Immune senescence and immune exhaustion in patients with chronic kindey disease under dialysis

End-stage renal disease(ESRD) is characterized by phenotypic alterations that resemble premature aging, and relate to immune alterations. However, there is inadequate data on the relation of these alterations to clinical parameters. Thus, aim of the present study was to evaluate the alterations in the expression of senescence markers on the surface of T and B-lymphocyte populations of patients undergoing chronic maintenance hemodialysis, to compare these changes with those of the healthy population and to correlate them with clinical parameters related to ESRD. To this point, 62 dialysis patients, aged 20 - 80 years participated in the study. T and B-lymphocyte subpopulations were determined by flow cytometry using conjugated antibodies against CD45RA, CCR7, CD28, CD31, CD57, PD1, CD19, CD27 and IgD. Patients were divided into three age groups and lymphocyte populations were compared both among groups and with 34 age and sex matched healthy controls. T and B-cell subpopulations were then associated with cardiovascular disease, frailty, residual renal function(RRF), CMV serostatus, and frequency of infections, dialysis prescription and humoral response to vaccination and mortality. Finally, dialysis patients phenotype was compared with the phenotype of 30 patients with systemic lupus erythematosus. ESRD patients had reduced naive T-lymphocyte subpopulations, to levels corresponding to these of 20 years older healthy individuals, while senescent T-cell subpopulations remained constant between the two groups. Severe B-lymphopenia was found in the patient group, and a greater effect of ESRD on IgM memory B-lymphocytes. In relation to age, a premature loss of low-differentiation memory T-populations and accumulation of senescent memory T-populations were found in the patients group compared to healthy individuals. However, B-lymphocytes were decreased with age in patients but not in healthy controls. Cardiovascular disease was significantly associated with a decrease of CD28 expression on CD8+ T lymphocytes, and a decrease in total B lymphocytes number. CD28 expression differed in frail patients in both CD4+ and CD8+ T-lymphocytes, while frailty was also associated with an increased number of CD8+ TEMRA and CD4+ exhausted T-lymphocytes. Chronic inflammation was negatively associated with naïve CD4+ subpopulations, while CMV+ patients had significantly increased numbers of senescent T-lymphocytes compared to CMV- patients. Patients with RRF had increased number of total CD4+ and naïve CD4+ T-lymphocytes. Moreover, a positive correlation of the senescent CD4+CD28-CD57+ subpopulation with antibody levels against SARS-CoV-2, four months after vaccination, was observed. In addition, hemodiafiltration was associated with reduced numbers of CD4+CD28- and hemofiltration volume was negatively correlated with senescent CD8+ EMRA T-lymphocytes. Finally, patients with a history of at least one serious infection prior to study had decreased numbers of naïve CD4+ and CD4+ RTEs T-cells, and increased numbers of CD4+CD57+ and CD8+ EMRA T-cells. In survival analysis, an increased percentage of exhausted CD4+ T-lymphocytes was shown to be significantly associated with increased overall 2-year mortality. In conclusion, patients with ESRD are characterized by a pronounced reduction of low-differentiated, naïve lymphocyte subsets, with preservation of senescent subpopulations. CMV infection likely contributes to this effect. However, by maintaining RRF and implementing improved dialysis techniques, these alterations can be potentially delayed.Η χρόνια νεφρική νόσος τελικού σταδίου(ΧΝΝ-ΤΝ) χαρακτηρίζεται από φαινοτυπικές μεταβολές, οι οποίες προσομοιάζουν σε πρόωρη γήρανση, και σχετίζονται με μεταβολές του ανοσοποιητικού. Ωστόσο μέχρι σήμερα ελάχιστα είναι τα δεδομένα σε σχέση με κλινικές παραμέτρους. Σκοπός της παρούσας μελέτης ήταν να αξιολογήσει τις μεταβολές της έκφρασης των δεικτών γήρανσης σε Τ και Β λεμφοκυτταρικούς πληθυσμούς ασθενών υπό αιμοκάθαρση, να συγκρίνει τις μεταβολές αυτές με τον υγιή πληθυσμό και να τις συσχετίσει με κλινικές παραμέτρους. Στην παρούσα μελέτη εντάχθηκαν 62 ασθενείς με ΧΝΝ-ΤΝ, ηλικίας 20-80 ετών. Προσδιορίστηκαν με κυτταρομετρία ροής υποπληθυσμοί Τ και Β-λεμφοκυττάρων, που σχετίζονται με τη γήρανση, με τη χρήση συζευγμένων αντισωμάτων έναντι CD45RA, CCR7, CD28, CD31, CD57, PD1, CD19, CD27 και IgD. Οι ασθενείς χωρίστηκαν σε τρεις ηλικιακές ομάδες και συγκρίθηκαν λεμφοκυτταρικοί πληθυσμοί μεταξύ των ομάδων και με αντίστοιχες ομάδες 34 υγιών μαρτύρων. Στη συνέχεια πραγματοποιήθηκε συσχέτιση με την παρουσία καρδιαγγειακής νόσου, ευπάθειας, υπολειπόμενης νεφρικής λειτουργίας(ΥΝΝ), λοίμωξης με κυτταρομεγαλοϊό και συχνότητας λοιμώξεων, τη συνταγογράφηση της αιμοκάθαρσης, την απάντηση στον εμβολιασμό και της θνητότητας. Τέλος, έγινε σύγκριση του φαινότυπου των ασθενών, με τον φαινότυπο 30 ασθενών με συστηματικό ερυθηματώδη λύκο. Στους ασθενείς διαπιστώθηκε μείωση των παρθένων Τ υποπληθυσμών σε σύγκριση με τους υγιείς, σε επίπεδα αντίστοιχα με υγιείς κατά 20 έτη μεγαλύτερους, ενώ οι γηρασμένοι Τ-υποπληθυσμοί παρέμειναν σταθεροί μεταξύ των δύο ομάδων. Στα Β-λεμφοκύτταρα διαπιστώθηκε βαριά λεμφοπενία στην ομάδα των ασθενών, κυρίως στο διαμέρισμα IgM μνήμης. Σε συνάρτηση με την ηλικία, διαπιστώθηκε ταχύτερη απώλεια των Τ πληθυσμών μνήμης χαμηλής διαφοροποίησης και συσσώρευση γηρασμένων Τ πληθυσμών μνήμης στους ασθενείς σε σύγκριση τους υγιείς. Ωστόσο, τα Β-λεμφοκύτταρα μειώθηκαν με την πάροδο της ηλικίας στους ασθενείς αλλά όχι στους υγιείς. Η ύπαρξη καρδιαγγειακής νόσου και το ΙΜΤ συσχετίστηκαν με την μείωση της έκφρασης του CD28 στην επιφάνεια των CD8+ T-λεμφοκυττάρων, και με την μείωση του αριθμού των συνολικών Β-λεμφοκυττάρων. Η έκφραση του CD28 παρουσίασε διαφορά και στους ευπαθείς ασθενείς και στα CD4+ και στα CD8+ T-λεμφοκύτταρα, ενώ η ευπάθεια σχετίστηκε και με αυξημένο αριθμό CD8+ TEMRA και CD4+ εξαντλημένων Τ-λεμφοκυττάρων. Η χρόνια φλεγμονή συσχετίστηκε αρνητικά με τους παρθένους CD4+ υποπληθυσμούς, ενώ, οι CMV+ ασθενείς είχαν αυξημένους αριθμούς γηρασμένων Τ λεμφοκυττάρων σε σχέση με τους CMV- ασθενείς. Οι ασθενείς με ΥΝΝ είχαν αυξημένο αριθμό συνολικών CD4+ και παρθένων CD4+ T-λεμφοκυττάρων. Επίσης, ο γηρασμένος υποπληθυσμός CD4+CD28-CD57+ σχετίστηκε θετικά με τα επίπεδα αντισωμάτων έναντι του SARS-CoV-2, τέσσερις μήνες μετά τον εμβολιασμό. Επιπλέον, η αιμοδιαδιήθηση σχετίστηκε με ελαττωμένο αριθμό CD4+CD28- T-λεμφοκυττάρων, ενώ ο όγκος αιμοδιήθησης, συσχετίστηκε αρνητικά με τα CD8+ EMRA Τ-λεμφοκύτταρα. Τέλος, ασθενείς με ιστορικό τουλάχιστον μίας σοβαρής λοίμωξης κατά τη διετία πριν την ένταξη στη μελέτη είχαν ελαττωμένο αριθμό παρθένων CD4+ και CD4+ RTEs Τ-λεμφοκυττάρων και αυξημένο αριθμό CD4+CD57+ και CD8+ EMRA T-λεμφοκυττάρων. Τέλος, στην ανάλυση επιβίωσης, αυξημένο ποσοστό εξαντλημένων CD4+ Τ-λεμφοκυττάρων σχετίστηκε σημαντικά με αυξημένη συνολική διετή θνητότητα. Συμπερασματικά, οι ασθενείς με ΧΝΝ-ΤΝ, χαρακτηρίζονται από μείωση των λεμφοκυτταρικών πληθυσμών χαμηλής διαφοροποίησης, με διατήρηση των γηρασμένων υποπληθυσμών. Το ιστορικό λοίμωξης με CMV συμβάλλει σε αυτή την εικόνα, ωστόσο, διατηρώντας την υπολειπόμενη νεφρική λειτουργία και εφαρμόζοντας βελτιωμένες τεχνικές κάθαρσης, ίσως οι μεταβολές αυτές μπορούν να επιβραδυνθούν

Microbiome in Chronic Kidney Disease

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

COVID-19 Infection and Response to Vaccination in Chronic Kidney Disease and Renal Transplantation: A Brief Presentation

Chronic kidney disease (CKD) is associated with phenotypic and functional changes in the immune system, followed by detrimental clinical consequences, such as severe infections and defective response to vaccination. Two years of the pandemic, due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have undoubtedly changed the world; however, all efforts to confront infection and provide new generation vaccines tremendously improved our understanding of the mechanisms of the immune response against infections and after vaccination. Humoral and cellular responses to vaccines, including mRNA vaccines, are apparently affected in CKD patients, as elimination of recent thymic emigrant and naïve lymphocytes and regulatory T-cells, together with contraction of T-cell repertoire and homeostatic proliferation rate, which characterized CKD patients are responsible for impaired immune activation. Successful renal transplantation will restore some of these changes, although several epigenetic changes are irreversible and even accelerated by the induction of immunosuppression. Response to vaccination is definitely impaired among both CKD and RT patients. In the present review, we analyzed the differences in immune response after vaccination between these patients and healthy individuals and depicted specific parameters, such as alterations in the immune system, predisposing to this deficient response

Cellular and Humoral Responses in Dialysis Patients after Vaccination with the BNT162b2 or mRNA-1273 Vaccines

The outbreak of SARS-CoV-2 has raised considerable concern about the detrimental effects it can induce in public health, with the interest of the scientific community being focused on the development of preventive and therapeutic approaches. Patients with end-stage renal disease (ESRD) are amongst vulnerable populations for critical illness owing to the presence of other comorbidities, their defective immune system, and their inability of self-isolation. To date, vaccination constitutes the most promising method to manage viral dispersion. Therefore, it is particularly important to investigate the effectiveness of available vaccines against SARS-CoV-2 in this risk group. Here, we summarize initial experience regarding the humoral and cellular immune responses elicited in dialysis patients after completion of the recommended vaccination regimen, as well as after booster dose administration, with one of the two mRNA vaccines, namely, BNT162b2 and mRNA-1273. In conclusion, a significantly diminished and delayed immune pattern was observed in ESRD patients compared to healthy population, with a peak in antibody titers occurring 3–5 weeks after the second dose. A booster dose significantly augmented the immune response in dialysis patients with either mRNA-based vaccine. Variables adversely correlating with the weak immunogenicity observed in dialysis patients include immunosuppressive therapy, older age, comorbidities, longer time in hemodialysis treatment, and higher body mass index. On the contrary, previous COVID-19 infection and administration of the mRNA-1273 vaccine are deemed to induce a more favorable immune response. Further investigation is needed to thoroughly understand the efficacy of mRNA-based vaccines in hemodialysis patients and define predictive factors that can influence it

Two Cases of Autoimmune Thyroid Disorders after COVID Vaccination in Dialysis Patients

SARS-CoV-2 infection and vaccination have been associated with autoimmune thyroid dysfunctions. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and molecular mimicry have been referred to as potential causes. Such a case has not been reported in immunocompromised end-stage renal disease (ESRD) patients. Herein we present two dialysis patients with no previous history of thyroid disease who developed immune mediated thyroid disorders after BNT162b mRNA vaccine against SARS-CoV-2. The first patient is a 29-year-old man on hemodialysis diagnosed with Grave’s disease four months post-vaccination and the second one is a 67-year-old female on peritoneal dialysis who developed Hashimoto’s thyroiditis two months post-vaccination. Grave’s disease is uncommon in dialysis patients, whereas Hashimoto’s thyroiditis has a higher incidence in this population. Time proximity in both cases suggests potential causality. To our knowledge, this is the first report of de novo immune-mediated thyroid disorders in dialysis patients following vaccination against SARS-CoV-2

Cellular and Humoral Responses in Dialysis Patients after Vaccination with the BNT162b2 or mRNA-1273 Vaccines

The outbreak of SARS-CoV-2 has raised considerable concern about the detrimental effects it can induce in public health, with the interest of the scientific community being focused on the development of preventive and therapeutic approaches. Patients with end-stage renal disease (ESRD) are amongst vulnerable populations for critical illness owing to the presence of other comorbidities, their defective immune system, and their inability of self-isolation. To date, vaccination constitutes the most promising method to manage viral dispersion. Therefore, it is particularly important to investigate the effectiveness of available vaccines against SARS-CoV-2 in this risk group. Here, we summarize initial experience regarding the humoral and cellular immune responses elicited in dialysis patients after completion of the recommended vaccination regimen, as well as after booster dose administration, with one of the two mRNA vaccines, namely, BNT162b2 and mRNA-1273. In conclusion, a significantly diminished and delayed immune pattern was observed in ESRD patients compared to healthy population, with a peak in antibody titers occurring 3–5 weeks after the second dose. A booster dose significantly augmented the immune response in dialysis patients with either mRNA-based vaccine. Variables adversely correlating with the weak immunogenicity observed in dialysis patients include immunosuppressive therapy, older age, comorbidities, longer time in hemodialysis treatment, and higher body mass index. On the contrary, previous COVID-19 infection and administration of the mRNA-1273 vaccine are deemed to induce a more favorable immune response. Further investigation is needed to thoroughly understand the efficacy of mRNA-based vaccines in hemodialysis patients and define predictive factors that can influence it

Type of ANCA May Be Indispensable in Distinguishing Subphenotypes of Different Clinical Entities in ANCA-Associated Vasculitis

The traditional nomenclature system for classifying antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) based on clinical phenotype describes granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis (MPA) as distinct clinical entities. This classification has proved its expedience in clinical trials and everyday clinical practice; yet, a substantial overlap in clinical presentation still exists and often causes difficulties in prompt definition and clinical distinction. Additionally, new insights into the AAV pathogenesis point out that PR3 and MPO-AAV may not represent expressions of the same disease spectrum but rather two distinct disorders, as they display significant differences. Thus, it is supported that a classification based on ANCA serotype (PR3-ANCA, MPO-ANCA or ANCA-negative) could be more accurate and also closer to the nature of the disease compared to the phenotype-based one. This review aims to elucidate the major differences between PR3 and MPO-AAV in terms of epidemiology, pathogenesis, histological and clinical manifestations and response to therapeutic approaches

ANCA-Associated Vasculitis May Result as a Complication to Both SARS-CoV-2 Infection and Vaccination

In the last two years, our world experienced one of the most devastating and fast-exploding pandemic, due to the wide spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The scientific community managed to develop effective vaccines, the main weapons to shield the immune system and protect people. Nevertheless, both SARS-CoV-2 infection and the vaccination against it have been associated with the stimulation of inflammatory cells such as T and B lymphocytes that results in a cytokine storm, endothelial inflammation and vascular injury, which can lead to different types of vasculitis. We present the first case of de novo MPO-ANCA-associated vasculitis, which developed shortly after SARS-CoV-2 vaccination, adequately responded to treatment, and subsequently relapsed after COVID-19 infection. With this case, we indicate an etiological connection between viral infection and disease development, as well as the possibility of a common immune mechanism between SARS-CoV-2 infection and vaccination, that can stimulate vascular events and lead to vasculitis. There have been several case reports of de novo vasculitis, affecting large, medium, or small vessels, following either infection or vaccination against COVID-19, during the pandemic outbreak. We summarize previous reports and also analyze proposed pathogenic mechanisms between SARS-CoV-2 and vasculitis

Serum OPG and RANKL Levels as Risk Factors for the Development of Cardiovascular Calcifications in End-Stage Renal Disease Patients in Hemodialysis

Cardiovascular calcifications (CVC) are frequently observed in chronic kidney disease (CKD) patients and contribute to their cardiovascular mortality. The aim of the present study was to investigate the impact of osteoprotegerin (OPG)/Receptor Activator of NF-κΒ (RANK)/RANK ligand (RANKL) pathway in the development and evolution of CVCs in hemodialysis patients. In total, 80 hemodialysis patients were assessed for the presence of vascular (abdominal aorta and muscular arteries) calcifications and results were correlated to serum OPG and RANKL levels and the OPG/RANKL ratio. Traditional cardiovascular risk factors and mineral bone disease parameters were also estimated. The presence of VCs was also evaluated 5 years after the initiation of the study, and results were correlated to the initial serum OPG levels. Age, diabetes mellitus, coronary artery disease and OPG levels (p p = 0.026), but they were not correlated with the progression of VCs. Serum OPG levels are positively and independently associated with VCs in HD patients, but not with their progression. RANKL levels did not show any associations, whereas further studies are needed to establish the significance of OPG/RANKL ratio

Different Types of Chronic Inflammation Engender Distinctive Immunosenescent Profiles in Affected Patients

Immunosenescence encompasses a spectrum of lymphocyte phenotypic alterations. The aim of the study was to evaluate immunosenescent effect of two different forms of chronic inflammation, Systemic Lupus Erythematosous (SLE), a systemic autoimmune disease, and End-Stage Kidney Disease (ESKD), a chronic inflammatory disorder. Certain lymphocyte surface molecules, including CD31, CD45RA, CCR7, CD28, CD57, for T, and IgD, CD27 for B lymphocytes, were analyzed by flow cytometry in 30 SLE and 53 ESKD patients on hemodialysis (HD), and results were compared to 31 healthy controls (HC) of similar age, gender, and nationality. Significant Lymphopenia was evident in both SLE and ESKD-HD patients, compared to HC, affecting B cells 75.4 (14.4–520.8), 97 (32–341), and 214 (84–576) cells/μL, respectively, p < 0.0001, and CD4 cells 651.2 (71.1–1478.2), 713 (234–1509), and 986 (344–1591) cells/μL, respectively, p < 0.0001. The allocation of B cell subpopulations was remarkably different between SLE and ESKD-HD patients. SLE showed a clear shift to senescence (CD19IgD-CD27−) cells, compared to ESKD-HD and HC, 11.75 (10)% vs. 8 (6) vs. 8.1 (10), respectively. Regarding T lymphocytes, Central Memory CD8 cells predominated in both SLE and ESKD-HD patients compared to HC, 53 (50)%, 52 (63), and 24 (64)%, respectively, while ESKD-HD but not SLE patients also had increased expression of CD4CD28− and CD8CD28− cells. In conclusion, both diseases are followed by significant lymphopenia; however, the senescent phenomenon affects the B lymphocyte compartment in SLE patients and T lymphocytes in ESKD-HD patients