常染色体显性多囊肾病遗传因素对疾病进展的影响及治疗策略的荟萃分析

发布时间：2018-07-14 22:29

【摘要】：研究目的：常染色体显性多囊肾病（ADPKD）是最常见的单基因遗传性肾病。主要表现为肾脏多发囊肿的不断生长，常在患者50岁左右缓慢进展至终末期肾病(ESRD)。本研究旨在分析：1、内皮型一氧化氮合酶(eNOS)基因多态性对ADPKD患者ESRD发病风险、ESRD发病年龄及高血压发病风险的影响；2、分别评估抑制cAMP通路药物、抗高血压药物和mTOR抑制剂治疗ADPKD的的有效性和安全性；3、比较腹腔镜手术与开腹手术切除ADPKD肾脏的的有效性和安全性。研究方法：计算机检索Medline数据库（1990年-2013年11月）、Embase数据库（1990年-2013年11月）、Google scholar、Web of Science database、中国生物医学文献数据库（1990年-2013年12月）和Cochrane组织RCT注册数据库（2013年第6期）。纳入相关文献进行荟萃分析。结果： 1、共6项研究评估了eNOS基因Glu298Asp多态性与ADPKD患者发生ESRD的风险，GG表型患者相比（GT+TT）表型患者降低了30%的患ESRD的风险(OR=0.70；95%CI，0.53，0.93；P=0.02)，GG相比T等位基因型可以延缓ADPKD患者进入ESRD1.93年（WMD=1.93；95%CI，0.71，3.15；P=0.002），但对ADPKD患者发生高血压风险的影响无统计学意义(OR=1.04；95%CI，0.66，1.66，P=0.86)。 2、关于生长抑素类似物延缓ADPKD共4项RCT研究，生长抑素类似物相比安慰剂能够抑制总肾脏体积（TKV）9%的年增长率（95%CI，-10.33，-7.58）；P 0.001）,降低TKV生长约85.73ml（95%CI，-134.9，-36.57，P 0.0006)，但对延缓GFR减退不具有统计学意义(WMD=0.89ml/min，95%CI，-7.76，-9.54，P=0.84)。托伐普坦可以有效保护ADPKD患者GFR (WMD2.58ml/min，95%CI0.28，4.87，P=0.03)并减少TKV的增长（WMD-138.51ml，95%CI，-162.00，-115.02，P 0.00001）。 3、肾素血管紧张素系统拮抗剂（RAAS-I）相比安慰剂和其他类降压药能够减少GFR下降值5.45ml/min（95%CI，-10.78，-0.11）；P=0.05），降低尿微量蛋白尿水平-18.66mg/d（-36.19，-1.14，P=0.04）。ARB最有可能（33%）成为疗效最好的降压药，疗效顺序从高到低分别为：血管紧张素受体阻断剂、血管紧张素转化酶抑制剂、β受体阻滞剂、安慰剂、利尿剂和钙离子拮抗剂。 4、mTOR抑制剂相比安慰剂不能减少TKV的增长(5项研究，619例患者，WMD-90.01ml，95%CI，-235.49，55.47，P=0.23)，对GFR同样没有显著影响（WMD4.94ml/min，95%CI，-0.81，10.68，P=0.09)。 5、腹腔镜肾切除ADPKD肾脏组患者的平均住院日显著短于开放手术组患者（WMD，-4.38d，95%CI，-5.93，-2.83，P=0.00001），输血风险比值比显著低于开放手术组患者（OR，0.25，，95%CI，0.10，0.62；P=0.003），但总并发症发生比值比没有统计学差异（OR，0.51，95%CI，0.24，1.06）。结论： 1、eNOS基因Glu298Asp多态性中GG表型减缓了ADPKD患者进入ESRD的时间，降低了ESRD的发病风险，但对ADPKD患者高血压的发病无显著影响。 2、生长抑素类似物可以有效抑制ADPKD患者TKV的增长，但对GFR的保护作用有待更长时间随访的研究来证明；托伐普坦是较好的延缓ADPKD患者GFR下降和TKV增长的药物。 3、降压药物延缓ADPKD肾病进展的疗效尚不确定，仍需要更多的RCT来证明。RAAS-I相比其他降压药是最适合ADPKD患者治疗高血压的药物。 4、mTOR抑制剂不能给ADPKD患者带来减少TKV和保护GFR的疗效，临床使用需谨慎。 5、应用腹腔镜肾切除术相比开放手术治疗ADPKD可以减少住院时间，输血风险。但手术时间会延长，两种手术方式的总并发症率无明显差异。
[Abstract]:Objective : autosomal dominant polycystic kidney disease ( ADPKD ) is the most common type of single - gene hereditary nephropathy . It is mainly characterized by the continuous growth of renal multiple cysts , which is slowly progressing slowly to end - stage renal disease ( end - stage renal disease ) at the age of 50 years . The aim of this study is to analyze the effects of 1 , endothelial nitric oxide synthase ( eNOS ) gene polymorphism on the risk of onset , age and risk of hypertension in patients with ADPKD .
2 , respectively evaluating the effectiveness and safety of inhibiting the treatment of ADPKD by the cAMP pathway drugs , the antihypertensive drugs and the mtor inhibitor ;
3 . To compare the efficacy and safety of laparoscopic surgery with open abdominal surgery for ADPKD kidney .

Study Methods : Computer - searched Medline database ( 1990 - November 2013 ) , Embase database ( 1990 - November 2013 ) , Google Analytics , Web of Science database , Chinese Biomedical Literature Database ( 1990 - December 2013 ) , and the RCTs registry database ( Phase 6 , 2013 ) . Meta - analysis was conducted in the relevant literature .

Results :

1 . A total of 6 studies assessed that the Glu298Asp polymorphism of eNOS gene was associated with the risk of patients with ADPKD and the risk of patients with GG phenotype ( GT + TT ) was reduced by 30 % ( OR = 0.70 ;
95 % CI , 0.53 , 0.93 ;
P = 0.02 ) , GG compared with T allele could delay ADPKD patients into ESRD1 . 93 years ( WMD = 1.93 ;
95 % CI , 0.71 , 3.15 ;
P = 0.002 ) , but there was no statistically significant effect on the risk of hypertension in ADPKD patients ( OR = 1.04 ;
95 % CI , 0.66 , 1.66 , P = 0.86 ) .

2 . With respect to somatostatin analogues delayed ADPKD total 4 RCTs , somatostatin analogues inhibited the annual growth rate of 9 % of total renal volume ( TKV ) compared to placebo ( 95 % CI , - 10.33 , - 7.58 ) ;
P 0.001 ) , reduced TKV growth by about 85.73 ml ( 95 % CI , - 134.9 , - 36.57 , P 0.0006 ) , but did not have statistical significance for slowing down GFR ( WMD = 0.89 ml / min , 95 % CI , - 7.76 , - 9.54 , P = 0.84 ) . torvastatin can effectively protect ADPKD patients from GFR ( WMD2.58ml / min , 95 % CI 0.28 , 4.87 , P = 0.03 ) and reduce TKV growth ( WMD - 138.51 ml , 95 % CI , - 162.00 , - 15.02 , P 0.00001 ) .

3 . RAAS - I reduced GFR by 5.45ml / min ( 95 % CI , - 10.78 , - 0.11 ) compared with placebo and other antihypertensive agents ;
P = 0.05 ) , urinary microalbuminuria level - 18.66mg / d ( - 36.19 , - 1.14 , P = 0.04 ) . ARBs are most likely ( 33 % ) to be the best antihypertensive agents for efficacy , ranging from high to low : angiotensin receptor blockers , angiotensin - converting enzyme inhibitors , beta - blocker , placebo , diuretic and calcium ion antagonists .

4 . There was no significant effect on GFR compared to placebo ( 5 studies , 619 patients , WMD - 90.01 ml , 95 % CI , - 235.49 , 55.47 , P = 0.23 ) , which did not significantly affect GFR ( WMD4.94 ml / min , 95 % CI , - 0.81 , 10.68 , P = 0.09 ) .

5 . The average hospitalization days of patients with ADPKD renal resection were significantly shorter than those in open surgery group ( WMD , - 4.38 , 95 % CI , - 5.93 , - 2.83 , P = 0.00001 ) , and the odds ratio of blood transfusion risk was significantly lower than that in open surgery group ( OR , 0.25 , 95 % CI , 0.10 , 0.62 ;
There was no statistical difference ( OR , 0.51 , 95 % CI , 0.24 , 1.06 ) .

Conclusion :

1 . The GG phenotype in the Glu298Asp polymorphism of eNOS gene slowed the time of entry of ADPKD patients into end - stage and reduced the risk of development , but had no significant effect on the onset of hypertension in ADPKD patients .

2 . The growth of TKV in ADPKD patients can be effectively inhibited by somatostatin analogues , but the protective effect on GFR needs to be proved by longer - term follow - up .
torvastatin is a good drug for delaying the decrease in GFR and TKV growth in ADPKD patients .

3 . The efficacy of antihypertensive drugs in delaying the progression of ADPKD nephropathy is uncertain , and more RCTs are needed to demonstrate that RAAS - I is the most suitable drug for the treatment of hypertension in patients with ADPKD .

4 . The effect of reducing TKV and protecting GFR in ADPKD patients is not brought to ADPKD patients , and careful clinical use is needed .

5 . Compared with open surgery , ADPKD can reduce the hospitalization time and blood transfusion risk compared with open surgery , but the operation time can be prolonged . There is no significant difference in the total complication rate of the two procedures .
【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R692

【参考文献】