Aztreonam can safely be used in combination with cyclosporin without aggravating nephrotoxicity

Abstract. The administration of antibiotics to renal transplant patients using cyclosporin can be difficult because of the risk of severe nephrotoxicity. An investigation was therefore carried out to determine whether aztreonam, a synthetic monocyclic β-lac-tam antibiotic, can safely be combined with cyclosporin. In this retrospective study 68 renal transplant patients who received preoperative antibiotic prophylaxis consisting of aztreonam, ampicillin, and lincomycin were compared with 68 patients who received ceftazidime instead of aztreonam. Both groups were treated with cyclosporin and prednisolone and followed for 3 months. After transplantation 28. 7% of the patients suffered from an acute renal failure and 1. 5% had a wound infection. There were no significant differences between the two groups in acute renal failure, wound infections, other infections, incidence of rejections, duration of admission, or graft survival. We therefore conclude that aztreonam can safely be administered together with cyclosporin. We also conclude that the combination of aztreonam, ampicillin, and lincomycin is a good preoperative antibiotic prophylaxis in renal transplant patients.     

Immunohistological analysis of renal allograft biopsies from cyclosporin-treated patients

Differentiation of cyclosporin nephrotoxicity from renal allograft rejection is often difficult. Induction of tubular HLA-class II antigens and elevated levels of leucocyte infiltration are associated with allograft rejection but their association with cyclosporin nephrotoxicity is unclear. In order to determine these relationships, transplant biopsies (n=32) from patients considered to have cyclosporin nephrotoxicity, allograft rejection or stable graft function were stained with monoclonal antibodies specific for HLA-class II antigens and infiltrating leucocytes. Leucocyte infiltration was elevated during rejection but not in cyclosporin nephrotoxicity or stable graft function. While HLA-class II antigen expression was induced in 71% of the biopsies obtained during clinical rejection, no increased expression was found in the other 29%. Induced antigens were detected in five of the nine biopsies obtained in the presence of cyclosporin nephrotoxicity 90 days after transplantation. In four of these, induction was attributed to prolongation of increased class II expression following previous rejection episodes. Thus, the presence of induced class II antigens in the renal allograft does not exclude a diagnosis of cyclosporin nephrotoxicity.     

Is the Beneficial Effect of Calcium Channel Blockers Against Cyclosporine A Toxicity Related to a Restoration of ATP Synthesis?

ATP synthesis inhibited by Cyclosporine A is restored by calcium channel blockers: nifedipine, verapamil, bepridil, diltiazem. ATP synthesis was estimated using liver mitochondria by measuring the rate of respiration during state 3 and a measure of the yield of ATP synthesis, the P/O ratio. The study of calcium fluxes through mitochondrial membrane indicates that calcium channel blockers counteract the mitochondrial calcium storage induced by Cyclosporine A. If the restoration of ATP synthesis observed in vitro also occurred in vivo, the increase in ATP pool might contribute to a better functioning of the Ca²⁺ extrusion pumps of the cells, thereby maintaining the cytosolic calcium concentration (Ca_i) in the normal range. The nephrotoxicity of Cyclosporine A appears to be due to a vasoconstrictive effect related to an increased Ca_i This result may account for the reduction of clinical Cyclosporine A toxicity by calcium channel blockers. Verapamil appears to be the most efficient in restoring ATP synthesis.     

急性氯化镉中毒肾损害大鼠尿γ－谷氨酰转换酶及其同工酶

大鼠一次ｉｐ氯化镉（１．５～１２．２ｍｇ·ｋｇ－１），染镉前和染毒后ｄ１，ｄ３，ｄ５观察尿β２－微球蛋白（β２－ＭＧ），Ｎ－乙酰－β－氨基葡萄糖苷酶（ＮＡＧ），尿蛋白，肾小球滤过率（ＧＦＲ）和尿γ－谷氨酰转换酶（ＧＧＴ）及其同工酶，同时观察肾脏形态学改变．结果大鼠尿中β２－ＭＧ，ＮＡＧ和蛋白排出增加，９．２ｍｇ·ｋｇ－１以上组ＧＦＲ下降，形态学检查发现以肾小管损害为主的病理改变．大鼠尿ＧＧＴ异常增加并出现异常ＧＧＴ同工酶区带．     

Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity

Recent studies in liver and kidney transplant recipients revealeda nephrotoxic adverse effect of the new macrolide immunosuppressantFK-506. Therefore the effect of FK-506 0.1 to 0.8 mg per kgper day was investigated in rats using clearance methods includinglithium clearance. In rats given FK-506 or placebo during 1week the nephrotoxicity of FK-506 was characterized by a slightreduction of inulin clearance. The end proximal delivery asmeasured by the lithium clearance was decreased by FK-506. Inrats treated for 4 weeks with FK-506 0.8 mg/kg/day the glomerularfiltration rate (GFR) had decreased to 23% of the GFR foundin controls (P<0.001), while end proximal delivery was only8% of normal. Renal histopathological investigation showed aslight but statistically significant increase of tubular basophiliaand atrophy in FK-506-treated rats. Skin transplantation studiesin the same rat strain showed a dose-dependent immunosuppressiveeffect of FK-506. FK-506 0.8 mg/kg was significantly more immunosuppressivethan 0.2 or 0.4 mg/kg, so it was concluded that the lower dosesof FK-506 did not fully exploit the drug's immunosuppressivepotential. Thus in a dosage inside the therapeutic range defined from skintransplantations, FK-506 generated a number of toxic effectsincluding a considerable nephrotoxic effect. The FK-506 inducedchanges in glomerular and tubular function was a close matchto the changes found in cyclosporin A nephrotoxicity. The presentstudy suggests that FK-506 nephrotoxicity is caused by constrictionof preglomerular vessels.     

Urinary beta-hexosaminidase excretion in patients treated with lithium, thymoleptic and/or neuroleptic drugs

In order to evaluate the nephrotoxic effect of serum lithium within the therapeutical range, the urinary excretion of beta-hexosaminidase was studied in 44 well-managed long-term lithium treated patients and in 27 healthy controls. In addition, six patients on thylmoleptic and 16 patients on neuroleptic drugs were studied. The enzyme excretion was slightly increased in the lithium treated patients, but not in the patients only treated with thymoleptic or neuroleptic drugs. The findings are consistent with the suggestion that long-term lithium treatment causes a slowly progressive nephropathy. To follow the urinary beta-hexosaminidase excretion might be a measure to identify patients at higher risk. In two cases of lithium intoxication the enzyme excretion was considerably increased.     

The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity.

A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg(-1) body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.     

龙胆泻肝汤对大鼠肾毒性的观察

目的:观察配伍不同剂量关木通的龙胆泻肝汤给药不同时间的大鼠肾功能和组织形态学变化。方法:用配伍不同剂量关木通的龙胆泻肝汤水煎剂按原药材每天13,14.5,17.5 g.kg^-1剂量(其中含关木通分别为1.5,3,6 g.kg^-1)给大鼠灌胃,连续12周,分别于给药第4,8,12周测定大鼠肾功能指标,观察肾脏组织形态学改变。结果:龙胆泻肝汤中配伍小剂量关木通(1.5 g.kg^-1)连续用药12周,未见肾功能明显损伤;配伍中剂量关木通(3 g.kg^-1)连续用药12周,肾近曲小管上皮细胞出现轻微损害;大剂量的关木通(6 g.kg^-1)连续用药4周即出现明显的肾损伤,且随着给药时间的延长,损伤程度逐渐加重;病理观察到肾损伤的部位主要是皮髓交界处的近曲肾小管。结论:龙胆泻肝汤的肾毒性与其关木通配伍用量和服药时间相关。龙胆泻肝汤中配伍小量关木通在较短时间内具有相对安全性,而大剂量使用关木通可引起肾损害。     

山药保护对乙酰氨基酚诱导的大鼠肝肾损伤

目的:研究台湾产的常用中药—山药对肝肾毒性的作用.方法:以对乙酰氨基酚诱导大鼠急性损伤方式进行山药水提取物之疗效评估.结果:山药显示突出的保肝护肾效果(P<0.01)病理组织学上发现山药对肾小管脱颗粒、坏死、崩溃伤等有良好的保护作用,并且对肝中央静脉发炎及实质组织坏死都有显著保护作用.结论:山药能同时对肝及肾细胞有益,而达保肝护肾效果.这是山药常常被使用如“六味地黄丸”之中的用于肝肾阴虚的机制.