Severe Renal Insufficiency Research Articles

Risk factors for acute kidney injury after pharmacomechanical thrombolysis for acute deep vein thrombosis

BackgroundPharmacomechanical thrombolysis (PMT) is an established treatment for selected patients with acute deep vein thrombosis (DVT). Despite significant clinical success, hemolysis can lead to acute kidney injury (AKI) with unknown longer term implications. Our aim was to characterize the rate of AKI after PMT and identify those patients at the greatest risk. MethodsA retrospective medical record review of patients with acute DVT who had undergone PMT in our institution from 2007 to 2018 was performed. The baseline demographics, comorbidities, preoperative clinical characteristics, procedural details, postoperative hospital course, and follow-up data were reviewed. The primary outcome was postoperative AKI (≥1.5 times preoperative creatinine), and longer term renal impairment. Logistic regression modeling was used to identify associated factors. ResultsA total of 137 patients (mean age, 47 ± 16.6 years; 49.6% male) who had undergone PMT for treatment of acute DVT were identified (85.4% AngioJet system; Boston Scientific Corp, Marlborough, Mass). Of the 137 patients, 30 (21.9%) had developed AKI in the periprocedural period, 1 of whom had required hemodialysis in the perioperative period. The patients who had developed AKI had had significantly greater rates of preoperative coronary artery disease (23.1% vs 4.7%; P = .002), diabetes mellitus (19.2% vs 6.6%; P = .045), dyslipidemia (42.3% vs 17.9%; P = .008), and hypertension (53.6% vs 29.3%; P = .018). No significant difference was found in preoperative creatinine (0.99 vs 0.92 mg/dL; P = .65) or glomerular filtration rate (GFR; 96.9 vs 91.8 mL/min; P = .52) between the two groups. Multivariate analysis demonstrated bilateral DVT (odds ratio [OR], 4.35; 95% confidence interval [CI], 1.47-12.86; P = .008), single-session PMT (OR, 3.05; 95% CI, 1.02-9.11; P = .046), and female sex (OR, 2.85; 95% CI, 1.01-8.04; P = .048) were significant predictors of AKI. Of the 30 patients, 10 had had normal renal function at discharge and 15 and 25 patients had had normal renal function at the first and subsequent clinical follow-up visits, respectively. The remaining five patients (3.6%) had progressed to moderate (GFR, <60 mL/min) or severe (GFR, <30 mL/min) renal insufficiency, with one requiring long-term hemodialysis. ConclusionsThe use of PMT for treatment of acute DVT conferred a risk of AKI that will progress to chronic renal failure in a small fraction of affected patients. Patients with bilateral extensive DVTs have a greater risk of AKI; thus, longer priming with a thrombolytic drip before PMT should be preferred for this population.

The Italian Medicines Agency Prospective Registry of Bortezomib-Based Treatment in AL Amyloidosis

Background: There is no licensed therapy for light chain (AL) amyloidosis; however, bortezomib (B) is considered standard upfront treatment. Existing data on safety and efficacy of B in AL amyloidosis derive from clinical trials and retrospective series from few referral centers and only partly reflect real-world practice. In 2011, the Italian Medicines Agency (AIFA) started a program to grant access to upfront B to patients with AL amyloidosis. Treated patients had to be enrolled in an online registry and prospectively followed during therapy. We report the treatment experience in this real-world setting. Methods: AL amyloidosis diagnosis required tissue typing with mass spectrometry or immuno-electron microscopy. Patients samples could be sent to the Pavia specialized center for typing, but patients were not treated under the supervision of the referral center. Subjects with multiple myeloma were excluded. Variables were collected at baseline and hematologic and cardiac responses were assessed after 8 weeks (approximately 2 cycles) according to the International Society of Amyloidosis criteria. The cox proportional model has been adopted to assess the risk of treatment discontinuation according to the baseline characteristics. Results: A total of 754 patients were treated between May 2011 and October 2019 and 605 were included in the analysis. Most common reasons for exclusion were retrospective data collection (45%), and incomplete data set (31%). Median age was 67 years (range 26-89 years). 82% of patients had heart involvement. Cardiac stage was I in 18% of subjects, II in 45%, IIIa in 21%, and IIIb, in 16%. Sixty-seven percent of patients had renal involvement, and 13% and 14% had severe (glomerular filtration rate [eGFR] between 30 and 15 mL/min) and end-stage (eGFR &amp;lt;15 mL/min) renal insufficiency, respectively. Differential free light chain level (dFLC) was &amp;gt;180 mg/L in 41% of cases. Bortezomib was administered with dexamethasone (D) alone in 41% of patients, with cyclophosphamide and D (CyBorD) in 44%, and with melphalan and D (BMDex) in 13% of subjects. Other combinations were used in 2% of patients. In the overall population, the initial dose of B was attenuated (&amp;lt;1.3 mg/m2) in 22% of patients. The proportion of patients receiving attenuated dosage was higher in stage III patients (38%). Fourteen percent of subjects required B dose reduction during therapy, while B dosage could be increased in 7% of patients who started at a reduced dose. A twice-weekly B schedule at treatment initiation was used in 22% of all subjects and in 16% of stage III patients. Fourteen percent of patients initially treated with the twice weekly schedule needed to be shifted to the once weekly schedule. After 8 weeks (approximately 2 cycles) the overall hematologic response rate was 58% (CR 3%, VGPR 20%) and cardiac response was attained in 14% of patients. The median number of cycles performed was 3 (range 1-9), median duration of monitored treatment was 4.3 months. Treatment was discontinued during monitoring due to achievement of satisfactory response or completion of maximum (9) allowed number of cycles in 3% of cases, progression in 14%, death in 8%, and toxicity in 1% of patients. The cause of discontinuation was defined as independent of drug and disease in the remaining 25.1% of subjects. Risk of treatment discontinuation was lower in patients who could tolerate a 1.3 mg/m2 dose of B from cycle 1 (HR 0.70, 95%CI 0.54-0.91). Second-line therapy with immunomodulators (most commonly lenalidomide) was started in 14% of patients. Conclusions: Patients with AL amyloidosis start treatment at an advanced stage and early deaths are common. The rate of severe/end-stage renal failure was higher (27%) than expected, possibly indicating that these patients are less likely to be referred to specialized centers. Remarkably, outside referral centers B is commonly administered with D alone. Dose reductions are frequently applied, but dosage can be escalated during therapy. Response rates at 8 weeks are comparable to those reported in other large studies and early cardiac responses are possible. To the best of our knowledge this is the only study prospectively evaluating treatment with B in a real-world setting. Treatment registries under the supervision of regulatory agencies are precious tools to assess common therapeutic practice in rare disease, to evaluate candidate comparators for future trials, and to assess unmet medical needs. Disclosures Palladini: Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Milani:Janssen: Other: Speaker honoraria; Celgene: Other: Travel support; Pfizer: Other: Speaker honoraria. Nuvolone:Janssen: Honoraria. OffLabel Disclosure: Bortezomib in AL amyloidosis

Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial.

Inclusion body myositis is the most frequent myositis in patients older than 50 years. Classical immunosuppressants are ineffective in treating inclusion body myositis, and to date there are no recommendations for pharmacological approaches to treatment. When used after organ transplantation, sirolimus can block the proliferation of effector T cells, while preserving T regulatory cells, and induce autophagy, all of which are processes that are impaired in inclusion body myositis. In this pilot study, we aimed to test the efficacy of sirolimus in patients with inclusion body myositis. This randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial was done at a single hospital in Paris, France. The study included men and women (aged 45-80 years) who had a defined diagnosis of inclusion body myositis according to established criteria. Eligible participants were randomly assigned (1:1) to receive once-daily oral sirolimus 2 mg or placebo. Centralised balanced block randomisation (blocks of four) was computer generated without stratification. The study comprised a 15-day screening period (days -15 to 0) and a 52-week treatment period (day 0 to month 12). The primary endpoint was the relative percentage change from baseline to month 12 in maximal voluntary isometric knee extension strength. Secondary endpoints included the following assessments at months 6 and 12: 6-min walking distance, isometric muscle strength for hand grip (finger flexors), knee flexion and elbow flexion and extension, forced vital capacity, muscle replacement with fat measured by quantitative nuclear MRI, Inclusion Body Myositis Weakness Composite Index (IBMWCI), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Health Assessment Questionnaire without Disability Index (HAQ-DI), and analyses of T-cell subpopulations by mass cytometry. The primary analysis was done on the intention-to-treat population. The trial is registered at ClinicalTrials.gov, NCT02481453. Between July 15, 2015, and May 13, 2016, we screened 285 patients, 44 of whom were randomly allocated to sirolimus (22 patients) or placebo (22 patients). We observed no difference in the primary outcome of relative percentage change from baseline to month 12 of the maximal voluntary isometric knee extension strength (median difference 3·78, 95% CI -10·61 to 17·31; p=0·85). For secondary outcomes, differences between the groups were not significant for changes in strength of other muscle groups (grip, elbow flexion and extension, or knee flexion), IBMWCI, IBMFRS, and lower limb muscle fat fraction. However, we observed significant differences in favour of sirolimus between the study groups for HAQ-DI, forced vital capacity, thigh fat fraction, and 6-min walking distance. Ten (45%) of 22 patients in the sirolimus group had a serious adverse event compared with six (27%) of 22 patients in the placebo group. Four (18%) patients in the sirolimus group stopped their treatment because of adverse events (severe mouth ulcers, aseptic pneumonia, renal insufficiency, and peripheral lower limb oedema), which resolved after treatment discontinuation. Canker sores were the most frequent side-effect and were mainly mild or moderate in ten patients. We found no evidence for efficacy of sirolimus for treating inclusion body myositis based on maximal voluntary isometric knee extension strength and other muscle strength measures, and the side-effects of treatment were substantial for some patients. However, we believe there was enough evidence of benefit in certain secondary outcomes to pursue a multicentre phase 3 trial to further assess the safety and efficacy of sirolimus. Institut national de la santé et de la recherche médicale, Direction générale de l'offre de soins, and Association Française contre les Myopathies.

Serum Zinc Concentrations of Adults in an Outpatient Clinic and Risk Factors Associated With Zinc Deficiency

Subclinical features of zinc deficiency can be challenging to recognize. The prevalence of zinc deficiency based on blood zinc concentration in an adult outpatient clinic setting has not been well-studied. To estimate the prevalence of low serum zinc concentrations among community-dwelling adults, and to characterize clinical features and risk factors associated with zinc deficiency. This retrospective pilot prevalence study took place from 2014 to 2017 at an outpatient clinic in southeast Ohio. Patients aged 50 years or older with a stable health status were categorized into a case group with zinc deficiency (serum zinc concentration, <0.66 µg/mL) and a control group (serum zinc concentration, ≥0.66 µg/mL). Measurements included serum zinc concentration, nutritional biomarkers (ie, magnesium, calcium, albumin, and total 25-hydroxy vitamin D levels), patient history of fractures and events such as hospitalization, antibiotic use, and self-reported falls that occurred within 1 year prior to the date serum zinc concentration was measured (index date). Patients were excluded if they had a serum zinc measurement within 2 months after a hospitalization, severe renal insufficiency (3 patients with serum creatinine concentration above 2.5 mg/dL), or serum zinc concentration above 1.20 µg/mL. This study included 157 patients, consisting of a case group of 41 (26%) patients with zinc deficiency and a control group of 116 (74%) without zinc deficiency. Mean (SD) zinc concentrations of the case and control groups were 0.58 (0.05) µg/mL and 0.803 (0.13) µg/mL, respectively (P<.01). Patients in the case group were more likely to have had a history of hospitalization, antibiotic use, a fall within 1 year before the index date, and a history of fractures and hip fracture (P<.01 in each case). Patients taking gastric acid suppressants had increased odds of lower zinc concentrations (odds ratio, 2.24; 95% CI, 1.08-4.63). Both logistic and multivariate linear regression models revealed that past fractures, hip fractures, and hypoalbuminemia (albumin <3.5 g/dL) were associated with zinc deficiency or lower zinc concentrations. This study revealed that 26% of patients in an outpatient adult clinic had zinc deficiency based on serum concentrations. Patients with fracture history and low serum albumin were at higher risk for zinc deficiency.

Incidental finding of a high creatinine

Incidental finding of a high creatinine Abstract. In up to 10 % of patient visiting their General Practitioner and having blood tests an elevated creatinine or reduced kidney function are detected incidentally by the often automatically reported estimation of glomerular filtration rate (eGFR) by a creatinine-based formula. The most important step in this situation is to evaluate whether reduced kidney function is due to chronic kidney disease or whether the patient presents with an acute kidney injury (AKI). Early detection of AKI is crucial as any delay in accurate therapy can lead to further decline of kidney function and elevated mortality. In addition, intrinsic kidney diseases, which are less common should not be missed because early access to specialised management is crucial. Clinical history including history of medication, context of consultation, clinical evaluation and additional laboratory values will help to provide a first suspicion diagnosis. Further investigations (abdominal sonography, urinary sediment, proteinuria) will help to confirm the diagnosis. In any case of absence of an obvious cause of AKI, young patient, threatening severe renal insufficiency with rapid progression of kidney failure or suspicious laboratory abnormalities, the patient should be referred without any delay to a nephrologist for further evaluation and management.

EP19 Renal sarcoidosis associated with certolizumab pegol treatment for psoriatic arthritis: a case report

EP19 Renal sarcoidosis associated with certolizumab pegol treatment for psoriatic arthritis: a case report

Tocilizumab versus the Covid19 tempest: All’s well that ends well or much ado about nothing?

Tocilizumab versus the Covid19 tempest: All’s well that ends well or much ado about nothing?

TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage.

Indoxyl sulfate (IS) is accumulated during severe renal insufficiency and known for its nephrotoxic properties. Transient receptor potential vanilloid 1 (TRPV1) is present in the kidney and acts as a renal sensor. However, the mechanism underlying IS-mediated renal tubular damage in view of TRPV1 is lacking. Here, we demonstrated that TRPV1 was expressed in tubular cells of Lilly Laboratories cell-porcine kidney 1 (LLC-PK1) and Madin-Darby canine kidney cells (MDCK). IS treatment in both cells exhibited tubular damage with increased LDH release and reduced cell viability in dose- and time-dependent manners. MDCK, however, was more vulnerable to IS. We, therefore, investigated MDCK cells to explore a more detailed mechanism. Interestingly, IS-induced tubular damage was markedly attenuated in the presence of selective TRPV1 blockers. IS showed no effect on TRPV1 expression but significantly increased arachidonate 12-lipoxygenase (ALOX12) protein, mRNA expression, and 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) amounts in a dose-dependent manner, indicating that the ALOX12/12(S)-HETE pathway induced TRPV1 hyperfunction in IS-mediated tubulotoxicity. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-α-cyanocinnamate or baicalein attenuated the effects of IS. Since aryl hydrocarbon receptor (AhR) activation after IS binding is crucial in mediating cell death, here, we found that the AhR blockade not only ameliorated tubular damage but also attenuated ALOX12 expression and 12(S)-HETE production caused by IS. The uremic toxic adsorbent AST-120, however, showed little effect on ALOX12 and 12(S)-HETE, as well as IS-induced cell damage. These results clearly indicated that IS activated AhR and then upregulated ALOX12, and this induced endovanilloid 12(S)-HETE synthesis and contributed to TRPV1 hyperfunction in IS-treated tubular cells. Further study on TRPV1 may attenuate kidney susceptibility to the functional loss of end-stage kidney disease via IS.

Current and Future MR Contrast Agents: Seeking a Better Chemical Stability and Relaxivity for Optimal Safety and Efficacy.

This review summarizes 30 years of experience in the development and clinical use of magnetic resonance (MR) contrast agents. Despite their undisputable usefulness for disease diagnosis, gadolinium (Gd)-based contrast agents (GBCAs) have gone through 2 major safety crises. Approximately 10 years ago, the regulatory agencies decided to restrict the use of GBCAs to minimize the risk of nephrogenic systemic fibrosis in patients with severe renal insufficiency. Yet, following the recent discovery of Gd retention in brain, the same agencies adopted different positions ranging from suspension of marketing authorizations, changes in GBCA safety labeling, and performing preclinical and clinical studies to assess the potential long-term consequences of Gd accumulation on motor and cognitive functions. Besides, magnetic resonance imaging (MRI) has benefited from MR technological advances, which provide alternative solutions to increase the MR signal, generate new contrasts on MRI scans, and accelerate their acquisition and analysis. Altogether, GBCAs in combination with new MR techniques have found their place in the diagnostic pathway of various diseases. Despite the large research efforts to identify and develop alternative Gd-free MR agents, manganese- and iron-based contrast agents have failed to reach market approval. In this context, the development of next-generation MR contrast agents should focus on high-stability and high-relaxivity GBCAs, such as gadopiclenol, which offer the possibility to adapt the administered Gd dose to each indication while ensuring an optimal patient safety.

Sickle cell disease and COVID-19: Atypical presentations and favorable outcomes.

Sickle cell disease and COVID-19: Atypical presentations and favorable outcomes.

Renal Insufficiency and Short-Term Outcomes of Acute Pulmonary Embolism: A Systemic Review and Meta-Analysis.

This article evaluates the association between renal insufficiency and short-term outcomes among patients with acute pulmonary embolism. The literature search was completed on December 31, 2019 and data were contracted from 13 cohort studies. Diagnosis of renal insufficiency was based on estimated glomerular filtration rate (eGFR), serum creatinine level, or self-report. The primary outcome was all-cause mortality of 30 days or during hospitalization. The pooled risk ratios (RRs), pooled mortality rates, and between-study heterogeneity were estimated by random-effect models. All the statistical analyses were performed using STATA/SE software. We included 13 studies (N = 35,662) in the meta-analysis, including two focused on acute kidney injury (AKI). Early all-cause mortality in patients with versus without renal insufficiency were 15% (95% confidence interval [CI] 9-22%) and 5% (95% CI 3-8%), respectively (RR 1.76, 95% CI 1.61-1.92). For patients with eGFR < 30 mL/min·1.73m-2, rates were 30% (95% CI 11-75%) versus 10% (95% CI 5-14%) (RR 3.32, 95% CI 1.53-6.70). For patients with AKI during hospitalization, rates were 32% (95% CI 11-75%) versus 13% (95% CI 4-29%) (RR 2.69, 95% CI 1.24-5.84). Pulmonary embolism (PE)-related death and fatal bleeding were significantly higher in patients with renal insufficiency. Renal insufficiency, especially AKI and severe renal insufficiency, was associated with early mortality in acute PE patients. Our results may escalate vigilance in risk stratification and management of PE patients with renal insufficiency in clinical practice.

P0397OUTCOMES OF PROTEINASE 3- AND MYELOPEROXIDASE ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY ASSOCIATED VASCULITIS IN DENMARK 2014-2017

Abstract Background and Aims Anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) defines an uncommon group of autoimmune diseases with antibodies directed against proteinase 3 (PR3) or myeloperoxidase (MPO). Incidence rates of PR3- and MPO-AAV differ geographically, and current evidence based on genetic variations and cluster analyses supports discrimination of associated vasculitis based on PR3- and MPO-positivity. Such discrimination could provide insights of scope for clinical trials with ramifications for improvement of treatment. With the aim of comparing patient characteristics and outcomes between PR3- and MPO-AAV, we report on results from a nationwide retrospective cohort study. Method Incident patients positive for PR3- and MPO-anti-neutrophil cytoplasmic antibodies were identified in central laboratories of three of four administrative regions (covering 80% of the population) in Denmark between 1/1-2014 and 31/12-2017. Patient characteristics were identified by cross-referencing of data from multiple national health care registers. Baseline renal function was calculated based on the CKD-EPI equation using plasma creatinine measurements recorded 365 to 7 days prior to index. Incidences of all-cause mortality and end-stage renal disease stratified on baseline eGFR were computed using the Aalen-Johansen estimator. Hazard ratios for specific predictors including strata of baseline eGFR were calculated based on a multiple Cox proportional hazards model adjusted for relevant confounders. Results In total 770 patients were included in the study (PR3 n=399 and MPO n=371). Annual incidence rates of PR3- and MPO-AAV were 22.6 and 21.1 per million, respectively. PR3-AAV was associated with greater preponderance for male gender (54.4% vs. 42.3%, p=0.001), lower patient age (61.9 years [IQR 41.6-73.0 years] vs. 64.9 years [IQR 50.0-74.0 years], p=0.016), and greater baseline renal function (eGFR 87 ml/min [IQR 56-101 ml/min] vs. 75 ml/min [IQR 36-92 ml/min] compared with MPO-AAV. Comorbid burden was comparable; 26% of patients had history of hypertension, 15% of patients had a history of ischemic heart disease, and 12% of patients had a history of cancer. Acute dialysis was initiated in 5.3% and 6.7%, plasmapheresis in 12.8% and 13.7%, and mechanical ventilation in 4.8% and 4.3% of patients with PR3- and MPO-AAV, respectively. Median follow-up was 564 days [234 – 932]. A total of 86 deaths and 25 end-stage renal disease endpoints were recorded during follow-up. Cumulative incidences of all-cause mortality and end-stage renal disease stratified on baseline eGFR are shown in Figure 1. Adjusted hazard ratios for all-cause death and/or end-stage renal disease showed increased risk associated with PR3-AAV, HR 1.51 (95% CI 1.03 – 2.25, p=0.036), non-European descent, HR 3.63 (95% CI 1.29-10.25, p=0.015) and patient age, HR 1.05 (95% CI 1.03-1.07, p&amp;lt;0.001). In both PR3- and MPO-AAV, only baseline eGFR ≤ 20ml/min/1.73m2 was associated with poorer prognosis (ref.: baseline eGFR &amp;gt;90 ml/min/1.73m2); MPO-AAV: eGFR 51-90 ml/min/1.73m2: HR 2.34 (95% CI 0.75 – 7.34, p=0.145), eGFR 21-50 ml/min/1.73m2: HR 2.11 (95% CI 0.60 – 7.47, p=0.246), and eGFR ≤ 20ml/min/1.73m2: 5.05 (95% CI 1.55 – 16.45, p=0.007); PR3-AAV: eGFR 51-90 ml/min/1.73m2: HR 1.54 (95%CI 0.53 – 4.46, p=0.427), eGFR 21-50 ml/min/1.73m2: HR 1.70 (95% CI 0.51 – 5.64, p=0.386), and eGFR ≤ 20ml/min/1.73m2: 8.06 (95% CI 2.83 – 23.0, p=&amp;lt;0.001). Conclusion In a nationwide cohort study comparing PR3- and MPO-AAV, PR3-AAV was associated with poorer 24-month outcomes in spite of superior renal function at baseline. Overall, poor prognosis was limited to patients with severe renal insufficiency (eGFR ≤20ml/min/1.73m2) at time of diagnosis in both PR3- and MPO-AAV.

Venous Thromboembolism Treatment and Prevention in Cancer Patients: Can We Use Pills Yet?

Cancer increases a patient's risk for developing a venous thromboembolism (VTE) and is a relatively common finding in this population. Traditionally, anticoagulants used to treat VTE have included low molecular weight heparin (LMWH) or vitamin K antagonists (VKA). However, within the last several years, a newer class of anticoagulant, the direct oral anticoagulants (DOACs), has emerged as a potential option for pharmacologic thromboprophylaxis and for treatment of VTE in patients with cancer. While data is still limited and evolving, DOACs offer several benefits that are worth considering, including ease of administration and similar efficacy compared to LMWH in preventing recurrent VTE. However, some studies have reported a notable risk of increased bleeding associated with the use of DOACs. Additional studies are underway to evaluate the role of DOACs compared to LMWH in the setting of cancer. In our practice, based on existing data, we have been using DOACs for the chronic treatment of acute VTE and prevention of recurrent VTE in patients who do not have contraindications to anticoagulation and do not have severe renal insufficiency (creatinine clearance < 30mL/min). For cancer patients admitted to the hospital with an acute medical illness, we use LMWH for primary prevention of VTE. In the perioperative setting, for patients undergoing major surgery with an active cancer, we prefer pharmacologic thromboprophylaxis with LMWH, although there is some emerging evidence that DOACs may be safe in this setting.

Critical Appraisal of the AUGUSTUS Trial

Citation: Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med 2019; 380:1509–1524. DOI: 10.1056/NEJMoa1817083Patient Population:. Adult patients with atrial fibrillation (AF) who were indicated for use of oral anticoagulation who developed an acute coronary syndrome (ACS) event or had undergone percutaneous coronary intervention (PCI) in the last 14 days, with planned use of a P2Y12 inhibitor for at least six months. Patients with severe renal insufficiency (defined as creatinine clearance less than 30 ml/min or serum creatinine greater than 2.5 mg/dL) and patients who were using anticoagulation for other conditions, such as prosthetic valves or venous thromboembolism, were excluded from the study.Intervention:. The trial was a two-by-two factorial design comparing apixaban with a vitamin K antagonist (VKA) and comparing aspirin (ASA) with a placebo. For the first factorial comparison, a total of 2,306 patients were randomized to receive apixaban. Of these randomized patients, 2,290 patients received at least one dose of apixaban. As for the second factorial comparison, 2,307 patients were randomized to receive ASA. Of these randomized patients, 2,277 patients received at least one dose of ASA.Comparison:. A total of 2,308 patients were randomized to receive VKA, and 2,259 patients received at least one dose of VKA. Those subjects had the dose adjusted to reach a target international normalized ratio (INR) within a range of 2.0 to 3.0. As for the second factorial comparison, a placebo was assigned to 2,307 patients. Of these patients, 2,279 had received at least one dose of the placebo.Outcome:. The primary outcome was a composite of major and clinically relevant nonmajor bleeding defined by the International Society on Thrombosis and Hemostasis with a follow-up period of six months. A secondary outcome evaluated was a composite of all-cause death and all-cause hospitalization, as well as a composite of death or ischemic events.

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease.

Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins—mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR−/− mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR−/− males. AhR−/− females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR−/− mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.

Assessment of Thrombotic and Bleeding Tendency in Two Mouse Models of Chronic Kidney Disease: Adenine-Diet and 5/6th Nephrectomy.

The coexistence of bleeding and thrombosis in patients with chronic kidney disease (CKD) is frequent and poorly understood. Mouse models are essential to understand complications of CKD and to develop new therapeutic approaches improving the health of patients. We evaluated the hemostasis in two models of renal insufficiency: adenine-diet and 5/6th nephrectomy (5/6Nx). Compared with 5/6Nx mice, mice fed with 0.25% adenine had more severe renal insufficiency and so higher levels of prothrombotic uremic toxins like indoxyl sulfate. More severe renal inflammation and fibrosis were observed in the adenine group, as demonstrated by histological and reverse transcription quantitative polymerase chain reaction experiments. Liver fibrinogen γ chain expression and level of plasma fibrinogen were increased only in adenine mice. In both CKD mouse models, tissue factor (TF) expression was increased in kidney and aorta extracts. Immunochemistry analysis of kidney sections showed that TF is localized in the vascular walls. Thrombin–antithrombin complexes were significantly increased in plasma from both adenine and 5/6Nx mice. Tail bleeding time increased significantly only in adenine mice, whereas platelet count was not significant altered. Finally, results obtained by intravital microscopy after laser-induced endothelial injury showed impaired platelet function in adenine mice and an increase in fibrin generation in 5/6Nx mice. To summarize, adenine diet causes a more severe renal insufficiency compared with 5/6Nx. The TF upregulation and the hypercoagulable state were observed in both CKD models. Bleeding tendency was observed only in the adenine model of CKD that recapitulates the whole spectrum of hemostasis abnormalities observed in advanced human CKD.

Mortality Factors for Cirrhotics in an Ivorian University Hospital (Ivory Coast)

Background: Cirrhosis, an ineluctable development of chronic liver disease, still has high mortality throughout the world despite many advances in physiopathology and therapy. This high mortality is closely related to the unpredictable course of cirrhosis with numerous complications. Objective: To evaluate the predictive factors of death during cirrhosis. Materials and methods: This is an observational, descriptive study on cirrhotic patients hospitalized in the hepatology unit of the Center Hospitalier Universitaire in Bouake (Ivory Coast) during the period from January 01, 2018 to December 31, 2019. The study focused on the data collected in the medical files (paper format) of hospitalized cirrhotics and the death register of the service. The diagnosis of cirrhosis and the death of the cirrhotic were the main criteria for judgment. The secondary criteria defined were: history of cirrhosis, reasons for consultation, clinical signs, biological signs, complications of cirrhosis and the treatment received. The relationship between the parameters was expressed as an odds ratio (OR) with a 95% confidence interval (CI) and the significance threshold fixed at p 0.05. Results: The study retained 206 files of cirrhotics including 146 men and 60 women. The hospital prevalence of cirrhosis was 44.17% and the mortality rate was 42.23%. The deceased patients were mainly men with an average age of 49 years. The etiologies of cirrhosis were dominated by viral hepatitis B, chronic alcohol poisoning and viral hepatitis C, respectively 46.95%, 37.35% and 10.84%. The predictors of death were: the presence of icterus (OR = 1.89, 95%CI [1.08 - 3.30], p = 0.036), hepatic encephalopathy (OR = 8.75, 95%CI [4.51 - 16.94], p = 2.23, 95%CI [1.25 - 3.98], p = 0.010); the presence in the biology of hepatic cytolysis (OR = 2.57, 95%CI [1.35 - 4.89], p = 0.006), severe hepatocellular insufficiency (OR = 2.57, 95%CI [1.38 - 4.77], p = 0.004), severe renal insufficiency (OR = 2.41, 95%CI [1.09 - 5.32], p = 0.044) and hyperleukocytosis (OR = 2.28, 95%CI [1.29 - 4.04], p = 0.007); Child-Pugh stage C (OR = 19.64, 95%CI [9.02 - 42.74], p 0.001); the presence on ultrasound of large liver and variable nodules (OR = 4.16, 95%CI [2.02 - 8.58], p Conclusion: Cirrhosis is a public health problem at the Bouake university hospiler center. Decompensated and complicated old cirrhosis, hepatic cytolysis, severe hepatocellular insufficiency, severe renal insufficiency and hyperleukocytosis, heterogeneous nodular large liver are the detrimental factors.

Implantation of BIV ICD with Near Zero Contrast Use in Patients with Advanced Renal Insufficiency Using Three Dimensional Electro-anatomical Mapping.

Biventricular (BIV) ICD implantations are traditionally performed using contrast and fluoroscopic guidance. Contrast use in patient with advanced renal disease can cause deterioration of renal function and even lead to dialysis. To evaluate the feasibility of utilizing 3 D mapping technique in reducing or eliminating contrast use in patient with advanced renal disease. The study consisted of 30 consecutive adult patients, in which BIV implantation was accomplished in advanced renal disease (stage III and IV GFR 15 to 59) by electroanatomical 3D mapping (EAM).Acute procedural success was 96% and only one patient LV lead implantation was unsuccessful due to unsuitable anatomy.47 % of patients had BIV ICD implantation with zero contrast. Average contrast exposure for the group was 4.3 ml only. Average ratio of contrast use to GFR (glomerular filtration rate) was only 0.1. Improved mean GFR was observed from 42 to 50 post procedure (P value<0.01), and continued to improve to 48 at 3 and 6 month (P value<0.01) and improvement decreased to 45 and 44 beyond 6 month and 1 year (P value NS). There was no single case of contrast induced acute renal insufficiency (CI-ARI) due to minimal use of contrast.69 % of the patients experienced an improvement in their functional class. A decrease in QRS duration was seen from 159 to 136 milliseconds (86% of patients had improved QRS duration); P value = <0.001. The average pre procedure ejection fraction (EF) for the group was 23%. The average EF post procedure for the group was 35%; P values = <0.001 (72% of patient had EF improvement).93% of patient had either EF and/or GFR improvement suggesting substantial clinical benefit from the procedure.There was no minor or major complications. Implantation of BiV ICD using EAM with near zero contrast is feasible, safe and effective in patients with moderate to severe renal insufficiency. There is an added renal protection and benefit from procedure in this group of patients.

3294Frequency, management and outcomes of patients with stable coronary artery disease eligible for COMPASS. An analysis of the CLARIFY registry

Abstract Background The COMPASS trial demonstrated that a combination of rivaroxaban and aspirin improved cardiovascular (CV) outcomes in high-risk patients with either peripheral artery disease (PAD) or stable coronary artery disease (CAD) compared with aspirin alone, at the price of increased bleeding. A previous analysis of the REACH Registry reported an eligibility rate of 52.9% within a population with stable vascular disease. However, most of cardiologists actually treat patients with stable CAD, rather than PAD. Data regarding eligibility to COMPASS in CAD patients from real life practice are scarce. Purpose We aimed to describe the proportion of patients eligible to COMPASS within the CLARIFY Registry. Additionally, we aimed to describe their management and outcomes, comparing patients excluded from the trial (COMPASS Excluded), patients eligible for the trial (COMPASS Eligible), and patients who did not meet the “enrichment criteria” for enrolment (COMPASS Not Included). Methods We used the CLARIFY Registry, an international observational registry of more than 30.000 patients with stable CAD. In accordance with COMPASS exclusion criteria, patients with a REACH bleeding risk score &gt;10, heart failure (HF), severe renal insufficiency, need for dual antiplatelet therapy (DAPT), or anticoagulant (AC) therapy were excluded. Then, COMPASS inclusion criteria were applied: CAD patients had to be 65 years or more, or, if younger, have documented atherosclerosis (PAD or revascularization involving at least two vascular beds) or at least two enrichment criteria (current smoker, diabetes mellitus, GFR &lt;60 mL/min, or non lacunar ischemic stroke).The ischemic outcome was a composite of CV death, MI, or stroke and bleeding outcome was a composite of bleeding leading to either admission or transfusion, or haemorrhagic stroke. Results Among 15.185 patients with comprehensive data allowing precise assessment of eligibility, 43.1% (n=6.540) had at least one exclusion criteria (COMPASS-Excluded), 23.1% (n=3.503) did not have enrichment criteria (COMPASS-Not Included) and 33.9% (n=5.142) were eligible. The vast majority of excluded patients were excluded due to high bleeding risk (62.7% needing DAPT, and 52.7% for high REACH bleeding risk score). The rates (100 patients/year) of ischemic and bleeding outcome were 2.3 [2.1–2.5] and 0.5 [0.4–0.6] respectively for COMPASS-Eligible, 3.0 [2.8–3.2] and 0.6 [0.5–0.7] for COMPASS-Excluded and 1.2 [1.0–1.4] and 0.2 [0.2–0.3] for COMPASS-Not Included. Ischemic and bleeding events Conclusion In a large contemporary registry of stable CAD patients, approximately one of three patients was potentially eligible for adjunction of low-dose rivaroxaban to aspirin. This group is at particularly high risk of ischemic outcome. Patients with exclusion criteria for COMPASS had the worse ischemic and bleeding outcomes and represent a group in need of improved therapy. Acknowledgement/Funding None

Characteristics of renal cortical perfusion and its association with renal function among elderly patients with renal artery stenosis

Objective: To evaluate the characteristics of renal cortical blood perfusion assessed by contrast-enhanced ultrasound (CEUS) in elderly patients with renal artery stenosis (RAS) and its relationship with renal function. Methods: Ninety-three elderly patients diagnosed with RAS, who were admitted in Beijing Hospital during June 2017 and December 2018, were retrospectively enrolled. According to the degree of RAS, 186 renal arteries were divided into normal renal artery group (n=79), mild RAS group (30% to 49%, n=59), moderate RAS group (50% to 70%, n=33), and severe RAS group (70% to 99%, n=15). Renal cortical blood perfusion and renal glomerular filtration rate (GFR) were measured by CEUS and radionuclide renal dynamic imaging. According to the renal GFR, 186 kidneys were divided into normal renal function group (GFR≥35 ml/min, n=42) and mild renal insufficiency group (35 ml/min>GFR≥25 ml/min, n=51), moderate renal insufficiency group (25 ml/min>GFR≥15 ml/min, n=75) and severe renal insufficiency group (GFR<15 ml/min, n=18). The renal cortical blood perfusion time-intensity curve (TIC) and related parameters were analyzed, including the area under the curve (AUC), the slope of the ascending branch (A), the peak intensity (PI), the peak time (TTP) and the mean transit time (MTT), the kidneys of different RAS groups and patients with different renal function groups were analyzed. Pearson correlation analysis was used to evaluate the correlation between renal cortical blood perfusion parameters and renal GFR. Results: (1) Renal cortical blood perfusion and GFR: CEUS showed that parameter A of TIC was significantly reduced, while TTP was prolonged in the mild renal artery stenosis group compared with the normal renal artery group (both P<0.05), GFP was similar between the two groups. Cortical perfusion parameters, such as AUC, A, PI and GFR were significantly lower, while TTP and MTT were significantly prolonged in the moderate and severe renal artery stenosis group than in the normal and mild stenosis groups (all P<0.05). Compared with the moderate stenosis group, AUC, A, PI and GFR were significantly lower while TTP, MTT were significantly prolonged in the severe renal artery stenosis group (all P<0.05). (2) TIC showed that the renal perfusion parameters, AUC, PI and A were significantly lower, while TTP was significantly longer in the mild renal dysfunction group than in the normal renal function group (all P<0.001). The changes aggravated in proportion with renal dysfunction. (3) Correlation between perfusion parameters and GFR: Pearson correlation analysis showed that the AUC (r=0.774, P<0.05), A (r=0.815, P<0.05) and PI (r=0.772, P<0.05) were positively correlated with GFR; serum creatinine level (r=-0.841, P<0.05), renal function grading (r=-0.731, P<0.05), TTP (r=-0.803, P<0.05) and MTT (r=-0.741, P<0.05) were negative correlated with GFR. The degree of stenosis was negatively correlated with GFR (r=-0.427, P<0.05). Conclusion: Cortical perfusion parameters differ significantly among patients with various degree of RAS and renal dysfunction. The renal cortical blood perfusion parameters are correlated with renal GFR.