SUBJECTS nephrotoxicity

The interaction of ciclosporin with fluconazole has been retrospectively evaluated in 19 kidney and pan-creas/kidney transplant recipients (90). Both intravenous and oral fluconazole altered the blood concentration of ciclosporin. Five subjects did not have a significant interaction and 15 did. No patient had nephrotoxicity or transplant rejection related to antifungal therapy. 

The effect of ketoconazole in ciclosporin-treated kidney transplant recipients has been the subject of a prospective randomized study (37). In 51 ketoconazole-treated patients and 49 controls there was a similar frequency of acute rejection episodes. However, in the control group, rejection episodes were more recurrent, with a poorer response to treatment. Acute ciclosporin nephrotoxicity was more common in the ketoconazole group, but this was encountered more at induction and rapidly reversed on further reduction of the dose of ciclosporin. Chronic graft dysfunction was significantly less in... 

Triamterene Indometacin Potentiation of nephrotoxicity, including subjects with normal renal function Combination contraindicated... 

In addition to the controversial cost issue, it is important to note that although lipid formulations have been shown, most of the times, to have less nephrotoxicity than AmB, they are not free of toxicity, and each has its clinically relevant adverse profile. Therefore, it is currently not the "standard of care" to start all patients on LFABs, especially if patients are considered low risk. For instance Roberto Berdicheski et al have recently shown that AmB is safe in hemodynamically stable subjects with initial normal renal function and who were given adequate sahne loading. They concluded that treatment of low risk patients with the expensive LFAB therapy is not warranted [216]. 

Numerous other examples of single nephrotoxic agents exist. The discussion here focuses on the effects of mixtures, the subject for the next section. 

Triamterene has been reported to cause photosensitivity reactions, increase in uric acid concentration, and blood dyscrasias.91 Nephrolithiasis may occur in susceptible patients. Megaloblastic anemia has been reported in patients with depleted folic acid stores such as those with hepatic cirrhosis. In a study conducted on rats, daily treatment of the animals with doses of 1.5, 3 and 4.5 mg/lOOg over the period of three weeks caused severe degenerative changes of renal cortical and medullary tubules resembling osmotic nephrosis.93 Reversible acute renal failure from combined triamterene and indomethacin in healthy subjects is reported.94 It is recommended that this potentially nephrotoxic association be avoided. 

With aminoglycosides, systemic therapy is associated with a risk of ototoxicity and nephrotoxicity. However, no toxicity has been reported in several well-controlled trials of inhaled tobramycin in which subjects received repetitive courses [31,32]. 

The majority of early treatment regimes used excessively high doses of EDTA, administered by rapid intravenous infusion, and this resulted in a number of cases of serious nephrotoxicity. The general rule today is that a patient should not receive more than 3 g of EDTA or DTPA within a 24 hour time period this corresponds to —40 mg ( — 150 pmol) of EDTA kg of body weight for a 70 kg subject. In practice a dose of 1 g day of either EDTA or DTPA would be more usual this corresponds to —50 and —30 pmol kg , respectively. The agent is administered by intravenous infusion, in a vehicle such as 5% dextrose-saline, over a period of several hours. 

Coal Tar Products. In an industrial health survey of employees in nine coal tar plants in which coal tar creosote and coal tar were the main treatments used, renal effects, including protein and cells in the urine, were noted in 1-8% (3-34 of 452) of the employees examined (TOMA 1981). Nevertheless, no clear relationship could be established because exposure routes in addition to dermal were likely, such as inhalation and oral. Also, the ability to relate renal effects to coal tar exposure was further confounded by the possibility that the subjects were also exposed to other chemicals and cigarette smoke (TOMA 1981). A study performed by Wright et al. (1992b) evaluated the nephrotoxic effects of commercial coal tar preparation for the scalp. The preparation was applied to healthy human subjects either for 15 minutes,... 

Despite early enthusiasm, more recent studies have yielded more equivocal information. In a randomized, double blind study, Wingard et al [146] have compared the safety of two Upid formulations of amphotericin B in febrile neutropenic patients. Subjects were randomized to receive amphotericin B lipid complex (ABLC) at a dose of 5 mg/kg/d (n=78), liposomal amphotericin B (L-Amph) at a dose of 3 mg/kg/ d (n=85), or L-Amph at a dose of 5 mg/kg/d (n=81). They found that the incidence of nephrotoxicity (doubhng of the base-... 

The indication for AmB is the presence of proved or suspected systemic fungal disease. As previously mentioned, pahents who receive AmB are usually immunocompromised and severely ill, with some degree of malnutrition, mulhple organ failure and life threatening infechons. The clinical condition of these patients may, therefore, confer an increased risk of nephrotoxicity. Once the decision to implement AmB has been made, an algorithm can be used to optimize therapy (Figure 8) [82]. The first step is to assess renal function, the sodium status of the patient, and to correct overt sodium depletion. It is important to realize that milder sodium depleted states which are not clinically apparent can substantially enhance the nephrotoxic potential of AmB. It is, therefore, important to assess whether the patient can tolerate sodium supplementation in addition to a normal salt intake. Otherwise healthy subjects usually tolerate a supplement of 150 mEq/ d over and above the normal sodium intake of 150 to 200 mEq/ d without difficulty. Increased sodium intake, however, may exacerbate cardiac failure, cirrhosis with ascites, or renal failure. 

It has been shown that subjects with renal diseases such as IgA nephropathy, membranous prohferative glomerulonephritis, focal sclerosis, and lupus nephritis have levels of endothelin that are significantly higher than those in healthy subjects [209]. Increased circulating ET-1 concentrations and urinary excretion of ET-1 have been observed in patients treated with the nephrotoxic immunosuppressive agents cyclosporine A and tacrolimus (FK-506) [210]. Other nephrotoxic agents, such as cisplatin, also increase urinary excretion of ET [211]. In patients with chronic renal disease, urinary excretion of ET-1 is significantly elevated when compared to normal values (Table 10). 

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