Nephrotoxic, definition

ACE inhibitors and angiotensin-receptor blockers (ARB) have definite benefits in patients with nephropathy and are believed to have renoprotective effects in most patients. Due to their ability to cause an initial bump in serum creatinine, these agents should be used cautiously when employed in combination with the calcineurin inhibitors. The dihydropyridine calcium channel blockers have demonstrated an ability to reverse the nephrotoxicity associated with cyclosporine and tacrolimus (Table 52-8). In general, antihypertensive therapy should focus on agents with proven benefit in reducing the progression of cardiovascular disease and should be chosen on a patient-specific basis.55 See Chapter 2 for further recommendations for treating HTN. 

It has been claimed that physicians should bear in mind the nephrotoxic potential of this drug (23), but there is no definite evidence that simvastatin is associated with the development of proteinuria (24). 

In animals, the tubular toxicity of imipenem was completely prevented by cilastatin. Accordingly, definite nephrotoxicity of this combination has not been documented in patients (25) or in healthy volunteers (28). The cilastatin component may even reduce the nephrotoxic effects of ciclosporin after kidney transplantation (29) or bone marrow transplantation (30). 

Although ciprofloxacin was initially thought to increase ciclosporin blood concentrations and enhance ciclosporin nephrotoxicity, no definite evidence to support this interaction has been found (245). A norfloxacin-induced increase in ciclosporin blood concentrations has been... 

There are wide variations in the reported incidence of contrast nephrotoxicity because of differences in patient selection, the type of radiological procedure, and the definition of renal impairment. Contrast nephrotoxicity is relatively uncommon in people with normal renal function, in whom it is 0-10%. Pre-existing renal impairment increases the frequency, with a reported incidence of 12-27% in several prospective controlled studies. In some studies the incidence was as high as 50%, in spite of the use of low-osmolar contrast agents and adequate hydration. Dialysis may be required in some of these patients (SEDA-22, 502). 

Nephrotoxicity has been reported in 1.7% to 58% of patients receiving aminoglycoside therapy. The large variance is in part due to the use of different definitions of toxicity, variability between agents in the class, as well as the risk factors in the study population. The management of nephrotoxicity, a major contributor to the total cost of aminoglycoside therapy, was estimated to be over 4500 per case in the late 1990s. 

Amphotericin B remains the antifungal drug of choice for most systemic infections, but dose-dependent nephrotoxicity occurs to varying degrees in many patients. Toxicity is seen initially with cumulative doses as low as 300 to 400 mg, and reaches an incidence of 80% when cumulative doses approach 4 g. Several liposomal amphotericin B formulations are now available. Although numerous studies demonstrate lower rates of nephrotoxicity with hposomal formulations compared to conventional amphotericin B, it is difficult to compare rates of toxicity between products and studies due to varying study populations eiuoUed, different doses administered, and inconsistent definitions of nephrotoxicity and methods of assessment. ... 

Cl-induced nephrotoxicity often manifests clinically in the same manner as acute or chronic rejection. A biopsy is the definitive diagnostic tool. 

Among the differential diagnoses are acute rejection, ATN, and/or cyclosporine or tacrolimus toxicity (see Chap. 46). These processes are not mutually exclusive. Definitive diagnosis is made by renal biopsy. In the presence of an elevated serum creatinine level, clinicians may reduce the dose of cyclosporine or tacrolimus to minimize the potential for drug nephrotoxicity and hasten the recovery from ATN. This practice may result in subtherapeutic immunosuppressant concentrations and hasten the occurrence of acute rejection. DGF predisposes patients to acute rejection. Induction therapy (e.g., using antibody preparations) and delaying the initiation of cyclosporine or tacrolimus administration may be useful in this setting. 

The incidence of AmB-induced renal impairment is highly variable depending on the definition of nephrotoxicity and upon the presence of underlying risk factors. Following AmB introduction, a survey of 56... 

Since interleukin-2 induced response rate in patients with metastatic melanoma or renal cell cancer is schedule and dose dependent, and because renal toxicity is the main cause of treatment discontinuation, continuing studies are needed to elucidate a better definition of the observed nephrotoxicity. 

NAG, along with other urinary enzymes, has been used to evaluate drug induced tubular damage as in the case of acetaminophen [113], 5-aminosalicyate/ sulfasalazine in patients being treated for inflammatory bowel disease [114], and the relative nephrotoxicity of differing aminoglycoside dose schedules in neonates [115]. Assess of the urinary excretion of NAG have also been reported in hypertensive patients [116] and in patients with chronic renal failure due to various causes [117]. However, to date, it is considered to be an ancillary but non-definitive marker of renal disease. 

Sometimes the additive effects are solely toxic (e.g. additive ototoxicity, nephrotoxicity, bone marrow depression, QT interval prolongation). Examples of these reactions are listed in Table 1.7 , (see below). It is common to use the terms additive , summation , synergy or potentiation to describe what happens if two or more drugs behave like this. These words have precise pharmacological definitions but they are often used rather loosely as synonyms because in practice it is often very difficult to know the extent of the increased activity, that is to say whether the effects are greater or smaller than the sum of the individual effects. 

A randomised, double-blind study in patients with sepsis showed the following incidence of definite nephrotoxicity ... 

On rare occasions, hepatotoxicity and toxic leukopenia have been observed during polymyxin-E (colistin) treatment, but a definite causal relationship has not been established. The most serious side effect of the polymyxins is their nephrotoxicity. Polymyxin-B is more nephrotoxic than polymyxin-E and the sulfate derivatives of both are more toxic than their corresponding methylsulfonates. The toxic effects are dose dependent and doses above the recommended range may be dangerous. The principal nephrotoxic effect of the polymyxins is on the epithelium of the renal... 

Incidence The incidence of contrast-induced nephrotoxicity also varies with the definition used. In a prospective study of 275 patients undergoing percutaneous coronary interventions (PCI) used ioxilan, a non-ionic, low-osmolar, low-viscosity monomer, the rate of nephrotoxicity was 3.3% when defined as an absolute increase in serum creatinine of at least 44 pmol/l (0.5 mg/dl) and 10% when it was defined as an increase in serum creatinine of at least 25% above baseline [18 ]. 

The possibility of drug nephrotoxicity has to be excluded, either directly caused by calcineurin inhibitors (ciclosporin, tacrolimus) or more indirectly amplified by drug interactions. Again, the definitive diagnosis is provided by the biopsy, showing acute or chronic lesions associated with calcineurin-in-hibitor-induced nephrotoxicity. 

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