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Elevated levels of circulating tumor necrosis factor receptors 1 and 2 (cTNFR1/2) predict chronic kidney disease (CKD) progression; however, the mechanisms of their release remain unknown. Whether acute kidney injury (AKI) drives cTNFR1/2 elevations and whether they predict disease outcomes after AKI remain unknown. In this study, we used AKI patient serum and urine samples, mouse models of kidney injury (ischemic, obstructive, and toxic), and progression to fibrosis, nephrectomy, and related single-cell RNA-sequencing datasets to experimentally test the role of kidney injury on cTNFR1/2 levels. We show that TNFR1/2 serum and urine levels are highly elevated in all of the mouse models of kidney injury tested, beginning within one hour post injury, and correlate with its severity. Consistent with this, serum and urine TNFR1/2 levels are increased in AKI patients and correlate with the severity of kidney failure. Kidney tissue expression of TNFR1/2 after AKI is only slightly increased and bilateral nephrectomies lead to strong cTNFR1/2 elevations, suggesting the release of these receptors by extrarenal sources. The injection of the uremic toxin indoxyl sulfate in healthy mice induces moderate cTNFR1/2 elevations. Moreover, TNF neutralization does not affect early cTNFR1/2 elevations after AKI. These data suggest that cTNFR1/2 levels in AKI do not reflect injury-induced TNF activity, but rather a rapid response to loss of kidney function and uremia. In contrast to traditional disease biomarkers, such as serum creatinine or BUN, cTNFR1/2 levels remain elevated for weeks after severe kidney injury. At these later timepoints, cTNFR1/2 levels positively correlate with remaining kidney injury. During the AKI-to-CKD transition, elevations of TNFR1/2 kidney expression and of cTNFR2 levels correlate with kidney fibrosis levels. In conclusion, our data demonstrate that kidney injury drives acute increases in cTNFR1/2 serum levels, which negatively correlate with kidney function. Sustained TNFR1/2 elevations after kidney injury during AKI-to-CKD transition reflect persistent tissue injury and progression to kidney fibrosis.

Global DNA hypermethylation and mitochondrial dysfunction are reported to be associated with the development of mild cognitive decline (MCI). The present study aims to generate preliminary data that connect the above association with post-surgical coronary artery bypass grafting (CABG) cognitive decline in patients. Data were collected from 70 CABG patients and 25 age-matched controls. Cognitive function was assessed using the Montreal Cognitive Assessment (MOCA) test on day 1 (before surgery) and on the day of discharge. Similarly, blood was collected before and one day after the CABG procedure for mitochondrial functional analysis and expression of DNA methylation genes. Test analysis score suggested 31 (44%) patients had MCI before discharge. These patients showed a significant decrease in complex I activity and an increase in malondialdehyde levels (p < 0.001) from the control blood samples. Post-surgical samples showed a significant reduction in blood MT-ND1 mRNA expression from control and from pre-surgical samples (p < 0.005), along with elevated DNMT1 gene expression (p < 0.047), with an insignificant increase in TET1 and TET3 gene expression. Correlation analysis showed a significant positive relation between cognitive decline and elevated blood DNMT1 and declined blood complex I activity, signifying that cognitive decline experienced by post-surgical CABG patients is associated with increased DNMT1 expression and declined complex I activity. Based on the data, we conclude that both DNA hypermethylation and mitochondrial dysfunction are associated with post-CABG MCI, where the former is negatively correlated, and the latter is positively correlated with post-surgical MCI in CABG cases. Additionally, a multimarker approach that comprises MOCA, DNA methylation, DNMT, and NQR activities can be utilized to stratify the population that is sensitive to developing post-CABG MCI.