The gut microbiome is a complex collection of microorganisms with discrete characteristics and activities. Its important role is not restricted to food digestion and metabolism, but extends to the evolution, activation and function of the immune system. Several factors, such as mode of birth, diet, medication, ageing and chronic inflammation, can modify the intestinal microbiota. Chronic kidney disease (CKD) seems to have a direct and unique effect, as increased urea levels result in alteration of the gut microbiome, leading to overproduction of its metabolites. Therefore, potentially noxious microbial uremic toxins, which have predominantly renal clearance, including p-cresyl sulfate, indoxyl sulfate and N-oxide of trimethylamine [Trimethylamine-N-Oxide (TMAO)], accumulate in human’s body, and are responsible not only for the clinical implications of CKD, but also for the progression of renal failure itself. Certain changes in gut microbiome are observed in patients with end stage renal disease (ESRD), either when undergoing hemodialysis or after kidney transplantation. The purpose of this review is to summarize the changes of gut microbiome and the protein bound uremic toxins which are observed in CKD and in different kidney replacement strategies. In addition, we attempt to review the connection between microbiome, clinical implications and immune response in CKD.

Background: The accumulation of protein-bound uremic toxins (PBUTs) in chronic kidney disease may affect patients’ immune status. The aim of the study was to evaluate their potential impacts on lymphocyte alterations in patients on hemodialysis (HD). Methods: The plasma levels of PBUTs were assessed in 54 patients on HD and 31 healthy individuals, using ultra-performance liquid chromatography. The results correlated with the senescent and exhausted status of lymphocytes, based on certain surface molecules, analyzed by flow cytometry. Results: The plasma levels of PBUTs were significantly increased in the patients on HD compared with the healthy controls. The patients with residual kidney function had reduced hippuric acid (HA) levels, total (p = 0.03) and free (p = 0.04), and free IxS levels (p = 0.02). The total and free HA levels correlated negatively with less differentiated subpopulations, CD4+CD45RA+CD31+ (p = 0.037 and p = 0.027), CD8+CD28+CD57− (p = 0.01, p = 0.01), and naïve B cells (CD19+IgD+CD27−) (p = 0.04, p = 0.03). Both the total and the free pCS levels correlated positively with exhausted CD4 cells, p = 0.02 and p = 0.01, respectively. A multivariate analysis showed that IxS and age were the main independent parameters implicated in the reduction intotal CD4 and B lymphocytes and their naïve and early differentiated subsets. Conclusions: Increased PBUTs levels are associated with immune disturbances of patients on HD, HA, and IxS in the immunosenescent and pCS in the immunoexhaustion alterations.

Background and Objectives: Cardiovascular events are the major cause of morbidity and mortality in patients on hemodialysis (HD). Identifying risk factors can help in the effort to reduce cardiovascular risk and improve life expectancy. The objective of this study was to evaluate the ability of the CHA₂DS₂-VASc score—the risk index of stroke in atrial fibrillation (AF)—to predict strokes, major cardiovascular events, and mortality in patients with end-stage kidney disease. Materials and Methods: The CHA₂DS₂-VASc and HAS-BLED scores (the bleeding risk from the use of anticoagulation in AF) were calculated in 237 HD patients, 99 women with a median age of 76 (15) years, at the time they commenced HD. The scores’ ability to predict long term cardiovascular morbidity and mortality was estimated, both in those with and without AF. Among the exclusion criteria were the change of dialysis method or loss of follow-up, HD due to acute renal failure, and incompliance with medical instructions, thus the sample is not representative of a broader population. Results: The CHA₂DS₂-VASc score was higher in AF (n = 69) compared to non-AF (n = 168) patients, 5 (2.5) vs. 4 (2), p < 0.0001, respectively. An increased CHA₂DS₂-VASc score was correlated with cardiovascular events, namely, heart failure (p = 0.007, p = 0.024), stroke (p < 0.0001, p < 0.0001), and risk of all-cause mortality (p < 0.0001, p < 0.0001) in AF and non-AF groups, respectively. The C statistics indicated that the referred score showed modest discrimination in AF and non-AF patients on HD for heart failure, stroke, and all-cause mortality, however for cardiovascular mortality this was found only in the AF group. Conclusions: An increased CHA₂DS₂-VASc score at the time of HD initiation can predict strokes, heart failure, and all-cause mortality in HD patients independent of the presence of AF. The risk of cardiovascular mortality could only be predicted in patients with AF.

Senescence-resembling alterations on the lymphocytes of patients undergoing dialysis have been widely described. However, the pathophysiology behind these phenomena has not been clarified. In this study, we examined the impact of dialysis prescription on T and B lymphocytes, in patients undergoing dialysis.: T and B cell subsets were determined with flow cytometry in 36 patients undergoing hemodialysis and 26 patients undergoing hemodiafiltration, according to the expression of CD45RA, CCR7, CD31, CD28, CD57, and PD1 for T cells, and IgD and CD27 for B cells. The immune phenotype was associated with dialysis modality, hemofiltration volume, and mortality. Compared with hemodialysis, patients undergoing hemodiafiltration had a significantly decreased percentage of CD4+CD28-CD57- T cells [3.8 (2.4–5.3) vs. 2.1 (1.3–3.3)%, respectively, p = 0.002] and exhausted CD4+ T cells [14.1 (8.9–19.4) vs. 8.5 (6.8–11.7)%, respectively, p = 0.005]. Additionally, the hemofiltration volume was negatively correlated with CD8+ EMRA T cells (r = −0.46, p = 0.03). Finally, the increased exhausted CD4+ T cell percentage was associated with increased all-cause mortality in patients undergoing dialysis, independent of age. Hemodiafiltration, especially with high hemofiltration volume, may have beneficial effects on senescence-related immune phenotypes. Immune phenotypes may also be a predicting factor for mortality in patients undergoing dialysis.

The impact of protein bound uremic toxins (PBUTs) and lymphocyte alterations in morbidity and mortality in patients on hemodialysis (HD) is of great concern. The aim of this study was the assessment of association between PBUTs, immunosenescent lymphocytes’ phenotype and clinical events [cardiovascular, severe infections (hospitalization due to infection, respiratory infection), all-cause mortality] during 2-year follow-up. In this prospective observational study, lymphocytes’ phenotype of 54 patients on HD and 31 age-matched controls was analyzed by flow cytometry, and simultaneously, PBUT serum levels [hippuric acid (HA), indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glycuronide (pCG), in-dole-3-acetic acid (IAA), and 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)] were quantified by ultra-performance liquid chromatography. Patients with increased levels of free IxS and total and free HA had higher mortality within a 2-year follow-up period (p = 0.049, p = 0.01, p = 0.01, respectively). In patients who experienced cardiovascular events, higher concentrations of CMPF (p = 0.015) were observed. Higher total and free HA levels associate with increased all-cause mortality in patients on HD, independently of age, dialysis vintage, and decreased count of CD4+CD45RA+CD31+ and naïve B cells (CD19+IgD+CD27−). In patients on HD, increased levels of total and free HA associate with an increased risk of death.