SGLT2 inhibition to target kidney aging.

Anti-aging therapy is the latest frontier in the world of medical science, especially for widespread diseases such as chronic kidney disease (CKD). Both renal aging and CKD are characterized by increased cellular senescence, inflammation and oxidative stress. A variety of cellular signalling mechanisms are involved in these processes, which provide new potential targets for therapeutic strategies aimed at counteracting the onset and progression of CKD. At the same time, sodium-glucose co-transporter 2 inhibitors (SGLT2is) continuously demonstrate large beneficial effects at all stages of the cardiorenal metabolic continuum. The broad-spectrum benefits of SGLT2is have led to changes in several treatment guidelines and to growing scientific interest in the underlying working principles. Multiple mechanisms have been studied to explain these great renal benefits, but many things remain to be solved. With this in mind, we provide an overview of the experimental evidence for the effects of SGLT2is on the molecular pathway's ability to modulate senescence, aging and parenchymal damage, especially at the kidney level. We propose to shed some light on the role of SGLT2is in kidney care by focusing on their potential to reduce the progression of kidney disease across the spectrum of aging and dysregulation of senescence.

SA-ß-Gal in Kidney Tubules as a Predictor of Renal Outcome in Patients with Chronic Kidney Disease.

Cellular senescence has emerged as an important driver of aging and age-related disease in the kidney. The activity of ß-galactosidase at pH 6 (SA-ß-Gal) is a classic maker of senescence in cellular biology; however, the predictive role of kidney tissue SA-ß-Gal on eGFR loss in chronic kidney disease (CKD) is still not understood. We retrospectively studied the expression of SA-ß-Gal in kidney biopsies obtained in a cohort [n = 22] of incident patients who were followed up for 3 years as standard of care. SA-ß-Gal staining was approximately fourfold higher in the tubular compartment of patients with CKD vs. controls [26.0 ± 9 vs. 7.4 ± 6% positive tubuli in patients vs. controls; p < 0.025]. Tubular expressions of SA-ß-Gal, but not proteinuria, at the time of biopsy correlated with eGFR loss at the follow up; moreover, SA-ß-Gal expression in more than 30% of kidney tubules was associated with fast progressive kidney disease. In conclusion, our study shows that SA-ß-Gal is upregulated in the kidney tubular compartment of adult patients affected by CKD and suggests that tubular SA-ß-Gal is associated with accelerated loss of renal function.

Diagnosing Fabry nephropathy: the challenge of multiple kidney disease.

Fabry disease (FD) is an X-linked inherited lysosomal disorder due to a deficiency of the enzyme alpha-galactosidase A (α-gla) due to mutations in the GLA gene. These mutations result in plasma and lysosome accumulation of glycosphingolipids, leading to progressive organ damage and reduced life expectancy. Due to the availability of specific disease-modifying treatments, proper and timely diagnosis and therapy are essential to prevent irreversible complications. However, diagnosis of FD is often delayed because of the wide clinical heterogeneity of the disease and multiple organ involvement developing in variable temporal sequences. This observation is also valid for renal involvement, which may manifest with non-specific signs, such as proteinuria and chronic kidney disease, which are also common in many other nephropathies. Moreover, an additional confounding factor is the possibility of the coexistence of FD with other kidney disorders. Thus, suspecting and diagnosing FD nephropathy in patients with signs of kidney disease may be challenging for the clinical nephrologist. Herein, also through the presentation of a unique case of co-occurrence of autosomal dominant polycystic kidney disease and FD, we review the available literature on cases of coexistence of FD and other renal diseases and discuss the implications of these conditions. Moreover, we highlight the clinical, laboratory, and histological elements that may suggest clinical suspicion and address a proper diagnosis of Fabry nephropathy.

The Contribution of Muscle Innate Immunity to Uremic Cachexia.

Protein energy wasting (PEW) is a common complication both in chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Of note, PEW is one of the stronger predictors of morbidity and mortality in this patient population. The pathogenesis of PEW involves several mechanisms, including anorexia, insulin resistance, acidosis and low-grade inflammation. In addition, "sterile" muscle inflammation contributes to PEW at an advanced CKD stage. Both immune and resident muscle cells can activate innate immunity; thus, they have critical roles in triggering "sterile" tissue inflammation. Toll-like receptor 4 (TLR4) can detect endogenous danger-associated molecular patterns generated or retained in blood in uremia and induce a sterile muscle inflammatory response via NF-κB in myocytes. In addition, TLR4, though the activation of the NLRP3 inflammasome, links the sensing of metabolic uremic stress in muscle to the activation of pro-inflammatory cascades, which lead to the production of IL-1ß and IL-18. Finally, uremia-induced accelerated cell senescence is associated with a secretory phenotype that favors fibrosis in muscle. Targeting these innate immune pathways could lead to novel therapies for CKD-related PEW.

Combined extracorporeal CO2 removal and renal replacement therapy in a pregnant patient with COVID-19: a case report.

Background. Pregnant women are at high risk of Coronavirus disease 2019 (COVID-19) complications, including acute respiratory distress syndrome. Currently, one of the cornerstones in the treatment of this condition is lung-protective ventilation (LPV) with low tidal volumes. However, the occurrence of hypercapnia may limit this ventilatory strategy. So, different extracorporeal CO2 removal (ECCO2R) procedures have been developed. ECCO2R comprises a variety of techniques, including low-flow and high-flow systems, that may be performed with dedicated devices or combined with continuous renal replacement therapy (CRRT). Case description. Here, we report a unique case of a pregnant patient affected by COVID-19 who required extracorporeal support for multiorgan failure. While on LPV, because of the concomitant hypercapnia and acute kidney injury, the patient was treated with an ECCO2R membrane inserted in series after a hemofilter in a CRRT platform. This combined treatment reducing hypercapnia allowed LPV maintenance at the same time while providing kidney replacement and ensuring maternal and fetal hemodynamic stability. Adverse effects consisted of minor bleeding episodes due to the anticoagulation required to maintain the extracorporeal circuit patency. The patient's pulmonary and kidney function progressively recovered, permitting the withdrawal of any extracorporeal treatment. At the 25th gestational week, the patient underwent spontaneous premature vaginal delivery because of placental abruption. She gave birth to an 800-gram female baby, who three days later died because of multiorgan failure related to extreme prematurity. Conclusions. This case supports using ECCO2R-CRRT combined treatment as a suitable approach in the management of complex conditions, such as pregnancy, even in the case of severe COVID-19.

Role of Uric Acid in Vascular Remodeling: Cytoskeleton Changes and Migration in VSMCs.

The mechanisms by which hyperuricemia induces vascular dysfunction and contributes to cardiovascular disease are still debated. Phenotypic transition is a property of vascular smooth muscle cells (VSMCs) involved in organ damage. The aim of this study was to investigate the effects of uric acid (UA) on changes in the VSMC cytoskeleton, cell migration and the signals involved in these processes. MOVAS, a mouse VSMC line, was incubated with 6, 9 and 12 mg/dL of UA, angiotensin receptor blockers (ARBs), proteasome and MEK-inhibitors. Migration property was assessed in a micro-chemotaxis chamber and by phalloidin staining. Changes in cytoskeleton proteins (Smoothelin B (SMTB), alpha-Smooth Muscle Actin (αSMA), Smooth Muscle 22 Alpha (SM22α)), Atrogin-1 and MAPK activation were determined by Western blot, immunostaining and quantitative reverse transcription PCR. UA exposition modified SMT, αSMA and SM22α levels (p < 0.05) and significantly upregulated Atrogin-1 and MAPK activation. UA-treated VSMCs showed an increased migratory rate as compared to control cells (p < 0.001) and a re-arrangement of F-actin. Probenecid, proteasome inhibition and ARBs prevented the development of dysfunctional VSMC. This study shows, for the first time, that UA-induced cytoskeleton changes determine an increase in VSMC migratory rate, suggesting UA as a key player in vascular remodeling.

Extracorporeal Carbon Dioxide Removal: From Pathophysiology to Clinical Applications; Focus on Combined Continuous Renal Replacement Therapy.

Lung-protective ventilation (LPV) with low tidal volumes can significantly increase the survival of patients with acute respiratory distress syndrome (ARDS) by limiting ventilator-induced lung injuries. However, one of the main concerns regarding the use of LPV is the risk of developing hypercapnia and respiratory acidosis, which may limit the clinical application of this strategy. This is the reason why different extracorporeal CO2 removal (ECCO2R) techniques and devices have been developed. They include low-flow or high-flow systems that may be performed with dedicated platforms or, alternatively, combined with continuous renal replacement therapy (CRRT). ECCO2R has demonstrated effectiveness in controlling PaCO2 levels, thus allowing LPV in patients with ARDS from different causes, including those affected by Coronavirus disease 2019 (COVID-19). Similarly, the suitability and safety of combined ECCO2R and CRRT (ECCO2R-CRRT), which provides CO2 removal and kidney support simultaneously, have been reported in both retrospective and prospective studies. However, due to the complexity of ARDS patients and the limitations of current evidence, the actual impact of ECCO2R on patient outcome still remains to be defined. In this review, we discuss the main principles of ECCO2R and its clinical application in ARDS patients, in particular looking at clinical experiences of combined ECCO2R-CRRT treatments.

DNMT3A epigenetically regulates key microRNAs involved in epithelial-to-mesenchymal transition in prostate cancer.

Epithelial-to-mesenchymal transition (EMT) is involved in prostate cancer (PCa) metastatic progression, and its plasticity suggests epigenetic implications. Deregulation of DNA methyltransferases (DNMTs) and several microRNAs (miRNAs) plays a relevant role in EMT, but their interplay has not been clarified yet. In this study, we provide evidence that DNMT3A interaction with several miRNAs has a central role in an ex vivo EMT PCa model obtained via exposure of PC3 cells to conditioned media from cancer-associated fibroblasts. The analysis of the alterations of the miRNA profile shows that miR-200 family (miR-200a/200b/429, miR-200c/141), miR-205 and miR-203, known to modulate key EMT factors, are down-regulated and hyper-methylated at their promoters. DNMT3A (mainly isoform a) is recruited onto these miRNA promoters, coupled with the increase of H3K27me3/H3K9me3 and/or the decrease of H3K4me3/H3K36me3. Most interestingly, our results reveal the differential expression of two DNMT3A isoforms (a and b) during ex vivo EMT and a regulatory feedback loop between miR-429 and DNMT3A that can promote and sustain the transition towards a more mesenchymal phenotype. We demonstrate the ability of miR-429 to target DNMT3A 3'UTR and modulate the expression of EMT factors, in particular ZEB1. Survey of the PRAD-TCGA dataset shows that patients expressing an EMT-like signature are indeed characterized by down-regulation of the same miRNAs with a diffused hyper-methylation at miR-200c/141 and miR-200a/200b/429 promoters. Finally, we show that miR-1260a also targets DNMT3A, although it does not seem to be involved in EMT in PCa.