Mineralocorticoid Receptor Antagonist Use and Hard Renal Outcomes in Real-World Patients With Chronic Kidney Disease

Background: Real-world evidence about mineralocorticoid receptor antagonist (MRA) use has been limited in chronic kidney disease, particularly regarding its association with hard renal outcomes. Methods: In this retrospective cohort study, adult chronic kidney disease outpatients referred to the department of nephrology at an academic hospital between January 2005 and December 2018 were analyzed. The main inclusion criteria were estimated glomerular filtration rate ≥10 and <60 mL/min per 1.73 m 2 and follow-up ≥90 days. The exposure of interest was MRA use, defined as the administration of spironolactone, eplerenone, or potassium canrenoate. The primary outcome was renal replacement therapy initiation, defined as the initiation of chronic hemodialysis, peritoneal dialysis, or kidney transplantation. A marginal structural model using inverse probability of weighting was applied to account for potential time-varying confounders. Results: Among a total of 3195 patients, the median age and estimated glomerular filtration rate at baseline were 66 years and 38.4 mL/min per 1.73 m 2 , respectively. During follow-up (median, 5.9 years), 770 patients received MRAs, 211 died, and 478 started renal replacement therapy. In an inverse probability of weighting-weighted pooled logistic regression model, MRA use was significantly associated with a 28%-lower rate of renal replacement therapy initiation (hazard ratio, 0.72 [95% CI, 0.53–0.98]). The association between MRA use and renal replacement therapy initiation was dose-dependent ( P for trend <0.01) and consistent across patient subgroups. The incidence of hyperkalemia (>5.5 mEq/L) was somewhat higher in MRA users but not significant (hazard ratio, 1.14 [95% CI, 0.88–1.48]). Conclusions: MRA users showed a better renal prognosis across various chronic kidney disease subgroups in a real-world chronic kidney disease population.

Inhaled anti-asthma therapies following hormone therapy in women: a nationwide cohort study

Research questionDoes menopausal hormone therapy with exogenous estrogens and progestogens change the use of inhaled anti-asthma medications in women with asthma?MethodsIn a population-based, matched cohort study using the Danish registries, we included women with asthma aged 45–65 years from June 1, 1995 to June 30, 2018. We investigated whether hormone therapy with estrogen and/or progestogens was associated with changes in use of inhaled anti-asthma therapies in the 12 months following initiation. We used exposure density matching to match exposed subjects with unexposed subjects on age, household income and level of education. An exposed subject was defined as receiving hormone therapy. We calculated mean dose of medications and odds ratios of increases in the 12 months following hormone therapy initiation.ResultsWe included 139 483 women with asthma, of whom 116 014 (83.2%) were unexposed subjects and 23 469 (16.8%) exposed subjects. Mean age was 53.0 (sd 5.2) years. Initiation of HT was not consistently associated with increased mean doses of inhaled corticosteroids, or long- and short-acting beta2-agonists. Women receiving systemic estrogens had increased odds ratios of large increases (>100 µg) in inhaled corticosteroids at six months (1.09; 95%CI 1.04–1.13; p<0.001) and nine months (1.07; 95%CI 1.03–1.12; p<0.001). Progestogens were protective against increases in inhaled corticosteroids at six and nine months (OR 0.87; 95%CI 0.82–0.93; p<0.001 and 0.86; 95%CI 0.81–0.91; p<0.001).ConclusionInitiation of hormone therapy did not change the use of inhaled medications in asthma. However, detrimental effects of estrogen, as well as beneficial effects of progestogens, cannot be excluded.

Methenamine for Recurrent Urinary Tract Infections in Solid Organ Transplantation

Introduction Recurrent urinary tract infections remain a challenge in solid organ transplant and have a negative impact on morbidity/mortality. Project Aim The purpose of this program evaluation was to determine the impact of methenamine on recurrent urinary tract infection in kidney and liver-kidney transplant recipients. Design This retrospective review included patients > 18 years of age who received a kidney or liver-kidney transplant. Patients were divided into the following groups: (1) Methenamine therapy initiation received methenamine for ≥ 180 days or (2) Non-methenamine therapy: did not receive recurrent urinary tract infection prophylaxis. A total of 60 patients were included. Results When comparing outcomes between methenamine therapy initiation and non-methenamine therapy group, a significant reduction in the rate of recurrent urinary tract infection was reported in the methenamine therapy initiation group (0.6 vs 1.3 per 180 patient days follow-up, P = 0.0005). A significant reduction was also noted with rate of asymptomatic bacteriuria, treatment failures, bacteremia, hospitalizations due to recurrent urinary tract infection, multi-drug resistant organism isolated, and the average duration of antibiotic use. A significant difference in the time to failure of methenamine therapy initiation versus non-methenamine therapy is noted up to 180 patient-days follow-up (RR 1.56, P = 0.0019). Conclusion This evaluation supported methenamine therapy for recurrent urinary tract infection in kidney and liver-kidney transplant. The most significant impact of methenamine recurrent urinary tract infection was seen in the first 30 days after initiation.

Multiparametric Magnetic Resonance Imaging for Immediate Target Hit Assessment of CD13—Targeted Tissue Factor tTF-NGR in Advanced Malignant Disease

Early assessment of target hit in anti-cancer therapies is a major task in oncologic imaging. In this study, immediate target hit and effectiveness of CD13-targeted tissue factor tTF-NGR in patients with advanced malignant disease enrolled in a phase I trial was assessed using a multiparametric MRI protocol. Seventeen patients with advanced solid malignancies were enrolled in the trial and received tTF-NGR for at least one cycle of five daily infusions. Tumor target lesions were imaged with multiparametric MRI before therapy initiation, five hours after the first infusion and after five days. The imaging protocol comprised ADC, calculated from DWI, and DCE imaging and vascular volume fraction (VVF) assessment. DCE and VVF values decreased within 5 h after therapy initiation, indicating early target hit with a subsequent decrease in tumor perfusion due to selective tumor vessel occlusion and thrombosis induced by tTF-NGR. Simultaneously, ADC values increased at five hours after tTF-NGR administration. In four patients, treatment had to be stopped due to an increase in troponin T hs, with subsequent anticoagulation. In these patients, a reversed effect, with DCE and VVF values increasing and ADC values decreasing, was observed after anticoagulation. Changes in imaging parameters were independent of the mean vessel density determined by immunohistochemistry. By using a multiparametric imaging approach, changes in tumor perfusion after initiation of a tumor vessel occluding therapy can be evaluated as early as five hours after therapy initiation, enabling early assessment of target hit.

The Effect of Early vs. Deferred Antiretroviral Therapy Initiation in HIV-Infected Patients With Cryptococcal Meningitis: A Multicenter Prospective Randomized Controlled Analysis in China

Background: The optimal timing for initiation of antiretroviral therapy (ART) in HIV-positive patients with cryptococcal meningitis (CM) has not, as yet, been compellingly elucidated, as research data concerning mortality risk and the occurrence of immune reconstitution inflammatory syndrome (IRIS) in this population remains inconsistent and controversial.Method: The present multicenter randomized clinical trial was conducted in China in patients who presented with confirmed HIV/CM, and who were ART-naïve. Subjects were randomized and stratified into either an early-ART group (ART initiated 2–5 weeks after initiation of antifungal therapy), or a deferred-ART group (ART initiated 5 weeks after initiation of antifungal therapy). Intention-to-treat, and per-protocol analyses of data for these groups were conducted for this study.Result: The probability of survival was found to not be statistically different between patients who started ART between 2–5 weeks of CM therapy initiation (14/47, 29.8%) vs. those initiating ART until 5 weeks after CM therapy initiation (10/55, 18.2%) (p = 0.144). However, initiating ART within 4 weeks after the diagnosis and antifungal treatment of CM resulted in a higher mortality compared with deferring ART initiation until 6 weeks (p = 0.042). The incidence of IRIS did not differ significantly between the early-ART group and the deferred-ART group (6.4 and 7.3%, respectively; p = 0.872). The percentage of patients with severe (grade 3 or 4) adverse events was high in both treatment arms (55.3% in the early-ART group and 41.8% in the deferred-ART group; p=0.183), and there were significantly more grade 4 adverse events in the early-ART group (20 vs. 13; p = 0.042).Conclusion: Although ART initiation from 2 to 5 weeks after initiation of antifungal therapy was not significantly associated with high cumulative mortality or IRIS event rates in HIV/CM patients compared with ART initiation 5 weeks after initiation of antifungal therapy, we found that initiating ART within 4 weeks after CM antifungal treatment resulted in a higher mortality compared with deferring ART initiation until 6 weeks. In addition, we observed that there were significantly more grade 4 adverse events in the early-ART group. Our results support the deferred initiation of ART in HIV-associated CM.Clinical Trials Registration:www.ClinicalTrials.gov, identifier: ChiCTR1900021195.

Imaging as a Selection Tool for Thrombectomy in Acute Ischemic Stroke

Large vessel occlusion (LVO) stroke represents a stroke subset associated with the highest morbidity and mortality. Multiple prospective randomized trials have shown that thrombectomy, alone or in conjunction with IV thrombolysis, is highly effective in reestablishing cerebral perfusion and improving clinical outcomes. In unselected patients and especially in patients with poor collaterals, the benefit of reperfusion therapy is exquisitely time sensitive; the earlier thrombectomy is started, the lower the likelihood of disability or death. Understanding both the pathophysiologic underpinnings and the modifying factors of this strong time-to-treatment effect demonstrated in numerous randomized clinical trials is important for implementation of intrahospital workflow measures to maximize time efficiency of thrombectomy. Reducing delays in reperfusion therapy initiation has become a priority in acute stroke care, and therefore a thorough understanding of the main systems-based factors responsible for these delays is critical. Because the time spent evaluating the patient in the emergency department, which typically includes neuroimaging studies performed in scanners remote from the angiography suite, represents the main source of delays in thrombectomy initiation, the direct to angiography (DTA) model has emerged as a means to substantially reduce treatment times and is being instituted at an increasing number of thrombectomy centers across the world. The aim of this report is to introduce DTA as an emerging stroke care paradigm for patients with suspicion of LVO stroke, review results from studies evaluating its feasibility and impact on outcomes, describe current barriers to its more widespread adoption, and propose potential solutions to overcoming these barriers.

Translating Results from VARSITY to Real World: Adalimumab vs Vedolizumab as First-line Biological in Moderate to Severe IBD

Background Selecting a first-line therapy remains challenging in IBD. Adalimumab (ADM) and vedolizumab (VDZ) effectively lead to endoscopic remission in moderate to severe IBD. The VARSITY trial showed superiority of VDZ over ADM in ulcerative colitis (UC) regarding clinical remission and endoscopic improvement at week 52. We explored these results in a real-world setting of UC and Crohn’s disease (CD). Methods This retrospective study followed a cohort of biologic-naïve patients starting ADM or VDZ from 2015-2019. Patients had moderate to severe disease (endoscopic Mayo score ≥2 for UC, presence of ulcerations for CD) prior to therapy initiation. For UC, endoscopic remission (endoscopic Mayo score 0) and improvement (endoscopic Mayo score ≤1) at week 52 were assessed. For CD, endoscopic remission (absence of ulcerations) and improvement (markedly better endoscopy despite ulcerations) at weeks 26-52 were studied. Treatment persistence was also evaluated. Results In total, 195 biologic-naïve patients (109 UC; 86 CD) were included. In UC, VDZ was superior to ADM regarding endoscopic remission (29% vs 11%, P = .03), endoscopic improvement (51% vs 26%, P = .01) at week 52, and treatment persistence (P = .04). In CD, no differences in endoscopic remission (VDZ 48% vs ADM 60%; P=0.37), improvement (VDZ 76% vs ADM 77%; P = 1.00), or treatment persistence (P=0.43) at weeks 26-52 were seen. Safety profiles were similar in UC and CD. Conclusions This real-world cohort study of biologic-naïve IBD patients found VDZ to be superior to ADM as first-line treatment for patients with UC—but not CD—regarding endoscopic remission at week 52 and treatment persistence.