Serum hepatocyte growth factor levels in patients with chronic renal disease - effect of GFR and pathogenesis

Hepatocyte growth factor (HGF) is a growth-promoting peptide that appears to act in a renotropic and nephroprotective manner during acute renal damage. Recent studies suggest that HGF is also of importance in chronic renal diseases. The serum HGF level is correlated with serum creatinine, and it has been suggested that glomerular and tubular diseases affect serum HGF differently. In the present study, levels of serum HGF were determined and correlated to glomerular filtration rate (GFR) in 118 patients with various chronic renal diseases. GFR was determined by 99m Tc-DTPA clearance, and the GFR values were evenly distributed in the interval 5-155 mL/min/1.73 m 2 . Serum HGF levels increased slightly with decreasing GFR; the Pearson correlation coefficient being 0.49 (p < 0.0001). In 21 additional patients with end-stage renal disease treated with continuous ambulatory peritoneal dialysis, there was a more marked increase in the serum levels of HGF. The effect of glomerular and tubular diseases on serum HGF was examined by comparing the HGF levels in two groups of patients with similar GFR values: 57 patients with mainly glomerular disorders (diabetic nephropathy with micro- or macroalbuminuria or glomerulonephritis) and 14 patients with mainly tubular disorders (polycystic kidney disease). There was no significant difference between the HGF levels of the two groups (p = 0.30). In conclusion: Serum HGF levels are correlated with GFR (for GFR &#85 5 mL/min/1.73 m 2 ) in patients with chronic renal diseases, and glomerular and tubular disorders seem to affect the HGF level similarly.     

前列腺癌患者外周血HGF检测及其临床意义

目的检测前列腺癌患者外周血中肝细胞生长因子（HGF）的表达水平,评价HGF对前列腺癌早期诊断的价值。方法采用酶联免疫吸附法对27例原位前列腺癌、20例远处转移前列腺癌患者以及15例前列腺正常者外周血HGF的表达水平进行检测。结果前列腺原位癌及转移癌患者血清HGF的表达水平均明显高于正常对照组（P〈0．0001）,分别为823．5±262．8pg／ml、1260．0±641．8pg／ml和405．3±129．4pg／ml。转移癌组又明显高于原位癌组（P〈0．002）。HGF在转移癌组的灵敏度要高于原位癌,分别为100％和70．4％,特异度均为93．3％。结论HGF可作为前列腺癌的早期血清学诊断指标。     

慢性乙型肝炎患者血清转化生长因子β1、肝细胞生长因子的检测及临床意义

目的探讨慢性乙型肝炎病理过程中血清转化生长因子β1(TGF-β1)、肝细胞生长因子(HGF)水平的变化及其临床意义。方法48例慢性乙型肝炎患者和20例健康人均于清晨空腹采血以双抗体夹心酶联免疫吸附测定法检测血清TGF-β1、HGF水平并同时检测肝功能和乙型肝炎病毒脱氧核糖核酸(HBV DNA)水平。结果慢性乙型肝炎患者轻度组、中度组、重度组血清TGF-β1、HGF水平均显著高于对照组,TGF-β1分别为(167.5±87.6)μg/L、(313.1±96.3)μg/L(、495.9±134.4)μg/L vs(81.4±40.7)μg/L,MGT分别为(1530.4±912.2)ng/L(、2461.5±1624.7)ng/L、(3805.2±2104.8)ng/L vs(270.3±123.5)ng/L(均P<0.05),且与丙氨酸转氨酶(ALT)、总胆红素(TBil)水平呈正相关(r=0.625,r=0.568,r=0.579,r=0.612);HBV DNA阳性组和阴性组血清TGF-β1、HGF水平比较差异无统计学意义。结论细胞因子TGF-β1、HGF参与了慢性乙型肝炎的病理生理过程,其水平变化与肝脏损伤程度密切相关。     

急性白血病患者肝细胞生长因子及血管内皮生长因子血清水平检测及临床意义

目的 检测急性白血病(AL)患者治疗前后外周血血清肝细胞生长因子(HGF)和血管内皮生长因子(VEGF)的水平,探讨血清HGF和VEGF与急性白血病的发生、发展及预后等方面的关系.方法 应用双抗体夹心酶联免疫吸附测定(ELSIA)法动态检测并分析患者疾病不同时期血清HGF和VEGF的水平.结果 急性非淋巴细胞白血病(ANLL)组血清HGF水平(1 196.86±282.31)ng/L明显高于正常对照组(332.55±65.16)ng/L(P<0.01);急性淋巴细胞白血病(ALL)组血清HGF水平(1 224.53±283.19)ng/L明显高于正常对照组水平(332.55±65.16)ng/L(P<0.01);ANLL患者CR组治疗前后血清HGF水平分别为(1 140.31±266.23)ng/L,(478.50±183.75)ng/L(P<0.01),NR组治疗前后血清HGF水平分别为(1 432.51±235.30)ng/L,(1 386.63±197.95)ng/L(P>0.05).结论 AL患者血清HGF及VEGF水平均较正常对照组HGF水平及VEGF水平升高.血清HGF及VEGF水平可作为监测AL的疗效指标.血清VEGF水平可作为AL的预后判断指标,血清HGF水平对白血病的预后判断有一定意义.     

Serum Erythropoietin levels and inhibitors of erythropoiesis in patients with chronic renal failure

The role of various factors in erythropoiesis was studied in 13 predialysis patients and 41 hemodialysis patients. Serum erythropoietin (ESF) was measured by the fetal mouse liver cell bioassay in vitro. The effect of uremic sera on heme synthesis and erythroid progenitor cell (CFU-E) formation was examined using normal human bone marrow cultures. Serum ESF levels in both predialysis (99.9 +/- 45.0 mU/ml) and dialysis (141.2 +/- 109.7 mU/ml) patients were significantly higher than those in normal controls (42.0 +/- 25.8 mU/ml), although the titers were not sufficiently increased to correct the anemia. Serum ESF concentrations did not correlate with hemoglobin level or inhibition of both heme synthesis and CFU-E formation. Bone marrow CFU-Es in uremic patients were normal in the number, the responsiveness to ESF and the percentage in S-phase. Significant decrease in heme synthesis was observed in dialysis patients. The degree of inhibition of CFU-E formation showed a relationship to hemoglobin levels in uremic patients. By the CFU-E formation assay, the difference in inhibitory effects of the sera obtained from dialysis patients immediately before and after a hemodialysis was significant only under a low ESF concentration (0.125 U/ml) but not under a high concentration (1.0 U/ml). In conclusion, inhibition of heme synthesis and CFU-E formation, in addition to inadequate ESF production, plays an important role in renal anemia.     

不同程度慢性阻塞性肺疾病患者血清胎盘生长因子水平的变化及意义

目的:探讨胎盘生长因子(PIGF)在不同程度慢性阻塞性肺疾病(COPD)患者中的水平及意义。方法:本研究应用双抗体夹心法(ELISA)测定PIGF在轻、中、重度COPD患者和健康志愿者(对照组)血清的水平,分析PIGF与1s用力呼气容积占预计值百分比(FEV1%)、肺动脉收缩压(PASP)、动脉血氧分压(PaO2)的相关性。结果:COPD各组PIGF水平显著高于对照组(P<0.01);COPD中度组PIGF水平较轻度组升高(P<0.01);COPD重度组PIGF水平较COPD轻度组和中度组升高(P<0.01);COPD组患者血清PIGF水平与FEV1%呈负相关(r=-0.879,-0.664,均P<0.01),与PASP呈正相关(r=0.85,P<0.01)。结论:PIGF可能在COPD发病机制中起作用。     

Serum levels and half-life of sotalol in chronic renal failure.

The elimination of sotalol was studied in 25 patients with chronic renal failure. All patients were given a single 160 mg dose of sotalol orally and their sotalol serum levels were determined after 4, 6, 8, 10 and 12 hours. The elmination of sotalol was distinctly slower as the serum creatinine concentration rose. The half-lives, calculated graphically, were in lenear ratio to the serum creatinine values (r = 0,91; p less than 0.001). In accordance with the results, it is probable that sotalol accumulates in chronic renal insufficiency. Since beta-blockers may impair renal function, even in therapeutic concentrations, the dosage of sotalol, in particular, must be reduced in patient with kidney disease.     

Serum levels of endostatin, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in patients with acute myocardial infarction undergoing early reperfusion therapy

Angiogenesis is controlled by anti-angiogenic factors as well as by angiogenic factors, such as VEGF (vascular endothelial growth factor) and HGF (hepatocyte growth factor). Endostatin, a potent endogenous angiogenesis inhibitor, is known to inhibit endothelial proliferation and suppress tumour growth. However, to date, little is known about the pathophysiology of endostatin in ischaemia/reperfusion. To investigate the mechanisms of angiogenesis induced by myocardial ischaemia/reperfusion in more detail, we studied the circulating levels of endostatin, VEGF and HGF in 17 patients with acute myocardial infarction, who underwent early reperfusion therapy. In all patients, serum endostatin, VEGF and HGF levels before reperfusion were increased significantly compared with those in 17 control subjects (endostatin, 49.2+/-11.7 ng/ml, but not detectable in controls; VEGF, 685.6+/-150.3 pg/ml compared with 173.7+/-33.6 pg/ml; HGF, 3638+/-1285 pg/ml compared with 59+/-13 pg/ml; values are means+/-S.E.M.). After reperfusion, the serum endostatin and VEGF levels decreased significantly, but still remained higher than those in control subjects (endostatin, 19.6+/-7.0 ng/ml; VEGF, 284.2+/-90.2 pg/ml). In contrast, serum HGF levels increased significantly (15 146+/-2230 pg/ml) after reperfusion. These data indicated that serum levels of endostatin changed in parallel with those of VEGF in response to myocardial ischaemia/reperfusion, and the marked increase in serum HGF levels after reperfusion seemed to be, at least in part, due to heparin administration. Our data offer a possible anti-endostatin therapy in patients with acute myocardial infarction to facilitate collateral vessel formation.     

Systemic administration of naked plasmid encoding hepatocyte growth factor ameliorates chronic renal fibrosis in mice

The progression of chronic renal diseases is considered as an irreversible process that eventually leads to end-stage renal failure characterized by extensive tissue fibrosis. At present, chronic renal fibrosis is incurable and the incidence of affected patients is on the rise worldwide. In this study, we demonstrate that delivery of hepatocyte growth factor (HGF) gene via systemic administration of naked plasmid vector markedly ameliorated renal fibrosis in an animal model of chronic renal disease induced by unilateral ureteral obstruction. A high level of exogenous HGF protein was detected in the obstructed kidneys following intravenous injection of naked plasmid encoding human HGF. Delivery of human HGF gene induced a sustained activation of extracellular signal-regulated kinases-1 and -2 in the obstructed kidneys. Exogenous HGF expression dramatically inhibited alpha-smooth muscle actin expression, attenuated renal interstitial accumulation and deposition of collagen I and fibronectin. In addition, exogenous HGF suppressed renal expression of pro-fibrogenic cytokine TGF-beta1 and its type I receptor in vivo. These results suggest that systemic administration of naked plasmid vector introduces a high level of exogenous HGF to the diseased kidneys, and that HGF gene transfer may provide a novel therapeutic strategy for amelioration of chronic renal fibrosis in vivo.     

Prognostic significance of hepatocyte growth factor and microvessel bone marrow density in patients with chronic myeloid leukaemia

Objective. The aims of the study were: (1) to perform a complex angiogenic assessment in chronic myeloid leukaemia (CML) patients using multiple parameters: bone marrow microvessel density (MVD), bone marrow immunohistochemical cellular expressions of vascular endothelial growth factor (VEGF) and its receptor KDR, as well as hepatocyte growth factor (HGF) and its receptor MET, and the plasma VEGF and HGF; and (2) to determine the clinical significance of these factors for patients with CML. Material and methods. The VEGF and HGF plasma levels were analysed by ELISA in 38 newly diagnosed CML patients. Immunohistochemical methods were used to visualize the MVD as well as the cellular VEGF/KDR and HGF/MET expression. Results. We found an increased MVD, cellular VEGF/KDR and HGF/MET expression and elevated plasma VEGF and HGF in CML patients. The plasma HGF, cellular HGF and MET expression correlated with the CML phase. The plasma HGF correlated with all markers reflecting the tumour burden (leucocytes, blast percentage, splenomegaly and LDH) as well as with the phase of CML and overall survival of the patients. Cox regression analysis determined the prognostic relevance of HGF and MVD parameters, but not for the plasma VEGF and cellular VEGF and KDR. Conclusions. Using a complex angiogenic assessment we determined an increased angiogenesis in CML patients. No prognostic relevance was found for VEGF plasma levels or VEGF/KDR cellular bone marrow expression. The increased cellular HGF and MET expressions could be considered high‐risk factors for these patients. Plasma HGF and MVD were shown to be independent prognostic parameters for patients' survival.     

Serum levels of vascular endothelial growth factor and its receptors in patients with severe autism

Objective:To study vascular endothelial growth factor (VEGF) and its soluble receptors sVEGFR-1 and -2 in autism.Design and methods:We measured serum levels of angiogenic molecules in 22 patients with severe autism and 28 controls.Results:Patients and controls had similar sVEGFR-2 levels, but VEGF levels were lower and sVEGFR-1 higher in patients with autism.Conclusion:The imbalance between VEGF and its receptor sVEGFR-1 may be involved in the pathophysiology of autism.     

Serum zinc levels and urinary zinc excretion in patients with renal transplants.

An investigation into serum and plasma zinc levels and the urinary excretion of zinc in renal allotransplant patients was undertaken. A remarkable number (53%) of low serum and plasma levels of zinc was obtained as well as a distinct increase (37%) in urinary excretion in the 33 patients investigated. Because of the general tendency in these cases to depletion of body stores of zinc, oral supplementation may prove of value.     

血清肝细胞生长因子在新生儿急性肾功能衰竭中的变化及意义

目的探讨新生儿急性肾功能衰竭(ARF)病程中血清肝细胞生长因子(HGF)的动态变化及意义。方法采用酶联免疫吸附法,测定39例ARF新生儿(肾衰组)少尿期、多尿期和恢复期血清HGF含量,并与正常对照组36例新生儿进行比较。结果肾衰组少尿期和多尿期血清HGF水平均显著高于正常对照组[(762.6±200.4)ng/L、(503.1±167.6)ng/L比(417.5±166.3)ng/L;分别为P<0.01和P<0.05],恢复期血清HGF降至正常。肾衰组少尿期血清HGF与同期血尿素氮和血肌酐呈显著正相关(r=0.359,P<0.05;r=0.606,P<0.01)。结论在新生儿ARF病程中血清HGF呈现相应变化,该变化与肾脏的损害及修复过程密切相关。     

胆总管扩张症患儿血清肝细胞生长因子的表达及临床意义

目的探讨血清肝细胞生长因子(HGF)在胆总管扩张症患儿术前及术后的表达情况,为临床治疗及预后的评价提供理论依据。方法选择30例胆总管扩张症患儿作为试验组,分别于术前(术前组)、术后1 d(术后1 d组)、3 d(术后3 d组)及7 d(术后7 d组)采取患儿血清并保存;根据术前有无黄疸分为术前黄疸组(13例)及术前非黄疸组(17例)。同期将30例健康体检患儿血清作为对照组;采用ELISA法检测试验组及对照组HGF血清浓度,对所得数据采用t检验或单因方差分析进行处理。结果术前组、术后1 d组及术后3 d组血清HGF浓度高于对照组,相比较差异有统计学意义[(101.85±46.14)pg/ml vs.(67.57±28.08)pg/ml,P<0.05;(186.02±83.37)pg/ml vs.(67.57±28.08)pg/ml,P<0.05;(119.30±54.83)pg/ml vs.(67.57±28.08)pg/ml,P<0.05]。术后1 d组血清HGF浓度显著高于术前组,相比较差异有统计学意义(P<0.05),术后7 d组血清HGF浓度高于对照组,相比较差异无统计学意义[(72.19±18.53)pg/ml vs.67.57±28.08)pg/ml,P>0.05]。术前黄疸组HGF水平高于术前非黄疸组,相比较差异无统计学意义[(126.54±72.76)pg/ml vs.(86.54±38.96)pg/ml,P>0.05]。结论动态监测胆总管扩张症患儿术前、术后血清HGF浓度,对于了解胆总管扩张症患儿肝功能损害可能有一定的临床应用价值,对于该病的治疗及预后的评价也可能存在一定的应用前景。     

Expression of hepatocyte growth factor, keratinocyte growth factor and their receptors in experimental chronic pancreatitis

BACKGROUND: Hepatocyte (HGF) and Keratinocyte growth factors (KGF) are key factors of tissue organization and regeneration. These peptide growth factors and their receptors c-met and keratinocyte growth factor receptor (KGFR) are overexpressed in pancreatic cancer. AIM: Expression and localization of ligands and receptors were investigated during the development of experimental chronic pancreatitis. METHODS: Chronic pancreatitis was induced in rats by intravenous injection of dibutyltin dichloride. One to 60 days after treatment, the expression of growth factors and receptors was analysed by competitive polymerase chain reaction, Western blot analysis and immunohistochemistry. RESULTS: HGF mRNA expression increased (10-fold) until days 7-14 followed by a decrease to control level. Expression of c-met mRNA constantly increased (15-fold). KGF and KGFR mRNA expression were increased after 14-28 days (5-fold) and then returned to control levels. mRNA expression patterns correlated with changes in the protein expression, whereas protein levels of KGF remained unchanged. Ligands were localized in mesenchymal cells and their receptors on epithelial cells. CONCLUSIONS: The significant increase of HGF and c-met expression suggests an essential role of this growth factor in the morphological changes during the development of chronic pancreatitis. Changes in the expression of KGF and KGFR are less pronounced.     

血清肝细胞生长因子与高血压患者高三酰甘油血症的相关性

目的:观察高三酰甘油血症对高血压患者血清肝细胞生长因子水平的影响。方法:选择2004-09/2005-10安徽医科大学附属医院心内科门诊和保健中心体检患者中资料完整的高血压患者70例,其中单纯高血压患者49例,高血压合并高三酰甘油血症(血三酰甘油浓度>1.70 mmol/L)患者21例,20例血压正常的健康体检者作为正常对照组。所有病例排除继发性高血压、心脏瓣膜病、心肌病、肺源性心脏病、糖尿病、脑血管疾病、心肺肝肾功能不全以及感染、出血、栓塞等全身性疾病,2周内未使用肝素、降压药物以及调脂药物。用双抗体夹心法测定血清肝细胞生长因子水平,同时测定血脂、血尿酸、血糖等指标并询问吸烟史和早发性心血管病家族史。结果:90例受试者全部试进入结果分析。①高血压合并高三酰甘油血症组患者血清肝细胞生长因子水平高于单纯高血压组和正常对照组[(1527.00±327.19),(1337.35±310.29),(789.20±114.59)ng/L,F=38.607,P<0.01];单纯高血压组高于正常对照组(P<0.01)。②除血压和三酰甘油浓度外,3组血脂、血尿酸、血糖、吸烟史和早发性心血管病家族史比较,差异均不显著(P>0.05)。结论:高血压患者血肝细胞生长因子增高,高三酰甘油血症可能会增加高血压患者血肝细胞生长因子水平。     

Acute changes in plasma levels of hepatocyte growth factor during low-density lipoprotein apheresis.

Hepatocyte growth factor (HGF) is a mesenchyme-derived pleiotropic factor, and angiogenesis is included in a variety of its functional effects. HGF levels were measured in 5 sessions of low-density lipoprotein (LDL) apheresis in 3 patients with severe hypercholesterolemia. Blood was collected at the start (T0) and at 1,000 ml (T1), 2,000 ml (T2), and 3,000 ml (T3) plasma treatments. During LDL apheresis, HGF levels increased from 1.59 +/- 0.78 (mean +/- SE, n = 5) ng/ml at T0 to 6.64 +/- 0.97 at T1, 6.28 +/- 0.97 at T2, and 5.20 +/- 0.94 at T3. In one apheresis session, HGF increased immediately at the 100 ml plasma treatment stage. HGF was adsorbed completely by a dextran-sulfate (DS) column. Despite the adsorption by the DS column, HGF in the patient blood increased to the levels with functional effects. The improvement of ischemic symptoms due to LDL apheresis may be related to the angiogenic activities of HGF.     

Serum 25-hydroxyvitamin D in patients with chronic renal disease

Abstract. Serum 25-hydroxyvitamin D (25-OH-D) was measured by means of a sensitive competitive protein binding assay in forty-five patients with conservatively treated renal disease and in fifteen patients on chronic dialysis. The mean concentration of 25-hydroxyvitamin D in twenty-five normal subjects was 41.4 nmol/l with a range from 19.2 to 90 nmol/l. Fourteen patients with chronic pyelonephritis (creatinine clearance over 25 ml/min) had normal serum 25-OH-D. Low values were found in twelve patients with nephrotic syndrome (mean 11.2 nmol/l, range 1–19 nmol/l) and in these subjects the serum 25-OH-D levels were inversely correlated with the 24 h urinary protein loss. In thirteen conservatively treated uraemic subjects without significant proteinuria, the mean 25-OH-D was 29.4 nmol/l (range 18.2–41.4 nmol/l), whereas in six uraemics losing more than 3 g protein in 24 h urine the mean was 14.2 nmol/l, range 5.2–23.2 nmol/l.
Fifteen patients on chronic dialysis were routinely given a multi-vitamin preparation providing 125 nmol (2000 i.u.) vitamin D₃ daily, and their mean 25-OH-D concentration in March 1975 was 51.4 nmol/l. In August 1975, 25-OH-D averaged 89.1 nmol/l suggesting seasonal variation and possible role of endogenous vitamin D production in the prevention of clinical signs of renal osteodystrophy.