Mechanisms of Drug-Induced Nephrotoxicity

Although the prevalence of nephrotoxicity in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs) is relatively low, the extensive use profile of these agents implies that many persons are at risk. At basal states of normal renal function, the role of renal prostaglandin production for maintenance of stable renal hemodynamic function is relatively limited. Nonetheless, in the clinical setting of reduced renal perfusion as seen in various forms of cardio-renal disease, dehydration, and the aging kidney, the adequacy of renal prostaglandin production mediated predominantly by cyclooxygenase-1 (COX-1) and, potentially, by COX-2 enzyme activity becomes of major significance in the activation of compensatory renal hemodynamics. Inhibition of renal prostaglandin production by the use of NSAIDs in these circumstances can potentially lead to the emergence of several distinct syndromes of disturbed renal function. These include fluid and electrolyte disorders, acute renal dysfunction, nephrotic syndrome/ interstitial nephritis, and renal papillary necrosis. In addition, by blunting the homeostatic renal effects of prostaglandins, NSAIDs can adversely influence blood pressure control, particularly during the use of angiotensin-converting enzyme (ACE) inhibitors, diuretics, and beta blockers. This is a matter of considerable public health concern, in that some 12 million US citizens are concurrently treated with NSAIDs and antihypertensive drugs. Finally, the risk of congestive heart failure is significantly increased when NSAIDs are given to patients receiving diuretic therapy who have cardiovascular risk factors. Physiologic factors, clinical presentations, diagnostic modalities, and clinical management strategies appropriate to these NSAID-induced renal syndromes are described.

The use of amphotericin B limited by dose-dependent nephrotoxicity. Elevated creatinine associated with amphotericin B is not only a marker for renal dysfunction, but is also linked to an increase in hospital costs and a substantial risk for the use of haemodialysis and a higher mortality rate. Therefore, amphotericin B nephrotoxicity is not a benign complication and its prevention is essential. Several manipulations have been proposed to minimize amphotericin B-induced nephrotoxicity. Mannitol and frusemide administration are reported to be protective based on anecdotal observational reports. Small prospective and randomized trials do not suggest a protective effect. Three new formulations have been developed in attempts to improve both efficacy and tolerability: amphotericin B in a lipid complex (ABLC; Abelcet); amphotericin B colloidal dispersion; and liposomal amphotericin B (AmBisome). Three prospective randomized studies have clearly shown that AmBisome is less nephrotoxic than amphotericin B. In a double-blind randomized trial significantly fewer patients receiving AmBisome had nephrotoxic effects. This significant reduction in azotaemia was also observed among subgroups of patients receiving concomitant therapy with nephrotoxic agents. Moreover, there were fewer patients with hypokalaemia in the group receiving AmBisome. A recent multicentre double-blind study has shown that AmBisome (3 or 5 mg/kg/day) has a better safety profile than Abelcet (5 mg/kg). Patients in both AmBisome treatment groups experienced less chills/rigors, less nephrotoxicity based on a doubling of serum creatinine, and fewer toxic reactions resulting in discontinuation of therapy. In conclusion, amphotericin B nephrotoxicity is observed frequently. It clearly increases patient mortality. Nephrotoxicity must be recognized early, based on tubular abnormalities and a mild increase in serum creatinine. Its prevention relies on the detection and suppression of risk factors and the use of AmBisome.