Treatment Of Lupus Nephritis Research Articles

Reversible dysregulation of renal circadian rhythm in lupus nephritis

BackgroundWe have found disruption of expression of major transcriptional regulators of circadian rhythm in the kidneys of several mouse models of lupus nephritis. Here we define the consequence of this disturbance with respect to circadian gene expression and renal homeostatic function in a mouse model of lupus nephritis.MethodsMolecular profiling of kidneys from 47 young and 41 nephritic female NZB/W F1 mice was performed at 4 hourly intervals over a 24 h period. Disruption of major circadian transcriptional regulators was confirmed by qPCR. Molecular data was normalized and analyzed for rhythmicity using RAIN analysis. Serum aldosterone and glucose and urine sodium and potassium were measured at 4 hourly intervals in pre-nephritic and nephritic mice and blood pressure was measured every 4 h. Analyses were repeated after induction of complete remission of nephritis using combination cyclophosphamide and costimulatory blockade.ResultsWe show a profound alteration of renal circadian rhythms in mice with lupus nephritis affecting multiple renal pathways. Using Cosinor analysis we identified consequent alterations of renal homeostasis and metabolism as well as blood pressure dipper status. This circadian dysregulation was partially reversed by remission induction therapy.ConclusionsOur studies indicate the role of inflammation in causing the circadian disruption and suggest that screening for loss of normal blood pressure dipping should be incorporated into LN management. The data also suggest a potential role for circadian agonists in the treatment of lupus nephritis.

Treatment for Severe Lupus Nephritis: A Cost-Effectiveness Analysis in China.

Background: Lupus nephritis (LN) is the most common secondary glomerular diseases that will cause end-stage renal disease (ESRD) and renal-related death. The cost-effectiveness of various treatments for LN recommended by official guidelines has not been investigated in China. Our study is to evaluate clinical prognosis and cost-effectiveness of the current treatments for severe LN.Methods: A Markov model was simulated for 1,000 LN patients of 30 years old, over a 3-years and 30-years lifetime horizon respectively. We assessed the cost-effectiveness of six therapeutic strategies from a societal perspective, with cyclophosphamide (CYC) or mycophenolate mofetil (MMF) induction therapy followed by CYC, MMF or azathioprine (AZA) maintenance therapy. Main outcomes included quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and clinical prognosis. One and three times gross domestic product (GDP) per capita were used as the willingness-to-pay (WTP) thresholds. We also carried out sensitivity analysis under a lifetime horizon.Results: Compared with the baseline strategy of CYC induction and maintenance, for a 3-years horizon the most cost-effective strategy was CYC induction and AZA maintenance with $448 per QALY gained, followed by MMF induction and AZA maintenance which however was not cost-effective under the one times GDP per capita WTP threshold. For a lifetime horizon, CYC induction and AZA maintenance remained the most cost-effective strategy but MMF induction and maintenance became cost-effective under the one times GDP per capita WTP threshold and achieved a higher complete remission rate (57.2 versus 48.9%) and lower risks of ESRD (3.3 versus 5.8%) and all-cause mortality (36.0 versus 40.8%). The risk of developing ESRD during maintenance was the most influential parameter affecting ICER.Conclusions: The strategy of CYC induction followed by AZA maintenance was the most cost-effective strategy in China for short-term treatment, while the strategy of MMF in both induction and maintenance became cost-effective and yielded more desirable clinical outcomes for lifetime treatment. The uncertainty analysis supported the need for monitoring the progression to ESRD.

Current status and difficulties on the diagnosis and treatment of lupus nephritis in children

系统性红斑狼疮是一种以多系统损害和血清中出现自身抗体为特征的自身免疫性疾病。狼疮性肾炎是系统性红斑狼疮临床中最常见和最重要的并发症，儿童狼疮性肾炎的发生率更高，预后与早期诊断、积极治疗相关。目前对于狼疮性肾炎的治疗方案主要为激素和免疫抑制剂，但部分患儿不能达到临床缓解或复发，新型的靶向生物制剂有望成为难治性狼疮性肾炎新的治疗方法。.

Recommendations for the diagnosis and management of lupus nephritis in China

Lupus nephritis (LN) refers to renal involvement in systemic lupus erythematosus and is characterized by hematuria, proteinuria, edema, hypertension and renal insufficiency. The complete remission rate of proliferative LN remains low using the current induction protocols and LN tends to flare. Scientific and standardized diagnosis and therapy are crucial for the treatment of LN. Therefore, based on the current international and domestic experiences and guidelines, the Chinese Rheumatology Association developed the recommendations of diagnosis and therapy for LN, with the purpose of enhancing efficacy, reducing flare, halting renal progression and improving outcome of LN.

Differences in rituximab use between pediatric rheumatologists and nephrologists for the treatment of refractory lupus nephritis and renal flare in childhood-onset SLE

BackgroundConsensus treatment plans have been developed for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in childhood-onset systemic lupus erythematosus. However, patients who do not respond to initial therapy, or who develop renal flare after remission, warrant escalation of treatment. Our objective was to assess current practices of pediatric nephrologists and rheumatologists in North America in treatment of refractory proliferative LN and flare.MethodsMembers of Childhood Arthritis and Rheumatology Research Alliance (CARRA) and the American Society for Pediatric Nephrology (ASPN) were surveyed in November 2015 to assess therapy choices (other than modifying steroid dosing) and level of agreement between rheumatologists and nephrologists for proliferative LN patients. Two cases were presented: (1) refractory disease after induction treatment with corticosteroid and cyclophosphamide (CYC) and (2) nephritis flare after initial response to treatment. Survey respondents chose treatments for three follow up scenarios for each case that varied by severity of presentation. Treatment options included CYC, mycophenolate mofetil (MMF), rituximab (RTX), and others, alone or in combination.ResultsSeventy-six respondents from ASPN and foty-one respondents from CARRA represented approximately 15 % of the eligible members from each organization. Treatment choices between nephrologists and rheumatologists were highly variable and received greater than 50 % agreement for an individual treatment choice in only the following 2 of 6 follow up scenarios: 59 % of nephrologists, but only 38 % of rheumatologists, chose increasing dose of MMF in the case of LN refractory to induction therapy with proteinuria, hematuria, and improved serum creatinine. In a follow up scenario showing severe renal flare after achieving remission with induction therapy, 58 % of rheumatologists chose CYC and RTX combination therapy, whereas the top choice for nephrologists (43 %) was CYC alone. Rheumatologists in comparison to nephrologists chose more therapy options that contained RTX in all follow up scenarios except one (p < 0.05).ConclusionsTherapy choices for pediatric rheumatologists and nephrologists in the treatment of refractory LN or LN flare were highly variable with rheumatologists more often choosing rituximab. Further investigation is necessary to delineate the reasons behind this finding. This study highlights the importance of collaborative efforts in developing consensus treatment plans for pediatric LN.

Prospects for the use of belimumab in lupus nephritis

Over the past 50 years the survival rate of patients with systemic lupus erythematosus (SLE) significantly improved, however, it is necessary to develop a new generation of drugs for the treatment of lupus nephritis (LN), the development of which is one of the main factors of high mortality risk in at least 50% of SLE patients. The international clinical trial BLISS-LN has demonstrated a high rate of achievement and maintenance of renal response (RR), confirmed by a higher rate of achievement of RR primary efficacy and complete renal response when using belimumab (BLM) in addition to standard therapy (ST) compared to ST alone in patients with LN. When using BLM, there was a statistically significant reduction in the risk of developing adverse renal events (in particular, deterioration of renal function) or death within 104 weeks compared with placebo. Improvement in LN outcomes was achieved in the setting of long-term reduction in glucocorticoids use after the induction phase. With BLM therapy, there was also a decrease in the total activity of SLE, a decrease in the number of severe exacerbations, and an improvement in serological markers. The benefit/risk ratio of BLM in combination with ST for LN treatment was favorable. BLM can be recommended for LN therapy in combination with standard treatment methods in order to achieve and maintain remission.

Comparison of iguratimod and conventional cyclophosphamide with sequential azathioprine as treatment of active lupus nephritis: study protocol for a multi-center, randomized, controlled clinical trial (iGeLU study)

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up.Methods/designThis study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test.DiscussionMost patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20–35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients.Trial registrationClinicalTrials.govNCT 02936375. Registered on October 18, 2016.

Remission after Six Months of Induction Immunosuppressive Treatment with Mycofenolate Mofetil and Prednisolone in Patients with Lupus Nephritis: A Descriptive Cross-sectional Study.

Treatment of lupus nephritis consists of six months of induction immunosuppression followed by years of maintenance immunosuppression. The aim of present study was to find the prevalence of remission after six months of induction immunosuppressive treatment with induction therapy in patients with lupus nephritis. A descriptive cross-sectional study was conducted in the nephrology unit of department of internal medicine of a tertiary care hospital from September 2018 to September 2020. The study was approved by institutional review committee of same institution (reference number 184/2018). Convenience sampling method was used and Statistical Package for Social Sciences version 26 was used for statistical analysis. Point estimate at 90% Confidence Interval was calculated along with frequency and proportion for binary data. Out of 24 patients, overall remission was seen in 21 patients (87.4%) (90% Confidence Interval= 76.26-98.54). Complete remission and partial remission were seen in 16 (66.6%) and 5 (20.8%) patients respectively resulting in an at the end of six months of induction immunosuppressive treatment. The most common class of lupus nephritis was class IV, 7 patients, followed by class IV+V, and class V, 6 patients in each respectively. The mean 24-hour urinary total protein, serum albumin and serum creatinine were 2492±1051 mg, 2.1±0.4 g/dl, and 0.9±0.1 mg/dl respectively. Adverse events were observed in 6 (25%) patients. Our study shows that good proportions of patients with lupus nephritis achieve clinical remission at the end of six months of induction immunosuppressive treatment with induction therapy, however, at the cost of some tolerable side effects.

Rituximab therapy for lupus nephritis: A meta‑analysis

The aim of the present study was to assess the clinical efficacy and safety of rituximab (RTX) therapy in the treatment of lupus nephritis by performing a meta‑analysis. For this purpose, the PubMed, Embase, Cochrane Library, Chinese Biomedical Literature, China National Knowledge Infrastructure, VIP Information and WANFANG databases were used to identify the eligible studies from January, 2000 to February, 2020. STATA16.0 and Review Manager Version 5.3 software were applied to pool the data. From the results of this search, 37 studies (30 case series and seven controlled trials) involving 1,273 patients were included. In the case series studies, the total remission (TR) rate was 81.9% (95% CI, 73.7‑88.8%) and the complete remission (CR) rate was 46.6% (95% CI, 36.4‑57.1%). Following treatment with RTX, the systemic lupus erythematosus disease activity index (SLEDAI) of patients with lupus nephritis decreased significantly [mean difference (MD), ‑8.91; 95% CI, ‑14.10 to ‑3.72, P&lt;0.01]. The level of proteinuria also decreased significantly [standardized mean difference (SMD), ‑1.05; 95% CI, ‑1.28 to ‑0.83, P&lt;0.01]. On the contrary, the level of serum albumin increased significantly (MD, 6.44; 95% CI, 4.42‑8.45; P&lt;0.01). In the controlled trials, both TR and CR were significantly higher than those of the control group (TR: OR, 2.48; 95% CI, 1.58‑3.89; P&lt;0.01; and CR: OR, 2.29; 95% CI, 1.17‑4.49; P&lt;0.05). Compared with the control group, the SLEDAI of patients in the RTX group decreased significantly (MD, ‑3.84; 95% CI, ‑5.99 to ‑1.69; P&lt;0.01) and the level of proteinuria in the RTX group also decreased significantly (MD, ‑1.24; 95% CI, ‑2.39 to ‑0.09; P&lt;0.05). At the same time, the level of serum albumin increased (MD, 0.54; 95% CI, 0.22‑0.86; P&lt;0.01). There was no difference in the relative risks of the adverse events between the two groups (OR, 0.37; P&gt;0.05). On the whole, the findings of the present study demonstrate that RTX exhibits favorable clinical efficacy in the treatment of lupus nephritis, which can significantly reduce the level of proteinuria and SLEDAI, and increase the level of serum albumin. Compared with traditional immunosuppressive therapy (corticosteroids + cyclophosphamide and/or mycophenolate), RTX was more effective in the treatment of lupus nephritis. Additionally, rituximab exhibited good safety.

Fish oil enhanced the efficacy of low-dose cyclophosphamide regimen for proliferative lupus nephritis: a randomized controlled double-blind trial.

BackgroundLupus nephritis (LN) is one of the most severe organ that damages the systemic lupus erythematosus (SLE). Cyclophosphamide is one of the main drugs used in the treatment of LN. Fish oil is a general term of all the oily substances in fish, whose main component is omega-3 fatty acid. This study aimed to investigate whether fish oil could be used as an adjunct to low-dose cyclophosphamide in proliferative LN treatment.MethodsA total of 237 patients with proliferative LN were recruited and randomized into two groups: cyclophosphamide + placebo group and cyclophosphamide + fish oil group. In the cyclophosphamide + placebo group, participants received prednisone + cyclophosphamide + placebo. In the cyclophosphamide + fish oil group, participants received prednisone + cyclophosphamide + fish oil. Before and after treatment, the clinical parameters of the patients in both groups were evaluated.ResultsIn the cyclophosphamide + fish oil group, the number of patients achieving complete remission (n = 45, 46.9%) was significantly higher than the cyclophosphamide + placebo group (n = 31, 32.6%). The number of patients achieving no response in the cyclophosphamide + fish oil group (n = 8, 8.3%) was significantly lower than the cyclophosphamide + placebo group (n = 22, 23.2%). Hematuria (P = 0.036), urine protein-creatinine ratio (uPCR) (P = 0.014), estimated glomerular filtration rate (eGFR) (P = 0.027), and renal SLE disease activity index (SLEDAI) (P = 0.009) improved more significantly in the cyclophosphamide + fish oil group. The number of patients with infection (P = 0.04) or urinary tract infection (P = 0.04) in the cyclophosphamide + fish oil group was lower than the cyclophosphamide + placebo group.ConclusionIn conclusion, the treatment of fish oil in LN patients enhances the efficiency of cyclophosphamide, alleviates nephritis-related parameters, and inhibits infection and urinary tract infection during the treatment. Thus, fish oil may serve as a potential adjuvant drug in the treatment of LN.

The landscape of systemic lupus erythematosus in Brazil: An expert panel review and recommendations.

PurposeThe objective of this review is to address the barriers limiting access to diagnosis and treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN) in Brazil, specifically for patients in the public healthcare system, arguably those with the least access to innovation.DesignA selected panel of Brazilian experts in SLE/LN were provided with a series of relevant questions to address in a multi-day conference. During the conference, responses were discussed and edited by the entire group through numerous drafts and rounds of discussion until a consensus was achieved.ResultsThe authors propose specific and realistic recommendations for implementing access to innovative diagnostic tools and treatment alternatives for SLE/LN in Brazil. Moreover, in creating these recommendations, the authors strived to address barriers and impediments for technology adoption. The multidisciplinary care required for SLE/LN necessitates the collective participation of all involved stakeholders.ConclusionA great need exists to expand the adoption of innovative diagnostic tools and treatments for SLE/LN not only in Brazil but also in most countries, as access issues remain an urgent demand. The recommendations presented in this article can serve as a strategy for new technology adoption in other countries in a similar situation.

Total Glucosides of Paeony Ameliorate Pristane-Induced Lupus Nephritis by Inducing PD-1 ligands+ Macrophages via Activating IL-4/STAT6/PD-L2 Signaling.

Macrophages, a major subset of innate immune cells, are main infiltrating cells in the kidney in lupus nephritis. Macrophages with different phenotypes exert diverse or even opposite effects on the development of lupus nephritis. Substantial evidence has shown that macrophage M2 polarization is beneficial to individuals with chronic kidney disease. Further, it has been reported that PD-1 ligands (PD-Ls) contribute to M2 polarization of macrophages and their immunosuppressive effects. Total glucosides of paeony (TGP), originally extracted from Radix Paeoniae Alba, has been approved in China to treat some autoimmune diseases. Here, we investigated the potentially therapeutic effects of TGP on lupus nephritis in a pristane-induced murine model and explored the molecular mechanisms regulating macrophage phenotypes. We found that TGP treatment significantly improved renal function by decreasing the urinary protein and serum creatinine, reducing serum anti-ds-DNA level and ameliorating renal immunopathology. TGP increased the frequency of splenic and peritoneal F4/80+CD11b+CD206+ M2-like macrophages with no any significant effect on F4/80+CD11b+CD86+ M1-like macrophages. Immunofluorescence double-stainings of the renal tissue showed that TGP treatment increased the frequency of F4/80+Arg1+ subset while decreasing the percentage of F4/80+iNOS+ subset. Importantly, TGP treatment increased the percentage of both F4/80+CD11b+PD-L1+ and F4/80+CD11b+PD-L2+ subsets in spleen and peritoneal lavage fluid as well as the kidney. Furthermore, TGP augmented the expressions of CD206, PD-L2 and phosphorylated STAT6 in IL-4-treated Raw264.7 macrophages in vitro while its effects on PD-L2 were abolished by pretreatment of the cells with an inhibitor of STAT6, AS1517499. However, TGP treatment did not affect the expressions of STAT1 and PD-L1 in Raw264.7 macrophages treated with LPS/IFN-γ in vitro, indicating a possibly indirect effect of TGP on PD-L1 expression on macrophages in vivo. Thus, for the first time, we demonstrated that TGP may be a potent drug to treat lupus nephritis by inducing F4/80+CD11b+CD206+ and F4/80+CD11b+PD-L2+ macrophages through IL-4/STAT6/PD-L2 signaling pathway.

Nephrotoxicity Risk of Cyclophosphamide in Lupus Model

Cyclophosphamide is one of the standard therapies for lupus, especially lupus nephritis based on its immunosuppressive effect. However, cyclophosphamide is also known as a nephrotoxic agent. Therefore, this research was aimed to measure the effect of cyclophosphamide at the dose that comparable to the human dose of 1 mg/kg BW on the kidney of lupus mice induced by means of 2,6,10,14-tetramethylpentadecane (TMPD). In this research, the IL-6 as a pro-inflammatory cytokine was tested by using flow cytometry method. In addition, the structural damage of the kidney tissues was assessed by means of Moroni’s kidney organ scoring method for lupus. The result showed that cyclophosphamide reduced the IL-6 significantly with the value of 36.72±22.79% for the TMPD-treated group; 32.59±9.97% for the cyclophosphamide group; and 30.25±4.48% for the naïve group. Moreover, the damages of the kidney tissues on the cyclophosphamide group were more severe than the TMPD-treated group. In conclusion, despite its anti-inflammatory effect which is useful for lupus, cyclophosphamide has a severe nephrotoxic effect which harms the patient. The effects may be a cause of the long interval use of cyclophosphamide. It can be a consideration for the further research and the next revision of the guideline for lupus nephritis treatment.

Lupus nephritis and ANCA-associated vasculitis: towards precision medicine?

Historically the treatment of lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was 'one size fits all'; however, with the emergence of precision medicine initiatives, the field is moving towards more personalized treatment approaches. The recent development of a more accurate and reproducible histopathological classification system for LN could lead to better disease categorization and therefore more targeted therapies. A better understanding of the pathophysiology of LN has provided evidence that not only T but also B cells play an important role, opening new opportunities for individualized treatment approaches. Recent trials have shown calcineurin inhibitors and the anti-CD20 antibodies rituximab and ofatumumab to be effective in the treatment of LN, adding new treatment options. State-of-the-art targeted therapy in ANCA-associated vasculitis (AAV) takes interindividual heterogeneity in disease severity, type of ANCA antibody [myeloperoxidase versus proteinase 3 (PR3)] and the risk for side effects of therapy into consideration. In addition, within an individual, induction therapy differs from maintenance therapy, the same holding true in incident and relapsing disease. Rituximab is now widely used in AAV and it has become clear that prolonged B cell depletion, as in LN, must be achieved to obtain a long-lasting clinical response, especially in anti-PR3-associated disease. Still, despite these advances, molecular and genetic markers are rarely incorporated into diagnostic and treatment algorithms and true precision medicine remains an aspiration that hopefully can be achieved.

Comprehensive Analysis of Clinical Trials Registration for Lupus Nephritis Therapy on ClinicalTrials.gov.

Objective: Clinical trials are the most effective method for evaluating therapeutic strategies. The purpose of this study was to comprehensively assess the characteristics of trials on lupus nephritis (LN) and provide a reference for LN treatment and research.Methods: Registered therapeutic trials on drug interventions for LN were obtained from ClinicalTrials.gov up to December 3, 2020. The general characteristics, methodological characteristics, detailed characteristics, investigated drugs, eligibility criteria, and outcome measures of these trials were analyzed.Results: A total of 126 eligible trials were evaluated, and these trials mainly investigated the initial treatment of adult proliferative LN. Half of the trials enrolled <50 participants, and 70.7% of the trials lasted for 6–24 months. In total, 95.2% of trials adopted an interventional study design. Of intervention trials, 56.6% were in phase 2 or phase 3, 76.7% were randomized, 77.5% employed a parallel assignment, and 41.7% were masked. The eligibility criteria and outcome measures of the included trials varied and involved a variety of indicators. Chemical agents and biologics are the most widely studied immunotherapies, of which mycophenolate mofetil, tacrolimus, and rituximab are the most studied. In addition, some trials studied cell transplantation treatment.Conclusions: The majority of clinical trials for LN therapy registered on ClinicalTrials.gov investigated the initial treatment of adult proliferative LN, and most of these trials were randomized, parallel assigned, and insufficiently masked interventional trials with small scale, short duration, various eligibility criteria, and outcome measures. We hope that more large-scale, long-term multicenter, and high-quality RCT trials with standardized inclusion criteria/exclusion criteria and treatment effect evaluation systems will be conducted and that more energy and funding will be put into exploring biological products and stem cell therapies. In addition, trials for membranous LN, childhood-onset LN, and maintenance phase LN are needed to establish optimal treatment strategies.

Depletion of Fractalkine ameliorates renal injury and Treg cell apoptosis via the p38MAPK pathway in lupus-prone mice

Fractalkine (FKN) is a chemokine with several roles, including chemotaxis; adhesion; and immune damage, which also participates in cell inflammation and apoptosis and responds to the pathogenesis of autoimmune diseases. Given the involvement of regulatory T cells (Treg) cells in autoimmune diseases, this study investigated the regulatory mechanism of FKN in renal injury and Treg apoptosis via the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway in lupus-prone mice. Lupus was induced in BALB/c female mice by injection of pristane, followed by isolation of CD4+CD25+ Treg cells from the spleen of lupus model mice. To deplete FKN, mice received injection of an anti-FKN antibody, and Treg cells were transfected with FKN small-interfering RNA. Lupus mice and Treg cells were treated with the p38MAPK inhibitor SB203580 and activator U-46619, respectively, and urine protein and serum urea nitrogen, creatinine, and autoantibodies were measured and renal histopathological changes analyzed. We determined levels of FKN, phosphorylated p38 (p-p38), and forkhead box P3 (FOXP3) in renal tissue and Treg cells, and analyzed apoptosis rates and levels of key apoptotic factors in Treg cells. The renal FKN and p-p38 levels increased, whereas renal FOXP3 level decreased in lupus-prone mice. Treatment with the anti-FKN antibody and the p38MAPK inhibitor ameliorated proteinuria and renal function, significantly reducing serum autoantibody, renal FKN, and p-p38 levels while increasing renal FOXP3 level in lupus-prone mice. Moreover, FKN knockdown and administration of the p38MAPK inhibitor reduced apoptosis and levels of pro-apoptotic factors, increased levels of anti-apoptotic factors, and suppressed activation of p38MAPK signaling in Treg cells derived from lupus model mice. Furthermore, treatment with the p38MAPK activator U-46619 had the opposite effect on these cells. These data indicated that depletion of FKN ameliorated renal injury and Treg cell apoptosis via inhibition of p38MAPK signaling in lupus nephritis, suggesting that targeting FKN represents a potential therapeutic strategy for treating Lupus nephritis.

Hydroxychloroquine use and blood pressure below 130/80 are associated with remission in lupus nephritis: A cohort study

IntroductionThe treatment of lupus nephritis, in addition to immunosuppression, includes the use of adjuvant therapies (antimalarials, statins, blockade of the renin–angiotensin system, and the achievement of blood pressure levels below 130/80). The evidence for the use of these strategies comes from non-autoimmune primary glomerulopathies and there is no information on their impact on the remission of this condition. ObjectiveTo determine, in patients with lupus nephritis, the use of adjuvant therapies and their association with remission at 12 months. Materials and methodsA retrospective cohort study was conducted, between 2005 and 2012. Patients who achieved complete remission of nephritis were compared with those who did not. Complete remission was defined by the American College of Rheumatology AdHoc Subcommittee. OutcomesPercentage of use of adjuvant therapies. Bivariate and multivariate analysis were performed to define association with remission. Results167 subjects were included (all eligible subjects); 85.6% used antimalarials, 65.5% angiotensin converting enzyme inhibitors, 33.5% angiotensin receptor blockers, 30.7% dual blockade, 29.3% statins, and 85% achieved the goal blood pressure. In the multivariate analysis, the use of hydroxychloroquine (OR=.149; 95% CI: .034–.647; p=.003) and the achievement of goal blood pressure (OR=.248; 95% CI: .1–.615; p=.003) were associated with remission. ConclusionsIn a cohort of patients with lupus nephritis, the use of hydroxychloroquine and achieving blood pressure values lower than 130/80 were associated with remission at 12 months.

Camptothecin and Topotecan, Inhibitors of Transcription Factor Fli-1 and Topoisomerase, Markedly Ameliorate Lupus Nephritis in (NZB × NZW)F1 Mice and Reduce the Production of Inflammatory Mediators in Human Renal Cells.

To examine the therapeutic effects of camptothecin (CPT) and topotecan (TPT), inhibitors of transcription factor Fli-1 and topoisomerase, on lupus nephritis in (NZB × NZW)F1 (NZBWF1) mice, and to examine the effects of CPT and TPT on inflammatory mediators in human renal cells. Female NZBWF1 mice were treated with vehicle, cyclophosphamide (CYC), CPT (1 mg/kg or 2 mg/kg), or TPT (0.03 mg/kg, 0.1 mg/kg, or 0. 3 mg/kg) by intraperitoneal injection twice a week, beginning at the age of 25 weeks (n = 8-10 mice per group). Blood and urine were collected for monitoring autoantibodies and proteinuria. Mice were euthanized at 40 weeks, and renal pathology scores were assessed. Human renal endothelial and mesangial cells were treated with CPT or TPT, and cytokine expression was measured. None of the NZBWF1 mice treated with 1 mg/kg or 2 mg/kg of CPT or 0.3 mg/kg of TPT had proteinuria >100 mg/dl at the age of 40 weeks. One of 8 mice treated with 0.1 mg/kg of TPT and 1 of 10 mice treated with CYC had proteinuria >300 mg/dl, whereas 90% of the mice treated with vehicle had proteinuria >300 mg/dl. Compared to vehicle control, mice treated with 1 mg/kg or 2 mg/kg of CPT, 0.1 mg/kg or 0.3 mg/kg of TPT, or CYC had significantly prolonged survival, attenuated renal injury, diminished splenomegaly, reduced anti-double-stranded DNA autoantibody levels, and reduced IgG and C3 deposits in the glomeruli (all P < 0.05). Human renal cells treated with CPT or TPT had reduced expression of Fli-1 and decreased monocyte chemotactic protein 1 production following stimulation with interferon-α (IFNα) or IFNγ. Our findings indicate that low-dose CPT and TPT could be repurposed to treat lupus nephritis.

BLISS in the Treatment of Lupus Nephritis.

The optimal treatment of lupus nephritis remains a vexing challenge for nephrologists. Induction therapy for patients with active disease usually includes cyclophosphamide or mycophenolate mofetil (MMF) in combination with corticosteroids. These treatments have improved outcomes. Yet, only 30%–50

A new old treatment for lupus nephritis

A new old treatment for lupus nephritis