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1.
Yonsei Med J ; 61(11): 951-957, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33107238

RESUMO

PURPOSE: To compare the clinical characteristics and renal outcomes between patients who initially had lupus nephritis (LN) at the onset of systemic lupus erythematosus (SLE) (initial-onset LN) and those who developed LN within 5 years after SLE onset (early-onset LN). MATERIALS AND METHODS: SLE patients with biopsy-proven LN were retrospectively reviewed. The clinical parameters and renal outcomes were compared between initial-onset and early-onset LN groups. We used Cox regression analysis to estimate risk of worse renal outcomes according to the onset time of LN. RESULTS: Of all 136 LN patients, 92 (67.6%) and 44 (32.4%) patients were classified into the initial-onset and early-onset LN groups, respectively. The initial-onset LN group had higher prevalences of class IV LN (54.3% vs. 34.1%, p=0.027), impaired renal function (34.8% vs. 11.4%, p=0.004), microscopic hematuria (73.9% vs. 54.5%, p=0.024), and higher urine protein/creatinine ratio [4626.1 (2180.0-6788.3) mg/g vs. 2410.0 (1265.0-5168.5) mg/g, p=0.006] at LN diagnosis. Renal relapse (46.3% vs. 25.7%, p=0.039) and progression to chronic kidney disease (CKD) or end-stage renal disease (ESRD) were more common (24.4% vs. 8.3%, p=0.042) in the initial-onset LN group. In Cox regression analysis, the initial-onset LN group had higher risks of renal relapse [adjusted hazard ratio (HR) 3.56, 95% confidence interval (CI) 1.51-8.35, p=0.004] and progression to CKD or ESRD (adjusted HR 4.57, 95% CI 1.03-20.17, p=0.045), compared with the early-onset LN group. CONCLUSION: Patients with LN at SLE onset may have more severe renal presentations and experience worse renal outcomes than those who develop LN within 5 years.


Assuntos
Falência Renal Crônica/etiologia , Rim/fisiopatologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/patologia , Adulto , Biópsia , Progressão da Doença , Feminino , Humanos , Lúpus Eritematoso Sistêmico/terapia , Nefrite Lúpica/complicações , Nefrite Lúpica/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Adulto Jovem
2.
F1000Res ; 92020.
Artigo em Inglês | MEDLINE | ID: mdl-32789005

RESUMO

Lupus nephritis is an important cause of both acute kidney injury and chronic kidney disease that can result in end-stage renal disease. Its pathogenic mechanisms are characterized by aberrant activation of both innate and adaptive immune responses, dysregulation of inflammatory signaling pathways, and increased cytokine production. Treatment of lupus nephritis remains a challenging issue in the management of systemic lupus erythematosus since the clinical presentation, response to treatment, and prognosis all vary considerably between patients and are influenced by ethnicity, gender, the degree of chronic kidney damage, pharmacogenomics, and non-immunological modulating factors. Elucidation of the various immunopathogenic pathways in lupus nephritis has resulted in the development of novel therapies, including biologics that target specific antigens on B lymphocytes to achieve B cell depletion, agents that modulate B cell proliferation and development, drugs that block co-stimulatory pathways, drugs that target T lymphocytes primarily, and therapies that target complement activation, signaling pathways, pro-inflammatory cytokines, and neutrophil extracellular traps. This review will discuss recent advances in the understanding of disease pathogenesis in lupus nephritis in the context of potential emerging therapies.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Linfócitos B , Citocinas , Humanos , Linfócitos T
3.
PLoS One ; 15(5): e0233138, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32421738

RESUMO

Naringenin is flavonoid mainly found in citrus fruits which has shown several biological properties. In this work, we evaluated the therapeutic potential of the flavonoid Naringenin. Five-month-old B6.MRL-Faslpr/J lupus-prone mice were administered daily orally with Naringenin for seven months. We showed that Naringenin treatment at 50 or 100 mg/kg inhibited the splenomegaly and decreased the levels of anti-nuclear and anti-dsDNA autoantibodies. Furthermore, a reduction in serum concentration of TNF-α, IFN-γ and IL-6 was observed in the mice provided with Naringenin. Interestingly, serum levels of IL-10 increased. Naringenin decreased the frequency and absolute numbers of splenic effector memory T cells. Additionally, in order to be able to evaluate whether Naringenin prevented kidney damage, twelve-week-old MRL/MpJ-Faslpr/J mice, an accelerated lupus model, were orally administered with Naringenin at 100 mg/kg for six weeks. Surprisingly, Naringenin treatment prevented kidney damage and reduced the development of fibrosis similar to cyclophosphamide group. Moreover, Naringenin treatment increased the percentage of regulatory T cells in this aggressive model of lupus. Together, these results suggest a potential ability of Naringenin to reduce the autoimmunity in lupus-prone mice by modulation of T-cell subsets and cytokines profile that mitigate the development of important lupus clinical manifestations.


Assuntos
Citocinas/imunologia , Flavanonas/farmacologia , Memória Imunológica/efeitos dos fármacos , Nefrite Lúpica/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Animais , Modelos Animais de Doenças , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Masculino , Camundongos , Linfócitos T Reguladores/patologia
4.
Am J Physiol Renal Physiol ; 318(5): F1258-F1270, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249615

RESUMO

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.


Assuntos
Linfócitos B/metabolismo , Rim/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/metabolismo , Ativação Linfocitária , Baço/metabolismo , Terpenos , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Autoanticorpos/sangue , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Rim/efeitos dos fármacos , Rim/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Baço/efeitos dos fármacos , Baço/patologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Proteína 1 de Ligação a X-Box/genética
5.
Ann Rheum Dis ; 79(6): 713-723, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32220834

RESUMO

OBJECTIVE: To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN). METHODS: Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. RESULTS: The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. CONCLUSIONS: We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.


Assuntos
Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Sociedades Médicas , Antirreumáticos/uso terapêutico , Azatioprina/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Quimioterapia Combinada , Europa (Continente) , Taxa de Filtração Glomerular , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Nefrite Lúpica/complicações , Nefrite Lúpica/patologia , Nefrite Lúpica/fisiopatologia , Ácido Micofenólico/uso terapêutico , Proteinúria/etiologia , Proteinúria/terapia
6.
Am J Kidney Dis ; 76(2): 265-281, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32220510

RESUMO

Systemic lupus erythematosus is a multisystem autoimmune disease that commonly affects the kidneys. Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus and a major risk factor for morbidity and mortality. The pathophysiology of LN is heterogeneous. Genetic and environmental factors likely contribute to this heterogeneity. Despite improved understanding of the pathogenesis of LN, treatment advances have been few and risk for kidney failure remains unacceptably high. This installment in the Core Curriculum of Nephrology provides an up-to-date review of the current understanding of LN epidemiology, pathogenesis, diagnosis, and treatment. Challenging issues such as the management of LN in pregnancy, timing of transplantation, and the evolving role of corticosteroid use in the management of LN are discussed. We review the currently accepted approach to care for patients with LN and highlight deficiencies that need to be addressed to better preserve long-term kidney health and improve outcomes in LN.


Assuntos
Corticosteroides/uso terapêutico , Fatores Imunológicos/uso terapêutico , Falência Renal Crônica/terapia , Transplante de Rim , Nefrite Lúpica , Diálise Renal , Imunidade Adaptativa/imunologia , Distribuição por Idade , Autoanticorpos/imunologia , Autoimunidade/imunologia , Biópsia , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Imunidade Inata/imunologia , Imunossupressores/uso terapêutico , Quimioterapia de Indução , Falência Renal Crônica/etiologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/epidemiologia , Nefrite Lúpica/patologia , Nefrite Lúpica/fisiopatologia , Quimioterapia de Manutenção , Masculino , Ácido Micofenólico/uso terapêutico , Gravidez , Complicações na Gravidez , Urinálise
7.
Transplant Proc ; 52(2): 614-618, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32057496

RESUMO

Renal transplantation is an ever-growing therapeutic option for patients with end-stage renal disease due to lupus nephritis. Outcomes for these patients are comparable to those of patients receiving renal transplantation for other causes. A known complication for these patients is recurrence of lupus nephritis in the renal graft (recurrent lupus nephritis [RLN]). Although disease severity at the time of recurrence is usually milder, a small number of cases have been reported to progress to allograft failure. There is a trend toward preemptive renal transplantation in patients with lupus nephritis, as more favorable outcomes have been observed with this treatment modality. While clinicians usually seek clinical remission of lupus prior to proceeding with renal transplantation, no guidelines are established regarding how often to check for serologic activity of lupus in patients with end-stage renal disease due to lupus nephritis and whether these serologic markers should be taken into account when deciding on the timing of transplantation. We present a case of early RLN co-occurring with acute cellular rejection 15 days after renal transplantation. The patient had been in clinical remission for more than 5 months prior to transplantation but had a rise in anti-double-stranded DNA antibody titers and a decrease in complement C3 level at the time of surgery. Although additional studies are needed to establish the extent to which serologic markers of lupus correlate with renal graft dysfunction, this case suggests hypocomplementemia and high double-stranded DNA antibody titers may be a risk factor for early RLN.


Assuntos
Anticorpos Antinucleares/sangue , Complemento C3/metabolismo , Transplante de Rim , Nefrite Lúpica/imunologia , Nefrite Lúpica/cirurgia , Rejeição de Enxerto , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/cirurgia , Nefrite Lúpica/patologia , Masculino , Recidiva , Fatores de Risco , Transplante Homólogo , Adulto Jovem
8.
J Immunol ; 204(6): 1448-1461, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060137

RESUMO

Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, has been shown to inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia, and multiple myeloma. In the current study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation, renal inflammation, and immune cells. Treatment of accelerated and severe lupus nephritis (ASLN) mice with Tris DBA resulted in improved renal function, albuminuria, and pathology, including measurements of glomerular cell proliferation, cellular crescents, neutrophils, fibrinoid necrosis, and tubulointerstitial inflammation in the kidneys as well as scoring for glomerulonephritis activity. The treated ASLN mice also showed significantly decreased glomerular IgG, IgM, and C3 deposits. Furthermore, the compound was able to 1) inhibit bone marrow-derived dendritic cell-mediated T cell functions and reduce serum anti-dsDNA autoantibody levels; 2) differentially regulate autophagy and both the priming and activation signals of the NLRP3 inflammasome; and 3) suppress the phosphorylation of JNK, ERK, and p38 MAPK signaling pathways. Tris DBA improved ASLN in mice through immunoregulation by blunting the MAPK (ERK, JNK)-mediated priming signal of the NLRP3 inflammasome and by regulating the autophagy/NLRP3 inflammasome axis. These results suggest that the pure compound may be a drug candidate for treating the accelerated and deteriorated type of lupus nephritis.


Assuntos
Inflamassomos/antagonistas & inibidores , Nefrite Lúpica/tratamento farmacológico , Ativação Linfocitária/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Linfócitos T Reguladores/imunologia , Animais , Autofagia/efeitos dos fármacos , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Organometálicos/uso terapêutico , Índice de Gravidade de Doença , Linfócitos T Reguladores/efeitos dos fármacos
9.
Lupus ; 29(3): 340-343, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31918602

RESUMO

Membranous nephropathy is one of the most common causes of nephrotic syndrome in the adult population. According to the underlying etiology, membranous nephropathy is classified as either primary or secondary. Systemic lupus erythematosus is an autoimmune disease that can affect the kidneys in 50% of patients in the course of the disease. Renal disease may be the first manifestation of systemic lupus erythematosus and the development of systemic findings may be delayed for about 1-5 years following the diagnosis of lupus nephritis. We present a 59-year-old male patient who had a diagnosis of idiopathic membranous nephropathy since 2007 and developed membranous lupus nephritis during the 12-year follow-up without any extrarenal systemic lupus erythematosus findings.


Assuntos
Glomerulonefrite Membranosa/patologia , Nefrite Lúpica/etiologia , Nefrite Lúpica/patologia , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/patologia , Anticorpos Antinucleares/sangue , Progressão da Doença , Glomerulonefrite Membranosa/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Receptores da Fosfolipase A2/imunologia
10.
Exp Mol Pathol ; 114: 104384, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31987844

RESUMO

Lupus nephritis (LN) is a chronic autoimmune disease. Recently, microRNA (miR)-133 has been demonstrated to play an important role in renal cell carcinoma. Our current study was designed to test the role of miR-133 and its potential target in LN. First, significant correlation of LASP1 and miR-133 levels was observed in the human LN tissue. Modification of miR-133 level in the human mesangial cells (HMCs) by either overexpression or knockdown demonstrated a suppressive role of miR-133 in cell proliferation and an inductive role in cell apoptosis. Modification of LASP1 level in the HMCs demonstrated the opposing effects of LASP1 to miR-133 on proliferation and apoptosis. In addition, luciferase assay showed miR-133 directly regulates LASP1 expression through its binding site in the 3'UTR of LASP1. At last, our data showed that the changes in properties, such as suppression in proliferation and induction in apoptosis, induced by overexpression of miR-133 were restored by additional expression of LASP1. In summary, our obtained data demonstrated that miR-133 suppresses proliferation and promotes apoptosis through its binding with LASP1 in human mesangial cells. This study revealed a new mechanism involving the interaction of miR-133 and LASP1 in the pathogenesis of LN.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proliferação de Células/genética , Proteínas do Citoesqueleto/genética , Proteínas com Domínio LIM/genética , Nefrite Lúpica/genética , MicroRNAs/genética , Adolescente , Adulto , Apoptose/genética , Movimento Celular/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Nefrite Lúpica/patologia , Masculino , Adulto Jovem
11.
Lupus ; 29(2): 213-215, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31924141

RESUMO

Systemic lupus erythematosus (SLE) is a hypercoagulable state due to a variety of mechanisms. Herein, we discuss the case of a 40-year-old gentleman who presented with cerebral venous sinus thrombosis (CVST) as the first manifestation of underlying SLE. On initial presentation, he did not endorse any other signs and symptoms to suggest the presence of an autoimmune condition. Work-up revealed an absence of antiphospholipid antibodies. Further evaluation uncovered the underlying etiology of the CVST as SLE-induced nephrotic syndrome. The existing literature on CVST suggests that there are only two other biopsy-proven cases of lupus nephritis leading to nephrotic range proteinuria as the etiology for CVST. Given the rarity of this presentation, there are no clearly delineated treatment strategies.


Assuntos
Rim/patologia , Nefrite Lúpica/complicações , Trombose dos Seios Intracranianos/diagnóstico por imagem , Adulto , Anticoagulantes/uso terapêutico , Humanos , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Imagem por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Microscopia Eletrônica , Trombose dos Seios Intracranianos/tratamento farmacológico
12.
Lupus ; 29(2): 205-209, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31924146

RESUMO

OBJECTIVE: This study aimed to compare choroidal thickness between patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) in complete renal remission to that of patients with SLE without LN. METHODS: This was a retrospective case-control study of 23 SLE patients meeting either the American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria and followed at Washington University School of Medicine Rheumatology or Nephrology, and Ophthalmology outpatient clinics. The diagnosis of LN was based on renal pathology, and complete renal remission was defined as proteinuria <500 mg/daily and serum creatinine at baseline. Extra-renal flare status was determined using modified Fortin criteria. Choroidal thickness was measured using spectral-domain optical coherence tomography and read by blinded reviewers. RESULTS: In SLE patients without extra-renal flare, choroidal thickness of LN patients was 281 ± 78 µm compared to 288 ± 70 µm in non-LN SLE patients (p = 0.766) at the fovea. CONCLUSION: Choroidal thickness was not different in patients with LN in remission compared to non-LN SLE patients in remission. Additional studies are needed to examine choroidal thickness in patients with SLE with active LN.


Assuntos
Corioide/patologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/patologia , Adulto , Corioide/diagnóstico por imagem , Feminino , Humanos , Rim/patologia , Rim/fisiopatologia , Lúpus Eritematoso Sistêmico/diagnóstico por imagem , Nefrite Lúpica/diagnóstico por imagem , Nefrite Lúpica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Indução de Remissão , Estudos Retrospectivos , Tomografia de Coerência Óptica
13.
Clin Exp Rheumatol ; 38(2): 239-244, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31287412

RESUMO

OBJECTIVES: Tubulointerstitial damage in lupus nephritis (LN) is an important predictor of renal prognosis. Here, we investigated the factors associated with aggravation of tubulointerstitial damage in patients with LN. METHODS: Patients with LN, who underwent repeated renal biopsy due to treatment failure at a tertiary referral hospital between 1997 and 2017 were identified. Clinicopathologic and laboratory data were collected. Aggravation of tubulointerstitial damage (tubular atrophy and/or interstitial fibrosis) was defined as progression of severity from none-to-mild to moderate-to-severe. Factors associated with aggravation of tubulointerstitial damage were evaluated using logistic regression analysis. RESULTS: A total of 52 LN patients were included for analysis. Aggravation of tubulointerstitial damage at the second renal biopsy was observed in 19 (36.5%) patients. In multivariable logistic regression analysis, use of hydroxychloroquine (adjusted OR 0.215, 95% CI 0.049-0.941, p=0.041) was inversely associated with aggravation of tubulointerstitial damage, and higher renal component of systemic lupus erythematosus disease activity index (SLEDAI) at first biopsy (adjusted OR 1.331, 95% CI 1.083-1.636, p=0.007) was associated with aggravation of tubulointerstitial damage. In terms of use of HCQ, both length of treatment with HCQ (adjusted OR 0.974, 95% CI 0.951-0.998, p=0.036) and cumulative dose of HCQ (log transferred value) (adjusted OR 0.485, 95% CI 0.262-0.896, p=0.020) were inversely associated with aggravation of tubulointerstitial damage. CONCLUSIONS: Use of hydroxychloroquine was associated with lower risk of aggravation in tubulointerstitial damage, and higher renal component of SLEDAI at first renal biopsy was associated with higher risk of aggravation in tubulointerstitial damage.


Assuntos
Biópsia/efeitos adversos , Túbulos Renais/patologia , Nefrite Lúpica , Progressão da Doença , Humanos , Hidroxicloroquina/uso terapêutico , Rim/patologia , Nefrite Lúpica/patologia , Prognóstico , Estudos Retrospectivos , Falha de Tratamento
14.
Nat Rev Nephrol ; 16(4): 238-250, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31853010

RESUMO

The immune mechanisms that cause tissue injury in lupus nephritis have been challenging to define. The advent of high-dimensional cellular analyses, such as single-cell RNA sequencing, has enabled detailed characterization of the cell populations present in small biopsy samples of kidney tissue. In parallel, the development of methods that cryopreserve kidney biopsy specimens in a manner that preserves intact, viable cells, has enabled the uniform analysis of tissue samples collected at multiple sites and across many geographic areas and demographic cohorts with high-dimensional platforms. The application of these methods to kidney biopsy samples from patients with lupus nephritis has begun to define the phenotypes of both infiltrating and resident immune cells, as well as parenchymal cells, present in nephritic kidneys. The detection of similar immune cell populations in urine suggests that it might be possible to non-invasively monitor immune activation in kidneys. Once applied to large patient cohorts, these high-dimensional studies might enable patient stratification according to patterns of immune cell activation in the kidney or identify disease features that can be used as surrogate measures of efficacy in clinical trials. Applied broadly across multiple inflammatory kidney diseases, these studies promise to enormously expand our understanding of renal inflammation in the next decade.


Assuntos
Células Epiteliais/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Sequenciamento Completo do Exoma/métodos , Biópsia por Agulha , Células Epiteliais/patologia , Feminino , Humanos , Imuno-Histoquímica , Nefrite Lúpica/genética , Masculino , Biologia Molecular/métodos , Sensibilidade e Especificidade , Análise de Sequência de RNA
15.
Clin Exp Immunol ; 199(1): 39-49, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31509231

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. One of the key factors associated with SLE pathogenesis is excessive production of type I interferons (IFNs). This could result from increased activation of type I IFN-stimulating pathways, but also from decreased activation of type I IFN-inhibitory pathways. Recently, we have identified that immunoglobulin (Ig)G immune complexes strongly inhibit type I IFN production in healthy individuals by inhibitory signaling through Fcγ receptor IIa (FcγRIIa) on dendritic cells (DCs). Because, in SLE patients, immune complexes are characteristically present, we assessed whether FcγR-induced suppression of type I IFN is functional in DCs of SLE patients. We divided the SLE patients into one group without, and one group with, previous major organ involvement, for which we chose nephritis as a prototypical example. We show that DCs of lupus nephritis patients displayed impaired FcγR-mediated type I IFN inhibition compared to SLE patients without major organ involvement or healthy controls. We verified that this impaired type I IFN inhibition was not related to differences in disease activity, medication, FcγRIIa expression or expression of IFN regulatory transcription factors (IRF)1 and IRF5. In addition, we identified that DCs of lupus nephritis patients show increased FcγR-induced interleukin (IL)-1ß production, which is another important cytokine that promotes kidney inflammation. Taken together, these data indicate that DCs of lupus nephritis patients display altered FcγR-mediated regulation of cytokine production, resulting in elevated levels of type I IFN and IL-1ß. This dysregulation may contribute to the development of nephritis in SLE patients.


Assuntos
Células Dendríticas/imunologia , Interferon Tipo I/imunologia , Interleucina-1beta/imunologia , Nefrite Lúpica/imunologia , Receptores de IgG/imunologia , Adulto , Células Dendríticas/patologia , Feminino , Humanos , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade
16.
J Immunol Res ; 2019: 5071687, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815154

RESUMO

Autophagy is an important biology process, central to the maintenance of biology process in both physiological and pathological situations. It is regarded as a "double-edged sword"-exerting both protective and/or detrimental effects. These two-way effects are observed in immune cells as well as renal resident cells, including podocytes, mesangial cells, tubular epithelial cells, and endothelial cells of the glomerular capillaries. Mounting evidence suggests that autophagy is implicated in the pathological process of various immune-related renal diseases (IRRDs) as well as the kidney that underwent transplantation. Here, we provide an overview of the pathological role of autophagy in IRRDs, including lupus nephritis, IgA nephropathy, membrane nephropathy, ANCA-associated nephritis, and diabetic nephropathy. The understanding of the pathogenesis and regulatory mechanisms of autophagy in these renal diseases may lead to the identification of new diagnostic targets and refined therapeutic modulation.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Proteínas Relacionadas à Autofagia/imunologia , Autofagia/imunologia , Nefropatias Diabéticas/imunologia , Glomerulonefrite por IGA/imunologia , Hematúria/imunologia , Nefrite Lúpica/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Anticitoplasma de Neutrófilos/biossíntese , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Células Dendríticas , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Regulação da Expressão Gênica , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/patologia , Hematúria/genética , Hematúria/patologia , Humanos , Transplante de Rim , Nefrite Lúpica/genética , Nefrite Lúpica/patologia , Macrófagos/imunologia , Macrófagos/patologia , Células Mesangiais/imunologia , Células Mesangiais/patologia , Podócitos/imunologia , Podócitos/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
17.
Int J Mol Sci ; 20(24)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835612

RESUMO

Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell transcription factors, cytokines and B cell-T cell interaction can result in aberrant B cell maturation and autoantibody production. These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients. Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications. While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells. Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation. Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell-T cell interaction. These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients. Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire. Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN. Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients.


Assuntos
Linfócitos B/patologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/tratamento farmacológico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Azatioprina/farmacologia , Azatioprina/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Ensaios Clínicos como Assunto , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Humanos , Imunossupressores/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico
18.
Front Immunol ; 10: 2681, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31849932

RESUMO

Mucosal-associated invariant T (MAIT) cells are a subset of innate-like lymphocytes that are restricted by major histocompatibility complex-related molecule 1 (MR1). In this study, we investigated the role of MAIT cells in the pathogenesis of lupus in FcγRIIb-/- Yaa mice, a spontaneous animal model of lupus. Using two approaches of MAIT cell deficiency, MR1 knockout animals and a newly synthesized inhibitory MR1 ligand, we demonstrate that MAIT cells augment the disease course of lupus by enhancing autoantibody production and tissue inflammation. MR1 deficiency reduced germinal center responses and T cell responses in these mice. Suppression of MAIT cell activation by the inhibitory MR1 ligand reduced autoantibody production and lupus nephritis in FcγRIIb-/- Yaa mice. MAIT cells directly enhanced autoantibody production by B cells in vitro. Our results indicate the contribution of MAIT cells to lupus pathology and the potential of these cells as novel therapeutic targets for autoimmune diseases such as lupus.


Assuntos
Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Células T Invariáveis Associadas à Mucosa/imunologia , Animais , Humanos , Camundongos
19.
Rev. méd. Chile ; 147(12): 1510-1517, dic. 2019. tab, graf
Artigo em Espanhol | LILACS | ID: biblio-1094184

RESUMO

Background Lupus nephritis (LN) is a complication of systemic lupus erythematosus that requires renal biopsy (RB). Proliferative classes III, IV-S, IV-G have especial clinical and pathological characteristics. Aim To determine the association between pathological features in RB with serum creatinine and urine protein levels. Material and Methods We analyzed 186 RB performed in adults aged 18 to 73 years, from a renal pathology reference center. Histopathological variables such as class and subclass of proliferative LN, endocapillary and extracapillary proliferation, activity and chronicity indexes, and vascular sclerosis were correlated with serum creatinine and urine protein levels, at the time of diagnosis. Results As compared with LN III, all the morphological and laboratory values were significantly more deteriorated in LN IV, with special focus on vascular sclerosis. Serum creatinine was the only variable that significantly differentiated LN IV-S from LN IV-G. Proteinuria was non-significantly higher in LN IV-G compared to LN IV-S. However, the difference became significant when proteinuria was compared between LN IV-G and LN III. Conclusions The significant difference in serum creatinine between LN IV-S and LN IV-G supports the concept that they are different subclasses. Proteinuria is a variable that differentiates classes III from IV-G, being significantly higher in the second. Severe arteriosclerosis is a constant and significant finding that differentiates LN III from LN IV. Thus, we propose its usefulness for distinguishing LN classes, and eventually, to be considered in the chronicity index.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Adulto Jovem , Nefrite Lúpica/patologia , Rim/patologia , Proteinúria/patologia , Biópsia , Índice de Gravidade de Doença , Estudos Retrospectivos , Creatinina/sangue
20.
Saudi J Kidney Dis Transpl ; 30(5): 1144-1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31696854

RESUMO

This descriptive observational study was conducted at the Department of Nephrology, Bahawal Victoria Hospital, Bahawalpur, Pakistan, from January 2012 to April 2018, to study the pattern of biopsy-proven kidney diseases in that region as a part to establish a national renal biopsy registry. All adult patients who underwent renal biopsy at the Bahawal Victoria Hospital, Bahawalpur, Pakistan, from January 2012 to April 2018, were included in the study. All the biopsies were evaluated by light microscopy and immunofluorescence. All the patients underwent urine dipstick, microscopic examination, and quantification of proteinuria. Hepatitis B surface antigen, anti-hepatitis C virus, human immunodeficiency virus, and serology (antinuclear antibody, anti-ds DNA, and C3 and C4) were checked in all the patients. There were a total of 195 patients, with a mean age of 30.5 ± 12.8 years. Females were comparatively younger than males (P = 0.0154). Primary glomerulonephritis (GN) accounted for 77% (155) of all the patients, whereas secondary GN contributed 15.8%. Focal and segmental glomerulosclerosis (FSGS) was the most common diagnosis (28.2%) followed by membranous nephropathy (MN) (18.9%). Lupus nephritis was the third-most common pathology, and it predominated among females (P= 0.0026). Out of the eight diabetic patients, one each had FSGS and crescentic GN. In conclusion, primary glomerular diseases were the predominant biopsy-proven kidney diseases, and FSGS and MN were the most common glomerular diseases. This pattern in South Punjab closely resembles that in southern and northern parts of the country.


Assuntos
Hospitais de Ensino , Nefropatias/epidemiologia , Nefropatias/patologia , Adolescente , Adulto , Idoso , Biópsia , Feminino , Glomerulonefrite Membranosa/epidemiologia , Glomerulonefrite Membranosa/patologia , Glomerulosclerose Segmentar e Focal/epidemiologia , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Nefrite Lúpica/epidemiologia , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Paquistão/epidemiologia , Valor Preditivo dos Testes , Prevalência , Adulto Jovem
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