目的 探讨糖尿病肾病(diabetic nephropathy，DN)维持性血液透析(maintenance hemodialysis，MHD)患者转化生长因子(transforming growth factor，TGF)-β1/p38丝裂素活化蛋白激酶(mitogen-activated protein kinase，MAPK)通路与动静脉内瘘(arteriovenous fistulas，AVF)失功的相关性。 方法 回顾性选取2019年6月—2021年6月贵州医科大学附属医院接受AVF手术并行MHD的DN患者为DN组，同期选取非DN的MHD患者为对照1组，非DN的2型糖尿病患者为对照2组。比较3组TGF-β1 mRNA、p38MAPK mRNA水平，Logistic回归分析DN MHD患者AVF失功的影响因素，ROC曲线分析TGF-β1 mRNA、p38MAPK mRNA对AVF失功的预测价值，并比较不同程度主动脉弓钙化患者TGF-β1 mRNA、p38MAPK mRNA水平。 结果 DN组(n=96)TGF-β1 mRNA水平高于对照1组(n=45)、对照2组(n=42)(t1=7.133，P1＜0.001；t2=9.929，P2＜0.001)；DN组p38MAPK mRNA水平高于对照1组、对照2组(t1=5.983，P1＜0.001；t2=8.046，P2＜0.001)。Logistic回归分析显示主动脉弓钙化(OR=5.020，95%CI：2.996～8.413，P＜0.001)、高水平校正血钙(OR=5.080，95% CI：3.026～8.527，P＜0.001)、血磷(OR=3.523，95%CI：2.089～5.943，P＜0.001)、TGF-β1 mRNA(OR=5.371，95%CI：3.197～9.025，P＜0.001)、p38MAPK mRNA(OR=5.636，95%CI：3.339～9.513，P＜0.001)为DN MHD患者AVF失功的危险因素。不同程度主动脉弓钙化患者(分为0级、1级、2级、3级)TGF-β1 mRNA比较：0级＜1级＜2级＜3级(0级与1级比较：t1=2.219，P1=0.033；1级与2级比较：t2=2.650，P2=0.011；2级与3级比较：t3=2.523，P3=0.015)，p38MAPK mRNA比较：0级＜1级＜2级＜3级(0级与1级比较：t1=2.530，P1＜0.001；1级与2级比较：t2=2.066，P2=0.045；2级与3级比较：t3=2.203，P3=0.032)。ROC曲线显示TGF-β1 mRNA、p38MAPK mRNA联合预测DN MHD患者AVF失功的AUC为0.820(95% CI：0.732～0.907)，敏感度为80.65%，特异度为76.40%。 结论 主动脉弓钙化及TGF-β1/p38MAPK通路激活是DN MHD患者AVF失功的独立危险因素，TGF-β1/p38MAPK通路激活可能通过促进主动脉弓钙化诱导AVF失功，TGF-β1、p38MAPK水平对AVF失功具有良好的预测价值。
Objective To study the correlation between TGF-β1/p38 MAPK pathway and arteriovenous fistulas (AVF) dysfunction in diabetic nephropathy (DN) patients on maintenance hemodialysis (MHD). Methods The DN patients undergoing AVF construction surgery and MHD in the Affiliated Hospital of Guizhou Medical University from June 2019 to June 2021 were retrospectively analyzed and defined as DN group. The non-diabetic nephropathy patients on MHD were recruited as control 1 group. The non-DN patients with type 2 diabetes were recruited as control 2 group. The levels of TGF-β1 mRNA and p38 MAPK mRNA were compared among the three groups. Logistic regression was used to identify the influencing factors for AVF dysfunction in DN group. ROC curve was used to evaluate the predictive value of TGF-β1 mRNA and p38 MAPK mRNA for AVF dysfunction. The levels of TGF-β1 and p38 MAPK mRNA were compared in patients with different degrees of aortic arch calcification. Results The level of TGF-β1 mRNA was higher in DN group (n=96) than in control 1 group (n=45; t=7.133, P<0.001) and control 2 group (n=42; t=9.929, P<0.001). The level of p38 MAPK mRNA was also higher in DN group (n=96) than in control 1 group (n=96; t=5.983, P<0.001) and control 2 group (n=42; t=8.046, P<0.001). Logistic regression showed that aortic arch calcification (OR=5.020, 95% CI: 2.996～8.413, P<0.001), higher levels of corrected blood calcium (OR=5.080, 95% CI: 3.026～8.527, P<0.001), blood phosphorus (OR=3.523, 95% CI: 2.089～5.943, P<0.001), TGF-β1 mRNA (OR=5.371, 95% CI: 3.197～9.025, P<0.001), and p38 MAPK mRNA (OR=5.636, 95% CI: 3.339～9.513, P<0.001) were the risk factors for AVF dysfunction in DN group. The degree of aortic arch calcification can be classified as grade 0, grade 1, grade 2 and grade 3. The order of TGF-β1 mRNA level was grade 0 < grade 1 < grade 2 < grade 3 (grade 0/grade 1: t=2.219, P=0.033; grade 1/grade 2: t=2.650, P=0.011; grade 2/grade 3: t=2.523, P=0.015). The order of p38 MAPK mRNA level was also grade 0 < grade 1 < grade 2 < grade 3 (grade 0/grade 1: t=2.530, P<0.001; grade 1/grade 2: t=2.066, P=0.045; grade 2/grade 3: t=2.203, P=0.032). ROC curve showed that the AUC of combined TGF-β1 mRNA and p38 MAPK mRNA to predict AVF dysfunction in DN group was 0.820 (95% CI: 0.732～0.907), with the sensitivity of 80.65%, and specificity of 76.40%. Conclusion Aortic arch calcification and activation of TGF-β1/p38 MAPK pathway are the independent risk factors for AVF dysfunction in DN patients on MHD. Activation of TGF-β1/p38 MAPK pathway may induce AVF dysfunction by promoting aortic arch calcification. TGF-β1 and p38 MAPK levels have a better value for the prediction of AVF dysfunction.
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