicity.58 The essential amino acid and a precursor of NO, L-arginine, has been shown to offer nephroprotection, while the NOS inhibitor, L-NAME, exerts the opposite effect.59

Both the animal and human studies have demonstrated that the use of diuretics (furosemide and mannitol) and hydration have markedly decreased the nephrotoxicity caused by cisplatin, carboplatin, and ormaplatin.35,60,61 Procaine (local anesthetic drug)62 and procainamide (antiarrhythmic drug)63 have been shown to enhance the therapeutic index of cisplatin and to reduce its nephrotoxicity without compromising its antitumour action. The methylxanthine derivative, pentoxifylline, and the nonselective adenosine receptor antagonist, theophylline, are reported to decrease the concentration of adenosine and severity of renal dysfunction induced by the nephro-toxic drugs.64 Several other studies have demonstrated that the compounds such as lycopene,65 edarabone,51 bismuth subnitrate,66 serum thymic factor,67 salicylate,68 and gum Arabica69 ameliorate the cisplatin nephrotoxicity.

Naturally occurring antioxidants of medicinal plant origin have been tested for their protective effect against cisplatin nephrotoxicity.70 Several natural plant products (phytochemicals) such as the extracts of a polypore fungus, Phellinuns rimosus,71 Cassia auriculata,72 and the flowers of Pongamia pinnata and Aerva lanata,73'74 lupeol, an antioxidant from the medicinal plant, Crataeva nurvala,75 xanththorrhizol, a protein kinase inhibitor from Curcuma xanthorrhiza,76 and capsaisin, a major pungent ingredient of hot red peppers,77 have been shown to offer protection against the cisplatin nephrotoxicity. Also, the gentamycin-induced nephrotoxicty has been shown to be ameliorated by Ginkgo biloba in the experimental animals.78

Reports have also been made on the protection against the cyclosporine-induced chronic nephrotoxicity by several natural antioxidants, nutrients, and drugs including colchicines,79 tea polyphenols,80 lazaroid,81 vitamins E and C,82 and calcium channel blocker, lacidipine.83 Melatonin, a pineal hormone,84 carvedilol, a beta blocker,85 and probucol86 have been reported to protect against the gentamycin-induced nephrotoxicity in rats.

SPIRULINA—A MEDICINAL BLUE-GREEN ALGA

Among several known medicinal plants at present, Spirulina, a microscopic filamentous blue-green alga, is emerging as a promising therapeutic aquatic microphyte. Spirulina, the simplest members among algae, are widely distributed both as the terrestrial and aquatic forms. They are referred in the literature by different names such as Cyanophyta, Myxophyta, Cyanochloronta, Cyanobacteria, blue-green algae, and blue-green bacteria. Blue-green algae are either unicellular or filamentous forms.87 Spirulina belongs to the kingdom Monera and division Cyanophyta. Spirulina is a genus of the phylum Cyanobacteria ("Cyano" from the Greek meaning blue). Spirulina is a freshwater blue-green alga found in most lakes and ponds. The word Spirulina originates from Latin denoting the helix or spiral nature (whorl) of the alga. The German scientist, Deurben had named it "Spirulina" in 1927. Spirulina has been orally consumed for thousands of years by humans among the Mexican (Aztecs, Mayans), African, and Asian societies and also is a popular food and nutritional supplement in Japan and the United States. Spirulina, wheat grass, barley grass, and Chlorella are often referred to as "green foods." Among several occurring species of Spirulina, the most commonly used in nutritional supplements are Spirulina platensis (also called Arthrospira platensis) and Spirulina maxima. Although the nutritional importance of Spirulina is greatly recognized, studies on its pharmacological and therapeutic properties are limited. Here, we present a comprehensive overview on the therapeutic effects of Spirulina in protection against the drug-induced nephrotoxicity.

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