Murine kidney transplant outcome is best measured by transdermal glomerular filtration rate.

Mouse kidney transplantation provides a powerful preclinical model for the study of kidney transplant alloimmunity. However, accurate measurement of graft function is difficult because of the inaccuracy of traditional surrogate markers serum creatinine and urea. We report the use of transdermal glomerular filtration rate measurement under the experimental conditions of unilateral nephrectomy and allogeneic kidney transplantation.

Novel anti-inflammatory effects of the IL-1 receptor in kidney myeloid cells following ischemic AKI.

Acute kidney injury (AKI) is one of the most common causes of organ failure in critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1β (IL-1β) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL-1R1) on leukocytes and kidney parenchymal cells. IL-1R1 on kidney tubular cells is known to amplify the immune response and exacerbate AKI.

Blood or Fat? Differentiating Hemopericardium versus Epicardial Fat Using Focused Cardiac Ultrasound.

Basic point-of-care ultrasound of the heart-also known as Focused Cardiac Ultrasound (FoCUS)-has emerged as a powerful bedside tool to narrow the differential diagnosis of causes of hypotension. The list of causes of hypotension that a FoCUS provider is expected to be able to recognize includes a compressive pericardial effusion due to hemopericardium (blood in the pericardial sac). But hemopericardium can be difficult to distinguish from a more common condition that is not immediately life-threatening: epicardial fat.

Metallothionein Alleviates Glutathione Depletion-Induced Oxidative Cardiomyopathy through CISD1-Dependent Regulation of Ferroptosis in Murine Hearts.

This study was designed to discern the effect of heavy scavenger metallothionein on glutathione (GSH) deprivation-evoked cardiac anomalies and mechanisms involved with an emphasis on ferroptosis. Wild-type and cardiac metallothionein transgenic mice received GSH synthase inhibitor buthionine sulfoximine (BSO; 30 mmol/L in drinking water) for 14 days before assessment of myocardial morphology and function. BSO evoked cardiac remodeling and contractile anomalies, including cardiac hypertrophy, interstitial fibrosis, enlarged left ventricular chambers, deranged ejection fraction, fraction shortening, cardiomyocyte contractile capacity, intracellular Ca handling, sarcoplasmic reticulum Ca reuptake, loss of mitochondrial integrity (mitochondrial swelling, loss of aconitase activity), mitochondrial energy deficit, carbonyl damage, lipid peroxidation, ferroptosis, and apoptosis.

TNF- α from the Proximal Nephron Exacerbates Aristolochic Acid Nephropathy.

Key Points: Proximal tubular TNF aggravates kidney injury and fibrogenesis in aristolochic acid nephropathy. Tubular TNF disrupts the cell cycle in injured tubular epithelial cells. TNF-mediated toxic renal injury is independent of systemic immune responses.

Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI.

Significance Statement: Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. However, blockade of IL-1 signaling in AKI has not consistently demonstrated kidney protection. The current murine experiments show that IL-1R1 activation in the proximal tubule exacerbates toxin-induced AKI and cell death through local suppression of apolipoprotein M.

Postoperative Acute Kidney Injury by Age and Sex: A Retrospective Cohort Association Study.

Background: Acute kidney injury (AKI) after noncardiac surgery is common and has substantial health impact. Preclinical and clinical studies examining the influence of sex on AKI have yielded conflicting results, although they typically do not account for age-related changes. The objective of the study was to determine the association of age and sex groups on postoperative AKI.

A macrophage-endothelial immunoregulatory axis ameliorates septic acute kidney injury.

The most common cause of acute kidney injury (AKI) in critically ill patients is sepsis. Kidney macrophages consist of both F4/80 and CD11b cells. The role of macrophage subpopulations in septic AKI pathogenesis remains unclear.

Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model.

Sepsis, defined as organ dysfunction caused by a dysregulated host-response to infection, is characterized by immunosuppression. The vasopressor norepinephrine is widely used to treat low blood pressure in sepsis but exacerbates immunosuppression. An alternative vasopressor is angiotensin-II, a peptide hormone of the renin-angiotensin system (RAS), which displays complex immunomodulatory properties that remain unexplored in severe infection.

Twist1 in T Lymphocytes Augments Kidney Fibrosis after Ureteral Obstruction.

Background: Twist1 is a basic helix-loop-helix domain-containing transcription factor that participates in diverse cellular functions, including epithelial-mesenchymal transition and the cellular immune response. Although Twist1 plays critical roles in the initiation and progression of kidney diseases, the effects of Twist1 in the T lymphocyte on the progression of renal fibrosis require elucidation.

Methods: 129/SvEv mice with a floxed allele for the gene encoding Twist1 or TNF were bred with CD4-Cre mice to yield CD4-Cre Twist1 (Twist1-TKO) or CD4-Cre TNF (TNF-TKO) mice with robust, but selective, deletion of Twist1 or TNF mRNA in T cells, respectively.

Identification of Trajectory-Based Acute Kidney Injury Phenotypes Among Cardiac Surgery Patients.

Background: Acute kidney injury (AKI) is a common and serious complication of cardiac surgical procedures for which unrecognized heterogeneity may underpin poor success in identifying effective therapies. We aimed to identify phenotypically similar groups of patients as defined by their postoperative creatinine trajectories.

Methods: This was a retrospective, single-center cohort study in an academic tertiary care center including patients undergoing coronary artery bypass graft procedures.

Postoperative Acute Kidney Injury Is Associated With Progression of Chronic Kidney Disease Independent of Severity.

Background: Both postoperative acute kidney injury (AKI) and preoperative chronic kidney disease (CKD) are associated with significantly worse outcomes following surgery. The relationship of both of these conditions with each other and with CKD progression after surgery remains poorly studied. Our objective was to assess if there was an interaction between preoperative kidney function estimated by preoperative estimated glomerular filtration rate (eGFR)/CKD stage, postoperative AKI, and eGFR/CKD progression within 1 year of surgery.

IL-1 receptor signaling in podocytes limits susceptibility to glomerular damage.

Interleukin (IL)-1 receptor type 1 (IL-1R1) activation triggers a proinflammatory signaling cascade that can exacerbate kidney injury. However, the functions of podocyte IL-1R1 in glomerular disease remain unclear. To study the role of IL-1R1 signaling in podocytes, we selectively ablated podocyte IL-1R1 in mice (PKO mice).

Twist1 in podocytes ameliorates podocyte injury and proteinuria by limiting CCL2-dependent macrophage infiltration.

The transcription factor Twist1 regulates several processes that could impact kidney disease progression, including epithelial cell differentiation and inflammatory cytokine induction. Podocytes are specialized epithelia that exhibit features of immune cells and could therefore mediate unique effects of Twist1 on glomerular disease. To study Twist1 functions in podocytes during proteinuric kidney disease, we employed a conditional mutant mouse in which Twist1 was selectively ablated in podocytes (Twist1-PKO).

Annexin A1 Tripeptide Mimetic Increases Sirtuin-3 and Augments Mitochondrial Function to Limit Ischemic Kidney Injury.

Acute kidney injury (AKI) is one of the most common organ failures following surgery. We have developed a tripeptide mimetic (ANXA1sp) of the parent annexin A1 molecule that shows promise as an organ protectant limiting cellular stress; however, its potential as a kidney protective agent remains unexplored, and its mechanism of action is poorly understood. Our hypothesis was that ANXA1sp would limit kidney injury following surgical ischemic kidney injury.

Association of Severe Acute Kidney Injury with Mortality and Healthcare Utilization Following Isolated Traumatic Brain Injury.

Background/objective: Traumatic brain injury (TBI) is a leading cause of morbidity, mortality, and disability in the USA. While cardiopulmonary dysfunction can result in poor outcomes following severe TBI, the impact of acute kidney injury (AKI) is poorly understood. We examined the association of severe AKI with hospital mortality and healthcare utilization following isolate severe TBI.

Apolipoprotein L1 (APOL1) Coding Variants Are Associated With Creatinine Rise After Cardiac Surgery.

Objective: Acute kidney injury (AKI) is a complication of cardiac surgery that is considerably more common in African Americans (1.5-fold). Although homozygous status for apolipoprotein L1 (APOL1) risk alleles is associated with chronic kidney disease in individuals of African ancestry, whether these coding variants confer AKI risk is unknown.

Yolk-sac-derived macrophages progressively expand in the mouse kidney with age.

Renal macrophages represent a highly heterogeneous and specialized population of myeloid cells with mixed developmental origins from the yolk-sac and hematopoietic stem cells (HSC). They promote both injury and repair by regulating inflammation, angiogenesis, and tissue remodeling. Recent reports highlight differential roles for ontogenically distinct renal macrophage populations in disease.

C-C Motif Chemokine Receptor 7 Exacerbates Hypertension Through Effects on T Lymphocyte Trafficking.

Activated T lymphocytes that infiltrate blood pressure control organs make a critical contribution to the pathogenesis of hypertension. Dendritic cells act as potent antigen-presenting cells to stimulate prohypertensive T cells. However, the mechanisms that facilitate the recruitment of prohypertensive T cells and dendritic cells into the kidney's draining lymph node during hypertension require elucidation.

Classical Dendritic Cells Mediate Hypertension by Promoting Renal Oxidative Stress and Fluid Retention.

FLT3L (Fms-like tyrosine kinase 3 ligand) stimulates the development of classical dendritic cells (DCs). Here we tested the hypothesis that classical DCs drive blood pressure elevation by promoting renal fluid retention. FLT3L-deficient (FLT3L) mice that lack classical DCs in the kidney had mean arterial pressures similar to wild-types (WTs) at baseline but had blunted hypertensive responses during 4 weeks of chronic Ang II (angiotensin II) infusion.

TNF-α in T lymphocytes attenuates renal injury and fibrosis during nephrotoxic nephritis.

Nephrotoxic serum nephritis (NTN) models immune-mediated human glomerulonephritis and culminates in kidney inflammation and fibrosis, a process regulated by T lymphocytes. TNF-α is a key proinflammatory cytokine that contributes to diverse forms of renal injury. Therefore, we posited that TNF-α from T lymphocytes may contribute to NTN pathogenesis.

The transcription factor Twist1 in the distal nephron but not in macrophages propagates aristolochic acid nephropathy.

Tubulointerstitial disease in the kidney culminates in renal fibrosis that portents organ failure. Twist1, a basic helix-loop-helix protein 38 transcription factor, regulates several essential biological functions, but inappropriate Twist1 activity in the kidney epithelium can trigger kidney fibrogenesis and chronic kidney disease. By contrast, Twist1 in circulating myeloid cells may constrain inflammatory injury by attenuating cytokine generation.

A20 in Myeloid Cells Protects Against Hypertension by Inhibiting Dendritic Cell-Mediated T-Cell Activation.

Rationale: The ubiquitin-editing protein A20 in dendritic cells (DCs) suppresses NF-κB (nuclear factor-κB) signaling and constrains DC-mediated T-cell stimulation, but the role of A20 in modulating the hypertensive response requires elucidation.

Objective: Here, we tested the hypothesis that A20 in CD11c-expressing myeloid cells mitigates Ang II (angiotensin II)-induced hypertension by limiting renal T-cell activation.

Methods And Results: Mice with heterozygous deletion of A20 in CD11c-expressing myeloid cells (DC ACT[]) have spontaneous DC activation but have normal baseline blood pressures.