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

Introduction: 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-1ß (IL-1ß) 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. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. The objective of the present study was to elucidate the function of myeloid cell IL-1R1 during AKI. As IL-1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we hypothesized that myeloid cells expressing IL-1R1 would exacerbate AKI. Methods: IL-1R1 was selectively depleted in CD11c+-expressing myeloid cells with CD11cCre + /IL-1R1 fl/fl (Myel KO) mice. Myel KO and littermate controls (CD11cCre - /IL-1R1 fl/fl-Myel WT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by blood urea nitrogen (BUN), serum creatinine and injury marker neutrophil gelatinase-associated lipocalin (NGAL) protein expression. Renal tubular cells (RTC) were co-cultured with CD11c+ bone marrow-derived dendritic cells (BMDC) from Myel KO and Myel WT mice. Results: Surprisingly, compared to Myel WT mice, Myel KO mice displayed exaggerated I/R-induced kidney injury, as measured by elevated levels of serum creatinine and BUN, and kidney NGAL protein expression. In support of these findings, in vitro co-culture studies showed that RTC co-cultured with Myel KO BMDC (in the presence of IL-1ß) exhibited higher mRNA levels of the kidney injury marker NGAL than those co-cultured with Myel WT BMDC. In addition, we observed that IL-1R1 on Myel WT BMDC preferentially augmented the expression of anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra/Il1rn), effects that were largely abrogated in Myel KO BMDC. Furthermore, recombinant IL-1Ra could rescue IL-1ß-induced tubular cell injury. Discussion: Our findings suggest a novel function of IL-1R1 is to serve as a critical negative feedback regulator of IL-1 signaling in CD11c+ myeloid cells to dampen inflammation to limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.

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. This paper reviews illustrative images of both epicardial fat and hemopericardium to provide practice guidance to the FoCUS user on how to differentiate these two phenomena.

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 Ca2+ handling, sarcoplasmic reticulum Ca2+ reuptake, loss of mitochondrial integrity (mitochondrial swelling, loss of aconitase activity), mitochondrial energy deficit, carbonyl damage, lipid peroxidation, ferroptosis, and apoptosis. Metallothionein itself did not affect myocardial morphology and function, although it mitigated BSO-provoked myocardial anomalies, loss of mitochondrial integrity and energy, and ferroptosis. Immunoblotting revealed down-regulated sarco(endo)plasmic reticulum Ca2+-ATPase 2a, glutathione peroxidase 4, ferroptosis-suppressing CDGSH iron-sulfur domain 1 (CISD1), and mitochondrial regulating glycogen synthase kinase-3ß phosphorylation with elevated p53, myosin heavy chain-ß isozyme, IκB phosphorylation, and solute carrier family 7 member 11 (SLC7A11) as well as unchanged SLC39A1, SLC1A5, and ferroptosis-suppressing protein 1 following BSO challenge, all of which, except glutamine transporter SLC7A11 and p53, were abrogated by metallothionein. Inhibition of CISD1 using pioglitazone nullified GSH-offered benefit against BSO-induced cardiomyocyte ferroptosis and contractile and intracellular Ca2+ derangement. Taken together, these findings support a regulatory modality for CISD1 in the impedance of ferroptosis in metallothionein-offered protection against GSH depletion-evoked cardiac aberration.

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. By contrast, IL-1R1 activation in endothelial cells ameliorates AKI by restoring VEGFA-dependent endothelial cell viability. Using this information, future delivery strategies can maximize the protective effects of blocking IL-1R1 while mitigating unwanted actions of IL-1R1 manipulation. BACKGROUND: Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. IL-1R1 is expressed on some myeloid cell populations and on multiple kidney cell lineages, including tubular and endothelial cells. Pharmacological inhibition of the IL-1R1 does not consistently protect the kidney from injury, suggesting there may be complex, cell-specific effects of IL-1R1 stimulation in AKI. METHODS: To examine expression of IL-1 and IL-1R1 in intrinsic renal versus infiltrating immune cell populations during AKI, we analyzed single-cell RNA sequencing (scRNA-seq) data from kidney tissues of humans with AKI and mice with acute aristolochic acid exposure. We then investigated cell-specific contributions of renal IL-1R1 signaling to AKI using scRNA-seq, RNA microarray, and pharmacological interventions in mice with IL-1R1 deletion restricted to the proximal tubule or endothelium. RESULTS: scRNA-seq analyses demonstrated robust IL-1 expression in myeloid cell populations and low-level IL-1R1 expression in kidney parenchymal cells during toxin-induced AKI. Our genetic studies showed that IL-1R1 activation in the proximal tubule exacerbated toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorated aristolochic acid-induced AKI by restoring VEGFA-dependent endothelial cell viability and density. CONCLUSIONS: These data highlight opposing cell-specific effects of IL-1 receptor signaling on AKI after toxin exposure. Disrupting pathways activated by IL-1R1 in the tubule, while preserving those triggered by IL-1R1 activation on endothelial cells, may afford renoprotection exceeding that of global IL-1R1 inhibition while mitigating unwanted actions of IL-1R1 blockade.

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. The authors hypothesized that younger females would display lower risk of postoperative AKI than males of similar age, and the protection would be lost in older females. METHODS: This was a multicenter retrospective cohort study across 46 institutions between 2013 and 2019. Participants included adult inpatients without pre-existing end-stage kidney disease undergoing index major noncardiac, nonkidney/urologic surgeries. The authors' primary exposure was age and sex groups defined as females 50 yr or younger, females older than 50 yr, males 50 yr or younger, and males older than 50 yr. The authors' primary outcome was development of AKI by Kidney Disease-Improving Global Outcomes serum creatinine criteria. Exploratory analyses included associations of ascending age groups and hormone replacement therapy home medications with postoperative AKI. RESULTS: Among 390,382 patients, 25,809 (6.6%) developed postoperative AKI (females 50 yr or younger: 2,190 of 58,585 [3.7%]; females older than 50 yr: 9,320 of 14,4047 [6.5%]; males 50 yr or younger: 3,289 of 55,503 [5.9%]; males older than 50 yr: 11,010 of 132,447 [8.3%]). When adjusted for AKI risk factors, compared to females younger than 50 yr (odds ratio, 1), the odds of AKI were higher in females older than 50 yr (odds ratio, 1.51; 95% CI, 1.43 to 1.59), males younger than 50 yr (odds ratio, 1.90; 95% CI, 1.79 to 2.01), and males older than 50 yr (odds ratio, 2.06; 95% CI, 1.96 to 2.17). CONCLUSIONS: Younger females display a lower odds of postoperative AKI that gradually increases with age. These results suggest that age-related changes in women should be further studied as modifiers of postoperative AKI risk after noncardiac surgery.

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 F4/80hi and CD11bhi cells. The role of macrophage subpopulations in septic AKI pathogenesis remains unclear. As F4/80hi macrophages are reported to contribute to immunomodulation following injury, we hypothesized that selective depletion of F4/80hi macrophages would worsen septic AKI. F4/80hi macrophages were depleted via diphtheria toxin injection in CD11cCre(+)/CX3CR1dtr/wt (F4/80 MKO mice) compared to CD11cCre(-)/CX3CR1dtr/wt (F4/80 MWT) mice. F4/80 MWT and F4/80 MKO mice were subjected to sham or cecal ligation and puncture to induce sepsis. Compared to F4/80 MWT mice, F4/80 MKO mice displayed worsened septic AKI at 24 hours as measured by serum creatinine and histologic injury scoring. Kidneys from F4/80 MKO mice elaborated higher kidney interleukin-6 levels. Mechanistically, single cell RNA sequencing identified a macrophage-endothelial cell immunoregulatory axis that underlies interleukin-6 expression. F4/80hi macrophages expressed interleukin-1 receptor antagonist and limited interleukin-6 expression in endothelial cells. In turn, anti-interleukin-6 therapy ameliorated septic AKI in F4/80 MKO mice. Thus, F4/80hi macrophages express interleukin-1 receptor antagonist and constrain interleukin-6 generation from endothelial cells to limit septic AKI, representing a targetable cellular crosstalk in septic AKI. These findings are particularly relevant owing to the efficacy of anti-interleukin-6 therapies during COVID-19 infection, a disease associated with high rates of AKI and endothelial dysfunction.

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. In a murine cecal ligation and puncture (CLP) model of sepsis, we found alterations in the surface levels of RAS proteins on innate leukocytes in peritoneum and spleen. Angiotensin-II treatment induced biphasic, angiotensin-II type 1 receptor (AT1R)-dependent modulation of the systemic inflammatory response and decreased bacterial counts in both the blood and peritoneal compartments, which did not occur with norepinephrine treatment. The effect of angiotensin-II was preserved when treatment was delivered remote from the primary site of infection. At an independent laboratory, angiotensin-II treatment was compared in LysM-Cre AT1aR-/- (Myeloid-AT1a-) mice, which selectively do not express AT1R on myeloid-derived leukocytes, and littermate controls (Myeloid-AT1a+). Angiotensin-II treatment significantly reduced post-CLP bacteremia in Myeloid-AT1a+ mice but not in Myeloid-AT1a- mice, indicating that the AT1R-dependent effect of angiotensin-II on bacterial clearance was mediated through myeloid-lineage cells. Ex vivo, angiotensin-II increased post-CLP monocyte phagocytosis and ROS production after lipopolysaccharide stimulation. These data identify a mechanism by which angiotensin-II enhances the myeloid innate immune response during severe systemic infection and highlight a potential role for angiotensin-II to augment immune responses in sepsis.

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. Our hypothesis was that AKI severity would be associated with a faster time to eGFR/CKD stage progression within 1 year of surgery in a graded-fashion, which would be exacerbated by preoperative kidney dysfunction. METHODS: This was a retrospective cohort study at Landspitali University Hospital in Iceland, which serves about 75% of the population. Participants included adults receiving their first major anesthetic between 2005 and 2018. Patients with CKD stage 5, undergoing major urologic procedures, or having missing creatinine values for follow-up of eGFR stage were excluded from analysis. The primary exposure was postoperative AKI stage within 7 days after surgery classified by the kidney disease improving global outcome (KDIGO) criteria. The primary outcome was time to progression of CKD by at least 1 eGFR/CKD stage within 1-year following surgery. Multivariable Cox proportional hazards models were used to estimate hazard of eGFR/CKD stage progression, including an interaction between AKI and preoperative CKD on eGFR/CKD stage progression. RESULTS: A total of 5548 patients were studied. In the multivariable model adjusting for baseline eGFR/CKD stage, when compared to patients without AKI, postoperative AKI stage 1 (hazard ratio [HR], 5.91; 95% confidence interval [CI], 4.34-8.05), stage 2 (HR, 3.86; 95% CI, 1.82-8.16), and stage 3 (HR, 3.61; 95% CI, 1.49-8.74) were all independently associated with faster time to eGFR/CKD stage progression within 1 year following surgery, though increasing AKI severity did not confer additional risk. The only significant interaction between the degree of AKI and the preexisting renal function was for stage 1 AKI, where the odds of 1-year eGFR/CKD stage progression actually decreased in patients with preoperative CKD categories 3a, 3b, and 4. CONCLUSIONS: KDIGO-AKI was independently associated with eGFR/CKD stage progression within the year following surgery after adjustment for baseline eGFR/CKD stage and without an interaction between worse preoperative kidney function and higher stage AKI. Our observations suggest that further studies are warranted to test whether CKD progression could be prevented by the adoption of perioperative kidney protective practices.

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. AKI phenotypes were evaluated through latent class mixed modeling of serum creatinine patterns (trajectories). To identify trajectory phenotypes, modeling was performed using postoperative creatinine values from 50% of patients (development cohort) and for comparison similarly conducted for the remaining sample (validation cohort). Subsequent assessments included comparisons of classes between development and validation cohorts for consistency and stability, and among classes for patient and procedural characteristics, complications, and long-term survival. RESULTS: We identified 12 AKI trajectories in both the development (n = 2647) and validation cohorts (n = 2647). Discrimination among classes was good (mean posterior class membership probability, 66%-88%), with differences in rate, timing, and degree of serum creatinine rise/fall, and recovery. In matched class comparisons between cohorts, many other phenotypic similarities were present. Notably, 4 high-risk phenotypes had greater long-term risk for death relative to lower risk classes. CONCLUSIONS: Latent class mixed modeling identified 12 reproducible AKI classes (serum creatinine trajectory phenotypes), including 4 with higher risk of poor outcome, in patients following coronary artery bypass graft procedures. Such hidden structure offers a novel approach to grouping patients for renoprotection investigations in addition to reanalysis of previously conducted trials.

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). We then subjected PKO mice and wild-type controls to two glomerular injury models: nephrotoxic serum (NTS)- and adriamycin-induced nephropathy. Surprisingly, we found that IL-1R1 activation in podocytes limited albuminuria and podocyte injury during NTS- and adriamycin-induced nephropathy. Moreover, deletion of IL-1R1 in podocytes drove podocyte apoptosis and glomerular injury through diminishing Akt activation. Activation of Akt signaling abrogated the differences in albuminuria and podocyte injury between wild-type and PKO mice during NTS. Thus, IL-1R1 signaling in podocytes limits susceptibility to glomerular injury via an Akt-dependent signaling pathway. These data identify an unexpected protective role for IL-1R1 signaling in podocytes in the pathogenesis of glomerular disease.NEW & NOTEWORTHY The present study establishes that activation of the receptor for interleukin-1 limits susceptibility to damage to the kidney glomerulus in preclinical mouse models by stimulating Akt signaling cascades inside the podocyte.

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). Deletion of Twist1 in podocytes augmented proteinuria, podocyte injury, and foot process effacement in glomerular injury models. Twist1 in podocytes constrained renal accumulation of monocytes/macrophages and glomerular expression of CCL2 and the macrophage cytokine TNF-α after injury. Deletion of TNF-α selectively from podocytes had no impact on the progression of proteinuric nephropathy. By contrast, the inhibition of CCL2 abrogated the exaggeration in proteinuria and podocyte injury accruing from podocyte Twist1 deletion. Collectively, Twist1 in podocytes mitigated urine albumin excretion and podocyte injury in proteinuric kidney diseases by limiting CCL2 induction that drove monocyte/macrophage infiltration into injured glomeruli. Myeloid cells, rather than podocytes, further promoted podocyte injury and glomerular disease by secreting TNF-α. These data highlight the capacity of Twist1 in the podocyte to mitigate glomerular injury by curtailing the local myeloid immune response.

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

Background: 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. Methods: In a blinded fashion, wildtype mice were assigned to receive vehicle control or ANXA1sp one hour prior to and one hour after kidney vascular clamping. Our primary outcomes were markers of kidney injury and function as measured by serum creatinine and histologic injury scoring of kidney tissue sections. Immunofluorescence microscopy, real-time PCR, and Western blot were used to assess cell death, oxidative stress, and mitochondrial biomarkers. An in vitro model of oxygen-glucose deprivation in immortalized kidney tubule cells was used. Results: ANXA1sp given prior to and after ischemic kidney injury abrogated ischemic kidney injury. ANXA1sp limited cell death both in vivo and in vitro and abrogated oxidative stress following ischemia. ANXA1sp significantly increased the expression of markers associated with protective mitophagy and limited the expression of markers associated with detrimental mitochondrial fission. ANXA1sp upregulated the expression of the mitochondrial protectant sirtuin-3 (SIRT3) in the mitochondria of kidney tubular cells. Silencing of SIRT3 reversed ANXA1sp-mediated protection against hypoxic cell death. Conclusions: ANXA1sp limits kidney injury, upregulates SIRT3, and preserves mitochondrial integrity following ischemic kidney injury. ANXA1sp holds considerable promise as a perioperative kidney protectant prior to ischemia inducing surgery and kidney transplantation.

Th17 Immunity in the Colon Is Controlled by Two Novel Subsets of Colon-Specific Mononuclear Phagocytes.

Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.

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 TNFα were bred with CD4-Cre mice to yield CD4-Cre+ Twist1flox/flox (Twist1-TKO) or CD4-Cre+ TNFflox/flox (TNF-TKO) mice with robust, but selective, deletion of Twist1 or TNFα mRNA in T cells, respectively. Twist1 TKO, TNF TKO, and WT controls underwent UUO with assessment of kidney fibrosis and T-cell phenotype at 14 days. Results: Compared with WT controls, obstructed kidneys from Twist1 TKO mice had attenuated extracellular matrix deposition. Despite this diminished fibrosis, Twist1 TKO obstructed kidneys contained more CD8+ T cells than in WTs. These intrarenal CD8+ T cells exhibited greater activation and higher levels of TNFα expression than those from WT obstructed kidneys. Further, we found that selective deletion of TNFα from T cells exaggerated renal scar formation and injury after UUO, highlighting the capacity of T-cell TNF to constrain fibrosis in the kidney. Conclusions: Twist1 in T cells promotes kidney fibrogenesis, in part, by curtailing the renal accumulation of TNF-elaborating T cells.

In reply to: "Intra-aortic balloon pump protects against hydrostatic pulmonary oedema during peripheral venoarterial-extracorporeal membrane oxygenation".

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is an increasingly utilized life-saving measure. However, left-ventricular distention from inadequate left-ventricular off-loading can lead to unwanted pulmonary and cardiac complications. We are writing to indicate our agreement with a recent article by Brechot et al. published in the June 2017 issue where the authors demonstrated that intra-aortic balloon pump provides mechanical support to off-load the left ventricle during VA-ECMO, which prevents pulmonary edema.

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. The present study examined whether APOL1 homozygous risk allele status was associated with AKI in African Americans after cardiac surgery. DESIGN: Retrospective analysis of a cohort. SETTING: Single-center university hospital. PARTICIPANTS: African American patients from the CATHeterization GENetics study cohort who underwent cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Genotyping of APOL1 alleles. MEASUREMENTS AND MAIN RESULTS: Data from 125 African American patients included 12 APOL1 risk (ie, homozygous for risk alleles) patients and 113 APOL1 control (ie, wildtype or heterozygous for risk alleles) patients. The primary outcome to reflect AKI was peak serum creatinine rise after surgery relative to the preoperative creatinine (%ΔCr). The secondary outcome was Kidney Disease: Improving Global Outcomes (KDIGO) AKI criteria. In the primary analysis, peak creatinine rise was higher in risk compared with control patients in both univariate (%ΔCr 69.1 v 29.6%; p = 0.005) and multivariate regression (%ΔCr 88.5 v 43.7%; p = 0.006) analyses. For the secondary outcome, a trend toward KDIGO AKI development was noted in APOL1 risk patients, but this was not statistically significant. CONCLUSIONS: African American cardiac surgery patients homozygous for APOL1 chronic kidney disease risk variants averaged a more than 2-fold higher postoperative creatinine rise even after adjustment for other risk factors, suggesting these alleles also are independent risk factors for AKI.

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. However, little is known about how these populations change over time in normal, uninjured kidneys. Prior reports demonstrated a high proportion of HSC-derived macrophages in the young adult kidney. Unexpectedly, using genetic fate-mapping and parabiosis studies, we found that yolk-sac-derived macrophages progressively expand in number with age and become a major contributor to the renal macrophage population in older mice. This chronological shift in macrophage composition involves local cellular proliferation and recruitment from circulating progenitors and may contribute to the distinct immune responses, limited reparative capacity, and increased disease susceptibility of kidneys in the elderly population.

Older people are more likely to develop kidney disease, which increases their risk of having other conditions such as a heart attack or stroke and, in some cases, can lead to their death. Older kidneys are less able to repair themselves after an injury, which may help explain why aging contributes to kidney disease. Another possibility is that older kidneys are more susceptible to excessive inflammation. Learning more about the processes that lead to kidney inflammation in older people might lead to better ways to prevent or treat their kidney disease. Immune cells called macrophages help protect the body from injury and disease. They do this by triggering inflammation, which aides healing. Too much inflammation can be harmful though, making macrophages a prime suspect in age-related kidney harm. Studying these immune cells in the kidney and how they change over the lifespan could help scientists to better understand age-related kidney disease. Now, Ide, Yahara et al. show that one type of macrophage is better at multiplying in older kidneys. In the experiments, mice were genetically engineered to make a fluorescent red protein in one kind of macrophage. This allowed Ide, Yahara et al. to track these immune cells as the mice aged. The experiments showed that this subgroup of cells is first produced when the mice are embryos. They stay in the mouse kidneys into adulthood, and are so prolific that, over time, they eventually become the most common macrophage in older kidneys. The fact that one type of embryonically derived macrophage takes over with age may explain the increased inflammation and reduced repair capacity seen in aging kidneys. More studies will help scientists to understand how these particular cells contribute to age-related changes in susceptibility to kidney 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. As CCR7 (C-C motif chemokine receptor type 7) directs the homing of lymphocytes and dendritic cells into lymph nodes, we posited that dendritic cell-mediated T lymphocyte stimulation in the renal lymph node is CCR7 dependent and required for a full hypertensive response. We found that CCR7-deficient (CCR7 KO) mice had a blunted hypertensive response in our model of chronic Ang II (angiotensin II) infusion. Ang II-infused CCR7 KO animals had exaggerated accumulation of CD8+ T cells in the kidney but reduced numbers of CD4+ and CD8+ T cells in the kidney's draining lymph node. To understand whether CCR7-dependent homing of T lymphocytes or dendritic cells into the lymph node regulates the hypertensive response, we injected CCR7 KO or wild-type T cells or dendritic cells into CCR7 KO recipients, neither of which restored the full hypertensive response to Ang II infusion. However, adoptive transfer of wild-type but not CCR7 KO T lymphocytes into RAG1 (recombination-activating gene 1)-deficient mice that lack a lymphocyte niche restored full blood pressure elevation during Ang II infusion. Thus, CCR7-dependent interactions between T lymphocytes and dendritic cells are essential for T lymphocyte stimulation and hypertension accruing from inappropriate activation of the renin-angiotensin system.

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. Here, mice with T cell-specific deletion of TNF-α (TNF TKO) and wild-type (WT) control mice were subjected to the NTN model. At 14 days after NTN, kidney injury and fibrosis were increased in kidneys from TNF TKO mice compared with WT mice. PD1+CD4+ T cell numbers and mRNA levels of IL-17A were elevated in NTN kidneys of TNF TKO mice, suggesting that augmented local T helper 17 lymphocyte responses in the TNF TKO kidney may exaggerate renal injury and fibrosis. In turn, we found increased accumulation of neutrophils in TNF TKO kidneys during NTN. We conclude that TNF-α production in T lymphocytes mitigates NTN-induced kidney injury and fibrosis by inhibiting renal T helper 17 lymphocyte responses and infiltration of neutrophils.