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Elevated angiopoietin-2 is associated with diverse inflammatory conditions, including sepsis, a leading global cause of mortality. During inflammation, angiopoietin-2 antagonizes the endothelium-enriched receptor Tie2 to destabilize the vasculature. In other contexts, angiopoietin-2 stimulates Tie2. The basis for context-dependent antagonism remains incompletely understood. Here, we show that inflammation-induced proteolytic cleavage of angiopoietin-2 converts this ligand from Tie2 agonist to antagonist. Conditioned media from stimulated macrophages induced endothelial angiopoietin-2 secretion. Unexpectedly, this was associated with reduction of the 75 kDa full-length protein and appearance of new 25 and 50 kDa C-terminal fragments. Peptide sequencing proposed cathepsin K as a candidate protease. Cathepsin K was necessary and sufficient to cleave angiopoietin-2. Recombinant 25 and 50 kDa angiopoietin-2 fragments (cANGPT225 and cANGPT250) bound and antagonized Tie2. Cathepsin K inhibition with the phase 3 small-molecule inhibitor odanacatib improved survival in distinct murine sepsis models. Full-length angiopoietin-2 enhanced survival in endotoxemic mice administered odanacatib and, conversely, increased mortality in the drug's absence. Odanacatib's benefit was reversed by heterologous cANGPT225. Septic humans accumulated circulating angiopoietin-2 fragments, which were associated with adverse outcomes. These results identify cathepsin K as a candidate marker of sepsis and a proteolytic mechanism for the conversion of angiopoietin-2 from Tie2 agonist to antagonist, with therapeutic implications for inflammatory conditions associated with angiopoietin-2 induction.

Lipoprotein modification by reactive dicarbonyls, including isolevuglandin (IsoLG), produces dysfunctional particles. Kidneys participate in lipoprotein metabolism, including tubular uptake. However, the process beyond the proximal tubule is unclear, as is the effect of kidney injury on this pathway. We found that patients and animals with proteinuric injury have increased urinary apolipoprotein AI (apoAI), IsoLG, and IsoLG adduct enrichment of the urinary apoAI fraction compared with other proteins. Proteinuric mice, induced by podocyte-specific injury, showed more tubular absorption of IsoLG-apoAI and increased expression of lipoprotein transporters in proximal tubular cells compared with uninjured animals. Renal lymph reflects composition of the interstitial compartment and showed increased apoAI and IsoLG in proteinuric animals, supporting a tubular cell-interstitium-lymph pathway for renal handling of lipoproteins. IsoLG-modified apoAI was not only a marker of renal injury but also directly damaged renal cells. IsoLG-apoAI increased inflammatory cytokines in cultured tubular epithelial cells (TECs), activated lymphatic endothelial cells (LECs), and caused greater contractility of renal lymphatic vessels than unmodified apoAI. In vivo, inhibition of IsoLG by a dicarbonyl scavenger reduced both albuminuria and urinary apoAI and decreased TEC and LEC injury, lymphangiogenesis, and interstitial fibrosis. Our results indicate that IsoLG-modified apoAI is, to our knowledge, a novel pathogenic mediator and therapeutic target in kidney disease.

Abstract Rationale Acute kidney injury may contribute to distant organ dysfunction. Few studies have examined kidney injury as a risk factor for delirium and coma. Objectives To examine whether acute kidney injury is associated with delirium and coma in critically ill adults. Methods In a prospective cohort study of intensive care unit patients with respiratory failure and/or shock, we examined the association between acute kidney injury and daily mental status using multinomial transition models adjusting for demographics, nonrenal organ failure, sepsis, prior mental status, and sedative exposure. Acute kidney injury was characterized daily using the difference between baseline and peak serum creatinine and staged according to Kidney Disease Improving Global Outcomes criteria. Mental status (normal vs. delirium vs. coma) was assessed daily with the Confusion Assessment Method for the ICU and Richmond Agitation-Sedation Scale. Measurements and Main Results Among 466 patients, stage 2 acute kidney injury was a risk factor for delirium (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.07–2.26) and coma (OR, 2.04; 95% CI, 1.25–3.34) as was stage 3 injury (OR for delirium, 2.56; 95% CI, 1.57–4.16) (OR for coma, 3.34; 95% CI, 1.85–6.03). Daily peak serum creatinine (adjusted for baseline) values were also associated with delirium (OR, 1.35; 95% CI, 1.18–1.55) and coma (OR, 1.44; 95% CI, 1.20–1.74). Renal replacement therapy modified the association between stage 3 acute kidney injury and daily peak serum creatinine and both delirium and coma. Conclusions Acute kidney injury is a risk factor for delirium and coma during critical illness.

Elevated angiopoietin-2 is associated with diverse inflammatory conditions, including sepsis, a leading global cause of mortality. During inflammation, angiopoietin-2 antagonizes the endothelium- enriched receptor Tie2 to destabilize the vasculature. In other contexts, angiopoietin-2 stimulates Tie2. The basis for context-dependent antagonism remains incompletely understood. Here, we show that inflammation-induced proteolytic cleavage of angiopoietin-2 converts this ligand from Tie2 agonist to antagonist. Conditioned media from stimulated macrophages induced endothelial angiopoietin- 2 secretion. Unexpectedly, this was associated with reduction of the 75 kDa full- length protein and appearance of new 25 and 50 kDa C-terminal fragments. Peptide sequencing proposed cathepsin K as a candidate protease. Cathepsin K was necessary and sufficient to cleave angiopoietin-2. Recombinant 25 and 50 kDa angiopoietin-2 fragments ([cANGPT2.sub.25] and [cANGPT2.sub.50]) bound and antagonized Tie2. Cathepsin K inhibition with the phase 3 small-molecule inhibitor odanacatib improved survival in distinct murine sepsis models. Full-length angiopoietin-2 enhanced survival in endotoxemic mice administered odanacatib and, conversely, increased mortality in the drug's absence. Odanacatib's benefit was reversed by heterologous [cANGPT2.sub.25]. Septic humans accumulated circulating angiopoietin-2 fragments, which were associated with adverse outcomes. These results identify cathepsin K as a candidate marker of sepsis and a proteolytic mechanism for the conversion of angiopoietin-2 from Tie2 agonist to antagonist, with therapeutic implications for inflammatory conditions associated with angiopoietin-2 induction.

Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid–binding protein (L-FABP), neutrophil gelatinase–associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70–0.86), which improved to 0.82 (95% confidence interval 0.75–0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.

BackgroundAlthough high-density lipoprotein (HDL) modulates many cell types in the cardiovascular system, little is known about HDL in the kidney. We assessed urinary excretion of apolipoprotein AI (apoAI), the main protein in HDL.MethodsWe enrolled 228 children with various kidney disorders and 40 controls. Urinary apoAI, albumin, and other markers of kidney damage were measured using ELISA, apoAI isoforms with Western blot, and renal biopsies stained for apoAI.ResultsPatients followed in nephrology clinic had elevated urinary apoAI vs. controls (median 0.074 μg/mg; interquartile range (IQR) 0.0160–0.560, vs. 0.019 μg/mg; IQR 0.004–0.118, p < 0.001). Patients with tubulopathies, renal dysplasia/congenital anomalies of the kidney and urogenital tract, glomerulonephritis, and nephrotic syndrome (NS) in relapse had the greatest elevations (p ≤ 0.01). Patients with NS in remission, nephrolithiasis, polycystic kidney disease, transplant, or hypertension were not different from controls. Although all NS in relapse had higher apoAI excretion than in remission (0.159 vs. 0.0355 μg/mg, p = 0.01), this was largely driven by patients with focal segmental glomerulosclerosis (FSGS). Many patients, especially with FSGS, had increased urinary apoAI isoforms. Biopsies from FSGS patients showed increased apoAI staining at proximal tubule brush border, compared to diffuse cytoplasmic distribution in minimal change disease.ConclusionsChildren with kidney disease have variably increased urinary apoAI depending on underlying disease. Urine apoAI is particularly elevated in diseases affecting proximal tubules. Kidney disease is also associated with high molecular weight (HMW) apoAI isoforms in urine, especially FSGS. Whether abnormal urinary apoAI is a marker or contributor to renal disease awaits further study.

OBJECTIVE. The Multiple Errands Test (MET) was designed to measure the effect of executive dysfunction on everyday life activities, but little is known about the cognitive requirements for successful performance. This study’s objective was to investigate cognitive functions associated with successful MET performance, specifically, the Baycrest-MET. METHOD. Correlation analysis examined relationships between Baycrest-MET performance and neuropsychological functioning in participants with acquired brain injury (ABI; N = 27). RESULTS. The association of tasks omitted with executive function (EF) accounted for 15.2%–42.3% of the variance; the association of tasks omitted with attention and processing speed, for 16.8%–24.0%; and the association of tasks omitted and total rule breaks with visuospatial memory, for 18.5%–31.4%. CONCLUSION. Poor performance on the Baycrest-MET in people with ABI is associated with impairments of EF, attention, memory, and processing speed. Different patterns of performance may arise from different constellations of impairments.

Regardless of age, education, or social status, we all experience moments where we ask ourselves, “what was I thinking?!?” Typically, we experience errors of this sort, or slips of action, during routine tasks that require a whole sequence of movements. However, most action slip research has focused on creating response conflict within single movements. The Slip Induction Task (SIT) is a step toward creating response conflict within truer to life action routines. As such, the SIT attempts to induce action slips in a well-learned movement routine through the occasional presentation of unexpected cues. We find that the SIT is able to reliably induce action slips, especially when the unexpected cue necessitates a movement to an unexpected target location. Furthermore, when participants are able to avoid an action slip, these changes in movement routine are accompanied by a cost in speed.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a significant clinical problem with unclear underlying mechanisms. Emerging evidence suggests that alterations in tryptophan metabolism, particularly in the production of downstream metabolites such as quinolinic acid (QA), play a role in renal pathophysiology. QA is a NAD biosynthesis intermediate metabolized by the enzyme quinolinate phosphoribosyltransferase (QPRT). In this study, we investigated the role of QA in the AKI-to-CKD transition using experimental mouse models and clinical observations and leveraging multiple omics approaches. Systematic metabolomic profiling identified endogenous QA as one of the most significantly elevated metabolites following folic acid-(FA) induced injury. Exogenous QA exacerbated FA-induced kidney dysfunction. Conversely, aged mice deficient in QPRT showed worsened expression of kidney fibrosis markers even in absence of kidney injury, while younger littermates exhibited worsened induced kidney injury. Mice lacking QA-producing enzymes resisted experimental AKI and AKI-to-CKD progression. Multimodal spatial metabolomics analysis of human AKI kidney biopsies revealed QA accumulation in regions of inflammatory infiltration. Finally, children with CKD exhibited higher urinary QA levels compared to healthy controls. These findings underscore QA as a potential mediator of kidney injury and a therapeutic target for preventing the progression from AKI to CKD.