Analysis Of Factors Affecting Renal Prognosis In Patients With Lupus Nephriti

Part ⅠInduction therapy on long-term prognosis in active lupus nephritis with poor kidney functionObjectiveLupus nephritis(LN)is one of the most common organ-threatening manifestations of systemic lupus erythematosus(SLE),especially in the Asia-Pacific region(40%-82%),and resulted to the development of chronic kidney disease(CKD),end-stage renal disease(ESRD)and increased morbidity.In the last 50 years,the renal prognosis of LN patients has improved significantly with the use of glucocorticoids(CS)combined with cyclophosphamide(CYC)or mycophenolate mofetil(MMF)as first-line therapy for LN.Despite the introduction of new and effective therapies in the last 20 years,the proportion of patients progressing to ESRD has not decreased,reported to be 10-30%within 15 years.Accordingly,it is critical to identify and save LN patients at high risk of renal deterioration to improve overall prognosis.Patients with poor baseline renal function are among the above-mentioned high-risk groups.It is unclear whether induction treatment would benefit lupus nephritis(LN)with poor renal function,which has been excluded from clinical trials.This study will investigate the efficacy response and explore the predictors of long-term prognosis in patients with LN with poor renal function.MethodsA cohort of 467 biopsy-proven LN cases at Peking Union Medical College Hospital from August 2012 to December 2018 was retrospectively analyzed,from which patients with poor baseline renal function(eGFR 15-60mL/min/1.73m2)and treated with induction therapy were screened for inclusion.Patients were grouped according to the renal outcome of ESRD for comparison of clinicopathological characteristics.Complete response(CR)was defined as proteinuria<0.5g/24 hours,with normal eGFR.Partial response(PR)was defined as ≥ 50%proteinuria reduction to sub-nephrotic levels(<3.5g/24 hours),with normal eGFR.No response was defined as all the other cases.The primary outcome was ESRD.Significant variables were screened by the least absolute shrinkage and selection operator method for the construction of a COX regression model for predicting ESRD and a logistic regression model for predicting NR.The predictive ability of renal CD163+cells for NR was analyzed by immunohistochemical CD 163 staining of renal tissues.ResultsA total of 107 patients(84.1%female,median age 33,IQR 23-46)were included.The level of proteinuria was 6.2g per 24 hours(IQR 3.7-10.3)and the median eGFR was 36.6 ml/min/1.73m2(IQR 27.0-49.4).Renal pathological classification was predominantly typeⅣ(64.5%).As for the induction schemes,71.0%of patients received methylprednisolone pulses,76.6%were treated with large doses of CS combined with CYC(CS-CYC),11.2%combined with MMF(CS-MMF),and 12.2%combined with other immunosuppressants.After 6th month induction therapy,18.7%,38.3%and 43.0%of patients achieved CR,PR and NR,respectively.During a median follow-up of 60(36-84)months,64 patients(59.3%)returned to the normal renal function,while 15 patients(14.0%)progressed to ESRD.The ESRD-free survival rate was significantly lower in the NR group than those of CR and PR(P<0.001).In multivariable analysis,NR at 6th month(HR 17.07,95%CI 2.16 to 135.24,P=0.007),baseline eGFR≤33ml/min/1.73m2(HR 3.50,95%CI 1.04 to 11.73,P=0.042)and fibrous crescent(HR 3.44,95%CI 1.03 to 11.49,P=0.045)independently predicted ESRD(C-index 0.911,0.866 to 0.956).Further,baseline hypertension(HR 2.52,95%CI 0.82 to 8.58,P=0.118),SLE duration(2.52,95%CI 1.01 to 7.23,P=0.048)and chronicity index(HR 1.75,95%CI 1.37 to 2.41,P<0.001)predicted NR at 6 months(C-index 0.833,0.756 to 0.910).In 46 LN patients with renal insufficiency,The mean number of glomerular CD163+cells was 1.4(1.0-3.4)/glomerulus and the mean number of tubulointerstitial CD 163+cells was 172(140-222)/mm2;multivariate logistic regression showed that tubulointerstitial CD163+cells was an independent risk factor for NR at 6 months(HR 5.185,95%CI 1.307-26.793,P=0.028)ConclusionLN patients with severely impaired renal function could benefit from induction treatment.Renal response at 6 months of induction therapy predicts long-term outcome.Part ⅡClinical features and renal prognosis in lupus nephritis patients with persistent antiphospholipid antibodyObjectiveLupus nephritis(LN)with anti-phospholipid antibodies(aPL)are at high risk for renal function progression.The seroprevalence rate of antiphospholipid antibody(aPL)positivity is about 36-49%in Chinese LN patients.Persistent aPL positivity is strongly associated with thrombotic events and adverse obstetric outcomes.Recent studies have further pointed out that LN patients with aPL have more severe clinical manifestations and worse renal prognosis.However,similar renal prognostic studies about LN with aPL are scarce in China.Therefore,this study retrospectively analyzed the clinical characteristics of LN patients with aPL in our center and its impact on the renal prognosis of LN.MethodsA cohort of 467 biopsy-proven LN cases at Peking Union Medical College Hospital from August 2012 to December 2018 was retrospectively analyzed,of whom 378 had complete aPL findings and 33 had persistent positive aPL.120 LN with aPL-negative were matched by sex and age as a control group.The clinical and prognosis of patients in both groups were compared.The primary endpoint was defined as end-stage renal disease(ESRD),and the secondary endpoint was defined as≥ 30%increase in serum creatinine from baseline.Univariable and multivariable COX regression models were constructed to identify risk factors of ESRD.ResultsThere were no significant differences between the two groups in terms of gender,age,duration of LN disease,the baseline laboratory indicators and pathological classification.The aPL-positive group had a lower SLEDAI score(P=0.024),a higher incidence of hemolytic anemia(P=0.006)and thrombotic events(P=0.023)than the control group.The proportion of thrombotic microangiopathy(TMA)lesions was higher in the aPL-positive group than controls(18.2%vs 2.5%,P=0.003).Anticoagulants were used more frequently in the aPL-positive group(60.6%vs.8.3%,P<0.001).After 49(34-67)months of follow-up,4 cases(12.5%)in the aPL-positive group and 9 cases(7.5%)in the control group respectively progressed to end-stage renal disease(P=0.412);while 8 cases(25.0%)in the aPL-positive group and 17 cases(14.2%)in the control group did not reach statistical differences in survival analysis with endpoints of≥30%increase in creatinine from baseline(P=0.172).Multivariate COX regression showed that the risk of serum creatinine elevation in the aPL-positive group was approximately two times higher than in the control group(P=0.079).ConclusionHemolytic anemia,thrombotic events,TMA lesions and anticoagulant use are more common in LN patients with aPL positivity,which has a tendency with a higher risk of increased creatinine.Further study with larger sample size and longer follow-up is in need.Part ⅢBlood microbiomics-based biomarker study of autoimmune nephritis diseaseObjectiveThe conventional concept is that the microbiota in the blood are only related to infectious disease.But in recent years,microbiota have been found in the blood of healthy population,as well as those with obesity,diabetes,cardiovascular disease,liver disease,cancer and other chronic Non-communicable disease.Blood microbiome has been proved to be closely related to systemic inflammation,immunity and metabolism,and can also be used as disease marker.In the field of renal diseases,more studies in recent years have pointed out the important role of microbiota in the mechanism of the disease,but the studies on blood microbiome are still less investigated.However,the role of blood microbiome in autoimmune nephritis(lupus nephritis(LN),IgA nephropathy(IgAN),and membranous nephropathy(MN))has not been investigated.The aim of this study was to investigate the biomarkers of autoimmune glomerulonephritis and their role in the pathogenesis of autoimmune glomerulonephritis based on blood microbiome.MethodsTwenty patients each diagnosed with IgAN,LN,and MN at Peking Union Medical College Hospital from August 2020 to August 2021 served as the disease group and did not receive immunosuppressive therapy for 6 months.Twenty healthy individuals were enrolled in the same period as the control group.Baseline clinicopathological data of the enrolled patients were collected for comparison between groups.Peripheral whole blood specimens were collected for 16S rRNA amplicon sequencing and 16S qPCR quantification,and serum specimens were assayed for endotoxin by ELISA to assess the intestinal mucosal barrier as well as IL-1,IL-6,IL-1β,TNF-α,and INF-γ to assess the inflammatory status of the organism.Strict quality control was performed during the blood microbiome experiments,the operation followed aseptic operation,sterilization of experimental reagents and consumables to reduce the introduction of contamination,adding negative controls during DNA extraction and PCR amplification,and removing contamination signals by means of traceability analysis and biochemical analysis.ResultsThe preliminary experiment included 10 patients with kidney disease and 1 sterile water negative control and the results showed that the number of OTUs in patients was 111(82-163),16S qPCR quantification was 12078(533-30773)copies/ul DNA.The blood microbiome was dominated by the proteobacteria phylum,followed by actinobacteria,bacteroides,acidobacteria,and firmicutes phylum.The composition of the blood microbiome differed between patients with different diseases,with higher abundance and diversity of bacteria in the disease group than in the negative control.Comparisons of differences between groups could not be made due to the limited number of cases.The results of blood microbiomics studies for patients with immune nephritis are not yet available due to the epidemic.ConclusionPre-experimental results showed that the blood microbiomics of patients with kidney disease was dominated by the proteobacteria phylum,and there were some differences in the composition and quantification of blood microbiota between patients with different kidney diseases.Studies on blood microbiomics for patients with immune nephritis are to be completed.