目的 探讨罗沙司他(roxadustat，Rox)对腹膜透析(peritoneal dialysis,PD)患者残余肾功能(residual renal function,RRF)的干预作用及可能的机制。 方法 行PD治疗的患者78例，分为红细胞生成素(erythropoiesis stimulating agent,ESA)治疗组(ESA组)和Rox治疗组(Rox组)。检测尿8-羟基脱氧鸟苷酸(8-hydroxydeoxyguanosine，8-OHdG)、β2-微球蛋白(β2-microglobulin,β2-MG)、N-乙酰-β氨基葡萄糖苷(N-acetyl-βglucosaminidase,NAG)酶、视黄醇结合蛋白(retinol binding protein,RBP)，血单核细胞核因子E2相关因子2(nuclear factor-erythoid2 related factor-2, Nrf2)mRNA及血红素氧合酶1(heme oxygenase-1,HO-1)mRNA。比较治疗后上述指标的差异，将Nrf2 mRNA、HO-1 mRNA表达水平及尿8-OHdG分别与其余指标做相关性分析。 结果 治疗后，Rox组尿 β2-MG、NAG酶、RBP及8-OHdG较治疗前下降(t=3.751、2.522、3.292、3.829,P＜0.001、0.014、0.002、＜0.001)，且低于ESA组(t=3.889、1.627、3.694、2.769，P＜0.001、0.035、＜0.001、P=0.007)，而Nrf2 mRNA及HO-1mRNA表达水平较治疗前升高(t=2.797、1.724，P=0.007、0.032)，且高于ESA组(t=3.507、2.087，P=0.001、0.040)，治疗后ESA组RRF高于ESA组(t=4.710，P＜0.001)。Nrf2 mRNA表达水平与尿β2-MG、NAG酶、RBP及8-OHdG呈负相关(r=-0.617、-0.511、-0.598、-0.591，P＜0.001、0.001、＜0.001、＜0.001)，与RRF呈正相关(r=0.579，P＜0.001)。HO-1 mRNA表达水平与尿β2-MG、RBP及8-OHd呈负相关(r=-0.668、 -0.406、0.606，P＜0.001、0.013、＜0.001)，与RRF呈正相关(r=0.532，P=0.001)。尿8-OHdG表达水平与尿β2-MG、NAG酶及RBP表达水平呈正相关(r=0.456、0.453、0.639，P=0.005、0.005、＜0.001)，与肾小管上皮细胞呈负相关(r=-0.343，P=0.038)。 结论 Rox可能通过活化Nrf2/HO-1信号通路，抑制氧化应激反应而减轻PD患者肾小管上皮细胞损伤，进而延缓RRF下降。
Objective To investigate the effect of Roxadustat (Rox) on residual renal function (RRF) in patients undergoing peritoneal dialysis (PD) and its possible mechanism. Methods A total of 78 patients undergoing PD were divided into erythropoietin (ESA) treatment group (ESA group) and Rox treatment group (Rox group). Urinary 8-hydroxydeoxyguanosine (8-OHdG), β2-microglobulin (β2-MG), N-acetyl-β glucosamine glucosidase (NAG) enzyme, retinol binding protein (RBP), blood Nrf2 mRNA and HO-1 mRNA were measured. These laboratory parameters were compared between the two groups before and after treatment. The correlations of the laboratory parameters with the levels of Nrf2 mRNA, HO-1 mRNA and urinary 8-OHdG were analyzed. Results At the end of follow-up in Rox group, urinary β2-MG, NAG enzyme, RBP and 8-OHdG were significantly lower than those before treatment (t=3.751, 2.522, 3.292 and 3.829 respectively; P＜0.001, =0.014, =0.002 and ＜0.001 respectively), and were significantly lower than those in ESA group (t=3.889, 1.627, 3.694 and 2.769 respectively; P＜0.001, =0.035,＜0.001 and P=0.007 respectively); while Nrf2 mRNA and HO-1 mRNA were significantly higher than those before the treatment (t=2.797 and 1.724 respectively; P=0.007 and 0.032 respectively) and those in ESA group (t=3.507 and 2.087 respectively, P=0.001 and 0.040 respectively). After the treatment, RRF was significantly higher in Rox group than in ESA group (t=4.710, P＜0.001). Nrf2 mRNA was negatively correlated with urinary β2-MG, NAG enzyme, RBP and 8-OHdG (r=-0.617, -0.511, -0.598 and -0.591 respectively; P＜0.001, =0.001, ＜0.001 and ＜0.001 respectively), and positively correlated with RRF (r=0.579, P＜0.001). HO-1 mRNA was negatively correlated with urinary β2-MG, RBP and 8-OHdG (r=-0.668, -0.406 and 0.606 respectively; P＜0.001, =0.013 and ＜0.001 respectively), and positively correlated with RRF (r=0.532, P=0.001). Urinary 8-OHdG was positively correlated with urinary β2-MG, NAG enzyme and RBP (r=0.456, 0.453 and 0.639 respectively; P =0.005, =0.005 and ＜0.001 respectively), and negatively correlated with RRF (r=-0.343, P=0.038). Conclusion Rox may alleviate the damage of renal tubular epithelial cells and protect RRF in PD patients by activating Nrf2/HO-1 signal pathway and inhibiting oxidative stress reaction.
[1]Assimon MM,Flythe JE.Ultrafiltration Rate and Residual Kidney Function Decline: Yet Another Good Reason to Ask About Urine[J].Am J Kidney Dis,2020,75(3): 322-324.
[2]Schwab S,Kleine CE,B?s D,et al.Beta-trace protein as a potential biomarker of residual renal function in patients undergoing peritoneal dialysis[J].BMC Nephrol,2021,22(1):87-95.
[3]Yu J,Zhou Q,Xu Y,et al.The Relationship Between Serum Folate Level and Residual Renal Function in CAPD Patients[J].Int J Gen Med,2022,15(2): 6977-6984.
[4]Canaud B,Kooman JP,Selby NM,et al.Dialysis-Induced cardiovascular and multiorgan morbidity[J].Kidney Int Rep,2020,5(11):1856-1869.
[5]Kobayashi T,Nakamura T,Uematsu M,et al.Evaluation of renal tubulointerstitial damage as a residual renal risk factor for adverse cardiac events in patients with myocardial infarction[J].J Cardiol,2021,78(2):114-119.
[6]Flythe JE,Chang TI,Gallagher MP,et al.Blood pressure and volume management in dialysis:conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference[J].Kidney Int,2020,97(5):861-876.
[7]Yang C,Ma X,Zhao W,et al.A longitudinal analysis of the relationship between serum uric acid and residual renal function loss in peritoneal dialysis patients[J]. Ren Fail,2020,42(1):447-454.
[8]Chen H,Jin G.Downregulation of Salusin-β protects renal tubular epithelial cells against high glucose-induced inflammation, oxidative stress, apoptosis and lipid accumulation via suppressing miR-155-5p[J].Bioengineered,2021,12(1): 6155-6165.
[9]Yu SM,Bonventre JV.Acute kidney injury and maladaptive tubular repair leading to renal fibrosis[J].Curr Opin Nephrol Hypertens,2020,29(3):310-318.
[10]Li X,Jiang B,Zou Y,et al.Roxadustat (FG-4592) facilitates recovery from renal damage by ameliorating mitochondrial dysfunction induced by folic acid[J].Front Pharmacol,2022,12:788977.
[11]Wu T,Qi YY,Ma S,et al.Efficacy of Roxadustat on anemia and residual renal function in patients new to peritoneal dialysis[J]. Ren Fail,2022,44(1):529-540.
[12]赵英政,常美玉,徐光翠等.矽肺患者PBMCs中LIAS和NRF2的表达及其与矽肺的相关性[J].中华劳动卫生职业病杂志,2021,39(12):893-898.
[13]Rayego-Mateos S,Campillo S,Rodrigues-Diez RR,et al.Interplay between extracellular matrix components and cellular and molecular mechanisms in kidney fibrosis[J].Clin Sci (Lond),2021,135(16):1999-2029.
[14]Wang Y,Huang M,Du X,et al.Renal tubular cell necroptosis:A novel mechanism of kidney damage in trichloroethylene hypersensitivity syndrome mice[J].J Immunotoxicol,2021,18(1):173-182.
[15]Andreucci M,Faga T,Pisani A,et al.The ischemic/nephrotoxic acute kidney injury and the use of renal biomarkers in clinical practice[J].Eur J Intern Med,2017, 39(11):1-8.
[16]Mohkam M.Novel urinary biomarkers for diagnosis of acute pyelonephritis in children[J].Iran J Kidney Dis,2020,14(1):1-7.
[17]Chandiramani R,Cao D,Nicolas J,et al.Contrast-induced acute kidney injury[J]. Cardiovasc Interv Ther,2020,35(3):209-217.
[18]Li Z,Lu S,Li X.The role of metabolic reprogramming in tubular epithelial cells during the progression of acute kidney injury[J].Cell Mol Life Sci,2021, 78(15):5731-5741.
[19]Angelova PR,Esteras N,Abramov AY.Mitochondria and lipid peroxidation in the mechanism of neurodegeneration: Finding ways for prevention[J].Med Res Rev, 2021,41(2):770-784.
[20]Lu J,Zhao Y,Liu M,et al.Toward improved human health:Nrf2 plays a critical role in regulating ferroptosis[J].Food Funct,2021,12(20):9583-9606.
[21]Ebert T,Neytchev O,Witasp A,et al.Inflammation and Oxidative Stress in Chronic Kidney Disease and Dialysis Patients[J].Antioxid Redox Signal,2021,35(17): 1426-1448.
[22]Stenvinkel P,Chertow GM,Devarajan P,et al.Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2[J].Kidney Int Rep,2021,6(7): 1775-1787.
[23]Cioffi F,Adam RHI,Bansal R,et al.A Review of Oxidative Stress Products and Related Genes in Early Alzheimer's Disease[J].J Alzheimers Dis,2021,83(3): 977-1001.
