中草药肾脏损害18例临床探讨

目的探讨中草药肾脏损害的特点。方法对18例中草药肾脏损害患者的临床和病理特点进行回顾性分析。结果 18例中草药肾脏损害患者中马兜铃酸肾病10例,其中急性起病7例,慢性起病3例。急性起病7例患者中2例为广防己中毒,尿糖阴性;5例为关木通中毒,尿糖阳性。急性起病有3种方式:急性肾衰竭伴Fanconi综合征1例,Fanconi综合征4例,急性肾衰竭2例。多为短期内服用大剂量木通。急性马兜铃酸肾病肾外表现为贫血,肝酶升高,胃肠道反应,肾脏表现为肾性糖尿,氨基酸尿,尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、视黄醇结合蛋白(RBP)升高,低尿酸血症,肾小管酸中毒。均无高血压。病理表现为急性肾小管坏死。2例肾功能恢复,4例转为慢性肾衰竭,1例正在随访。3例慢性马兜铃酸肾病患者均长期小剂量服用马兜铃属中药,起病隐匿,表现为慢性肾衰竭,1例并发Fanconi综合征。肾功能不全的发生具有滞后性。病理表现为慢性间质性肾炎,细胞浸润少见。3例服用中药不含已知马兜铃属植物的患者和5例所服中药成分不明的患者肾脏损害的起病方式与马兜铃酸肾病相近,均以急性肾衰竭为主,并发Fanconi综合征6例,但肾功能损害较轻。结论短期内大量服用马兜铃酸者表现为急性马兜铃酸肾病,长期小剂量服用马兜铃酸者表现为慢性马兜铃酸肾病。除含马兜铃酸的中药外,另有其他中草药亦可导致肾脏损害,但马兜铃酸肾病的肾功能损害更严重,肾脏预后更差。不含马兜铃属植物或成分不明的中药肾毒性患者,肾功能损害较轻,肾功能恢复的概率增加。     

马兜铃酸引起肾功能不全（附11例报告）

目的：探讨马兜铃酸引起的肾脏损害及其作用机制。方法：观察马兜铃酸引起的、慢性肾功能不全的临床表现、实验室检查及肾穿刺病理改变。结果：急性肾功能不全主要病理改变为急性肾小管坏死，慢性肾功能不全主要病理改变为寡细胞性肾间质纤维化。结论：短期大量服用含马兜铃酸中药后，可发生ARF，长期间断服用小量含马兜铃酸中药，可发生CRF。     

警惕含马兜铃酸中药、左旋咪唑、盐酸芬氟拉明的严重不良反应

本刊讯公众应警惕含马兜铃酸中药的安全性问题,左旋咪唑等咪唑类驱虫药与脑炎综合征,盐酸芬氟拉明的心血管系统严重不良反应。这是由国家食品药品监督管理局日前发布的第6期《药品不良反应信息通报》披漏的。通报内容指出:近年国内外研究证实马兜铃酸具有肾毒性,含马兜铃酸中药材的肾毒性作用与其马兜铃酸含量和用药时间长短有一定关系:短期大剂量服用可引起急性马兜铃酸肾病,病理表现为急性肾小管坏死,临床出现急性肾功能衰竭;长期间断或持续小剂量服用可引起慢性马兜铃酸肾病,病理表现为寡细胞性肾间质纤维化,临床出现慢性进行性肾功能衰…     

马兜铃酸肾病的临床及病理表现

目的研究马兜铃酸肾病(AAN)的临床特点、病理表现,以及影响预后的相关因素。方法回顾性分析我院2006年9月至2012年9月期间住院诊断为马兜铃酸肾病的患者36例,分析各组患者的人口学资料,临床及病理学资料,治疗经过,分析影响患者临床预后的因素。结果马兜铃酸肾病进展隐袭,表现缺乏特异性,部分患者就诊时即有肾功能不全,病理表现为中-重度肾脏小管-间质损害,炎性细胞浸润较少,可见广泛纤维化改变,部分患者在病程中出现恶性肿瘤,预后较差。结论长期服用含有马兜铃酸的药物,可引起马兜铃酸在体内的蓄积,造成肾脏,尤其是肾间质持续不可逆性损害,最终引起肾功能衰竭,也可出现恶性肿瘤。应深入研究马兜铃酸对肾脏损害的机制,寻找有效的治疗手段。     

马兜铃酸肾病研究的新进展

根据近年有关研究和报道对含马兜铃酸中药的毒性成分、马兜铃酸的代谢、马兜铃酸肾病的发病机制、临床特征及其诊断方法进行综述,旨在对马兜铃酸的毒理学及马兜铃酸肾病的诊治加深认识。     

慢性马兜铃酸肾病的临床研究

中药是祖国医学传统药物，数千年来广泛应用干临床，一直被视为无任何不良反应，安全有效。近年来．关木通及广防己等中药引起肾损害已被确认，并日益受到重视。国内外学者经研究认为此种肾损害是由马兜铃酸（aristolochic acid．AA）所致，因此国内称为“马兜铃酸肾病（aristolochic acid nephmpathy，AAN）”，根据马兜铃酸肾病的临床表现及病理改变分为肾小管功能障碍型和慢性马兜铃酸肾病型2种。现将我科2001年4月-2004年5月，诊治的42例马兜铃酸肾病患者资料进行分析，以提高对此病的认识。     

111例马兜铃酸肾病调查分析

目的 分析含有马兜铃酸成分的药物引起马兜铃酸肾病的临床特点和规律。方法 回顾性研究 111例服用含马兜铃酸成分的药物致肾损害患者的临床资料，分析马兜铃酸肾病的临床特点、服药及治疗方法等。结果 111例患者中，女性多于男性（2.58∶1），大于50岁的101例（90.99%）；年龄（63.70±11.67）岁；平均用药时间（8.08±6.94）年；涉及冠心苏合丸和龙胆泻肝丸共106例（95.50%）；血肌酐升高108例，尿素氮升高106例，血红蛋白降低103例，多见低比重尿、轻中度蛋白尿和潜血；B 超检查示肾脏均不同程度受损。肾脏病理活检为肾小管损害。多数患者起病隐匿，进展程度不一，与年龄、服药时间不成正比，临床上肾功能呈进行性损害, 多数不可逆、预后较差。结论 肾损害患者个体差异较大,肾损伤与服用马兜铃酸药物时间长短、剂量不平行；马兜铃酸肾病进展迅速，且停止服用含马兜铃酸药物后病情依然进展。加强药物警戒工作，实施早期的诊断和有效的干预，有助于减少马兜铃酸肾病的发生，延缓其发展。     

马兜铃酸肾病肾移植术后并发泌尿系肿瘤临床分析

我科马兜铃酸。肾病尿毒症患者肾移植术后并发泌尿系肿瘤4例．分析报告如下。 1临床资料 4例患者中男1例,女3例,年龄49—71岁。均有服用含马兜铃酸成分药物病史,诊断马兜铃酸肾病,尿毒症期行同种肾移植术,术后应用环孢素A、霉酚酸脂和泼尼松免疫抑制治疗,肾功能正常。并发泌尿系肿瘤时间为术后1～5年,其中膀胱移行细胞癌2例,均为多发;原肾肾盂、输尿管、膀胱移行细胞癌1例;原肾透明细胞癌、膀胱移行细胞癌1例。     

马兜铃酸肾病11例临床分析

近年来,含马兜铃酸成分中药引起的肾损害受到极大关注。关木通所致的肾小管间质肾病,被证实与中药的马兜铃酸成分有关,命名为马兜铃酸肾病。我们收治了11例服含马兜铃酸成分的中草药所致的慢性肾功能衰竭,现报告如下。1资料与方法1.1临床资料:所有病例均为本院2000—2005年门诊     

药品不良反应信息通报

41警惕含马兜铃酸中药的安全性问题1.1基本情况:近年国内外研究证实马兜铃酸具有肾毒性,含马兜铃酸中药材的肾毒作用与其马兜铃酸含量和用药时间长短有一定关系:短期大剂量服用可引起急性马兜铃酸肾病,病理表现为急性肾小管坏死,临床出现急性肾功能衰竭;长期间断或持续小剂量服用可引起慢性马兜铃酸肾病,病理表现为寡细胞性肾间质纤维化,临床出现慢性进行性肾功能衰竭(持续服用者肾损害进展较快);小剂量间断服用数周至数月可出现肾小管功能障碍型马兜铃酸肾病,病理表现为肾小管变性及萎缩,临床出现肾小管酸中毒和(或)范可尼综合征,而血清肌…     

百令胶囊加泼尼松治疗慢性马兜铃酸肾病的临床观察

目的 :探讨百令胶囊加泼尼松治疗慢性马兜铃酸肾病 (AAN)的疗效。方法 :治疗组 14例慢性AAN患者用百令胶囊加泼尼松治疗 ,治疗效果与单用泼尼松治疗组 (对照组 ) 12例比较。结果 :治疗组治疗后血Cr、尿蛋白较治疗前降低 (P <0 .0 1;P <0 .0 5 ) ,治疗组血Cr低于对照组 (P <0 .0 5 )。治疗组有效率 85 .7% ;对照组有效率 6 6 .7%。结论 :用百令胶囊加泼尼松治疗慢性AAN可降低尿蛋白 ,改善肾功能。     

Expression of histone deacetylase-1 and p300 in aristolochic acid nephropathy models

Aristolochic acid nephropathy (AAN) is mainly caused by aristolochic acid I (AAI), but the actual mechanism is still uncertain. The current study explored the correlation among the expression of Smad7, p300, histone deacetylase-1 (HDAC1) and the development of AAN using transmission electron microscopy (TEM), RT-PCR, and western blotting in the AAN mouse model and in the AAN cell model. TEM revealed that the renal tubular epithelial cells from the AAI-treated mice presented organelle damages and nuclear deformation. We found that a certain dose of AAI caused renal fibrosis and induced renal tubular epithelial cells to differentiate into myofibroblasts. There was a gradual increase in the expression of HDAC1 mRNA and protein observed using RT-PCR and western blotting in the AAN cell model compared with the control group. Gradual decrease in the expression of Smad7 and p300 mRNA and protein was revealed in the AAN mouse and cell models compared with the control group. These results suggest that AAI dose dependently contributed to the development of AAN, and HDAC1 and p300 participate in the modulation of TGF-β/Smad pathway-mediated renal interstitial fibrosis.     

Mast cell infiltration associated with tubulointerstitial fibrosis in chronic Aristolochic Acid Nephropathy

Aristolochic Acid Nephropathy (AAN) is regarded as a kind of toxic nephropathy caused by the formation of DNA- aristolochic acid adducts in renal parenchymal cells. However, the underlying mechanisms driving the progression of renal interstitial fibrosis in AAN still remains unclear. This study aims to elucidate the role of some immunological factors, especially mast cells (MCs), in the pathogenesis of AAN. Sixteen patients with AAN were enrolled in this study, including five acute and 11 chronic AAN. Monoclonal antibodies against human tryptase, alpha smooth muscle actin (alpha-SMA), and CD68 were applied on serial sections, which were further counterstained with Periodic Acid-Schiff. It was found that massive tryptase-positive MCs were observed in the fibrotic areas in chronic AAN, especially around thickened tubular basement membranes where myofibroblasts accumulated too. In contrast, MCs infiltrated to a less extent in acute AAN, and were barely found in normal control kidneys. In chronic AAN, the number of MCs in the tubulointerstitium was positively correlated with the degree of renal fibrosis (r=0.64, P <0.05), but not with serum creatinine levels. Meanwhile, the recruitment of MCs into the renal interstitium is accompanied with local proliferation of myofibroblasts. Macrophages were not abundant, neither in acute nor in chronic AAN. Our findings show for the first time that mast cell infiltration seems to be associated with the progression of fibrosis in the renal tubulointerstitium in chronic AAN.     

Protective effect of BMP-7 against aristolochic acid-induced renal tubular epithelial cell injury

Aristolochic acid nephropathy (AAN) is regarded as a kind of rapidly progressive renal fibrosis caused by the ingestion of herbal remedies containing aristolochic acid (AA). Recent studies showed that bone morphogenetic protein-7 (BMP-7) exerts beneficial effects on acute and chronic kidney injuries induced by different pathological conditions. We examined whether BMP-7 protects human renal tubular epithelial cells (HK-2) against AA-induced injury in vitro. HK-2 cells were cultured with different concentrations of AA and BMP-7 for 48 h. Cell viability was determined by Cell Counting Kit-8 assay and lactate dehydrogenase (LDH) release. The apoptosis rate and the activity of caspase 3 protease were also examined. Epithelial-to-mesenchymal transition (EMT) was determined by cell morphology, E-cadherin and α-smooth muscle actin (α-SMA) protein expression, and TGF-β₁ and collagen III secretion. Additionally, the effect of anti-TGF-β1 antibody on AA-induced EMT was assessed. Our results indicated that BMP-7 significantly increased cell proliferation, decreased apoptosis rate and attenuated activation of caspase-3, resulting in the protection of HK-2 cells from AA-induced cytotoxicity. In addition, studies on EMT revealed that BMP-7 could inhibit AA-induced myofibroblast phenotype and restored the epithelial morphology in a dose-dependent manner. It was partially through reducing the activation of a myofibroblast phenotype and production TGF-β1. Treatment with neutralizing anti-TGF-β1 antibody also blocked AA-induced EMT and collagen III secretion. Together, these observations strongly suggest that BMP-7 is a potent inhibitor of AA-induced renal tubular epithelial cell injury and might be a promising agent for aristolochic acid-induced kidney damage.     

Mild to severe lithium-induced nephropathy models and urine N-acetyl-beta-D-glucosaminidase in rats

Long-term treatment with lithium induces functional and/or structural disturbances in the kidneys. However, no procedure has been established for the early diagnosis of lithium intoxication. In this study, we prepared mild to severe lithium-induced nephropathy rat models and examined the usefulness of urine N-acetyl-beta-D-glucosaminidase (NAG) for the early diagnosis of lithium-induced renal insufficiency. Lithium was administered by repeated intraperitoneal injection (1, 2 and 4 mEq/kg/day for 10 days). We also measured the plasma creatinine and paraaminohippuric acid (PAH) clearance, and observed renal histological changes. Lithium pretreatment elevated the plasma creatinine level and decreased PAH clearance in a dose-dependent manner. The NAG level in the lithium 4 mEq/kg group was very high. The levels in the lithium 1 mEq/kg and 2 mEq/kg groups were almost the same and were higher than the control group. A histological examination of the kidney revealed glomerular congestion and/or atrophy and tubular expansion in all of the groups except the control group. These histological changes were dose-dependent. In conclusion, urine NAG may be useful in the early diagnosis of renal side effects caused by lithium therapy. When the urine NAG level becomes high in a patient taking lithium for bipolar disorder, the physician may need to consider lithium-induced renal insufficiency.     

Long-term clinical effects, bioavailability, and kinetics of minoxidil in relation to renal function.

Minoxidil was used to treat 26 patients (17 to 67 years old) with severe hypertension and varying degrees of renal function. Our object was to assess long-term clinical efficacy, kinetics (acute and chronic), and bioavailability of minoxidil in chronic renal insufficiency. Minoxidil, 27 to 30 mg per day, decreased systolic and diastolic blood pressure during the first three months of therapy. Between the third and 24th months (30 months in one patient) there was no further change. Propranolol or clonidine was needed to control heart rate, and furosemide or dialysis was needed to control edema induced by minoxidil. Renal function improved in some of the mildy azotemic patients. Minoxidil kinetics after the customary dose did not differ whether the drug was taken as tablet or solution. Kinetic parameters during chronic administration of minoxidil did not differ from those after acute administration. The kinetics in chronic renal insufficiency do not differ from these in subjects with normal renal function.     

关木通生品及其制品的药效学及毒理学研究

目的为评价关木通生品及其制品是否具有利尿作用和其安全性,对二者进行药效学、急性毒性和长期毒性的比较研究。方法采用正常大鼠水负荷的动物模型,观察关木通生品、制品水煎剂的一次性给药和连续3d(1次/d)给药的利尿作用。结果关木通生品、制品水煎剂均无明显的利尿作用。关木通生品水煎剂的LD50为50.32g/kg,关木通制品的LD50为226.62g/kg,且该药急性毒性小鼠的死亡时间主要分布于药后48～72h之间。经过本研究初步拟定的炮制工艺炮制后的关木通制品,对肾脏的毒性明显低于同等剂量的关木通生品。结论关木通生品及其制品均没有利尿作用,炮制可以达到减毒的目的。     

Detection of renal impairment in cases of chronic abuse of analgesics by administration of desamino-D-arginine vasopressin

An early diagnosis of renal dysfunction is particularly important in patients with chronic abuse of analgesics. First morphological changes in cases of analgesic nephropathy are found in the renal medulla. Therefore, urinary osmolarity as well as the urinary excretion of cyclic adenosine monophosphate (AMP) and kallikrein were measured after application of desamino-D-arginine vasopressin (DDAVP) as parameters of the renal tubular function in 21 patients with normal creatinine clearance and a regular, excessive use of analgesics. The results were compared with those of 17 healthy volunteers and 8 patients with chronic renal insufficiency after analgesic nephropathy. In patients with analgesic nephropathy the urine osmolarity after 12 h of thirst was 367 +/- 28 mOsm/kg and did not increase after DDAVP. The results obtained from healthy volunteers were 781 +/- 39 mOsm/kg. Half of the patients with chronic misuse of analgesics had lower values of urine osmolarity after thirst and DDAVP compared to the reference area of healthy subjects. Similar results were found when the effect of DDAVP under conditions of water-loading was tested. The excretion of cyclic AMP as a second messenger of DDAVP and of kallikrein did not differ between patients with chronic abuse of analgesics and healthy volunteers. The excretion of kallikrein in patients with manifest analgesic nephropathy, however, was decreased. Thus the renal concentration test with DDAVP proved to be useful in early diagnosis of renal dysfunction caused by analgesics.     

慢性肾炎患者尿表皮生长因子的检测及意义（附176例报告）

目的 了解慢性肾炎患者尿表皮生长因子（ＥＧＦ）含量的变化及意义。方法 用放射免疫法测定尿ＥＧＦ含量。结果 １３７例肾功能正常组患者尿中ＥＧＦ含量显著高于正常组（Ｐ〈０．０１）,３９例肾功能不全组患者尿中ＥＧＦ含量显著低于正常人组（Ｐ〈０．０１）。结论 肾功能正常组尿ＥＧＦ与肾功能不全组尿ＥＧＦ存在显著差异,说明ＥＧＦ在慢性肾炎的病变发生、发展中可能有重要的意义。     

Acute pressure-natriuresis relationship following withdrawal of chronic noradrenaline infusion

1. Pathological changes to the kidney, such as vascular remodelling, have been found in several models of hypertension and may contribute to the maintenance of hypertension or confer susceptibility to redeveloping hypertension after the original prohypertensive stimulus is withdrawn. 2. To investigate whether noradrenaline-induced hypertension induces persistent, functionally important changes to the kidney, the acute pressure-natriuresis relationship was characterized in anaesthetized rats under controlled neural and hormonal conditions following chronic (14 days) intravenous infusion of noradrenaline (48 microg/kg per h) or vehicle (0.04 mg/mL ascorbic acid and 0.156 mg/mL NaH2PO4 2 H2O in 10 IU/mL heparinized saline). 3. Conscious mean arterial pressure was significantly elevated by infusion of noradrenaline at 48 microg/kg per h (+10 +/- 2 mmHg at Day 14; P < 0.01 vs vehicle group). The acute relationships between arterial pressure and renal blood flow, glomerular filtration rate, Na+ excretion and urine flow were not significantly different between the noradrenaline- and vehicle-infused rats immediately after termination of noradrenaline infusion. 4. In summary, chronic intravenous noradrenaline infusion did not cause persistent changes in renal function, indicating that, in contrast with many models of hypertension, this model does not induce underlying prohypertensive changes to the kidney.