Nephrotoxicity—

The renal system consists of the kidneys and their vasculature and innervation, the kidneys each draining through a ureter into a single median urinary bladder, and the latter draining to the exterior via a single duct, the urethra. The kidney has three major anatomical areas the cortex, the medulla, and the papilla. 

Global changes and extensive industrialization during the twentieth century made animals and humans become exposed to a variety of chemicals. Exposure to chemical forms of mercury (e.g., elemental mercury vapor [Hg°], inorganic mercury [Hg+] and mercuric [Hg2+], organic mercury [R-Hg+ or R—Hg—R]) 

Several heavy metals, particularly lead, are known to cause major adverse effects to the mammalian kidney, resulting in kidney function impairment. Adverse effects to the mammalian kidney caused by lead include lesions on the proximal tubule and Henle s loop, and the presence of lead inclusion bodies. The metal also is known to cause aminoaciduria, phosphaturia, glycosuria, and renal tubular acidosis. Workers associated with lead-smelting industries also have shown kidney cancer. 

Nephrotoxicity is caused by drugs that principally affect the renal hemodynamics of the patient depended on vasodilator prostaglandin biosynthesis or angiotensin converting enzyme (ACE) mediated vasoconstriction drugs causing nephrotoxicity include NSAIDs (fenprofen), ACE inhibitors (captopril, and cyclosporin). 

Groups of 11-12 male C57L/J mice were administered 0, 4, 20 or 100 mg sodium chlorite/l and 100 mg sodium chloride/l as a high-salt control in their drinking-water for 30, 90 and 180 days. The sodium chlorite doses were equal to 1.0, 4.7 and 23 mg/kg bw per day at 30 days, 0.9, 4.2 and 22 mg/kg bw per day at 90 days and 0.9, 4.9 and 23 mg/kg bw per day at 180 days (approximately 0.7, 3.5 and 16 mg/kg bw per day, expressed as chlorite, at all time points). Upon completion of the treatment period, animals were weighed and sacrificed, and the kidneys were removed and examined using light and transmission electron microscopy. No treatment-related effects were observed, and the kidneys appeared normal (Connor et al 1985), 

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Effects of repeated ethylene glycol peroral overexposure in treated rats and mice can result in kidney, Hver, and nervous system damage. The most sensitive indicators of ethylene glycol toxicity are disturbances in acid—base balance and nephrotoxic (kidney) effects. Effects of repeated chronic peroral overexposure of diethylene glycol in treated rats result in kidney and Hver damage (48). 

In experimental animals and in vitro, DHBs show a variety of biological effects including binding of metaboHtes to various proteins. Clastogenic effects have been observed in vitro and in some in vivo studies with the three compounds. No reproductive effects have been shown by conventional studies with either hydroquinone, catechol, or resorcinol (122). Hydroquinone has been shown to induce nephrotoxicity and kidney tumors at very high doses in some strains of rat (123) catechol induces glandular stomach tumors at very high dose (124). Repeated dermal appHcation of resorcinol did not induce cancer formation (125). 

The nephrotoxic amino acid, lyskioalanine [18810-04-3] formed upon alkaline treatment of proteki, was reported ki 1964 (108). Its toxicity seems to be mitigated ki proteki ki that it is not released by normal digestion (109). Naturally occurring new amino acids, which can be classified as protekiaceous or non-protekiaceous, can, as ki the case of those from some legumes, show a remarkable toxicity (110). Eor the details of amino acid toxicity, see reference 6. Enzyme inhibition by amino acids and thek derivatives have been reviewed (111). 

Aminophenol is a selective nephrotoxic agent and intermpts proximal tubular function (121,122). Disagreement exists concerning the nephrotoxity of the other isomers although they are not as potent as 4-aminophenol (123,124). Respiration, oxidative phosphorylation, and ATPase activity are inhibited in rat kidney mitochondria (125). The aminophenols and their derivatives are inhibitors of 5-Hpoxygenase (126) and prostaglandin synthetase... 

Fth oxya ceta n i1 i de possesses both antipyretic and analgesic properties, but it is of Httie value for the reUef of severe pain. Its use for prolonged periods should be avoided because one of its minor metaboUtes ( 2-hydroxyphenetidine) is nephrotoxic and may be involved in the formation of methemoglobinemia. The oral LD q in rats is 1.65 g/kg (198). 

The principal arninoglycoside toxicides are neuromuscular paralysis, ototoxicity, and nephrotoxicity. Neuromuscular paralysis is a relatively rare complication resulting from high aminoglycoside concentrations at the neuromuscular junctions following, for example, rapid bolus intravenous injection or peritoneal instillation, rather than the normal intravenous infusion. The mechanism apparentiy involves an inhibition of both the presynaptic release of acetylcholine and the acetylcholine postsynaptic receptors (51). 

A novel approach to the problem of amiaoglycoside nephrotoxicity has been to search for compounds that can inhibit toxicity without compromising efficacy. A number of agents have been reported to reduce amiaoglycoside toxicity ia animal models the most extensively studied of these is sodium polyaspartate (103—107). 

Other chemicals of possible concern for health and safety found ia yeast proteias iaclude tyramiae (0—2.25 mg/g) and histamine (0.2—2.8 mg/g), formed by decarboxylation of the corresponding amino acids (38). These compounds are also found ia other fermeated (including pickled) foods. Their preseace ia yeast extracts used as condiments coatributes very Htde to human iatake. Likewise, the nephrotoxic compouad lysiaoalaniae has beea ideatified ia alkah-treated yeast extracts, at a level of 0.12 mg/g. However, the chemical occurs at similar low coaceatratioas ia almost all heat- and alkaU-treated foods. 

In addition to variable chemical stabiUty the carbapenems are susceptible to P-lactam cleavage by a dehydropeptidase en2yme (DHP-I) located on the bmsh borders of the kidney (53). Clinically, MK 0787 (18) is used with an inhibitor of this en2yme, cil a sta tin [78852-98-9] (MK 0791) (34), 16 26 2 5 dramatic effect not only on the urinary recovery of the drug, but also reduces any nephrotoxic potential (52) (see Enzyme... 

Generally, nephrotoxicity is not a problem. Some cephalosporins, especially those with the 3-methylthiotetrazole side chain, such as moxalactam (48), show a tendency to promote bleeding. This appears to be due to a reduction in the synthesis of prothrombin and can be a problem especially in elderly patients, patients with renal insufficiency, or patients suffering from malnutrition (219). The same side chain seems to promote a disulfiramlike reaction in patients consuming alcohol following a cephalosporin dose (80,219). 

Some polymyxins are sold for second-line systemic therapy. Polymyxin B sulfate and colistimethate sodium can be used for intravenous, intramuscular, or intrathecal administration, especially for Pseudomonas aerupinosa mP QXiosis, but also for most other gram-negative organisms, such as those resistant to first-line antibiotics. Nephrotoxicity and various neurotoxicities are common in parenteral, but not in topical, use. Resistance to polymyxins develops slowly, involves mutation and, at least in some bacteria, adaptation, a poorly understood type of resistance that is rapidly lost on transfer to a medium free of polymyxin. Resistance can involve changes in the proteins, the lipopolysaccharides, and lipids of the outer membrane of the cell (52). Polymyxin and colistin show complete cross-resistance. 

Bacitracin given parenteraHy is sufftciendy nephrotoxic that it is rarely used in human medicine for other than topical indications (80). Thus safe and effective use, especially as the zinc salt, is limited almost completely to ointments, sprays, and solutions for skin and ophthalmic use in concentrations of 250 to 1000 units per milliliter. Bacitracin is only rarely skin sensitizing. As in the case of polymyxin, bacitracin is usually combined with other antibiotics to enlarge its spectmm of activity, or with corticoids or analgesics to reUeve pain or itching. 

Gapreomycin, Viomycin, and Enviomycin. Capreomycin (Capastat, Lilly), a bacteriostatic, antimycobacterial peptide mixture isolated from Streptomjces capreolus was first reported in 1961 (106—108). This tuberactinomycin family member, shown in Table 4, was introduced into the U.S. market in 1971 where it has remained a usehil but nephrotoxic and ototoxic second-line alternative to first-line tuberculosis therapies. Because capreomycin is somewhat less toxic than viomycin (tuberoactinomycin B [32988-50-4]) C25H42N23O2Q (109,110), capreomycin has now displaced viomycin in the United States and most other markets. The stmcture of viomycin is shown in Figure 2. The related enviomycin (tuberactinomycin N [33103-22-9]), C23H43N23O2Q,... 

The first human kidney and bone marrow transplants using cyclosporine were reported in 1978. Oral or intravenous cyclosporine is an immunosuppressant for transplantation of these and other organs and investigations are underway for its possible use in a variety of autoimmune diseases including rheumatoid arthritis, severe psoriasis, and Crohn s disease. Dose-dependent nephrotoxicity (261—264) remains the primary limitation of the dmg and necessitates close monitoring of patients, including measurement of dmg levels in blood. Cyclosporine research has been reviewed (265—274). 

Amphotericin B (15) is an antifimgal macioHde antibiotic produced by Streptomjces nodosus that has been used as an alternative, albeit more toxic, dmg to the antimonials. It acts as a leishmanicide against the visceral and mucocutaneous forms of the disease. To overcome its potentially severe nephrotoxicity, the dmg must be adrninistered over an extended period of time. 

TABLE 5.16 Nephrotoxic Compounds in Occupational and General Environments... 

Carboplatin (96) is significantly less toxic in the clinic than cisplatin. Most particularly, it is much less nephrotoxic. Use of a bidentate ligand also ensures formation of a ds complex. Its synthesis begins with cis-diammine platinum diiodide (94) which is reacted with silver sulfate to give cis-diaquodiam mine platinum sulfate (95). This is reacted with the barium salt of 1,1-cyclo-butanedicarboxylic acid to yield carboplatin [23],... 

The only prominent antitumor tetravalent platinum complex so far is iproplatin (102). In vitro it has been shown to cause interstrand DNA-breaking and cross linking. Free radical scavengers inhibit these effects. The complex is less neurotoxic and less nephrotoxic than cisplatin. Its synthesis begins with hydrogen peroxide oxidation of cis-dichlorobis(isopropvlamine) platinum (100) to the dimethylacetamide complex 101. The latter is heated in vacuum to liberate iproplatin [25]. 

Rapamycin has been known for many years to possess immunosuppressive activity by interfering with the activation of B- and T-cells by interleukin-2. Indeed the first clinically approved indication for rapamycin was renal transplantation. Currently, rapamycin and RAD001 also show promise in liver transplantation and cardiac transplantation, respectively. Generally, treatment protocols utilize a combination of an mTORCl inhibitor, a calcineurin inhibitor and steroids to optimize immunosuppression and minimize nephrotoxicity and other side effects. Rapalogs are also... 

Nausea, vomiting, diarrhea, hypersensitivity reactions, nephrotoxicity, headache, hematologic reactions Same as cefaclor... 

Other adverse reactions that may be seen with administration of the cephalosporins are headache, dizziness, nephrotoxicity (damage to the kidneys by a toxic substance), malaise, heartburn, and fever. Intramuscular (IM) administration often results in pain, tenderness, and inflammation at the injection site Intravenous (IV) administration has resulted in thrombophlebitis and phlebitis. 

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