RESUMO
Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN has evolved, with the identification of specific autoantibodies against novel podocyte antigens and the unraveling of intricate pathogenic pathways. Although the anti-CD20 monoclonal antibody rituximab is favored as part of the initial therapy in MN, a subgroup of MN patients may be resistant to rituximab necessitating the use of alternative agents such as cytotoxic therapies. In addition, newer agents such as novel anti-CD20 monoclonal antibodies, therapies targeting the CD38-positive plasma cells and anti-complement therapy are being studied in patients who are resistant to traditional treatment strategies. This manuscript furnishes a review of the novel developments in the pathophysiology of MN including the identification of target antigens and current treatment standards for MN, concentrating on evidenced-based interventions designed to attain remission and to prevent disease progression.
Assuntos
Glomerulonefrite Membranosa , Humanos , Glomerulonefrite Membranosa/tratamento farmacológico , Rituximab/uso terapêutico , Anticorpos Monoclonais , Autoanticorpos , Complexo Antígeno-Anticorpo , Receptores da Fosfolipase A2RESUMO
Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.
Assuntos
Glomerulonefrite Membranosa , Humanos , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/terapia , Consenso , Autoanticorpos , Nefrectomia , Membrana Basal Glomerular/patologia , Receptores da Fosfolipase A2RESUMO
BACKGROUND: Treatment of proliferative GN with monoclonal Ig deposits (PGNMID) is not established. A monoclonal anti-CD38 antibody (daratumumab) is effective in treating multiple myeloma. Abnormal plasma cell clones may play a role in the pathogenesis of PGNMID. METHODS: We evaluated daratumumab's safety and efficacy in an open-label, phase 2 trial in 11 adults with PGNMID and one with C3 glomerulopathy (C3G) with monoclonal gammopathy. Patients had an eGFR >20 ml/min per 1.73 m2 and proteinuria >1 g/d. They received daratumumab intravenously (16 mg/kg) once weekly for 8 weeks, and then every other week for eight additional doses. Primary outcome was safety, defined as major infections, grade 3 or 4 anemia, leukopenia, or thrombocytopenia. Secondary outcomes were rate of complete remission (proteinuria <500 mg/d with <15% decline in baseline eGFR) or partial remission (>50% reduction in 24-hour proteinuria with <30% decline in eGFR) and proteinuria at 6 and 12 months. RESULTS: One patient with C3G had GN unrelated to the monoclonal gammopathy, and one with PGNMID did not complete the first infusion. Five serious adverse events occurred. During the 12 months of the trial, six of the ten patients with PGNMID who received at least one dose of daratumumab had a partial response, and four had a complete response (an overall response rate of 100%). Three patients experienced relapse, two of whom re-entered partial remission after resuming daratumumab therapy. Proteinuria declined significantly, from a median of 4346 mg/d to 1264 mg/d by 12 months. CONCLUSIONS: Daratumumab demonstrated an acceptable safety profile and resulted in significant improvement in proteinuria while stabilizing kidney function in patients with PGNMID, suggesting the drug merits further investigation. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Daratumumab in Treatment of PGNMID and C3 GN, NCT03095118.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Imunoglobulina G , Paraproteinemias/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Glomerulonefrite Membranoproliferativa/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Paraproteinemias/complicações , Projetos Piloto , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Studies comparing all treatment options for frequently-relapsing/steroid-dependent (FR/SD) minimal change disease (MCD) in adults are lacking. METHODS: Medical records of 76 adults with FR/SD MCD who were treated with corticosteroids as the first-line therapy were reviewed. Treatment options were compared for the time to relapse, change of therapy and progression (relapse on full-dose treatment). RESULTS: Second-line treatments included rituximab (RTX; n = 13), mycophenolate mofetil (MMF; n = 12), calcineurin inhibitors (CNI; n = 26) and cyclophosphamide (CTX; n = 16). During the second-line treatments, 48 (71.6%) patients relapsed at median 17 (range 2-100) months. The majority of relapses occurred during dose tapering or off drug. Twenty of 65 (30.8%) changed therapy after the first relapse. The median time to relapse after the second line was 66 versus 28 months in RTX versus non-RTX groups (P = 0.170). The median time to change of treatment was 66 and 44 months, respectively (P = 0.060). Last-line treatment options included RTX (n = 8), MMF (n = 4), CNI (n = 3) and CTX (n = 2). Seven (41.2%) patients had a relapse during the last-line treatment at median 39 (range 5-112) months. The median time to relapse was 48 versus 34 months in the RTX versus non-RTX groups (P = 0.727). One patient in the RTX group died presumably of heart failure. No major adverse event was observed. During the median follow-up of 81 (range 9-355) months, no patients developed end-stage renal disease. CONCLUSIONS: Relapse is frequent in MCD in adults. Patients treated with RTX may be less likely to require a change of therapy and more likely to come off immunosuppressive drugs.
Assuntos
Nefrose Lipoide , Adulto , Humanos , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Nefrose Lipoide/tratamento farmacológico , Recidiva , Rituximab , Esteroides , Resultado do TratamentoRESUMO
Advances in the diagnosis and treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have led to continued improvement in survival and prognosis over the course of the last 4 decades. Nevertheless, the most acute and severe disease manifestations, including severe kidney disease and alveolar hemorrhage, continue to be associated with increased early mortality from disease activity or treatment complications as well as risk for the development of end-stage kidney disease (ESKD), which in turn directly affects the overall prognosis of ANCA-associated vasculitis. Plasma exchange (PLEX) has long been proposed and used for these most severe disease manifestations under the assumption that its effects are swift and supported by our understanding of the pathogenic role of ANCA. Yet convincing evidence of a beneficial effect of PLEX in ANCA-associated vasculitis has been lacking, as early studies and small trials have generated conflicting results. The controversy regarding PLEX has been accentuated recently as the largest randomized controlled trial ever conducted in ANCA-associated vasculitis, the Plasma Exchange and Glucocorticoids in Severe ANCA-associated Vasculitis trial, which was specifically designed to evaluate the efficacy of PLEX in patients with severe renal disease or alveolar hemorrhage, failed to show a difference in the combined primary outcome measure of death or ESKD in patients who received PLEX versus those who did not. In light of these disappointing results, we herein review the currently available data on PLEX for ANCA-associated vasculitis and explain why we believe that these data no longer support the use of PLEX in ANCA-associated vasculitis.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Hemorragia/etiologia , Falência Renal Crônica/etiologia , Troca Plasmática/efeitos adversos , Plasmaferese/efeitos adversos , Ensaios Clínicos como Assunto , HumanosRESUMO
BACKGROUND: Fibrillary glomerulonephritis (FGN) is a rare type of glomerulonephritis with poor prognosis, with no known effective therapies available for treatment. The objective of the study was to evaluate the efficacy and safety of rituximab in treatment of patients with FGN and to investigate the effect of rituximab on DNAJB9 levels. METHODS: This was a pilot prospective clinical trial in which patients with idiopathic FGN were treated with two courses of rituximab (1 g each) 2 weeks apart at the beginning and then again at 6 months. Primary outcome was defined as preservation of kidney function at 12 months with stable or increased creatinine clearance. Secondary outcome was defined as achieving complete remission (CR) defined as proteinuria <300 mg/24 h or partial remission (PR) with proteinuria <3 g/24 h and at least 50% reduction in the proteinuria. DNAJB9 levels were also measured in the serum at baseline, 6 and 12 months. RESULTS: The creatinine clearance did not change significantly during this time, from 47.7 mL/min/1.73 m2 at baseline to 43.7 mL/min/1.73 m2 during follow-up (P = 0.15). Proteinuria declined from 4.43 (1.6-5.53) g/24 h at baseline to 1.9 (0.46-5.26) g/24 h at 12 months but did not reach significance (P = 0.06). None of the patients reached CR, and 3 of the 11 achieved PR. There was no change in the DNAJB9 levels following treatment with rituximab. The most common adverse event was nasal congestion, fatigue and muscle cramps. CONCLUSIONS: Treatment of patients with two courses of rituximab over a span of 6 months was associated with stabilization of renal function but did not result in a significant change in proteinuria and with no change in the DNAJB9 levels.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores/análise , Glomerulonefrite/tratamento farmacológico , Rituximab/uso terapêutico , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Glomerulonefrite/classificação , Glomerulonefrite/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Microhematuria is common in immunoglobulin A nephropathy (IgAN). However, current prognostication is based on proteinuria and mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubulointerstitial fibrosis and crescent (MEST-C) scores. METHODS: In this retrospective study, we evaluated whether MEST-C score components are associated with the presence of microhematuria at biopsy and whether the degree of microhematuria during follow-up is associated with change in estimated glomerular filtration rate (eGFR), after adjusting for clinical and histological parameters. We identified 125 patients with biopsy-proven IgAN and MEST-C scoring who were not on immunosuppressive therapy at biopsy. Microhematuria was defined as ≥3 red blood cells (RBCs)/high-power field (hpf). RESULTS: Of the 125 patients, 97 had microhematuria at baseline and were more likely to have M1, E1 and C ≥ 1 lesions (P < 0.05 for all) compared with patients without microhematuria. Of the 125 patients, 72 had follow-up data available. An increase in the degree of microhematuria was significantly associated with an eGFR decline of -0.81 mL/min/1.73 m2 [95% confidence interval (CI) -1.44 to -0.19, P = 0.01], after adjusting for follow-up time, proteinuria and T score. Severe microhematuria (≥21 RBCs/hpf) was associated with an even larger decline in eGFR (-3.99 mL/min/1.73 m2; 95% CI -6.9411 to -1.0552, P = 0.008), after similar adjustments. CONCLUSION: Degree of microhematuria during follow-up is an independent predictor of eGFR decline after adjusting for clinical and histological parameters. Therefore, monitoring the degree of microhematuria as well as proteinuria is important when evaluating patients with IgAN. Additional studies using improvement in microhematuria as a primary surrogate outcome are needed.
Assuntos
Glomerulonefrite por IGA , Adulto , Biópsia , Fibrose , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/patologia , Humanos , Rim/patologia , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Proteinúria/patologia , Estudos Retrospectivos , Esclerose/patologiaRESUMO
BACKGROUND: Little is known about the rate and predictors of finding lesions of monoclonal gammopathy (MG) of renal significance (MGRS) on kidney biopsy specimens among patients with MG. METHODS: We reviewed the medical records from 2013 to 2018 at the Mayo Clinic in Rochester, Minnesota, to identify patients with MG and whether they had undergone a kidney biopsy. In a more select group of patients with MG from 2017 to 2018, we conducted a review of records to determine how many had underlying CKD, which of those with CKD had undergone a kidney biopsy, and reasons for deferring a kidney biopsy. RESULTS: Between 2013 and 2018, we identified 6300 patients who had MG, 160 (2.5%) of whom had undergone a kidney biopsy. Of the 160 patients, 64 (40%) had an MGRS lesion; amyloid light chain amyloidosis, the most common finding, accounted for nearly half of these lesions. In the non-MGRS group comprising 96 patients, 23 had arteriosclerosis, the most common finding. In multivariate analysis, strong predictors of finding an MGRS lesion included the presence of an elevated free light chain ratio, proteinuria, and hematuria. Among 596 patients with CKD and MG from 2017 to 2018, 62 (10.4%) underwent a kidney biopsy. Kidney biopsy was deferred for 70 patients (20%); for 62 of the 70, the diagnosis was already known, and eight were not candidates for therapy. Younger age and higher proteinuria and serum creatinine levels increased the likelihood that the patient would undergo a kidney biopsy. CONCLUSIONS: Proteinuria ≥1.5 g/d, hematuria, and an elevated free light chain ratio increase the likelihood of finding MGRS, and a kidney biopsy should be highly considered in such patients.
Assuntos
Nefropatias/epidemiologia , Nefropatias/patologia , Paraproteinemias/complicações , Paraproteinemias/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Padrões de Prática Médica , Encaminhamento e Consulta , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Treatment of patients with ANCA-associated vasculitis (AAV) and severe renal involvement is not established. We describe outcomes in response to rituximab (RTX) versus cyclophosphamide (CYC) and plasma exchange (PLEX). METHODS: A retrospective cohort study of MPO- or PR3-ANCA-positive patients with AAV (MPA and GPA) and severe kidney disease (eGFR <30 ml/min per 1.73 m2). Remission, relapse, ESKD and death after remission-induction with CYC or RTX, with or without the use of PLEX, were compared. RESULTS: Of 467 patients with active renal involvement, 251 had severe kidney disease. Patients received CYC (n=161) or RTX (n=64) for remission-induction, and 51 were also treated with PLEX. Predictors for ESKD and/or death at 18 months were eGFR <15 ml/min per 1.73 m2 at diagnosis (IRR 3.09 [95% CI 1.49 to 6.40], P=0.002), renal recovery (IRR 0.27 [95% CI 0.12 to 0.64], P=0.003) and renal remission at 6 months (IRR 0.40 [95% CI 0.18 to 0.90], P=0.027). RTX was comparable to CYC in remission-induction (BVAS/WG=0) at 6 months (IRR 1.37 [95% CI 0.91 to 2.08], P=0.132). Addition of PLEX showed no benefit on remission-induction at 6 months (IRR 0.73 [95% CI 0.44 to 1.22], P=0.230), the rate of ESKD and/or death at 18 months (IRR 1.05 [95% CI 0.51 to 2.18], P=0.891), progression to ESKD (IRR 1.06 [95% CI 0.50 to 2.25], P=0.887), and survival at 24 months (IRR 0.54 [95% CI 0.16 to 1.85], P=0.330). CONCLUSIONS: The apparent benefits and risks of using CYC or RTX for the treatment of patients with AAV and severe kidney disease are balanced. The addition of PLEX to standard remission-induction therapy showed no benefit in our cohort. A randomized controlled trial is the only satisfactory means to evaluate efficacy of remission-induction treatments in AAV with severe renal involvement.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Fatores Imunológicos/uso terapêutico , Troca Plasmática , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Rituximab/uso terapêutico , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Anticorpos Anticitoplasma de Neutrófilos , Terapia Combinada , Ciclofosfamida/uso terapêutico , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Imunossupressores/uso terapêutico , Estimativa de Kaplan-Meier , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Insuficiência Renal Crônica/complicações , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Rituximab, a type I anti-CD20 antibody, has been shown to be an effective therapy in treatment of patients with MN associated with M-type phospholipase A2 receptor (PLA2R) antibodies. Despite its effectiveness, up to 40% of patients may fail to respond to rituximab, which may be related to higher PLA2R antibody titers. Obinutuzumab, a type II anti-CD20 depleter, has been shown to produce a more profound CD20 depletion and be more efficacious in treating certain hematologic malignancies compared with rituximab. We report 3 patients with PLA2R-associated MN for whom rituximab failed to induce immunologic or clinical remisison, but who were successfully treated with obinutuzumab. Obinutuzumab resulted in complete immunologic remission in all 3 cases and was followed by partial remission in 2 of the cases. Obinutuzumab appears to be a promising treatment strategy for PLA2R-associated MN that fails to respond to rituximab.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Glomerulonefrite Membranosa/terapia , Receptores da Fosfolipase A2/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Autoanticorpos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodosRESUMO
RATIONALE & OBJECTIVE: Fibrillary glomerulonephritis (FGN) is a rare glomerular disease that often progresses to kidney failure requiring kidney replacement therapy. We have recently identified a novel biomarker of FGN, DnaJ homolog subfamily B member 9 (DNAJB9). In this study, we used sequential protocol allograft biopsies and DNAJB9 staining to help characterize a series of patients with native kidney FGN who underwent kidney transplantation. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Between 1996 and 2016, kidney transplantation was performed on 19 patients with a reported diagnosis of FGN in their native/transplant kidneys. Using standard diagnostic criteria and DNAJB9 staining, we excluded 5 patients (4 atypical cases diagnosed as possible FGN and 1 donor-derived FGN). Protocol allograft biopsies had been performed at 4, 12, 24, 60, and 120 months posttransplantation. DNAJB9 immunohistochemistry was performed using an anti-DNAJB9 rabbit polyclonal antibody. Pre- and posttransplantation demographic and clinical characteristics were collected. Summary statistical analysis was performed, including nonparametric statistical tests. OBSERVATIONS: The 14 patients with FGN had a median posttransplantation follow-up of 5.7 (IQR, 2.9-13.8) years. 3 (21%) patients had recurrence of FGN, detected on the 5- (n=1) and 10-year (n=2) allograft biopsies. Median time to recurrence was 10.2 (IQR, 5-10.5) years. Median levels of proteinuria and iothalamate clearance at the time of recurrence were 243mg/d and 56mL/min. The remaining 11 patients had no evidence of histologic recurrence on the last posttransplantation biopsy, although the median time of follow-up was significantly less at 4.4 (IQR, 2.9-14.4) years. 3 (21%) patients had a monoclonal protein detectable in serum obtained pretransplantation; none of these patients had recurrent FGN. LIMITATIONS: Small study sample and shorter follow-up time in the nonrecurrent versus recurrent group. CONCLUSIONS: In this series, FGN had an indolent course in the kidney allograft in that detectable histologic recurrence did not appear for at least 5 years posttransplantation.
Assuntos
Glomerulonefrite/cirurgia , Proteínas de Choque Térmico HSP40/análise , Transplante de Rim , Rim/química , Proteínas de Membrana/análise , Chaperonas Moleculares/análise , Adulto , Idoso , Biomarcadores/análise , Biópsia , Feminino , Glomerulonefrite/patologia , Humanos , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
Kidney biopsy is the gold standard to diagnose membranous nephropathy (MN). Approximately 70%-80% of patients with primary MN have anti-phospholipase A2 receptor (PLA2R) antibodies. We hypothesized that PLA2R antibody testing without kidney biopsy may be a valid strategy to make a non-invasive diagnosis of MN in patients with a negative work-up for secondary causes. The medical records of all Mayo Clinic patients in Minnesota, Florida, and Arizona with serum PLA2R antibody tests between January 2015 and June 2018 were reviewed. PLA2R antibody testing was performed in 838 unique patients, with 143 testing positive. In 132 of these patients, a native kidney biopsy was performed. The primary diagnosis in all biopsies was MN. Potential secondary causes were identified in 35 cases, with the most common being malignancy and autoimmunity. Ninety-seven patients had a negative work-up for secondary causes of MN. Sixty of those 97 patients had an estimated glomerular filtration rate (eGFR) >60 ml/min/1.73m2. In these patients, the kidney biopsy did not provide significant information that altered management; one patient had a superimposed diabetic nephropathy and a second patient had a superimposed focal segmental glomerulosclerosis (FSGS) lesion. Among the 37 patients with primary MN and eGFR <60 ml/min/1.73m2, additional findings included acute interstitial nephritis, diabetic nephropathy, and cellular crescents in one case each. Thus, among patients with preserved kidney function and no evidence of secondary causes, a positive PLA2R antibody test highly predicts a tissue diagnosis of PLA2R-associated MN. Further validation in a prospective study is warranted to determine whether PLA2R antibody testing be used as a non-invasive diagnostic test to guide therapy.
Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/diagnóstico , Receptores da Fosfolipase A2/imunologia , Adulto , Autoanticorpos/imunologia , Feminino , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/imunologia , Humanos , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Biópsia Líquida/métodos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
INTRODUCTION: C3 glomerulonephritis (C3GN) is a form of proliferative glomerulonephritis characterized by dominant glomerular C3 deposition. There is currently no consensus guideline on therapy for this disease. Experience with corticosteroids alone is scant in C3GN. We report the experience of treating patients with C3GN in association with monoclonal gammopathy with corticosteroid at a single center. MATERIALS AND METHODS: Corticosteroid therapy alone was used to treat 6 patients with C3GN who were also found to have monoclonal gammopathy at the time of presentation. RESULTS: Median age of this cohort was 65 years. Median estimated glomerular filtration rate (eGFR) by MDRD equation was 31.6 mL/min/1.73m2 at presentation. After a median duration of follow-up of 23.5 months, all patients showed improvement in proteinuria: median proteinuria reduced from 2.3 to 0.5 g/d. Four of 6 patients showed improvement in kidney function. One patient who had required renal replacement therapy recovered renal function. Median eGFR at follow-up was 38.7 mL/min/1.73m2. DISCUSSION: In patients with C3GN in association with monoclonal gammopathy, corticosteroid therapy alone may be a viable treatment option. Work-up should be done to exclude a hematologic neoplasm and inherited complement abnormalities before proceeding to corticosteroid therapy.â©.
Assuntos
Corticosteroides/uso terapêutico , Glomerulonefrite Membranoproliferativa/complicações , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Paraproteinemias/complicações , Idoso , Complemento C3/metabolismo , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite Membranoproliferativa/metabolismo , Glomerulonefrite Membranoproliferativa/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteinúria/etiologia , Adulto JovemRESUMO
Renal histologic expression of the podocyte-specific protein, nephrin, but not podocin, is reduced in preeclamptic compared with normotensive pregnancies. We hypothesized that renal expression of podocyte-specific proteins would be reflected in urinary extracellular vesicles (EVs) of podocyte origin and accompanied by increased urinary soluble nephrin levels (nephrinuria) in preeclampsia. We further postulated that podocyte injury and attendant formation of EVs are related mechanistically to cellfree fetal hemoglobin (HbF) in maternal plasma. Our study population included preeclamptic (n=49) and normotensive (n=42) pregnant women recruited at delivery. Plasma measurements included HbF concentrations and concentrations of the endogenous chelators haptoglobin, hemopexin, and α1- microglobulin. We assessed concentrations of urinary EVs containing immunologically detectable podocyte-specific proteins by digital flow cytometry and measured nephrinuria by ELISA. The mechanistic role of HbF in podocyte injury was studied in pregnant rabbits. Compared with urine from women with normotensive pregnancies, urine from women with preeclamptic pregnancies contained a high ratio of podocin-positive to nephrin-positive urinary EVs (podocin+ EVs-to-nephrin+ EVs ratio) and increased nephrinuria, both of which correlated with proteinuria. Plasma levels of hemopexin, which were decreased in women with preeclampsia, negatively correlated with proteinuria, urinary podocin+ EVs-to-nephrin+ EVs ratio, and nephrinuria. Administration of HbF to pregnant rabbits increased the number of urinary EVs of podocyte origin. These findings provide evidence that urinary EVs are reflective of preeclampsia-related altered podocyte protein expression. Furthermore, renal injury in preeclampsia associated with an elevated urinary podocin+ EVs-to-nephrin+ EVs ratio and may be mediated by prolonged exposure to cellfree HbF.
Assuntos
Vesículas Extracelulares , Nefropatias/urina , Podócitos/ultraestrutura , Pré-Eclâmpsia/urina , Adulto , Animais , Feminino , Humanos , Gravidez , Complicações na Gravidez/urina , CoelhosRESUMO
Focal segmental glomerulosclerosis (FSGS) is a lesion and not a disease. This conundrum is the crux of controversies regarding interventions to alter its natural history. In the broadest sense, the lesion can be primary (idiopathic), or secondary to a process originating outside the kidneys or to a genetic mutation. The organ-based target is the podocyte, and the mechanisms responsible for the podocytopathy are numerous and diverse. Recurrence of primary FSGS in renal allografts provides the best evidence for the existence of a circulating factor or factors, the nature of which remains uncertain. The separation of primary from secondary FSGS clinically and pathologically is challenging, but full-blown nephrotic syndrome and diffuse (universal) foot process effacement are strong signals for a primary form of FSGS. It is imperative that clinical trials designed to investigate therapeutic strategies for patients with a lesion of FSGS pay careful attention to the separation of primary from secondary forms of FSGS. This critical review provides a rationale and a process for helping to ensure that this is accomplished, such that clinical trials provide useful information and treatment responsiveness applicable to the primary forms of FSGS.
Assuntos
Ensaios Clínicos como Assunto/normas , Glomerulosclerose Segmentar e Focal/terapia , Projetos de Pesquisa/normas , HumanosRESUMO
BACKGROUND: An increased number of podocyte-derived extracellular vesicles (pEVs) may reflect podocyte injury in renal disease. Elevated glomerular pressure and other insults may injure podocytes, yet it remains unclear whether the numbers of pEVs are altered in hypertensive patients. We tested the hypothesis that urinary pEV levels would be elevated in patients with renovascular hypertension (RVH) compared with essential hypertension (EH) or healthy volunteers (HVs). METHODS: We prospectively enrolled patients with EH ( n = 30) or RVH ( n = 31) to study renal blood flow (RBF) and cortical perfusion using multidetector computed tomography under controlled condition (regulated sodium intake and renin-angiotensin blockade). After isolation from urine samples, pEVs (nephrin and podocalyxin positive) were characterized by flow cytometry. Fourteen RVH patients were studied again 3 months after stenting or continued medical therapy. HVs ( n = 15) served as controls. RESULTS: The fraction of pEV among urinary EVs was elevated in RVH compared with HVs and EH (11.4 ± 6.4, 6.8 ± 3.4 and 6.3 ± 3.7%, respectively; P < 0.001) and remained unchanged after 3 additional months of therapy and after controlling for clinical parameters. However, eGFR- and age-adjusted pEV levels did not correlate with any clinical or renal parameters. CONCLUSIONS: In hypertensive patients under controlled conditions, urinary pEV levels are elevated in patients with RVH and low eGFR compared with patients with EH and relatively preserved renal function. These pEVs may reflect podocyte injury secondary to kidney damage, and their levels might represent a novel therapeutic target.
Assuntos
Micropartículas Derivadas de Células/patologia , Hipertensão Renovascular/patologia , Hipertensão Renovascular/urina , Podócitos/patologia , Idoso , Micropartículas Derivadas de Células/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Podócitos/metabolismo , Estudos Prospectivos , Circulação RenalRESUMO
BACKGROUND: Complement activation plays an important role in the pathophysiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although it remains unclear which pathway is activated. Whether pauci-immune necrotizing crescentic glomerulonephritis (pauci-immune GN) with negative ANCA serology is part of the spectrum of AAV or a different disease entity is essentially unknown. METHODS: We used proteomic analysis to delineate the complement profile in a series of 13 kidney biopsies of patients with pauci-immune GN, with either proteinase 3 (PR3) (five patients) or myeloperoxidase (MPO) antibodies (four patients) or with consistently negative ANCA serology (four patients). Immunofluorescence staining of glomeruli was essentially negative in the PR3-ANCA and MPO-ANCA groups, while a mild staining for C3 was seen in the ANCA-negative cases. No electron-dense deposits were found in the PR3-ANCA and MPO-ANCA groups, but mesangial and few subepithelial deposits were clearly present in the ANCA-negative specimens. RESULTS: Mass spectrometry revealed low spectra numbers for C3 and immunoglobulins in both PR3-positive and MPO-positive patients with minimal or no C4 and C9. In contrast, larger spectra numbers for C3, moderate spectra numbers for C9, complement factor H-related protein-1 and low spectra numbers for C4, C5 and immunoglobulins were found in the ANCA-negative cases. CONCLUSION: While complement activation is noted in AAV, the complement activation appears to be more prominent in the ANCA-negative glomerulonephritis. The larger amount of C3 and moderate amount of C9 in the ANCA-negative glomerulonephritis implies activation of the alternate and terminal pathway of complement, suggesting that this entity may be caused or promoted by a genetic or acquired defect in the alternative pathway.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Ativação do Complemento/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Mieloblastina/imunologia , Peroxidase/imunologia , Proteoma/análise , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Feminino , Glomerulonefrite/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Proteômica/métodos , Adulto JovemRESUMO
BACKGROUND: To determine the effect of statins on renal hemodynamics in normal volunteers and those with autosomal dominant polycystic kidney disease either with mild or moderate renal dysfunction. METHODS: Thirty-two study subjects were enrolled in this study: 11 normal volunteers, 11 study subjects with autosomal dominant polycystic kidney disease (ADPKD) and mild kidney disease and 10 study subjects with ADPKD and moderate kidney disease. Subjects in each group received simvastatin 40 mg once daily for a period of 4 weeks. Renal blood flow was measured based on para-amino-hippurate (PAH) clearance and with the use of a magnetic resonance (MR) scanner at the beginning and following 4 weeks of therapy with statins. RESULTS: At the end of the study, except for the lipid profile, which was significantly lower in all groups, other laboratory results showed no change. Four weeks of therapy with simvastatin resulted in no change in serum creatinine, 24-h urinary protein, sodium, iothalamate clearance, PAH clearance or renal blood flow as measured by MRI or based on PAH clearance. CONCLUSIONS: Four weeks of therapy with simvastatin did not change renal blood flow in the study subjects with ADPKD with mild-to-moderate renal dysfunction or in healthy volunteers. CLINICAL TRIAL REGISTRATION NUMBER: NCT02511418.
Assuntos
Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/fisiopatologia , Rim Policístico Autossômico Dominante/fisiopatologia , Circulação Renal/efeitos dos fármacos , Sinvastatina/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/tratamento farmacológicoRESUMO
Recent reports suggest that deep hematologic responses to chemotherapy are associated with improved renal outcomes in monoclonal immunoglobulin deposition disease (MIDD). Here we describe the long term outcomes and identify prognostic factors after first line treatment of the largest reported series of patients with MIDD. Between March 1992 and December 2014, 88 patients with MIDD were seen at Mayo Clinic, MN. Renal responses were defined using criteria used for light chain amyloidosis (AL) or those used by the IMWG. Sixty-one (69%) patients had a GFR < 30 mL/min/1.73 m2 and 16 (18%) were on renal replacement therapy at diagnosis. The interval between albuminuria or elevation in creatinine and MIDD diagnosis was 12 months suggesting a delay in diagnosis. Thirty-seven patients (42%) had at least a hematologic CR/VGPR. Fifty-three (60%) received an autologous stem cell transplant (ASCT) or proteasome inhibitor (PI)-based treatments. Patients receiving ASCT or PI-based therapies were more likely to achieve at least a hematologic CR/VGPR compared to those receiving other therapies: 66% vs 2%, p < 0.0001. Patients that achieved a hematologic CR were more likely to achieve a renal response (53% vs 24%, p = 0.001). Five year overall and renal survival for the entire cohort was 67% and 57%, respectively. In multivariate analyses, a baseline GFR < 20 mL/min/1.73 m2 and a renal response (using AL or IMWG criteria) were independently predictive of progression to dialysis. This study confirms that deep hematologic responses, best achieved with ASCT or PI-based therapies, are a prerequisite to achieving renal responses. Am. J. Hematol. 91:1123-1128, 2016. © 2016 Wiley Periodicals, Inc.