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Abstract: Rnd proteins are a family of small GTPases that have been involved in axon path finding and CNS development by their control of actin cytoskeleton dynamics. Rnd proteins are constitutively activated and, subsequently, their functions determined by their localization and expression levels. In this work we have analyzed by Western blot and immunohistochemistry the levels and localization of Rnd3/RhoE during mouse postnatal development. CNS was found to be the main tissue for RhoE protein expression, which was detected in all regions of the adult brain and spinal cord, with the highest levels in the olfactory bulb and cortex. RhoE protein levels were considerably higher in all the regions of the CNS the first 2–3 weeks of postnatal development, undergoing later a decrease that led to low levels in the adult. Immunohistochemical detection of RhoE at postnatal day 21 showed an intense and widespread labelling throughout the CNS. RhoE immunoreactivity was detected in the granular and mitral cells and anterior olfactory nuclei of the olfactory bulb and in all cerebral layers. In the striatum, diencephalon, mesencephalon, pons, medulla oblongata and spinal cord, RhoE was widely distributed with higher intensity in the motoneurones and in some brainstem nuclei such as the red nucleus or the reticulotegmental nucleus. The pyramidal cells of CA1-3 and the polymorph layer, but not the granular cells of the dentate gyrus in the hippocampus were strongly labelled. At earlier stages the labelling was nearly similar; however, a prominent labelling was detected in the cells of the rostral migratory stream and in the external granule cells of the cerebellum. Our results suggest that RhoE can play important roles in the postnatal development and maturation of the CNS, especially in the migratory processes affecting the neurones. [Copyright &y& Elsevier]

To investigate the possible relationships between blood pressure, parathyroid hormone (PTH) and platelet cytosolic Ca concentration ([Ca]) in patients with essential hypertension, we studied 17 patients with this disease aged 48±2 years and 17 normotensive controls aged 44±3 years. Platelet [Ca] was measured by spectrofluorimetry using the dye Fura-2 acetoxymethylester. Patients with essential hypertension displayed lower levels of serum ionized Ca (0.99±0.03 versus 1.1±0.01 mmol/l, <0.05) and higher serum intact PTH levels (37±3 versus 26±2 pg/ml, <0.01) than the normotensive controls. Although serum levels of intact PTH were significantly correlated with mean arterial pressure (MAP) in the combined group of subjects (=0.42, <0.05), there was no correlation when each group was considered separately. Resting platelet [Ca] was also higher in patients than in controls (57±3 versus 48±2nmol/l, <0.005). When platelets were stimulated with thrombin, the increment in [ca] was also greater in patients than in controls in the presence of extracellular Ca (264±24 versus 194±19 nmol/l, <0.05) but not in its absence (123±12 versus 112±10 nmol/l). The thrombin-induced increment in [ca] was correlated with MAP in the hypertensive patients (=0.64, <0.01) and in the combined group of subjects (=0.42, <0.05). There was no relationship between resting or thrombin-induced [Ca] and serum PTH in either group of patients or in the combined group of subjects. Furthermore, preincubation of platelets with PTH had no effect neither on resting platelet [Ca] or on thrombin-induced increments in [ca], both in the presence and in the absence of extracellular Ca in either group of subjects. Therefore, despite platelet [Ca] and serum PTH seem to be related to blood pressure, it appears that PTH does not participate directly in the elevated platelet [Ca] found in patients with essential hypertension. [ABSTRACT FROM PUBLISHER]

Direct stimulation of the antitumor activity of immune system through checkpoint inhibitors (ICIs) has demonstrated efficacy in the treatment of different cancer types. The activity of these antibodies takes place in the immunological synapse blocking the binding of the negative immunoregulatory proteins, thus leading to the finalization of the immune response. Despite having a favorable toxicity profile, its mechanism of action impedes the negative regulation of the immune activity which can potentially favor autoimmune attacks to normal tissues. Renal toxicity has been described in several ICI but not with atezolizumab, an IgG1 monoclonal antibody targeting PD-L1 (programmed death ligand 1), approved by FDA as a second-line therapy for advanced urothelial carcinoma. Here we present a patient with a single kidney and metastatic renal cell carcinoma treated with atezolizumab and bevacizumab combination, with biopsy-proven acute interstitial nephritis, who had a complete resolution of renal dysfunction after steroid therapy. [ABSTRACT FROM AUTHOR]

Introduction: Dialysis catheter-associated bacteremia in Intensive Care Units (ICUs) increases morbidity and mortality, prolongs hospital admission and increases admission costs. Taurolidine-Citrate-Heparin Locking Solution (TCHLS) is a catheter-locking solution with a broad antimicrobial activity against gram-positive and gram-negative bacteria and fungi. The aim of this study was to analyze the effect of systematic sealing of hemodialysis catheters in the ICUs of the Hospital Clínic de Barcelona on the incidence of hemodialysis catheter-related blood stream infections (CRBSI)., Material and Methods: CRBSI episodes of patients who underwent intermittent hemodialysis (IHD) during ICU admission were reviewed. TCHLS was established as a routine dialysis catheter sealing solution in the hospital ICUs in 2015. As a control group an historic pre-TCHLS group from 2010 to 2014 was used. The post-TCHLS period comprised from 2015 to 2018., Results: A total of 243 and 266 patients required IHD in the pre- and post TCHLS periods, respectively. The number of CRBSI in the pre-TCHLS period was 18 (7.43%) as compared to 9 (3.38%) in the post-TCHLS period ( p  = 0.043). All infections were from percutaneous catheters except for three catheters that were tunneled. There was no association between the location of the catheter and the incidence of CRBSI. The most frequent isolated microorganisms were Gram positive bacteria (48.38%), with a global predominance of Staphylococcus epidermidis (32.25%). There were no significant differences in the median days from the start of hemodialysis to the onset of bacteremia (23.5 days in pre-TCHLS group vs 21 days in the post-TCHLS). There were also no significant differences between the days of ICU stay in the CRBSI in both groups or in mortality, being the overall mortality of 65.9%., Conclusions: In our population, the systematic application of TCHLS in the sealing of dialysis catheters in critically ill patients reduces the incidence of CRBSI in ICUs., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Canine inflammatory mammary carcinoma (IMC) is an aggressive and rare type of mammary gland cancer in dogs where vascular endothelial growth factor and cyclooxigenase-2 overexpression usually occur, which contribute to its invasive and angiogenic nature. This study aimed to evaluate the efficacy and safety of a combined treatment regimen of toceranib phosphate and carprofen in dogs with measurable IMC. Fifteen female dogs with histopathologically confirmed IMC were included, undergoing a regimen of toceranib (2.4-2.75 mg/kg PO, three times weekly) and carprofen (4.4 mg/kg/24 h PO). Initial evaluations included physical exams, tumor measurements, complete blood count, biochemistry, urinalysis, three view thoracic radiographs, and abdominal ultrasound. Follow-up assessments of physical condition and quality of life (QOL) were conducted bi-weekly, with tumor response evaluations monthly, using RECIST v1.0 criteria. While no complete or partial responses were observed, 60% of the dogs maintained stable disease, with a median progression-free survival of 76 days and an overall survival of 90 days. Notably, 60% of the dogs showed clinical benefit through improved QOL and disease stabilization. The treatment was well-tolerated, with only grade I/II toxicities reported. Despite limited biological activity against the cancer, this protocol may enhance QOL in dogs with IMC, offering a valuable palliative option.

Background & Aims: The management of acute kidney injury (AKI) in cirrhosis is challenging. The EASL guidelines proposed an algorithm for the management of AKI, but this has never been validated. We aimed to prospectively evaluate this algorithm in clinical practice., Methods: We performed a prospective cohort study in consecutive hospitalized patients with cirrhosis and AKI. The EASL management algorithm includes identification/treatment of precipitating factors, 2-day albumin infusion in patients with AKI ≥stage 1B, and treatment with terlipressin in patients with hepatorenal syndrome (HRS-AKI). The primary outcome was treatment response, which included both full and partial response. Secondary outcomes were survival and adverse events associated with terlipressin therapy., Results: A total of 202 AKI episodes in 139 patients were included. Overall treatment response was 80%, while renal replacement therapy was required in only 8%. Response to albumin infusion was achieved in one-third of episodes. Of patients not responding to albumin, most (74%) did not meet the diagnostic criteria of HRS-AKI, with acute tubular necrosis (ATN) being the most common phenotype. The response rate in patients not meeting the criteria for HRS-AKI was 70%. Only 30 patients met the diagnostic criteria for HRS-AKI, and their response rate to terlipressin was 61%. Median time from AKI diagnosis to terlipressin initiation was only 2.5 days. While uNGAL (urinary neutrophil gelatinase-associated lipocalin) could differentiate ATN from other phenotypes (AUROC 0.78), it did not predict response to therapy in HRS-AKI. Ninety-day transplant-free survival was negatively associated with MELD-Na, ATN and HRS-AKI as well as uNGAL. Three patients treated with terlipressin developed pulmonary edema., Conclusions: The application of the EASL AKI algorithm is associated with very good response rates and does not significantly delay initiation of terlipressin therapy., Impact and Implications: The occurrence of acute kidney injury (AKI) in patients with cirrhosis is associated with poor short-term mortality. Improving its rapid identification and prompt management was the focus of the recently proposed EASL AKI algorithm. This is the first prospective study demonstrating that high AKI response rates are achieved with the use of this algorithm, which includes identification of AKI, treatment of precipitating factors, a 2-day albumin challenge in patients with AKI ≥1B, and supportive therapy in patients with persistent AKI not meeting HRS-AKI criteria or terlipressin with albumin in those with HRS-AKI. These findings support the use of this algorithm in clinical practice., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In this study, we investigated if the therapeutic potential of peripheral blood mononuclear cell (PBMC) therapy in a murine model of ischemic AKI is related with the survival pattern of monocyte/macrophages in tissue. CD-1 mice were subjected to bilateral renal ischemia followed by reperfusion to induce AKI. M2-polarized PBMCs isolated from CD-1 mice were administered intravenously at different time points post-injury. Our results demonstrate that early administration of PBMC therapy attenuates renal tissue damage, reduces tissue cell death and prevents fibrosis development. Reduction of tissue pyroptosis was observed by reduction on NLRP3 inflammasome activation and decreasing IL-1beta and Caspase-1 expression in the kidney. Furthermore, the therapy was shown to mitigate ferroptosis by inducing GPX4 overexpression. Early administration of PBMCs increased the survival pattern of renal tissue-macrophages, promoting a "pro-survival phenotype" resulting in decreased pyroptotic marker NLRP3, IL-1beta and Caspase 1 and increased anti-ferroptotic gene GPX4. Conversely, delayed administration of PBMC therapy exhibits diminished efficacy in preventing cell death and fibrosis in tissue and provoked a decrease in the pro-survival phenotype of both monocyte /macrophages in tissue. Our findings highlight the therapeutic potential of PBMC therapy in mitigating AKI and preventing CKD progression by modulating tissue-resident macrophage survival and reducing their cell death pathways. The fact that the effectiveness of the therapy depends on the time of administration after the injury underscores the importance of early intervention in AKI management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension and is associated with a higher cardiometabolic risk than essential hypertension. The aim of this consensus is to provide practical clinical recommendations for its surgical and medical treatment, pathology study and biochemical and clinical follow-up, as well as for the approach in special situations like advanced age, pregnancy and chronic kidney disease, from a multidisciplinary perspective, in a nominal group consensus approach of experts from the Spanish Society of Endocrinology and Nutrition (SEEN), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN), Spanish Society of Internal Medicine (SEMI), Spanish Radiology Society (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Society of Laboratory Medicine (SEQC(ML)), Spanish Society of Anatomic-Pathology and Spanish Association of Surgeons (AEC)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension (HT), and is associated with a higher cardiometabolic risk than essential HT. However, PA remains underdiagnosed, probably due to several difficulties clinicians usually find in performing its diagnosis and subtype classification. The aim of this consensus is to provide practical recommendations focused on the prevalence and the diagnosis of PA and the clinical implications of aldosterone excess, from a multidisciplinary perspective, in a nominal group consensus approach by experts from the Spanish Society of Endocrinology and Nutrition (SEEN), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN), Spanish Society of Internal Medicine (SEMI), Spanish Radiology Society (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Society of Laboratory Medicine (SEQC(ML)), Spanish Society of Anatomic-Pathology, Spanish Association of Surgeons (AEC)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Contrast-induced encephalopathy is a neurological complication related to contrast used in endovascular procedures or computed tomography (CT). The main risk factors are arterial hypertension, diabetes mellitus, chronic kidney disease (CKD), hyperosmolar contrasts, the amount of infused contrast and its direct infusion in the posterior cerebral territory, or pathologies with blood-brain barrier damage. Symptomatology is non-specific and may present as altered level of consciousness, neurological focality or seizures. Diagnosis is done by exclusion after ischemic or hemorrhagic stroke has been ruled out; CT or MRI are useful for differentiation. Generally, it appears shortly after exposure and the symptoms lasts 48-72h with complete recovery, although cases with persistence of symptoms or longer duration have been described. Treatment consists of monitoring, supportive measures and kidney replacement therapy (KRT) with hemodialysis (HD) in patients in chronic KRT program. It is important for the nephrologist to be aware of this entity given the susceptibility of the patient on HD as well as its potential therapeutic role in these patients., (Copyright © 2023 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Macrophages must remove apoptotic cells to shield tissues from the deleterious components of dying cells. The development of chronic inflammation and autoimmune symptoms in systemic lupus is influenced by a deficiency in phagocytosis of apoptotic cells but the underlying mechanism is still unknown. Modifications in monocyte/macrophage phenotype brought on by an increase in their inflammatory phenotype would cause them to decrease the expression of CPT1a, which would reduce their ability to phagocytose, aggravating kidney damage in lupus nephritis. We aim to demonstrate that the deficiency of CPT1A in the immunological system determines lupus. For this purpose, we will monitor CPT1a expression in blood monocytes and phagocytosis and CPT1a expression of macrophages isolated from kidneys and the inflammatory state in kidneys in two experimental models of lupus nephritis such as lupus induced pristane model and in the OVA-IC in vivo model. Additionally, we will test if reestablishing CPT1a expression in tissue macrophages restores the lost phagocytic function. We evidenced that blood monocytes and macrophages isolated from kidneys in the two in vivo models have a reduced expression of CPT1a and a reduced phagocytosis. Phagocytosis could be restored only if macrophage administration leads to an increase in CPT1a expression in kidney macrophages. A new cell therapy to reduce kidney nephritis in lupus could be developed based on these results., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Macrophage activation is a complex process with multiple control elements that ensures an adequate response to the aggressor pathogens and, on the other hand, avoids an excess of inflammatory activity that could cause tissue damage. In this study, we have identified RND3, a small GTP-binding protein, as a new element in the complex signaling process that leads to macrophage activation. We show that RND3 expression is transiently induced in macrophages activated through Toll receptors and potentiated by IFN- γ . We also demonstrate that RND3 increases NOTCH signaling in macrophages by favoring NOTCH1 expression and its nuclear activity; however, Rnd3 expression seems to be inhibited by NOTCH signaling, setting up a negative regulatory feedback loop. Moreover, increased RND3 protein levels seem to potentiate NF κ B and STAT1 transcriptional activity resulting in increased expression of proinflammatory genes, such as Tnf - α , Irf-1 , or Cxcl-10 . Altogether, our results indicate that RND3 seems to be a new regulatory element which could control the activation of macrophages, able to fine tune the inflammatory response through NOTCH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflicts of interest., (Copyright © 2024 María José Romero de Ávila et al.)