Remission Of Nephritis Research Articles

Voclosporin Induces Systemic Lipidomic Alterations: Implications for Lupus Nephritis Remission

Voclosporin Induces Systemic Lipidomic Alterations: Implications for Lupus Nephritis Remission

MAIT cells altered phenotype and cytotoxicity in lupus patients are linked to renal disease severity and outcome.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which circulating immune complexes can cause different types of glomerulonephritis, according to immune deposits and to the type of glomerular cell injury. Proliferative lesions represent the most severe form of lupus nephritis (LN) and often lead to kidney failure and death. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that recognize microbial-derived ligands from the riboflavin synthesis pathway. Although abundant in peripheral blood, MAIT cells are enriched in mucosal and inflamed tissues. While previous studies have reported concordant results concerning lower MAIT cell frequencies in the blood of SLE patients, no information is known about MAIT cell function and LN severity and outcome. In the current study, we analyzed the baseline phenotype and function of peripheral blood MAIT cells by flow cytometry in 26 patients with LN and in a control group of 16 healthy individuals. We observe that MAIT cell frequencies are markedly reduced in blood of LN patients. MAIT cells from patients have an altered phenotype in terms of migration, proliferation and differentiation markers, notably in most severe forms of LN. Frequencies of PMA/ionomycin stimulated MAIT cells secreting effector molecules, such as proinflammatory IL-17 and cytotoxic protein granzyme B, are higher in LN patients. Patients undergoing a complete renal remission after immunosuppressive therapy had higher MAIT cell frequency, lower expression of proliferation marker Ki-67 and granzyme B (GzB) at inclusion. Remarkably, GzB production defines a predictive model for complete remission. We report here that blood MAIT cells display proinflammatory and cytotoxic function in severe lupus nephritis which may play a pathogenesis role, but without association with systemic lupus activity. Finally, low cytotoxic profile of MAIT cells may represent a promising prognostic factor of lupus nephritis remission one year after induction therapy.

CD11c+ T-bet+ CD21hi B Cells Are Negatively Associated With Renal Impairment in Systemic Lupus Erythematosus and Act as a Marker for Nephritis Remission.

Lupus nephritis (LN) is one of the most common manifestations of systemic lupus erythematosus (SLE), characterized by abnormal B cell activation and differentiation to memory or plasma effector cells. However, the role of these cells in the pathogenesis of LN is not fully understood, as well as the effect of induction therapy on B cell subsets, possibly associated with this manifestation, like aged-associated B cells (ABCs). Consequently, we analyzed the molecules defining the ABCs subpopulation (CD11c, T-bet, and CD21) through flow cytometry of blood samples from patients with lupus presenting or not LN, following up a small sub-cohort after six months of induction therapy. The frequency of ABCs resulted higher in LN patients compared to healthy subjects. Unexpectedly, we identified a robust reduction of a CD21hi subset that was almost specific to LN patients. Moreover, several clinical and laboratory lupus features showed strong and significant correlations with this undefined B cell subpopulation. Finally, it was observed that the induction therapy affected not only the frequencies of ABCs and CD21hi subsets but also the phenotype of the CD21hi subset that expressed a higher density of CXCR5. Collectively, our results suggest that ABCs, and more importantly the CD21hi subset, may work to assess therapeutic response since the reduced frequency of CD21hi cells could be associated with the onset of LN.

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.

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.

Successful treatment of a rare variant of mesangioproliferative glomerulonephritis with IgM deposits with Cyclosporin A

We present a case with a rare variant of glomerulonephritis, IgM nephropathy, which occurs mainly with nephrotic syndrome. The clinical features of this variant of kidney damage are characterized; the pathogenetic and the transformation of this form of nephritis into focal segmental glomerulosclerosis are discussed. The development of severe nephrotic syndrome at the beginning of the disease, the formation of secondary steroid resistance have confirmed this hypothesis and have justified the treatment with cyclosporin A aimed at the recovery of the function of the podocyte with remission of nephritis.

Double Negative B Cell Is Associated With Renal Impairment in Systemic Lupus Erythematosus and Acts as a Marker for Nephritis Remission.

Objective: Recent studies on double negative B cells (DN B cells) suggested that they have potential pathogenic roles in systemic lupus erythematosus (SLE). This study aimed to determine the circulating DN B cells in SLE patients and analyzed the clinical significance of this cell subset.Methods: Fifty-seven SLE patients and fifty healthy controls (HCs) were recruited in this study. Among the 57 SLE patients, 25 had lupus nephritis (LN). All patients were followed up for 24 weeks. Peripheral B cell subsets were analyzed by flow cytometry.Results: DN B cells were significantly elevated in the SLE patients, especially in the patients with LN (p < 0.01). DN B showed a positive correlation with 24-h urine protein excretion (24 h-UPE) levels (r = 0.444, p = 0.034) in LN patients, and inversely correlated with evaluated glomerular filtration rate (eGFR) (r = −0.351, p = 0.011). DN B cells had a positive correlation with plasma cells (r = 0.484, p < 0.001) and memory B cells (r = 0.703, p < 0.001). After treatment, decreased DN B cells were associated with LN alleviation (p = 0.002). In the follow-up, the remission rate of LN patients with decreased DN B cells was significantly higher than LN patients with increased DN B cells (83.33 vs. 25.00%, p = 0.030) at week 24.Conclusions: This study suggests that the peripheral DN B cells are positively correlated with the severity of renal damage in LN patients and may potentially be used as a prognostic marker in LN.

Modern classification, progression factors, treatment and outcomes of primary mesangial proliferative glomerulonephritis

The choice of treatment of mesangial proliferative glomerulonephritis (post-infection, immunoglobulin A, G and M nephritis) is performed taking into account the remission achievement, slowing of progression and reduction of the risk of recurrences of glomerulonephritis. The efficiency of etiologic factor removing is debatable: glomerulonephritis associated with infections usually resolves after their elimination; individual patients achieve immunoglobulin A nephritis remission with persistent antimicrobial treatment of focal infection, but surgical removal of the focus (tonsillectomy) does not affect the long-term prognosis, therefore it is not recommended. Treatment of immunoglobulin A nephritis with oral prednisone for up to 4 months, sometimes in combination with cyclophosphamide (cyclophosphane), reduces the likelihood of its relapse. At low risk of progression of immunoglobulin A nephritis with proteinuria less than 1 g/day, long-term therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is indicated with administration of maximum tolerated doses for proteinuria more than 1 g/day. Also fish oil 3 g/day is administered for up to 2 years. If proteinuria more than 1 g/day persists for 3-6 months, corticosteroids are recommended for 6 months. With mild renal dysfunction, corticosteroids are prescribed orally or in pulse-therapy with high doses intravenously and maintenance therapy with low doses orally. Immunosuppressive therapy - cyclophosphamide, cyclosporine, azathioprine, mycophenolate mofetil - in combination with corticosteroids is indicated in rapid loss of renal function or massive/moderate proteinuria. In minimal proteinuria immunosuppressive therapy is considered to be unreasonable. Use of intravenous immunoglobulin for immunoglobulin A nephritis from the point of view of lesser toxic effect is possible only as the induction therapy. Currently, there are no clinical recommendations for the treatment of immunoglobulin M nephritis, in case of nephrotic syndrome, corticosteroids are the drugs of the 1st line. There are isolated studies of the use of cyclophosphamide, mycophenolate mofetil, and cyclosporine, with the achievement of remission in frequent relapses of nephrotic syndrome or steroid drug resistance. The cases of immunoglobulin M nephritis treates with retuximab with a positive effect are described. The effectiveness of immunoglobulin G nephritis treatment is less studied, the choice of treatment is similar to that of immunoglobulin A and M nephritis.

Partial and simultaneous remission of nephritis and autoimmune hemolytic anemia in patients with lupus after treatment with biological agent: a case report

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, systemic, of unknown cause and autoimmune nature. It features variable prognosis, depending on the affected organ or system. The renal impairment is the condition most often related to morbidity and mortality. This manuscript aims to contribute to the further evidence that early diagnosis of lupus associated with quickly aggressive therapy could increase the success outcome rate. Also, immediate recognition of therapeutic failures and change the treatment strategy must be applied. In this regard, a new therapeutic option seems to be the biological drug rituximab described in this study and which it is emphasised because of its possible and still supposed ability to act as a rescue agent for nephritis and hemolytic lupus anaemia, simultaneously, with effectiveness and safety. This article presents the case of female lupus patient with both severe refractory hematologic disorder and renal impairment, which had an evolution of the simultaneous restoration of urine output, and clinical and laboratory improvement of autoimmune anaemia after rituximab administration. The persistence of renal damage could not be ruled out, so the response to treatment was considered to be partial

Hydroxychloroquine for autoimmune diseases

Hydroxychloroquine (HCQ) is by far the most frequently used antimalarial for the management of Systemic Autoimmune Diseases. It has immunomodulatory, hypolipidemic, hypoglycemic and antithrombotic properties and it diminishes the risk of malignancies. The most important mechanisms to explain the immunomodulatory actions are its ability to reduce inflammatory pathways and Toll-like receptors activation. The safety profile is favorable. In spite of its low frequency, retinal toxicity is potentially severe. In systemic lupus erythematous HCQ therapy reduces activity, the accrual of organ damage, risk of infections and thrombosis and improves the cardiometabolic profile. It contributes to induce lupus nephritis remission, spares steroid use and increases survival rates. In rheumatoid arthritis, it improves cardiometabolic risk and has a favorable effect in joint inflammation. In Sjögren's syndrome, an increased lacrimal quality as well as an improvement in objective and subjective inflammatory markers has been demonstrated with HCQ. In Antiphospholipid Syndrome, HCQ is effective in primary and secondary thrombosis prevention. The effectiveness of the drug in other systemic autoimmune diseases is less established. HCQ therapy may improve dermatological manifestations in Dermatomyositis and may have a positive effects in the treatment of Sarcoidosis and Still disease.

Pulmonary Mucormycosis in a Patient with Systemic Lupus Erythematosus: A Diagnostic and Treatment Challenge.

Pulmonary mucormycosis is commonly encountered in patients with diabetic ketoacidosis, hematologic malignancies, neutropenia, organ or hematopoietic stem cell transplantation, and malignancy, but it rarely occurs in high-risk patients with systemic lupus erythematosus (SLE). We present the case of a 40-year-old SLE female with fulminant pneumonia after remission of nephritis treated with rituximab, who developed severe pulmonary mucormycosis that led to her rapid death from acute respiratory failure and acute respiratory distress syndrome. Pulmonary mucormycosis has a high mortality rate. However, with early diagnosis and antifungal therapy with lipid formulation-liposomal amphotericin B and surgical removal of the infected area, the outcome can be improved.

IFN-α Confers Resistance of Systemic Lupus Erythematosus Nephritis to Therapy in NZB/W F1 Mice

The critical role of IFN-α in the pathogenesis of human systemic lupus erythematosus has been highlighted in recent years. Exposure of young lupus-prone NZB/W F1 mice to IFN-α in vivo leads to an accelerated lupus phenotype that is dependent on T cells and is associated with elevated serum levels of BAFF, IL-6, and TNF-α, increased splenic expression of IL-6 and IL-21, formation of large germinal centers, and the generation of large numbers of short-lived plasma cells that produce IgG2a and IgG3 autoantibodies. In this study, we show that both IgG2a and IgG3 autoantibodies are pathogenic in IFN-α-accelerated lupus, and their production can be dissociated by using low-dose CTLA4-Ig. Only high-dose CTLA4-Ig attenuates both IgG2a and IgG3 autoantibody production and significantly delays death from lupus nephritis. In contrast, BAFF/APRIL blockade has no effect on germinal centers or the production of IgG anti-dsDNA Abs but, if given at the time of IFN-α challenge, delays the progression of lupus by attenuating systemic and renal inflammation. Temporary remission of nephritis induced by combination therapy with cyclophosphamide, anti-CD40L Ab, and CTLA4-Ig is associated with the abrogation of germinal centers and depletion of short-lived plasma cells, but relapse occurs more rapidly than in conventional NZB/W F1 mice. This study demonstrates that IFN-α renders NZB/W F1 relatively resistant to therapeutic intervention and suggests that the IFN signature should be considered when randomizing patients into groups and analyzing the results of human clinical trials in systemic lupus erythematosus.

Rituximab and mycophenolate mofetil for relapsing proliferative lupus nephritis: a long-term prospective study

Subsequent to cyclophosphamide-based induction therapy of lupus nephritis, and despite maintenance chronic immunosuppressive treatment, many patients experience relapses. This prospective, observational study included 10 women with biopsy-proven relapse of proliferative lupus nephritis occurring during maintenance with mycophenolate mofetil (MMF) or azathioprine. The long-term outcome after a single course of the B-cell depleting anti-CD20 antibody rituximab (4 weekly infusions of 375 mg/m(2)), combined with daily MMF (2 g) and prednisolone (0.5 mg/ kg/day for 4 weeks, tapered thereafter) is presented. While renal function was not severely impaired at baseline, partial remission (>50% improvement in all abnormal renal parameters) was achieved in eight patients at a median of 3.5 months. In seven patients, with 24-h urinary protein of 2.5 +/- 1.1 g (mean +/- SD), complete remission, associated with increases in serum complement levels and decreases in anti-dsDNA titres, was subsequently established (normal serum creatinine/albumin levels, inactive urine sediment and 24-h urinary protein <0.5 g). Complete nephritis remission was sustained at the follow-up end (median of 38 months) in six patients. Combination treatment was well tolerated. The efficacy of this low-toxicity combination was particularly evident in patients with subnephrotic proteinuria due to proliferative lupus nephritis relapse. Controlled trials to define the role of rituximab/MMF in this condition are warranted.

Mycophenolate Mofetil for Induction Therapy of Lupus Nephritis

Although the accepted standard of care for induction of lupus nephritis has been cyclophosphamide, recent trials suggest that mycophenolate mofetil may be as or more effective and less toxic. A systematic review and meta-analysis were performed to determine the risk for failure to induce remission of lupus nephritis in patients who were treated with mycophenolate mofetil compared with cyclophosphamide. Studies were identified by a search of electronic databases, bibliographies, and conference proceedings and by contacting experts. Randomized trials that compared mycophenolate mofetil with cyclophosphamide for induction therapy in adults with biopsy-proven lupus nephritis were eligible. The primary outcome was failure to induce a remission of nephritis as defined by the original studies (based on proteinuria, renal function, and urine sediment). Four studies that included 268 patients and had homogeneous results across studies were identified. In a fixed-effects model, the pooled relative risk for failure to induce remission for mycophenolate mofetil compared with cyclophosphamide was 0.70. The relative risk for the composite outcome of death or end-stage renal disease for mycophenolate mofetil compared with cyclophosphamide was 0.44. Leukopenia and amenorrhea occurred more frequently in cyclophosphamide-treated patients. Treatment of lupus nephritis with mycophenolate mofetil compared with cyclophosphamide reduces the risk for failure to induce remission during induction therapy and may reduce the risk for death or end-stage renal disease. Mycophenolate mofetil may be considered as a first-line induction therapy for the treatment of lupus nephritis in patients without severe renal dysfunction.

Lupus nephritis remission, albeit with positive anti-doping test

A 39-year-old woman developed systemic lupus erythematosus with nephropathy after a holiday in Jamaica. She was prescribed with prednisone, azathioprine and aspirin. As she was obsessed with aesthetic procedures, she decided not to take the prescription. Instead, she took her bodybuilding trainer's advice of one intramuscular injection of stanozolol for 10 weeks in order to increase her gluteus area. One week after finishing the latter regimen, there was no disease activity. Whether lupus remission in this patient was spontaneous or a consequence of stanozolol administration will remain a riddle for this fortunate outcome.

Rituximab treatment for glomerulonephritis in HCV-associated mixed cryoglobulinaemia: efficacy and safety in the absence of steroids

Rituximab, an anti-CD20 monoclonal antibody, has been used in lupus nephritis and membranous idiopathic nephropathy and has proved effective in non-renal manifestations of type II mixed cryoglobulinaemia (MC) syndrome. We investigated the possible efficacy and safety of rituximab in the treatment of cryoglobulinaemic nephritis. Five patients with active, biopsy-proven, glomerulonephritis in hepatitis C virus (HCV)-related type II MC syndrome were treated with four weekly infusions of rituximab (375 mg/m2) in monotherapy, without steroids whenever possible. Rituximab was the first-line therapy in three cases. A rapid and sustained renal response was observed in all patients, in one of them without retreatment up to the last follow-up (month 21+). Renal biopsy was repeated after 6 months in one patient and histopathological improvement was documented. Three patients relapsed, at months +5, +7 and +12 of follow-up, respectively. Two of them were then retreated with rituximab and again presented a rapid improvement in renal function. Maintenance therapy with rituximab was performed in two patients: nephritis remission was maintained in both. Fc-gamma receptor 3a (FcgammaRIIIa) genotype characterization was consistent with the clinical response observed. Rituximab also proved effective against other active MC manifestations, when present. No major side-effects occurred and steroids were not required in the follow-up. Rituximab may provide effective and safe therapy in type II MC-related glomerulonephritis, possibly as first-line therapy, avoiding steroids and hazardous immunosuppressive treatment.

Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down‐regulation of the T cell costimulatory molecule CD40 ligand: An open‐label trial

Autoreactive B cells play a key role in tissue injury in systemic autoimmune disease, and therefore a treatment resulting in B cell depletion could have benefit. This open-label study was undertaken to evaluate the efficacy of the anti-CD20 monoclonal antibody rituximab in the treatment of lupus nephritis. Lupus patients with active proliferative nephritis (4 with focal disease and 6 with diffuse disease) received rituximab (4 weekly infusions of 375 mg/m(2)) combined with oral prednisolone. Clinical, laboratory, and immunologic responses, including peripheral lymphocyte subsets measured by flow cytometry, were prospectively assessed at monthly intervals for 12 months. Complete remission of nephritis was defined as normal serum creatinine and albumin levels, inactive urine sediment, and 24-hour urinary protein <500 mg. Partial remission was defined as >50% improvement in all renal parameters that were abnormal at baseline. B cell depletion lasted from 1 month to 7 months and was well tolerated. Partial remission was achieved in 8 of 10 patients within a median of 2 months (range 1-4 months); in 5 of them, complete remission was subsequently established (at a median of 3 months from baseline), and it was sustained at 12 months in 4. As early as 1 month from baseline, the expression of the costimulatory molecule CD40 ligand on CD4+ T cells was decreased by 4-fold, and it was almost blocked when partial remission was clinically evident. The expression of T cell activation markers CD69 and HLA-DR was significantly decreased at time points when partial remission was observed, and was further decreased during complete remission. In contrast, in patients who did not exhibit a response or when relapse was detected in patients in whom an initial remission had been achieved, such decreases were not prominent. Serum concentrations of double-stranded DNA autoantibodies were decreased in all patients, regardless of clinical outcome. Following B cell depletion, clinical remission of lupus nephritis is associated with a decrease in T helper cell activation, suggesting an additional role for B cells, independent of autoantibody production, in promoting disease. A controlled trial to confirm these promising clinical results is warranted.

Fluctuations of antibody to ribosomal P proteins correlate with appearance and remission of nephritis in SLE

Antibodies to ribosomal P proteins are found in widely variable proportions (up to 42%) of patients with SLE depending on the ethnic background of the patient population. Neuropsychiatric disease was first recognized to have increased prevalence with anti-P and more recently liver and renal disease. We describe four patients with SLE and circumscribed episodes of nephritis of relatively short duration. In two patients, antibodies to ribosomal P protein were the only specificity detected at the time of appearance of active nephritis; and in the other two patients, the appearance and disappearance of anti-ribosomal P was simultaneously found with similar fluctuations in anti-dsDNA titers. Anti-ribosomal P antibodies were measured by Western blot and a P peptide-specific ELISA. These data raise the possibility for a pathogenic role for anti-ribosomal P antibodies in lupus nephritis.

Immunopharmacological studies on experimental glomerulonephritis.

Immunopharmacological studies on modified nephrotoxic serum (NTS) nephritis in rats were conducted. The modified NTS nephritis was produced by an intravenous (i.v.) injection of NTS in a subnephrotoxic dose (sub-dose) into the rats which had been previously immunized with rabbit IgG (RGG) and complete Freund's adjuvant (CFA). In previously immunized rats, typical nephritic syndrome was demonstrated with respect to the elevation of urinary protein, serum cholesterol, blood urea nitrogen (BUN) and histopathologic scores of the kidneys. No changes in complement levels were found. By adoptive transfer experiments, it was found that sensitized lymphocytes were essential for causing the nephritis. The potency of the sensitized lymphocytes was reinforced by passing them through a nylon wool or Sephadex G-10 column after treatment with rabbit anti-rat F(ab')2 antibody and complement. The administration of cyclophosphamide, prednisolone, tilorone or cis-1-methyl-4-isohexylcyclohexane carboxylic acid (IG-10) showed a clear remission of nephritis. Cobra venom factor (CoVF) and Cu-chlorophyllin complement inhibitors showed a contradictory efficacy on the nephritis. CoVF which decreased the serum CH50 value did not produce any remission of the nephritis, whereas Cu-chlorophyllin, which slightly decreased CH50 values produced a significant decrease in urinary protein and serum cholesterol. The macrophage-toxic agents carrageenan and dextran sulfate, also did not produce a remission of nephritis. These findings suggest that the participation of T cells is important for the onset of this nephritis and that macrophages and complement do not appear to be involved.