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Chronic kidney disease (CKD) incidence is growing worldwide, with a significant percentage of CKD patients reaching end-stage renal disease (ESRD) and requiring kidney replacement therapies (KRT). Peritoneal dialysis (PD) is a convenient KRT presenting benefices as home therapy. In PD patients, the peritoneum is chronically exposed to PD fluids containing supraphysiologic concentrations of glucose or other osmotic agents, leading to the activation of cellular and molecular processes of damage, including inflammation and fibrosis. Importantly, peritonitis episodes enhance peritoneum inflammation status and accelerate peritoneal injury. Here, we review the role of immune cells in the damage of the peritoneal membrane (PM) by repeated exposure to PD fluids during KRT as well as by bacterial or viral infections. We also discuss the anti-inflammatory properties of current clinical treatments of CKD patients in KRT and their potential effect on preserving PM integrity. Finally, given the current importance of coronavirus disease 2019 (COVID-19) disease, we also analyze here the implications of this disease in CKD and KRT. [ABSTRACT FROM AUTHOR]

Although antiretroviral therapy (ART) has increased life expectancy in people with HIV-1 (PWH), acute and chronic kidney disease remain common in this population and are associated with poor outcomes. A broad spectrum of kidney disorders can be observed in PWH, some of which are directly related to intrarenal HIV infection and gene expression. HIV-associated nephropathy (HIVAN) was the most common kidney disease in PWH before ART became available. Animal models and human biopsy studies established the causal relationships between direct HIV-1 infection of renal epithelial cells and HIVAN, expression of viral genes in renal epithelial cells, and dysregulation of host genes involved in cell differentiation and cell cycle. In this review, we provide a summary of the body of work demonstrating HIV-1 infection of epithelial cells in the kidney and recent advancements in the understanding of viral entry mechanisms and consequences of HIV-1 gene expression in those cells. [ABSTRACT FROM AUTHOR]

During hemorrhagic shock, blood loss causes a fall in blood pressure, decreases cardiac output, and, consequently, O2 transport. The current guidelines recommend the administration of vasopressors in addition to fluids to maintain arterial pressure when life-threatening hypotension occurs in order to prevent the risk of organ failure, especially acute kidney injury. However, different vasopressors exert variable effects on the kidney, depending on the nature and dose of the substance chosen as follows: Norepinephrine increases mean arterial pressure both via its α-1-mediated vasoconstriction leading to increased systemic vascular resistance and its β1-related increase in cardiac output. Vasopressin, through activation of V1-a receptors, induces vasoconstriction, thus increasing mean arterial pressure. In addition, these vasopressors have the following different effects on renal hemodynamics: Norepinephrine constricts both the afferent and efferent arterioles, whereas vasopressin exerts its vasoconstrictor properties mainly on the efferent arteriole. Therefore, this narrative review discusses the current knowledge of the renal hemodynamic effects of norepinephrine and vasopressin during hemorrhagic shock. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury is a frequent consequence among intensive care unit cases with severe illness (ICU). It is currently considered that the incidence of acute kidney injury is substantially higher than previously anticipated, with over fifty percent of ICU cases having acute kidney injury at some stage during critical illness. More than fifty percent of ICU cases with acute kidney injury and multiorgan failure are reported to die. Those requiring renal replacement treatment (RRT) have a mortality rate of up to 80 percent. Acute kidney injury is defined by an abrupt, hours-to-days-long decline in kidney function, leading in the buildup of waste products. Objective: This review article aimed to assess and examine Cases in ICU with acute kidney injury. Methods: A comprehensive search was conducted in PubMed, Google Scholar, and Science Direct for information on acute kidney injury, ICU, Kidney, Liver function and RRT. However, only the most current or comprehensive study from May 2011 to November 2022 was considered. The authors also assessed references from pertinent literature. Documents in languages other than English have been disregarded since there are not enough resources for translation. Unpublished manuscripts, oral presentations, conference abstracts, and dissertations were examples of papers that were not considered to be serious scientific research. Conclusion: Acute kidney injury is responsible for poor outcome in hospitalised cases. In critical cases, the underlying cause of acute kidney injury is renal hypoperfusion during shock episodes. Therefore, prevention is the most effective therapy. [ABSTRACT FROM AUTHOR]

The study of transient receptor potential (TRP) channels has dramatically increased during the past few years. TRP channels function as sensors and effectors in the cellular adaptation to environmental changes. Here, we review literature investigating the physiological and pathophysiological roles of TRPC channels in the renal tubular system with a focus on TRPC3 and TRPC6. TRPC3 plays a key role in Ca2+ homeostasis and is involved in transcellular Ca2+ reabsorption in the proximal tubule and the collecting duct. TRPC3 also conveys the osmosensitivity of principal cells of the collecting duct and is implicated in vasopressin-induced membrane translocation of AQP-2. Autosomal dominant polycystic kidney disease (ADPKD) can often be attributed to mutations of the PKD2 gene. TRPC3 is supposed to have a detrimental role in ADPKD-like conditions. The tubule-specific physiological functions of TRPC6 have not yet been entirely elucidated. Its pathophysiological role in ischemia-reperfusion injuries is a subject of debate. However, TRPC6 seems to be involved in tumorigenesis of renal cell carcinoma. In summary, TRPC channels are relevant in multiples conditions of the renal tubular system. There is a need to further elucidate their pathophysiology to better understand certain renal disorders and ultimately create new therapeutic targets to improve patient care. [ABSTRACT FROM AUTHOR]

Mitochondria have many forms and can change their shape through fusion and fission of the outer and inner membranes, called "mitochondrial dynamics". Mitochondrial outer membrane proteins, such as mitochondrial fission protein 1 (FIS1), mitochondrial fission factor (MFF), mitochondrial 98 dynamics proteins of 49 kDa (MiD49), and mitochondrial dynamics proteins of 51 kDa (MiD51), can aggregate at the outer mitochondrial membrane and thus attract Dynamin-related protein 1 (DRP1) from the cytoplasm to the outer mitochondrial membrane, where DRP1 can perform a scissor-like function to cut a complete mitochondrion into two separate mitochondria. Other organelles can promote mitochondrial fission alongside mitochondria. FIS1 plays an important role in mitochondrial–lysosomal contacts, differentiating itself from other mitochondrial-fission-associated proteins. The contact between the two can also induce asymmetric mitochondrial fission. The kidney is a mitochondria-rich organ, requiring large amounts of mitochondria to produce energy for blood circulation and waste elimination. Pathological increases in mitochondrial fission can lead to kidney damage that can be ameliorated by suppressing their excessive fission. This article reviews the current knowledge on the key role of mitochondrial-fission-associated proteins in the pathogenesis of kidney injury and the role of their various post-translational modifications in activation or degradation of fission-associated proteins and targeted drug therapy. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a complex and multifactorial disease, and one of the most prevalent worldwide. Chronic kidney disease–mineral bone disorders (CKD–MBD) with biochemical and hormonal alterations are part of the complications associated with the progression of CKD. Pathophysiology of CKD–MBD focused on abnormalities in serum levels of several biomarkers (such as FGF-23, klotho, phosphate, calcium, vitamin D, and PTH) which are discussed in this review. We therefore examine the prognostic association between CKD–MBD and the increased risk for cardiovascular events, mortality, and CKD progression to end-stage kidney disease (ESKD). Lastly, we present specific treatments acting on CKD to prevent and treat the complications associated with secondary hyperparathyroidism (SHPT): control of hyperphosphatemia (with dietary restriction, intestinal phosphate binders, and adequate dialysis), the use of calcimimetic agents, vitamin D, and analogues, and the use of bisphosphonates or denosumab in patients with osteoporosis. [ABSTRACT FROM AUTHOR]

Kidneys maintain internal milieu homeostasis through a well-regulated manipulation of body fluid composition. This task is performed by the correlation between structure and function in the nephron. Kidney diseases are chronic conditions impacting healthcare programs globally, and despite efforts, therapeutic options for its treatment are limited. The development of chronic degenerative diseases is associated with changes in protein O-GlcNAcylation, a post-translation modification involved in the regulation of diverse cell function. O-GlcNAcylation is regulated by the enzymatic balance between O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) which add and remove GlcNAc residues on target proteins, respectively. Furthermore, the hexosamine biosynthetic pathway provides the substrate for protein O-GlcNAcylation. Beyond its physiological role, several reports indicate the participation of protein O-GlcNAcylation in cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the impact of protein O-GlcNAcylation on physiological renal function, disease conditions, and possible future directions in the field. [ABSTRACT FROM AUTHOR]

The Na+/H+ exchanger transporters (NHE) play an important role in various biologic processes including Na+ absorption, intracellular pH homeostasis, cell volume regulation, proliferation, and apoptosis. The wide expression pattern and cellular localization of NHEs make these proteins pivotal players in virtually all human tissues and organs. In addition, recent studies suggest that NHEs may be one of the primeval transport protein forms in the history of life. Among the different isoforms, the most well-characterized NHEs are the Na+/H+ exchanger isoform 1 (NHE1) and Na+/H+ exchanger isoform 3 (NHE3). However, Na+/H+ exchanger isoform 8 (NHE8) has been receiving attention based on its recent discoveries in the gastrointestinal tract. In this review, we will discuss what is known about the physiological function and potential role of NHE8 in the main organ systems, including useful overviews that could inspire new studies on this multifaceted protein. [ABSTRACT FROM AUTHOR]

Sepsis is a critical condition characterized by increased levels of pro-inflammatory cytokines and proliferating cells such as neutrophils and macrophages in response to microbial pathogens. Such processes lead to an abnormal inflammatory response and multi-organ failure. MicroRNAs (miRNA) are single-stranded non-coding RNAs with the function of gene regulation. This means that miRNAs are involved in multiple intracellular pathways and thus contribute to or inhibit inflammation. As a result, their variable expression in different tissues and organs may play a key role in regulating the pathophysiological events of sepsis. Thanks to this property, miRNAs may serve as potential diagnostic and prognostic biomarkers in such life-threatening events. In this narrative review, we collect the results of recent studies on the expression of miRNAs in heart, blood, lung, liver, brain, and kidney during sepsis and the molecular processes in which they are involved. In reviewing the literature, we find at least 122 miRNAs and signaling pathways involved in sepsis-related organ dysfunction. This may help clinicians to detect, prevent, and treat sepsis-related organ failures early, although further studies are needed to deepen the knowledge of their potential contribution. [ABSTRACT FROM AUTHOR]

The advances in transplant immunosuppression have reduced substantially the incidence of kidney graft rejection. In recent years, the focus has moved from preventing rejection to preventing the long-term consequences of long-standing immunosuppression, including nephrotoxicity induced by calcineurin inhibitors (CNI), as well as infectious and neoplastic complications. Since the appearance in the late 1990s of mTOR inhibitors (mTORi), these unmet needs in immunosuppression management could be addressed thanks to their benefits (reduced rate of viral infections and cancer). However, management of side effects can be troublesome and hands-on experience is needed. Here, we review all the available information about them. Thanks to all the basic, translational and clinical research achieved in the last twenty years, we now use mTORi as de novo immunosuppression in association with CNI. Another possibility is represented by the conversion of either CNI or mycophenolate (MPA) to an mTORi later on after transplantation in low-risk kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Normal processes of embryonic development and abnormal transformation to cancer have many parallels, and in fact many aberrant cancer cell capabilities are embryonic traits restored in a distorted, unorganized way. Some of these capabilities are cell autonomous, such as proliferation and resisting apoptosis, while others involve a complex interplay with other cells that drives significant changes in neighboring cells. The correlation between embryonic development and cancer is driven by shared proteins. Some embryonic proteins disappear after embryogenesis in adult differentiated cells and are restored in cancer, while others are retained in adult cells, acquiring new functions upon transformation to cancer. Many embryonic factors embraced by cancer cells are transcription factors; some are master regulators that play a major role in determining cell fate. The paired box (PAX) domain family of developmental transcription factors includes nine members involved in differentiation of various organs. All paired box domain proteins are involved in different cancer types carrying pro-tumorigenic or anti-tumorigenic roles. This review focuses on PAX8, a master regulator of transcription in embryonic development of the thyroid, kidney, and male and female genital tracts. We detail the role of PAX8 in each of these organ systems, describe its role during development and in the adult if known, and highlight its pro-tumorigenic role in cancers that emerge from PAX8 expressing organs. [ABSTRACT FROM AUTHOR]

An adverse outcome pathway (AOP) is a conceptual construct of causally and sequentially linked events, which occur during exposure to stressors, with an adverse outcome relevant to risk assessment. The development of an AOP is a means of identifying knowledge gaps in order to prioritize research assessing the health risks associated with exposure to physical or chemical stressors. In this paper, a review of knowledge was proposed, examining experimental and epidemiological data, in order to identify relevant key events and potential key event relationships in an AOP for renal impairment, relevant to stressors such as uranium (U). Other stressors may promote similar pathways, and this review is a necessary step to compare and combine knowledge reported for nephrotoxicants. U metal ions are filtered through the glomerular membrane of the kidneys, then concentrate in the cortical and juxtaglomerular areas, and bind to the brush border membrane of the proximal convoluted tubules. U uptake by epithelial cells occurs through endocytosis and the sodium-dependent phosphate co-transporter (NaPi-IIa). The identified key events start with the inhibition of the mitochondria electron transfer chain and the collapse of mitochondrial membrane potential, due to cytochrome b5/cytochrome c disruption. In the nucleus, U directly interacts with negatively charged DNA phosphate, thereby inducing an adduct formation, and possibly DNA strand breaks or cross-links. U also compromises DNA repair by inhibiting zing finger proteins. Thereafter, U triggers the Nrf2, NF-κB, or endoplasmic reticulum stress pathways. The resulting cellular key events include oxidative stress, DNA strand breaks and chromosomal aberrations, apoptosis, and pro-inflammatory effects. Finally, the main adverse outcome is tubular damage of the S2 and S3 segments of the kidneys, leading to tubular cell death, and then kidney failure. The attribution of renal carcinogenesis due to U is controversial, and specific experimental or epidemiological studies must be conducted. A tentative construction of an AOP for uranium-induced kidney toxicity and failure was proposed. [ABSTRACT FROM AUTHOR]

Advances in aging studies brought about by heterochronic parabiosis suggest that aging might be a reversable process that is affected by changes in the systemic milieu of organs and cells. Given the broadness of such a systemic approach, research to date has mainly questioned the involvement of "shared organs" versus "circulating factors". However, in the absence of a clear understanding of the chronological development of aging and a unified platform to evaluate the successes claimed by specific rejuvenation methods, current literature on this topic remains scattered. Herein, aging is assessed from an engineering standpoint to isolate possible aging potentiators via a juxtaposition between biological and mechanical systems. Such a simplification provides a general framework for future research in the field and examines the involvement of various factors in aging. Based on this simplified overview, the kidney as a filtration organ is clearly implicated, for the first time, with the aging phenomenon, necessitating a re-evaluation of current rejuvenation studies to untangle the extent of its involvement and its possible role as a potentiator in aging. Based on these findings, the review concludes with potential translatable and long-term therapeutics for aging while offering a critical view of rejuvenation methods proposed to date. [ABSTRACT FROM AUTHOR]

The seminal studies conducted by Giebisch and coworkers in the 1960s paved the way for understanding the renal mechanisms involved in Kþ homeostasis. It was demonstrated that differential handling of Kþ in the distal segments of the nephron is crucial for proper Kþ balance. Although aldosterone had been classically ascribed as the major ion transport regulator in the distal nephron, thereby contributing to Kþ homeostasis, it became clear that aldosterone per se could not explain the ability of the kidney to modulate kaliuresis in both acute and chronic settings. The existence of alternative kaliuretic and antikaliuretic mechanisms was suggested by physiological studies in the 1980s but only gained form and shape with the advent of molecular biology. It is now established that the kidneys recruit several endocrine and paracrine mechanisms for adequate kaliuretic response. These mechanisms include the direct effects of peritubular Kþ, a gut-kidney regulatory axis sensing dietary Kþ levels, the kidney secretion of kallikrein during postprandial periods, the upregulation of angiotensin II receptors in the distal nephron during chronic changes in Kþ diet, and the local increase of prostaglandins by low-Kþ diet. This review discusses recent advances in the understanding of endocrine and paracrine mechanisms underlying the modulation of Kþ secretion and how these mechanisms impact kaliuresis and Kþ balance. We also highlight important unknowns about the regulation of renal Kþ excretion under physiological circumstances. [ABSTRACT FROM AUTHOR]

Kidneys, one of the vital organs in our body, are responsible for maintaining whole body homeostasis. The complexity of renal function (e.g., filtration, reabsorption, fluid and electrolyte regulation, and urine production) demands diversity not only at the level of cell types but also in their overall distribution and structural framework within the kidney. To gain an in depth molecularlevel understanding of the renal system, it is imperative to discern the components of kidney and the types of cells residing in each of the subregions. Recent developments in labeling, tracing, and imaging techniques have enabled us to mark, monitor, and identify these cells in vivo with high efficiency in a minimally invasive manner. In this review, we summarize different cell types, specific markers that are uniquely associated with those cell types, and their distribution in the kidney, which altogether make kidneys so special and different. Cellular sorting based on the presence of certain proteins on the cell surface allowed for the assignment of multiple markers for each cell type. However, different studies using different techniques have found contradictions in cell type-specific markers. Thus, the term "cell marker" might be imprecise and suboptimal, leading to uncertainty when interpreting the data. Therefore, we strongly believe that there is an unmet need to define the best cell markers for a cell type. Although the compendium of renal-selective marker proteins presented in this review is a resource that may be useful to researchers, we acknowledge that the list may not be necessarily exhaustive. [ABSTRACT FROM AUTHOR]

We performed a systematic review and meta-analysis to examine the relationship between heavy metals (HMs) exposure and the risk of chronic kidney disease (CKD). Databases of Web of Science, Embase, MEDLINE, and Scopus were searched through June 2020 to identify studies assessing the relationships between exposure to HMs (i.e. cadmium, lead, arsenic, mercury) and the risk of CKD, evaluated by decreased estimated glomerular filtration rate (eGFR) and/or increased proteinuria risks in adults (≥18 years). Data were pooled by random-effects models and expressed as weighted mean differences and 95% confidence intervals. The risk of bias was assessed by the Newcastle–Ottawa scale (NOS). Twenty-eight eligible articles (n = 107,539 participants) were included. Unlike eGFR risk (p = 0.10), Cadmium exposure was associated with an increased proteinuria risk (OR = 1.35; 95% CI: 1.13, 1.61; p < 0.001; I2 = 79.7%). Lead exposure was associated with decreased eGFR (OR = 1.12; 95%CI: 1.03, 1.22; p = 0.008; I2 = 87.8%) and increased proteinuria (OR = 1.25; 95% CI: 1.04, 1.49; p = 0.02; I2 = 79.6) risks. Further, arsenic exposure was linked to a decreased eGFR risk (OR = 1.55; 95% CI: 1.05, 2.28; p = 0.03; I2 = 89.1%) in contrast to mercury exposure (p = 0.89). Only two studies reported the link between arsenic exposure and proteinuria risk, while no study reported the link between mercury exposure and proteinuria risk. Exposure to cadmium, lead, and arsenic may increase CKD risk in adults, albeit studies were heterogeneous, warranting further investigations. Our observations support the consideration of these associations for preventative, diagnostic, monitoring, and management practices of CKD. [ABSTRACT FROM AUTHOR]

Melanocortin hormone system plays a key role in maintaining the homeostasis of our body via their neuro-immune-endocrine activities and regulates a diverse array of physiological functions, including melanogenesis, inflammation, immunomodulation, adrenocortical steroidogenesis, hemodynamics, natriuresis, energy homeostasis, sexual function, and exocrine secretion. The pathobiologic actions of all melanocortins are conveyed by melanocortin receptors. As the last melanocortin receptor to be cloned and characterized, melanocortin receptor 5 (MC5R) is widely expressed in both central nervous system and a number of peripheral organ systems in man. However, the exact effect of the MC5R mediated melanocortinergic signaling remains largely uncertain. Owing to the recent advances in developing highly selective peptidomimetic agonists and antagonists of MC5R and also to studies in MC5R knockout animals, our understanding of MC5R pathobiology has been greatly expanded and strengthened. Evidence suggests that MC5R plays a key role in governing immune reaction and inflammatory response, and is pivotal for the regulation of sexual behavior, thermoregulation, and exocrine secretion, like sebogenesis, lacrimal secretion and release of sex pheromones. As such, recent translational efforts have focused on developing novel sebum-suppressive therapies for seborrhoea and acne vulgaris based on antagonizing MC5R. Conversely, selective MC5R agonists have demonstrated promising beneficial effects in immune-mediated diseases, metabolic endocrinopathies and other disease conditions, such as glomerular diseases and dry eyes, skin and mouth. Thus, MC5R-mediated signaling is essential for health. Therapeutic targeting of MC5R represents a promising and pragmatic therapeutic strategy for diverse diseases. This review article delineates the biophysiology of MC5R-mediated biophysiology of the melanocortin hormone system, discusses the existing data on MC5R-targeted therapy in experimental disease models, and envisages the translational potential for treating human diseases. [ABSTRACT FROM AUTHOR]

Influx and efflux kidney tubular transporters are major determinants of the disposition of xenobiotics, including pharmaceutical drugs. On the basolateral membrane of proximal tubular cells, there are influx transporters, such as organic cation transporters. On the apical membrane of proximal tubular cells, there are efflux transporters, such as multidrug and toxin extrusion proteins. The secretion process across the apical membrane into the lumen occurs via efflux transporters which plays an important role in serum creatinine (sCr) elimination in urine. The interference of a pharmaceutical drug with transporters can lead to changes in sCr with no alterations in biomarkers or light microscopic evidence indicative of renal injury. Identification of transporters that influence drug disposition, toxicity, and overall nonclinical safety assessment is important in drug discovery and development programs. This mini review describes some key aspects of kidney tubular transporters and drug-induced renal toxicities in safety risk assessment and drug development. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury of the kidney is caused by the sudden and temporary obstruction of blood flow to the organ. Renal ischemia-reperfusion injury is associated with high morbidity and mortality, but effective therapies are lacking. Sexual dimorphism in renal injury has been acknowledged since the 1940s, and the possible role of sex hormones has been intensively investigated in the past decades. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism of renal ischemia-reperfusion injury, with emphasis on molecular mechanisms and potential novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Opportunistic infections, and in particular tuberculosis (TB), carry substantial morbidity and mortality in solid organ transplant recipients. We report a 39-year-old man who underwent a cadaveric renal transplant. Three months postoperatively, he was diagnosed to have tuberculous infection of his graft kidney manifested as fever and renal impairment. The diagnosis was confirmed by renal biopsy, which showed granuloma formation and positive stain for acid-fast bacilli (AFB). His systemic symptoms responded well to a complete course of anti-tuberculous therapy, but his renal function continued to deteriorate. Graft nephrectomy was performed and the patient underwent a second kidney transplant 1 year later. He remained well and a symptomatic thereafter. No signs of recurrence of tuberculous infection were noted up until the present time. This case illustrates that TB remains an important threat to transplant recipients. Although reactivation of dormant TB is the usual mode of infection, acquisition from the donor graft is also possible. The latter may account for the infection in our case, as our patient had a negative tuberculin skin test and normal chest radiograph prior to transplant. The identification of AFB in the kidney graft less than 3 months postoperatively also suggested that causal relationship. While diagnosing TB in post-transplant recipients is difficult and may require renal biopsy, as in our case, treatment on the other hand is no different from the standard protocols. However, no consensus has been reached on the safety of retransplantation. Also, the need for graft nephrectomy and chemoprophylaxis remains unclear. [ABSTRACT FROM AUTHOR]