The prognostic value of two histopathologic classification models of ANCA-associated glomerulonephritis: a prospective study.

BACKGROUND: Berden Classification and anti-neutrophil cytoplasmic antibody (ANCA) Renal Risk Score are classification models for rating renal histology and predicting outcome in patients with ANCA-associated Vasculitis/Glomerulonephritis (AAV/GN). In the present study we compare their ability to predict renal function outcome in short- and long-term follow up. METHODS: Patients with an initial diagnosis of AAV/GN based on kidney biopsy were classified according to Berden and Renal Risk Score, started on the same treatment protocol, and were followed prospectively for up to 60 months. Renal function was recorded at 3mo(T3), 6mo(T6) and 60mo(T60), and results were compared to both classification systems. RESULTS: Ninety four AAV/GN patients, M/F = 36/58, age = 60.05 (18-82)yrs were included. Based on Berden classification, patients grouped as Focal (n = 24), Crescentic (n = 35), Mixed (n = 21) and Sclerotic (n = 14), had significant differences in estimated glomerular filtration rate (eGFR) only at T3, while the percentage of those requiring hemodialysis differed at T0, T3, T6 but not at T60. According to the Renal Risk Score, patients were classified as Low (n = 8), Medium (n = 47) and High (n = 39) risk, and showed significant differences in both eGFR levels, proportion of hemodialysis, at T0, T3, T6 and end-stage kidney disease (ESKD) at T60. Even patients classified as Mixed (Berden) and as Medium or High risk (Renal Risk Score) had significant improvement from T0 to T6. Relapse could not be predicted by either system. CONCLUSION: Both methods were able to predict short-term renal function outcome and need for hemodialysis, but the Renal Risk Score showed significant superiority in predicting renal function outcome and ESKD after long-term follow up.

Cardiovascular Events and Mortality in Patients on Hemodialysis: The Prognostic Value of the CHA2DS2-VASc Score.

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.

Complement and Non-Complement Binding Anti-HLA Antibodies Are Differentially Detected with Different Antigen Bead Assays in Renal Transplant Recipients.

Two semi-quantitative, Luminex-based, single-antigen bead (SAB) assays are available to detect anti-HLA antibodies and evaluate their reactivity with complement binding. Sera from 97 patients with positive panel reactive antibody tests (>5%) were analyzed with two SAB tests, Immucor (IC) and One-Lambda (OL), for anti-HLA antibody detection and the evaluation of their complement-binding capacity. IC detected 1608/8148 (mean fluorescent intensity (MFI) 4195 (1995-11,272)) and 1136/7275 (MFI 6706 (2647-13,184)) positive anti-HLA class I and II specificities, respectively. Accordingly, OL detected 1942/8148 (MFI 6185 (2855-12,099)) and 1247/7275 (MFI 9498 (3630-17,702)) positive anti-HLA class I and II specificities, respectively. For the IC assay, 428/1608 (MFI 13,900 (9540-17,999)) and 409/1136 (MFI 11,832 (7128-16,531)) positive class I and II specificities bound C3d, respectively. Similarly, OL detected 485/1942 (MFI 15,452 (9369-23,095)) and 298/1247 (MFI18,852 (14,415-24,707)) C1q-binding class I and II specificities. OL was more sensitive in detecting class I and II anti-HLA antibodies than IC was, although there was no significant difference in the number of class II specificities per case. MFI was higher for complement vs. non-complement-binding anti-HLA antibodies in both assays. Both methods were equal in detecting complement-binding anti-HLA class I antibodies, whereas the C3d assay was more sensitive in detecting complement-binding anti-HLA class II antibodies.

Humoral and Cellular Immunity Are Significantly Affected in Renal Transplant Recipients, following Vaccination with BNT162b2.

BACKGROUND: Renal transplant recipients (RTRs) tend to mount weaker immune responses to vaccinations, including vaccines against the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: Humoral immunity was assessed using anti-receptor binding domain (RBD) and neutralizing antibodies (NAb) serum levels measured by ELISA, and cellular immunity was assessed using T-, B-, NK, natural killer-like T (NKT)-cell subpopulations, and monocytes measured by flow cytometry, and also specific T-cell immunity, at predefined time points after BNT162b2 vaccination, in 57 adult RTRs. RESULTS: Administration of three booster doses was necessary to achieve anti-RBD and NAb protective levels in almost all patients (92.98%). Ab production, at several time points, was positively correlated with the corresponding renal function and inversely correlated with hemodialysis vintage (HDV) and treatment with mycophenolic acid (MPA). A gradual rise in several cell subpopulations, including total lymphocytes (p = 0.026), memory B cells (p = 0.028), activated CD4 (p = 0.005), and CD8 cells (p = 0.001), was observed even after the third vaccination dose, while a significant reduction in CD3+PD1+ (p = 0.002), NKT (p = 0.011), and activated NKT cells (p = 0.034) was noted during the same time interval. Moreover, SARS-CoV-2-specific T-cells were present in 41% of the patients who were unable to develop Nabs, and their positivity rates four months after the second dose were in inverse correlation with monocytes (p = 0.045) and NKT cells (p = 0.01). CONCLUSIONS: SARS-CoV-2-specific T-cell responses preceded the humoral ones, while two booster doses were needed for this group of immunocompromised patients to mount a protective immune response.

Immune Profile Determines Response to Vaccination against COVID-19 in Kidney Transplant Recipients.

BACKGROUND AND AIM: Immune status profile can predict response to vaccination, while lymphocyte phenotypic alterations represent its effectiveness. We prospectively evaluated these parameters in kidney transplant recipients (KTRs) regarding Tozinameran (BNT162b2) vaccination. METHOD: In this prospective monocenter observational study, 39 adult KTRs, on stable immunosuppression, naïve to COVID-19, with no protective humoral response after two Tozinameran doses, received the third vaccination dose, and, based on their immunity activation, they were classified as responders or non-responders. Humoral and cellular immunities were assessed at predefined time points (T0: 48 h before the first, T1: 48 h prior to the third and T2: three weeks after the third dose). RESULTS: Responders, compared to non-responders, had a higher total and transitional B-lymphocyte count at baseline (96.5 (93) vs. 51 (52)cells/µL, p: 0.045 and 9 (17) vs. 1 (2)cells/µL, p: 0.031, respectively). In the responder group, there was a significant increase, from T0 to T1, in the concentrations of activated CD4+ (from 6.5 (4) to 10.08 (11)cells/µL, p: 0.001) and CD8+ (from 8 (19) to 14.76 (16)cells/µL, p: 0.004) and a drop in CD3+PD1+ T-cells (from 130 (121) to 30.44 (25)cells/µL, p: 0.001), while naïve and transitional B-cells increased from T1 to T2 (from 57.55 (66) to 1149.3 (680)cells/µL, p < 0.001 and from 1.4 (3) to 17.5 (21)cells/µL, p: 0.003). The percentages of memory and marginal zone B-lymphocytes, and activated CD4+, CD8+ and natural killer (NK) T-cells significantly increased, while those of naïve B-cells and CD3+PD1+ T-cells reduced from T0 to T1. CONCLUSIONS: Responders and non-responders to the third BNT162b2 dose demonstrated distinct initial immune cell profiles and changes in cellular subpopulation composition following vaccination.

Immunosenescence and Immune Exhaustion Are Associated with Levels of Protein-Bound Uremic Toxins in Patients on Hemodialysis.

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.

Increase in Double Negative B Lymphocytes in Patients with Systemic Lupus Erythematosus in Remission and Their Correlation with Early Differentiated T Lymphocyte Subpopulations.

B and T lymphocytes demonstrate important alterations in patients with systemic lupus erythematous (SLE), with a significant upregulation of double negative (DN) B cells. The aim of this study was to evaluate the correlation of T cell immunity changes with the distinct B-cell-pattern SLE. In the present study, flow cytometry was performed in 30 patients in remission of SLE and 31 healthy controls to detect DN B cells (CD19+IgD-CD27-) and a wide range of T lymphocyte subpopulations based on the presence of CD45RA, CCR7, CD31, CD28, and CD57, defined as naive, memory, and advanced differentiated/senescent T cells. Both B and T lymphocytes were significantly reduced in SLE patients. However, the percentage of DN B cells were increased compared to HC (12.9 (2.3-74.2) vs. 8 (1.7-35), p = 0.04). The distribution of CD4 and CD8 lymphocytes demonstrated a shift to advanced differentiated subsets. The population of DN B cells had a significant positive correlation with most of the early differentiated T lymphocytes, CD4CD31+, CD4CD45RA+CD28+, CD4CD45RA+CD57-, CD4CD45RA-CD57-, CD4CD28+CD57-, CD4CD28+CD57+, CD4 CM, CD8 CD31+, CD8 NAÏVE, CD8CD45RA-CD57-, CD8CD28+CD57-, and CD8CD28+CD57+. Multiple regression analysis revealed CD4CD31+, CD8CD45RA-CD57-, and CD8CD28+CD57- cells as independent parameters contributing to DN B cells, with adjusted R2 = 0.534 and p < 0.0001. The predominance of DN B cells in patients with SLE is closely associated with early differentiated T lymphocyte subsets, indicating a potential causality role of DN B cells in T lymphocyte activation.

Prospective Analysis of B Lymphocyte Subtypes, before and after Initiation of Dialysis, in Patients with End-Stage Renal Disease.

End-stage renal disease (ESRD) is followed by alterations in adaptive immunity. The aim of this study was to evaluate B lymphocyte subtypes in ESRD patients before and after hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD). PATIENTS AND METHODS: CD5, CD27, BAFF, IgM and annexin were evaluated by flow cytometry on CD19+ cells in ESRD patients (n = 40), at time of initiating HD or CAPD (T0) and 6 months later (T6). RESULTS: A significant reduction in ESRD-T0 compared to controls was noticed for CD19+, 70.8 (46.5) vs. 171 (249), p < 0.0001, CD19+CD5-, 68.6 (43) vs. 168.9 (106), p < 0.0001, CD19+CD27-, 31.2 (22.1) vs. 59.7 (88.4), p < 0.0001, CD19+CD27+, 42.1 (63.6) vs. 84.3 (78.1), p = 0.002, CD19+BAFF+, 59.7 (37.8) vs. 127.9 (123.7), p < 0.0001 and CD19+IgM+ cells, 48.9 (42.8) vs. 112.5 (81.7) (K/µL), p < 0.0001. The ratio of early/late apoptotic B lymphocytes was reduced (16.8 (10.9) vs. 110 (25.4), p = 0.03). CD19+CD5+ cells were the only cell type with an increased proportion in ESRD-T0 patients (2.7 (3.7) vs. 0.6 (1.1), p < 0.0001). After 6 months on CAPD or HD, CD19+CD27-(%) and early apoptotic lymphocytes were reduced further. The HD patients also showed a significant increase in late apoptotic lymphocytes, from 1.2 (5.7) to 4.2 (7.2) K/mL, p = 0.02. CONCLUSIONS: B cells and most of their subtypes were significantly reduced in ESRD-T0 patients compared to controls, the only exception being CD19+CD5+ cells. Apoptotic changes were prominent in ESRD-T0 patients and were exacerbated by HD.

Effect of Lymphocyte Phenotypic Alterations on the Humoral Response to Vaccination Against SARS-COV-2 in Dialysis Patients.

Background: The response to vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies depending on comorbidities. This study evaluated the clinical and immunological factors affecting the humoral response of patients with end-stage renal disease (ESRD) to the BNT162b2 vaccine. Methods: Humoral immunity was evaluated in 54 ESRD patients using serum levels of anti-receptor-binding domain (RBD) and neutralizing antibodies (NAbs), measured by a chemiluminescent immunoassay 30 (T1), 60 (T2), and 120 (T3) days after the second vaccine dose. The results were correlated to baseline patient T- and B-lymphocyte subpopulations determined by flow cytometry. Results: The proportion of seroconverted patients based on the NAb titer decreased from 83.3% at T1 to 53.7% at T3. Age was negatively correlated to the NAb titer at T1 and T2. Patients receiving hemodiafiltration had higher NAb titers at T3. Diabetes was associated with a lower response rate at T3. Univariate analysis revealed a positive correlation between the naïve CD4 T-lymphocyte population and RBD titer at T1 and the NAb titer at T3, with no association observed with naïve CD8 T lymphocytes. NAb titers at T3 were significantly correlated with late-differentiated CD4 T lymphocytes and terminally differentiated effector memory cells re-expressing CD45RA (TEMRA) CD8 T lymphocytes. RBD levels were positively correlated with naïve and memory B-lymphocyte counts at T3. Conclusions: Age, diabetes, and hemodialysis prescription had significant impacts on the response to vaccination. T- and B-lymphocyte phenotypes are major determinants of the humoral response potency to SARS-CoV-2 vaccination with BNT162b2 in patients with ESRD.

The prognostic value of CHA2 DS2 -VASc and modified-CHADS2 scores for cardiovascular events in diabetics and non-diabetics haemodialysis patients.

AIM: CHA2 DS2 -VASc and modified-CHADS2 score can easily estimate the risk of stroke in atrial fibrillation. Study's purpose was to evaluate these in haemodialysis patients, and assess the effect of diabetes mellitus (DM). METHODS: The scores calculated in 237 haemodialysis patients, 121 diabetics (58 females) and 116 non-diabetics (41 females). Results correlated to cardiovascular events (acute myocardial infarction, atrial fibrillation, heart failure, peripheral arterial disease, stroke, mortality). RESULTS: CHA2 DS2 -VASc score correlated with the occurrence of stroke and heart failure (p < .01, p < .01), (p < .01, p < .01), respectively in diabetics and non-diabetics. CHA2 DS2 -VASc score could predict the risk of all-cause mortality in both groups, p = .03, p < .01, respectively, however, the risk of cardiovascular death could be predicted in non-diabetics, p < .01. Modified-CHADS2 score associated with heart failure (p = .04), cardiovascular (p < .01) and all-cause mortality (p < .01) only on non-diabetics. C statistics indicated that the first score showed modest discrimination in patients with and without DM, for stroke and all-cause mortality. The second score performed modestly only on patients without DM for all-cause mortality. Both scores showed poor calibration. Stroke was a common cause of cardiovascular death (OR = 3.52, 95% CI = 1.92-6.47, p < .01) and associated with central venous catheter (OR = 2.19, 95% CI = 1.12-4.27, p = .02) and pre-existing atrial fibrillation (OR = 1.94, 95% CI = 1.06-3.58, p = .03). CONCLUSION: CHA2 DS2 -VASc score correlated with stroke, heart failure and all-cause mortality in haemodialysis patients with and without DM. The risk of cardiovascular death could be predicted only in non-diabetics patients. Modified-CHADS2 score correlated with heart failure, cardiovascular and all-cause mortality only on non-diabetics. Both had modest discrimination and poor calibration.

Relapse of Monoclonal Gammopathy of Renal Significance after mRNA COVID-19 Vaccination: A Case Report.

This case report represents the first suspected case of light chain deposition disease relapse associated with mRNA COVID-19 vaccination. The 75-year-old female patient of Greek ethnicity was admitted to the clinic for the investigation of worsening renal function detected on routine lab examinations, two weeks after she received the second dose of the Moderna COVID-19 vaccine (mRNA-1273). Rapidly progressive glomerulonephritis and anemia were the most notable findings. She had a history of LCDD, which had remained stable for four years. Serum protein immunofixation showed monoclonal kappa zones, and a bone marrow biopsy revealed 5% plasma cell infiltration. These, along with other investigations, established the diagnosis of LCDD recurrence. The patient was started on chemotherapy, which improved her immunological profile, but not her renal function. The patient has remained on hemodialysis since. The association between mRNA vaccinations and LCDD relapse may be grounds for investigations into the pathophysiology of MGRS, given the patient's previous long-term remission. This case report is not intended to directly inform changes in clinical practice. We must stress the importance of following all standardized vaccination protocols, especially in immunocompromised patients.

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 < 0.001) were associated with VCs, whereas RANKL levels were not. Multivariate analysis though revealed that only OPG levels were significantly associated with abdominal aorta calcifications (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.

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.

From KDIGO 2012 towards KDIGO 2021 in idiopathic membranous nephropathy guidelines: what has changed over the last 10 years?

The recommendations in the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines regarding Idiopathic Membranous Nephropathy (IMN) management include significant changes as compared to those published in 2012. According to the recent guidelines, a biopsy is not always needed for IMN diagnosis; since diagnosis can be allowed for by the detection of circulating antibodies against the M-type transmembrane phospholipase A2 receptor (anti-PLA2R). Moreover, alterations in anti-PLA2R concentrations, along with other serum and urinary markers, may guide further follow-up. The findings of numerous recent studies which compared different immunosuppressive treatments resulted in substantial changes in treatment indications in the KDIGO 2021 guidelines, suggesting the stratification of patients into four risk categories. The definition of resistant cases and relapses was likewise modified. All the above will lead to a more granular and personalized approach, whose results need to be tested over time. In this commentary, we discuss the changes in the 2012 and 2021 guidelines, adding information from the most recent literature.

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.

An Approach to Identify HLA Class II Immunogenic Epitopes in the Greek Population through Machine Learning Algorithms.

Current pre-transplantation routine matching involves serum anti-HLA antibodies quantification but cannot always preclude unfavorable graft outcomes. Epitope-based matching is proposed as a more precise approach, but to date no epitope-matching algorithm provides a satisfactory predictive tool for transplantation outcomes. In this study, anti-HLA-II loci responses from 1748 patients were analyzed with unsupervised machine learning algorithms, namely principal component analysis (PCA) and antigenic distances, projected as dendrograms. PCA for anti-HLA-DR anti-bodies revealed three main clusters of responses: anti-HLA-DR51 combined with anti-HLA-DRB1*01, anti-HLA-DR52 combined with anti-HLA-DRB1*08 and anti-HLA-DR53 combined with anti-HLA-DRB1*10. The dendrogram for anti-HLA-DR confirmed the pattern and showed further bisection of each cluster. Common epitopes present exclusively in all HLA molecules of each cluster were determined following the HLA epitope registry. Thus, we propose that 19 out of 123 HLA-DR epitopes are those that mainly lead anti-HLA-DR responses in the studied population. Likewise, we identified 22 out of 83 epitopes responsible for anti-HLA-DQ and 13 out of 62 responsible for anti-HLA-DP responses. Interpretation of these results may elucidate mechanisms of interlocus cross-reactivity, providing an alternative way of estimating the significance of each epitope in a population and thus suggesting a novel strategy towards optimal donor selection.

Exhausted but Not Senescent T Lymphocytes Predominate in Lupus Nephritis Patients.

Lupus nephritis (LN), a chronic inflammatory disease, is characterized by the substantial disruption of immune homeostasis. This study examines its effects on the T lymphocyte phenotype and, particularly, its senescence- and exhaustion-related immune alterations. T cell subpopulations were determined with flow cytometry in 30 LN patients and 20 healthy controls (HCs), according to the expression of senescence- (CD45RA, CCR7, CD31, CD28, CD57), and exhaustion- (PD1) related markers. The immune phenotype was associated with disease activity and renal histology. LN patients were characterized by pronounced lymphopenia, mainly affecting the CD4 compartment, with a concurrent reduction in the naïve, central and effector memory subsets compared to the HCs. In the CD8 compartment, the naïve subsets were significantly lower than that of the HCs, but a shift in the T cells occurred towards the central memory population. CD4+PD1+ and CD8+PD1+ cells were increased in the LN patients compared to the HCs. However, in CD4 T cells, the increase was limited to CD45RA+, whereas in CD8 T cells, both CD45RA+ and CD45RA- subsets were affected. Disease activity was correlated with CD4+PD1+ and highly differentiated CD4+CD28-CD57+ cells. Histology was only associated with CD4 T cell disturbances, with stage IV presenting reduced naïve and increased senescent subsets. Exhausted T lymphocyte subpopulations predominate within LN patients, while the T cell phenotype varies depending on disease activity.

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.

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.

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.