Acute kidney injury (AKI) is defined by a sudden loss of excretory kidney function. AKI is part of a range of conditions summarized as acute kidney diseases and disorders (AKD), in which slow ...deterioration of kidney function or persistent kidney dysfunction is associated with an irreversible loss of kidney cells and nephrons, which can lead to chronic kidney disease (CKD). New biomarkers to identify injury before function loss await clinical implementation. AKI and AKD are a global concern. In low-income and middle-income countries, infections and hypovolaemic shock are the predominant causes of AKI. In high-income countries, AKI mostly occurs in elderly patients who are in hospital, and is related to sepsis, drugs or invasive procedures. Infection and trauma-related AKI and AKD are frequent in all regions. The large spectrum of AKI implies diverse pathophysiological mechanisms. AKI management in critical care settings is challenging, including appropriate volume control, nephrotoxic drug management, and the timing and type of kidney support. Fluid and electrolyte management are essential. As AKI can be lethal, kidney replacement therapy is frequently required. AKI has a poor prognosis in critically ill patients. Long-term consequences of AKI and AKD include CKD and cardiovascular morbidity. Thus, prevention and early detection of AKI are essential.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Mesenchymal stem cells form a population of self-renewing, multipotent cells that can be isolated from several tissues. Multiple preclinical studies have demonstrated that the administration of ...exogenous MSC could prevent renal injury and could promote renal recovery through a series of complex mechanisms, in particular via immunomodulation of the immune system and release of paracrine factors and microvesicles. Due to their therapeutic potentials, MSC are being evaluated as a possible player in treatment of human kidney disease, and an increasing number of clinical trials to assess the safety, feasibility, and efficacy of MSC-based therapy in various kidney diseases have been proposed. In the present review, we will summarize the current knowledge on MSC infusion to treat acute kidney injury, chronic kidney disease, diabetic nephropathy, focal segmental glomerulosclerosis, systemic lupus erythematosus, and kidney transplantation. The data obtained from these clinical trials will provide further insight into safety, feasibility, and efficacy of MSC-based therapy in renal pathologies and allow the design of consensus protocol for clinical purpose.
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Increasing evidence has demonstrated the bidirectional link between acute kidney injury (AKI) and chronic kidney disease (CKD) such that, in the clinical setting, the new concept of a unified ...syndrome has been proposed. The pathophysiological reasons, along with the cellular and molecular mechanisms, behind the ability of a single, acute, apparently self-limiting event to drive chronic kidney disease progression are yet to be explained. This acute injury could promote progression to chronic disease through different pathways involving the endothelium, the inflammatory response and the development of fibrosis. The interplay among endothelial cells, macrophages and other immune cells, pericytes and fibroblasts often converge in the tubular epithelial cells that play a central role. Recent evidence has strengthened this concept by demonstrating that injured tubules respond to acute tubular necrosis through two main mechanisms: The polyploidization of tubular cells and the proliferation of a small population of self-renewing renal progenitors. This alternative pathophysiological interpretation could better characterize functional recovery after AKI.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The first case of the new coronavirus, COVID-19, was reported in China on 17 November 2019. By the end of March 2020, the rapid global spread of infection affected over 1 million people. Italy is one ...of the countries most impacted, with over 100,000 positive cases identified. The first detected cases were reported on 21 February 2020 in two Italian towns: Vo' Euganeo in the Province of Padua, Veneto region, and Codogno, in the Province of Lodi, Lombardy. In the next weeks the epidemic spread quickly across the country but mainly in the north of Italy. The two regions: Veneto and Lombardy, implemented different strategies to control the viral spread. In Veneto, health personnel tested both symptomatic and asymptomatic subjects, while in Lombardy only symptomatic cases were investigated. We analyzed the evolution of the epidemic in these regions and showed that testing both symptomatic and asymptomatic cases is a more effective strategy to mitigate the epidemic impact. We strongly recommend that decision-makers: ensure early isolation of symptomatic patients and rapid identification of their contacts; maximize testing rapidly, especially among people with multiple daily contacts with infected populations, high exposure to the public in essential services; rapidly increase diagnostic capacity by mobilizing trained personnel capable of performing rRT-PCR on respiratory samples; equip the population with protective masks.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Following kidney injury, repair can result in functional tissue becoming a patch of cells and disorganized extracellular matrix--a scar--or it can recapitulate the original tissue architecture ...through the process of regeneration. Regeneration can potentially occur in all animal species and humans. Indeed, the repair of portions of the existing nephron after tubular damage, a response that has been designated classically as cellular regeneration, is conserved in all animal species from the ancestral phases of evolution. By contrast, another type of regenerative response--nephron neogenesis--has been described in lower branches of the animal kingdom, but does not occur in adult mammals. Converging evidence suggests that a renal progenitor system is present in the adult kidney across different stages of evolution, with renal progenitors having been identified as the main drivers of kidney regenerative responses in fish, insects, rodents and humans. In this Review, we describe similarities and differences between the renal progenitor systems through evolution, and propose explanations for how progressive kidney adaptation to environmental changes both required and permitted neonephrogenesis to be given up and for cellular regeneration to be retained as the main regenerative strategy. Understanding the mechanisms that drive renal progenitor growth and differentiation represent the key step for modulating this potential for therapeutic purposes.
In acute organ failure, rapid compensation of function loss assures survival. Dedifferentiation and/or proliferation of surviving parenchymal cells could imply a transient (and potentially fatal) ...impairment of residual functional performance. However, evolution has selected two flexible life-saving mechanisms acting synergistically on organ function recovery. Sustaining residual performance is possible when the remnant differentiated parenchymal cells avoid cell division, but increase function by undergoing hypertrophy via endoreplication, leading to polyploid cells. In addition, tissue progenitors, representing a subset of less-differentiated and/or self-renewing parenchymal cells completing cytokinesis, proliferate and differentiate to regenerate lost parenchymal cells. Here, we review the evolving evidence on polyploidization and progenitor-driven regeneration in acute liver, heart, and kidney failure with evolutionary advantages and trade-offs in organ repair.
Acute injuries of heart, liver, and kidney, which present clinically as diverse syndromes, share numerous pathophysiological mechanisms. Survival of dedifferentiated parenchymal cells and/or widespread proliferation is often spoken of as a potential mechanism of repair for acute injuries. Recently, two types of responses after acute organ failure have appeared to be shared in the liver, heart, and kidney: (i) surviving differentiated parenchymal cells undergo cell hypertrophy via polyploidization; and (ii) a population of progenitors, mostly identified as resident, more immature diploid parenchymal cells, self-renew and differentiate to replace lost cells.
In order to guarantee uninterrupted life-saving functional performance after acute failure, essential organs such as the heart, liver, and kidney avoid widespread proliferation that would be largely counterproductive because it implies a transient loss of the specialized cellular functions. Therefore, these organs require polyploidization in order to sustain organ function.
In the liver, polyploidization after acute failure is the predominant but not the only response. Indeed, the increase in hepatocyte ploidy precedes the proliferation of diploid hepatocyte progenitors. Polyploidization of hepatocytes drives functional recovery, increasing the metabolic function in output, whereas, hepatocyte progenitor proliferation drives the restoration of liver mass by generating new hepatocytes.
In the heart, it is still debated whether newly generated cardiomyocytes originate from pre-existing cardiomyocytes that retain their proliferative capacity throughout adulthood or from a population of cardiomyocyte progenitors. Cardiomyocyte progenitors can proliferate following injury but this ability declines with aging in the mammalian heart. In the mammalian neonate the heart exhibits a high regenerative capacity due to the presence of diploid cardiomyocyte progenitors. In the mammalian adult heart, the regenerative capacity is almost lost and an increase of polyploidy results in scars in the long run.
In the kidney, polyploidization in response to injury, was known solely in podocytes. However, recent findings have demonstrated that injured tubules respond to acute tubular necrosis through two main mechanisms: (i) endoreplication-mediated hypertrophy of remnant tubular epithelial cells, aiming to sustain renal function despite significant epithelial cell necrosis; and (ii) survival and proliferation of tubular progenitors, aiming to replace tubular cell loss. Since polyploid cells mostly maintain a single nucleus, their identification has become feasible thanks to an advanced technology of cell cycle phase live imaging combined with DNA quantitation.
Benefits of polyploidization and proliferation associate with distinct trade-offs, including fibrosis, senescence, and cancer. Evolution has favored the coexistence of both mechanisms in the same organs, ensuring a correct self-balance of these responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
T helper (Th) 17 cells represent a novel subset of CD4+ T cells that are protective against extracellular microbes, but are responsible for autoimmune disorders in mice. However, their properties in ...humans are only partially known. We demonstrate the presence of Th17 cells, some of which produce both interleukin (IL)-17 and interferon (IFN)-gamma (Th17/Th1), in the gut of patients with Crohn's disease. Both Th17 and Th17/Th1 clones showed selective expression of IL-23R, CCR6, and the transcription factor ROR gamma t, and they exhibited similar functional features, such as the ability to help B cells, low cytotoxicity, and poor susceptibility to regulation by autologous regulatory T cells. Interestingly, these subsets also expressed the Th1-transcription factor T-bet, and stimulation of these cells in the presence of IL-12 down-regulated the expression of ROR gamma t and the production of IL-17, but induced IFN-gamma. These effects were partially inhibited in presence of IL-23. Similar receptor expression and functional capabilities were observed in freshly derived IL-17-producing peripheral blood and tonsillar CD4+ T cells. The demonstration of selective markers for human Th17 cells may help us to understand their pathogenic role. Moreover, the identification of a subset of cells sharing features of both Th1 and Th17, which can arise from the modulation of Th17 cells by IL-12, may raise new issues concerning developmental and/or functional relationships between Th17 and Th1.
Chemokines are a group of peptides of low molecular weight that induce the chemotaxis of different leukocyte subtypes. The major function of chemokines is the recruitment of leukocytes to ...inflammation sites, but they also play a role in tumoral growth, angiogenesis, and organ sclerosis. In the last few years, experimental evidence accumulated supporting the concept that interferon-γ (IFN-γ) inducible chemokines (CXCL9, CXCL10, and CXCL11) and their receptor, CXCR3, play an important role in the initial stage of autoimmune disorders involving endocrine glands. The fact that, after IFN-γ stimulation, endocrine epithelial cells secrete CXCL10, which in turn recruits type 1 T helper lymphocytes expressing CXCR3 and secreting IFN-γ, thus perpetuating autoimmune inflammation, strongly supports the concept that chemokines play an important role in endocrine autoimmunity. This article reviews the recent literature including basic science, animal models, and clinical studies, regarding the role of these chemokines in autoimmune endocrine diseases. The potential clinical applications of assaying the serum levels of CXCL10 and the value of such measurements are reviewed. Clinical studies addressing the issue of a role for serum CXCL10 measurement in Graves’ disease, Graves’ ophthalmopathy, chronic autoimmune thyroiditis, type 1 diabetes mellitus, and Addison’s disease have been considered. The principal aim was to propose that chemokines, and in particular CXCL10, should no longer be considered as belonging exclusively to basic science, but rather should be used for providing new insights in the clinical management of patients with endocrine autoimmune diseases.
Abstract
The important achievements in kidney physiological and pathophysiological mechanisms can largely be ascribed to progress in the technology of microscopy. Much of what we know about the ...architecture of the kidney is based on the fundamental descriptions of anatomic microscopists using light microscopy and later by ultrastructural analysis provided by electron microscopy. These two techniques were used for the first classification systems of kidney diseases and for their constant updates. More recently, a series of novel imaging techniques added the analysis in further dimensions of time and space. Confocal microscopy allowed us to sequentially visualize optical sections along the z-axis and the availability of specific analysis software provided a three-dimensional rendering of thicker tissue specimens. Multiphoton microscopy permitted us to simultaneously investigate kidney function and structure in real time. Fluorescence-lifetime imaging microscopy allowed to study the spatial distribution of metabolites. Super-resolution microscopy increased sensitivity and resolution up to nanoscale levels. With cryo-electron microscopy, researchers could visualize the individual biomolecules at atomic levels directly in the tissues and understand their interaction at subcellular levels. Finally, matrix-assisted laser desorption/ionization imaging mass spectrometry permitted the measuring of hundreds of different molecules at the same time on tissue sections at high resolution. This review provides an overview of available kidney imaging strategies, with a focus on the possible impact of the most recent technical improvements.
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