Randomized Multi Center Study Comparing Nephrotoxicity of Ceftazidime Versus the Combination of Piperacillin and Netilmicin with and without Furosemide

Abstract

In human subjects, it is very difficult to correlate the extent of tissue damage and change in kidney function during administration of potentially nephrotoxic durgs (1–3). The rise of creatinine in the serum and the decrease of creatinine clearance are a late manifestation of renal nephrotoxicity (4). In early phases of renal nephrotoxicity, the so-called “creatinine blind phase”, the release of several renal tissue enzymes can be used an markers of early tissue damage (5). Among those enzymes are: alanine-aminopeptidase (AAP), alkaline phosphatase (AP), gamma-glutamyl- transpeptidase (g-GT), n-acetyl-3-d-glucosaminidase (NAG) etc.(6). Previous clinical results did show that increasing elimiation of the brush border enzyme AAP always preceded changes of functional parameters (7). For assessment of tubular toxicity of drugs in clinical trials AAP determination in urine is useful because of the recognition of tubular alteration or injury in an early phase long before glomerular paramenters show definite changes. Effects of aminoglycosides in recommended dosages lead to an alteration of tubular cells with the release of increasing amounts of marker enzymes into urine according to the accumulation of the drug in the tubular cells (8). AAP elimination in urine is dependent on dose regimen and sex (9). During tubular alteration of the total amount of enzyme activity in tubular cells increase (10). Lesions of tubular cells are characterized by the appearance of aggregates of enzymes and membrane fragments in urine. In this stage the creatinine-clearance decrease. During tubular necrosis filaments and cytoskeleton appears in urine (6), e.g. under treatment with cis-paltiniam (7). In volunteer studies we need such early phase paramenters, since it would not be ethical to continue the application of drugs up to the point when we recognize changes in serum creatinine or decreasing creatinine-clearance. For the following reasons we chose the AAP as an useful parameter for determination of toxic tubular alteration or damage.