Mitochondrial dysfunction is important in the pathogenesis of various kidney diseases and the mitochondria potentially serve as therapeutic targets necessitating further investigation. Alterations in mitochondrial biogenesis, imbalance between fusion and fission processes leading to mitochondrial fragmentation, oxidative stress, release of cytochrome c and mitochondrial DNA resulting in apoptosis, mitophagy, and defects in energy metabolism are the key pathophysiological mechanisms underlying the role of mitochondrial dysfunction in kidney diseases. Currently, various strategies target the mitochondria to improve kidney function and kidney treatment. The agents used in these strategies can be classified as biogenesis activators, fission inhibitors, antioxidants, mPTP inhibitors, and agents which enhance mitophagy and cardiolipin-protective drugs. Several glucose-lowering drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1-RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors are also known to have influences on these mechanisms. In this review, we delineate the role of mitochondrial dysfunction in kidney disease, the current mitochondria-targeting treatment options affecting the kidneys and the future role of mitochondria in kidney pathology.

Chronic kidney disease (CKD) is one of the most important public health concerns of the century, and is associated with high rates of morbidity, mortality and social costs. CKD evolving towards end-stage kidney disease (ESKD) is on the rise resulting in a greater number of patients requiring peritoneal dialysis (PD) and hemodialysis (HD). The aim of this manuscript is to review the current literature on the interplay of residual renal function (RRF) with clinical outcomes in ESKD. The persistence of RRF is one of the most important predictors of decreased morbidity, mortality, and better quality of life in both PD and HD patients. RRF contributes to the well-being of ESKD patients through various mechanisms including higher clearance of solutes, maintenance of fluid balance, removal of uremic toxins and control of electrolytes. Furthermore, RRF has beneficial effects on inflammation, anemia, malnutrition, diabetes mellitus, obesity, changes in the microbiota, and cardiac diseases. Several strategies have been proposed to preserve RRF, such as blockade of the renin–angiotensin–aldosterone system, better blood pressure control, incremental PD and HD. Several clinical trials investigating the issue of preservation of RRF are ongoing. They are needed to broaden our understanding of the interplay of RRF with clinical outcomes in ESKD. Graphical abstract

Kidney transplant recipients and dialysis patients constitute a risk group for severe COVID-19. They are highly advised to get vaccinated according to the current guidelines. However, data on antibody response, cell responses and protection from events, and factors that might alter this response after a routine full series of vaccination remain incomplete for these populations. The aim of this article was to analyze the antibody responses after a full series of mRNA-based SARS-CoV-2 vaccination in kidney transplantation and dialysis patients and to define the factors that alter seroconversion status in these populations. In this systematic review, 18 studies investigating the antibody response to full vaccination with two doses of COVID-19 mRNA vaccines in hemodialysis, peritoneal dialysis, and kidney transplant patients were included. Kidney transplant and dialysis patients have a lower seroconversion rate after mRNA-based SARS-CoV-2 vaccination than the healthy population: 27.2% for kidney transplantation, 88.5% for dialysis patients while all healthy control in these studies seroconverted. Moreover, anti-S antibody titers were lower in seroconverted kidney transplantation or dialysis patients than in healthy control in all studies that assessed this variable. Older age and dialysis vintage, immunosuppressive or chemotherapy treatment, and lower serum albumin, white blood cell, lymphocyte and hemoglobin counts were associated with lower/no antibody response to vaccination. Dialysis patients and kidney transplant recipients have lower seroconversion rates after a full series of mRNA-based SARS-CoV-2 vaccination than the general population. Several factors are associated with an altered antibody response. A third dose could be considered in this patient group.

The best treatment for patients with end-stage kidney disease is kidney transplantation, which, if successful provides both a reduction in mortality and a better quality of life compared to dialysis. Although there has been significant improvement in short-term outcomes after kidney transplantation, long-term graft survival still remains insufficient. As a result, there has been an increase in the number of individuals who need dialysis again after kidney transplant failure, and increasingly contribute to kidney transplant waiting lists. Starting dialysis after graft failure is a difficult task not only for the patients, but also for the nephrologists and the care team. Furthermore, recommendations for management of dialysis after kidney graft loss are lacking. Aim of this narrative review is to provide a perspective on the role of dialysis in the management of patients with failed kidney allograft. Although numerous studies have reported higher mortality in patients undergoing dialysis following kidney allograft failure, reports are contrasting. A patient-centered, individualized approach should drive the choices of initiating dialysis, dialysis modality, maintenance of immunosuppressive drugs and vascular access. Graphical abstract

Glioblastoma (GBM) is an aggressive primary brain tumor associated with a median survival of approximately 15 months following diagnosis. Current standard-of-care treatment includes surgical resection followed by radiotherapy and chemotherapy with the DNA-alkylating agent temozolomide (TMZ). However, tumor recurrence in a therapy-resistant state remains a major driver of poor patient outcomes. To investigate the molecular mechanisms underlying TMZ resistance, we generated in vitro models of acquired resistance by exposing initially TMZ-sensitive GBM cells to escalating doses of TMZ. Transcriptomic and chromatin accessibility profiling revealed extensive remodeling of DNA damage response (DDR) and DNA repair pathways that favored protection against TMZ-induced genotoxic stress. Although upregulation of O-6-methylguanine-DNA methyltransferase (MGMT) emerged as a dominant determinant of resistance in our models, the data suggested that additional adaptive resistance mechanisms contribute to the resistant phenotype. To identify targetable epigenetic dependencies associated with TMZ resistance, we performed a chemical screen using an epigenetic probe library. This screen identified multiple histone deacetylase (HDAC) inhibitors that selectively impaired the viability of TMZ-resistant cells, either as monotherapy or in combination with TMZ. Among these, HDAC6-selective inhibitors, including Ricolinostat, were particularly effective at inducing cell death in TMZ-resistant GBM models. Mechanistically, HDAC6 inhibition reduced the expression of key DDR-associated genes, while MGMT responses varied depending on cellular context and treatment duration. Furthermore, pharmacological inhibition and loss-of-function studies demonstrated that targeting HDAC6 could restore TMZ sensitivity by altering the balance of DNA repair pathway activity, potentially acting as a compensatory mechanism for MGMT-mediated resistance. Collectively, our findings identify HDAC6 as an epigenetic vulnerability in acquired TMZ-resistant GBM and support the therapeutic potential of HDAC6 inhibition as a strategy to overcome TMZ resistance in glioblastoma patients.

Even though insulin therapy is the cornerstone of diabetes mellitus management, multiple daily injections are associated with poor adherence. Once-weekly basal insulin therapy has emerged as a novel therapeutic approach and is being evaluated in multiple ongoing clinical trials. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of once-weekly insulin efsitora therapy compared with once-daily basal insulin therapy in patients with type 1 or type 2 diabetes mellitus. Primary endpoints include glycemic control, assessed via HbA1c reduction, and hypoglycemia, classified as level 1 (54-69 mg/dL), level 2 (<54 mg/dl), or level 3 (any hypoglycemic episode characterized by altered mental and/or physical functioning requiring assistance). We have performed a systematic review and meta-analysis through an extensive literature search of major databases including Scopus, PubMed/Medline, and Cochrane databases, and have only included randomized controlled trials. We have included 5 randomized controlled trials comprising a total of 2,562 patients: 1,358 (53%) in the insulin efsitora arm and 1,204 (47%) in the insulin degludec arm. Our data show that insulin efsitora therapy achieved a similar HbA1c reduction overall (estimated treatment difference (ETD) 0.08%, 95% CI -0.01 to 0.17; I² = 42.6%), in patients with type 1 diabetes mellitus (ETD 0.10%, 95% CI -0.64-0.85; I² =24.0%) and in patients with type 2 diabetes mellitus (ETD 0.05%, 95% CI -0.25 – 0.26; I² = 38.1%) compared with insulin degludec therapy. Moreover, no statistically significant differences were identified in overall hypoglycemic events, level 2 or 3 hypoglycemic episodes, or nocturnal hypoglycemia, irrespective of diabetes mellitus subtype. Our meta-analysis shows no statistically significant difference between once-weekly insulin efsitora therapy and insulin degludec therapy in terms of glycemic control and hypoglycemic events.