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Adenine phosphoribosyltransferase (APRT) deficiency in humans is an autosomal recessive syndrome characterized by the urinary excretion of adenine and the highly insoluble compound 2,8-dihydroxyadenine (DHA) that can produce kidney stones or renal failure. Targeted homologous recombination in embryonic stem cells was used to produce mice that lack APRT. Mice homozygous for a null Aprt allele excrete adenine and DHA crystals in the urine. Renal histopathology showed extensive tubular dilation, inflammation, necrosis, and fibrosis that varied in severity between different mouse backgrounds. Thus, biochemical and histological changes in these mice mimic the human disease and provide a suitable model of human hereditary nephrolithiasis.Adenine phosphoribosyltransferase (APRT; EC 2.4.2.7) is a ubiquitously expressed enzyme that catalyzes the synthesis of adenosine monophosphate from adenine and 5-phosphoribosyl-1-pyrophosphate (1). Adenine is produced endogenously as a by-product of the polyamine pathway and by the reaction of adenosine with S-adenosylhomocysteine hydrolase (2, 3). In the absence of functional APRT, adenine is oxidized by xanthine dehydrogenase (XDH; EC 1.2.3.2), by an 8-hydroxy intermediate, to 2,8-dihydroxyadenine (DHA) (4). The sparingly soluble nature of DHA at the normal pH of human urine (5) results in the excretion of DHA crystals in the urine and, frequently, the deposition of DHA stones in the kidneys. Adenine, which is not normally found in the urine at detectable levels, is also excreted.Clinical symptoms of APRT deficiency vary from benign to life-threatening and may be present from birth or have onset late in life (reviewed in ref.

The relative nephrotoxicities of netilmicin (Sch 20569) and gentamicin were compared in rats at doses of 30, 60, 90, and 120 mg/kg per day for 15 days. Both drugs caused proteinuria and a decrease in urine osmolality; however, netilmicin produced significantly less changes at all doses than gentamicin. Whereas gentamicin resulted in a decline in creatinine clearance at all doses, netilmicin failed to cause a decline in creatinine clearance. Renal-cortical concentrations of antibiotic at sacrifice were similar in animals receiving either drug. Lightmicroscopic changes were less severe with netilmicin than gentamicin. Cytosegresomes with myeloid bodies were identified electron microscopically in the kidneys of animals receiving either netilmicin or gentamicin at all doses. Electron-microscopic manifestations were similar. The data indicate that in the rat, netilmicin is distinctly less nephrotoxic than gentamicin.Netilmicin (Sch 20569) is a new semisynthetic aminoglycoside which has in vitro bactericidal efficacy against both gentamicin-sensitive and gentamicin-resistant microorganisms (11). In vitro studies have shown that the spectrum of activity of netilmicin is similar to that of gentamicin against most gram-negative bacteria and Staphylococcus aureus. Although it has been shown to be active against many gentamicin-resistant organisms, it is somewhat less active than gentamicin against strains of Pseudomonas aeruginosa (12). In molecular structure, it closely resembles gentamicin C,a, MATERIALS AND METHODS Adult, male Sprague-Dawley rats weighing 200 to 225 g were selected, housed singly in metabolic cages, allowed free access to water, and fed a standard Purina rat diet ad libitum. The metabolic cages were equipped with screens below the animals' living space to avoid contamination of the urine specimens with feces or other debris. The design of the cages was such that the animals were unable to contaminate the specimens with drinking water. The 24-h urine samples were collected under mineral oil to preclude evaporation.Four groups of 24 rats each, half of which received netilmicin and half of which received gentamicin, were studied. Eight control animals which received saline diluent accompanied each of the four experimental groups. Groups 1, 2, 3, and 4 received the drugs subcutaneously in 1 ml of saline diluent at doses of 30, 60, 90, and 120 mg/kg per day, respectively. Urine specimens were collected on days 3, 5, 8, 10, 12, and 15, at which time urine volume, urine protein excretion, and urine osmolality were measured.Eight animals from each group, four receiving netilmicin and four receiving gentamicin, were sacrificed 24 h after a previous injection of antibiotic on days 5, 10, and 15. Four control animals for each group were sacrificed on days 5 and 15. Serum was collected for the measurement of urea nitrogen and creatinine clearance. The kidneys were removed and were examined by light and electron microscopy. In addition, homogenates were prepared for the measurement of antibiotic concentrations in ...

To examine CDDP induced nephrotoxicity in patients with testicular carcinoma, we measured renal function prior to therapy and at six month intervals for twelve months in fifteen patients and twenty-four months in seven patients. CDDP was given iv at 20 mg/M2 per day for five days at three week intervals. Eight patients received three courses, four received four courses and three received more than four courses. The mean creatinine clearance +/- SD prior to treatment was 112 +/- 12 ml/min. By six months, it had decreased to 68.5 +/- ml/min (p less than 0.01) and it remained at that level. Plasma creatinine and blood urea nitrogen increased significantly. Subjects receiving other potential nephrotoxins in addition to CDDP developed a greater decrease in creatinine clearance (p less than 0.05). Proteinuria and functional tubular disturbances were not observed. Microscopic features were characterized by hydropic degeneration of the renal tubular epithelium, thickened tubular basement membranes and mild interstitial fibrosis. Electron microscopy revealed phagolysosomes filled with flocculent material. CDDP resulted in a permanant, nonspecific renal injury in our patients. Although the renal injury has remained subclinical, future courses of CDDP may lead to clinically important chronic renal failure.

Netilmicin, gentamicin, tobramycin, amikacin, kanamycin, streptomycin, and sisomicin were given daily for 15 days to groups of rats at three dosage levels corresponding to 10, 15, or 25 times the dose recommended for humans on a weight basis. Decreased urinary osmolality and increased urinary excretion of protein and beta-N-acetyl hexosaminidase were dose-related features of nephrotoxicity. Decreased tubular resorption of glucose and phosphate were observed with the most toxic regimens after extensive renal damage had occurred. All aminoglycosides accumulated in renal tissue; however, the concentration of drug in the renal cortex at the time the rats were killed was not useful for the prediction of renal impairment. Streptomycin and netilmicin exhibited a flat dose-reponse curve with respect to histological damage, as compared with the curves for the other drugs. Results of studies of creatinine clearance and examination of renal tissue suggested the following order of increasing toxicity of the treatment regimens: (1) 0.9% NaCl and uninjected controls; (2) streptomycin; (3) netilmicin; (4) tobramycin; (5) sisomicin, amikacin, and kanamycin; and (6) gentamicin.