RESUMO
Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.
Assuntos
Creatinina , Glomerulonefrite por IGA , Proteínas Recombinantes de Fusão , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/urina , Glomerulonefrite por IGA/diagnóstico , Método Duplo-Cego , Feminino , Masculino , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/administração & dosagem , Adulto , Pessoa de Meia-Idade , Creatinina/urina , Creatinina/sangue , Resultado do Tratamento , Proteinúria/tratamento farmacológico , Proteinúria/urina , Receptores Fc/uso terapêutico , Adulto Jovem , Taxa de Filtração Glomerular/efeitos dos fármacosRESUMO
BACKGROUND: IgA nephropathy is a chronic immune-mediated kidney disease and a major cause of kidney failure worldwide. The gut mucosal immune system is implicated in its pathogenesis, and Nefecon is a novel, oral, targeted-release formulation of budesonide designed to act at the gut mucosal level. We present findings from the 2-year, phase 3 NefIgArd trial of Nefecon in patients with IgA nephropathy. METHODS: In this phase 3, multicentre, randomised, double-blind, placebo-controlled trial, adult patients (aged ≥18 years) with primary IgA nephropathy, estimated glomerular filtration rate (eGFR) 35-90 mL/min per 1·73 m2, and persistent proteinuria (urine protein-creatinine ratio ≥0·8 g/g or proteinuria ≥1 g/24 h) despite optimised renin-angiotensin system blockade were enrolled at 132 hospital-based clinical sites in 20 countries worldwide. Patients were randomly assigned (1:1) to receive 16 mg/day oral capsules of Nefecon or matching placebo for 9 months, followed by a 15-month observational follow-up period off study drug. Randomisation via an interactive response technology system was stratified according to baseline proteinuria (<2 or ≥2 g/24 h), baseline eGFR (<60 or ≥60 mL/min per 1·73 m2), and region (Asia-Pacific, Europe, North America, or South America). Patients, investigators, and site staff were masked to treatment assignment throughout the 2-year trial. Optimised supportive care was also continued throughout the trial. The primary efficacy endpoint was time-weighted average of eGFR over 2 years. Efficacy and safety analyses were done in the full analysis set (ie, all randomly assigned patients). The trial was registered on ClinicalTrials.gov, NCT03643965, and is completed. FINDINGS: Patients were recruited to the NefIgArd trial between Sept 5, 2018, and Jan 20, 2021, with 364 patients (182 per treatment group) randomly assigned in the full analysis set. 240 (66%) patients were men and 124 (34%) were women, and 275 (76%) identified as White. The time-weighted average of eGFR over 2 years showed a statistically significant treatment benefit with Nefecon versus placebo (difference 5·05 mL/min per 1·73 m2 [95% CI 3·24 to 7·38], p<0·0001), with a time-weighted average change of -2·47 mL/min per 1·73 m2 (95% CI -3·88 to -1·02) reported with Nefecon and -7·52 mL/min per 1·73 m2 (-8·83 to -6·18) reported with placebo. The most commonly reported treatment-emergent adverse events during treatment with Nefecon were peripheral oedema (31 [17%] patients, vs placebo, seven [4%] patients), hypertension (22 [12%] vs six [3%]), muscle spasms (22 [12%] vs seven [4%]), acne (20 [11%] vs two [1%]), and headache (19 [10%] vs 14 [8%]). No treatment-related deaths were reported. INTERPRETATION: A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy. Nefecon was also well tolerated, with a safety profile as expected for a locally acting oral budesonide product. FUNDING: Calliditas Therapeutics.
Assuntos
Glomerulonefrite por IGA , Adulto , Masculino , Humanos , Feminino , Adolescente , Glomerulonefrite por IGA/tratamento farmacológico , Ásia , Budesonida/efeitos adversos , Europa (Continente) , Proteinúria/tratamento farmacológico , Proteinúria/etiologiaRESUMO
BACKGROUND: Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. METHODS: PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. FINDINGS: Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m2 per year versus -3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1-week 110) was -2·9 mL/min per 1·73 m2 per year versus -3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI -0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (-42·8%, 95% CI -49·8 to -35·0, with sparsentan versus -4·4%, -15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. INTERPRETATION: Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function. FUNDING: Travere Therapeutics.
Assuntos
Glomerulonefrite por IGA , Falência Renal Crônica , Feminino , Humanos , Masculino , Antagonistas de Receptores de Angiotensina/efeitos adversos , Método Duplo-Cego , Glomerulonefrite por IGA/tratamento farmacológico , Irbesartana/efeitos adversos , Proteinúria/tratamento farmacológico , Resultado do Tratamento , AdultoRESUMO
IgA nephropathy (IgAN) is the most common glomerular disease in the world. However, the approach to treatment remains controversial. There has been an explosion of clinical trials over the past decade both to further examine corticosteroid use and usher in additional treatment considerations, including 2 newly approved therapies for IgAN. Sodium glucose cotransporter 2 inhibitors are proving to be effective therapy across proteinuric chronic kidney diseases, and IgAN is not likely to be an exception. Further supportive agents are looking highly promising and so are novel agents that specifically focus on the pathophysiology of this disease, including endothelin blockade, complement inhibition, and B-cell targeted strategies. We suggest a present-day approach to treatment of individuals with IgAN, expose the limitations in our knowledge, and discuss new treatments that may arise, hoping they come with evidence about optimal utilization. Change appears to be inevitable for our approach to the treatment of IgA nephropathy. This is truly an exciting and optimistic time.
Assuntos
Glomerulonefrite por IGA , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
RATIONALE & OBJECTIVE: Membranoproliferative glomerulonephritis (MPGN), encompassing several distinct diseases, is a rare but significant cause of kidney failure in the United States. The potential etiologies of MPGN are unclear, but prior studies have suggested dysregulation of the alternative complement pathway and, recently, autoimmunity as potential mechanisms driving MPGN pathogenesis. In this study, we examined HLA associations with end-stage kidney disease (ESKD) due to MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse US-based cohort. STUDY DESIGN: Case-control study. SETTING & PARTICIPANTS: Using US Renal Data System (USRDS) and United Network for Organ Sharing (UNOS) data, we identified 3,424 patients with kidney failure due to MPGN and 263 due to DDD. We matched patients to kidney donor controls on designated race and ethnicity in a 1:15 ratio. EXPOSURE: 58 class I and II HLA serotypes. OUTCOME: Case-control status. ANALYTICAL APPROACH: For each disease cohort, univariable and multivariable logistic regression analyses were used to investigate associations between the disease and 58 HLA serotypes. In subgroup analyses, we investigated HLA associations in White and Black patients. We also studied antiglomerular basement membrane (anti-GBM) nephritis as a positive-control outcome. We applied a Bonferroni correction to account for multiple comparisons. RESULTS: Eighteen serotypes were significantly associated with the odds of having MPGN in univariable analyses, with DR17 having the strongest association (odds ratio [OR], 1.55 [95% CI, 1.44-1.68], P=4.33e-28). No significant associations were found between any HLA serotype and DDD. Designated race-specific analyses showed comparable findings. We recapitulated known HLA associations in anti-GBM nephritis. LIMITATIONS: Reliance on HLA serotypes (rather than genotype), lack of biopsy-confirmed diagnoses. CONCLUSIONS: HLA-DR17 is associated with ESKD due to MPGN in a racially and ethnically diverse cohort. The strength of association was similar in White and Black patients, suggesting a role in the pathogenesis of MPGN. No HLA associations were observed in patients with DDD. PLAIN-LANGUAGE SUMMARY: Prior studies have suggested dysregulation of the alternative complement pathway as a potential etiology of membranoproliferative glomerulonephritis (MPGN), but recent evidence from a British White population has implicated an autoimmune mechanism in MPGN pathogenesis. We investigated HLA associations between MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse cohort of patients. We found that HLA-DR17 is associated with end-stage kidney disease (ESKD) due to MPGN in both White and Black patients. By contrast, no significant HLA associations with ESKD due to DDD were identified. These results suggest a role for autoimmunity in some cases of MPGN and highlight differences in the disease etiology of MPGN compared with DDD.
Assuntos
Glomerulonefrite Membranoproliferativa , Falência Renal Crônica , Humanos , Sorogrupo , Estudos de Casos e Controles , Falência Renal Crônica/etiologia , Antígenos HLARESUMO
BACKGROUND: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response. METHODS: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia. RESULTS: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time. CONCLUSIONS: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment.
Assuntos
Pressão Sanguínea , Dislipidemias , Hipertensão , Síndrome Nefrótica , Humanos , Síndrome Nefrótica/urina , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/complicações , Síndrome Nefrótica/epidemiologia , Síndrome Nefrótica/sangue , Masculino , Criança , Feminino , Estudos Longitudinais , Hipertensão/epidemiologia , Hipertensão/tratamento farmacológico , Hipertensão/diagnóstico , Hipertensão/etiologia , Pré-Escolar , Dislipidemias/epidemiologia , Dislipidemias/sangue , Adolescente , Lipídeos/sangue , Prevalência , LactenteRESUMO
BACKGROUND: Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression. METHODS: Anthropometric measurements in children < 18 years enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression. RESULTS: A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04 years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (N = 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (- 0.13 ± 1.21 vs. - 0.23 ± 1.71, p = 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (ß - 7.5 × 10-6, CI - 1.2 × 10-5, - 3 × 10-6, p = 0.001) and incident cases of NS (vs. prevalent) (ß - 1.1, CI - 2.22, - 0.11, p = 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (ß 0.16, CI 0.04, 0.29, p = 0.01) over time. CONCLUSION: Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score.
Assuntos
Estatura , Síndrome Nefrótica , Humanos , Síndrome Nefrótica/tratamento farmacológico , Masculino , Feminino , Criança , Pré-Escolar , Estatura/efeitos dos fármacos , Adolescente , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/diagnóstico , Estudos Longitudinais , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversosRESUMO
Many patients with immunoglobulin A nephropathy (IgAN) progress to kidney failure even with optimal supportive care. An improved understanding of the pathophysiology of IgAN in recent years has led to the investigation of targeted therapies with acceptable tolerability that may address the underlying causes of IgAN or the pathogenesis of kidney injury. The complement system-particularly the lectin and alternative pathways of complement-has emerged as a key mediator of kidney injury in IgAN and a possible target for investigational therapy. This review will focus on the lectin pathway. The examination of kidney biopsies has consistently shown glomerular deposition of mannan-binding lectin (1 of 6 pattern-recognition molecules that activate the lectin pathway) together with IgA1 in up to 50% of patients with IgAN. Glomerular deposition of pattern-recognition molecules for the lectin pathway is associated with more severe glomerular damage and more severe proteinuria and hematuria. Emerging research suggests that the lectin pathway may also contribute to tubulointerstitial fibrosis in IgAN and that collectin-11 is a key mediator of this association. This review summarizes the growing scientific and clinical evidence supporting the role of the lectin pathway in IgAN and examines the possible therapeutic role of lectin pathway inhibition for these patients.
Assuntos
Glomerulonefrite por IGA , Humanos , Glomerulonefrite por IGA/patologia , Lectinas/metabolismo , Glomérulos Renais/patologia , Rim/patologia , Imunoglobulina A/metabolismoRESUMO
The therapeutic potential of a novel, targeted-release formulation of oral budesonide (Nefecon) for the treatment of IgA nephropathy (IgAN) was first demonstrated by the phase 2b NEFIGAN trial. To verify these findings, the phase 3 NefigArd trial tested the efficacy and safety of nine months of treatment with Nefecon (16 mg/d) versus placebo in adult patients with primary IgAN at risk of progressing to kidney failure (ClinicalTrials.gov: NCT03643965). NefIgArd was a multicenter, randomized, double-blind, placebo-controlled two-part trial. In Part A, 199 patients with IgAN were treated with Nefecon or placebo for nine months and observed for an additional three months. The primary endpoint for Part A was 24-hour urine protein-to-creatinine ratio (UPCR) after nine months. Secondary efficacy outcomes evaluated included estimated glomerular filtration rate (eGFR) at nine and 12 months and the UPCR at 12 months. At nine months, UPCR was 27% lower in the Nefecon group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo (both significant). Nefecon was well-tolerated, and treatment-emergent adverse events were mostly mild to moderate in severity and reversible. Part B is ongoing and will be reported on later. Thus, NefIgArd is the first phase 3 IgA nephropathy trial to show clinically important improvements in UPCR and eGFR and confirms the findings from the phase 2b NEFIGAN study.
Assuntos
Budesonida , Glomerulonefrite por IGA , Adulto , Humanos , Budesonida/administração & dosagem , Método Duplo-Cego , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/tratamento farmacológico , Testes de Função Renal , Resultado do TratamentoRESUMO
The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.
Assuntos
Glomerulosclerose Segmentar e Focal , Nefrologia , Nefrose Lipoide , Síndrome Nefrótica , Humanos , Glomerulosclerose Segmentar e Focal/patologia , Nefrose Lipoide/diagnóstico , Inibidor Tecidual de Metaloproteinase-1 , Síndrome Nefrótica/diagnóstico , Fatores de Necrose Tumoral/uso terapêuticoRESUMO
RATIONALE & OBJECTIVE: The effects of race, ethnicity, socioeconomic status (SES), and disease severity on acute care utilization in patients with glomerular disease are unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,456 adults and 768 children with biopsy-proven glomerular disease enrolled in the Cure Glomerulonephropathy (CureGN) cohort. EXPOSURE: Race and ethnicity as a participant-reported social factor. OUTCOME: Acute care utilization defined as hospitalizations or emergency department visits. ANALYTICAL APPROACH: Multivariable recurrent event proportional rate models were used to estimate associations between race and ethnicity and acute care utilization. RESULTS: Black or Hispanic participants had lower SES and more severe glomerular disease than White or Asian participants. Acute care utilization rates were 45.6, 29.5, 25.8, and 19.2 per 100 person-years in Black, Hispanic, White, and Asian adults, respectively, and 55.8, 42.5, 40.8, and 13.0, respectively, for children. Compared with the White race (reference group), Black race was significantly associated with acute care utilization in adults (rate ratio [RR], 1.76 [95% CI, 1.37-2.27]), although this finding was attenuated after multivariable adjustment (RR, 1.31 [95% CI, 1.03-1.68]). Black race was not significantly associated with acute care utilization in children; Asian race was significantly associated with lower acute care utilization in children (RR, 0.32 [95% CI 0.14-0.70]); no significant associations between Hispanic ethnicity and acute care utilization were identified. LIMITATIONS: We used proxies for SES and lacked direct information on income, household unemployment, or disability. CONCLUSIONS: Significant differences in acute care utilization rates were observed across racial and ethnic groups in persons with prevalent glomerular disease, although many of these difference were explained by differences in SES and disease severity. Measures to combat socioeconomic disadvantage in Black patients and to more effectively prevent and treat glomerular disease are needed to reduce disparities in acute care utilization, improve patient wellbeing, and reduce health care costs.
Assuntos
Etnicidade , Disparidades em Assistência à Saúde , Nefropatias , Aceitação pelo Paciente de Cuidados de Saúde , Adulto , Criança , Humanos , População Negra , Hispânico ou Latino , Estudos Prospectivos , Classe Social , Povo Asiático , População Branca , Aceitação pelo Paciente de Cuidados de Saúde/etnologiaRESUMO
BACKGROUND: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. METHODS: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. RESULTS: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). CONCLUSIONS: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).
Assuntos
Ciclosporina/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Imunossupressores/uso terapêutico , Rituximab/uso terapêutico , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclosporina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/efeitos adversos , Infusões Intravenosas , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteinúria/tratamento farmacológico , Indução de Remissão , Rituximab/efeitos adversos , Falha de Tratamento , Adulto JovemRESUMO
Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents myriad questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anticomplement therapy trials either planned or under way, the National Kidney Foundation facilitated an all-virtual scientific workshop entitled "Improving Clinical Trials for Anti-Complement Therapies in Complement-Mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anticomplement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, participant risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.
Assuntos
Proteínas Inativadoras do Complemento , Nefropatias , Proteínas Inativadoras do Complemento/uso terapêutico , Proteínas do Sistema Complemento , Humanos , RimRESUMO
Outcomes relevant to treatment decision-making are inconsistently reported in trials involving glomerular disease. Here, we sought to establish a consensus-derived set of critically important outcomes designed to be reported in all future trials by using an online, international two-round Delphi survey in English. To develop this, patients with glomerular disease, caregivers and health professionals aged 18 years and older rated the importance of outcomes using a Likert scale and a Best-Worst scale. The absolute and relative importance was assessed and comments were analyzed thematically. Of 1198 participants who completed Round 1, 734 were patients/caregivers while 464 were health care professionals from 59 countries. Of 700 participants that completed Round 2, 412 were patients/caregivers and 288 were health care professionals. Need for dialysis or transplant, kidney function, death, cardiovascular disease, remission-relapse and life participation were the most important outcomes to patients/caregivers and health professionals. Patients/caregivers rated patient-reported outcomes higher while health care professionals rated hospitalization, death and remission/relapse higher. Four themes explained the reasons for their priorities: confronting death and compounded suffering, focusing on specific targets in glomerular disease, preserving meaning in life, and fostering self-management. Thus, consistent reporting of these critically important outcomes in all trials involving glomerular disease is hoped to improve patient-centered decision-making.
Assuntos
Cuidadores , Diálise Renal , Adulto , Técnica Delphi , Humanos , Avaliação de Resultados em Cuidados de Saúde , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging. METHODS: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes. RESULTS: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features. CONCLUSIONS: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes.
Assuntos
Apolipoproteína L1/genética , Glomerulosclerose Segmentar e Focal , Alelos , Genótipo , Glomerulosclerose Segmentar e Focal/genética , Humanos , Síndrome Nefrótica/genéticaRESUMO
AIMS: End-stage renal disease (ESRD) is a strong cardiovascular risk factor. We aimed to determine the extent to which cause of kidney disease independently contributes to this risk. METHODS AND RESULTS: Using a national US ESRD registry, we selected patients with eight different causes of ESRD who initiated dialysis 1997-2014. We used proportional sub-distribution hazard models, with non-cardiovascular death or kidney transplantation as competing risks, to estimate hazard ratios (HRs) for a first composite cardiovascular event (myocardial infarction, ischaemic stroke, or cardiovascular or cerebrovascular death), by cause of ESRD. The population was restricted to those using Medicare insurance at Day 91 after dialysis initiation (when most patients become Medicare eligible). Outcomes were ascertained from Medicare claims or Death Notifications. Among the 658 168 patients identified, composite event rates ranged from 3.5/100 person-years in IgA nephropathy to 14.6/100 person-years in diabetic nephropathy (DN). After adjusting for demographics, socioeconomic factors, comorbidities, dialysis modality, and laboratory values, cardiovascular event HRs differed significantly by cause of ESRD. Comparing to IgA nephropathy, the adjusted HR was highest for DN [aHR = 2.97, 95% confidence interval (CI) 2.77-3.20], next highest for lupus nephritis (aHR = 1.86, 95% CI 1.71-2.03), and thereafter ranged from 1.29 (95% CI 1.19-1.39) in autosomal dominant polycystic kidney disease to 1.67 (95% CI 1.52-1.83) in membranous nephropathy. CONCLUSION: High cardiovascular event rates in dialysis patients vary considerably by cause of ESRD. Determining underlying reasons for these differences might provide new insights in to cardiovascular disease mechanisms as well as inform future drug development and clinical trial design.
Assuntos
Nefropatias Diabéticas/complicações , Diálise/efeitos adversos , Glomerulonefrite por IGA/complicações , Nefropatias/complicações , Falência Renal Crônica/etiologia , Adulto , Morte Encefálica/fisiopatologia , Isquemia Encefálica/fisiopatologia , Estudos de Coortes , Comorbidade , Morte , Nefropatias Diabéticas/epidemiologia , Diálise/métodos , Diálise/tendências , Feminino , Glomerulonefrite por IGA/epidemiologia , Humanos , Nefropatias/epidemiologia , Falência Renal Crônica/terapia , Masculino , Medicare/normas , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Estados Unidos/epidemiologiaRESUMO
The majority of patients with immunoglobulin light chain amyloidosis (AL) fail to achieve a complete response (CR) to standard light chain suppressive chemotherapy, and almost all patients eventually experience hematologic relapse and progression of organ involvement. Additional well-tolerated treatment options are needed. We present our retrospective experience of 25 consecutive previously treated AL patients who received daratumumab, a CD38-directed monoclonal antibody approved for the treatment of multiple myeloma. Daratumumab was administered at 16 mg/kg weekly for 8 weeks, then every 2 weeks for 8 doses, and then every 4 weeks. Patients had received a median of 3 prior lines of therapy, with a previous hematologic CR in only 5 patients. The overall hematologic response rate to daratumumab was 76%, including CR in 36% and very good partial response in 24%. Median time to response was 1 month. Therapy was well tolerated, even among the 72% of patients with cardiac AL involvement. Grade 1-2 infusion reactions occurred in 15 patients, but no grade 3 or 4 reactions were observed. Daratumumab is a highly effective agent that produced rapid and deep hematologic responses without unexpected toxicity in our cohort of heavily pretreated AL patients.
Assuntos
Amiloidose/sangue , Amiloidose/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Cadeias Leves de Imunoglobulina/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Standard methods for detecting and monitoring of IgA nephropathy (IgAN) have conventionally required kidney biopsies or suffer from poor sensitivity and specificity. The Kidney Injury Test (KIT) Assay of urinary biomarkers has previously been shown to distinguish between various kidney pathologies, including chronic kidney disease, nephrolithiasis, and transplant rejection. This validation study uses the KIT Assay to investigate the clinical utility of the non-invasive detection of IgAN and predicting the progression of renal damage over time. The study design benefits from longitudinally collected urine samples from an investigator-initiated, multicenter, prospective study, evaluating the efficacy of corticosteroids versus Rituximab for preventing progressive IgAN. A total of 131 urine samples were processed for this study; 64 urine samples were collected from 34 IgAN patients, and urine samples from 64 demographically matched healthy controls were also collected; multiple urinary biomarkers consisting of cell-free DNA, methylated cell-free DNA, DMAIMO, MAMIMO, total protein, clusterin, creatinine, and CXCL10 were measured by the microwell-based KIT Assay. An IgA risk score (KIT-IgA) was significantly higher in IgAN patients as compared to healthy control (87.76 vs. 14.03, p < 0.0001) and performed better than proteinuria in discriminating between the two groups. The KIT Assay biomarkers, measured on a spot random urine sample at study entry could distinguish patients likely to have progressive renal dysfunction a year later. These data support the pursuit of larger prospective studies to evaluate the predictive performance of the KIT-IgA score in both screening for non-invasive diagnosis of IgAN, and for predicting risk of progressive renal disease from IgA and utilizing the KIT score for potentially evaluating the efficacy of IgAN-targeted therapies.