Abstract: 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.

Key words: Diabetic nephropathy, Maintenance hemodialysis, Arteriovenous fistula dysfunction, Aortic arch calcification, TGF-β1/p38 MAPK pathway