-
The Journal of Antimicrobial... Jan 2020Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and... (Review)
Review
Drug-induced nephrotoxicity is responsible for 20% to 60% of cases of acute kidney injury in hospitalized patients and is associated with increased morbidity and mortality in both children and adults. Antimicrobials are one of the most common classes of medications prescribed globally and also among the most common causes of nephrotoxicity. A broad range of antimicrobial agents have been associated with nephrotoxicity, but the features of kidney injury vary based on the agent, its mechanism of injury and the site of toxicity within the kidney. Distinguishing nephrotoxicity caused by an antimicrobial agent from other potential inciting factors is important to facilitate both early recognition of drug toxicity and prompt cessation of an offending drug, as well as to avoid unnecessary discontinuation of an innocuous therapy. This review will detail the different types of antimicrobial-induced nephrotoxicity: acute tubular necrosis, acute interstitial nephritis and obstructive nephropathy. It will also describe the mechanism of injury caused by specific antimicrobial agents and classes (vancomycin, aminoglycosides, polymyxins, antivirals, amphotericin B), highlight the toxicodynamics of these drugs and provide guidance on administration or monitoring practices that can mitigate toxicity, when known. Particular attention will be paid to paediatric patients, when applicable, in whom nephrotoxin exposure is an often-underappreciated cause of kidney injury.
Topics: Acute Kidney Injury; Anti-Infective Agents; Child; Humans; Kidney; Kidney Diseases; Nephritis, Interstitial
PubMed: 31369087
DOI: 10.1093/jac/dkz325 -
Journal of Nephrology Feb 2021The increased prevalence of chronic kidney disease (CKD) in elderly patients recognizes, as main cause, the long-term exposure to atherosclerosis and hypertension.... (Review)
Review
The increased prevalence of chronic kidney disease (CKD) in elderly patients recognizes, as main cause, the long-term exposure to atherosclerosis and hypertension. Chronic ischemic damage due to critical renal arterial stenosis induces oxidative stress and intra-renal inflammation, resulting in fibrosis and microvascular remodelling, that is the histological picture of atherosclerotic renal vascular disease (ARVD). The concomitant presence of a long history of hypertension may generate intimal thickening and luminal narrowing of renal arteries and arterioles, glomerulosclerosis, interstitial fibrosis and tubular atrophy, more typically expression of hypertensive nephropathy. These complex mechanisms contribute to the development of CKD and the progression to End Stage Kidney Disease. In elderly CKD patients, the distinction among these nephropathies may be problematic; therefore, ischemic and hypertensive nephropathies can be joined in a unique clinical syndrome defined as atherosclerotic nephropathy. The availability of novel diagnostic procedures, such as intra-vascular ultrasound and BOLD-MRI, in addition to traditional imaging, have opened new scenarios, because these tools allow to identify ischemic lesions responsive to renal revascularization. Indeed, although trials have deflated the role of renal revascularization on the renal outcomes, it should be still used to avoid dialysis initiation and/or to reduce blood pressure in selected elderly patients at high risk. Nonetheless, lifestyle modifications (smoking cessation, increased physical activity), statins and antiplatelet use, as well as cautious use of renin-angiotensin system inhibitors, remain the main therapeutic approach aimed at slowing the renal damage progression. Mesenchymal stem cells and Micro-RNA are promising target of anti-fibrotic therapy, which might provide potential benefit in ARVD patients, though safety and efficacy profile in humans is unknown too.
Topics: Aged; Atherosclerosis; Humans; Hypertension; Kidney; MicroRNAs; Renal Artery Obstruction; Renal Insufficiency, Chronic
PubMed: 32270411
DOI: 10.1007/s40620-020-00733-0 -
Frontiers in Immunology 2023Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of...
Excessive renal fibrosis is a common pathology in progressive chronic kidney diseases. Inflammatory injury and aberrant repair processes contribute to the development of kidney fibrosis. Myeloid cells, particularly monocytes/macrophages, play a crucial role in kidney fibrosis by releasing their proinflammatory cytokines and extracellular matrix components such as collagen and fibronectin into the microenvironment of the injured kidney. Numerous signaling pathways have been identified in relation to these activities. However, the involvement of metabolic pathways in myeloid cell functions during the development of renal fibrosis remains understudied. In our study, we initially reanalyzed single-cell RNA sequencing data of renal myeloid cells from Dr. Denby's group and observed an increased gene expression in glycolytic pathway in myeloid cells that are critical for renal inflammation and fibrosis. To investigate the role of myeloid glycolysis in renal fibrosis, we utilized a model of unilateral ureteral obstruction in mice deficient of , an activator of glycolysis, in myeloid cells and their wild type littermates ( ). We observed a significant reduction in fibrosis in the obstructive kidneys of mice compared to mice. This was accompanied by a substantial decrease in macrophage infiltration, as well as a decrease of M1 and M2 macrophages and a suppression of macrophage to obtain myofibroblast phenotype in the obstructive kidneys of mice. Mechanistic studies indicate that glycolytic metabolites stabilize HIF1α, leading to alterations in macrophage phenotype that contribute to renal fibrosis. In conclusion, our study implicates that targeting myeloid glycolysis represents a novel approach to inhibit renal fibrosis.
Topics: Animals; Mice; Fibrosis; Glycolysis; Kidney; Kidney Diseases; Macrophages; Phosphofructokinase-2
PubMed: 38035106
DOI: 10.3389/fimmu.2023.1259434 -
Renal Failure Dec 2023Type XXVIII collagen (COL28) is involved in cancer and lung fibrosis. COL28 polymorphisms and mutations might be involved in kidney fibrosis, but the exact role of COL28...
Type XXVIII collagen (COL28) is involved in cancer and lung fibrosis. COL28 polymorphisms and mutations might be involved in kidney fibrosis, but the exact role of COL28 in renal fibrosis is unknown. This study explored the function of COL28 in renal tubular cells by examining the expression of COL28 mRNA and the effects of COL28 overexpression in human tubular cells. COL28 mRNA expression and localization were observed in normal and fibrotic kidney tissues from humans and mice using real-time PCR, western blot, immunofluorescence, and immunohistochemistry. The consequences of COL28 overexpression on cell proliferation, migration, cell polarity, and epithelial-to-mesenchymal transition (EMT) induced by TGF-β1 were examined in human tubular HK-2 cells. COL28 expression was low in human normal renal tissues, mainly observed in the renal tubular epithelial cells and especially in proximal renal tubules. COL28 protein expression in human and mouse obstructive kidney disease was higher than in normal tissues ( < 0.05) and more significant in the UUO2-Week than the UUO1-Week group. The overexpression of COL28 promoted HK-2 cell proliferation and enhanced their migration ability (all < 0.05). TGF-β1 (10 ng/ml) induced COL28 mRNA expression in HK-2 cells, decreased E-cadherin and increased α-SMA in the COL28-overexpression group compared with controls ( < 0.05). ZO-1 expression decreased while COL6 increased in the COL28-overexpression group compared with controls ( < 0.05). In conclusion, COL28 overexpression promotes the migration and proliferation of renal tubular epithelial cells. The EMT could also be involved. COL28 could be a therapeutic target against renal- fibrotic diseases.
Topics: Animals; Humans; Mice; Cell Proliferation; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Kidney Diseases; Kidney Tubules; RNA, Messenger; Transforming Growth Factor beta1
PubMed: 36883360
DOI: 10.1080/0886022X.2023.2187236 -
Scientific Reports Dec 2019Urinary tract obstruction during kidney development causes tubular apoptosis, tubular necrosis, and interstitial inflammation. Necroptosis is a subtype of programmed...
Urinary tract obstruction during kidney development causes tubular apoptosis, tubular necrosis, and interstitial inflammation. Necroptosis is a subtype of programmed necrosis mediated by the receptor-interacting serine/threonine-protein kinase-3 (RIPK3) and the pseudokinase mixed lineage kinase domain-like (MLKL). Necrosis induces inflammation and stimulates cell death in an autoamplification loop named necroinflammation. Here, we studied necroptosis and necroinflammation in obstructive nephropathy induced by unilateral ureteral obstruction (UUO) in neonatal C57Bl/6J mice. Ureteral obstruction induced tubular dilatation, tubular basement membrane thickening, cast formation, and increased expression of kidney injury molecule-1 (KIM-1). Morphological investigations showed either apoptotic or necrotic cells in the tubular compartment. Biochemical analysis revealed increased caspase-8 activity and upregulation of RIPK3 as well as phosphorylated-MLKL in UUO-kidneys. Pro-inflammatory cytokines (IL-1α, INF-γ, TNF-α) were upregulated following UUO. Taken together we show that necroptosis and necroinflammation are accompanied phenomena in neonatal kidneys with obstruction. These findings may help to develop novel strategies to treat congenital obstructive nephropathy.
Topics: Animals; Animals, Newborn; Apoptosis; Cytokines; Inflammation; Kidney; Kidney Diseases; MAP Kinase Kinase Kinases; Mice; Mice, Inbred C57BL; Necroptosis; Phosphorylation; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 31819111
DOI: 10.1038/s41598-019-55079-w -
Acta Pharmacologica Sinica Nov 2022Nucleotide-binding oligomerization domain-like receptors (NLRs), including NLRAs, NLRBs (also known as NAIPs), NLRCs, and NLRPs, are a major subfamily of pattern... (Review)
Review
Nucleotide-binding oligomerization domain-like receptors (NLRs), including NLRAs, NLRBs (also known as NAIPs), NLRCs, and NLRPs, are a major subfamily of pattern recognition receptors (PRRs). Owing to a recent surge in research, NLRs have gained considerable attention due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, which is a central phenomenon in the pathogenesis of multiple diseases, including renal diseases. NLRs are expressed in different renal tissues during pathological conditions, which suggest that these receptors play roles in acute kidney injury, obstructive nephropathy, diabetic nephropathy, IgA nephropathy, lupus nephritis, crystal nephropathy, uric acid nephropathy, and renal cell carcinoma, among others. This review summarises recent progress on the functions of NLRs and their mechanisms in the pathophysiological processes of different types of renal diseases to help us better understand the role of NLRs in the kidney and provide a theoretical basis for NLR-targeted therapy for renal diseases.
Topics: Humans; NLR Proteins; Immunity, Innate; Diabetic Nephropathies; Kidney; Carrier Proteins
PubMed: 35365780
DOI: 10.1038/s41401-022-00886-7 -
Journal of Cellular and Molecular... May 2023Chronic kidney diseases affect a substantial percentage of the adult population worldwide. This observation emphasizes the need for novel insights into the molecular...
Chronic kidney diseases affect a substantial percentage of the adult population worldwide. This observation emphasizes the need for novel insights into the molecular mechanisms that control the onset and progression of renal diseases. Recent advances in genomics have uncovered a previously unanticipated link between the non-coding genome and human kidney diseases. Here we screened and analysed long non-coding RNAs (lncRNAs) previously identified in mouse kidneys by genome-wide transcriptomic analysis, for conservation in humans and differential expression in renal tissue from healthy and diseased individuals. Our data suggest that LINC01187 is strongly down-regulated in human kidney tissues of patients with diabetic nephropathy and rapidly progressive glomerulonephritis, as well as in murine models of kidney diseases, including unilateral ureteral obstruction, nephrotoxic serum-induced glomerulonephritis and ischemia/reperfusion. Interestingly, LINC01187 overexpression in human kidney cells in vitro inhibits cell death indicating an anti-apoptotic function. Collectively, these data suggest a negative association of LINC01187 expression with renal diseases implying a potential protective role.
Topics: Animals; Humans; Mice; Diabetic Nephropathies; Down-Regulation; Glomerulonephritis; Kidney; RNA, Long Noncoding
PubMed: 37056054
DOI: 10.1111/jcmm.17014 -
Nutrients Apr 2023The kidney is a crucial organ that eliminates metabolic waste and reabsorbs nutritious elements. It also participates in the regulation of blood pressure, maintenance of... (Review)
Review
The kidney is a crucial organ that eliminates metabolic waste and reabsorbs nutritious elements. It also participates in the regulation of blood pressure, maintenance of electrolyte balance and blood pH homeostasis, as well as erythropoiesis and vitamin D maturation. Due to such a heavy workload, the kidney is an energy-demanding organ and is constantly exposed to endogenous and exogenous insults, leading to the development of either acute kidney injury (AKI) or chronic kidney disease (CKD). Nevertheless, there are no therapeutic managements to treat AKI or CKD effectively. Therefore, novel therapeutic approaches for fighting kidney injury are urgently needed. This review article discusses the role of α-lipoic acid (ALA) in preventing and treating kidney diseases. We focus on various animal models of kidney injury by which the underlying renoprotective mechanisms of ALA have been unraveled. The animal models covered include diabetic nephropathy, sepsis-induced kidney injury, renal ischemic injury, unilateral ureteral obstruction, and kidney injuries induced by folic acid and metals such as cisplatin, cadmium, and iron. We highlight the common mechanisms of ALA's renal protective actions that include decreasing oxidative damage, increasing antioxidant capacities, counteracting inflammation, mitigating renal fibrosis, and attenuating nephron cell death. It is by these mechanisms that ALA achieves its biological function of alleviating kidney injury and improving kidney function. Nevertheless, we also point out that more comprehensive, preclinical, and clinical studies will be needed to make ALA a better therapeutic agent for targeting kidney disorders.
Topics: Animals; Thioctic Acid; Kidney; Renal Insufficiency, Chronic; Antioxidants; Acute Kidney Injury; Disease Models, Animal
PubMed: 37049574
DOI: 10.3390/nu15071732 -
Congenital Anomalies Nov 2022Herlyn-Werner-Wunderlich (HWW) syndrome is a rare complex female urogenital anomaly, with diverse anatomical presentations. Due to obstruction, most patients with HWW... (Review)
Review
Herlyn-Werner-Wunderlich (HWW) syndrome is a rare complex female urogenital anomaly, with diverse anatomical presentations. Due to obstruction, most patients with HWW syndrome need to be addressed surgically. The treatment strategy should be tailored to the different anatomical variants of each patient. Therefore, a detailed and comprehensive preoperative evaluation is needed. In this review, we describe the embryology and clinical manifestations of HWW syndrome and discuss and illustrate its diverse preoperative magnetic resonance imaging presentations to guide clinical treatment.
Topics: Humans; Female; Kidney; Syndrome; Urogenital Abnormalities; Uterus; Kidney Diseases; Abnormalities, Multiple; Magnetic Resonance Imaging
PubMed: 35941518
DOI: 10.1111/cga.12489 -
Cellular and Molecular Life Sciences :... Aug 2022p53 is a major regulator of cell cycle arrest, apoptosis, and senescence. While involvement of p53 in tumorigenesis is well established, recent studies implicate p53 in... (Review)
Review
p53 is a major regulator of cell cycle arrest, apoptosis, and senescence. While involvement of p53 in tumorigenesis is well established, recent studies implicate p53 in the initiation and progression of several renal diseases, which is the focus of this review. Ischemic-, aristolochic acid (AA) -, diabetic-, HIV-associated-, obstructive- and podocyte-induced nephropathies are accompanied by activation and/or elevated expression of p53. Studies utilizing chemical or renal-specific inhibition of p53 in mice confirm the pathogenic role of this transcription factor in acute kidney injury and chronic kidney disease. TGF-β1, NOX, ATM/ATR kinases, Cyclin G, HIPK, MDM2 and certain micro-RNAs are important determinants of renal p53 function in response to trauma. AA, cisplatin or TGF-β1-mediated ROS generation via NOXs promotes p53 phosphorylation and subsequent tubular dysfunction. p53-SMAD3 transcriptional cooperation downstream of TGF-β1 orchestrates induction of fibrotic factors, extracellular matrix accumulation and pathogenic renal cell communication. TGF-β1-induced micro-RNAs (such as mir-192) could facilitate p53 activation, leading to renal hypertrophy and matrix expansion in response to diabetic insults while AA-mediated mir-192 induction regulates p53 dependent epithelial G/M arrest. The widespread involvement of p53 in tubular maladaptive repair, interstitial fibrosis, and podocyte injury indicate that p53 clinical targeting may hold promise as a novel therapeutic strategy for halting progression of certain acute and chronic renal diseases, which affect hundreds of million people worldwide.
Topics: Animals; Fibrosis; Humans; Kidney; Kidney Diseases; Mice; Renal Insufficiency, Chronic; Signal Transduction; Transforming Growth Factor beta1; Tumor Suppressor Protein p53
PubMed: 35941392
DOI: 10.1007/s00018-022-04505-w