基于数据挖掘探讨刘旭生教授治疗良性小动脉性肾硬化的用药规律

<正>高血压可导致肾动脉硬化,继而出现肾小球或肾小管的功能损害而形成良性小动脉性肾硬化,又称高血压肾硬化症[1]。我国高血压病患病率逐年增高,因高血压病而导致的终末期肾病(ESRD)的发生率也在不断攀高,占24%[2]。有效防治高血压肾损害、延缓疾病发展进程、改善患者生活质量具有重要意义[3]。中医药在防治良性小动脉性肾硬化方面具有独特的优势,近年来也取得了诸多成绩[4～6]。本研究运用"中医传承辅助平台"对广东省名中医刘旭生教授治疗良性小动脉性肾硬化的病例资料进行分析,总结用药特点,以期为临床治疗良性小动脉性肾硬化提供较客观的依据和参考。资料与方法     

高血压性肾损害

临床上将高血压造成的肾脏结构和功能的改变，称为高血压性肾损害，主要为小动脉性肾硬化。高血压持续5～10年．即可引起肾脏小动脉硬化（弓状动脉及小叶间动脉肌内膜增厚、入球小动脉玻璃样变）、管壁增厚、管腔变窄，进而继发肾实质缺血性损害，包括肾小球缺血性皱缩、硬化，肾小管萎缩，肾间质炎细胞浸润及纤维化，导致良性小动脉性肾硬化症；而急进性高血压或恶性高血压所致的恶性小动脉性肾硬化症目前相对少见。     

高血压性肾病诊断治疗及中医研究进展

肾脏既是血压调节的重要器官，也是高血压损害的主要靶器官之一，无论原发性或继发性高血压，都可以造成肾脏损害。原发性高血压性肾损害分恶性小动脉性肾硬化和良性小动脉肾硬化，前者现已很少见，后者即临床所称的高血压性肾病，其病理特征为广泛的人球小动脉透明样变和小叶问动脉内膜增厚，同时出现肾小球和肾小管间质缺血性表现。     

特发性膜性肾病患者高尿酸血症患病率及相关危险因素分析

目的:探讨分析高尿酸血症(hyperuricemia, HUA)在特发性膜性肾病(idiopathic membranous nephropathy, IMN)中的患病率及其临床与病理相关危险因素。方法:将经肾活检诊断为IMN的282例患者分为尿酸正常组(208例)及高尿酸组(74例),对其临床及病理特征进行回顾性分析,计算HUA在IMN患者以及不同慢性肾脏病(chronic kidney diease, CKD)分期中的患病率,分析HUA在IMN中的相关危险因素。结果:IMN患者中HUA的患病率为26.2%,其中在CKD1、2、3期的患病率分别为20.7%、40.1%、60%。血清肌酐值、eGFR、三酰甘油、高血压病史、病理有小动脉病变的患者比例在高尿酸组及尿酸正常组差异有统计学意义(P0.05)。结论:IMN患者HUA的患病率为26.2%,CKD分期越高,患病率越高。血肌酐及三酰甘油升高,eGFR下降,有高血压病史及小动脉病变为IMN患者患有HUA的相关危险因素。血肌酐升高及有高血压病史为IMN患者患有HUA的独立危险因素。     

慢性肾脏病患者病理类型与血压水平及昼夜节律变化的关系

目的分析慢性肾脏病(CKD)患者不同病理类型与血压水平和昼夜节律异常的相关性,及后者与肾小动脉病变程度的关系。方法收集济南军区总医院、解放军117医院、北京大学第三医院2008年至2013年行肾活检且行24 h动态血压监测的CKD患者1 746例,根据2013年欧洲高血压实践指南对患者血压进行分析判断。24 h平均血压≥130/80 mmHg为高血压;夜间血压下降幅度=[(白天血压-夜间血压)/白天血压]×100%;夜间血压下降20%为深勺型节律,10%~20%为勺型节律,10%为非勺型节律,0%为反勺型节律;将深勺型和勺型定义为正常血压节律,非勺型和反勺型定义为异常血压节律。病理诊断与分型参照1995年WHO肾小球疾病组织学分型修订方案和国内2001年肾活检病理诊断标准指导意见。肾脏小动脉损伤评分参照IgA肾病牛津分型的评分标准进行评分。结果 (1)1 746例患者年龄(47.4±24.9)岁,男性929例(占53.2%);24 h平均血压≥130/80 mmHg 560例(32.1%)、白天平均血压≥135/85 mmHg 474例(27.1%)、夜间平均血压≥120/70 mmHg 762例(43.6%);深勺型血压38例(2.2%)、勺型血压647例(37.1%)、非勺型血压908例(52.0%)、反勺型血压155例(8.9%)。(2)不同病理类型CKD患者高血压发生率为,糖尿病肾病75.5%(74例)、局灶节段肾小球硬化症41.8%(62例)、IgA肾病39.2%(246例)、狼疮性肾炎25.2%(41例)、膜性肾病22.3%(37例)、肾小球轻微病变与系膜增生性肾小球肾炎18.4%(100例),各组之间差异有统计学意义(χ2=163.309,P0.001)。不同病理类型CKD患者血压昼夜节律异常发生率为,糖尿病肾病81.6%(80例)、局灶节段肾小球硬化症64.2%(95例)、IgA肾病66.7%(419例)、狼疮肾炎58.9%(96例)、膜性肾病51.8%(86例)、肾小球轻微病变与系膜增生性肾小球肾炎52.9%(287例),各组之间差异有统计学意义(χ2=48.087,P0.001)。(3)根据IgA肾病牛津评分对肾组织小动脉进行评分,0~1分(未见小动脉明显病变)789例,其中高血压发生率10.6%(84例)、血压节律异常发生率57.9%(457例);2~4分(肾小动脉轻度病变)632例,其中高血压发生率35.4%(224例)、血压节律异常发生率56.0%(354例);5~7分(肾小动脉重度病变)326例,其中高血压发生率77.3%(252例)、血压节律异常发生率74.2%(242例),分别比较差异有统计学意义(χ2=475.8,χ2=219.647;P0.001)。秩相关性分析显示,血压水平越高以及夜间血压水平下降越少,肾脏小动脉损伤越重。结论 CKD患者高血压和血压节律异常发生率高,尤其是糖尿病肾病和IgA肾病患者;CKD患者肾脏小动脉病变程度与高血压及血压节律异常相关。     

拟诊高血压肾硬化患者的临床病理分析

目的 探讨拟诊高血压肾硬化(HN)患者的临床特征及影响预后的因素，以期提高临床对该病诊断及治疗的认识。方法 回顾性分析我科63例最初拟诊HN且有肾活检诊断的患者的临床资料。根据肾脏病理学结果分为原发性肾炎(PN)组、良性肾小动脉硬化症(BN)组及恶性肾小动脉硬化症(MN)组，比较各组间临床参数及组织学特征。对确诊HN的患者分析影响其预后的临床及病理因素。结果 63例临床拟诊为HN的患者经肾组织活检病理诊断，37例(58.7%)为BN；12例(19.0%)为MN；14例(22.2%)为PN，HN诊断符合率为77.7%。BN组患者男性较多，年龄较大，高血压家族史比例及高血压病程明显高于PN组，而PN组尿蛋白定量高于BN及MN组。MN组左心室心肌重量指数(LVMI)高于PN组。BN组视网膜病变主要为0~Ⅱ级，占78%，而MN组则主要为Ⅲ~Ⅳ级。PN组球性硬化肾小球比率及小管慢性化指数(CI)积分均高于MN及BN组。MN及BN组肌内膜细胞增殖、小动脉玻璃样变等血管病变均较PN组明显，其中BN组改变最为显著。多因素回归分析提示收缩压(SBP)、尿蛋白定量、尿酸(UA)、总胆固醇(TC)是影响肾脏病进展的危险因素，优势比分别为2.563、2.467、2.323、2.357。结论 临床拟诊HN的患者不能排除PN。部分HN与PN患者临床表现相似，单纯依据病史及实验室检查难以区分。肾组织病理检查是确诊的最佳手段。 SBP、尿蛋白、TC、UA等因素可加速HN的病变进展。     

超声造影定量参数评价慢性肾脏病分期及与临床指标的相关性研究

目的探讨分析超声造影定量参数在评价慢性肾脏病(CKD)各分期肾皮质血流灌注情况的应用价值及其与临床指标间的相关性。方法共纳入研究80例CKD患者,根据CKD分期分为1、2、3、4～5期4组,每组各20例,另选取20例健康志愿者作为对照组,所有研究对象均行双肾超声造影检查,选择肾皮质区域建立时间强度曲线(TIC),获得血流灌注参数包括造影剂到达时间(AT)、达峰时间(TTP)、绝对增强强度(ΔI)及曲线下面积(AUC),比较各组超声造影定量参数的差异,并分析超声造影参数与临床指标间的相关性。结果超声造影显示对照组AUC明显高于CKD各组,差异有统计学意义(P0.05);随着CKD分期增高,双肾AUC减少,差异有统计学意义(P0.05);各组间双肾AT、TTP差异无统计学意义(P0.05)。双肾ΔI与肌酐、尿酸呈负相关(P0.05);双肾AUC与肌酐、尿酸、尿素氮呈负相关(P0.05);双肾AUC与血红蛋白呈正相关(P0.05);其余超声造影灌注参数与临床指标间无显著相关性(P0.05)。结论超声造影可以对CKD各分期肾皮质微循环血流灌注进行定量参数分析,能准确、敏感、有效地评价CKD患者的肾脏功能。超声造影定量参数还能反映不同分期CKD肾功能受损的严重程度,为临床早期诊治CKD提供可靠的客观指标。     

高血压与肾病变

高血压与肾病变的因果关系一直是1836年(Bright)以来的研究课题。在肾血管性高血压和肾实质性高血压时的肾病变以及高血压性血管损害所致的肾病变,均被看成高务压的原因,称之为肾硬化。但是,由于肾硬化也包括非高血压性肾血管病变,故高血压性肾血管损害与肾硬化并不是同义语。     

肾小球滤过率下降与肾血管病变的相关性分析

长期高血压对肾血管具有重要的影响,但在不少肾脏疾病中,组织学检查显示有明显肾血管病变的患者而临床上并无高血压。为了明确肾血管病变除受血压等因素影响外,是否与肾脏功能的丢失有关,我们将两者进行了相关性分析。材料与方法1.病例:回顾性选择140例患者,除外原发性高血压、年龄超过50岁、糖尿病及吸烟患者。考虑到不同的原发病对肾血管病变的影响,故本组选择的病例均为肾活检示原发性IgA肾病患者。收集所有患者的临床资料,以MDRD简化公式评估肾小球滤过率(GFR),并按K/DOQI慢性肾脏疾病(CKD)的分期标准将IgA肾病分期。2.临床分组…     

165例特发性膜性肾病临床及病理特征与肾功能的相关性分析

目的 研究特发性膜性肾病（IMN）患者肾功能水平与临床及病理特征之间的相关性。方法 对2010年1月至2016年12月于深圳大学附属第一医院确诊的165例IMN患者的临床及病理资料进行回顾性分析；按照基线肾功能水平eGFR（估算肾小球滤过率）分为CKD1期组、CKD2期组、CKD3+4+5期组,比较患者人口学、临床生化指标及病理指标等的差异。采用相关性方程分析肾功能与年龄、24 h尿蛋白量、血压、临床生化指标及病理指标的相关性。采用二元logistic回归方程分析影响肾功能下降的危险因素。结果 ①患者年龄14～84（45.33±15.19）岁，临床表现为肾病综合征82例（49.6%）,伴高血压76例（46.1%）,合并水肿129例（78.1%）；②与CKD1期的患者相比，CKD2期以上的患者临床及病理具有男性比例高、高龄、高血压及肾病综合征发生率高的特点,且CKD分期越高（即eGFR水平越低）的患者，肾小球节段硬化、肾间质炎症细胞浸润及肾小动脉壁增厚的比例越高；③相关性分析结果提示，肾功能与年龄、高血压、24 h尿蛋白、血清尿酸水平、肾间质炎症细胞浸润、肾小管萎缩、肾小动脉壁增厚呈负相关（P<0.05）；④logistic多因素回归分析显示性别、24 h尿蛋白定量、高尿酸血症、肾间质炎症细胞浸润为IMN患者肾功能损害的独立危险因素。结论 IMN患者初诊时年龄、是否合并肾病综合征及高血压是eGFR下降的相关因素；男性、大量蛋白尿、高尿酸血症、肾间质炎症细胞浸润是影响IMN患者肾功能重要的预测因子。     

Hypertension in black South Africans--new perspectives on old material

Autopsy material was examined from cases diagnosed as malignant nephrosclerosis in the years 1956-1961, a period when adequate antihypertensive therapy had not yet become available, a second group of malignant nephrosclerosis from the years 1970-1980, an era during which effective antihypertensive therapy was available, and a third group of essential benign nephrosclerosis, once more from the early pretreatment period (1956-1961). The observations suggest that malignant and benign hypertension may be two different diseases. Further studies will be pursued to assess whether hypertensive renal changes seen in this study are a spectrum of one disease extending from malignant nephrosclerosis de novo presenting with acute renal failure or chronic renal failure to benign hypertensive nephrosclerosis.     

Nationwide multicenter kidney biopsy study of Japanese patients with hypertensive nephrosclerosis

Background

Nephrosclerosis is an increasingly reason for dialysis in Japan. However, kidney biopsy specimens for hypertensive nephrosclerosis are very limited; thus, the pathologic evaluation of hypertensive nephrosclerosis currently remains unclear.

Methods

Clinical and pathologic data of a total of 184 biopsy-confirmed hypertensive nephrosclerosis patients were collected from 13 centers throughout Japan. Seven pathological findings were assessed in this study. The outcomes of interest for this study were dialysis, composite kidney events, cardiovascular events, and all-cause mortality.

Results

The Green and Yellow (G&Y), Orange, and Red groups of the chronic kidney diseases (CKD) heat map contained 36, 57, and 91 cases, respectively. The mean observation period was 7.3 ± 5.2 (median, IQR; 6.1, 2.6–9.7) years. Global glomerulosclerosis (GScle), interstitial fibrosis and tubular atrophy (IFTA), arteriolar hyalinosis in Red exhibited higher scores than those in G&Y and Orange. The incidence rates of the composite kidney end points in 100 person-years for the G&Y, Orange, and Red groups were 1.42, 2.16, and 3.98, respectively. In the univariate Cox analysis for the composite kidney end points, GScle, IFTA and interstitial cell infiltration exhibited statistically significant high hazard ratios (1.18, 1.84, 1.69, respectively). However, after adjustment for clinical and medication data, the Red group in the CKD heat map category was risk factor for the composite kidney end points (HR 9.51).

Conclusions

In summary, although pathologic findings had minor impacts on the prediction of composite outcomes in this study, the clinical stage of the CKD heat map is a good predictor of composite kidney events.

     

Decompensated benign nephrosclerosis and secondary malignant nephrosclerosis

Using semiquantitative morphometric methods, the clinical picture of decompensated benign nephrosclerosis is distinguished from that of secondary malignant nephrosclerosis, designated as the consequence of high pressure. It is shown that hypertensive glomerulopathy triggered by high pressure and postglomerular interstitial fibrosis with tubular atrophy are in the foreground of pathologic changes in decompensated benign nephrosclerosis, whereas the preglomerular vessel network is most often affected in secondary malignant nephrosclerosis. The preglomerular vascular lesions in secondary malignant nephrosclerosis lead to such heavy stenosis of the afferent vessels that the clinical picture of hypertensive glomerulopathy is rarely observed, while that of ischemic glomerular capillary collapse is frequent. The preferred affliction of the glomeruli and the postglomerular vessel network leads in decompensated benign nephrosclerosis to severe interstitial fibrosis, which has a pyramidal form, decreasing from the base of the pyramid at the corticomedullary boundary to the outer renal cortex. In secondary malignant nephrosclerosis fibrosis of the renal cortical interstitium is homogeneous in all layers of the renal cortex. Clinically, decompensated benign nephrosclerosis and secondary malignant nephrosclerosis, which occur predominantly in young to middle-aged males, manifest malignant hypertension. They are also accompanied by progressive renal insufficiency.     

Hypertensive nephrosclerosis

Hypertensive nephrosclerosis is the leading cause of end stage renal disease (ESRD) in France, however, in prospective clinical trials of hypertension, ESRD accounts only for a small fraction of all events (incidence rate 0.2 to 0.4% by year). Hypertensive nephrosclerosis is characterized histologically by a series of vascular injury, none of which is truly specific and that can be observed also in obesity or normal aging. Hypertensive nephrosclerosis is mildly symptomatic, but the prognosis is never benign, due to cardiovascular and renal burden. This unspecific presentation may explain why the diagnosis of hypertensive nephrosclerosis is easily carried by excess, the main differential diagnoses are atherosclerotic ischemic renal disease, poorly symptomatic primitive nephropathies or the sequelae of unnoticed malignant hypertensive nephrosclerosis. The very high prevalence of hypertensive nephrosclerosis in populations from African ancestry has suggested a genetic predisposition. MYH9/APOL1 gene variants have recently been identified and are strongly associated with hypertensive nephrosclerosis, however the pathophysiological link between these variants and renal disease is still unclear. The treatment is mainly based on blocking the renin angiotensin system, especially when proteinuria is present. The target blood pressure is less firmly established, the latest data from the AASK study, however, do suggest a benefit on progression of lower values < 135/80 or even < 130/80 mmHg, especially in patients with proteinuria.     

Renal arteriolar obstruction without hypertension.

Selective partial occlusion of the intrarenal arteriolar bed with microspheres in rats resulted in contracted kidneys simulating those of benign nephrosclerosis in man. There was no elevation of blood pressure, renal vein plasma measured by radioimmunoassay, or juxtaglomerular indices of affected kidneys. It is unlikely that arteriolar lesions are pathogenetically related to the development of hypertension.     

Arteriolar vascular smooth muscle cell differentiation in benign nephrosclerosis

Background Benign nephrosclerosis (bN) is the most prevalent form of hypertensive damage in kidney biopsies. It is defined by early hyalinosis and later fibrosis of renal arterioles. Despite its high prevalence, very little is known about the contribution of arteriolar vascular smooth muscle cells (VSMCs) to bN. We examined classical and novel candidate markers of the normal contractile and the pro-fibrotic secretory phenotype of VSMCs in arterioles in bN. Methods Sixty-three renal tissue specimens with bN and eight control specimens were examined by immunohistochemistry for the contractile markers caldesmon, alpha-smooth muscle actin (alpha-SMA), JunB, smoothelin and the secretory marker S100A4 and by double stains for caldesmon or smoothelin with S100A4. Results Smoothelin immunostaining showed an inverse correlation with hyalinosis and fibrosis scores, while S100A4 correlated with fibrosis scores only. Neither caldesmon, alpha-SMA nor JunB correlated with hyalinosis or fibrosis scores. Cells in the arteriolar wall were exclusively positive either for caldesmon/smoothelin or S100A4. Conclusions This is the first systematic analysis of VSMC differentiation in bN. The results suggest that smoothelin is the most sensitive marker for the contractile phenotype and that S100A4 could be a novel marker for the secretory phenotype in vivo. The other markers did not seem to differentiate these phenotypes in bN. Thus, VSMC phenotype markers should be defined in the context of the vessel segment and disease under examination. S100A4 could not only be a marker of pro-fibrotic secretory VSMCs in bN but also an important mediator of arteriolar fibrosis.     

Marked proteinuria in hypertensive nephrosclerosis

Heavy proteinuria in patients with essential hypertension raises the question of underlying primary renal disease. While malignant hypertension may be associated with proteinuria in the nephrotic range, it is generally held that protein excretion in benign nephrosclerosis is almost invariably less than 0.5-1.0 g/24 h. We report 18 patients with biopsy-proven hypertensive nephropathy and heavy proteinuria, of which only 6 had malignant hypertension. In the remaining 12 patients with benign nephrosclerosis, protein excretion reached up to 6.5 g/24 h, and nephrotic range proteinuria was present in 3 patients. All patients with heavy proteinuria suffered from long-standing moderate or severe, poorly controlled hypertension and were azotemic. We suggest that hypertensive nephrosclerosis be included in the differential diagnosis of massive proteinuria accompanying azotemia in poorly controlled hypertensives.     

肾小管上皮细胞程序性坏死对慢性肾脏病患者肾损伤的影响

目的:分析不同分期慢性肾脏病（chronic kidney disease,CKD）患者肾组织中发生程序性坏死的肾小管上皮细胞数量及其与临床病理指标的相关性,探讨肾小管上皮细胞程序性坏死在CKD患者肾小管上皮细胞过度死亡、慢性肾损伤进展中的作用。方法:收集2017年6月至2019年6月于海南医学院第一附属医院行肾活检且...     

慢性肾脏病患者血清胎球蛋白A水平与脂质代谢紊乱的相关性研究

目的 观察未接受透析治疗的慢性肾脏病（CKD）3～5期患者血清胎球蛋白A水平变化,探讨CKD患者血清胎球蛋白A水平与脂质代谢紊乱的相关性。方法将2008年8月至2009年1月我院64例CKD患者分为3组,其中CKD3期组17例,CKD4期组16例,CKD5期组31例,另选择健康体检者20名为对照组,分别检测各组血清胎球蛋白A水平以及清蛋白（Alb）、三酰甘油（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、载脂蛋白A（ApoA）、载脂蛋白B（ApoB）、脂蛋白a[LP（a）]、血肌酐（SCr）、尿素氮（BUN）、半胱氨酸蛋白酶抑制剂C（cystatinc）、血钙（Ca^2＋）、血磷（p3＋）、甲状旁腺素（PTH）,比较各组胎球蛋白A水平,并分析血清胎球蛋白A水平的独立影响因素。结果CKD3期组血清胎球蛋白A水平与对照组无差异（P〉0．05）,CKD4期组和CKD5期血清胎球蛋白A水平较对照组降低（P〈0．05）,ApoA、ApoB、ApoA／ApoB比值和cystatinC被选人多元线性回归模型。结论CKD非透析患者血清胎球蛋白A水平可能随着肾功能的逐步恶化而降低,其水平与脂质代谢紊乱相关。