Regulated cell death in chronic kidney disease: current evidence and future clinical perspectives.

Chronic kidney disease (CKD) is the progressive loss of kidney function/structure over a period of at least 3 months. It is characterised histologically by the triad of cell loss, inflammation and fibrosis. This literature review focuses on the forms of cell death that trigger downstream inflammation and fibrosis, collectively called regulated cell death (RCD) pathways.

Human proximal tubular epithelial cell-derived small extracellular vesicles mediate synchronized tubular ferroptosis in hypoxic kidney injury.

Hypoxia is the key pathobiological trigger of tubular oxidative stress and cell death that drives the transition of acute kidney injury (AKI) to chronic kidney disease (CKD). The mitochondrial-rich proximal tubular epithelial cells (PTEC) are uniquely sensitive to hypoxia and thus, are pivotal in propagating the sustained tubular loss of AKI-to-CKD transition. Here, we examined the role of PTEC-derived small extracellular vesicles (sEV) in propagating the 'wave of tubular death'.

Spatial Transcriptomics in Kidney Tissue.

Unlike bulk and single-cell/single-nuclei RNA sequencing methods, spatial transcriptome sequencing (ST-seq) resolves transcriptome expression within the spatial context of intact tissue. This is achieved by integrating histology with RNA sequencing. These methodologies are completed sequentially on the same tissue section placed on a glass slide with printed oligo-dT spots, termed ST-spots.

Cellular milieu in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is globally the most prevalent renal cancer. The cells of origin in ccRCC have been identified as proximal tubular epithelial cells (PTEC); however, the transcriptomic pathways resulting in the transition from normal to malignant PTEC state have remained unclear. Immunotherapy targeting checkpoints have revolutionized the management of ccRCC, but a sustained clinical response is achieved in only a minority of ccRCC patients.

Hypoxic human proximal tubular epithelial cells undergo ferroptosis and elicit an NLRP3 inflammasome response in CD1c dendritic cells.

Inflammasomes are multiprotein platforms responsible for the release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Mouse studies have identified inflammasome activation within dendritic cells (DC) as pivotal for driving tubulointerstitial fibrosis and inflammation, the hallmarks of chronic kidney disease (CKD). However, translation of this work to human CKD remains limited.

Spatially Resolved Transcriptomes of Mammalian Kidneys Illustrate the Molecular Complexity and Interactions of Functional Nephron Segments.

Available transcriptomes of the mammalian kidney provide limited information on the spatial interplay between different functional nephron structures due to the required dissociation of tissue with traditional transcriptome-based methodologies. A deeper understanding of the complexity of functional nephron structures requires a non-dissociative transcriptomics approach, such as spatial transcriptomics sequencing (ST-seq). We hypothesize that the application of ST-seq in normal mammalian kidneys will give transcriptomic insights within and across species of physiology at the functional structure level and cellular communication at the cell level.

Promoting Plant-Based Therapies for Chronic Kidney Disease.

Chronic kidney disease (CKD) is debilitating, increasing in incidence worldwide, and a financial and social burden on health systems. Kidney failure, the final stage of CKD, is life-threatening if untreated with kidney replacement therapies. Current therapies using commercially-available drugs, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and calcium channel blockers, generally only delay the progression of CKD.

Adenine overload induces ferroptosis in human primary proximal tubular epithelial cells.

The pathogenesis of crystal nephropathy involves deposition of intratubular crystals, tubular obstruction and cell death. The deposition of 8-dihydroxyadenine (DHA) crystals within kidney tubules, for instance, is caused by a hereditary deficiency of adenine phosphoribosyl transferase in humans or adenine overload in preclinical models. However, the downstream pathobiological patterns of tubular cell attrition in adenine/DHA-induced nephropathy remain poorly understood.

T-Cell Expression and Release of Kidney Injury Molecule-1 in Response to Glucose Variations Initiates Kidney Injury in Early Diabetes.

Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk.

Molecular and functional profiling of apical versus basolateral small extracellular vesicles derived from primary human proximal tubular epithelial cells under inflammatory conditions.

Proximal tubular epithelial cells (PTEC) are central players in inflammatory kidney diseases. However, the complex signalling mechanism/s via which polarized PTEC mediate disease progression are poorly understood. Small extracellular vesicles (sEV), including exosomes, are recognized as fundamental components of cellular communication and signalling courtesy of their molecular cargo (lipids, microRNA, proteins).

The Emerging Role of Renal Tubular Epithelial Cells in the Immunological Pathophysiology of Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a systemic, autoimmune disease that can involve virtually any organ of the body. Lupus nephritis (LN), the clinical manifestation of this disease in the kidney, is one of the most common and severe outcomes of SLE. Although a key pathological hallmark of LN is glomerular inflammation and damage, tubulointerstitial lesions have been recognized as an important component in the pathology of LN.

Oxidative stress and inflammasome activation in human rhabdomyolysis-induced acute kidney injury.

Acute kidney injury (AKI) is a life-threatening complication of rhabdomyolysis. The pathophysiological mechanisms of rhabdomyolysis-induced AKI (RIAKI) have been extensively studied in the murine system, yet clinical translation of this knowledge to humans is lacking. In this study, we investigated the cellular and molecular pathways of human RIAKI.

Role of inflammation and inflammasome activation in human bile cast nephropathy.

Bile cast nephropathy (BCN) is an underdiagnosed cause of acute kidney injury (AKI). The precise pathogenesis of bilirubin tubular toxicity remains unknown. The aim of this study is to explore the cellular and molecular pathophysiology of human BCN.

Underlying Histopathology Determines Response to Oxidative Stress in Cultured Human Primary Proximal Tubular Epithelial Cells.

Proximal tubular epithelial cells (PTEC) are key players in the progression of kidney diseases. PTEC studies to date have primarily used mouse models and transformed human PTEC lines. However, the translatability of these models to human kidney disease has been questioned.

Specialized Roles of Human Natural Killer Cell Subsets in Kidney Transplant Rejection.

Human natural killer (NK) cells are key functional players in kidney transplant rejection. However, the respective contributions of the two functionally distinct human NK cell subsets (CD56 cytokine-producing vs. CD56 cytotoxic effector) in episodes of allograft rejection remain uncertain, with current immunohistochemical methods unable to differentiate these discrete populations.

Biomarkers and the role of mast cells as facilitators of inflammation and fibrosis in chronic kidney disease.

Chronic kidney disease (CKD) is a clinical syndrome with many adverse sequelae and is currently a major global health and economic burden. Regardless of aetiology, inflammation and fibrosis are common manifestations of CKD. Unfortunately, the underlying pathophysiological mechanisms are poorly understood, and robust prognostic and early diagnostic biomarkers of CKD are lacking.

Human Tissue-Resident Mucosal-Associated Invariant T (MAIT) Cells in Renal Fibrosis and CKD.

Background: Mucosal-associated invariant T (MAIT) cells represent a specialized lymphocyte population associated with chronic inflammatory disorders. Little is known, however, about MAIT cells in diseases of the kidney, including CKD.

Methods: To evaluate MAIT cells in human native kidneys with tubulointerstitial fibrosis, the hallmark of CKD, we used multicolor flow cytometry to identify, enumerate, and phenotype such cells from human kidney tissue biopsy samples, and immunofluorescence microscopy to localize these cells.

Pigment Nephropathy: Novel Insights into Inflammasome-Mediated Pathogenesis.

Pigment nephropathy is an acute decline in renal function following the deposition of endogenous haem-containing proteins in the kidneys. Haem pigments such as myoglobin and haemoglobin are filtered by glomeruli and absorbed by the proximal tubules. They cause renal vasoconstriction, tubular obstruction, increased oxidative stress and inflammation.

Natural Killer Cells in Kidney Health and Disease.

Natural killer (NK) cells are a specialized population of innate lymphocytes that have a major effector function in local immune responses. While their immunological functions in many inflammatory diseases are well established, comparatively little is still known about their roles in kidney homeostasis and disease. Our understanding of kidney NK cells is rapidly evolving, with murine studies highlighting the functional significance of NK cells in acute and chronic forms of renal disease.

Identification and Quantitation of Leukocyte Populations in Human Kidney Tissue by Multi-parameter Flow Cytometry.

Inflammatory immune cells play direct pathological roles in cases of acute kidney injury (AKI) and chronic kidney disease (CKD). However, the identification and characterization of distinct populations of leukocytes in human kidney biopsies have been confounded by the limitations of immunohistochemical (IHC)-based techniques used to detect them. This methodology is not amenable to the combinations of multiple markers necessary to unequivocally define discrete immune cell populations.

Effector γδ T cells in human renal fibrosis and chronic kidney disease.

Background: γδ T cells are effector lymphocytes recognized as key players during chronic inflammatory processes. Mouse studies suggest a pathological role for γδ T cells in models of kidney disease. Here we evaluated γδ T cells in human native kidneys with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease.