Discovery of NEU1 as a candidatedone. renal biomarker for proliferative lupus nephritis chronicity

ObjectiveProteomic approach was applied to identify candidate biomarkers of chronicity in patients with proliferative lupus nephritis (LN), and their clinicopathological significance and prognostic values were investigated.MethodsThis study recruited 10 patients with proliferative LN and 6 normal controls (NCs) with proteomic data to compare protein expression profiles, 58 patients with proliferative LN and 10 NCs to verify proteomic data by immunohistochemistry, and 14 patients with proliferative LN with urine samples to evaluate the urinary expression of the biomarker by western blot assay. The composite endpoints included end-stage renal disease and ≥50% reduction from baseline estimated glomerular filtration rate (eGFR).ResultsProteomics detected 48 proteins upregulated in the group with chronicity index (CI) ≥1 compared with the CI=0 and NC groups. Further pathway analysis was enriched in ‘other glycan degradation’. Neuraminidase 1 (NEU1), the most predominant protein in the pathway of other glycan degradation, was highly expressed in the kidney of patients with proliferative LN and could co-localise with podocyte, mesangial cells, endothelial cells and tubule cells. NEU1 expression in the tubulointerstitium area was significantly higher in the CI ≥1 group compared with the CI=0 and NC groups. Moreover, NEU1 expression was significantly correlated with serum creatinine value, eGFR and CI scores, respectively. Urinary NEU1 excretion in the CI ≥1 group was higher than in the CI=0 group and was also positively correlated with CI scores. Furthermore, the high expression of renal NEU1 was identified as an independent risk factor for renal prognosis by multivariate Cox regression analysis (HR, 6.462 (95% CI 1.025 to 40.732), p=0.047).ConclusionsRenal NEU1 expression was associated with pathological CI scores and renal outcomes in patients with proliferative LN.

B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial

ObjectiveRandomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies.MethodsPatients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2.ResultsA total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI −3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab.ConclusionsImproved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified.Trial registration numberNCT02550652.

Induction Therapy and Outcome of Proliferative Lupus Nephritis in the Top End of Northern Australia – A single centre study retrospective study

BackgroundLupus nephritis is a common manifestation of Systemic Lupus Erythematosus. Mycophenolate is recommended by guidelines for induction therapy in patients with proliferative lupus nephritis and nephrotic range proteinuria Class V lupus nephritis. Indigenous Australians suffer disproportionally from systemic lupus erythematosus compared to non-Indigenous Australians. MethodsWe retrospectively identified patients with newly diagnosed biopsy-proven class III lupus nephritis, class IV lupus nephritis and class V lupus nephritis with nephrotic range proteinuria from 1st Jan 2010 to 31st Dec 2019 in our institution and examined for the patterns of prescribed induction therapy and clinical outcome. The primary efficacy outcome of interest was the incidence of complete response (CR) and partial response (PR) at one-year post diagnosis as defined by the Kidney Disease: Improving Global Outcome (KDIGO) guideline. Secondary efficacy outcome was a composite of renal adverse outcome in the follow-up period. Adverse effect outcome of interest was any hospitalisations secondary to infections in the follow-up period. Continuous variables were compared using Student’s t-test or Mann-Whitney U-test. Categorical variables were summarised using frequencies and percentages and assessed by Fisher’s exact test. Time-to-event data was compared using the Kaplan-Meier method and Log-rank test. Count data were assessed using the Poisson’s regression method and expressed as incident rate ratio.Results20 of the 23 patients included in the analysis were managed with mycophenolate induction upfront. Indigenous Australian patients (N=15), compared to non-Indigenous patients (N=5) received lower cumulative dose of mycophenolate mofetil over the 24 weeks (375g vs. 256g, p<0.05), had a non-significant lower incidence of complete remission at 12 months (60% vs. 40%, p=0.617), higher incidence of composite renal outcome (0/5 patients vs. 5/15 patients, p=0.20) and higher incidence of infection related hospitalisations, (incident rate ratio 3.66, 95% confidence interval 0.89-15.09, p=0.073). ConclusionMycophenolate as upfront induction in Indigenous Australian patients were associated with lower incidence of remission and higher incidence of adverse outcomes. These observations bring the safety and efficacy profile of mycophenolate in Indigenous Australians into question.

Early predictors of renal outcome in patients with proliferative lupus nephritis: a 36-month cohort study

Objectives To identify predictors of complete renal response (CRR) and renal flares in SLE patients with active proliferative LN. Methods This was a retrospective cohort study over 36 months including patients with biopsy-proven proliferative LN (class III/IV), from two European tertiary centres. CRR and renal flare were defined as proteinuria &lt;0.5 g/day with normal renal function and proteinuria &gt;1 g/day after CRR attainment, respectively. Demographic, clinical and analytic parameters were evaluated as early predictors of renal outcome, using survival analysis. Candidate variables were tested as predictors for CRR at time 0, 3 and 6 months after starting induction treatment. Potential predictors for renal flare were evaluated at time of reaching CRR. Variables with P &lt; 0.10 on univariate analysis with log-rank tests were further tested with multivariate Cox proportional hazards regression models. Results We included 104 patients [81.7% female, mean (s.d.) age at baseline 32.0 (13.3) years]. Over follow-up, 91.7% reached CRR, within a median time of 6.0 months. Proteinuria &lt;2 g/day at baseline [hazard ratio (HR) = 1.80, 95% CI 1.16, 2.79, P &lt; 0.01] and 3 months (HR = 2.32, 95% CI 1.24, 4.32, P &lt; 0.01) after starting induction therapy were independent predictors of CRR. Renal flares occurred in 18.4% of patients reaching CRR, after a mean time of 16.5 (8.6) months. Age up to 25 years at time of LN diagnosis (HR = 5.41, 95% CI 1.72, 16.97, P &lt; 0.01) and positive anti-RNP (HR = 3.52, 95% CI 1.21, 10.20, P = 0.02) were independent predictors of renal flares. Conclusion In patients with SLE and proliferative LN, factors assessed at baseline and 3 months from starting induction treatment can predict CRR and renal flares once CRR is achieved.

Correlation between the clinical remission and histological remission in repeat biopsy findings of quiescent proliferative lupus nephritis

Background The optimal duration of maintenance therapy is controversial in proliferative lupus nephritis (LN). Discordance between clinical parameters of renal remission and histological findings has made repeat biopsy a compulsory tool to confirm the histological remission (HR), but the timing is debatable. Aim of this study was to find the correlation of sustained complete clinical remission (CR) in sever lupus nephritis with histological findings on repeat kidney biopsy and appropriate duration of treatment in maintenance phase after achieving complete clinical remission. Methods Repeated kidney biopsy (biopsy 2) was performed on patients of biopsy proven (biopsy 1) proliferative LN who had been in CR for at least 2-years. The clinical and histologic findings of these groups (biopsy 1 and biopsy 2) were compared. Total 29 patients were included for the final analysis. Group 2 was further divided as per the duration of sustained CR (>48 months & <48 months). Regression analysis were used to find predictors of the HR. Results Average time taken to achieve CR was 9(range 2–24) months. Average duration of follow up and maintenance therapy was 68 ± 17.8 and 62.5 ± 14.2 months respectively. In the repeat kidney biopsy, HR was observed in 93.1% patients. Immunofluorescence study (IF) was normal in 72% of the patients. Normal light microscopy (LM) findings were observed in 58% patients. Transformation from proliferative to nonproliferative LN was noted in 82% cases. Other than the duration of CR on maintenance therapy and blood pressure, rest of the variables failed to predict HR. In sustained remission for more than 48-months group, 100% patients achieved HR whereas only 84% in 24–48-months group. Conclusion Sustained CR on maintenance immunosuppressive therapy for more than 48-months duration predicts HR in repeat kidney biopsy findings in quiescent proliferative LN. Hence the minimum duration of maintenance therapy in proliferative LN should be at least for another 48 months after achieving CR.