Retrospective Analysis Of Clinical Charactors And Prognosis On Lupus Nephritis With Antineutrophil Cytoplasmic Antibodies

BackgroundSystemic lupus erythematosus(SLE) is an autoimmune disease that can affect essentially any organ or tissue. A variety of autoantibodies and immunological abnormalities can be detected in serum of the patient. Autoantibodies profiles are characterized by antinuclear antibodies, anti-ds DNA antibodies and anti-Sm antibodies have high specificity to the diagnosis of SLE. Lupus nephritis(LN) is one of the most serious complications of SLE since it is the major predictor of poor prognosis, and the renal failure caused by the LN is the major death reason of SLE. The pathogenesis of LN is unclear, but most regard it as a kind of immune complexes nephritis. Autoantibodies can be combined in the blood and kidney antigen, then formatting immune complex, activating the complement system, and finally causes inflammation. The presence of autoantibodies directed against several cytoplasmic and nuclear antigens plays a very important role in the pathogenesis of LN.Antineutrophil cytoplasmic autoantibodies(ANCA) are a distinct class of autoantibodies directed against cytoplasmic constituents of human neutrophils, which included proteinase 3(PR3), myeloperoxidase(MPO), cathepsin G, lysozyme, lactoferrin. Since Davis fist reported that ANCA were found in the serum of patients with necrotizing glomerulonephritis, more and more research was focused on the relationship between ANCA and autoimmune disease. ANCA currently has been widely used in the diagnosis of vasculitis, especially for systemic small vasculitis. In 2012, the Chapel Hill Consensus Conference(CHCC) defined ANCA-associated vasculitis as microscopic polyangiitis(MPA), granulomatosis with polyangiitis(GPA) and eosinophilic granulomatosis with polyangiitis(EGPA). It can affect all the small vessels, especially for the kidney. When the renal is affected alone, it is called renal limited vasculitis(RLV).ANCA plays an important role in systemic vasculitis, and vasculitis is the common clinical manifestations in LN patients. Earlier studies have found that ANCA could be detected in the serum of SLE patients, and the positive rate in LN group was obviously higher than that in non-LN group, those patients often developed crescent nephritis, and had poor prognosis. As mentioned above, these reports indicate that ANCA may be involved in the pathogenesis of LN. However, some researchers found there was no correlationship between ANCA and SLE, the clinical manifestations and disease activity index between ANCA-positive and ANCA-negative groups had no significant difference.Whether ANCA was involved in the pathogenesis of LN is still uncertain, and the prognosis of LN patients with ANCA is also unclear. Here we retrospective analysis the clinical data of LN patients. At the same time, we collect the information about the conditions of prognosis, analysis of the risk factors for poor prognosis.Patients and MethodsPatientsA total of 154 Chinese patients, from January 2011 to December 2013, who fulfilled at least four of the 2012 American College of Rheumatology(ACR) revised criteria for the diagnosis of SLE, and had renal involvement confirmed by renal biopsy were enrolled. The drug induced LN and patients who complicated with other autoimmune diseases were excluded. All the 154 patients did not have a history of using propylthiouracil, isoniazide or hydralazine, which could cause ANCA positive.MeasurementsThe patients of demographic and clinical data were reviewed retrospectively for age, gender, medical history, medications, follow-up duration by medical records. Clinical features included butterfly erythema, fever, oral ulcer, arthritis, nervous system disorder, serositis, alopecia, and photosensitivity. Laboratory data contained levels of erythrocyte, leukocyte, platelet, neutrophil to lymphocyte ratio(NLR), hemoglobin, albumin, erythrocyte sedimentation rate, serum creatine, uric acid, complement factors C3, 24-hour proteinuria, autoantibodies, estimated glomerular filtration(e GFR). The classifications of LN, glomerular lesions, renal tubular injury, and renal interstitial lesions were also analyzed. The follow-up information included urine protein, serum creatine and complications.Statistical AnalysisAll statistical analyses were performed using SPSS version 20.0. For continuous variables, datas were expressed as mean+standard deviation, median(range) or median(interquartile range), as appropriate. Categorical variables were reported as number and frequency. One sample K-S test was used to determine the normality of the data distribution. According to their normality, continuous variables were compared with the independent samples t test, paired samples t test or Mann-Whitney U test. Comparisons were based on Chi-square test or Fischer exact test for categorical variables. Kaplan-Meier analysis was used to compare renal survival between the ANCA-positive and ANCA-negative groups. The risk factors of adverse renal outcomes were evaluated by multivariate Cox regression model. Relevant variables significantly associated with adverse renal outcomes by univariate analysis were included in multivariate models. All tests were two-sided, and P< 0.05 was considered significant.Results1.26 out of 154 LN patients(16.88%) were seropositive for ANCA. There were 24 LN patients with MPO-ANCA and in 2 LN patients with PR3-ANCA. 4 men and 22 women were included in the ANCA-psitive group. There were no significant differences of sex, age, disease duration and treatmeant between the ANCA-positive and ANCA-negative group.2. The incidence of alopecia, oral ulcer, photosensitivity and skin lesion, psychosomatic manifestations in ANCA-positive group was significant higher than that in ANCA-negative group(P=0.007, 0.016, 0.022 and 0.028 respectively). There were no significant differences in other clinical features.3.Serum C3 level appeared much lower in ANCA-positive group than that in ANCA-negative group(P=0.034). The positive rate of anti-nucleosome antibodies, anti-histone antibodies, antimitochondrial antibody-M2 and anticardiolipin antibodies were significantly higher in ANCA-positive patients than in ANCA-negative patients(P=0.000, 0.000, 0.032, 0.005 respectively). There was no significant difference about the other laboratory parameters and autoantibodies between the two groups.4.As to the renal pathology, we observed that the distributions of LN classifications were similar in the two groups. The incidence and proportion of glomerular sclerosis were higher in ANCA-positive group than in ANCA-negative group(P=0.003, 0.004 respectively). There was no significant difference in the scores of SLEDAI, AI, CI and TIL between the two groups. Meanwhile, we found that ANCA-positive group had a notable higher score of chronicity index compared with ANCA-negative group(P=0.013).5.All the 26 ANCA-positive patients were following up for 1 to 38 months(mean 15.0+10.6 months). At the end of the study, one patient died; two patients underwent maintenance hemodialysis(one patient was received renal transplantation after 11 months); two patients developed the fifth stage of chronic kidney disease(CKD); another two patients had serum creatine doubling increased; 6 patients reached the complete remission. In the ANCA-negative group, nine patients were lost to follow-up, the remaning 119 patient were following up for 1 to 40 months(mean 17.9+9.8 months). 4 patients died; 3 patients underwent maintenance hemodialysis; 3 patients were developed the fifth stage of CKD; 59 patients were reached the complete remission. Mortality rates between the two groups have no statistical difference, but the complete remission rate in ANCA-negative group was obviously higher than that in ANCA-positive group(χ2=6.060,P=0.014). The cumulative renal survival rate in ANCA-positive group was significantly lower than that in ANCA-negative group(Log-Rank=6.585, P=0.010).6.Univariate Cox regression analysis showed that e GFR [hazard ratio(HR) =0.976, P<0.001], NLR(HR=1.285, P<0.001), ANCA(HR=3.253, P=0.017), crescent formation(HR=2.887, P=0.037) and glomerulosclerosis(HR=2.718, P=0.040) were risk factors for LN renal survival. The e GFR [hazard ratio(HR) =0.982, P=0.011], NLR(HR=1.198, P=0.025) and ANCA(HR=3.019, P=0.035) were independent risk factors of LN renal survival by multivariate Cox regression analysis.Conclusions1.The rate of seropositive for ANCA in LN is 16.88%. The majority of ANCA is MPO-ANCA.2. The incidence of alopecia, oral ulcer, photosensitivity and skin lesion, psychosomatic manifestations was significant higher in ANCA-positive group than that in ANCA-negative group. ANCA-positive group had a significant lower serum C3 level compared with ANCA-negative group. The positive rate of anti-nucleosome antibodies, anti-histone antibodies, antimitochondrial antibody-M2 and anticardiolipin antibodies in ANCA-positive patients were significantly higher than that in ANCA-negative group. Compared with the ANCA-negative group, the incidence and proportion of glomerular sclerosis and the score of chronicity index were significant higher in the ANCA-positve group.3. The cumulative renal survival rate and the complete remission rate in ANCA-positive group were significantly lower than that in ANCA-negative group. Through the multivariate Cox regression analysis, our data had shown that the e GFR, NLR and ANCA were independent risk factors of LN renal survival.4.These results suggest that ANCA should play a role in the pathogenesis of LN. ANCA test should be as a routine examination for the LN patients. Once LN patients with ANCA positive, especially with poor renal function and high NLR, positive treatment should be intervented timely and it should improve the survival rate of patient.