RESUMEN
The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one-year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two-years after biopsy. Trajectories of eGFR after a baseline one-year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to revaluate risk one- or two-years after biopsy.
RESUMEN
BACKGROUND AND HYPOTHESIS: The MENTOR trial (MEmbranous Nephropathy Trial Of Rituximab) showed that rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria and was superior in maintaining proteinuria remission. However, the cost of rituximab may prohibit first-line use for some patients and health care payers. METHODS: A Markov model was used to determine the incremental cost-effectiveness ratio (ICER) of rituximab compared with cyclosporine for the treatment membranous nephropathy from the perspective of a health care payer with a life-time time horizon. The model was informed by data from the MENTOR trial where possible; additional parameters including cost and utility inputs were obtained from the literature. Sensitivity analyses were performed to evaluate the impact of reduced cost biosimilar rituximab. RESULTS: Rituximab for the treatment of membranous nephropathy was cost-effective (assuming a willingness-to-pay threshold of ${\$}$50 000 per quality adjusted life year (QALY) gained; ${\$}$US 2021) compared with cyclosporine, with an ICER of ${\$}$8 373/QALY over a lifetime time horizon. The incremental cost of rituximab therapy was ${\$}$28 007 with an additional 3.34 QALYs compared with cyclosporine. Lower cost of rituximab biosimilars resulted in a more favourable ICER, and in some cases resulted in rituximab being dominant (lower cost and great benefit) compared to cyclosporine. CONCLUSIONS: Despite the greater cost of rituximab, it may be a cost-effective option for the treatment of membranous nephropathy when compared with cyclosporine. The cost-effectiveness of rituximab is further improved with the use of less expensive biosimilars.
RESUMEN
BACKGROUND: IgA nephropathy is the most common primary GN. Clinical features of IgA nephropathy include proteinuria, which is the strongest known surrogate of progression to kidney failure. Complement pathway activation is a critical driver of inflammation and tissue injury in IgA nephropathy. Cemdisiran is an investigational RNA interference therapeutic that suppresses hepatic production of complement component 5 (C5), thereby potentially reducing proteinuria in IgA nephropathy. We evaluated the efficacy and safety of cemdisiran in adult patients with IgA nephropathy at high risk of kidney disease progression. METHODS: In this phase 2, 36-week, double-blind study, adult patients with IgA nephropathy and urine protein ≥1 g/24 hours were randomized (2:1) to subcutaneous cemdisiran 600 mg or placebo every 4 weeks in combination with the standard of care. The primary end point was percentage change from baseline at week 32 in urine protein-to-creatinine ratio (UPCR) measured by 24-hour urine collection. Additional end points included change from baseline in UPCR measured by spot urine, serum C5 level, and safety assessments. RESULTS: Thirty-one patients were randomized (cemdisiran, N =22; placebo, N =9). Cemdisiran-treated patients had a placebo-adjusted geometric mean change in 24-hour UPCR of -37.4% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.69 [0.10]) at week 32. Spot UPCR was consistent with 24-hour UPCR placebo-adjusted change of -45.8% (cemdisiran-adjusted geometric mean ratio to baseline [SEM], 0.73 [0.11]). Mean (SD) change in serum C5 level from baseline at week 32 was -98.7% (1.2) with cemdisiran and 25.2% (57.7) with placebo. Over 36 weeks, most adverse events were mild or moderate and transient; the most common adverse event after cemdisiran treatment was injection-site reaction (41%). CONCLUSIONS: These findings indicate that treatment with cemdisiran resulted in a reduction of proteinuria at week 32 and was well tolerated.
Asunto(s)
Glomerulonefritis por IGA , Adulto , Humanos , Glomerulonefritis por IGA/tratamiento farmacológico , Tasa de Filtración Glomerular , Proteinuria/tratamiento farmacológico , Proteinuria/etiología , Pruebas de Función Renal , Método Doble CiegoRESUMEN
BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.
Asunto(s)
Glomerulonefritis por IGA , Vasculitis por IgA , Nefritis , Adulto , Niño , Humanos , Masculino , Adolescente , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/patología , Vasculitis por IgA/complicaciones , Vasculitis por IgA/tratamiento farmacológico , Vasculitis por IgA/patología , Tasa de Filtración Glomerular , Riñón/patología , Nefritis/complicaciones , Proteinuria/etiología , Biopsia , Estudios RetrospectivosRESUMEN
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.
Asunto(s)
Glomerulonefritis Membranosa , Humanos , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/terapia , Consenso , Autoanticuerpos , Nefrectomía , Membrana Basal Glomerular/patología , Receptores de Fosfolipasa A2RESUMEN
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.
Asunto(s)
Glomerulonefritis Membranosa , Humanos , Glomerulonefritis Membranosa/diagnóstico , Glomerulonefritis Membranosa/terapia , Consenso , Autoanticuerpos , Nefrectomía , FenotipoRESUMEN
BACKGROUND: The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend following anti-phospholipase A2 receptor (PLA2R) antibody levels as a marker of treatment response in membranous nephropathy; however, the optimal timing to evaluate antibody levels and how to combine them with other clinical variables are currently unknown. METHODS: We used a cohort of 85 patients from the Membranous Nephropathy Trial Of Rituximab (MENTOR) with anti-PLA2R antibodies ≥14 RU/ml to identify risk factors for not experiencing proteinuria remission after 12 months of treatment with cyclosporine or rituximab. Three landmark times were considered: at baseline and after 3 and 6 months of treatment. Logistic regression model performance was evaluated using C-statistics and model fit (Akaike information criterion [AIC], R 2 ). RESULTS: The model at baseline that best predicted no remission included anti-PLA2R antibodies >323 RU/ml and creatinine clearance; the best model after 3 months included the change from baseline in both antibody and albumin levels; and the best model after 6 months included antibody levels >14 RU/ml, creatinine clearance, and the change from baseline in albumin. Compared with the model at baseline, the model at 3 months had better model fit (AIC 70.9 versus 96.4, R 2 51.8% versus 30.1%) and higher C-statistic (0.93 versus 0.83, P = 0.008). The model at 6 months had no difference in performance compared with the model at 3 months (AIC 68.6, R 2 53.0%, C-statistic 0.94, P = 0.67). CONCLUSIONS: In patients with membranous nephropathy treated with cyclosporine or rituximab in the MENTOR trial, we found that the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R antibody levels combined with albumin levels after 3 months of treatment, which was significantly better than using antibody levels alone or risk factor evaluation at baseline, with no added benefit of waiting until 6 months of treatment. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_10_09_CJN0000000000000237.mp3.
Asunto(s)
Glomerulonefritis Membranosa , Humanos , Glomerulonefritis Membranosa/tratamiento farmacológico , Rituximab/uso terapéutico , Receptores de Fosfolipasa A2 , Creatinina , Ciclosporina/uso terapéutico , Factores de Riesgo , Albúminas , AutoanticuerposRESUMEN
RATIONALE & OBJECTIVE: Kidney failure is an established risk factor for active tuberculosis (TB) but the risk of TB has not been reported in specific kidney diseases. We sought to determine the incidence of and risk factors for active TB in patients with glomerular disease. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: A provincial kidney pathology registry (2000-2012) was used to identify 3,079 adult patients with IgA nephropathy, focal segmental glomerulosclerosis (FSGS), antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis, lupus nephritis, membranous nephropathy, minimal change disease, or "other" glomerular diseases in British Columbia, Canada. EXPOSURE: Predictors included demographics, immigration status, comorbidities, immunosuppression use, estimated glomerular filtration rate (eGFR), and proteinuria. OUTCOME: A diagnosis of active TB was ascertained using administrative data linkages and defined based on (1) the dispensation of 1 or more unique combinations of medications used to treat active TB, or (2) physician or hospital visits for active TB. ANALYTICAL APPROACH: The definition of TB was validated in an external cohort linked to the Provincial TB registry at the BC Centre for Disease Control (BCCDC). Standardized incidence ratios were calculated using the age-matched general population. Risk factors for active TB were identified using Cox proportional hazards regression analysis. RESULTS: The sensitivity and specificity of the outcome definition of active TB were 87.6% and 99.5%, respectively. During a median follow-up of 6.2 years, 41 patients developed active TB with an incidence of 197 of 100,000 person-years, approximately 23 times as high as the general population and>6 times higher than the threshold of 30 per 100,000 used to define high TB incidence. A high incidence was observed in all glomerular diseases (range, 110-403 per 100,000), in both Canadian- and foreign-born patients (range, 124-424 per 100,000), and in patients exposed or not to immunosuppression (282 vs 147 per 100,000). Factors associated with higher TB risk included immigration from a high-incidence country (HR, 3.90 [95% CI, 1.75-8.68]), diminished eGFR (HR, 2.81 [95% CI, 1.18-6.69]), higher levels of proteinuria (HR, 1.15 [95% CI, 1.04-1.27]), lupus nephritis (HR, 2.79 [95% CI, 1.37-5.68]), and immunosuppression use (HR, 2.13 [95% CI, 1.13-4.03]). LIMITATIONS: A relatively low number of events contributed to uncertainty in risk estimates. CONCLUSIONS: Patients with glomerular disease have a high incidence of active TB irrespective of disease type, demographics, or use of immunosuppression. Prospective studies are needed to evaluate the utility of screening for latent TB infection in this population. PLAIN-LANGUAGE SUMMARY: Patients with kidney failure are at high risk of developing tuberculosis (TB), a major infection that can be prevented by identifying and treating patients who have had prior exposure to TB. The risk of TB in specific kidney diseases is unknown. In this Canadian study of 3,079 patients with glomerular disease, a group of autoimmune kidney conditions, the rate of TB was 23 times higher than in the general population. The rate was high irrespective of the use of immunosuppressive drugs or whether patients had immigrated to Canada from another country. These findings suggest that screening patients with glomerular disease for prior TB exposure may be beneficial; however, this needs to be evaluated in a prospective study.
Asunto(s)
Glomerulonefritis por IGA , Nefritis Lúpica , Insuficiencia Renal , Tuberculosis , Adulto , Humanos , Estudios de Cohortes , Estudios Prospectivos , Incidencia , Tuberculosis/epidemiología , Glomerulonefritis por IGA/patología , Factores de Riesgo , Colombia Británica/epidemiología , ProteinuriaRESUMEN
PURPOSE OF REVIEW: The use of corticosteroids to treat IgA nephropathy (IgAN) has been limited by many controversies related to uncertain benefit and safety concerns. Recent trials have tried to address these limitations. RECENT FINDINGS: After being paused because of an excess of adverse events in the full-dose steroid arm, the TESTING trial compared a reduced dose of methylprednisolone to placebo in patients with IgAN after optimization of supportive therapy. Steroid treatment was associated with a significant reduction in the risk of a 40% decline in estimated glomerular filtration rate (eGFR), kidney failure and kidney death as well as a sustained decrease in proteinuria compared with placebo. Serious adverse events were more frequent with the full dose regimen but less common in the reduced dose regimen. A phase III trial evaluating a new formulation of targeted-release budesonide showed a significant reduction in short-term proteinuria and has resulted in accelerated FDA approval for use in the United States. In a subgroup analysis of DAPA-CKD trial, sodium-glucose transport protein 2 inhibitors reduced the risk of kidney function decline in patients who have completed or are not eligible for immunosuppression. SUMMARY: Both reduced-dose corticosteroids and targeted-release budesonide are new therapeutic options that can be used in patients with high-risk disease. More novel-targeted therapies with a better safety profile are currently under investigations.
Asunto(s)
Glomerulonefritis por IGA , Humanos , Glomerulonefritis por IGA/tratamiento farmacológico , Inmunosupresores/efectos adversos , Corticoesteroides/efectos adversos , Budesonida/uso terapéutico , Esteroides/efectos adversos , Tasa de Filtración Glomerular , Proteinuria/tratamiento farmacológico , Proteinuria/etiologíaRESUMEN
BACKGROUND: Although case reports have described relapses of glomerular disease after COVID-19 vaccination, evidence of a true association is lacking. In this population-level analysis, we sought to determine relative and absolute risks of glomerular disease relapse after COVID-19 vaccination. METHODS: In this retrospective population-level cohort study, we used a centralized clinical and pathology registry (2000-2020) to identify 1105 adult patients in British Columbia, Canada, with biopsy-proven glomerular disease that was stable on December 14, 2020 (when COVID-19 vaccines first became available). The primary outcome was disease relapse, on the basis of changes in kidney function, proteinuria, or both. Vaccination was modeled as a 30-day time-varying exposure in extended Cox regression models, stratified on disease type. RESULTS: During 281 days of follow-up, 134 (12.1%) patients experienced a relapse. Although a first vaccine dose was not associated with relapse risk (hazard ratio [HR]=0.67; 95% confidence interval [95% CI], 0.33 to 1.36), exposure to a second or third dose was associated with a two-fold risk of relapse (HR=2.23; 95% CI, 1.06 to 4.71). The pattern of relative risk was similar across glomerular diseases. The absolute increase in 30-day relapse risk associated with a second or third vaccine dose varied from 1%-2% in ANCA-related glomerulonephritis, minimal change disease, membranous nephropathy, or FSGS to 3%-5% in IgA nephropathy or lupus nephritis. Among 24 patients experiencing a vaccine-associated relapse, 4 (17%) had a change in immunosuppression, and none required a biopsy. CONCLUSIONS: In a population-level cohort of patients with glomerular disease, a second or third dose of COVID-19 vaccine was associated with higher relative risk but low absolute increased risk of relapse.
Asunto(s)
COVID-19 , Glomerulonefritis por IGA , Adulto , Humanos , Vacunas contra la COVID-19/efectos adversos , Estudios Retrospectivos , Estudios de Cohortes , COVID-19/epidemiología , COVID-19/prevención & control , Glomerulonefritis por IGA/patología , Recurrencia , Enfermedad Crónica , VacunaciónRESUMEN
BACKGROUND AND OBJECTIVES: C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123 patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. RESULTS: Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitial fibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. CONCLUSIONS: Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.
Asunto(s)
Glomerulonefritis Membranoproliferativa , Glomerulonefritis , Insuficiencia Renal , Atrofia , Biopsia , Fibrosis , Glomerulonefritis/diagnóstico , Glomerulonefritis Membranoproliferativa/patología , Humanos , Inmunoglobulinas , Proteinuria/etiología , Insuficiencia Renal/complicaciones , Estudios RetrospectivosRESUMEN
Lipoprotein glomerulopathy (LPG) is caused by a mutation in the apolipoprotein E gene (APOE) gene and is characterized by lipoprotein thrombi in glomerular capillaries. Here, we describe a case of LPG, the first to be reported from Canada and the first case of LPG in North America to be associated with the APOE Tokyo/Maebashi mutation (p.Leu162_Lys164del, traditional nomenclature 142_144del). A 49-year-old man of Chinese descent with a previous diagnosis of dyslipidemia and a new diagnosis of hypertension was found to have proteinuria on routine urinalysis. Renal biopsy showed markedly dilated glomerular capillaries filled with pale staining mesh-like material that stained positive for Oil-Red-O, consistent with lipoprotein thrombi. APOE gene sequencing confirmed the diagnosis of LPG. The patient was treated with fenofibrate and perindopril. His lipid profile normalized and proteinuria dropped to minimal levels. Repeat renal biopsy 2 years after the first showed resolution of lipoprotein thrombi but with rare residual granular densities by electron microscopy consistent with lipoprotein in the subendothelial space, supporting the hypothesis that this subendothelial material contains precursors to lipoprotein thrombi.
RESUMEN
RATIONALE & OBJECTIVE: Little is known about the risk of cardiovascular disease (CVD) in patients with various primary glomerular diseases. In a population-level cohort of adults with primary glomerular disease, we sought to describe the risk of CVD compared with the general population and the impact of traditional and kidney-related risk factors on CVD risk. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Adults with membranous nephropathy (n = 387), minimal change disease (n = 226), IgA nephropathy (n = 759), and focal segmental glomerulosclerosis (n = 540) from a centralized pathology registry in British Columbia, Canada (2000-2012). EXPOSURE: Traditional CVD risk factors (diabetes, age, sex, dyslipidemia, hypertension, smoking, prior CVD) and kidney-related risk factors (type of glomerular disease, estimated glomerular filtration rate [eGFR], proteinuria). OUTCOME: A composite CVD outcome of coronary artery, cerebrovascular, and peripheral vascular events, and death due to myocardial infarction or stroke. ANALYTICAL APPROACH: Subdistribution hazards models to evaluate the outcome risk with non-CVD death treated as a competing event. Standardized incidence rates (SIR) calculated based on the age- and sex-matched general population. RESULTS: During a median 6.8 years of follow-up, 212 patients (11.1%) experienced the CVD outcome (10-year risk, 14.7% [95% CI, 12.8%-16.8%]). The incidence rate was high for the overall cohort (24.7 per 1,000 person-years) and for each disease type (range, 12.2-46.1 per 1,000 person-years), and was higher than that observed in the general population both overall (SIR, 2.46 [95% CI, 2.12-2.82]) and for each disease type (SIR range, 1.38-3.98). Disease type, baseline eGFR, and proteinuria were associated with a higher risk of CVD and, when added to a model with traditional risk factors, led to improvements in model fit (R2 of 14.3% vs 12.7%), risk discrimination (C-statistic of 0.81 vs 0.78; difference, 0.02 [95% CI, 0.01-0.04]), and continuous net reclassification improvement (0.4 [95% CI, 0.2-0.6]). LIMITATIONS: Ascertainment of outcomes and comorbidities using administrative data. CONCLUSIONS: Patients with primary glomerular disease have a high absolute risk of CVD that is approximately 2.5 times that of the general population. Consideration of eGFR, proteinuria, and type of glomerular disease may improve risk stratification of CVD risk in these individuals. PLAIN-LANGUAGE SUMMARY: Patients with chronic kidney disease are known to be at high risk of cardiovascular disease. Cardiovascular risk in patients with primary glomerular diseases is poorly understood because these conditions are rare and require a kidney biopsy for diagnosis. In this study of 1,912 Canadian patients with biopsy-proven IgA nephropathy, minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy, the rate of cardiovascular events was 2.5 times higher than in the general population and was high for each disease type. Consideration of disease type, kidney function, and proteinuria improved the prediction of cardiovascular events. In summary, our population-level study showed that patients with primary glomerular diseases have a high cardiovascular risk, and that inclusion of kidney-specific risk factors may improve risk stratification.
Asunto(s)
Enfermedades Cardiovasculares , Glomerulonefritis por IGA , Glomerulonefritis Membranosa , Glomeruloesclerosis Focal y Segmentaria , Nefrosis Lipoidea , Adulto , Humanos , Glomeruloesclerosis Focal y Segmentaria/patología , Glomerulonefritis Membranosa/patología , Enfermedades Cardiovasculares/epidemiología , Glomerulonefritis por IGA/patología , Nefrosis Lipoidea/patología , Proteinuria , Tasa de Filtración Glomerular , Factores de Riesgo , Colombia Británica/epidemiologíaRESUMEN
The International IgA Nephropathy (IgAN) Prediction Tool is the preferred method in the 2021 KDIGO guidelines to predict, at the time of kidney biopsy, the risk of a 50% drop in estimated glomerular filtration rate or kidney failure. However, it is not known if the Prediction Tool can be accurately applied after a period of observation post-biopsy. Using an international multi-ethnic derivation cohort of 2,507 adults with IgAN, we updated the Prediction Tool for use one year after biopsy, and externally validated this in a cohort of 722 adults. The original Prediction Tool applied at one-year without modification had a coefficient of variation (R2) of 55% and 54% and four-year concordance (C statistic) of 0.82 but poor calibration with under-prediction of risk (integrated calibration index (ICI) 1.54 and 2.11, with and without race, respectively). Our updated Prediction Tool had a better model fit with higher R2 (61% and 60%), significant increase in four-year C-statistic (0.87 and 0.86) and better four-year calibration with lower ICI (0.75 and 0.35). On external validation, the updated Prediction Tool had similar R2 (60% and 58%) and four-year C-statistics (both 0.85) compared to the derivation analysis, with excellent four-year calibration (ICI 0.62 and 0.56). This updated Prediction Tool had similar prediction performance when used two years after biopsy. Thus, the original Prediction Tool should be used only at the time of biopsy whereas our updated Prediction Tool can be used for risk stratification one or two years post-biopsy.
Asunto(s)
Glomerulonefritis por IGA , Insuficiencia Renal , Adulto , Biopsia/efectos adversos , Estudios de Cohortes , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/patología , Humanos , PronósticoRESUMEN
Background: Glomerulonephritis (GN) is a leading cause of kidney failure and accounts for 20% of incident cases of end-stage kidney disease (ESKD) in Canada annually. Reversal of kidney injury and prevention of progression to kidney failure is possible; however, limited knowledge of underlying disease mechanisms and lack of noninvasive biomarkers and therapeutic targets are major barriers to successful therapeutic intervention. Multicenter approaches that link longitudinal clinical and outcomes data with serial biologic specimen collection would help bridge this gap. Objective: To establish a national, patient-centered, multidimensional web-based clinical database and federated virtual biobank to conduct human-based molecular and clinical research in GN in Canada. Design: Multicenter, prospective observational registry, starting in 2019. Setting: Nine participating Canadian tertiary care centers. Patients: Adult patients with a histopathologic pattern of injury consistent with IgA nephropathy, focal and segmental glomerulosclerosis, minimal change disease, membranous nephropathy, C3 glomerulopathy, and membranoproliferative GN recruited within 24 months of biopsy. Measurements: Initial visits include detailed clinical, histopathological, and laboratory data collection, blood, urine, and tonsil swab biospecimen collection, and a self-administered quality of life questionnaire. Follow-up clinical and laboratory data collection, biospecimen collection, and questionnaires are obtained every 6 months thereafter. Methods: Patients receive care as defined by their physician, with study visits scheduled every 6 months. Patients are followed until death, dialysis, transplantation, or withdrawal from the study. Key outcomes include a composite of ESKD or a 40% decline in estimated glomerular filtration rate (eGFR) at 2 years, rate of kidney function decline, and remission of proteinuria. Clinical and molecular phenotypical data will be analyzed by GN subtype to identify disease predictors and discover therapeutic targets. Limitations: Given the relative rarity of individual glomerular diseases, one of the major challenges is patient recruitment. Initial registry studies may be underpowered to detect small differences in clinically meaningful outcomes such as ESKD or death due to small sample sizes and short duration of follow-up in the initial 2-year phase of the study. Conclusions: The Canadian Glomerulonephritis Registry (CGNR) supports national collaborative efforts to study glomerular disease patients and their outcomes. Trial registration: NCT03460054.
Contexte: Les glomérulonéphrites (GN) sont des causes importantes d'insuffisance rénale; elles représentent 20 % des cas incidents d'insuffisance rénale terminale (IRT) au Canada chaque année. Inverser la néphropathie et prévenir la progression vers l'insuffisance rénale est possible, mais deux obstacles majeurs freinent la réussite de l'intervention thérapeutique: une compréhension limitée des mécanismes sous-jacents de la maladie, de même que l'absence de biomarqueurs non invasifs et de cibles thérapeutiques. Les approches multicentriques reliant les données cliniques longitudinales et les résultats de santé à la collecte d'échantillons biologiques en série permettraient de combler cette lacune. Objectif: Créer une base de données cliniques nationale en ligne, multidimensionnelle et axée sur le patient, de même qu'une biobanque virtuelle fédérée pour permettre de mener des recherches moléculaires et cliniques humaines sur les GN au Canada. Type d'étude: Registre d'observation prospectif multicentrique débuté en 2019. Cadre: Neuf centres de soins tertiaires canadiens. Sujets: Des patients adultes recrutés dans les 24 mois suivant la biopsie et présentant un profil histopathologique de lésion compatible avec une néphropathie à IgA, une hyalinose segmentaire et focale, une maladie à changement minime, une glomérulonéphrite extra-membraneuse, une glomérulopathie à C3 et une glomérulonéphrite membranoproliférative. Mesures: La première visite comporte une collecte détaillée des données cliniques, histopathologiques et de laboratoire, la collecte d'échantillons biologiques (sang, urine et écouvillonnage des amygdales), ainsi qu'un questionnaire autoadministré sur la qualité de vie. Pour le suivi, la collecte des données cliniques et de laboratoire, la collecte des échantillons biologiques et les questionnaires s'effectuent tous les six mois. Méthodologie: Les patients reçoivent des soins comme établi par leur médecin, et les visites d'étude sont programmées tous les six mois. Les patients sont suivis jusqu'au décès ou jusqu'à la dialyse, à la transplantation ou au retrait de l'étude. Un critère de jugement combiné (IRT, ou diminution de 40 % du débit de filtration glomérulaire estimé après deux ans), ainsi que le taux de déclin de la fonction rénale et la rémission de la protéinurie sont les principaux critères de jugement. Les données phénotypiques cliniques et moléculaires seront analysées par sous-types de GN afin d'identifier les prédicteurs de la maladie et de découvrir de nouvelles cibles thérapeutiques. Limites: Le recrutement des sujets demeure un des principaux défis puisque les maladies glomérulaires prises individuellement sont relativement rares. La faible taille des échantillons et la courte durée du suivi pendant les deux ans de la phase initiale de l'étude pourraient faire en sorte que les études initiales issues du registre ne soient pas assez puissantes pour détecter de légères différences dans les résultats cliniquement significatifs comme l'IRT ou le décès. Conclusion: Le Canadian Glomerulonephritis Registry (CGNR) appuie les efforts de collaboration nationale visant à étudier les patients atteints de maladies glomérulaires et leur évolution clinique. Enregistrement de l'essai: NCT03460054.
RESUMEN
Background: Adults with primary focal segmental glomerulosclerosis (FSGS) are frequently resistant to multiple immunosuppressive agents, which is associated with ongoing complications of nephrotic syndrome and a high risk of progression to end-stage renal disease (ESRD). Rituximab, a monoclonal antibody against the B cell CD20 antigen, has shown some preliminary evidence in treating nephrotic syndrome. Objectives: Describe the usage and the efficacy of rituximab for adults with FSGS in British Columbia (BC) (Canada) and perform a literature review of multi-immunosuppressive drug resistant FSGS in adult patients treated with rituximab to estimate the overall response rate. Design: Case series report and a literature review. Patients: For the case-series, all BC patients who received rituximab for a diagnosis of primary FSGS were included. The literature review included all cases of immunosuppressive-resistant FSGS patients treated with rituximab. We excluded transplant and pediatric patients in both groups. Methods: We describe all cases of adults with native-kidney FSGS resistant to conventional immunosuppressive medications from our provincial health database who were treated with rituximab from 2014 to 2018. A review of the existing literature was performed via PubMed, MEDLINE, and Embase using the following keywords: rituximab, focal segmental glomerulosclerosis, and FSGS up to August 2019. Results: We characterize four immunosuppressive-resistant FSGS patients who were treated with rituximab as part of our provincial program, all of whom showed a response to rituximab with a sustained remission. We found 29 specific cases in the literature of adults with native-kidney FSGS treated with rituximab after being resistant to other immunosuppressive medications, of whom 15 cases showed a response to rituximab. This has increased the total response rate from 15/29 (52%) to 19/33 (58%). Limitations: Literature on this topic is coming predominantly from case series. Prospective trials are needed to confirm efficacy, tolerability, and duration of remission. Conclusions: Due to the low number of currently reported cases and variable response rates, these four cases provide critical data to generate a more accurate understanding of the role of rituximab in adults with resistant FSGS. Adding these results to the confirmed literature cases of multiple-immunosuppressive-resistant FSGS patients treated with rituximab results in a total remission rate of 19/33 cases.
Contexte: Il arrive fréquemment que les adultes atteints d'une glomérulosclérose segmentaire focale primaire (focal segmental glomerulosclerosisFSGS) soient résistants à de multiples agents immunosuppresseurs. Cette résistance est associée à des complications du syndrome néphrotique et à un risque élevé de progression vers l'insuffisance rénale terminale (IRT). Le rituximab, un anticorps monoclonal contre l'antigène CD20 des lymphocytes B, a montré quelques résultats préliminaires prometteurs pour le traitement du syndrome néphrotique. Objectifs: Décrire l'utilisation du rituximab et son efficacité chez les adultes atteints de FSGS en Colombie-Britannique (C.-B.) (Canada) et estimer le taux de réponse global par le biais d'une revue de la littérature portant sur les cas de FSGS résistante à plusieurs agents immunosuppresseurs chez des patients adultes traités par rituximab. Conception de l'étude: Rapport de série de cas et revue de la littérature. Sujets: Ont été inclus pour la série de cas tous les patients britanno-colombiens qui recevaient du rituximab pour un diagnostic de FSGS primaire. La revue de la littérature a porté sur tous les cas de patients atteints de FSGS résistante aux immunosuppresseurs et traités par rituximab. Les patients transplantés et les enfants ont été exclus des deux groupes. Méthodologie: Nous décrivons tous les cas répertoriés d'adultes atteints d'une FSGS résistante aux immunosuppresseurs conventionnels dans un rein natif et traités par rituximab dans la base de données de santé provinciale entre 2014 et 2018. Une revue de la littérature existante a été réalisée dans PubMed, Medline et Embase en utilisant les mots-clés suivants: Rituximab, focal segmental glomerulosclerosis (glomérulosclérose segmentaire focale) et FSGS jusqu'en août 2019. Résultats: Nous caractérisons les cas de quatre patients atteints de FSGS résistante aux immunosuppresseurs et traités par rituximab dans le cadre de notre program provincial; tous ont répondu au rituximab avec une rémission durable. Dans la littérature, nous avons répertorié 29 cas particuliers d'adultes atteints d'une FSGS de rein natif ayant été traités par rituximab après avoir été résistants à d'autres médicaments immunosuppresseurs. De ces 29 cas, 15 ont répondu au rituximab. Le taux de réponse total est ainsi passé de 52 % (15/29) à 58 % (19/33). Limites: La littérature sur ce sujet provient principalement de séries de cas. Des essais prospectifs sont nécessaires pour confirmer l'efficacité, la tolérance et la durée de la rémission. Conclusion: Compte tenu du faible nombre de cas actuellement signalés et des taux de réponse variables, ces quatre cas fournissent des données cruciales qui permettent de mieux comprendre le rôle du rituximab chez les adultes atteints de FSGS résistante aux agents immunosuppresseurs. L'ajout de ces résultats confirmés dans la littérature aux cas de patients atteints de FSGS résistante à plusieurs immunosuppresseurs traités par rituximab a entraîné un taux de rémission total de 19 cas sur 33.
RESUMEN
AIMS: To assess the effect of sodium-glucose cotransporter-2 inhibitor dapagliflozin on natriuresis, blood pressure (BP) and volume status in patients with chronic kidney disease (CKD) without diabetes. MATERIALS AND METHODS: We performed a mechanistic open-label study (DAPASALT) to evaluate the effects of dapagliflozin on 24-hour sodium excretion, 24-hour BP, extracellular volume, and markers of volume status during a standardized sodium diet (150 mmol/d) in six patients with CKD. In parallel, in a placebo-controlled double-blind crossover trial (DIAMOND), we determined the effects of 6 weeks of dapagliflozin on markers of volume status in 53 patients with CKD. RESULTS: In DAPASALT (mean age 65 years, mean estimated glomerular filtration rate [eGFR] 39.4 mL/min/1.73 m2 , median urine albumin:creatinine ratio [UACR] 111 mg/g), dapagliflozin did not change 24-hour sodium and volume excretion during 2 weeks of treatment. Dapagliflozin was associated with a modest increase in 24-hour glucose excretion on Day 4, which persisted at Day 14 and reversed to baseline after discontinuation. Mean 24-hour systolic BP decreased by -9.3 (95% confidence interval [CI] -19.1, 0.4) mmHg after 4 days and was sustained at Day 14 and at wash-out. Renin, angiotensin II, urinary aldosterone and copeptin levels increased from baseline. In DIAMOND (mean age 51 years, mean eGFR 59.0 mL/min/1.73 m2 , median UACR 608 mg/g), compared to placebo, dapagliflozin increased plasma renin (38.5 [95% CI 7.4, 78.8]%), aldosterone (19.1 [95% CI -5.9, 50.8]%), and copeptin levels (7.3 [95% CI 0.1, 14.5] pmol/L). CONCLUSIONS: During a standardized sodium diet, dapagliflozin decreased BP but did not increase 24-hour sodium and volume excretion. The lack of increased natriuresis and diuresis may be attributed to activation of intra-renal compensatory mechanisms to prevent excessive water loss.
Asunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Renal Crónica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Anciano , Aldosterona , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéutico , Biomarcadores , Presión Sanguínea , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Tasa de Filtración Glomerular , Glucosa/farmacología , Glucósidos , Humanos , Persona de Mediana Edad , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Renina , Sodio , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéuticoRESUMEN
IgA nephropathy (IgAN) is a leading cause of kidney failure, yet little is known about the immunopathogenesis of this disease. IgAN is characterized by deposition of IgA in the kidney glomeruli, but the source and stimulus for IgA production are not known. Clinical and experimental data suggest a role for aberrant immune responses to mucosal microbiota in IgAN, and in some countries with high disease prevalence, tonsillectomy is regarded as standard-of-care therapy. To evaluate the relationship between microbiota and mucosal immune responses, we characterized the tonsil microbiota in patients with IgAN versus nonrelated household-matched control group participants and identified increased carriage of the genus Neisseria and elevated Neisseria-targeted serum IgA in IgAN patients. We reverse-translated these findings in experimental IgAN driven by BAFF overexpression in BAFF-transgenic mice rendered susceptible to Neisseria infection by introduction of a humanized CEACAM-1 transgene (B × hC-Tg). Colonization of B × hC-Tg mice with Neisseria yielded augmented levels of systemic Neisseria-specific IgA. Using a custom ELISPOT assay, we discovered anti-Neisseria-specific IgA-secreting cells within the kidneys of these mice. These findings suggest a role for cytokine-driven aberrant mucosal immune responses to oropharyngeal pathobionts, such as Neisseria, in the immunopathogenesis of IgAN. Furthermore, in the presence of excess BAFF, pathobiont-specific IgA can be produced in situ within the kidney.
Asunto(s)
Glomerulonefritis por IGA , Microbiota , Animales , Humanos , Inmunidad Humoral , Inmunoglobulina A , Ratones , Tonsila Palatina/patologíaRESUMEN
INTRODUCTION: Patients with glomerular disease experience symptoms that impair their physical and mental health while managing their treatments, diet, appointments and monitoring general and specific indicators of health and their illness. We sought to describe the perspectives of patients and their care partners on self-management in glomerular disease. METHODS: We conducted 16 focus groups involving adult patients with glomerular disease (n = 101) and their care partners (n = 34) in Australia, Hong Kong, the United Kingdom, and United States. Transcripts were analyzed thematically. RESULTS: We identified the following 4 themes: empowered in autonomy (gaining confidence through understanding, taking ownership of disease and treatment, learning a positive health approach); overwhelmed by compounding treatment burdens (financially undermined and depleted, demoralized by side effects and harms, frustrated by fragmented and inflexible care, fear of possible drug harms); striving for stability and normalcy (making personal sacrifices, maximizing life participation, attentiveness to bodily signs, avoiding precarious health states, integrating medicines into routines); and necessity of health-sustaining relationships (buoyed by social support, fulfilling meaningful responsibilities, sharing and normalizing experiences, seeking a trusting and respectful alliance). CONCLUSION: Patients with glomerular disease and their care partners value their capacity for autonomy and disease ownership, stability of their health, and relationships that support self-management. Strategies directed at strengthening these factors may increase self-efficacy and improve the care and outcomes for patients with glomerular disease.