Functional polymorphism of the myeloperoxidase gene in hypertensive nephrosclerosis dialysis patients.

Myeloperoxidase (MPO) may play an important role not only in host defense reactions but also in local inflammations, especially in atherosclerotic diseases such as hypertensive nephrosclerosis (HN). Paradoxically, MPO-deficient mice have been reported to show increased atherosclerosis compared with wild mice, although higher MPO levels are thought to exacerbate atherosclerotic disease. To clarify the genetic role of MPO in HN, we examined the function and distribution of the -463G/A polymorphism located in the promoter region of the MPO gene with ex vivo flow cytometry analysis and a study in end-stage renal disease patients, respectively. This polymorphism has been reported to have a functional significance in vitro, with the A allele being associated with lower MPO expression. In the present study, we also found significantly higher reactive oxygen species (ROS) production with peripheral neutrophils isolated from subjects with the GG genotype compared with those from subjects with other genotypes by flow cytometry assay with 2-[6-(4'-amino) phenoxy-3H-xanthen-3-on-9-yl] benzoic acid (APF), which shows higher sensitivity with hypochlorite (OCl(-)). Genotyping the -463G/A polymorphism in HN, chronic glomerulonephritis (CGN) and diabetic nephropathy (DM) patients who were under hemodialysis treatment demonstrated that the GG genotype was more frequent in the HN group than in the CGN and DM groups. However, the distribution of the GG genotype in the HN group was similar to that in healthy individuals. Although the -463G/A polymorphism is associated with ROS production, careful interpretation may be required to conclude that the -463G/A polymorphism can serve as a useful marker of atherosclerosis and cardiovascular events in dialysis patients.     

Effects of angiotensin inhibitors on renal injury and angiotensin receptor expression in early hypertensive nephrosclerosis.

Angiotensin converting enzyme inhibitors (ACEI) are known to inhibit the progression of established renal failure. The aim of this study was to compare the efficacy of an ACEI and an AT1 receptor antagonist (AT1R-Ant) in preventing the development of renal disease, at an early stage of hypertensive nephrosclerosis. SHRSP/Izm rats (n = 61) were treated from 10 wk until 22 wk with the ACEI delapril (40 mg/kg/d) or the AT1R-Ant candesartan cilexetil (1 mg/kg/d). Proteinuria, and structural/ultrastructural changes were assessed at 14 and 22 wk. Treatment with either agent resulted in reductions in blood pressure and cardiovascular hypertrophy. Neither proteinuria nor major renal histological changes were evident at 14 wk. At 22 wk, however, proteinuria accompanied by nephrosclerotic changes was seen in the untreated SHRSP/Izm. Treatment with either ACEI or AT1R-Ant resulted in similar reductions in proteinuria (untreated, 32.2 +/- 7.4; delapril-treated, 5.5 +/- 1.2; candesartan-treated, 3.9 +/- 0.3 mg/100 g/d). Prominent sclerosis of small-to-medium sized renal arteries was seen in the untreated SHRSP/Izm at 22 wk, but was similarly attenuated by the ACEI and AT1R-Ant. The glomerular ultrastructure was comparable between the two groups. No significant changes in renal AT1a or AT1b receptor subtype mRNA expression were seen throughout the course of the study. In contrast, a decrease in AT2 receptor mRNA was seen in the drug-treated groups at 14 wk but not at 22 wk. These results suggest that both ACEI and AT1R-Ant have similar efficacy in attenuating the onset of renal injury in early hypertensive nephrosclerosis, and that treatment with either agent is associated with a transient decrease in AT2 receptor mRNA expression.     

高血压肾损害的临床病理特点及预后

目的:探讨行肾活检的高血压肾损害(HN)患者的临床、病理特点及长期预后,比较良性肾动脉硬化(BN)及恶性肾动脉硬化(MN)组患者的临床病理特征。方法:选取2003年1月至2012年12月在南京军区南京总医院肾脏科经临床及肾活检明确诊断的HN患者179例,回顾性分析其临床病理特点,探讨影响肾脏预后的危险因素。结果:HN患者平均年龄(43.8±11.2)岁,本组患者以男性为主(82%),肾活检时中位高血压病程5.0年,最高收缩压及舒张压分别为(196.5±35.9)mm Hg和(127.8±25.6)mm Hg,中位血清肌酐(SCr)144.1μmol/L,中位估算的肾小球滤过率(e GFR)47.1 ml/(min·1.73m2),中位蛋白尿0.8 g/24h。BN和MN的比例分别为54.7%及45.3%。MN组患者与BN组患者相比,高血压病程短、平均血压水平高,SCr及尿酸高、蛋白尿多,贫血较严重,靶器官损害(眼底、心脏)发生率高,且终末期肾脏病(ESRD)的发生率高。本组HN患者肾活检后随访时间0.3~10.8年,中位时间为2.9年,33例(18.4%)患者进入ESRD,5年和10年累积肾存活率分别为82.6%、38.4%。肾活检时e GFR下降、蛋白尿水平上升、动脉的恶性病变、肾小球硬化比例高是HN患者进展至ESRD的独立危险因素。结论:HN患者肾活检时e GFR、蛋白尿量,动脉恶性病变、肾小球硬化比例等对肾脏预后具有独立预测价值;MN和BN组患者临床、病理表现及预后明显差异。     

Reversible renal insufficiency due to angiotensin converting enzyme inhibitors in hypertensive nephrosclerosis

OBJECTIVE: To review the incidence of reversible renal insufficiency in patients with hypertensive nephrosclerosis undergoing antihypertensive therapy. DESIGN: Retrospective analysis of 73 patients in a long-term blood pressure control study that compared the effects of an angiotensin converting enzyme (ACE) inhibitor plus conventional antihypertensive agents compared with placebo plus antihypertensive agents. SETTING: Hospital-based outpatient treatment center. INTERVENTIONS: Patients were divided into group 1, which received enalapril plus conventional antihypertensives, and group 2, which received placebo plus conventional antihypertensives. MEASUREMENTS: Blood pressure and serum creatinine levels were measured, and imaging studies of the main renal arteries were done. MAIN RESULTS: In group 1, eight of 42 patients (19%, 95% CI, 9% to 34%) developed reversible renal insufficiency, defined as an unexpected increase in serum creatinine of 88 mumol/L or higher. Six episodes of reversible renal insufficiency occurred during July and August when temperatures were 32.2 degrees C to 37.8 degrees C (90 degrees F to 100 degrees F). Renal artery stenosis was excluded by renal arteriogram or ultrasonic duplex scanning. All eight group-1 patients had a significant decrease in mean arterial pressure below their baseline level during reversible renal insufficiency (mean change, -28 +/- 10 mm Hg, P less than 0.001). The increase in the serum creatinine level was inversely correlated with the decrease in the mean arterial pressure (r = -0.68, P less than 0.01). Reversible renal insufficiency was successfully managed by withdrawing or reducing enalapril as well as other antihypertensive agents. Subsequently, enalapril was tolerated by seven of the eight patients without recurrence of renal insufficiency. In contrast, none of 31 (CI, 0% to 11%) patients in group 2 developed reversible renal insufficiency despite the fact that both the incidence of decreases in mean arterial pressure in 6 of 31 patients (19%) and the magnitude of the decreases in mean arterial pressure (mean change, -33 +/- 16 mm Hg) were similar to those observed in group 1. CONCLUSIONS: Reversible renal insufficiency in hypertensive nephrosclerosis associated with ACE inhibitor therapy correlates with relative hypotension, is not dependent on renal artery stenosis, and can usually be managed by dose reduction.     

The MTHFR 677TT and 677CT/1298AC genotypes in Cypriot patients may be predisposing to hypertensive nephrosclerosis and chronic renal failure.

AIM: The homozygous 677TT mutation of the MTHFR gene has been linked to deep vein thrombosis and to arterial atherosclerotic events of the coronary, carotid and peripheral arteries. Its putative association with renal arteriosclerosis and chronic renal failure (CRF) in the presence of hypertensive nephrosclerosis is yet to be investigated. METHODS: Two hundred and twenty-one Greek-Cypriot patients with CRF from one single renal unit in Cyprus were divided into 6 diagnostic categories: 49 due to chronic glomerulonephritis (22.2%), 43 due to diabetes mellitus (19.4%), 26 due to autosomal dominant polycystic kidney disease (11.8%), 30 due to essential hypertension leading to nephrosclerosis (13.6%), including 4 patients with primary malignant hypertension, 32 with other rarer causes of CRF (14.5%) and 41 of uncertain etiology (18.5%). These 221 CRF patients had their MTHFR C677T and A1298C genotypes analyzed by the polymerase chain reaction and agarose gel electrophoresis after restriction enzyme digestion. The frequency of the homozygous states 677TT and 1298CC and the double heterozygous 677CT/1298AC were compared to those of 210 unrelated normal local controls. RESULTS: A statistically significant increase in the frequency of the 677TT genotype compared to controls was only found in the hypertensive nephrosclerosis CRF sub-group of patients. The prevalence rate of the 677TT genotype was 46.7% (controls 17.6%, P=0.0007). Combined together the homozygous 677TT and the double heterozygous 677CT/1298AC genotypes were found in 86.7% of the hypertensive nephrosclerotic CRF patients, compared to 46.6% in normal controls (P=0.0001). CONCLUSIONS: The findings support the hypothesis that Caucasian patients with essential hypertension, homozygous for 677TT or doubly heterozygous for 677CT/1298AC genotypes, are predisposed to develop hypertensive nephrosclerosis and CRF.     

拟诊高血压肾硬化的非良性肾小动脉硬化症的临床及病理学分析

目的探讨拟诊高血压肾硬化（HN）患者的临床特征,以期提高对良性肾小动脉硬化症（BN）及类似疾病的认识.方法回顾性分析我科63例HN患者年龄、性别、家族史、血压、尿蛋白排泄、血清学各项指标以及眼底、心脏结构等临床参数.通过肾脏病理学检查明确诊断,分析比较各组间临床参数差异及组织学特征.结果依据病理诊断将患者分为BN（35例）、恶性肾小动脉硬化症（MN,12例）、原发性肾炎（PN,10例）、局灶节段性肾小球硬化症（FSGS,6例）四组.10例PN患者中IgA肾病7例（11.1%）,系膜增生性肾炎2例（3.2%）,间质性肾炎1例（1.6%）,HN诊断符合率为74.6%.BN组患者男性居多,年龄高于PN、FSGS组;高血压家族史及高血压病程均较PN、FSGS高;血尿发生率及血尿程度均低于另两组;蛋白定量亦低于PN、FSGS组,尤其与FSGS组比较差异有统计学意义;HN组左心室心肌重量指数（LVMI）明显高于PN、FSGS组,且与PN组差异有统计学意义（P〈0.05）.但BN组与上述两组相差不显著.BN组视网膜病变主要为0～Ⅱ级,占76%,而MN、FSGS则以Ⅲ～Ⅳ级病变为主.组织学显示PN组球性硬化的肾小球比率高于HN、FSGS组,小管慢性化指标PN组高于HN组,但无明显统计学意义.HN、BN组肌内膜细胞增殖、小动脉玻璃样变等血管病变较FSGS组明显,尤以BN组病变最显著.结论临床拟诊HN患者不能排除PN、FSGS.部分BN、MN与PN患者临床特征相似,单纯依据病史、化验等手段难以鉴别,肾组织病理检查是明确诊断的最佳手段.     

Mibefradil prevents L-NAME-exacerbated nephrosclerosis in spontaneously hypertensive rats.

OBJECTIVE: To determine the potential renal protective effects of a novel calcium channel blocker mibefradil in chronic renal failure. METHOD: We compared the long-term effects of mibefradil with an angiotensin-converting enzyme inhibitor cilazapril on blood pressure, proteinuria, renal function and histological alterations in N-nitro-L-arginine methylester (L-NAME)-treated spontaneously hypertensive rats (SHR). Three groups of SHR were studied for 45 days: group 1 (n = 14), treated with L-NAME only (50 mg/l in the drinking water); group 2 (n = 15) L-NAME plus co-treatment with mibefradil (30 mg/kg per day); group 3 (n = 15), L-NAME plus co-treatment with cilazapril (10 mg/kg per day). RESULTS: Both mibefradil and cilazapril attenuated the increased systolic blood pressure, and prevented the development of proteinuria and the decreased creatinine clearance (Ccr) seen at day 42 in the group treated with L-NAME alone. Notably, mibefradil had similar effects to cilazapril on proteinuria and Ccr, despite a reduced antihypertensive effect All animals receiving mibefradil co-treatment remained alive throughout the experiment, whereas the mortality rate was 43% in SHR treated with L-NAME alone. Both mibefradil and cilazapril completely prevented renal structural damage as assessed by scoring glomerular, tubulo-interstitial and vascular lesions. CONCLUSIONS: Our data show that mibefradil prevented the development of hypertension and proteinuria, renal functional impairment and nephrosclerosis, and also improved animal survival. The renal protective effects of mibefradil were at least equivalent to those of an ACE inhibitor in this animal model of chronic renal failure.     

Effects of renin-angiotensin system blockade on macrophage infiltration in patients with hypertensive nephrosclerosis.

The mechanisms of hypertensive nephrosclerosis are not fully understood. In experimental models of the disease, inflammatory reactions such as macrophage infiltration play an important role. In human hypertensive nephrosclerosis, however, there have been few studies examining the role of inflammation histologically. We investigated whether the number of infiltrating macrophages was increased in human hypertensive nephrosclerosis, and evaluated the effects of a blockade of the renin-angiotensin system on clinical and histological findings. We examined macrophage infiltration using immunohistochemistry in renal biopsy specimens obtained from 16 patients with hypertensive nephrosclerosis, 5 patients with IgA nephropathy, 5 patients with membranous nephropathy, and 5 patients with minimal change nephrotic syndrome. The number of infiltrating macrophages in glomeruli was significantly larger in the patients with hypertensive nephrosclerosis than in those with minimal change nephrotic syndrome. The patients with hypertensive nephrosclerosis were divided into groups based on their use of antihypertensive agents at the time of renal biopsy. We investigated the effects of antihypertensive agents on clinical findings, macrophage infiltration, and monocyte chemoattractant protein-1 expression. There was no difference in clinical findings between the hypertensive groups. The numbers of infiltrating macrophages and monocyte chemoattractant protein-1-positive cells in glomeruli were significantly smaller in patients treated with an angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor blocker, whereas calcium channel blockers had no influence on histological findings. In conclusion, inflammation is involved in the progression of human hypertensive nephrosclerosis and the inflammatory process is inhibited by blocking the renin-angiotensin system.     

高血压肾损害与肾实质性高血压胰岛素受体基因第17外显子多态性研究

目的探讨原发性高血压（EH）肾损害及肾实质性高血压胰岛素受体（INSR）基因第17外显子多态性,从遗传学角度寻求其病因。方法应用多聚酶链反应和单链构象多态性分析（SSCP）等技术,对原发性高血压肾功能正常（EH-NRF组）、高血压肾损害肾功能衰竭（EH-CRF组）、肾实质性高血压肾功能正常（RH-NRF组）、肾实质性高血压肾功能衰竭（RH-CRF组）及正常血压（NC组）的全血INSR基因第17外显子多态性进行研究。结果四组患者与正常对照组INSR基因第17外显子SSCP均显示三种不同的带型,分别称为带型Ⅰ（野生型）、带型Ⅰ（突变型）、带型Ⅱ（突变型）。EH-NRF组及EH-CRF组突变频率（带型Ⅱ＋带型Ⅲ）明显高于RH-NR组、RH-CRF组及NC组（P〈0．05）。各带型在RH-NRF组、RH-CRF组及NC组间出现的频率无显著性差异。结论①INSR基因第17外显子多态性与中国人EH有关,EH患者突变率明显高于RH患者。INSR基因第17外显子多态性改变与EH是否并发肾损害无关。②肾实质性高血压患者无论是否并发肾功能衰竭,均未发现INSR基因第17外显子多态性改变。     

Stent angioplasty of severe atherosclerotic ostial renal artery stenosis in patients with diabetes mellitus and nephrosclerosis.

Atherosclerotic renal artery stenosis (ARAS) may lead to deterioration of renal function or hypertension. The clinical outcome after stent angioplasty of ARAS on renal function and blood pressure control in patients with diabetes and nephrosclerosis is the subject of some controversy. We have analyzed the results of our single-center experience with stent angioplasty for severe (>/= 70%) ostial ARAS and present here the results of a subgroup analysis of those patients who had diabetes mellitus and nephrosclerosis. From 1996 to 2001, 241 patients underwent stent angioplasty for the treatment of ARAS at our center. Of these, 99 patients had diabetes mellitus (41%) and 176 patients (73%) had nephrosclerosis defined as intrarenal resistance index (RI) >/= 0.7 diagnosed by duplex ultrasound. All lesions (n = 355) were treated successfully. Mean blood pressure at baseline was comparable and significantly improved immediately after the intervention in all groups (nondiabetics: 102 +/- 12 to 93 +/- 10 mm Hg; diabetics: 102 +/- 14 to 93 +/- 11 mm Hg; RI < 0.7: 105 +/- 13 to 95 +/- 10 mm Hg; RI = 0.7-0.8: 100 +/- 12 to 92 +/- 10 mm Hg; RI > 0.8: 102 +/- 15 to 92 +/- 11 mm Hg; P < 0.0001 each). Baseline serum creatinine was not significantly lower in nondiabetics compared to diabetics (1.46 +/- 0.9 vs. 1.62 +/- 1.2 mg %; P < 0.05) and increased in patients with nephrosclerosis (RI < 0.7: 1.18 +/- 0.6 mg %; RI = 0.7-0.8: 1.57 +/- 1.1 mg %; RI > 0.8: 1.96 +/- 1.6 mg %). Except for patients without nephrosclerosis who had a normal baseline creatinine, serum creatinine decreased significantly in all subgroups during follow-up. Stent angioplasty of ARAS offers favorable acute and long-term clinical results for the preservation of the renal function and for blood pressure control in patients with diabetes mellitus and nephrosclerosis.     

Cilnidipine is as effective as benazepril for control of blood pressure and proteinuria in hypertensive patients with benign nephrosclerosis.

To investigate the beneficial effects of cilnidipine, a calcium channel blocker that shows high selectivity for N-type receptors, on the progression of chronic renal insufficiency, we compared the efficacy of cilnidipine to that of benazepril, an angiotensin-converting enzyme (ACE) inhibitor with known renal protective effects, in a one-year trial evaluating hypertensive control, serum creatinine, and albuminuria in a cohort of patients. Given the seeming importance of the etiology of chronic renal insufficiency in determining drug efficacy, we limited our study to 20 patients with a single common condition, benign nephrosclerosis. The average age of the patients was 62+/-4 years old. The changes in systolic and diastolic blood pressure over the course of the study year revealed a similar reduction with cilnidipine and benazepril. Both cilnidipine and benazepril induced similar reductions in systolic and diastolic blood pressure over the course of the study year. The baseline levels of serum creatinine were 1.40+/-0.2 mg/dl and urinary excretion of albumin was 168+/-10 mg daily. The levels of serum creatinine were not significantly changed throughout the study in either group, although the levels of urinary excretion of albumin were significantly decreased in both groups. There were no significant differences in either of these values between the two groups. In conclusion, both cilnidipine and benazepril equally and effectively reduced blood pressure and albuminuria in hypertensive patients with benign nephrosclerosis in a one-year trial.     

Candesartan cilexetil and renal hemodynamics in hypertensive patients

This randomized, double-blind, placebo-controlled crossover study evaluated the effects of the angiotensin II type 1 (AT1)-receptor blocker candesartan cilexetil on renal blood perfusion and glomerular filtration in patients with primary hypertension with diastolic blood pressure of 100 to 114 mm Hg. After a 4-week placebo run-in period, patients were randomized to receive either 16 mg candesartan cilexetil or placebo once daily for 6 weeks, after which they were switched to the alternative treatment. At the end of each period, 24 h after the last dose, renal assessments were made and the plasma renin activity, plasma concentrations of angiotensin II, aldosterone, and catecholamines were measured. Compared with placebo, candesartan cilexetil significantly reduced mean arterial pressure, by 8 mm Hg (95% confidence interval [CI], 3;12). Renal vascular resistance was significantly reduced by 0.03 mm Hg/mL min(-1) (95% CI, 0.01; 0.06). There was a small nonsignificant increase in renal plasma flow. The filtration fraction fell slightly from 0.24 to 0.22 (95% CI, -0.00, 0.04). As expected, angiotensin II concentrations and plasma renin activity were increased and the aldosterone concentrations were reduced. Catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with 16 mg candesartan cilexetil once daily induced a reduction of renal vascular resistance and a trend toward increased renal plasma flow despite a reduction in mean arterial pressure. Because the glomerular filtration rate was maintained the filtration fraction was reduced, indicating a decreased glomerular capillary pressure.     

Differences in the rates of Na/Li-countertransport in the erythrocyte membranes of hypertensive and renal hypertensive patients

Erythrocyte membrane permeability was studied by means of sodium-lithium countertransport measurement in patients with essential and renal hypertension and in healthy volunteers. In essential hypertension, erythrocyte membrane permeability was 60 per cent higher than the control value. There was no difference between permeability values of renal hypertensive patients and healthy subjects. Erythrocyte membrane permeability was not related to age or sex in normotensive subjects. Permeability pattern is assumed to be a useful parameter for differential diagnosis of arterial hypertensions and for establishing hereditary origin of essential hypertension.     

Glucose tolerance and age-associated decline in renal function of hypertensive patients.

BACKGROUND: Renal function is thought to decrease with age in the general population, but the determinants of this age-associated evolution are poorly understood. Hypertension and diabetes mellitus, two leading causes of chronic renal failure in the elderly, may accelerate this decline. PATIENTS AND METHODS: Urinary clearances of [99mTc]diethylene triaminopentaacetic acid (DTPA) (glomerular filtration rate) and [131I]hippuran (effective renal plasma flow) were assessed in 227 never-treated essential hypertensives aged 20-69 years. Based on the oral glucose tolerance test, the study population consisted of 4% patients with previously unknown diabetes mellitus, 24% with impaired glucose tolerance and 72% with normal glucose tolerance. RESULTS: When the population of 218 non-diabetic subjects was considered, glomerular filtration rate was inversely correlated with age and arterial blood pressure, and positively correlated with effective renal plasma flow, filtration fraction and fasting plasma glucose. In multivariate analysis, age and blood pressure were independent determinants of renal plasma flow, whereas renal plasma flow, age and fasting plasma glucose were independent determinants of glomerular filtration rate. The slope of the regression line relating glomerular filtration rate to age was steeper in patients with impaired glucose tolerance than in those with normal glucose tolerance (-1.52 +/- 0.28 versus -0.65 +/- 0.12, P < 0.01). CONCLUSIONS: These results suggest that impaired glucose tolerance, which is seldom searched for in patients with essential hypertension, may be an important determinant of the age-associated decline in renal function.     

老年原发高血压肾损害患者纤溶活性与D二聚体的变化

目的：了解纤溶活性和血、尿Ｄ二聚体（Ｄ－ｄ）水平变化在老年高血压肾小动脉硬化症（ＨＡＮＳ）中的应用。方法采用ＥＬＩＳＡ法测定血、尿Ｄ－ｄ用发色底物法测定纤溶酶活性（ｐＡ）、组织型纤棠麦原激活物活性（ｔｐＡＡ）及纤溶酶原抑制剂活性（ＰＡＩＡ）。结果原发性高血压（ＰＨ）组及ＨＡＮＳ组与正常对照比较;ｐＡ和ｔｐＡＡ明显降低,ＰＡＩＡ和血,尿Ｄ－ｄ水平显著升高;ＨＮＡＳ组与ＰＨ组比较,仅血浆ＰＡＩＡ,尿Ｄ     

Bone biopsy to diagnose hyperoxaluria in patients with renal failure.

Primary hyperoxaluria is a rare congenital disorder characterized by large quantities of urinary oxalate with resultant nephrocalcinosis and nephrolithiasis and by deposits of calcium oxalate in other organs. Renal failure occurs early in life. Reports of unsuccessful renal transplantation attempts in this disorder underscore the need for antemortem diagnosis. Percutaneous bone biopsy is a relatively new procedure that is easily done at bedside, safe, and of potentially high yield in the demonstration of tissue oxalate. Three cases presented here show the characteristic histologic picture seen in this disease. In one case, the diagnosis was established by bone biopsy.