环孢霉素A肾毒性研究进展

环孢霉素A(CsA)是目前治疗器官移植排斥反应的重要药物,肾毒性是其主要副作用。本 文就CsA肾毒性机制的研究进展作一综述。     

环孢霉素A肾毒性研究进展

环孢霉素A(CsA)是目前治疗器官移植排斥反应的重要药物，肾毒性是其主要副作用。本文就CsA肾毒性机制的研究进展作一综述。     

环孢霉素A治疗成人原发性肾病综合征的系统评价

目前治疗原发性肾病综合征的一线药物主要为糖皮质激素,但对于那些频繁复发、激素依赖、激素抵抗的患者,常加用免疫抑制剂联合治疗。自1985年环孢霉素A首次应用于治疗肾病综合征以来,已广泛应用于临床自身免疫性疾病的治疗中,并且取得了较好的效果。近年来随着其不良反应,如肾脏损害、高血钾、高血压、神经系统毒性、胃肠系统毒性、多毛症等报道的不断增多,人们对环孢霉素A的临床应用存在广泛争议。在此情况下,有必要对这些研究进行系统评价,以了解环孢霉素A治疗原发性肾病综合征的疗效和安全性。     

环孢素A肾毒性机制的研究进展

环孢素A(CsA)做为免疫抑制剂 ,明显改善了器官和骨髓移植者的生活质量和生存率。随着该药使用时间的延长和应用范围的扩展 ,对其副作用的认识也逐渐增加[1,2 ] 。CsA最突出的副作用就是肾毒性 ,但其发病机制尤其是分子学机制目前尚不清楚。本文就这一方面的进展作一综述。一、CsA肾毒性的形态学改变1.肾小管病变 :近曲小管上皮细胞对CsA的毒性作用尤其敏感 ,在形态学上表现为细胞内等大的空泡变性和坏死 ,小管上皮细胞内可见包涵体及微小钙化 ,病变以皮髓质交界处为重。电镜研究发现 ,包涵体为巨大的线粒体。虽然在肾缺血损伤时肾小管上…     

雷帕霉素对环孢素A诱导的慢性肾毒性的影响

目的　了解雷帕霉素 (RPM)对环孢素A(CsA)诱导的慢性肾毒性的影响。方法　对进低盐饮食的大鼠给予RPM与CsA溶剂、RPM (0 .5mg·kg-1·d-1与 1mg·kg-1·d-1)、CsA (4mg·kg-1·d-1与 8mg·kg-1·d-1)以及两者联用 ,均用药 2 8d。结果　接受RPM 1mg·kg-1·d-1的大鼠血糖明显升高 ,加重CsA(4mg·kg-1·d-1)诱导的慢性肾毒性作用 ;而亚治疗剂量的RPM (0 .5mg·kg-1·d-1)与CsA(4mg·kg-1·d-1)联用只引起轻度的血糖上升及肾小管细胞受损与间质纤维化 ,与前者相比 ,P <0 .0 5。治疗剂量的RPM(1mg·kg-1·d-1)与CsA(8mg·kg-1·d-1)联用则导致更为显著的肾功能受损、结构改变与高糖血症。结论　亚治疗剂量的RPM与CsA的联用可协同产生慢性肾毒性作用     

肾移植患者环孢霉素A药代动力学及临床应用研究

环孢霉素A系从真菌代谢产物中提取的一种由11个氨基酸组成的环状多肽,可逆地作用于淋巴细胞,是一种强效免疫抑制剂且选择性高,临床上为抑制器官和组织移植后排异反应的首选药物。能选择性地和可逆性地抑制T-辅助z细胞产生生长因子,因而对免疫系统显示较高的效能,可明显提高器官存活率。本文就环孢霉素A的药代动力学及药物相互作用的研究进展综述如下。     

THE COMBINED EFFECT OF CYCLOSPORINE A AND GENTAMICIN ON ENZYMURIA IN THE SPRAGUE-DAWLEY RAT

Male Sprague-Dawley rats (8 per group) were administered a single oral dose of cyclosporine A (10, 30 and 50 mg/day) for 5 days or vehicle (corn oil, 1.5 mL/kg) and urinary enzymes excretion was monitored. Only minor changes in enzymuria were observed in the 10 and 30 mg/kg group. However, in the 50 mg/kg group, nephrotoxicity was evident by significant increase in the excretion of N-acetyl-β-D-glucosaminidase (NAG), glutamate dehydrogenase (GDH), and lactate dehydrogenase (LDH on day 2 of treatment. As chemotherapeutic drug interaction with cyclosporine A (CyA) is thought to aggravate its nephrotoxicity, the effect of combined CyA (30 mg/kg) and the antibiotic gentamicin (50 mg/kg) for 5 days was investigated. Gentamicin alone caused a significant enzymuria, whilst co-treatment of rats with CyA gave rise to increased changes in enzymuria on days 1 and 2, between the groups receiving gentamicin + vehicle and those receiving CyA + gentamicin. This was particularly marked by significant changes in LDH excretion. In contrast these observed differences were not paralleled by changes in serum creatinine and other functional parameters. Treatment with gentamicin, appears to enhance CyA nephrotoxicity, but only in the first 2 days, after this there was no significant differences between the two groups. Our data suggest that urinary enzyme measurements could serve as a valuable non-invasive means of monitoring renal performance in animals or humans who may be exposed to combination of drugs. CyA is found not to potentiate the nephrotoxic effect of gentamicin in the animal model used in this study. It therefore appears safe to use the combined therapy particularly in the treatment of transplant patients.     

外用环孢素A联合CTLA4Ig延长异体移植鼠耳存活的研究

目的　探讨局部外用环孢素 A(Cs A)联合细胞毒性淋巴细胞相关抗原 4融合蛋白 (CTL A4 Ig)对异体复合组织移植的免疫抑制及诱导免疫耐受的作用。方法　建立吻合血管的同种异体大鼠耳廓移植模型 ,术后在移植耳皮肤表面外涂 Cs A并联合 CTL A4 Ig腹腔注射治疗 ,观察移植物的排斥反应及存活时间 ,检测移植后受体血清白细胞介素 - 2 (IL- 2 )含量变化。结果　对照组平均存活时间为 (7.8± 1.7)天 ;单纯用 Cs A治疗组为 (15 .2± 1.9)天 ,单纯CTL A4 Ig治疗组为 (16 .6± 2 .1)天 ;Cs A +CTL A4 Ig联合治疗组为 (2 8.8± 3.5 )天 ,与其它各组相比均有统计学意义 (P<0 .0 1) ;且联合治疗组的受体血清 IL - 2含量最低 ,尤以第 5、7天为著 ,与其它各组相比有统计学意义 (P<0 .0 1)。结论　局部外用 Cs A联合 CTL A4 Ig能有效抑制异体复合组织移植排斥反应 ,显著延长移植物存活时间。     

冬虫夏草对环孢素A急性肾毒性保护作用的实验研究

利用急性环孢素Ａ肾毒性动物模型，观察冬虫夏草对大鼠肾功能、尿钠、钾排出量、肾组织促上皮生长因子及对肾皮质线粒体酶功能的保护作用，并与异博定治疗组相对照。实验证明：冬虫夏草对环孢素Ａ急性肾毒性有明显保护作用，且部分作用优于异博定。     

BREAST CANCER: AETIOLOGICAL FACTORS AND ASSOCIATIONS (A POSSIBLE PROTECTIVE ROLE OF PHYTOESTROGENS)

Background : In spite of many known and suspected factors associated with the risk of breast cancer there has until recently been no explanation for its continuing increase in women of Western societies over recent decades or why there has not been an equivalent increase in women of most Asian and other less Westernized societies. It has long been suspected that a significant factor has been an increasing change of diet in Western societies from one predominantly vegetarian to one with a high content of meat and dairy products as well as ‘refined’ foods. Although diet has long been suspected there has otherwise been no real explanation as to the mechanism of the change in incidence of breast cancer. Methods : A comprehensive literature review has been made of aetiological factors and associations concerning breast cancer to determine whether any consistent trend can explain the rising incidence in Western societies. Results : There are a number of likely contributory factors but there is now accumulating evidence that the single most important difference is that people having a vegetarian diet have a high intake of legumes and other plant foods containing a variety of lignans and isoflavonoids. These appear to have an important role as nature'sex hormone modulators. These agents appear to be biologically active in a number of ways not yet completely understood but they do have both a weak oestrogenic effect and an anti-oestrogenic competitive effect, thus reducing the potential carcinogenic action of prolonged oestrogen activity. A probable additional benefit of such diets could be the role of dietary fibre. Conclusions : A major problem of Western diets may not be the presence of meat or dairy products in the diet but the absence of desirable ingredients of vegetarian diets, namely dietary fibre and certain plant lignans and isoflavonoids. A modification of diet to include a greater proportion of fibre and soy or other leguminous plant food should be studied. Alternatively addition of more fibre and lignans and especially isoflavonoids to traditional Western diets would seem worthy of serious investigation. Such influences appear to have their greatest impact early in life and therefore could be especially important for girls and young women in Western societies.     

OXIDATIVE STRESS-MEDIATED RENAL DYSFUNCTION BY CYCLOSPORINE A IN RATS: ATTENUATION BY TRIMETAZIDINE

Cyclosporine A (CsA) is one of the first line immunosuppressants employed in the management of solid organ transplantation and autoimmune diseases. The clinical utility of CsA is limited by the frequent occurrence of chronic nephrotoxicity, characterized by tubular atrophy, interstitial fibrosis and progressive renal impairment. The pathogenesis of CsA nephrotoxicity is still not well delineated. Recent evidences suggest that reactive oxygen species (ROS) play an important role in CsA nephrotoxicity. The present study was designed to demonstrate the role of oxidative stress, its relation to renal dysfunction and to investigate the effect of trimetazidine (TMZ), an anti-ischemic agent with free radical scavenging property, in CsA-induced nephrotoxicity. TMZ (2.5 mg/kg, p.o., twice a day) was administered 24 h before and 21 days concurrently with CsA (20 mg/kg, s.c.). Tissue lipid peroxidation was measured as thiobarbituric acid reacting substances (TBARS). Renal function was assessed by measuring the plasma and urine creatinine concentrations, blood and urine urea nitrogen levels and the creatinine and urea clearances. Renal morphological alterations were assessed by histopathological examination of Hematoxylin-Eosin, PAS and Masson's trichome stained sections of the kidneys. CsA (20 mg/kg, s.c) administration for 21 days produced elevated levels of TBARS and decreased renal function as assessed by increased plasma creatinine, BUN and decreased creatinine and urea clearances as compared to vehicle treated rats. The kidneys of CsA treated rats showed severe striped interstitial fibrosis, arteriolopathy, glomerular basement thickening, tubular vacuolization and hyaline casts. TMZ (2.5 mg/kg) markedly reduced elevated levels of TBARS, significantly attenuated renal dysfunction and the morphological changes in CsA treated rats. These results clearly demonstrate the pivotal role of reactive oxygen species and their relation to renal dysfunction and point to the therapeutic potential of an anti-ischemic agent, trimetazidine, in CsA-induced nephrotoxicity.     

PROTECTIVE ROLE OF ENALAPRIL FOR CHRONIC TUBULOINTERSTITIAL LESIONS OF HYPEROXALURIA

PURPOSE: Hyperoxaluria is a recognized cause of tubulointerstitial lesions and it may contribute to chronic renal failure. In previous studies we demonstrated that enalapril was effective against the progression of tubulointerstitial lesions in a 4-week hyperoxaluria rat model. We evaluated whether the action of enalapril on the tubulointerstitial lesions produced by hyperoxaluria persisted for a long period. MATERIALS AND METHODS: Two-month-old male Sprague-Dawley rats were divided into 4 groups of 12 each, including 1--control animals given tap water, 2--animals with hyperoxaluria, 3--animals with hyperoxaluria plus enalapril, 4--animals with enalapril. Hyperoxaluria in groups 2 and 3 rats was induced by administering 1% ethylene glycol, a precursor for oxalates, in the tap water continuously throughout the whole study. Meanwhile, groups 3 and 4 received 20 mg./l. enalapril in the drinking water. At the end of the study renal tubulointerstitial lesions were evaluated by immunostaining using monoclonal antibodies against macrophage infiltrates (ED1), tubulointerstitial alpha-smooth muscle actin and transforming growth factor-beta1. The lesions were quantified by semiquantitative scores. Creatinine clearance and urinary albumin excretion were also determined. RESULTS: There was no difference in urine oxalate excretion in groups 2 and 3. Group 3 rats treated with enalapril showed fewer tubulointerstitial lesions than nontreated group 2 rats, as indicated by the mean scores plus or minus standard error of mean for inflammatory infiltrate (2.16 +/- 0.2 versus 0.83 +/- 0.16), tubular atrophy (2 +/- 0.27 versus 0.66 +/- 0.14), interstitial fibrosis (2.5 +/- 0.15 versus 0.5 +/- 0.1), glomerular ED1 (1.75 +/- 0.25 versus 0.16 +/- 0.11), interstitial ED1 (2.33 +/- 0.18 versus 0.58 +/- 0.10) tubular transforming growth factor-beta1 (2.09 +/- 0.08 versus 0.91 +/- 0.14), interstitial transforming growth factor-beta 1 (2.33 +/- 0.22 versus 0.66 +/- 0.12), tubulointerstitial alpha-smooth muscle actin (2.91 +/- 0.22 versus 0.83 +/- 0.16), lower urinary albumin excretion (35.5 +/- 2.7 mg. daily versus 10.9 +/- 1) and higher creatinine clearance (2.29 +/- 0.04 ml. per minute versus 2.54 +/- 0.03, all p <0.05). CONCLUSIONS: Based on our results we believe that enalapril would provide a beneficial effect against chronic tubulointerstitial lesions caused by oxalates.     

A longitudinal study of TGF-beta1 protein levels in renal allograft recipients converted from CsA to MMF or AZA

Cyclosporine (CsA) is thought to enhance transforming growth factor (TGF)-beta1 production in vitro and in vivo and this may have a negative effect on long-term graft survival. Therefore, we studied TGF-beta1, plasma levels in 30 patients before kidney transplantation, after transplantation during CsA treatment and after conversion from CsA to azathioprine (AZA) or mycophenolate mofetil (MMF). We questioned whether TGF-beta1 plasma levels would decrease after the discontinuation of CsA and whether the TGF-beta1 plasma levels did correlate with CsA trough levels and kidney function, measured by serum creatinine levels. TGF-beta1 plasma levels measured 1 yr after transplantation were lower compared to levels measured before transplantation, however not significantly (p = 0.08). After conversion from CsA to MMF or AZA, a slight increase was observed in some patients, but in the total group TGF-beta1 levels remained unaffected. No correlation was found between the TGF-beta1 levels and CsA trough levels nor with creatinine levels. In conclusion, we did not observe higher TGF-beta1 plasma levels in plasma levels of patients receiving CsA treatment compared to blood from the same patients while on AZA or MMF.     

Cyclosporin A (CsA) and azathioprine (AZA) combination in renal allografts with CsA nephrotoxicity

Cyclosporin A (CsA) is a potent immunosuppressive drug whose effect is well known in the organ transplantation field. Treatment with CsA reduces the incidence of rejection and improves graft survival after renal transplantation (RT). However, to set against the clear advantages of CsA, a most important problem is nephrotoxicity [1, 3]. Scientists are therefore seeking new non-nephro-toxic Cs derivatives, but the search has not yet borne fruit. Teams working in organ transplantation attempt to avoid nephrotoxicity by switching to conventional treatment with azathioprine (AZA), starting 1, 3 or 6 months after transplantation [8, 11]. Conversion from CsA to AZA has not always been successful due to the high incidence of rejection [4]. AZA has also been started immediately after transplantation in combination with CsA at low doses [5], and in some instances no CsA is administered when oliguric acute tubular necrosis is present [10]. In a previous report [2], we presented the short-term results of the treatment with a CsA—AZA combination, reducing the CsA dose and giving a moderate dose of AZA in 21 transplanted patients not achieving acceptable graft function. In the present study we analysed the long-term results in a group of patients whose kidney biopsy examination results were compatible with CsA nephrotoxicity.     

PROTEINURIA IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS: ROLE OF CIRCULATING FACTORS AND THERAPEUTIC APPROACH

The clinical course of primary Focal Segmental Glomerulosclerosis (FSGS) is frequently complicated by nephrotic range proteinuria and progression to renal failure. The high recurrence rate of the disease in transplanted kidney suggests the hypothesis that such patients have a circulating factor that alters glomerular capillary permeability. In recent years some authors found that serum from patients with FSGS increases glomerular permeability to albumin and partially identified the permeability factor (PF) as a protein of 30–50 Kd m.w. The removal of this protein by means of Plasma Exchange (PE) or plasma Immunoadsorption by Protein A (IA) decreased proteinuria. In this report we provide preliminary data about the prevalence of PF and the therapeutic effect of its removal by IA, in 3 pts with recurrence in the transplanted kidney, and 4 with FSGS of the native kidneys. They were resistant to corticosteroids (CS) and immunosuppressive (IS) therapy. 10 IA sessions were performed in 4 weeks: if a remission was achieved IA was gradually tapered. The level of PF in the serum was measured by an in vitro assay to determine the glomerular permeability to albumin. The FSGS was histologically proven in all cases and the degree of evolution was evaluated. PF levels, serum creatinine, daily proteinuria and serum albumin were monitored. The 3 patients with recurrent FSGS had a normalization of the PF levels; 2 had a clinical remission. In FSGS of native kidneys PF was elevated in 3/4 cases; 1 had a clinical remission; 2 with extensive sclerohyalinosis and 1 without PF levels did not improve. Our results confirm that most patients with FSGS have high PF serum levels and suggest that its removal can be beneficial.     

rhGH在大鼠肝脏缺血再灌注损伤中保护和修复的作用

目的 探讨重组人生长激素（rhGH）在肝脏缺血再灌注损伤中的保护和修复作用及其机理。方法 Pringles法建立180只肝脏缺血再灌注损伤模型,随机分为：A、B、C、D四组。A组：rhGH预处理组（n=50）,B组：作为A组的对照组（n=50）;A组：建模前连续7d给予重组人生长激素（rhGH）针剂皮下注射0．2IU／100g（体重）／d,B组分别给予等量的生理盐水。观察ALT、TNF-α、1L-α、丙二醛（MDA）肝脏能荷（Energycharge,EC）的变化,电镜观察肝脏超微结构变化。C组：rhGH治疗组（n=40）,D组：作为C组的对照组（n=40）实验组建立模型后7d每天给予rhGH针剂皮下注射（0．2IU／100g）,对照组分别给予等量的生理盐水;检测ALT、TNF-α、IL-1αEC、电镜观察肝脏超微结构的变化。结果 A、B两组：A组ALT、TNF—a、、IL-1α和MDA在各个时间点的水平明显低于B组（P〈0．05）。A组EC水平明显高于B组（P〈0．05）;B组电镜下可见肝窦内皮细胞破坏,肝细胞线粒体结构改变,A组肝细胞超微结构明显改善。C、D两组：ALT、TNF-α、明显降低,在7d（和）或14dC组与D组有显著性差异;C组EC7d、14d明显高于D组（P〈0．05）;C组肝细胞超微结构较D组亦有明显改善。结论 rhGH可能通过抑制了细胞因子（TNF-α、IL-1α,进一步减少MDA的生成,从而减轻了这些因子对肝脏损伤,rhGH对肝脏缺血再灌注损伤具有保护和修复作用;可以在肝脏缺血再灌注损伤后促进线粒体功能恢复,改善肝细胞能量代谢状态;rhGH在肝脏缺血再灌注损伤过程中,具有促进肝脏再生的作用。