Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury

We hypothesized that the store-operated calcium entry (SOCE) channel, Orai1, participates in the activation of Th17 cells and influences renal injury. In rats, following renal ischemia/reperfusion (I/R), there was a rapid and sustained influx of Orai1+ CD4 T cells and IL-17 expression was restricted to Orai1+ cells. When kidney CD4+ cells of post-acute kidney injury (post-AKI) rats were stimulated with angiotensin II and elevated Na+ (10-7 M/170 mM) in vitro, there was an enhanced response in intracellular Ca2+ and IL-17 expression, which was blocked by SOCE inhibitors 2APB, YM58483/BTP2, or AnCoA4. In vivo, YM58483/BTP2 (1 mg/kg) attenuated IL-17+ cell activation, inflammation, and severity of AKI following either I/R or intramuscular glycerol injection. Rats treated with high-salt diet (5-9 weeks after I/R) manifested progressive disease indicated by enhanced inflammation, fibrosis, and impaired renal function. These responses were significantly attenuated by YM58483/BTP2. In peripheral blood of critically ill patients, Orai1+ cells were significantly elevated by approximately 10-fold and Th17 cells were elevated by approximately 4-fold in AKI versus non-AKI patients. Further, in vitro stimulation of CD4+ cells from AKI patients increased IL-17, which was blocked by SOCE inhibitors. These data suggest that Orai1 SOCE is a potential therapeutic target in AKI and CKD progression

Acute kidney injury contributes to worse physical and quality of life outcomes in survivors of critical illness

Objectives: Survivors of critical illness and acute kidney injury (AKI) are at risk of increased morbidity. The purpose of this study was to compare physical, emotional, and cognitive health in survivors of critical illness with and without AKI. Methods: Retrospective cohort study of adult (≥ 18 years old) survivors of critical illness due to sepsis and/or acute respiratory failure who attended follow-up in a specialized ICU Recovery Clinic. Outcomes were evaluated during 3-month visit and comprised validated tests for evaluation of physical function, muscle strength, cognitive and emotional health, and self-reported health-related quality of life (HRQOL). Descriptive statistics and group comparisons were performed. Results: A total of 104 patients with median age of 55 [49-64] years, 54% male, and median SOFA score of 10 [8-12] were analyzed. Incidence of AKI during ICU admission was 61 and 19.2% of patients required renal replacement therapy (RRT). Patients with AKI stage 2 or 3 (vs. those with AKI stage 1 or no AKI) walked less on the 6-min walk test (223 ± 132 vs. 295 ± 153 m, p = 0.059) and achieved lower of the predicted walk distance (38% vs. 58%, p = 0.041). Similar patterns of worse physical function and more significant muscle weakness were observed in multiple tests, with overall worse metrics in patients that required RRT. Patients with AKI stage 2 or 3 also reported lower HRQOL scores when compared to their counterparts, including less ability to return to work or hobby, or reengage in driving. There were no significant differences in cognitive function or emotional health between groups. Conclusions: Survivors of critical illness and AKI stage 2 or 3 have increased physical debility and overall lower quality of life, with more impairment in return to work, hobby, and driving when compared to their counterparts without AKI or AKI stage 1 at 3 months post-discharge

Global Perspectives in AKI: Peru

Peru is a middle-income Latin American country with an estimated population of more than 31 million inhabitants.1 Although our country has experienced significant improvements in some social determinants of health, the main causes of death are still related to socioeconomic status, which means people with lower incomes have higher mortality rates because of less access to health care, education, basic services, and employment, among other aspects.1 There are other challenges in the Peruvian health system, such as its fragmented nature which makes it one of the most dysfunctional and unequal health systems in Latin America. For example, the Peruvian Ministry of Health (MINSA) covers 50% of the population through the Government health insurance, whereas approximately 20% of Peruvians have access to the Social Health Insurance (EsSalud).2 However, although the health system has improved in terms of health insurance outreach, it continues to be centralized and precarious and has structural and organizational problems that have an effect not only on health care coverage but also on its delivery and quality.2–5 In this context, along with the barriers to access basic health care services6 and the effects of climate change, the incidence of AKI is increasing in Peru and in other low- and middle-income countries.7 Despite the fact that AKI constitutes a public health burden of growing repercussion in Peru and surroundings, there are lack of public health data and policy, as well as suboptimal patient and provider education and clinical care. Herein, we describe important challenges and provide perspectives and possible solutions to improve AKI care in Peru

Sepsis-Associated Acute Kidney Disease and Long-term Kidney Outcomes

Rationale & Objective: Sepsis-associated acute kidney injury often leads to acute kidney disease (AKD), predisposing patients to long-term complications such as chronic kidney disease (CKD), kidney failure with replacement therapy (KFRT), or mortality. Risk stratification of patients with AKD represents an opportunity to assist with prognostication of long-term kidney complications. Study Design: Single-center retrospective cohort. Setting & Participants: 6,290 critically ill patients admitted to the intensive care unit with severe sepsis or septic shock. Patients were separated into cohorts based on incident acute kidney injury or not, and survivors identified who were alive and free of KFRT up to 90 days. Predictors: AKD stage (0A, 0C, or ≥1) using the last serum creatinine concentration available by discharge or up to 90 days postdischarge. Outcome: Time to development of incident CKD, progression of CKD, KFRT, or death. Analytical Approach: Multivariable Cox proportional hazards models. Results: Patients surviving kidney injury associated with sepsis often fail to return to baseline kidney function by discharge: 577/1,231 (46.9%) with stage 0C or 1 or greater AKD. AKD stage was significantly associated with the composite primary outcome. Stages 0C AKD and 1 or greater AKD were significantly and progressively associated with the primary outcome when compared with stage 0A AKD (adjusted HR [aHR], 1.74; 95% CI, 1.32-2.29, and aHR, 3.25; 95% CI, 2.52-4.20, respectively). Additionally, stage 1 or greater AKD conferred higher risk above stage 0C AKD (aHR, 1.87; 95% CI, 1.44-2.43). CKD incidence or progression and KFRT, more so than mortality, occurred with greater frequency in higher stages of AKD. Limitations: Retrospective design, single center, exclusion of patients with KFRT within 90 days of discharge, potential ascertainment bias, and inability to subclassify above AKD stage 1. Conclusions: Risk stratification using recommended AKD stages at hospital discharge or shortly thereafter associates with the development of long-term kidney outcomes following sepsis-associated acute kidney injury

Vortioxetine in major depressive disorder : from mechanisms of action to clinical studies. An updated review

Introduction: Vortioxetine is a multimodal-acting antidepressant that provides improvements on cognitive function aside from antidepressants and anxiolytic effects. Vortioxetine has been found to be one of the most effective and best tolerated options for major depressive disorder (MDD) in head-to-head trials. Areas covered: The present review intends to gather the most relevant and pragmatic data of vortioxetine in MDD, specially focusing on new studies that emerged between 2015 and 2020. Expert opinion: Vortioxetine is the first antidepressant that has shown improvements both in depression and cognitive symptoms, due to the unique multimodal mechanism of action that combine the 5-HT reuptake inhibition with modulations of other key pre- and post-synaptic 5-HT receptors (agonism of 5-HT receptor, partial agonism of 5-HT receptor, and antagonism of 5-HT, 5-HT and 5-HT receptors). This new mechanism of action can explain the dose-dependent effect and can be responsible for its effects on cognitive functioning and improved tolerability profile. Potential analgesic and anti-inflammatory properties observed in preclinical studies as well as interesting efficacy and tolerability results of clinical studies with specific target groups render it a promising therapeutic option for patients with MDD and concomitant conditions (as menopause symptoms, pain, inflammation, apathy, sleep and/or metabolic abnormalities)

Capacity for the management of kidney failure in the International Society of Nephrology Latin America region:Report from the 2023 ISN Global Kidney Health Atlas (ISN-GKHA)

Successful management of chronic kidney disease (CKD) in Latin America (LA) continues to represent a challenge due to high disease burden and geographic disparities and difficulties in terms of capacity, accessibility, equity, and quality of kidney failure care. Although LA has experienced significant social and economic progress over the past decades, there are still important inequities in healthcare access. Through this third iteration of the International Society of Nephrology Global Kidney Health Atlas, the indicators regarding kidney failure care in LA are updated. Survey responses were received from 22 (71%) of 31 countries in LA representing 96.5% of its total population. Median CKD prevalence was 10.2% (IQR 8.4 - 12.3), median CKD disability-adjusted life year (DALYs) were 753.4 days (IQR 581.3 -1,072.5), and median CKD mortality was 5.5% (IQR 3.2 - 6.3). Regarding dialysis modality, hemodialysis (HD) continued to be the most utilized therapy, while peritoneal dialysis (PD) reached a plateau and kidney transplantation increased steadily over the past 10 years. In 20 (91%) countries, >50% of people with kidney failure could access dialysis; and in only 2 (9%) countries, people who had access to dialysis could initiate dialysis with PD. A mix of public and private systems collectively funded most aspects of kidney replacement therapy (KRT; dialysis and transplantation) with many people incurring up to 50% of out-of-pocket costs. Few LA countries had CKD/KRT registries and almost no acute kidney injury (AKI) registries were reported. There was large variability in the nature and extent of kidney failure care in LA mainly related to countries’ funding structures and limited surveillance and management initiatives