Colony stimulating factor-1 receptor drives glomerular parietal epithelial cell activation in focal segmental glomerulosclerosis.

Parietal epithelial cells (PECs) are kidney progenitor cells with similarities to a bone marrow stem cell niche. In focal segmental glomerulosclerosis (FSGS) PECs become activated and contribute to extracellular matrix deposition. Colony stimulating factor-1 (CSF-1), a hematopoietic growth factor, acts via its specific receptor, CSF-1R, and has been implicated in several glomerular diseases, although its role on PEC activation is unknown. Here, we found that CSF-1R was upregulated in PECs and podocytes in biopsies from patients with FSGS. Through in vitro studies, PECs were found to constitutively express CSF-1R. Incubation with CSF-1 induced CSF-1R upregulation and significant transcriptional regulation of genes involved in pathways associated with PEC activation. Specifically, CSF-1/CSF-1R activated the ERK1/2 signaling pathway and upregulated CD44 in PECs, while both ERK and CSF-1R inhibitors reduced CD44 expression. Functional studies showed that CSF-1 induced PEC proliferation and migration, while reducing the differentiation of PECs into podocytes. These results were validated in the Adriamycin-induced FSGS experimental mouse model. Importantly, treatment with either the CSF-1R-specific inhibitor GW2580 or Ki20227 provided a robust therapeutic effect. Thus, we provide evidence of the role of the CSF-1/CSF-1R pathway in PEC activation in FSGS, paving the way for future clinical studies investigating the therapeutic effect of CSF-1R inhibitors on patients with FSGS.

B- and T-lymphocyte attenuator could be a new player in accelerated atherosclerosis associated with chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), cardiovascular morbi-mortality is higher than in general population. Atherosclerotic cardiovascular disease is accelerated in CKD, but specific CKD-related risk factors for atherosclerosis are unknown. METHODS: CKD patients from the NEFRONA study were used. We performed mRNA array from blood of patients free from atheroma plaque at baseline, with (n=10) and without (n=10) de novo atherosclerotic plaque development 2 years later. Selected mRNA candidates were validated in a bigger sample (n=148). Validated candidates were investigated in vivo in an experimental model of CKD-accelerated atherosclerosis, and in vitro in murine macrophages. RESULTS: mRNA array analysis showed 92 up-regulated and 67 down-regulated mRNAs in samples from CKD patients with de novo plaque development. The functional analysis pointed to a paramount role of the immune response. The validation in a bigger sample confirmed that B- and T-lymphocyte co-inhibitory molecule (BTLA) down-regulation was associated with de novo plaque presence after 2 years. However, BTLA down-regulation was not found to be associated with atherosclerotic progression in patients with plaque already present at baseline. In a model of CKD-accelerated atherosclerosis, mRNA and protein expression levels of BTLA were significantly decreased in blood samples and atheroma plaques. Plaques from animals with CKD were bigger, had more infiltration of inflammatory cells, higher expression of IL6 and IL17 and less presence of collagen than plaques from control animals. Incubation of macrophages with rat uremic serum decreased BTLA expression. CONCLUSIONS: BTLA could be a potential biomarker or therapeutic target for atherosclerosis incidence in CKD patients.

Incidence and characteristics of adverse drug reactions in a cohort of patients treated with PD-1/PD-L1 inhibitors in real-world practice.

Background: Data related to adverse drug reactions (ADRs), specifically immune-related adverse events (irAEs), in long-term treatment with immunotherapy in real-world practice is scarce, as is general information regarding the management of ADRs. Objectives: To characterize and describe the incidence of ADRs in patients who began immunotherapy treatment in clinical practice. Methods: In a prospective observational study cancer patients ≥18 years of age who were treated with a monotherapy regime of PD-1/PD-L1 inhibitors were evaluated. The study period was from November 2017 to June 2019 and patients were followed up until June 2021. Patients were contacted monthly by telephone and their electronic health records were reviewed. Each ADR was graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). Results: Out of 99 patients, 86 met the inclusion criteria. Most were male (67.4%), with a median age of 66 (interquartile range, IQR: 59-76). The most frequent cancer was non-small cellular lung cancer (46 cases, 53.5%), followed by melanoma (22, 25.6%). A total of 74 patients (86%) were treated with anti-PD-1 drugs and 12 (14%) were treated with anti-PD-L1 drugs. The median treatment durations were 4.9 (IQR: 1.9-17.0) and 5.9 months (IQR: 1.2-12.3), respectively. Sixty-three patients (73%) developed from a total of 156 (44% of the total number of ADR) irADRs, wherein the most frequent were skin disorders (50 cases, 32%, incidence = 30.5 irADRs/100 patients per year [p-y]), gastrointestinal disorders (29, 19%, 17.7 irADRs/100 p-y), musculoskeletal disorders (17, 11%, 10.4 irADRs/100 p-y), and endocrine disorders (14, 9%, 8.6 irADRs/100 p-y). A total of 22 irADRs (14%) had a latency period of ≥12 months. Twelve irADRs (7.7%) were categorized as grade 3-4, and while 2 (1.3%) were categorized as grade 5 (death). Sixty-one irADRs (39.1%) in 36 patients required pharmacological treatment and 47 irADRs (30.1%) in 22 patients required treatment with corticosteriods. Conclusion: The majority of patients treated with anti-PD1/PDL1-based immunotherapy experienced adverse reactions. Although most of these reactions were mild, 11.5% were categorized as grade 3 or above. A high percentage of the reactions were immune-related and occurred throughout the treatment, thereby indicating that early identification and close monitoring is essential.

The Increase in FGF23 Induced by Calcium Is Partially Dependent on Vitamin D Signaling.

BACKGROUND: Increased FGF23 levels are an early pathological feature in chronic kidney disease (CKD), causing increased cardiovascular risk. The regulation of FGF23 expression is complex and not completely understood. Thus, Ca2+ has been shown to induce an increase in FGF23 expression, but whether that increase is mediated by simultaneous changes in parathyroid hormone (PTH) and/or vitamin D is not fully known. METHODS: Osteoblast-like cells (OLCs) from vitamin D receptor (VDR)+/+ and VDR-/- mice were incubated with Ca2+ for 18 h. Experimental hypercalcemia was induced by calcium gluconate injection in thyro-parathyroidectomized (T-PTX) VDR +/+ and VDR-/- mice with constant PTH infusion. RESULTS: Inorganic Ca2+ induced an increase in FGF23 gene and protein expression in osteoblast-like cells (OLCs), but the increase was blunted in cells lacking VDR. In T-PTX VDR +/+ and VDR-/- mice with constant PTH levels, hypercalcemia induced an increase in FGF23 levels, but to a lower extent in animals lacking VDR. Similar results were observed in FGF23 expression in bone. Renal and bone 1α-hydroxylase expression was also modulated. CONCLUSIONS: Our study demonstrates that Ca2+ can increase FGF23 levels independently of vitamin D and PTH, but part of the physiological increase in FGF23 induced by Ca2+ is mediated by vitamin D signaling.

PTEN Deletion in Adult Mice Induces Hypoinsulinemia With Concomitant Low Glucose Levels.

The PI3K/AKT pathway, negatively regulated by PTEN, plays a paramount role in glucose metabolism regulation due to its activation by the insulin receptor signaling pathway. We generated a PTEN-KO mouse to evaluate the systemic effect of the overactivation of the PI3K/AKT pathway in insulin signaling and glucose homeostasis. Our results demonstrate that PTEN-KO mice show very low glucose levels in the fasted state, which poorly respond to glucose and pyruvate administration. Insulinemia decreased without alterations in pancreatic islets. Among the possible reasons, we uncover the deregulation of the expression of proximal tubule glucose transporter and consequent glycosuria. Moreover, we evidence an altered activation of hepatic gluconeogenesis-related genes. In addition, the expression of several genes related to ß-oxidation showed a delayed or even absent response to fasting, suggesting that the lack of PTEN not only impairs glucose metabolism but also slows down the use of lipids as a metabolic fuel. We conclude that the inducible full PTEN-KO mice could be a good model to study the metabolic interactions between glycidic and lipidic metabolism in hypoinsulinemic hypoglycemia and that PTEN could be an important mediator in the disease and/or a potential drug target.

Molecular Mechanisms of Kidney Injury and Repair.

Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing the need to better understand the molecular mechanisms of damage and regeneration in the kidney. CKD predisposes to acute kidney injury (AKI) which, in turn, promotes CKD progression. This implies that CKD or the AKI-to-CKD transition are associated with dysfunctional kidney repair mechanisms. Current therapeutic options slow CKD progression but fail to treat or accelerate recovery from AKI and are unable to promote kidney regeneration. Unraveling the cellular and molecular mechanisms involved in kidney injury and repair, including the failure of this process, may provide novel biomarkers and therapeutic tools. We now review the contribution of different molecular and cellular events to the AKI-to-CKD transition, focusing on the role of macrophages in kidney injury, the different forms of regulated cell death and necroinflammation, cellular senescence and the senescence-associated secretory phenotype (SAPS), polyploidization, and podocyte injury and activation of parietal epithelial cells. Next, we discuss key contributors to repair of kidney injury and opportunities for their therapeutic manipulation, with a focus on resident renal progenitor cells, stem cells and their reparative secretome, certain macrophage subphenotypes within the M2 phenotype and senescent cell clearance.

Withdrawal of hospital outpatient treatments in severe diseases due to unacceptable toxicity: A retrospective study from the register of patients and treatments.

AIM: To retrospectively analyse hospital outpatient treatment (HOT) withdrawal due to unacceptable toxicity at our hospital. Information regarding unacceptable toxicity leading to treatment withdrawal was recorded. METHODS: HOT interruptions because of unacceptable toxicity were identified from the Register of Patients and Treatments (RPT) (January 2014 to December 2017). Information regarding the demographic and clinical characteristics of patients, adverse drug reactions (ADRs) and drug treatments was retrieved from electronic health records. Causality and previous knowledge of ADRs were assessed according to the Spanish Pharmacovigilance System algorithm. Information regarding HOT risk management plans (RMPs) and their classification as inverted black triangle medicines was obtained from the European Medicines Agency (EMA). RESULTS: HOTs were withdrawn due to unacceptable toxicity in 136 (1.5%) registries corresponding to 135 (1.7%) patients. Fifty-one different HOTs (38.6% of those registered) were involved in 240 ADR/HOT pairs: 24 (47%) were additional monitoring medicines and 37 (72.5%) were EMA RMPs. The most frequent medicines involved in ADRs were lenalidomide (30, 12.5%) (mainly neutropenia, thrombocytopenia and bicytopenia), bevacizumab (19, 7.9%) (mainly venous and pulmonary thromboembolism) and sunitinib (13, 5.4%) (mainly thromboembolic events, diarrhoea and worsening of chronic renal failure). Cytopenia (40, 17.3%), diarrhoea (15, 6.5%), asthenia (9, 3.9%) and neuropathy (6, 2.6%) were the most frequent ADRs. All ADRs were severe, 10 (6 patients) had been poorly described or were unknown and only 9 (5 patients) had been reported by spontaneous notification. CONCLUSIONS: Valuable information regarding severe and unknown ADRs was obtained from the RPT. Such registers are useful tools to complement spontaneous ADR notifications.

Drug-induced gambling disorder: A not so rare but underreported condition.

The widespread use of dopaminergic agents for the treatment of Parkinson's disease has revealed the presence of gambling disorder (GD) as an uncommon, but serious, adverse reaction to these agents. We describe the main characteristics of drug-induced GD reports received by the Spanish Pharmacovigilance System during the period from 1983 to 2016. Fifteen reports of GD have been identified. Dopaminergic agonists, especially pramipexole, are the main drugs involved in inducing GD. Physicians prescribing these drugs should warn patients and families about this disorder. Knowledge of this disorder will encourage early diagnosis, treatment, and reporting of this clinically and socially relevant disorder.

Comprehensive analysis of three TYK2 gene variants in the susceptibility to Chagas disease infection and cardiomyopathy.

Tyrosine kinase 2 (TYK2) is a member of the Janus kinases family implicated in the signal transduction of type I interferons and several interleukins. It has been described that genetic mutations within TYK2 lead to multiple deleterious effects in the immune response. In this work, we have analyzed three functional independent variants from the frequency spectrum on the TYK2 gene (common and low-frequency variants) suggested to reduce the function of the gene in mediating cytokine signaling and the susceptibility to infections by Trypanosoma cruzi and/or the development of Chagas cardiomyopathy in the Colombian population. A total of 1,323 individuals from a Colombian endemic region for Chagas disease were enrolled in the study. They were classified as seronegative (n = 445), seropositive asymptomatic (n = 336), and chronic Chagas Cardiomyopathy subjects (n = 542). DNA samples were genotyped using TaqMan probes. Our results showed no statistically significant differences between the allelic frequencies of the three analyzed variants when seropositive and seronegative individuals were compared, therefore these variants were not associated with susceptibility to Chagas disease. Moreover, when Chagas cardiomyopathy patients were compared to asymptomatic patients, no significant associations were found. Previous reports highlighted the association of this gene in immune-related disorders under an autoimmunity context, but not predisposing patients to infectious diseases, which is consistent with our findings. Therefore, according to our results, TYK2 gene variants do not seem to play an important role in Chagas disease susceptibility and/or chronic Chagas cardiomyopathy.

Epigenetic Modification Mechanisms Involved in Inflammation and Fibrosis in Renal Pathology.

The growing incidence of obesity, hypertension, and diabetes, coupled with the aging of the population, is increasing the prevalence of renal diseases in our society. Chronic kidney disease (CKD) is characterized by persistent inflammation, fibrosis, and loss of renal function leading to end-stage renal disease. Nowadays, CKD treatment has limited effectiveness underscoring the importance of the development of innovative therapeutic options. Recent studies have identified how epigenetic modifications participate in the susceptibility to CKD and have explained how the environment interacts with the renal cell epigenome to contribute to renal damage. Epigenetic mechanisms regulate critical processes involved in gene regulation and downstream cellular responses. The most relevant epigenetic modifications that play a critical role in renal damage include DNA methylation, histone modifications, and changes in miRNA levels. Importantly, these epigenetic modifications are reversible and, therefore, a source of potential therapeutic targets. Here, we will explain how epigenetic mechanisms may regulate essential processes involved in renal pathology and highlight some possible epigenetic therapeutic strategies for CKD treatment.

Riesgo de hipercalcemia e hipervitaminosis D por calcifediol. Revisión de casos notificados al Sistema Español de Farmacovigilancia / Risk of hypercalcemia and hipervitaminosis D induced by calcifediol. Review of cases reported to the Spanish Pharmacovigilance System

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