Clinical Research Of Thromboembolic Events In Primary Membranous Nephropathy

Background and ObjectivesThromboembolic events,the well recognized complication of nephrotic syndrome,occur much more frequently in primary membranous nephropathy(PMN)than in other kidney diseases.Large cohort researches that systematically studied about these were still in lack.The aims of this study were to retrospectively assess incidences and characteristics of ATEs and VTEs in patients with PMN in Chinese population,and to identify the predisposing risk factors of the thromboembolic events at this situation.In addition,we tried to explore the effects of medicines such as LMWH/warfarin,aspirin,statin,glucocoticoids and immunosuppressive agents to the thromboembolic events.MethodsA total of 766 consecutive Chinese patients with IMN were enrolled in this retrospective cohort study.The cumulative incidences of newly diagnosed ATEs and VTEs were calculated using Kaplan-Meier methods.Univariable risk prediction models analysis followed by multivariable survival analysis was used to evaluate the potential risk factors of ATE and VTE.Propensity score matching(PSM)model was used to assess effects of prophylaxis use of LMWH/warfarin or aspirin to the thromboembolic events.Roles of administrations of statins,glucocoticoids and immunosuppressive agents were determined.Results1.At 0.5,1,2,3,and 5 years after biopsy diagnosis of PMN,cumulative incidence rates of newly diagnosed ATEs were 4.31%,5.69%,6.25%,7.10%,and 7.95%,while VTEs were 5.87%,6.75%,6.91%,6.96%,and 7.15%,respectively.ATEs were mainly cardiovascular diseases(50%)and thrombotic ischemic stroke(45%),and VTEs were mostly deep vein thrombosis(60%).ATEs were associated with higher level of proteinuria and classic risk factors for atherosclerosis,including age,smoking history,hypertension and prior ATE.Hypoalbuminemia was the dominant independent risk factor for VTE.Besides,VTEs tend to occur more frequently than ATEs when patients were at nephrotic syndrome status.2.In patients with a mean serum albumin level of 22.4±6.4g/L,prophylaxis use of LMWH/warfarin can not reduce the incidences of ATE and VTE(10.8%vs 21.6%,p= 0.21;8.1%vs 10.8%,p= 0.69);Among patients aged 52.3 ± 13.4 y and with a mean serum albumin level of 27.1±5.8g/L,aspirin can lower the risk of VTE(2.1%vs 10.6%,p= 0.02),but seemed to have no obvious effect to the risk of ATE(5.3%vs 7.4%,p= 0.55).3.Multivariable survival analysis model showed that hazard ratio for VTE and ATE in statin users versus non-users was 0.4(95%CI:0.1-0.7,p= 0.03)and 0.8(95%CI:0.6-1.4,p= 0.12),respectively.There is no difference in different intensities of statins in reducing incidence of VTE.High-intensity statins and medium-intensity statins have more advantages than low-intensity stains in reducing incidence of ATE(5.0%vs 4.3%vs 14.3%,p= 0.02).4.Compared with patients treated by prednisone combined with cyclophosphamide,incidences of ATE and VTE were lower in patients treated by prednisone combined with calcineurin inhibitors(2.2%vs 7.5%,p=0.04;2.2%vs 9.5%,p=0.01).Conclusions1.Patients with PMN were at higher risks for ATEs and VTEs,especially within the first 6 months after diagnosis with biopsy.Higher level of proteinuria and classic risk factors for atherosclerosis all were associated with ATEs and hypoalbuminemia could independently predict VTEs,and both of them occurred particularly frequent during the period of nephrotic syndrome.2.In patients with PMN,prophylaxis use of LMWH/warfarin can not reduce the incidences of ATE and VTE;aspirin can lower VTE risk,but seemed to have no obvious effect to the risk of ATE.3.In patients with PMN,the administration of statin can lower the incidence of VTE,and there is no difference in different intensities of statins.Statin also showed the protective effect of ATE,and high-intensity statins and medium-intensity statins have more advantages than low-intensity stains in reducing the incidence of ATE,but still need to be further confirmed.4.Remission of nephrotic syndrome was associated with lower risks of ATE and VTE,and therapeutic regime of prednisone combined with calcineurin inhibitors seemed superior to prednisone combined with cyclophosphamide.