Modifiable Lifestyle Behaviors and CKD Progression: A Narrative Review.

Living a healthy lifestyle is one of the safest and most cost-effective ways to improve one's quality of life and prevent and/or manage chronic disease. As such, current CKD management guidelines recommend that patients adhere to a healthy diet, perform ≥150 minutes per week of physical activity, manage their body weight, abstain from tobacco use, and limit alcohol. However, there are limited studies that investigate the relationship between these lifestyle factors and the progression of CKD among people with established CKD. In this narrative review, we examine the reported frequencies of health lifestyle behavior engagement among individuals with non-dialysis-dependent CKD and the existing literature that examines the influences of diet, physical activity, weight management, alcohol consumption, and tobacco use on the progression of CKD, as measured by decline in GFR, incident ESKD, or elevated proteinuria or albuminuria in individuals with CKD. Many of the available studies are limited by length of follow-up and small sample sizes, and meta-analyses were limited because the studies were sparse and had heterogeneous classifications of behaviors and/or referent groups and of CKD progression. Further research should be done to determine optimal methods to assess behaviors to better understand the levels at which healthy lifestyle behaviors are needed to slow CKD progression, to investigate the effect of combining multiple lifestyle behaviors on important clinical outcomes in CKD, and to develop effective techniques for behavior change. Despite the lack of evidence of efficacy from large trials on the ability of lifestyle behaviors to slow CKD progression, maintaining a healthy lifestyle remains a cornerstone of CKD management given the undisputed benefits of healthy lifestyle behaviors on cardiovascular health, BP control, and survival.

Antigenic Restimulation of Virus-Specific Memory CD8+ T Cells Requires Days of Lytic Protein Accumulation for Maximal Cytotoxic Capacity.

In various infections or vaccinations of mice or humans, reports of the persistence and the requirements for restimulation of the cytotoxic mediators granzyme B (GrB) and perforin (PRF) in CD8+ T cells have yielded disparate results. In this study, we examined the kinetics of PRF and GrB mRNA and protein expression after stimulation and associated changes in cytotoxic capacity in virus-specific memory cells in detail. In patients with controlled HIV or cleared respiratory syncytial virus (RSV) or influenza virus infections, all virus-specific CD8+ T cells expressed low PRF levels without restimulation. Following stimulation, they displayed similarly delayed kinetics for lytic protein expression, with significant increases occurring by days 1 to 3 before peaking on days 4 to 6. These increases were strongly correlated with, but were not dependent upon, proliferation. Incremental changes in PRF and GrB percent expression and mean fluorescence intensity (MFI) were highly correlated with increases in HIV-specific cytotoxicity. mRNA levels in HIV-specific CD8+ T-cells exhibited delayed kinetics after stimulation as with protein expression, peaking on day 5. In contrast to GrB, PRF mRNA transcripts were little changed over 5 days of stimulation (94-fold versus 2.8-fold, respectively), consistent with posttranscriptional regulation. Changes in expression of some microRNAs, including miR-17, miR-150, and miR-155, suggested that microRNAs might play a significant role in regulation of PRF expression. Therefore, under conditions of extremely low or absent antigen levels, memory virus-specific CD8+ T cells require prolonged stimulation over days to achieve maximal lytic protein expression and cytotoxic capacity.IMPORTANCE Antigen-specific CD8+ T cells play a major role in controlling most virus infections, primarily by perforin (PRF)- and granzyme B (GrB)-mediated apoptosis. There is considerable controversy regarding whether PRF is constitutively expressed, rapidly increased similarly to a cytokine, or delayed in its expression with more prolonged stimulation in virus-specific memory CD8+ T cells. In this study, the degree of cytotoxic capacity of virus-specific memory CD8+ T cells was directly proportional to the content of lytic molecules, which required antigenic stimulation over several days for maximal levels. This appeared to be modulated by increases in GrB transcription and microRNA-mediated posttranscriptional regulation of PRF expression. Clarifying the requirements for maximal cytotoxic capacity is critical to understanding how viral clearance might be mediated by memory cells and what functions should be induced by vaccines and immunotherapies.