scholarly journals P0350THE DURATION OF PROTEINURIA REMISSION AND CLINICAL OUTCOMES IN IGA NEPHROPATHY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Mark Canney ◽  
Sean Barbour ◽  
Sophia Zheng ◽  
Rosanna Coppo ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Disease Progression ◽  
Iga Nephropathy ◽  
Primary Outcome ◽  
Hazard Ratio ◽  
Surrogate Outcome ◽  
Therapeutic Trials ◽  
Non Linear ◽  
Risk Of Disease

Abstract Background and Aims A relative reduction in proteinuria has been proposed as a surrogate outcome for therapeutic trials in IgA nephropathy. It is currently unknown how long a reduction in proteinuria needs to be maintained in order to mitigate the long-term risk of disease progression. To address this knowledge gap we sought to quantify the association between duration of proteinuria remission and the risk of disease progression in IgA nephropathy. Method In this retrospective multi-ethnic international cohort of adult patients with biopsy-proven IgA nephropathy, we defined proteinuria remission based on three criteria: (i) peak proteinuria on/after biopsy ≥1g/day; (ii) an absolute reduction in proteinuria to <1g/day; (iii) a ≥25% reduction in proteinuria from the peak value. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. The primary outcome was the occurrence of end-stage kidney disease or a sustained 50% reduction in estimated glomerular filtration rate (eGFR). The association between duration of remission and the primary outcome was visualized using restricted cubic splines, and quantified using extended Cox proportional hazards regression models. Results A total of 1864 patients met criteria for remission, which occurred a median of 8.3 months after biopsy (IQR 3.6-22). They had a median age of 36.8 (IQR 29.4-46.6) years and a median eGFR of 78 (IQR 55-104) mL/min/1.73m2. Median proteinuria was 1.54 (IQR 1.09-2.4) g/day at the time of biopsy and 0.55 (IQR 0.33-0.76) g/day at the time of entering remission. During a median follow-up of 3.9 years, 274 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and the primary outcome was non-linear (Figure). Each 3 months in sustained remission up to 51 months was associated with an additional 9% reduction in the risk of disease progression (hazard ratio 0.91, 95% confidence interval 0.89-0.93). In contrast, each additional 3 months in remission beyond 51 months was associated with a smaller non-significant risk reduction (hazard ratio 0.99, 95% confidence interval 0.96-1.03). These finding were robust to multivariable adjustment and were consistent across subgroups based on the MEST histology score, and whether or not the remission occurred while on renin-angiotensin-aldosterone-system blockade or after immunosuppression treatment. Results were similar when relapse was defined as either a 50% or 100% increase in proteinuria from the nadir value after remission to an absolute value of ≥1g/day. Conclusion We observed a strong non-linear dose-response relationship between the duration of proteinuria remission and the risk of disease progression in patients with IgA nephropathy. The ability to quantitate the renal survival benefit related to the duration of remission is an important advance for patients and their physicians. Rather than there being a minimum duration of proteinuria remission in IgA nephropathy, our results demonstrate that even short durations in remission, or small increases in remission duration, are both associated with significant reductions in the risk of disease progression. For future therapeutic trials in IgA nephropathy using proteinuria as a surrogate outcome, our findings illustrate the need to consider the duration of proteinuria reduction, in addition to the magnitude of proteinuria reduction, when evaluating the anticipated treatment effect on long-term clinical endpoints.

scholarly journals Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy

2020 ◽  
Vol 32 (2) ◽  
pp. 436-447
Author(s):  
Mark Canney ◽  
Sean J. Barbour ◽  
Yuyan Zheng ◽  
Rosanna Coppo ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Disease Progression ◽  
Iga Nephropathy ◽  
Primary Outcome ◽  
Proportional Hazards ◽  
Meta Analysis ◽  
Total Duration ◽  
Cox Proportional Hazards ◽  
Sustained Remission ◽  
Surrogate Outcome ◽  
Risk Of Disease

BackgroundOn the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown.MethodsIn this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to <1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR).ResultsDuring a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups.ConclusionsOur findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.

scholarly journals Apixaban versus No Anticoagulation in Patients Undergoing Long-Term Dialysis with Incident Atrial Fibrillation

2020 ◽  
Vol 15 (8) ◽  
pp. 1146-1154 ◽  
Author(s):  
Thomas A. Mavrakanas ◽  
Katherine Garlo ◽  
David M. Charytan
Keyword(s):  
Atrial Fibrillation ◽  
Confidence Interval ◽  
Transient Ischemic Attack ◽  
Lower Incidence ◽  
Primary Outcome ◽  
Hazard Ratio ◽  
Intracranial Bleeding ◽  
Nonvalvular Atrial Fibrillation ◽  
Maintenance Dialysis ◽  
Ischemic Attack

Background and objectivesThe relative efficacy and safety of apixaban compared with no anticoagulation have not been studied in patients on maintenance dialysis with atrial fibrillation. We aimed to determine whether apixaban is associated with better clinical outcomes compared with no anticoagulation in this population.Design, setting, participants, & measurementsThis retrospective cohort study used 2012–2015 US Renal Data System data. Patients on maintenance dialysis with incident, nonvalvular atrial fibrillation treated with apixaban (521 patients) were matched for relevant baseline characteristics with patients not treated with any anticoagulant agent (1561 patients) using a propensity score. The primary outcome was hospital admission for a new stroke (ischemic or hemorrhagic), transient ischemic attack, or systemic thromboembolism. The secondary outcome was fatal or intracranial bleeding. Competing risk survival models were used.ResultsCompared with no anticoagulation, apixaban was not associated with lower incidence of the primary outcome: hazard ratio, 1.24; 95% confidence interval, 0.69 to 2.23; P=0.47. A significantly higher incidence of fatal or intracranial bleeding was observed with apixaban compared with no treatment: hazard ratio, 2.74; 95% confidence interval, 1.37 to 5.47; P=0.004. A trend toward fewer ischemic but more hemorrhagic strokes was seen with apixaban compared with no treatment. No significant difference in the composite outcome of myocardial infarction or ischemic stroke was seen with apixaban compared with no treatment. Compared with no anticoagulation, a significantly higher rate of the primary outcome and a significantly higher incidence of fatal or intracranial bleeding and of hemorrhagic stroke were seen in the subgroup of patients treated with the standard apixaban dose (5 mg twice daily) but not in patients who received the reduced apixaban dose (2.5 mg twice daily).ConclusionsIn patients with kidney failure and nonvalvular atrial fibrillation, treatment with apixaban was not associated with a lower incidence of new stroke, transient ischemic attack, or systemic thromboembolism but was associated with a higher incidence of fatal or intracranial bleeding.PodcastThis article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_05_29_CJN11650919.mp3

scholarly journals Blood Pressure Variability, Mortality, and Cardiovascular Outcomes in CKD Patients

2019 ◽  
Vol 14 (2) ◽  
pp. 233-240 ◽  
Author(s):  
Francesca Mallamaci ◽  
Giovanni Tripepi ◽  
Graziella D’Arrigo ◽  
Silvio Borrelli ◽  
Carlo Garofalo ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Cardiovascular Events ◽  
Prognostic Value ◽  
Clinic Visit ◽  
Hazard Ratio ◽  
Interquartile Range ◽  
Short Term ◽  
End Point

Background and objectivesShort-term BP variability (derived from 24-hour ambulatory BP monitoring) and long-term BP variability (from clinic visit to clinic visit) are directly related to risk for cardiovascular events, but these relationships have been scarcely investigated in patients with CKD, and their prognostic value in this population is unknown.Design, setting, participants, & measurementsIn a cohort of 402 patients with CKD, we assessed associations of short- and long-term systolic BP variability with a composite end point of death or cardiovascular event. Variability was defined as the standard deviation of observed BP measurements. We further tested the prognostic value of these parameters for risk discrimination and reclassification.ResultsMean ± SD short-term systolic BP variability was 12.6±3.3 mm Hg, and mean ± SD long-term systolic BP variability was 12.7±5.1 mm Hg. For short-term BP variability, 125 participants experienced the composite end point over a median follow-up of 4.8 years (interquartile range, 2.3–8.6 years). For long-term BP variability, 110 participants experienced the composite end point over a median follow-up of 3.2 years (interquartile range, 1.0–7.5 years). In adjusted analyses, long-term BP variability was significantly associated with the composite end point (hazard ratio, 1.24; 95% confidence interval, 1.01 to 1.51 per 5-mm Hg higher SD of office systolic BP), but short-term systolic BP variability was not (hazard ratio, 0.92; 95% confidence interval, 0.68 to 1.25 per 5-mm Hg higher SD of 24-hour ambulatory systolic BP). Neither estimate of BP variability improved risk discrimination or reclassification compared with a simple risk prediction model.ConclusionsIn patients with CKD, long-term but not short-term systolic BP variability is related to the risk of death and cardiovascular events. However, BP variability has a limited role for prediction in CKD.

P1731High-sensitivity troponin with sex-specific thresholds in suspected acute coronary syndrome

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
K K Lee ◽  
A V Ferry ◽  
A Anand ◽  
F E Strachan ◽  
A R Chapman ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Coronary Syndrome ◽  
Confidence Interval ◽  
Myocardial Injury ◽  
Primary Outcome ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Coronary Syndrome ◽  
Diagnostic Thresholds ◽  
The Impact

Abstract Background/Introduction Major disparities between women and men in the diagnosis, management and outcome of acute coronary syndrome are well recognised. Whether sex-specific diagnostic thresholds for myocardial infarction will address these differences is uncertain. Purpose To evaluate the impact of implementing a high-sensitivity cardiac troponin I (hs-cTnI) assay with sex-specific diagnostic thresholds for myocardial infarction in women and men with suspected acute coronary syndrome. Methods In a stepped-wedge, cluster-randomized controlled trial across ten hospitals we evaluated the implementation of a hs-cTnI assay in 48,282 (47% women) consecutive patients with suspected acute coronary syndrome. During a validation phase the hs-cTnI assay results were suppressed and a contemporary cTnI assay with a single threshold was used to guide care. Myocardial injury was defined as any hs-cTnI concentration >99th centile of 16 ng/L in women and 34 ng/L in men. The primary outcome was myocardial infarction after the initial presentation or cardiovascular death at 1 year. In this prespecified analysis, we evaluated outcomes in men and women before and after implementation of the hs-cTnI assay. Results Use of the hs-cTnI assay with sex-specific thresholds increased myocardial injury in women by 42% (from 3,521 (16%) to 4,991 (22%)) and by 6% in men (from 5,068 (20%) to 5,369 (21%)). Whilst treatment increased in both sexes, women with myocardial injury remained less likely than men to undergo coronary revascularisation (15% versus34%), or to receive dual anti-platelet (26% versus43%), statin (16% versus26%) or other preventative therapies (P<0.001 for all). The primary outcome occurred in 18% (369/2,072) and 17% (488/2,919) of women with myocardial injury during the validation and implementation phase respectively (adjusted hazard ratio 1.11, 95% confidence interval 0.92 to 1.33), compared to 18% (370/2,044) and 15% (513/3,325) of men (adjusted hazard ratio 0.85, 95% confidence interval 0.71 to 1.01). Patient management Conclusion Use of sex-specific thresholds identified five-times more additional women than men with myocardial injury, such that the proportion of women and men with myocardial injury is now similar. Despite this increase, women received approximately half the number of treatments for coronary artery disease as men and their outcomes were not improved. Acknowledgement/Funding The British Heart Foundation

scholarly journals The Prognostic Value of Histopathologic Lesions in Native Kidney Biopsy Specimens: Results from the Boston Kidney Biopsy Cohort Study

2018 ◽  
Vol 29 (8) ◽  
pp. 2213-2224 ◽  
Author(s):  
Anand Srivastava ◽  
Ragnar Palsson ◽  
Arnaud D. Kaze ◽  
Margaret E. Chen ◽  
Polly Palacios ◽  
...  
Keyword(s):  
Cohort Study ◽  
Kidney Disease ◽  
Confidence Interval ◽  
Disease Progression ◽  
Kidney Biopsy ◽  
Hazard Ratio ◽  
Prognostic Information ◽  
Biopsy Specimens ◽  
Native Kidney ◽  
Kidney Disease Progression

Background Few studies have evaluated whether histopathologic lesions on kidney biopsy provide prognostic information beyond clinical and laboratory data.Methods We enrolled 676 individuals undergoing native kidney biopsy at three tertiary care hospitals into a prospective, observational cohort study. Biopsy specimens were adjudicated for semiquantitative scores in 13 categories of histopathology by two experienced renal pathologists. Proportional hazards models tested the association between histopathologic lesions and risk of kidney disease progression (≥40% eGFR decline or RRT).Results Mean baseline eGFR was 57.5±36.0 ml/min per 1.73 m2. During follow-up (median, 34.3 months), 199 individuals suffered kidney disease progression. After adjustment for demographics, clinicopathologic diagnosis, and laboratory values, the following lesions (hazard ratio; 95% confidence interval) were independently associated with progression: inflammation in nonfibrosed interstitium (0.52; 0.32 to 0.83), moderate and severe versus minimal interstitial fibrosis/tubular atrophy (2.14; 1.24 to 3.69 and 3.42; 1.99 to 5.87, respectively), moderate and severe versus minimal global glomerulosclerosis (2.17; 1.36 to 3.45 and 3.31; 2.04 to 5.38, respectively), moderate and severe versus minimal arterial sclerosis (1.78; 1.15 to 2.74 and 1.64; 1.04 to 2.60, respectively), and moderate and severe versus minimal arteriolar sclerosis (1.63; 1.08 to 2.46 and 2.33; 1.42 to 3.83, respectively). An 11-point chronicity score derived from semiquantitative assessments of chronic lesions independently associated with higher risk of kidney disease progression (hazard ratio per one-point increase, 1.19; 95% confidence interval, 1.12 to 1.27).Conclusions Across a diverse group of kidney diseases, histopathologic lesions on kidney biopsy provide prognostic information, even after adjustment for proteinuria and eGFR.

Incidence and predictors of venous thromboembolism in post-acute care patients

2010 ◽  
Vol 104 (10) ◽  
pp. 734-740 ◽  
Author(s):  
Walter Ageno ◽  
Andrea Airoldi ◽  
Erminio Bonizzoni ◽  
Mauro Campanini ◽  
Gualberto Gussoni ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Confidence Interval ◽  
Multivariable Analysis ◽  
Hazard Ratio ◽  
Term Care ◽  
Risk Of Death ◽  
Increased Risk ◽  
Rehabilitation Facilities ◽  
Overall Mortality

SummaryFew studies have addressed the topic of venous thromboembolism (VTE) in patients hospitalised in rehabilitation facilities. This patient population is rapidly growing, and data aimed to better define VTE risk in this setting are needed. Primary aim of this prospective observational study was to evaluate the frequency of symptomatic, objectively confirmed VTE in a cohort of unselected consecutive patients admitted to rehabilitation facilities, after medical diseases or surgery. Further objectives were to assess overall mortality, to identify risk factors for VTE and mortality, and to assess the attitude of physicians towards thromboprophylaxis. A total of 3,039 patients were included in the study, and the median duration of hospitalisation was 26 days. Seventy-two patients (2.4%) had symptomatic VTE. The median time to VTE from admission to the long-term care unit was 13 days. According to multivariable analysis, previous VTE (hazard ratio 5.67, 95% confidence interval 3.30–9.77) and cancer (hazard ratio 2.26, 95% confidence interval 1.36–3.75) were significantly associated to the occurrence of VTE. Overall in-hospital mortality was 15.1%. Age over 75 years, male gender, disability, cancer, and the absence of thromboprophylaxis were significantly associated to an increased risk of death (multivariable analysis). In-hospital antithrombotic prophylaxis was administered to 75.1% of patients, and low-molecular-weight heparin was the most widely used agent. According to our study, patients admitted to rehabilitation facilities remain at substantially increased risk for VTE. Because this applies to the majority of these patients, there is a great need for clinical trials assessing optimal prophylactic strategies.

Evaluation of local control in patients with non-metastatic Ewing sarcoma of the bone: A report from the Children's Oncology Group

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10013-10013
Author(s):  
S. G. DuBois ◽  
M. D. Krailo ◽  
E. F. Cook ◽  
N. J. Tarbell ◽  
C. J. Fryer ◽  
...  
Keyword(s):  
Disease Progression ◽  
Local Control ◽  
Ewing Sarcoma ◽  
Tumor Size ◽  
Cumulative Incidence ◽  
Hazard Ratio ◽  
Local Failure ◽  
Control Mode ◽  
Distant Failure ◽  
Risk Of Disease

10013 Background: Options for local control in patients (pts) with Ewing sarcoma (EWS) include surgery (S), radiation (R), or surgery plus radiation (S+R). The choice of local control depends on factors that also impact outcome in EWS, including tumor site, tumor size, and age. Our objective was to determine if risk of disease progression differs between local control methods, after controlling for potential confounders. Methods: We analyzed the cohort of pts with non-metastatic EWS of the bone treated on Intergroup Study-0091 (Grier et al, NEJM, 2003). Local control decisions were made on an individual basis. We excluded pts with tumors of the skull/face, progression prior to end of local control, or incomplete local control data. Disease progression was recorded from end of local control. Cumulative incidence of disease progression was determined using a competing risks approach. We constructed a Cox proportional hazards model of progression free survival incorporating local control mode and potential confounders into the model. Secondary analyses evaluated overall survival, local failure, and distant failure. Results: 329 pts met eligibility criteria for analysis. 122 pts received S, 142 received R, and 65 received S+R. The cumulative incidence of disease progression at 5 years was 22.1% (95% CI 15.1–29.9%) for S, 36.9% (29.0–44.9%) for R, and 48.1% (35.5- 59.7%) for S+R. Using R as the reference group and controlling for age, tumor size, tumor location, and chemotherapy regimen, the hazard ratio for progression was 0.66 (95% CI 0.38–1.13) for S and 1.55 (0.96–2.49) for S+R. The hazard ratio for death was 0.77 (95% CI 0.44–1.34) for S and 1.46 (0.88–2.42) for S+R. The hazard ratio for local failure was 0.38 (95% CI 0.15–0.98; p=0.04) for S and 0.77 (0.34–1.75) for S+R. The hazard ratio for distant failure was 0.78 (0.42–1.46) for S and 1.60 (0.91–2.82) for S+R. Conclusions: Observed differences in outcome between local control groups are largely due to confounding factors that affect outcome and local control choice. Risk of disease progression, distant failure, or death does not differ between pts who receive S or R. Pts who receive S have a decreased risk of local failure compared to pts who receive R. No significant financial relationships to disclose.

scholarly journals Sleep-related hypermotor epilepsy

Neurology ◽  
2016 ◽  
Vol 88 (1) ◽  
pp. 70-77 ◽  
Author(s):  
Laura Licchetta ◽  
Francesca Bisulli ◽  
Luca Vignatelli ◽  
Corrado Zenesini ◽  
Lidia Di Vito ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Age At Onset ◽  
Hazard Ratio ◽  
Seizure Freedom ◽  
Brain Disorder ◽  
Long Term Outcome

Objective:To assess the long-term outcome of sleep-related hypermotor epilepsy (SHE).Methods:We retrospectively reconstructed a representative cohort of patients diagnosed with SHE according to international diagnostic criteria, sleep-related seizures ≥75% and follow-up ≥5 years. Terminal remission (TR) was defined as a period of ≥5 consecutive years of seizure freedom at the last follow-up. We used Kaplan-Meier estimates to calculate the cumulative time-dependent probability of TR and to generate survival curves. Univariate and multivariate Cox regression analyses were performed.Results:We included 139 patients with a 16-year median follow-up (2,414 person-years). The mean age at onset was 13 ± 10 years. SHE was sporadic in 86% of cases and familial in 14%; 16% of patients had underlying brain abnormalities. Forty-five percent of patients had at least 1 seizure in wakefulness lifetime and 55% had seizures only in sleep (typical SHE). At the last assessment, 31 patients achieved TR (TR group, 22.3%), while 108 (NTR group, 77.7%) still had seizures or had been in remission for <5 years. The cumulative TR rate was 20.4%, 23.5%, and 28.4% by 10, 20, and 30 years from inclusion. At univariate analysis, any underlying brain disorder (any combination of intellectual disability, perinatal insult, pathologic neurologic examination, and brain structural abnormalities) and seizures in wakefulness were more frequent among the NTR group (p = 0.028; p = 0.043). Absence of any underlying brain disorder (hazard ratio 4.21, 95% confidence interval 1.26–14.05, p = 0.020) and typical SHE (hazard ratio 2.76, 95% confidence interval 1.31–5.85, p = 0.008) were associated with TR.Conclusions:Our data show a poor prognosis of SHE after a long-term follow-up. Its outcome is primarily a function of the underlying etiology.

scholarly journals Statistical Analysis Plan for the Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study (TESTING)

2021 ◽  
Author(s):  
Laurent Billot ◽  
Helen Monaghan ◽  
Muh Geot Wong ◽  
Vlado Perkovic
Keyword(s):  
Statistical Analysis ◽  
Iga Nephropathy ◽  
Controlled Trial ◽  
Renin Angiotensin System ◽  
Statistical Analysis Plan ◽  
Therapeutic Evaluation ◽  
Global Study ◽  
Risk Of Disease ◽  
Double Blinded

The TESTING (Therapeutic Evaluation of STeroids in IgA Nephropathy Global) study is a multicenter, double-blinded, randomised, placebo-controlled trial designed to evaluate the long-term efficacy and safety of oral methylprednisolone, on a background of routine renin angiotensin system (RAS) inhibitor therapy, in preventing kidney events in patients with IgA nephropathy with features suggestive of a high risk of disease progression. This statistical analysis plan (SAP) provides the details of all pre-specified analyses to be conducted at the end of the trial. The SAP was written by the trial statistician, chief investigator, study director and project manager and approved by the management committee.

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