Faculty Bibliography
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Clinical journal of the American Society of Nephrology : CJASN. 2020:15(6):805-812.DOI: 10.2215/CJN.06810619
Intradialytic Hypotension and Cardiac Arrhythmias in Patients Undergoing Maintenance Hemodialysis: Results from the Monitoring in Dialysis Study
BACKGROUND AND OBJECTIVES/OBJECTIVE:Patients receiving maintenance hemodialysis (HD) have a high incidence of cardiac events, including arrhythmia and sudden death. Intradialytic hypotension (IDH) is a common complication of HD and is associated with development of reduced myocardial perfusion, a potential risk factor for arrhythmia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:(decline in systolic BP 0-20 mm Hg from predialysis systolic BP) with clinically significant arrhythmia (bradycardia≤40 bpm for ≥6 seconds, asystole≥3 seconds, ventricular tachycardia ≥130 bpm for ≥30 seconds, or patient-marked events) during HD. RESULTS:was associated with a seven-fold higher rate (incidence rate ratio, 7.2; 95% confidence interval, 2.1 to 25.4). CONCLUSIONS:IDH is common in patients on maintenance HD and is associated with a greater risk of developing intradialytic clinically significant arrhythmia.
PMID: 32381584
ISSN: 1555-905x
CID: 4437292
Canagliflozin and risk of skin and soft tissue infections in people with diabetes mellitus and kidney disease-a post-hoc analysis of the credence trial [Meeting Abstract]
Background and Aims: The skin's hypertonic microenvironment has a hypothesized protective antimicrobial function that may be disrupted by SGLT2i. The association between sodiumglucose cotransporter inhibitors (SGLT2i) and genital mycotic infections is well established, but it is not known if these agents increase the risk of other skin and soft tissue infections (SSTI).We aimed to describe SSTI in the CREDENCE trial, and determine whether canagliflozin affects the risk of skin and soft tissue infections (SSTIs) overall and in subgroups.
Method(s): We performed a post-hoc analysis of the CREDENCE trial that randomised people with type 2 diabetes and albuminuric stage 2 and 3 chronic kidney disease to either canagliflozin 100mg daily or placebo. Infections reported as adverse events were assessed by two blinded authors following predetermined criteria for SSTI with discrepancies resolved by consensus. We analysed the risks of SSTIs in the on-treatment population as the more conservative approach, with a sensitivity analysis conducted in the intention-to-treat population. Univariable time-to first-event regression models were assessed.
Result(s): Overall 373/4397 (8.5%) participants experienced 478 events comprising 252 bacterial skin infections (including 2 episodes of necrotising fasciitis), 94 fungal skin infections, 109 other skin infections and 23 soft tissue infections. Of these, 136/478 (28%) were serious. Drug was continued in 290/373 (78%) of first events, with similar frequency of subsequent events between groups (31/133 (23%) and 33/157 (21%) for those continuing canagliflozin and placebo respectively). In both cases of necrotising fasciitis, drug was withdrawn and the participants recovered.Canagliflozin did not increase the risk of SSTI (HR 0.85 [95% Confidence Interval (CI) 0.69-1.04] p=0.11) (Figure 1). Results were similar in the intention-to-treat population (HR 0.88 [95% CI 0.73-1.07] p=0.20), in analyses confined to serious SSTI (HR 0.83 [95% CI 0.58-1.21] p=0.33), and in the predefined subgroups.
Conclusion(s): Although other studies suggest that SGLT2i may reduce the sodium content of the skin, we found that canagliflozin does not increase the risk of skin and soft tissue infections, overall or in any subgroup, in people with type 2 diabetes mellitus and albuminuric chronic kidney disease. (Figure Presented)
Method(s): We performed a post-hoc analysis of the CREDENCE trial that randomised people with type 2 diabetes and albuminuric stage 2 and 3 chronic kidney disease to either canagliflozin 100mg daily or placebo. Infections reported as adverse events were assessed by two blinded authors following predetermined criteria for SSTI with discrepancies resolved by consensus. We analysed the risks of SSTIs in the on-treatment population as the more conservative approach, with a sensitivity analysis conducted in the intention-to-treat population. Univariable time-to first-event regression models were assessed.
Result(s): Overall 373/4397 (8.5%) participants experienced 478 events comprising 252 bacterial skin infections (including 2 episodes of necrotising fasciitis), 94 fungal skin infections, 109 other skin infections and 23 soft tissue infections. Of these, 136/478 (28%) were serious. Drug was continued in 290/373 (78%) of first events, with similar frequency of subsequent events between groups (31/133 (23%) and 33/157 (21%) for those continuing canagliflozin and placebo respectively). In both cases of necrotising fasciitis, drug was withdrawn and the participants recovered.Canagliflozin did not increase the risk of SSTI (HR 0.85 [95% Confidence Interval (CI) 0.69-1.04] p=0.11) (Figure 1). Results were similar in the intention-to-treat population (HR 0.88 [95% CI 0.73-1.07] p=0.20), in analyses confined to serious SSTI (HR 0.83 [95% CI 0.58-1.21] p=0.33), and in the predefined subgroups.
Conclusion(s): Although other studies suggest that SGLT2i may reduce the sodium content of the skin, we found that canagliflozin does not increase the risk of skin and soft tissue infections, overall or in any subgroup, in people with type 2 diabetes mellitus and albuminuric chronic kidney disease. (Figure Presented)
EMBASE:633422527
ISSN: 1460-2385
CID: 4694872
Canagliflozin and risk of genital infections and urinary tract infections in people with diabetes mellitus and kidney disease-a post-hoc analysis of the credence trial [Meeting Abstract]
Background and Aims: To describe genital mycotic infections (GMI) and urinary tract infections (UTI) in the CREDENCE trial, determine whether canagliflozin increased the risk of these infections overall and in subgroups, and describe predictors of risk for genital mycotic infections.
Method(s): The CREDENCE trial randomised people with type 2 diabetes and albuminuric stage 2 and 3 chronic kidney disease to canagliflozin 100mg daily or placebo. We analysed the risk of GMI and UTI with canagliflozin compared to placebo overall and in patient subgroups. The primary analysis was conducted in the on-treatment population, as the more conservative approach with sensitivity analyses conducted using an intention-to-treat population. When canagliflozin increased risk, we determined patient risk factors for GMIs using multivariable Cox regression models adjusting for age, gender, race, markers of disease severity (body mass index (BMI), haemoglobin A1c, diabetes duration, other glucose lowering medications at baseline and kidney function).
Result(s): Overall 31/2905 (1.1%) men and 32/1492 (2.1%) women experienced 91 GMIs and 166/2905 (5.7%) men and 300/1492 (20.1%) women experienced 669 UTIs. Canagliflozin increased the risk of GMI (HR 3.83 [95% CI 2.08-7.06] p<0.0001). The hazard ratio for canagliflozin compared to placebo was consistent across most subgroups, though the risk with canagliflozin was greater in those with a higher BMI (HR 5.91 [95% CI 2.65-13.15] for BMI >=30 kg/m2 vs HR 1.36 [95% CI 0.47-3.92] for BMI<30 kg/m2, p interaction=0.03) and was higher in men (HR 9.30 [95% CI 2.83-30.60] vs HR 2.10 [95% CI 1.00-4.45] for men and women respectively, p interaction= 0.04). In those who were randomised to canagliflozin, independent risk factors for GMI were higher BMI (HR 1.53 [95% CI 1.29-1.83] per 5 units p<0.0001) and longer diabetes duration (HR 1.18 [95% CI 1.01-1.40] per 5 years p=0.04). Canagliflozin did not affect the risk of UTI over placebo (HR 1.08 [95% CI 0.90-1.29] p=0.42) overall or in any subgroup, however risk was higher in women (HR 1.23 [95% CI 0.98-1.54] vs HR 0.82 [0.60-1.11] for women and men respectively, p interaction=0.04).58/669 (8.7%) UTIs but no GMIs were reported as serious. Drug was continued in 56/63 (89%) of first GMIs, with similar frequency of subsequentGMI in those continuing on canagliflozin (13/43, 30.2%) or placebo (4/13, 30.8%). Drug was continued in 385/466 (82.6%) first UTIs, with similar frequency of subsequent UTIs in those continuing on cangliflozin (50/199 (25.1%) or placebo 49/186 (26.3%). All findings were similar when conducted using an intention-to-treat approach.
Conclusion(s): Canagliflozin increased the risk of genital mycotic infections but not urinary tract infections. The risk of genital mycotic infections from canagliflozin over placebo was higher in men and those with higher BMI. In those treated with canagliflozin, higher BMI and longer diabetes duration independently predicted infection. Most participants continued treatment following their first infection with similar recurrence rates in the canagliflozin and placebo groups.These findings will be useful in clinical care, and help identify those at greatest risk for genital infections with canagliflozin treatment
Method(s): The CREDENCE trial randomised people with type 2 diabetes and albuminuric stage 2 and 3 chronic kidney disease to canagliflozin 100mg daily or placebo. We analysed the risk of GMI and UTI with canagliflozin compared to placebo overall and in patient subgroups. The primary analysis was conducted in the on-treatment population, as the more conservative approach with sensitivity analyses conducted using an intention-to-treat population. When canagliflozin increased risk, we determined patient risk factors for GMIs using multivariable Cox regression models adjusting for age, gender, race, markers of disease severity (body mass index (BMI), haemoglobin A1c, diabetes duration, other glucose lowering medications at baseline and kidney function).
Result(s): Overall 31/2905 (1.1%) men and 32/1492 (2.1%) women experienced 91 GMIs and 166/2905 (5.7%) men and 300/1492 (20.1%) women experienced 669 UTIs. Canagliflozin increased the risk of GMI (HR 3.83 [95% CI 2.08-7.06] p<0.0001). The hazard ratio for canagliflozin compared to placebo was consistent across most subgroups, though the risk with canagliflozin was greater in those with a higher BMI (HR 5.91 [95% CI 2.65-13.15] for BMI >=30 kg/m2 vs HR 1.36 [95% CI 0.47-3.92] for BMI<30 kg/m2, p interaction=0.03) and was higher in men (HR 9.30 [95% CI 2.83-30.60] vs HR 2.10 [95% CI 1.00-4.45] for men and women respectively, p interaction= 0.04). In those who were randomised to canagliflozin, independent risk factors for GMI were higher BMI (HR 1.53 [95% CI 1.29-1.83] per 5 units p<0.0001) and longer diabetes duration (HR 1.18 [95% CI 1.01-1.40] per 5 years p=0.04). Canagliflozin did not affect the risk of UTI over placebo (HR 1.08 [95% CI 0.90-1.29] p=0.42) overall or in any subgroup, however risk was higher in women (HR 1.23 [95% CI 0.98-1.54] vs HR 0.82 [0.60-1.11] for women and men respectively, p interaction=0.04).58/669 (8.7%) UTIs but no GMIs were reported as serious. Drug was continued in 56/63 (89%) of first GMIs, with similar frequency of subsequentGMI in those continuing on canagliflozin (13/43, 30.2%) or placebo (4/13, 30.8%). Drug was continued in 385/466 (82.6%) first UTIs, with similar frequency of subsequent UTIs in those continuing on cangliflozin (50/199 (25.1%) or placebo 49/186 (26.3%). All findings were similar when conducted using an intention-to-treat approach.
Conclusion(s): Canagliflozin increased the risk of genital mycotic infections but not urinary tract infections. The risk of genital mycotic infections from canagliflozin over placebo was higher in men and those with higher BMI. In those treated with canagliflozin, higher BMI and longer diabetes duration independently predicted infection. Most participants continued treatment following their first infection with similar recurrence rates in the canagliflozin and placebo groups.These findings will be useful in clinical care, and help identify those at greatest risk for genital infections with canagliflozin treatment
EMBASE:633422365
ISSN: 1460-2385
CID: 4694882
Oxalate Nephropathy in an Oxalobacter formigenes-Negative Subject [Case Report]
PMCID:7210700
PMID: 32405600
ISSN: 2468-0249
CID: 4431442
Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial
BACKGROUND:Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR). METHODS:) and linear mixed effects models to analyze the effects on eGFR slope. RESULTS:). CONCLUSIONS:. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER/UNASSIGNED:Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.
PMID: 32354987
ISSN: 1533-3450
CID: 4438642
Management of Coronary Disease in Patients with Advanced Kidney Disease
BACKGROUND:Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease. METHODS:We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. RESULTS:At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03). CONCLUSIONS:Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).
PMID: 32227756
ISSN: 1533-4406
CID: 5451232
SAT-156 RENAL, CARDIOVASCULAR, AND SAFETY OUTCOMES OF CANAGLIFLOZIN ACCORDING TO BASELINE ALBUMINURIA: A CREDENCE SECONDARY ANALYSIS [Meeting Abstract]
Introduction: Albuminuria is a strong risk factor for kidney disease progression and cardiovascular disease as reflected in the KDIGO categories of urinary ACR <30mg/g, 30-300 and >300 mg/g. The CREDENCE trial recruited participants with substantial levels of albuminuria. We examined the relative and absolute effects of canagliflozin according to baseline albuminuria among people in the CREDENCE trial.
Method(s): The CREDENCE double-blind randomised study of 4401 participants with eGFR 30-<90mL/min/1.73m2 and urinary albumin:creatinine ratio [uACR]>300-5000mg/g, demonstrated that canagliflozin significantly reduced renal and cardiovascular outcomes including the primary composite of end-stage kidney disease, doubling serum creatinine, or renal or cardiovascular death. We analysed the effect of canagliflozin on these and renal safety outcomes according to categories of baseline uACR of <=1000, >1000-<3000 and >=3000mg/g.
Result(s): At baseline, 2348 (53.4%), 1547 (35.2%), and 506 (11.5%) participants had uACR <=1000, >1000-<3000, >=3000mg/g, respectively. Higher categories of uACR were associated with higher rates of events (Figure). Canagliflozin reduced renal and cardiovascular endpoints, with no statistical evidence the effect varied in different uACR groups (all p heterogeneity >0.17). Canagliflozin led to a greater absolute reduction in renal events in those with higher grades of uACR (number needed to treat [NTT] to prevent one episode of the primary composite: 22 and 8 for uACR >1000-<3000 and >=3000mg/g, respectively). Rates of renal-related adverse events were lower overall with canagliflozin, with greater relative reduction greater in higher grades of uACR (p heterogeneity=0.003). Canagliflozin had no significant effect on the individual events of acute kidney injury, volume depletion, hyperkalaemia, urinary tract infections or hypoglycaemia, with no differences among grades of uACR (all p heterogeneity >0.12).
Conclusion(s): Albuminuria predicts renal and cardiovascular risk at high levels of albuminuria. Canagliflozin safely reduces renal and cardiovascular events in people with type 2 diabetes and substantial albuminuria, with the greatest absolute renal benefit in those with albuminuria of 3000-5000mg/g. [Formula presented]
Copyright
Method(s): The CREDENCE double-blind randomised study of 4401 participants with eGFR 30-<90mL/min/1.73m2 and urinary albumin:creatinine ratio [uACR]>300-5000mg/g, demonstrated that canagliflozin significantly reduced renal and cardiovascular outcomes including the primary composite of end-stage kidney disease, doubling serum creatinine, or renal or cardiovascular death. We analysed the effect of canagliflozin on these and renal safety outcomes according to categories of baseline uACR of <=1000, >1000-<3000 and >=3000mg/g.
Result(s): At baseline, 2348 (53.4%), 1547 (35.2%), and 506 (11.5%) participants had uACR <=1000, >1000-<3000, >=3000mg/g, respectively. Higher categories of uACR were associated with higher rates of events (Figure). Canagliflozin reduced renal and cardiovascular endpoints, with no statistical evidence the effect varied in different uACR groups (all p heterogeneity >0.17). Canagliflozin led to a greater absolute reduction in renal events in those with higher grades of uACR (number needed to treat [NTT] to prevent one episode of the primary composite: 22 and 8 for uACR >1000-<3000 and >=3000mg/g, respectively). Rates of renal-related adverse events were lower overall with canagliflozin, with greater relative reduction greater in higher grades of uACR (p heterogeneity=0.003). Canagliflozin had no significant effect on the individual events of acute kidney injury, volume depletion, hyperkalaemia, urinary tract infections or hypoglycaemia, with no differences among grades of uACR (all p heterogeneity >0.12).
Conclusion(s): Albuminuria predicts renal and cardiovascular risk at high levels of albuminuria. Canagliflozin safely reduces renal and cardiovascular events in people with type 2 diabetes and substantial albuminuria, with the greatest absolute renal benefit in those with albuminuria of 3000-5000mg/g. [Formula presented]
Copyright
EMBASE:2005255770
ISSN: 2468-0249
CID: 4359542
Accelerated Venovenous Hemofiltration as a Transitional Renal Replacement Therapy in the Intensive Care Unit
BACKGROUND:Continuous renal replacement therapy (CRRT) is commonly employed in the intensive care unit (ICU), though there are no guidelines around the transition between CRRT and intermittent hemodialysis (iHD). Accelerated venovenous hemofiltration (AVVH) is a modality utilizing higher hemofiltration rates (4-5 L/h) with shorter session durations (8-10 h) to "accelerate" the clearance and volume removal that normally is spread out over a 24-h period in CRRT. We examined AVVH as a transition therapy between CRRT and iHD, with the aim of decreasing time on CRRT and providing a more graduated transition for hemodynamically unstable patients requiring RRT. METHODS:Retrospective cohort study describing the clinical outcomes and quality initiative experience of the integration of AVVH into the CRRT program at an academic tertiary care center. Outcomes of interest included mortality, ICU length of stay and readmission rates, and technical characteristics of treatments. RESULTS:In total, 97 patients received a total of 298 AVVH treatments (3.1 ± 3.3 treatments per patient). Totally, 271/298 (91%) treatments were completed successfully. During an average treatment time of 9.5 ± 1.6 h with 4.2 ± 0.5 L/h -replacement fluid rate, urea reduction ratio was 23 ± 26% per 10-h treatment, and net ultrafiltration volume was 2.4 ± 1.3 L/treatment. Inpatient mortality was 32%, mean total hospital length of stay was 54 ± 47 days. Sixty-four out of 97 (66%) patients recovered renal function by discharge. Among those who transferred out of the ICU, 7/62 (11%) patients required readmission to the ICU after developing hypotension on iHD. CONCLUSION/CONCLUSIONS:AVVH can serve as a transition therapy between CRRT and iHD in the ICU and has the potential to decrease total time on CRRT, improve patient mobility, and sustain low ICU readmission rates. Future study is needed to analyze the implications on resource use and cost of this modality.
PMID: 32097936
ISSN: 1421-9670
CID: 4324302
Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Chronic Kidney Disease According to Baseline HbA1c, Including Those with HbA1c <7%: Results From the CREDENCE Trial
Traditional management of diabetes mellitus has focused on glycemic control, beginning with lifestyle changes, followed by metformin, and then other classes of antiglycemic agents.1 Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) events, including CV death, myocardial infarction (MI) and heart failure, and slow progression of renal dysfunction, including prevention of end-stage kidney disease (ESKD).2-3 Because initial clinical trials included mostly patients with baseline HbA1c >7%, current guidelines have recommended this class as add-on therapy for patients whose HbA1c is not at goal, typically ≥7%.1 We hypothesized that there would be similar benefits on CV and renal endpoints regardless of baseline HbA1c, including those with HbA1c <7%.
PMID: 31707795
ISSN: 1524-4539
CID: 4186692
Coronary Microvascular Dysfunction, Left Ventricular Remodeling and Clinical Outcomes in Patients with Chronic Kidney Impairment
Background: Cardiac dysfunction and cardiovascular (CV) events are prevalent among patients with chronic kidney disease (CKD) without overt obstructive coronary artery disease (CAD) but the mechanisms remain poorly understood. Coronary microvascular dysfunction (CMD) has been proposed as a link between abnormal renal function and impairment of cardiac function and CV events. We sought to investigate the relationships between CKD, CMD, cardiac dysfunction and adverse CV outcomes. Methods: Patients undergoing cardiac stress positron emission tomography (PET), echocardiogram and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score < 3 & without history of ischemic heart disease), valvular and end-organ disease were followed for adverse composite outcome of death, hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from PET. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic [global longitudinal (GLS), radial (GRS) and circumferential strain (GCS)]. Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic, systolic indices and adverse CV outcomes were assessed in adjusted models and mediation analyses. Results: 352 patients (median age 65 years, 63% women and 22% black) were studied. 35% of patients had eGFR<60 ml/min/1.73 m2, median LVEF of 62% and median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future CV events (all p<0.05). In multivariable models, CFR but not eGFR was independently associated with cardiac mechanics and CV events. The associations between eGFR, cardiac mechanics and CV events were partly mediated via CFR. Conclusions: CMD but not eGFR was independently associated with abnormal cardiac mechanics and an increased risk of CV events. CMD may mediate the effect of CKD on abnormal cardiac function and CV events in those without overt CAD.
PMID: 31779467
ISSN: 1524-4539
CID: 4216192
