摘要
目的：本课题依据原发性肾病综合征(PNS)湿热证与感染密切相关,湿热、感染因素对PNS均具有复发、加重、迁延等相似的病理影响,及我们的部分前期临床研究基础,提出了PNS湿热证与炎症因子可能存在一定相关性的假说。以PNS湿热证为研究对象,系统收集6年来我院PNS住院病例,明确湿热证的发病率,湿热因素对PNS病情的影响及PNS湿热证感染发生率,为临床加强清热利湿治疗、提高PNS的防治效果提供理论依据。再进行PNS湿热证与促炎症因子的相关性研究,系统、深入探讨PNS湿热证与促炎症因子的相关性,揭示PNS湿热证的本质及湿热致病的病理机制,促进PNS湿热证诊断的标准化,客观化研究。
方法：本课题先采用横断面、前瞻、回顾性调查研究方法,收集我院2004年1月-2010年1月符合纳入标准的PNS病例的一般情况、症状、体征及部分实验室检查指标,统计近6年来我院PNS湿热证的发病率,分析湿热因素对PNS病情的影响,湿热证与感染并发症的相关性等。再采用前瞻、随机对照的临床研究方法,选择PNS湿热证40例和非湿热证20例,观察两组患者血清hs-CRP、IL-6、NF-κB,尿MCP-1含量的差异；再将湿热证组随机分为对照组和黄葵胶囊治疗组各20例,比较分析两组患者治疗前后湿热证候与促炎症因子水平的变化情况,总体评价湿热证与促炎症因子的相关性。
结果：
(一)原发性肾病综合征湿热证与感染相关性研究
1、PNS证型构成情况比较本研究共纳入病例290例,其中湿热证组118例(40.69%),脾肾阳虚证组43例(14.83%),脾肾气虚证组46例(15.86%),气阴两虚证组33例(11.38%),其他证50例(17.24%)。PNS湿热证的发病率明显高于其他各非湿热证。
2、PNS各组年龄比湿热证组患病年龄26.36±10.80岁,明显小于其他各非湿热证组,经统计学检验,有显著性差异(p<0.05,p<0.01)
3、各组病理类型比较290例PNS有病理报告者133例,占总病例的45.86%。各组主要病理类型：湿热证组轻微病变19例(35.85%),系膜增生性肾炎16例(30.19%)；脾肾阳虚证组系膜增生性肾炎和膜性肾病各7例(各占35.0%)；脾肾气虚证组微小病变7例(36.84%)；气阴两虚证组轻微病变和系膜增生性肾炎各6例(各占28.57%)；其他证组系膜增生性肾炎8例(40.0%)。因各组有病理报告者偏少,未能进行统计学分析。
4、PNS各组实验室指标比较湿热证组中性粒细胞总数(7.94±4.79)×10e9／L、中性粒细胞百分比(69.78±14.05)%、尿蛋白量(7.42±3.59g／24h),较脾肾阳虚证组、脾肾气虚证组、气阴两虚证组、其他证组明显升高,经统计学检验,有统计学意义(P<0.05,P<0.01)。湿热证组血清总蛋白(38.09±6.77g／L),白蛋白(17.19±5.68g／L)较其他四组明显下降；血清总胆固醇(11.50±3.63mmol／L),低密度脂蛋白(7.85±2.99mmol／L)较其他四组显著升高；经统计学检验,均有统计学意义(P<0.05,P<0.01)。
5、湿热证与感染并发症的关系290例PNS中发生感染者124例(42.76%)。湿热证组感染发生率(59.3%)明显高于脾肾阳虚证组(41.9%)、脾肾气虚证组(23.9%)、气阴两虚证组(12.1%)和其他证组(42.0%),经统计学检验,有显著性差异(P<0.05或P<0.01)。
各组感染部位：湿热证组呼吸系统感染55例(78.57%),皮肤感染11例(15.71%),尿路及胃肠道感染各4例(分别占5.71%),其他部位感染2例(2.86%),两部位以上感染6例(8.57%)。其余各组均以呼吸系统感染最多见。各组感染部位经统计学处理,无显著性差异(P>0.05)。
(二)原发性肾病综合征湿热证与促炎症因子的相关性研究
1、湿热证组与非湿热证组促炎症因子检测结果比较
湿热证组血hs-CRP(3.79±1.43ug／L)明显高于非湿热证组(2.89±0.96 ug／L)；湿热证组尿MCP-1(32.55±5.90 pg／ml)亦高于非湿热证组(29.12±3.95 pg／ml),经统计学检验,有统计学意义(P<0.05,P<0.05)。
湿热证组血清IL-6(43.47±7.21 pg／ml)明显高于非湿热证组(35.77±5.27pg/ml)；湿热证组NF-κB活性(0.85±0.22)亦高于非湿热证组(0.66±0.20),经统计学处理,有显著性差异(P<0.01,P<0.01)。
2、湿热证治疗前两组症候积分及促炎症因子含量比较
治疗前湿热证治疗组、对照组症候积分分别为4.50±0.80,4.58±1.20,经统计学检验,无显著性差异(P>0.05)。治疗前治疗组hs-CRP.IL-6含量分别为3.69±1.42 ug／L,41.51±6.35 pg／ml,尿MCP-1含量为34.30±5.10pg/ml,PBMC NF-κB活性为0.89±0.24；对照组hs-CRP、IL-6含量分别为3.89±1.47 ug／L,45.44±7.64 pg／ml,尿MCP-1为30.81±6.25 pg／ml,PBMC NF-κB活性为0.81±0.19,经统计学检验,两组上述指标均无统计学意义(P>0.05)。
3、湿热证治疗后两组症候积分及促炎症因子水平比较
湿热证治疗4周后,治疗组症候积分为2.45±0.99,对照组症候积分为3.85±1.30,两组症候积分与治疗前相比均明显下降,经统计学检验,有显著性差异(P<0.01,P<0.05)；治疗后治疗组症候积分与对照组相比亦明显下降,经统计学检验,有显著性差异(P<0.01)。
治疗4周后治疗组与对照组hs-CRP含量分别为2.63±0.67 ug／L,3.32±0.89ug／L,与治疗前比较两组hs-CRP含量均显著下降,经统计学检验,有统计学意义(P<0.01,P<0.05)；治疗后两组hs-CRP含量比较,治疗组明显低于对照组,经统计学检验,有统计学意义(P<0.01),显示治疗组hs-CRP水平下降更明显。
治疗后治疗组与对照组NF-κB活性分别为0.54±0.19,0.68±0.23,两组NF-κB活性与治疗前相比均显著下降,经统计学检验,有统计学意义(P<0.01,P<0.05)；治疗后治疗组NF-κB活性明显低于对照组,经统计学检验,有显著性差异(P<0.05)。
治疗后治疗组IL-6含量为23.36±3.64 pg／ml,对照组IL-6含量为34.68±6.79pg／ml,与治疗前相比两组IL-6含量均显著下降,经统计学检验,有统计学意义(均P<0.01)；治疗后治疗组IL-6含量明显低于对照组,经统计学检验,有显著性差异(P<0.01)。
治疗后治疗组与对照组MCP-1含量分别为22.17±3.67pg／ml,25.50±5.02pg／ml,两组MCP-1含量与治疗前相比均显著下降,经统计学检验,有统计学意义(均P<0.01)；治疗后治疗组MCP-1含量明显低于对照组,经统计学检验,有显著性差异(P<0.05)。
治疗结束时对照组和治疗组各选取10例检测PBMC中IL-6 mRNA表达水平。结果治疗组IL-6 mRNA表达水平(0.74±0.19)明显低于对照组(0.96±0.23),经统计学检验,有显著性差异(P<0.05)。与血清IL-6检测结果变化相同。
4、湿热证与24h尿蛋白量、NF-κB活性、血清IL-6、尿MCP-1含量相关性分析
分析40例PNS湿热证患者治疗前症候积分与24h尿蛋白量、NF-κB活性、血清IL-6、尿MCP-1含量的之间相关性,结果表明,湿热证症候积分与尿蛋白量有显著正相关(r=0.46,p<0.01),与NF-κB活性、血清IL-6、尿MCP-1水平亦呈正相关(r分别为0.52,0.53,0.42,均p<0.01)。
结论：
1、通过对2004.1-2010.1近6年来我院290例PNS患者统计分析发现,湿热证是原发性肾病综合征的主要中医证型之一,本研究其发生率为40.69%。
2、通过对PNS湿热证与非湿热证病例尿蛋白、血清蛋白、血脂、感染发生率等资料分析结果表明,湿热因素是加重PNS病情的重要原因,湿热证与感染密切相关。
3、通过对PNS湿热证组和非湿热证组促炎症因子hs-CRP、IL-6、MCP-1、NF-κB水平差异的比较,PNS湿热证治疗组与对照组治疗前后症候积分和促炎症因子水平的变化及湿热证症候积分与促炎症因子水平相关性分析,结果显示PNS湿热证hs-CRP、IL-6、MCP-1、NF-κB等促炎症因子水平异常增高,PNS湿热证与促炎症因子水平增高具有一定的相关性。
Objective:According to Damp-heat syndrome is closely related to infection in primary nephrotic syndrome (PNS), Damp-heat and infection have a similar pathological effects on PNS such as relapse, condition deteriorated and persistent, and some of our pre-clinical research, this study presents a hypothes that PNS Damp-heat syndrome may be related with inflammatory cytokines. We chose PNS Damp-heat syndrome patients as research objects, systematically collected PNS cases nearly 6 years in our hospital, observed Damp-heat syndrome incidence rate, the impact of Damp-heat factor on PNS conditions and infection rate in Damp-heat syndrome cases, in order to provide a theoretical basis for clinical treatment of strengthening clearing away heat and draining dampness and improve therapeutic efficacy. Further the correlation between PNS Damp-heat syndrome and pro-inflammatory cytokines was studied to systemicly and thoroughly investigate the relevance of PNS Damp-heat syndrome and pro-inflammatory factors, reveal the nature of PNS damp-heat syndrome and the pathogenesis, and promote the diagnosis of PNS Damp-heat syndrome standardized and objective.
Methods:Using cross-sectional, prospective, retrospective study methods, we collected PNS cases met the inclusion criteria from 2004.1 to 2010.1 in our hospital, investgated the patients in general, symptoms, signs, and some laboratory indicators, counted the incidence of Damp-heat syndrome, analyze the influence of Damp-heat on patient's condition, and correlation between Damp-heat syndrome and infection. Then using prospective, randomized controlled clinical research methods, we selected 40 Damp-heat syndrome cases and 20 non Damp-heat syndrome cases, observed the difference between the two groups in serum hs-CRP, IL-6, NF-κB and urine MCP-1 levels; again the Damp-heat syndrome group was randomly divided into control group and Huangkui Capsule treatment group,20 patients in each, compared the changes of pro-inflammatory cytokines and Damp-heat syndrome in each group before and after treatment, overall evaluated the correlation between pro-inflammatory cytokines and Damp-heat syndrome.
Result:
㈠The correlational study between PNS Damp-heat syndrome and infection
1. The comparison of PNS syndrome composition
This study included 290 cases, in which Damp-heat syndrome group 118 cases (40.69%), deficiency of spleen and kidney yang syndrome group 43 cases (14.83%), asthenia of spleen and kidney qi syndrome group 46 cases (15.86%), deficiency of both qi and yin syndrome group 33 cases (11.38%), the other syndrome group 50 cases (17.24%). Damp-heat syndrome incidence was significantly higher than that Damp-heat syndrome in PNS cases.
2. The comparison of age among all syndrome groups suffer from PNS
The age of Damp-heat syndrome group was 26.36±10.80 years old, which is significantly younger than that of the other four non Damp-heat syndrome groups, by statistical tests, there were significant difference (p<0.05, p<0.01)).
3. The comparison of renal biopsy type among groups
133 of 290 PNS cases had renal biopsy reports, accounting for 45.86% of total cases. The main pathological types in each group:Damp-heat syndrome group included 19 cases(35.85%) of Glomerular minor lesion,16 cases(30.19%) of Mesangial proliferative glomerulonephritis, deficiency of spleen and kidney yang syndrome group included 7 cases (35.0%, respectively) of Mesangial proliferative glomerulonephritis and Membranous nephropathy respectively, asthenia of spleen and kidney qi syndrome group contained 7 cases (36.84%) of Minimal change nephropathy, deficiency of both qi and yin syndrome group included 6 cases (28.57%, respectively) of Glomerular minor lesion and Mesangial proliferative glomerulonephritis respectively, the other syndrome group contained 8 cases (40.0%) of Mesangial proliferative glomerulonephritis. In each group there were few renal biopsy to be statistically analyzed.
4. The comparison of laboratory indicators among PNS syndrome groups
The total number of neutrophils (7.94±4.79)×10e9/L, neutrophil percentage (69.78±14.05)%, urinary protein (7.42±3.59) g/24h of Damp-heat syndrome group were significantly higher, compared with those of deficiency of spleen and kidney yang syndrome group, asthenia of spleen and kidney qi syndrome group, deficiency of both qi and yin syndrome group and the other syndrome group. By statistical tests, there were significant difference (P<0.05, P<0.01). The serum total protein (38.09±6.77)g/L, albumin (17.19±5.68)g/L of Damp-heat syndrome group were obviously lower than those of the other four groups, the serum total cholesterol (11.50±3.63)mmol/L, low density lipoprotein (7.85±2.99) mmol/L of Damp-heat syndrome group were significantly higher than those of the other four groups, by statistical tests, there were statistical significance (P<0.05, P<0.01).
5. The relationship between Damp-heat syndrome and infection
In all 290 PNS patients there were 124 infection cases (42.76%). The infection rate in Damp-heat syndrome group (59.3%) was significantly higher than in deficiency of spleen and kidney yang syndrome group (41.9%), asthenia of spleen and kidney qi syndrome group(23.9%), deficiency of both qi and yin syndrome group(12.1%) and the other syndrome group(42.0 %).By statistical tests, there were significant differences (P<0.05, P<0.01).
Infection sites in each group:Damp-heat syndrome group includes 55 cases (78.57%) of respiratory infection,11 cases of skin infection (15.71%), 4 cases of urinary tract and gastrointestinal infection each (5.71%, respectively),2 cases of other infection sites (2.86%),6 cases of two or more infection sites (8.57%). Respiratory system is the most common infection sites in the other four non Damp-heat syndrome groups. Infection sites in each group showed no statistical difference (P>0.05).
㈡The correlational research between PNS Damp-heat syndrome and pro-inflammatory cytokines
1.The comparison of pro-inflammatory cytokines expression levels between Damp-heat syndrome group and non Damp-heat syndrome
The serum hs-CRP (3.79±1.43ug/L) content was significantly higher in Damp-heat syndrome group than in non Damp-heat syndrome group (2.89±0.96 ug/L); urinary MCP-1 (32.55±5.90 pg/ml) content was also higher in Damp-heat syndrome group than in non Damp-heat syndrome group (29.12±3.95 pg/ml). By Statistical analysis, there were significant difference (P<0.05,P<0.05).
The serum IL-6 (43.47±7.21pg/ml) level of Damp-heat syndrome was significantly higher than that of non Damp-heat syndrome group (35.77±5.27pg/ml); also the NF-κB activity (0.85±0.22) of Damp-heat syndrome group was higher than hat of non Damp-heat syndrome group (0.66±0.20), the statistical tests showed there were significant difference (P<0.01,P<0.01).
2. The comparison of Damp-heat symptom scores and pro-inflammatory cytokines levels in treatment group and control group before treatment
Before treatment, the Damp-heat symptom scores in treatment group was 4.50±0.80, in control group was 4.58±1.20, there were no significant difference (P> 0.05). In treatment group, the serum hs-CRP, IL-6 contents respectively were 3.69±1.42 mg/L,41.51±6.35pg/ml, urine MCP-1 content was 34.30±5.10pg/ml, PBMC NF-κB activity was 0.89±0.24. In control group, the serum hs-CRP, IL-6 expression levels respectively were 3.89±1.47mg/ L,45.44±7.64 pg/ml, urinary MCP-1 content was 30.81±6.25 pg/ml, PBMC NF-κB activity was 0.81±0.19. The statistical tests showed there were no difference between the two groups on these indicators (P>0.05)
3. The comparison of Damp-heat symptom scores and pro-inflammatory cytokines levels in treatment group and control group after treatment
After treatment for 4 weeks, Damp-heat symptom score in treatment group was 2.45±0.99, in control group was 3.85±1.30, symptom scores in the two groups were significantly decreased compared with treatment before, by statistical test, there were significant differences (P<0.01, P<0.05). After treatment Damp-heat symptom score in treatment group was lower than in control group, by statistical test, there was significant differences (P<0.01).
After treatment for 4 weeks, the serum hs-CRP level in treatment group and control group was respectively 2.63±0.67ug/L,3.32±0.89ug/L. Compared with treatment before, the serum hs-CRP level in the two groups were significantly decreased, by statistical test, there were statistically significant (P<0.01, P<0.05). The serum hs-CRP level in treatment group was significantly lower than in control group, by statistical test,there was statistically significant (P<0.01).
After treatment NF-κB activity in treatment group and control group was respectively 0.54±0.19,0.68±0.23, NF-κB activity in the two groups were significantly decreased compared with treatment before (P<0.01, P<0.05). NF-κB activity in treatment group was also lower than in control group, by statistical test, there was statistically significant (P<0.05).
After treatment the serum IL-6 level in treatment group was 23.36±3.64pg/ml, in control group was 34.68±6.79pg/ml, the serum IL-6 level in the two groups were significantly decreased compared with treatment before, the statistical tests showed there were significant difference (all P<0.01). The serum IL-6 in treatment group was significantly lower than in control group, by statistical test, there were significant differences (P<0.01).
MCP-1 levels in treatment group and control group was respectively 22.17±3.6pg/ml,25.50±5.02pg/ml, there were significantly decreased compared with treatment before in the two groups, by statistical test, there were significant differences (all P<0.01). MCP-1 levels in treatment group was lower than in control group, the statistical tests showed there was significant difference (P<0.05).
At the end of the treatment, the control group and the treatment group were respectively selected 10 cases to detect PBMC IL-6 mRNA expression, the result showed that IL-6 mRNA expression level (0.74±0.19) was significantly lower in treatment group than in control group (0.96±0.23), and there were statistically significant difference (P<0.05).
4. The correlation analysis between Damp-heat factors and 24h urinary protein, NF-κB activity, serum IL-6 and urine MCP-1 content By correlation analysis of 40 damp-heat syndrome cases between damp-heat symptom scores and 24h urinary protein, damp-heat symptom scores and NF-κB activity, serum IL-6 and urine MCP-1 content before treatment, the results showed that damp-heat symptom scores was significantly positively correlated with 24h urinary protein (r=0.46,p<0.01), it also positively correlated with NF-κB activity, serum IL-6 and urine MCP-1 content (r Respectively=0.52,0.53,0.42, all p<0.01).
Conclusion:
1.By analysing 290 PNS cases from 2004.1 to 2010.1 in our hospital, the showed showed that Damp-heat syndrome is the principal syndrome of PNS, the occurrence in this study was 40.69%.
2. From the data of PNS cases'urinary protein, serum protein, lipids, incidence of infection, etc, the results showed that Damp-heat factor is an important reason leading to PNS patients'condition worsen. Damp-heat syndrome and infection are closely interrelated.
3. Though comparing the levels of hs-CRP, IL-6, NF-κB, MCP-1 between Damp-heat syndrome group and non Damp-heat syndrome group, comparing changes of Damp-heat symptom scores and pro-inflammatory cytokines expression in Damp-heat syndrome treatment group and control group before and after treatment, analyzing the correlation between Damp-heat symptom scores and pro-inflammatory cytokines,the study showed that hs-CRP、IL-6、MCP-1-. NF-κB in Damp-heat syndrome cases abnormally increase, PNS Damp-heat syndrome is closely related to pro-inflammatory cytokines.
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