mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations that frequently cause stroke. CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of MEKK3-KLF2/4 signaling in vascular endothelial cells. Gain-of-function mutations in PIK3CA (encoding the enzymatic subunit of the PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions. METHODS: We recently developed a model of CCM formation that closely reproduces key events in human CCM formation through inducible CCM loss-of-function and PIK3CA gain-of-function in mature mice. In the present study, we use this model to test the ability of rapamycin, a clinically approved inhibitor of the PI3K effector mTORC1, to treat rapidly growing CCMs. RESULTS: We show that both intraperitoneal and oral administration of rapamycin arrests CCM growth, reduces perilesional iron deposition, and improves vascular perfusion within CCMs. CONCLUSIONS: Our findings further establish this adult CCM model as a valuable preclinical model and support clinical testing of rapamycin to treat rapidly growing human CCMs.

Cavernous Angioma Symptomatic Hemorrhage (CASH) Trial Readiness II: Imaging Biomarkers and Trial Modeling.

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast enhanced quantitative perfusion (DCEQP) MRI sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cavernous angiomas. We assessed their prospective changes in cavernous angiomas with symptomatic hemorrhage (CASH) in a multisite trial readiness project ( clinicaltrials.gov NCT03652181 ). Methods: Patients with CASH in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of CASH lesion were acquired at baseline, and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined lesional symptomatic hemorrhage (SH) or asymptomatic change (AC). Sample size calculations for hypothesized therapeutic effects were conducted. Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (p= 0.019). Annual QSM increase by ≥ 6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with AC during the same epoch, and 3.82 times more frequently than clinical events. DCEQP change had lower sensitivity for SH and AC than QSM change, and greater variance. A trial with smallest sample size would detect a 30% difference in QSM annual change in 34 or 42 subjects (one and two-tailed, respectively), power 0.8, alpha 0.05. Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in CASH. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the U.S. F.D.A. of QSM as a biomarker of drug effect in CASH.

Risk of outcomes in a Spanish population with chronic kidney disease.

Objectives: To assess mortality and cardiovascular and renal outcomes among patients with chronic kidney disease (CKD) (primary objective), with a particular focus on heart failure (HF) risk following diagnosis of CKD (secondary objective) in Spain. Methods: We conducted an observational study comprising cross-sectional and longitudinal retrospective analyses using secondary data from electronic health records. For the primary objective, adults with prevalent CKD [estimated glomerular filtration rate (eGFR) <60 or ≥60 mL/min/1.73 m2 with a urine albumin:creatinine ratio (UACR) ≥30 mg/g at the index date (1 January 2017)] were included. For the secondary objective, adults with incident CKD in 2017 were enrolled. Results: In the prevalent population, 46 786 patients with CKD without HF [75.8 ± 14.4 years, eGFR 51.4 ± 10.1 mL/min/1.73 m2; 75.1% on renin-angiotensin system inhibitors (RASis)] and 8391 with CKD and HF (79.4 ± 10.9 years, eGFR 46.4 ± 9.8 mL/min/1.73 m2) were included. In the prevalent population, the risk of all-cause death {hazard ratio [HR] 1.107 [95% confidence interval (CI) 1.064-1.153]}, HF hospitalization [HR 1.439 (95% CI 1.387-1.493)] and UACR progression [HR 1.323 (95% CI 1.182-1.481)] was greater in those patients with CKD and HF versus CKD only. For the incident population, 1594 patients with CKD without HF and 727 with CKD and HF were included. Within 24 months from the CKD diagnosis (with/without HF at baseline), 6.5% of patients developed their first HF hospitalization. Although 60.7% were taking RASis, only 3.4% were at maximal doses and among diabetics, 1.3% were taking sodium-glucose cotransporter-2 inhibitors. Conclusions: The presence of HF among CKD patients markedly increases the risk of outcomes. CKD patients have a high risk of HF, which could be partially related to insufficient treatment.

Epidemiology, clinical profile, management, and two-year risk complications among patients with chronic kidney disease in Spain.

OBJECTIVES: To describe the epidemiology, clinical profile, treatments, and to determine cardiovascular and renal outcomes after two years of follow-up in a contemporary chronic kidneay disease (CKD) population in Spain. This was also analyzed among the DAPA-CKD-like population (patients who met most inclusion criteria of DAPA-CKD trial). METHODS: Observational, retrospective, population-based study using BIG-PAC database. The CKD population was defined as patients ≥18 years, with at least one diagnostic code of CKD prior to the index date (January 1st, 2018). CKD was defined as estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2 (CKD-EPI), or albuminuria >30mg/g. RESULTS: We identified 56,435 CKD patients after exclusions (76.4 years, 52.2% men, urine albumin-to-creatinine ratio 390.8mg/g, eGFR 49.7mL/min/1.73m2). CKD prevalence was 4.91% and incidence 2.10 per 1000 patient-years. Regarding treatments, 69.2% were taking renin-angiotensin system inhibitors (only 4.2% at maximal doses) and 3.5% of diabetic patients SGLT-2 inhibitors. During the two years of follow-up, rates of heart failure, all-cause death, myocardial infarction, stroke, and CKD were 17.9, 12.1, 7.2, 6.3, and 5.9 events per 100 patient-years, respectively. During this period, 44% of patients were hospitalized, and 6.8% died during hospitalization. Cardiovascular outcomes were more common in the DAPA-CKD-like population. CONCLUSIONS: In Spain, CKD population is older and comorbidities, including diabetes and heart failure, are common. Cardiovascular and renal outcomes are frequent. There is room for improvement in CKD management, particularly through the use of drugs with proven cardiovascular and renal benefit.

Costs and healthcare utilisation of patients with chronic kidney disease in Spain.

BACKGROUND: Data about the impact of chronic kidney disease (CKD) on health care costs in Spain are scarce This study was aimed to evaluate cumulative costs and healthcare utilisation in CKD in Spain. METHODS: Observational, retrospective, population-based study, which included adults who received care for CKD between 2015 and 2019. Healthcare and medication costs were summarized on a yearly basis starting from the index date (1st January 2015), and then cumulatively until 2019. RESULTS: We identified 44,214 patients with CKD (year 2015: age 76.4 ± 14.3 years, 49.0% women, albumin-to-creatinine ratio 362.9 ± 176.8 mg/g, estimated glomerular filtration rate 48.7 ± 13.2 mL/min/1.73 m2). During the 2015-2019 period, cumulative CKD associated costs reached 14,728.4 Euros, being cardiovascular disease hospitalizations, particularly due to heart failure and CKD, responsible for 77.1% of costs. Total medication cost accounted for 6.6% of the total cost. There was a progressive decrease in cardiovascular disease hospital costs per year (from 2741.1 Euros in 2015 to 1.971.7 Euros in 2019). This also occurred with cardiovascular and diabetic medication costs, as well as with the proportion of hospitalizations and mortality. Costs and healthcare resources use were higher in the DAPA-CKD like population, but also decreased over time. CONCLUSIONS: Between 2015 and 2019, costs of patients with CKD in Spain were high, with cardiovascular hospitalizations as the key determinant. Medication costs were responsible for only a small proportion of total CKD costs. Improving CKD management, particularly with the use of cardiovascular and renal protective medications may be helpful to reduce CKD burden.

Epidemiology, clinical profile, management, and two-year risk complications among patients with chronic kidney disease in Spain.

OBJECTIVES: To describe the epidemiology, clinical profile, treatments, and to determine cardiovascular and renal outcomes after two years of follow-up in a contemporary chronic kidneay disease (CKD) population in Spain. This was also analyzed among the DAPA-CKD-like population (patients who met most inclusion criteria of DAPA-CKD trial). METHODS: Observational, retrospective, population-based study using BIG-PAC database. The CKD population was defined as patients ≥18 years, with at least one diagnostic code of CKD prior to the index date (January 1st, 2018). CKD was defined as estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2 (CKD-EPI), or albuminuria >30mg/g. RESULTS: We identified 56,435 CKD patients after exclusions (76.4 years, 52.2% men, urine albumin-to-creatinine ratio 390.8mg/g, eGFR 49.7mL/min/1.73m2). CKD prevalence was 4.91% and incidence 2.10 per 1000 patient-years. Regarding treatments, 69.2% were taking renin-angiotensin system inhibitors (only 4.2% at maximal doses) and 3.5% of diabetic patients SGLT-2 inhibitors. During the two years of follow-up, rates of heart failure, all-cause death, myocardial infarction, stroke, and CKD were 17.9, 12.1, 7.2, 6.3, and 5.9 events per 100 patient-years, respectively. During this period, 44% of patients were hospitalized, and 6.8% died during hospitalization. Cardiovascular outcomes were more common in the DAPA-CKD-like population. CONCLUSIONS: In Spain, CKD population is older and comorbidities, including diabetes and heart failure, are common. Cardiovascular and renal outcomes are frequent. There is room for improvement in CKD management, particularly through the use of drugs with proven cardiovascular and renal benefit.

Aortic thrombus in patients with severe COVID-19: review of three cases.

Coronavirus disease 2019 (COVID-19) could predispose to both venous and arterial thromboembolism, in an exaggerated immune response to the virus, especially in severe patients. Even though aortic clots are a rare entity, the pro-coagulant nature of COVID-19 is associated with thrombosis in atypical locations and should be considered in patients with severe abnormalities in coagulation parameters. We describe a series of three cases of aortic thrombi diagnosed by computerized tomography (CT) angiography in patients with confirmed SARS-CoV-2 infection.

Costs and healthcare utilisation of patients with heart failure in Spain.

BACKGROUND: Increasing the knowledge about heart failure (HF) costs and their determinants is important to ascertain how HF management can be optimized, leading to a significant decrease of HF costs. This study evaluated the cumulative costs and healthcare utilisation in HF patients in Spain. METHODS: Observational, retrospective, population-based study using BIG-PAC database, which included data from specialized and primary care of people ≥18 years, from seven autonomous communities in Spain, who received care for HF between 2015 and 2019. The healthcare and medication costs were summarized on a yearly basis starting from the index date (1st January 2015), and then cumulatively until 2019. RESULTS: We identified 17,163 patients with HF (year 2015: mean age 77.3 ± 11.8 years, 53.5% men, 51.7% systolic HF, 43.6% on NYHA functional class II). During the 2015-2019 period, total HF associated costs reached 15,373 Euros per person, being cardiovascular disease hospitalizations the most important determinant (75.8%), particularly HF hospitalizations (51.0%). Total medication cost accounted for 7.0% of the total cost. During this period, there was a progressive decrease of cardiovascular disease hospital costs per year (from 2834 Euros in 2015 to 2146 Euros in 2019, P < 0.001), as well as cardiovascular and diabetic medication costs. CONCLUSIONS: During the 2015-2019 period, costs of HF patients in Spain were substantial, being HF hospitalizations the most important determinant. Medication costs represented only a small proportion of total costs. Improving HF management, particularly through the use of drugs that reduce HF hospitalization may be helpful to reduce HF burden.

Haemodialysis patients have worse postural balance with an associated risk of falls. / Los pacientes en hemodiálisis presentan peor equilibrio postural, que se relaciona con el riesgo de caídas.

INTRODUCTION: Postural balance is the result of a complex interaction of sensory input which keeps us upright. Haemodialysis patients have alterations which can lead to postural instability and a risk of falls. Our objective was to analyse postural stability and its relationship with the risk of falls in haemodialysis patients using a force platform. MATERIAL AND METHODS: This was a prospective cross-sectional study. Postural balance was recorded using a force platform in prevalent haemodialysis patients. We collected epidemiological, dialysis, analytical and treatment data. The incidence of falls was recorded over the 6 months following the tests. The postural stability analysis was performed with a portable strain gauge platform (AMTI AccuGait®) and a specific software unit for stabilometry (Balance Trainer® program). We measured 31 balance parameters; the balance variables used were: Area95; AreaEffect; VyMax; Xrange and Yrange. The stabilometry studies were performed in 3 situations: with eyes open; with eyes closed; and with the patient performing a simultaneous task. We performed one study at the start of the dialysis session, and a second study at the end. Stabilometry was measured in a control group under similar conditions. RESULTS: We studied 32 patients with a mean age of 68 years old; of this group, 20 subjects were male and 12 were female. Their mean weight was 74kg, with a mean BMI of 27.6kg/m2. In the controls, there were no significant differences in the stabilometry between the 3 situations studied. Both pre- and post-haemodialysis, patients with closed eyes showed greater imbalance, and there were significant differences with the other situations and controls. We found a significant increase in instability after the haemodialysis session, and greater instability in the 13 patients with diabetes (P<.05). The 4 patients with hyponatraemia (Na<136mmol/l) had worse balance in the simultaneous task situation (P=.038). Various drugs, such as insulin (P=.022), antiplatelet agents (P=.036) and beta-blockers (P=.029), were associated with imbalance. The 10 patients who suffered falls had greater imbalance, Yrange, Xrange, Area95 and AreaEffect, both pre- and post-haemodialysis (P<.05) than those without falls. CONCLUSIONS: Haemodialysis patients have alterations which can lead to postural instability and a risk of falls. Prevention programmes which include specific exercises to improve balance could be beneficial in reducing the risk of falls in this population.

Hypomagnesaemia in haemodialysis is associated with increased mortality risk: its relationship with dialysis fluid. / La hipomagnesemia en hemodiálisis se asocia a mayor riesgo de mortalidad: su relación con el líquido de diálisis.

Hypomagnesaemia in haemodialysis (HD) is associated with increased mortality risk: its relationship with dialysis fluid (DF). INTRODUCTION: Low concentrations of magnesium (Mg) in blood have been linked to the development of diabetes, hypertension, arrhythmias, vascular calcifications and an increased risk of death in the general population and in haemodialysis patients. The composition of the dialysis fluid in terms of its magnesium concentration is one of the main determinants of magnesium in haemodialysis patients. OBJECTIVE: To study magnesium concentrations in haemodialysis patients, their predictive mortality rate and what factors are associated with hypomagnesaemia and mortality in haemodialysis. METHODS: Retrospective study of a cohort of prevalent haemodialysis patients followed up for two years. Serum magnesium was measured every six months. The analysis used the initial and average magnesium values for each patient, comparing patients with magnesium below the mean (2.1mg/dl) with those with magnesium above the mean. During the follow-up, three types of dialysis fluid were used: type 1, magnesium 0.5 mmol/l; type 3, magnesium 0.37 mmol/l (both with acetate); and type 2, magnesium 0.5 mmol/l with citrate. RESULTS: We included 137 haemodialysis patients in the study, of which 72 were male and 65 were female, with a mean age of 67 (15) [26-95] years old. Of this group, 57 patients were diabetic, 70 were on online haemodiafiltration (OL-HDF) and 67 were on high-flow haemodialysis (HF-HD). The mean magnesium of the 93 patients with dialysis fluid type 1 was 2.18 (0.37) mg/dl. In the 27 patients with dialysis fluid type 3 it was 2.02 (0.42) mg/dl. And in the 17 with dialysis fluid type 2 it was 1.84 (0.24) mg/dl (p=.01). There was a pronounced direct relationship between Mg and P and albumin. After a mean follow-up of 16.6 (8.9) [3-24] months, 77 remained active, 24 had died and 36 had been transplanted or transferred. Patients with magnesium above than 2.1mg/dl had a longer survival (p=.008). The survival of patients with the three types of dialysis fluid did not differ significantly (Log-Rank, p=.424). Corrected for blood magnesium, patients with dialysis fluid with citrate have better survival (p=.009). The COX regression analysis shows how age, serum albumin, magnesium, dialysis technique and type of dialysis fluid have an independent predictive mortality rate. CONCLUSIONS: Low serum magnesium levels have a greater association with an increased risk of mortality compared to high levels. The type of dialysis fluid affects the magnesium concentration and the risk of death.

[High prevalence of asymptomatic COVID-19 in haemodialysis: learning day by day in the first month of the COVID-19 pandemic]. / Alta prevalencia de COVID-19 asintomático en hemodiálisis. Aprendiendo día a día el primer mes de pandemia de COVID-19.

Dialysis patients are a risk group for SARS-CoV-2 infection and possibly further complications, but we have little information. The aim of this paper is to describe the experience of the first month of the SARS-CoV-2 pandemic in a hospital haemodialysis (HD) unit serving the district of Madrid with the second highest incidence of COVID-19 (almost 1,000 patients in 100,000h). In the form of a diary, we present the actions undertaken, the incidence of COVID-19 in patients and health staff, some clinical characteristics and the results of screening all the patients in the unit. We started with 90 patients on HD: 37 (41.1%) had COVID-19, of whom 17 (45.9%) were diagnosed through symptoms detected in triage or during the session, and 15 (40.5%) through subsequent screening of those who, until that time, had not undergone SARS-CoV-2 PCR testing. Fever was the most frequent symptom, 50% had lymphopenia and 18.4% <95% O2 saturation. Sixteen (43.2%) patients required hospital admission and 6 (16.2%) died. We found a cluster of infection per shift and also among those using public transport. In terms of staff, of the 44 people involved, 15 (34%) had compatible symptoms, 4 (9%) were confirmed as SARS-CoV-2 PCR cases by occupational health, 9 (20%) required some period of sick leave, temporary disability to work (ILT), and 5 were considered likely cases. CONCLUSIONS: We detected a high prevalence of COVID-19 with a high percentage detected by screening; hence the need for proactive diagnosis to stop the pandemic. Most cases are managed as outpatients, however severe symptoms are also appearing and mortality to date is 16.2%. In terms of staff, 20% have required sick leave in relation to COVID-19.

Unlike Kt, high Kt/V is associated with greater mortality: The importance of low V. / El Kt/V alto, a diferencia del Kt, se asocia a mayor mortalidad: importancia de la V baja.

INTRODUCTION: Kt/V has been used as a synonym for haemodialysis dose. Patient survival improved with a Kt/V>1; this target was subsequently increased to 1.2 and 1.3. The HEMO study revealed no significant relationship between Kt/V and mortality. The relationship between Kt/V and mortality often shows a J-shaped curve. Is V the confounding factor in this relationship? The objective of this study is to determine the relationship between mortality and Kt/V, Kt and body water content (V) and lean mass (bioimpedance). METHODS: We studied a cohort of 127 prevalent haemodialysis patients, who we followed-up for an average of 36 months. Kt was determined by ionic dialysance, and V and nutrition parameters by bioimpedance. Kt/V, Kt corrected for body surface area (Kt/BSA) and target Kt/BSA were calculated. The mean data from 18,998 sessions were used as haemodialysis parameters, with a mean of 155 sessions per patient. RESULTS: Mean age was 70.4±15.3 years and 61% were male; 76 were dialysed via an arteriovenous fistula and 65 were on online haemodiafiltration. Weight was 70.6 (16.8)kg; BSA 1.8 (0.25) m2; total body water (V) 32.2 (7.41) l and lean mass index (LMI) 11.1 (2.7)kg/m2. Mean Kt/V was 1.84 (0.44); Kt 56.1 (7)l and Kt/BSA 52.8 (10.4)l. The mean target Kt/BSA was 49.7 (4.5)l. Mean Kt/BSA-target Kt/BSA +6.4 (7.0)l. Patients with a higher Kt/V had worse survival rates than others; with Kt this is not the case. Higher Kt/V values are due to a lower V, with poorer nutrition parameters. LMI and serum albumin were the parameters that best independently predicted the risk of death and are lower in patients with a higher Kt/V and lower V. CONCLUSION: Kt/V is not useful for determining dialysis doses in patients with low or reduced body water. Kt or the Kt/BSA are proposed as an alternative.

Follow a recipe to prescribe phosphate during hemodialysis. / Receta para prescribir fósforo durante hemodiálisis.

The addition of phosphorus (P) to the dialysate (LD) in the form of enema Casen® is common practice in patients with hypophosphatemia. The estimation of the amount to be used and the identification of the problems that may can occur are not well defined. As a result of our work we propose a practical approach of how to proceed to increase phosphate concentration in the hemodialysate. We present a reasoned formula to calculate how much enema has to be added and the problems that may arise.

Is it useful to increase dialysate flow rate to improve the delivered Kt?

BACKGROUND: Increasing dialysate flow rates (Qd) from 500 to 800 ml/min has been recommended to increase dialysis efficiency. A few publications show that increasing Qd no longer led to an increase in mass transfer area coefficient (KoA) or Kt/V measurement. Our objectives were: 1) Studying the effect in Kt of using a Qd of 400, 500, 700 ml/min and autoflow (AF) with different modern dialysers. 2) Comparing the effect on Kt of water consumption vs. dialysis time to obtain an individual objective of Kt (Ktobj) adjusted to body surface. METHODS: This is a prospective single-centre study with crossover design. Thirty-one patients were studied and six sessions with each Qd were performed. HD parameters were acquired directly from the monitor display: effective blood flow rate (Qbe), Qd, effective dialysis time (Te) and measured by conductivity monitoring, final Kt. RESULTS: We studied a total of 637 sessions: 178 with 500 ml/min, 173 with 700 ml/min, 160 with AF and 126 with 400 ml/min. Kt rose a 4% comparing 400 with 500 ml/min, and 3% comparing 500 with 700 ml/min. Ktobj was reached in 82.4, 88.2, 88.2 and 94.1% of patients with 400, AF, 500 and 700 ml/min, respectively. We did not find statistical differences between dialysers. The difference between programmed time and Te was 8' when Qd was 400 and 500 ml/min and 8.8' with Qd = 700 ml/min. Calculating an average time loss of eight minutes/session, we can say that a patient loses 24' weekly, 312' monthly and 62.4 hours yearly. Identical Kt could be obtained with Qd of 400 and 500 ml/min, increasing dialysis time 9.1' and saving 20% of dialysate. CONCLUSIONS: Our data suggest that increasing Qd over 400 ml/min for these dialysers offers a limited benefit. Increasing time is a better alternative with demonstrated benefits to the patient and also less water consumption.