Chronic kidney disease (CKD) presents an ever-growing disease burden for the world’s aging population. It is characterized by numerous changes to the kidney, including a decrease in renal mass, renal fibrosis, and a diminished glomerular filtration rate. The premature aging phenotype observed in CKD is associated with cellular senescence, particularly of renal tubular epithelial cells (TECs), which contributes to chronic inflammation through the production of a proinflammatory senescence associated secretory phenotype (SASP). When coupled with changes in immune system composition and progressive immune dysfunction, the accumulation of senescent kidney cells acts as a driver for the progression of CKD. The targeting of senescent cells may well present an attractive therapeutic avenue for the treatment of CKD. We propose that the targeting of senescent cells either by direct inhibition of pro-survival pathways (senolytics) or through the inhibition of their proinflammatory secretory profile (senomorphics) together with immunomodulation to enhance immune system surveillance of senescent cells could be of benefit to patients with CKD.

Background: In the general adult population, lymphopaenia is associated with an increased risk for hospitalisation with infection and infection-related death. The quality of evidence and strength of association between perioperative lymphopaenia across different surgical procedures and mortality/morbidity has not been examined by systematic review or meta-analysis. Methods: We searched MEDLINE, Embase, Web of Science, Google Scholar, and Cochrane databases from their inception to June 29, 2020 for observational studies reporting lymphocyte count and in-hospital mortality rate in adults. We defined preoperative lymphopaenia as a lymphocyte count 1.0e1.5Â10 9 L À1 . Meta-analysis was performed using either fixed or random effects models. Quality was assessed using the NewcastleeOttawa Scale. The I 2 index was used to quantify heterogeneity. The primary outcome was in-hospital mortality rate and mortality rate at 30 days. Results: Eight studies met the inclusion criteria for meta-analysis, comprising 4811 patients (age range, 46e91 yr; female, 20e79%). These studies examined preoperative lymphocyte count exclusively. Studies were of moderate to high quality overall, ranking >7 using the NewcastleeOttawa Scale. Preoperative lymphopaenia was associated with a threefold increase in mortality rate (risk ratio [RR]¼3.22; 95% confidence interval [CI], 2.19e4.72; P<0.01, I 2 ¼0%) and more frequent major postoperative complications (RR¼1.33; 95% CI, 1.21e1.45; P<0.01, I 2 ¼6%), including cardiovascular morbidity (RR¼1.77; 95% CI, 1.45e2.15; P<0.01, I 2 ¼0%), infections (RR¼1.45; 95% CI, 1.19e1.76; P<0.01, I 2 ¼0%), and acute renal dysfunction (RR¼2.66; 95% CI, 1.49e4.77; P<0.01, I 2 ¼1%). Conclusion: Preoperative lymphopaenia is associated with death and complications more frequently, independent of the type of surgery. Prospero registry number: CRD42020190702.

Background and ObjectivesAging is known to exacerbate neuroinflammation, and in the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), an older age is associated with a worse prognosis. We have previously shown the activation of cell senescence pathways in the proteome of peripheral blood mononuclear cells and the increase of proinflammatory cytokines in blood from individuals living with ALS. In this single-center, retrospective study, we investigated the expression of senescent-like blood mononuclear cells in ALS.MethodsWe first applied multidimensional cytometry by time-of-flight (CyTOF) to study the senescent immunophenotype of blood mononuclear cells from 21 patients with ALS and 10 healthy controls (HCs). We then used targeted flow cytometry (FC) to investigate frequencies of senescent blood lymphocytes in 40 patients with ALS and 20 HCs. Longitudinal analysis included 2 additional time points in 17 patients with ALS. Frequencies of senescent-like lymphocytes were analyzed in relation to survival.ResultsUnsupervised clustering of CyTOF data showed higher frequencies of senescent CD4+CD27−CD57+T cells in patients with ALS compared with those in HCs (p= 0.0017, false discovery (FDR)-adjustedp= 0.029). Moderate to strong negative correlations were identified between CD4 T central memory–cell frequencies and survival (R = −061,p= 0.01; FDR-adjustedp< 0.1) and between CD95 CD8 cells and ALS functional rating scale revised at baseline (R = −0.72,p= 0.001; FDR-adjustedp< 0.1).Targeted FC analysis showed higher memory T regulatory cells (p= 0.0052) and memory CD8+T cell (M-Tc;p= 0.0006) in bulbar ALS (A-B) compared with those in limb ALS (A-L), while late memory B cells (LM-B) were also elevated in A-B and fast-progressing ALS (p= 0.0059). Higher M-Tc levels separated A-B from A-L (AUC: 0.887;p< 0.0001). A linear regression model with prespecified clinical independent variables and neurofilament light chain plasma concentration showed that higher frequencies of LM-B predicted a shorter survival (hazard ratio: 1.094, CI: 1.026–1.167;p= 0.006).DiscussionOur data suggest that a systemic elevation of senescent and late memory T and B lymphocytes is a feature of faster progressing ALS and of ALS individuals with bulbar involvement. Lymphocyte senescence and their memory state may be central to the immune dysregulation known to drive disease progression in ALS and a target for biomarkers and therapeutics discovery.

Monocytes expressing the inflammation suppressing active CD11b, a beta2 integrin, may regulate neuroinflammation and modify clinical outcomes in amyotrophic lateral sclerosis (ALS). In this single site, retrospective study, peripheral blood mononuclear cells from 38 individuals living with ALS and 20 non-neurological controls (NNC) were investigated using flow cytometry to study active CD11b integrin classical (CM), intermediate (IM) and non-classical (NCM) monocytes during ALS progression. Seventeen ALS participants were sampled at the baseline (V1) and at two additional time points (V2 and V3) for longitudinal analysis. Active CD11b+ CM frequencies increased steeply between the baseline and V3 (ANOVA repeated measurement, p < 0.001), and the V2/V1 ratio negatively correlated with the disease progression rate, similar to higher frequencies of active CD11b+ NCM at the baseline (R = −0.6567; p = 0.0031 and R = 0.3862; p = 0.0168, respectively). CD11b NCM, clinical covariates and neurofilament light-chain plasma concentration at the baseline predicted shorter survival in a multivariable and univariate analysis (CD11b NCM—HR: 1.05, CI: 1.01–1.11, p = 0.013. Log rank: above median: 43 months and below median: 21.22 months; p = 0.0022). Blood samples with the highest frequencies of active CD11b+ IM and NCM contained the lowest concentrations of soluble CD11b. Our preliminary data suggest that the levels of active CD11b+ monocytes and NCM in the blood predict different clinical outcomes in ALS.