With aging, the kidney undergoes inexorable and progressive changes in structural and functional performance. These aging-related alterations are more obvious and serious in diabetes mellitus (DM). Renal accelerated aging under DM conditions is associated with multiple stresses such as accumulation of advanced glycation end products (AGEs), hypertension, oxidative stress, and inflammation. The main hallmarks of cellular senescence in diabetic kidneys include cyclin-dependent kinase inhibitors, telomere shortening, and diabetic nephropathy-associated secretory phenotype. Lysosome-dependent autophagy and antiaging proteins Klotho and Sirt1 play a fundamental role in the accelerated aging of kidneys in DM, among which the autophagy-lysosome system is the convergent mechanism of the multiple antiaging pathways involved in renal aging under DM conditions. Metformin and the inhibitor of sodium–glucose cotransporter 2 are recommended due to their antiaging effects independent of antihyperglycemia, besides angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. Additionally, diet intervention including low protein and low AGEs with antioxidants are suggested for patients with diabetic nephropathy (DN). However, their long-term benefits still need further study. Exploring the interactive relationships among antiaging protein Klotho, Sirt1, and autophagy-lysosome system may provide insight into better satisfying the urgent medical needs of elderly patients with aging-related DN.

Diabetic kidney disease (DKD), a significant complication associated with diabetes mellitus, presents limited treatment options. The progression of DKD is marked by substantial lipid disturbances, including alterations in triglycerides, cholesterol, sphingolipids, phospholipids, lipid droplets, and bile acids (BAs). Altered lipid metabolism serves as a crucial pathogenic mechanism in DKD, potentially intertwined with cellular ferroptosis, lipophagy, lipid metabolism reprogramming, and immune modulation of gut microbiota (thus impacting the liver-kidney axis). The elucidation of these mechanisms opens new potential therapeutic pathways for DKD management. This research explores the link between lipid metabolism disruptions and DKD onset.

Trimethylamine N-oxide (TMAO) derived from gut microbiota causes kidney-heart damage in chronic kidney disease (CKD) patients. However, it is controversial whether CKD patients with higher TMAO are associated with a higher risk of death. We aimed to assess the correlation between circulating TMAO concentration and the risk of all-cause and cardiovascular death in CKD patients of different dialysis statuses and different races by dose-response analyses, and the underlying mechanisms were also explored by analyzing the correlations of TMAO with glomerular filtration rate (GFR) and inflammation. PubMed, Web of Science, and EMBASE were systematically searched up to 1 July 2022. A total of 21 studies involving 15,637 individuals were included. Stata 15.0 was used to perform the meta-analyses and dose-response analyses with extracted data. Subgroup analyses were conducted to recognize possible sources of heterogeneity. The risk of all-cause mortality was increased in non-dialysis CKD patients (RR = 1.26, 95%CI = 1.03-1.54, p = 0.028) and non-black dialysis patients (RR = 1.62, 95%CI = 1.19-2.22, p = 0.002) with the highest circulating TMAO concentration, and the association was confirmed to be linear. In addition, an increased risk of cardiovascular mortality was also found in non-black dialysis patients with the highest circulating TMAO concentration (RR = 1.72, 95%CI = 1.19-2.47, p = 0.004), likewise, a linear association was identified. However, for dialysis patients including blacks with high TMAO concentrations, there was no significant increase in either all-cause mortality (RR = 0.98, 95%CI = 0.94-1.03, p = 0.542) or cardiovascular mortality (RR = 0.87, 95% CI = 0.65-1.17, p = 0.362). Meanwhile, we verified strong correlations between TMAO and both GFR (r= -0.49; 95% CI= -0.75, -0.24; p < 0.001) and inflammatory markers (r = 0.43; 95% CI= 0.03, 0.84; p = 0.036) in non-dialysis patients. Increased circulating TMAO concentrations increase the risk of all-cause mortality in non-dialysis and non-black dialysis CKD patients. Moreover, elevated TMAO levels raise the cardiovascular mortality risk in non-black dialysis patients.Key messagesNon-dialysis and non-black dialysis CKD patients with higher circulating TMAO concentrations are associated with an increased risk of all-cause mortality.Non-black dialysis patients with higher concentrations of TMAO are associated with an increased risk of cardiovascular mortality.Circulating TMAO concentrations have a strong negative correlation with GFR and a positive correlation with inflammation biomarkers in non-dialysis CKD patients.

The catabolic process that delivers cytoplasmic constituents to the lysosome for degradation, known as autophagy, is thought to act as a cytoprotective mechanism in response to stress or as a pathogenic process contributing towards cell death. Animal and human studies have shown that autophagy is substantially dysregulated in renal cells in diabetes, suggesting that activating autophagy could be a therapeutic intervention. However, under prolonged hyperglycaemia with impaired lysosome function, increased autophagy induction that exceeds the degradative capacity in cells could contribute toward autophagic stress or even the stagnation of autophagy, leading to renal cytotoxicity. Since lysosomal function is likely key to linking the dual cytoprotective and cytotoxic actions of autophagy, it is important to develop novel pharmacological agents that improve lysosomal function and restore autophagic flux. In this review, we first provide an overview of the autophagic‐lysosomal pathway, particularly focusing on stages of lysosomal degradation during autophagy. Then, we discuss the role of adaptive autophagy and autophagic stress based on lysosomal function. More importantly, we focus on the role of autophagic stress induced by lysosomal dysfunction according to the pathogenic factors (including high glucose, advanced glycation end products (AGEs), urinary protein, excessive reactive oxygen species (ROS) and lipid overload) in diabetic kidney disease (DKD), respectively. Finally, therapeutic possibilities aimed at lysosomal restoration in DKD are introduced.

Diabetic kidney disease (DKD) is a prevailing complication arising from diabetes mellitus. Unfortunately, there are no trustworthy and efficacious treatment modalities currently available. In recent times, compelling evidence has emerged regarding the intricate correlation between the kidney and the gut microbiota, which is considered the largest immune organ within the human physique. Various investigations have demonstrated that the perturbation of the gut microbiota and its associated metabolites potentially underlie the etiology and progression of DKD. This phenomenon may transpire through perturbation of both the innate and the adaptive immunity, leading to a burdensome allostatic load on the body and ultimately culminating in the development of DKD. Within this literature review, we aim to delve into the intricate interplay between the gut microbiota, its metabolites, and the immune system in the context of DKD. Furthermore, we strive to explore and elucidate potential chemical interventions that could hold promise for the treatment of DKD, thereby offering invaluable insights and directions for future research endeavors.

Background: Mobile health interventions utilising telephone calls are promising tools for diabetes management. However, there is still a lack of convincing evidence demonstrating their beneficial effects on cardiovascular risk factors. The aim of this meta-analysis of randomised controlled trials was to assess the effect of telephone calls on glycaemic control and other cardiovascular risk factors in type 2 diabetes mellitus patients. Methods: Two independent reviewers searched three online databases (PubMed, the Cochrane Library and EMBASE) to identify relevant English-language randomised controlled trials up to September 2017. Randomised controlled trials that assessed the effects of telephone calls on glycaemic control and other cardiovascular risk factors in type 2 diabetes mellitus patients were included. Effect size was calculated for changes in glycosylated haemoglobin A1c, weight, blood pressure and lipid levels using fixed- or random-effects models. Results: Eighteen studies involving 3954 patients were included in the meta-analysis. Compared with usual care, telephone calls significantly decreased glycosylated haemoglobin A1c, by 0.12% (95% confidence interval: −0.22% to −0.02%). Univariate regression analysis showed that none of the covariates (number of participants, baseline age, baseline glycosylated haemoglobin A1c, duration of diabetes, call maker, number of calls and duration of study) had an impact on glycosylated haemoglobin A1c. For other cardiovascular risk factors, telephone calls significantly reduced systolic blood pressure by 0.19 mm Hg (95% confidence interval: −0.34% to −0.03%) but non-significantly changed diastolic blood pressure, body mass index, low-density lipoprotein cholesterol, total cholesterol, triglyceride or high-density cholesterol levels. Conclusions: This meta-analysis supports the hypothesis that telephone calls offer moderate benefits for glycosylated haemoglobin A1c and systolic blood pressure reduction among type 2 diabetes mellitus patients. However, the data remain insufficient regarding the association of telephone calls with lowered diastolic blood pressure, body mass index or improved lipoprotein profiles.