Ischemic stroke is highly prevalent in chronic kidney disease (CKD) patients and has been associated with a higher risk of neurological deterioration and in-hospital mortality. To date, little is known about the processes by which CKD worsens ischemic stroke. This work aimed to investigate the cellular and molecular mechanism associated with ischemic stroke severity in an in vivo model of CKD. CKD was induced through right kidney cortical electrocautery in 8-week-old female C57BL/6 J mice followed by left total nephrectomy. Transient middle cerebral artery occlusion (tMCAO) was performed 6 weeks after left nephrectomy. Twenty-four hours after tMCAO, the infarct volumes were significantly wider in CKD than in SHAM mice. CKD mice displayed decreased neuroscore, impaired ability to remain on rotarod device, weaker muscular strength and decreased prehensile score. Apoptosis, neuronal loss, glial cells recruitment and microglia/macrophages M₁ signature genes CD32, CD86, IL-1β, IL-6, MCP1 and iNOS were significantly increased within ischemic lesions of CKD mice. This effect was associated with decreased AMP kinase phosphorylation and increased activation of the NFΚB pathway. Pharmacological targeting of AMP kinase activity, which is known to block microglia/macrophages M₁ polarization, appears promising to improve stroke recovery in CKD.

Background: Uremic toxins have emerged as potential mediators of morbidity and mortality in patients with chronic kidney disease (CKD). Indole-3-acetic acid (IAA, a tryptophan-derived uremic toxin) might be a useful biomarker in patients with CKD. The objectives of the present study were to (i) describe IAA concentrations in a cohort of non-transplanted patients with CKD and a cohort of transplanted patients with CKD, and (ii) investigate the possible relationship between IAA levels and adverse outcomes in the two cohorts. Methods: Levels of free and total IAA were assayed in the two prospective CKD cohorts (140 non-transplanted patients and 311 transplanted patients). Cox multivariate analyses were used to evaluate the association between IAA levels and outcomes (mortality, cardiovascular events, and graft loss). Results: In the non-transplanted CKD cohort, free and total IAA increased progressively with the CKD stage. In the transplanted CKD cohort, free and total IAA levels were elevated at the time of transplantation but had fallen substantially at one-month post-transplantation. Indole acetic acid concentrations were lower in transplanted patients than non-dialysis non-transplanted patients matched for estimated glomerular filtration rate (eGFR), age, and sex. After adjustment for multiple confounders, the free IAA level predicted overall mortality and cardiovascular events in the non-transplanted CKD cohort (hazard ratio [95% confidence interval]: 2.5 [1.2–5.1] and 2.5 [1.3–4.8], respectively). In the transplanted CKD cohort, however, no associations were found between free or total IAA on one hand, and mortality, CV event, or graft survival on the other. Conclusion: We demonstrated that levels of IAA increase with the CKD stage, and fall substantially, even normalizing, after kidney transplantation. Free IAA appears to be a valuable outcome-associated biomarker in non-transplanted patients, but—at least in our study setting—not in transplanted patients.

Chronic kidney disease (CKD) is associated with the systemic accumulation of uremic toxins (UTs) due to impaired renal elimination. Among these, indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are particularly challenging because of their high protein binding and limited removal by dialysis. In addition to renal excretion, the transport of IS and PCS, and their microbiota-derived precursors, indole and p-cresol, across key physiological barriers—the intestinal barrier, blood–brain barrier, and renal proximal tubule—critically influences their distribution and elimination. This review provides an overview of transporter-mediated mechanisms involved in the disposition of IS, PCS, and their microbial precursors, indole and p-cresol. It also examines how these UTs may interact with commonly prescribed drugs in CKD, particularly those that share transporter pathways as substrates or inhibitors. These drug–toxin interactions may influence the pharmacokinetics and toxicity of IS and PCS, but remain poorly characterized and largely overlooked in clinical settings. A better understanding of these processes may guide future efforts to optimize pharmacotherapy and support more informed management of CKD patients, particularly in the context of polypharmacy.

In kidney transplant recipients (KTRs), scarce evidence has associated low blood bicarbonate levels with mineral metabolic disturbance and reduced allograft survival. However, the contribution of the blood pH to these observations remains unassessed. Equally, little is known about the influence of the blood provenance (arteriovenous fistula vs peripheral vein) on bicarbonate values. We analyzed blood gas parameters in a single‐center cohort of 1260 stable KTRs, 3 months after transplantation. Inspection of pO₂ distribution allowed the unambiguous identification of the arterial (N = 914) or venous (N = 346) origin of the samples. In patients with arterial blood samples, 435 (46%) had bicarbonate levels below 22 mmol/L. Among them, 196 (40%) were acidemic (blood pH <7.38). In multivariate analysis, low arterial blood pH was associated with increased blood ionized calcium and phosphate and reduced fibroblast growth factor 23 and calcitriol, but not with outcome. In contrast, low bicarbonate concentration predicted allograft loss independently of measured glomerular filtration rate and other potential confounders (hazard ratio [HR] 1.70; 95% confidence interval [CI] 1.04‐2.80). In KTRs, reduced arterial blood bicarbonate levels predict outcome while acidemia is associated with altered mineral metabolism.

Extracellular vesicles (EVs) have a key role in intercellular communication. We hypothesized that EVs are biomarkers of nephropathy or kidney allograft rejection. We screened patients with chronic kidney disease (CKD) and kidney transplant (KT) recipients. We measured the urine and plasma levels of total EVs overall and EV subpopulations (positive for podocalyxin, aquaporin-1, CD133, CD144, CD19, CD3, CD16, CD56, or CD41). We included 92 patients with CKD, 70 KT recipients, and 33 healthy volunteers. In CKD, the total urine EV concentration was correlated positively with the estimated glomerular filtration rate (eGFR), but none of the subpopulations was identified as a potential biomarker of nephropathy. Among the KT recipients, 30 had good allograft function and 40 had allograft disease (13 with antibody-mediated rejections (ABMR), 12 with T-cell-mediated rejection (TCMR), and 15 with allograft dysfunction). Patients with ABMR had low plasma levels of EVs derived from B-cells, T-cells, and endothelium (p = 0.003, 0.009, and 0.005, respectively). Patients with TCMR had a low urine level of EVs derived from endothelium (p = 0.05). EVs derived from B-cells, T-cells, and endothelium might be biomarkers of kidney allograft rejection. However, we did not identify biomarkers of nephropathy in CKD.