Background and objectives Chronic kidney disease (CKD) and its management can adversely affect patients' quality of life and mental health. Many patients are often inadequately informed about their condition and the available treatment options. A considerable number of people with advanced kidney disease have insufficient knowledge about their condition and the available treatment options. This study aims to investigate the impact of an educational intervention on quality of life, psychological resilience, anxiety, and depression. This study specifically aims to evaluate the effectiveness of this intervention on variables such as quality of life, psychological resilience, anxiety, and depression. Methods A prospective randomized study was conducted on patients with CKD stage 4-5 to evaluate the effectiveness of an educational intervention in improving the aforementioned parameters. Furthermore, the correlation between these outcomes and the level of satisfaction with the intervention was analyzed. Participants were randomized (3:1) into two groups: an educational intervention group (33 patients) and a control group (12 patients). In the intervention group, we performed educational presentations accompanied by a relevant video. Participants completed the questionnaires both before and after the intervention. Participants in the control group were only asked to complete the questionnaires again after the same time period as the intervention group. Results Higher satisfaction with the intervention was significantly associated with a reduction in anxiety (r = -0.38, p = 0.03) and depression scores (r = -0.44, p = 0.01), along with a notable improvement in social functioning (r = 0.40, p = 0.02). Furthermore, a marginally significant positive correlation was observed between the satisfaction scale and psychological resilience (r = 0.32, p = 0.07). Conclusion The level of satisfaction with the intervention is a critical factor in determining its effectiveness. Tailoring the intervention to address the unique needs of each patient may significantly enhance its impact.

Abstract Background and Aims The aim of the study is to investigate the prescribing patterns and polypharmacy in Greek hemodialysis patients and make comparisons between renal units. Polypharmacy and hyperpolypharmacy emerged as a concerning problem, that affects patient's adherence, causes drug-drug interactions, adverse drug events, increases morbidity and economically strains the health system. Patients in Europe, are prescribed on average 10–12 drugs despite recommendations on polypharmacy. Method This is a multicenter retrospective study (2018-2021), in Northeastern Greece, of 270 patients (male = 168, female = 102) with mean age of 63.8±15 years and median dialysis duration of 45(18-96) months. The medications and laboratory values were documented for a period of 12 months, provided that there were no major changes on their therapy that time. The 4 public health dialysis units participating on the survey, were classified as secondary (179 patients) and tertiary care (91 patients) depending on the bed capacity (>600) and the availability of health services. Statistical analysis was conducted using SPSS ver26. Results The mean number of prescribed medications was 10.4 (SD 2.9, range 2–20). Of the participants, 97.4% were experiencing polypharmacy (≥5 medications per person) and 62.6% hyperpolypharmacy (≥10 medications). The average number of prescribed medications in tertiary care was substantially lower comparing with secondary care (mean: 8,7 vs 11,3, p<0.001). The difference in the mean number, remained significant even when the result was adjusted for age, gender, cardiovascular disease, primary disease and dialysis duration. Notably, despite the fewer medications, there was no statistically significant difference between the two groups, in achieving the most recent Kidney Disease Improving Global Outcomes (KDIGO) guidelines for URR (Urea Ruction Ratio), renal mineral bone disease and renal anemia (chi-sqaure, p>0.05 for all variables). The most frequently prescribed group of medications were EPO analogues (87%), Vitamin D supplements (83%), Proton Pump Inhibitors (68%), β-blockers (56%), Antiplatelets (45%) and Loop diuretics (37%). It is important to note the alarming number of patients receiving medication for mental illness (35.2%), mainly benzodiazepines (26%), with women to be more vulnerable (42.2% vs 30.1%, OR:1.63). Conclusion This study reports that Greek prescribing practices follow the same worrisome patterns as other European countries. Rural hospitals appear to prescribe more drugs than tertiary facilities.

Background: The aim of this study was to evaluate the prognostic value of automated office blood pressure (AOBP) measurement in patients with hypertension and chronic kidney disease (CKD) stage 3–5 not on dialysis. Methods: At baseline, 140 patients were recruited, and blood pressure (BP) measurements with 3 different methods, namely, office blood pressure (OBP), AOBP, and ambulatory blood pressure measurement (ABPM), were recorded. All patients were prospectively followed for a median period of 3.4 years. The primary outcome of this study was a composite outcome of cardiovascular (CV) events (both fatal and nonfatal) or a doubling of serum creatine or progression to end-stage kidney disease (ESKD), whichever occurred first. Results: At baseline, the median age of patients was 65.2 years; 36.4% had diabetes; 21.4% had a history of CV disease; the mean of estimated glomerular filtration rate (eGFR) was 33 mL/min/1.73 m2; and the means of OBP, AOBP, and daytime ABPM were 151/84 mm Hg, 134/77 mm Hg, and 132/77 mm Hg, respectively. During the follow-up, 18 patients had a CV event, and 37 patients had a renal event. In the univariate cox regression analysis, systolic AOBP was found to be predictive of the primary outcome (HR per 1 mm Hg increase in BP, 1.019, 95% CI 1.003–1.035), and after adjustment for eGFR, smoking status, diabetes, and a history of CV disease and systolic and diastolic AOBP were also found to be predictive of the primary outcome (HR per 1 mm Hg increase in BP, 1.017, 95% CI 1.002–1.032 and 1.033, 95% CI 1.009–1.058, respectively). Conclusions: In patients with CKD, AOBP appears to be prognostic of CV risk or risk for kidney disease progression and could, therefore, be considered a reliable means for recording BP in the office setting.

Abstract Background and Aims Flushing peritoneal cavity with dialysis fluid with short time dwells it is a necessity in some cases for peritoneal dialysis patients. Such cases are overhydration with pulmonary congestion or peritonitis before the initiation of antibiotic treatment as an effort to reduce pain. The aim of this study was to investigate the effect of frequent exchanges with peritoneal dialysis (PD) fluid with bicarbonate as a buffer on acid base balance of peritoneal dialysis patients. Method This is a single center cohort study of 18 stable PD patients (m=10.f=8). Their median age was 57 (47, 71) years, their median PD duration was 33 (16, 89) months and they all fulfill the criteria for achieving adequacy targets [median Kt/V 2.17 (1.99, 3.3)] with good nutrition markers [ median albumin levels 3.9 (3.6, 4) gr/dl]. A sample of arterial blood gas (ABG) was taken from the patients before the procedure and after full drainage of the peritoneal cavity . The procedure included 4 times flushing of 1000 ml of dialysis fluid remaining for15 minutes In the peritoneal cavity each time . At the end of the procedure a new blood sample for ABG was taken. We used PD solution with bicarbonate as a buffer (34 mmol/Lt). We estimated the alterations of pH, of bicarbonate (HCO3-), of pCO2, of Base Excess(ΒΕ), of ionized calcium (iCa++) and lactate (Lac) Results Using the non parametric related samples Wilcoxon signed method we found a statistically significant increase in arterial HCO3- concentration between the values before and after the procedure [HCO3-before:25.4 (22, 28), HCO3after:26.5 (24, 29) mEq/lt-P = .023]. Likewise there was a statistically significant increase in BE with median values before the procedure 1 (-1.2,2.9) and after the flushing 2 (-0.6,3,8), P = .018. Even though there was a statistically significant increase in the bases expression of the acid base balance of the patients there wasn't any statistically significant alterations in pH levels- i.e. Alkalemia (pHbefore=7.41,pHafter=7.42 – P = .35) or pCO2 levels i.e. Compensatory Respiratory Acidosis (pCO2προ=40, pCO2μετα=40 – P = .179) nor to the levels of ionized calcium Conclusion Flushing of peritoneal cavity using peritoneal dialysis solution with bicarbonate as a buffer is safe and in this study was not correlated with the development of metabolic alkalosis

Abstract Background and Aims Peritoneal Dialysis (P.D.) Adequacy includes a variety of targets such as the sufficient uremic toxins removal (Κt/V), patients’ euvolemia, acid-base and electrolyte balance etc.. Based on incremental PD prescription NIPD is often a reasonable modality choice when there is adequate Residual Renal Function (RRF). Eventually due to RRF decrease patients need to increase their PD adequacy by adding a solution during the day i.e Icodextrin (CCPD). The aim of this study was to evaluate the alteration of Cyclers’ ultrafiltration(UF) as well as Total Ultrafiltration (sum of Cycler ultrafiltration and the UF of the initial drainage) when transferring patients from NIPD to CCPD Method This is a single center retroprospective study of 16 patients (m = 9,f = 7). These patients were transferred from NIPD to CCPD due to inadequate PD adequacy. The patients’ mean age was 53.4±19 years, their mean PD duration was 74.3±25.7 months and their mean Peritoneal Solute Transfer Rate (PSTR-D/Pcr) was 0.69±0.12. We evaluated small solute clearance targets (Kt/V – t:total,p:peritoneal,r:renal), RRF (eGFR, Vurine), Cycler’ ultrafiltration, the UF of the initial drainage and the sum of them (Total UF) on three consecutive days before the initiation of CCPD and three consecutive days after the initiation. The patients’ cycler treatment program remain constant and all of them received an initial day volume of 1000 ml with Icodextrin. Results We compared the alterations with Paired t-Test (normal distripution) We found a statistically significant improvement of the peritoneal fraction of Kt/V when applying CCPD (p = 0.01), on the other hand we found a statistically significant decrease from Cycler's UF (p<0.05) as well as from Total UF (p<0.05) without any statistically significant increase in urine's volume. Additionally, from the regression analysis there was statistically significant correlation between PSTR and ΔUF(UFNIPD-UFCCPDtotal) showing that the faster the transporter the greater the ultrafiltration loss (p = 0.035, R = 0.58). Conclusion Transferring patients with adequacy problems from NIPD to CCPD improves small solute clearances but in some cases the risk for total ultrafiltration decrease is important and may lead to overhydration. It is necessary to contact perspective studies with hydration status evaluation ie Bioimpedance Spectroscopy.

Vascular calcification (VC) is an active process, resulting from the disturbance of balance between inhibitors and promoters of calcification, in favor of the latter. Matrix Gla Protein, a powerful inhibitor of VC, needs vitamin K to become active. In vitamin K depletion, plasma levels of the inactive form of MGP, dephosphorylated, uncarboxylated MGP (dp-ucMGP) are increased and associated with VC and cardiovascular (CV) outcomes. End Stage Renal Disease (ESRD) patients have increased circulating dp-ucMGP levels and accelerated VC. VItamin K In PEritoneal DIAlysis (VIKIPEDIA) is a prospective, randomized, open label, placebo-controlled trial, evaluating the effect of vitamin K2 supplementation on arterial stiffness and CV events in ESRD patients undergoing peritoneal dialysis (PD). Forty-four PD patients will be included in the study. At baseline, dp-ucMGP and pulse-wave velocity (PWV) will be assessed and then patients will be randomized (1:1 ratio) to vitamin K (1000 μg MK-7/day) or placebo for 1.5 years. The primary endpoint of this trial is the change in PWV in the placebo group as compared to the treatment group. Secondary endpoints are the occurrence of CV events, mortality, changes in PD adequacy, change in 24-hour ambulatory blood pressure indexes and aortic systolic blood pressure and changes in calcium/phosphorus/parathormone metabolism. VIKIPEDIA is a new superiority randomized, open label, placebo-controlled trial aiming to determine the effect of vitamin K2 supplementation on VC, CV disease and calcium/phosphorus metabolism, in PD patients. Trial registration: The protocol of this study is registered at ClinicalTrials.gov with identification number NCT04900610 (25 May 2021).

Background: The creation of an arteriovenous fistula in obese patients with end-stage-renaldisease, might not lead to a successful hemodialysis session, partly due to excess adipose tissue overlapping the enlarged vein. This review summarizes the available evidence on superficialization methods in studies dealing with obese patients. Methods: An English-language literature search was undertaken in the MEDLINE/SCOPUS databases looking for publications that described procedures of salvaging autologous arteriovenous access in upper extremities of obese patients. Perioperative outcomes including technical and clinical success, mean vein depth reduction, wound complications and patency rates were compared within all identified techniques. Results: We identified 12 prospective and 8 retrospective studies. A total of 1149 patients with a mean age 57.2 (range: 49-68) years and a mean BMI 35.8 (range: 28.2-40.8) kg/m(2) underwent mainly radial-cephalic and brachial-cephalic arteriovenous fistula superficialization procedures [transposition, 54%; elevation, 11.1%; lipectomy, 26.1%; liposuction, 2.4%; implantation of a venous window needle guide device, 6.4%]. Technical success was similar between all methods (>= 96%). However, successful cannulation was lower after liposuction and elevation (81.5% and 78.1% respectively). Transposition achieved lower mean vein depth reduction and clinical success when compared with lipectomy (4.9 mm vs. 8.8 mm and 90% vs. 92.7% respectively). Transposition and liposuction had the lowest and highest complication rate respectively (1.6% vs. 40.8%). Primary and secondar y patency rates were lower with liposuction (51.8% and 76.6% respectively), while lipectomy and elevation achieved the highest primary patency rates (68.3% and 71.6% respectively) at 12 months. Conclusions: In obese patients, all superficialisation techniques report high technical success rates. Although limited by the design of individual published studies and lack of a standard for reporting outcomes, these results lead to satisfactory postoperative and early outcomes. In aggregate, lipectomy and transposition are more clinically effective and more durable procedures.

Abstract BACKGROUND AND AIMS Hypervolemia is common in peritoneal dialysis (PD) and contributes to hypertension and left ventricular hypertrophy, thus increasing the cardiovascular risk of these patients. The achievement of adequate water and sodium balance is considered a major determinant of dialysis adequacy and seems to have a greater effect on PD outcome than Kt/V and small solute clearances. However, the contribution of different PD modalities to dialytic sodium removal remains not well defined. The aim of this study was to explore the effect of different PD modalities on sodium and water removal. METHOD This is a single-center cohort study of 21 patients (m = 12, f = 9). They were examined according to their modality of PD: CAPD (continuous ambulatory PD n = 9) and APD (continuous cycler PD n = 12). CAPD patients’ median age was 74 years (66–79), median time on PD was 37 months (24–59), median Kt/V 2.4 (1.9–3.1) and median eGFR 9.9 mL/min (3.5–12.4). APD patients’ median age was 47 years (32–75), median time on PD 65 months (52–87), median Kt/V 2.439 (2.12–2.8) and median eGFR 2.3 mL/min (0–5). We used the modified peritoneal equilibration test (PET with DW 4.25%) and double mini-PET to calculate the small solute transport rate (D/P of creatinine), water removal (FWT—free water transport, ΔNa—sodium dip, OCG—osmotic conductance of glucose) and mesothelial cell integrity (CA125 appearance rate in dialysis effluent). We also calculate the total amount of sodium excretion from the 24 h PD effluent collection and urine collection. Using bioimpedance spectroscopy we calculate the patients’ total body water, the overhydration and the intracellular and extracellular volume (ECV). RESULTS We did not find between the two groups any statistically significant difference for water movement through the membrane (ΔNa P = 0.427; FWT P = 0.384; OCG P = 0.27), for the marker of mesothelial cell mass (CA125AR P > 0.05) or for hydration status (OH, ECV). There was a statistically significant difference between the two groups for the small solute transport rate (Cr d/p, P = 0.025), for the total daily amount of sodium excretion through the membrane (P < 0.001), i.e. patients on APD having faster solute movement and excrete more sodium during the day compared to CAPD patients. Additionally, from the regression analysis there was statistically significant correlation between the daily dialysis sodium excretion and solute movement (P = 0.007, r = 0.58) and total time on PD (P = 0.004, r = 0.612). CONCLUSION These results indicate that there is no inferiority of APD compared to CAPD for sodium excretion due to the smaller time duration of the cycles (sodium sieving). Additionally, we notice that even though the patients on APD remained longer on PD and received larger daily volumes of PD effluent there was not any difference in mesothelial cell marker or water transport indicators. Inevitable time probably through neo angiogenesis results in faster solute transport.

OBJECTIVES:Recent evidence has linked circadian rhythm dysregulation to an increased risk of metabolic disorders. This study explores a potential association between variation in genes regulating the endogenous circadian timing system (clock genes) and the risk of type 2 diabetes (T2D) in a sample of Greek elderly people.STUDY DESIGN:Variants within and upstream or downstream of PPARA, PPARD, CLOCK/TMEM165, PER1, PER2 and PER3 genes were genotyped in 716 individuals with T2D (A) and 569 normoglycemic controls (B), and allele frequencies were compared between the groups in a case control study design.MAIN OUTCOME MEASURES:Samples were genotyped on Illumina Human PsychArray. Permutation test analysis was implemented to determine statistical significance. To avoid the possibility of subjects with prediabetes being included in the control group, people with HbA1c <5.7% and fasting glucose <100 mg/dl comprised group C (n = 393), for whom a separate analysis was performed (secondary analysis).RESULTS:A protective role against T2D was identified for 14 variants in the PPARA gene. The rs7291444, rs36125344, rs6008384 in PKDREJ, located upstream of PPARA, and rs2859389 in UTS2, located upstream of PER3, demonstrated a protective role against T2D in both analyses. In contrast, rs6744132, located between HES6 and PER2, was positively correlated with T2D risk. Only in the secondary analysis, rs2278637 in VAMP2, located downstream of PER1, and rs11943456 in CLOCK/TMEM165 were found to confer protection against T2D. In a recessive model analysis of all groups, PPARD variants exhibited a protective role against disease.CONCLUSIONS:Our findings suggest a possible implication of clock genes in T2D susceptibility. Further studies are needed to clarify the mechanisms that connect circadian rhythm dysfunction and T2D pathogenesis.

INTRODUCTION:HCV infection in patients under hemodialysis for end stage chronic kidney disease (ESCKD) may exist despite the absence of anti-HCV antibodies. Molecular methods are widely accepted as "gold standard" techniques for the detection of viral RNA. However, the molecular methods are more expensive in comparison to conventional methods and their replacement is not cost-effective. The aim of this study was to estimate the prevalence of HCV RNA positivity in anti-HCV negative hemodialysis patients and evaluate new diagnostic methods for the detection and the monitoring of hepatitis C in ESCKD patients.METHODS:The study was performed in four hospitals of Thrace region of Greece and 233 patients with no history of hepatitis C were enrolled. Measurement of anti-HCV antibodies and HCV core antigen was performed by microparticle chemiluminescence immunoassay. Molecular detection of viral RNA was performed by the real-time RT PCR.RESULTS:The mean age of the patients was 64.9 ± 23.3 years. HCV-Ag was positive in 2/233 patients (0.86%). Nevertheless, viral RNA was negative in those patients.CONCLUSIONS:The results of the present study showed that the incidence of HCV-RNA in patients with negative anti-HCV Abs, in hemodialysis patients in Thrace region of Greece was negligible (0/233).

Abstract Background and Aims Peritoneal Dialysis (PD) is a well-established method for dialysis of end stage kidney disease patients. Peritoneal membrane alters with time from several causes such as bioincompatible PD solutions, uremia, and the cumulative effect of peritonitis episodes. Each center follows a specific training program to prevent the appearance of peritonitis episodes. The aim of this study was to retrospectively evaluate the influence of proper and continuous training on the mortality of peritoneal dialysis patients. Method This is a single center retrospective study of 133 PD patients conducted for the time period 2009 – 2019 (10 years). The training course was taught one-on-one, nurse-to-patient at the initiation of dialysis and then once every 6 months at their regular visit or sooner if there was a peritonitis episode. The program included a rated questioner based on the Canadian Association of Nephrology Nurses for Nursing Standards and Practice Recommendations published on August 2008. The patients were divided into two groups according to the mean value (34) of their questioner sum (QS). Group A included 69 patients with mean age of 66 ± 15 years (36 M, 33 F) with mean PD duration of 45 ± 30 months and they achieved a score less than 34. Group B included 64 patients with mean age of 61 ± 18 years (42 M, 22 F) with mean PD duration of 62± 32 months and they achieved a score greater than 34. The cumulative all-cause survival of the PD patients was calculated by Kaplan Meier, was compared using Long Rang analysis and was also adjusted for their age, gender, the modality of PD applied, the presence of Diabetes and their level of education. Using Cox Regression, we tried to find independent risk factors such as the score they achieved in the questioner. The two groups were compared also for their overhydration and their frequency appearance of peritonitis or exit site infection. Results The cumulative survival using Kaplan-Meier analysis revealed statistically significant deference between the two groups (Log Rank p<0.001) with Group B (QS>34) achieving better survival. When the survival was adjusted for age, sex, Diabetes, PD modality the result remains the same. Trying to find among the total of our patients the possible risk factors for mortality, using Cox Regression analysis, their QS score (representing their training level for PD) was statistically significant (HR 0,931 {0.892, 0.971}, p=0.001) independent risk factor, as well as age and PD modality, for our patient survival. Additionally, Group B (QS>34) had statistically significant a smaller number of peritonitis episodes (p<0.001) and presence of peripheral edema (p<0.001). Conclusion In our study we concluded that continuous and monitored training of peritoneal dialysis patients has a significant effect on their survival and the frequency of peritonitis appearance.

BackgroundMyasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date.MethodsWe performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders.ResultsWe confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10−13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders.DiscussionOur gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

The gut microbiome is known as an important predictive tool for perceiving characteristic shifts in disease states. Multiple renal diseases and pathologies seem to be associated with gut dysbiosis which directly affects host homeostasis. The gastrointestinal-kidney dialogue confers interesting information about the pathogenesis of multiple kidney diseases. Moreover, aging is followed by specific shifts in the human microbiome, and gradual elimination of physiological functions predisposes the microbiome to inflammaging, sarcopenia, and disease. Aging is characterized by a microbiota with an abundance of disease-associated pathobionts. Multiple factors such as the immune system, environment, medication, diet, and genetic endowment are involved in determining the age of the microbiome in health and disease. Our present review promotes recently acquired knowledge and is expected to inspire researchers to advance studies and investigations on the involved pathways of the gut microbiota and kidney axis.

Background: Approximately one third of type 2 diabetes mellitus (T2DM) cases present with diabetic nephropathy (DN), the leading cause of end-stage renal disease. Inflammation plays an important role in T2DM disease and DN pathogenesis. NLRP3 inflammasomes are complexes that regulate interleukin-1B (IL-1B) and IL-18 secretion, both involved in inflammatory responses. Activation of NLRP3 is associated with DN onset and progression. Here, we explore whether DN is associated with variants in genes encoding key members of the NLRP3 inflammasome pathway. Methods: Using genome-wide association data, we performed a pilot case-control association study, between 101 DN-T2DM and 185 non-DN-T2DM cases from the Hellenic population across six NLRP3 inflammasome pathway genes. Results: Three common CARD8 variants confer decreased risk for DN, namely rs11665831 (OR = 0.62, p = 0.016), rs11083925 (OR = 0.65, p = 0.021), and rs2043211 (OR = 0.66, p = 0.026), independent of sex or co-inheritance with an IL-1B variant. Conclusion: CARD8 acts as an NLRP3, NF-κB and caspase-1 inhibitor; perhaps, alterations in the cross-talk between CARD8, NF-κB, and NLRP3, which could affect the pro-inflammatory environment in T2DM, render diabetic carriers of certain common CARD8 variants potentially less likely to develop T2DM-related pro-inflammatory responses followed by DN. These preliminary, yet novel, observations will require validation in larger cohorts from several ethnic groups.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background: Approximately one third of type 2 diabetes mellitus (T2DM) cases present with diabetic nephropathy (DN), the leading cause of end-stage renal disease. Inflammation plays an important role in T2DM disease and DN pathogenesis. NLRP3 inflammasomes are complexes that regulate interleukin-1B (IL-1B) and IL-18 secretion, both involved in inflammatory responses. Activation of NLRP3 is associated with DN onset and progression. Here, we explore whether DN is associated with variants in genes encoding key members of the NLRP3 inflammasome pathway. Methods: Using genome-wide association data, we performed a pilot case-control association study, between 101 DN-T2DM and 185 non-DN-T2DM cases from the Hellenic population across six NLRP3 inflammasome pathway genes. Results: Three common CARD8 variants confer decreased risk for DN, namely rs11665831 (OR = 0.62, p = 0.016), rs11083925 (OR = 0.65, p = 0.021), and rs2043211 (OR = 0.66, p = 0.026), independent of sex or co-inheritance with an IL-1B variant. Conclusion: CARD8 acts as an NLRP3, NF-κB and caspase-1 inhibitor; perhaps, alterations in the cross-talk between CARD8, NF-κB, and NLRP3, which could affect the pro-inflammatory environment in T2DM, render diabetic carriers of certain common CARD8 variants potentially less likely to develop T2DM-related pro-inflammatory responses followed by DN. These preliminary, yet novel, observations will require validation in larger cohorts from several ethnic groups.

AbstractBackgroundMyasthenia Gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction. Here, we investigate the genetic architecture of MG performing a genomewide association study (GWAS) of the largest MG dataset analyzed to date.MethodsWe integrated GWAS from three different datasets (1,401 cases, 3,508 controls) and performed MG GWAS and onset-specific analyses. We also carried out HLA fine-mapping, gene-based, gene ontology and tissue enrichment analyses and investigated genetic correlation to other autoimmune disorders.FindingsWe observed the strongest MG association toTNFRSF11A(rs4369774, p=1.09×10−13; OR=1.4). Gene-based analysis revealedAGRNas a novel MG susceptibility gene. HLA fine-mapping pointed to two independent loci significantly associated with MG:HLA-DRB1(with a protective role) andHLA-B. MG onset-specific analysis, reveals differences in the genetic architecture of Early-Onset vs Late-Onset MG. Furthermore, we find MG to be genetically correlated with Type 1 Diabetes, Rheumatoid Arthritis and late-onset Vitiligo.InterpretationOverall, our results are consistent with previous studies highlighting the role of the HLA andTNFRSF11Ain MG etiology and different risk genes in EOMG vs LOMG. Furthermore, our gene-based analysis implicates, for the first time,AGRNas a MG susceptibility locus.AGRNencodes agrin, which is involved in neuromuscular junction formation. Mutations inAGRNhave been found to underlie congenital myasthenic syndrome. Gene ontology analysis suggests an intriguing role for symbiotic processes in MG etiology. We also uncover genetic correlation of MG to Type 1 Diabetes, Rheumatoid Arthritis and late-onset Vitiligo, pointing to shared underlying genetic mechanisms.FundingThis work was supported by NSF award #1715202, the European Social Fund and Greek funds through the National Strategic Reference Framework (NSRF) THALES Programme 2012–2015 and the NSRF ARISTEIA II Programme 2007–2013 to PP, and grants from the Association Francaise contre les Myopathies (AFM, Grant No. 80077) to ST.Research in contextEvidence before this studyMyasthenia Gravis (MG) is a complex disease caused by the interaction of genetic and environmental factors that lead to autoimmune activation. Previous studies have shown that the human leukocyte antigen (HLA) displays the most robust genetic association signals to MG. Additional susceptibility genes that have emerged through genomewide association studies (GWAS), includeCTLA4andTNFRSF11A. Previous studies also support the hypothesis of distinct risk loci underlying Early-Onset versus Late-Onset MG subgroups (EOMG vs LOMG). For instance,PTPN22andTNIP1genes have been implicated in EOMG andZBTB10in LOMG. In the GWAS studies published so far,HLAandTNFRSF11Aassociations appear to be confirmed; however, the association of other implicated genes still requires replication.Added value of this studyWe present the largest GWAS for MG to date, integrating three different datasets. We identifyAGRNas a novel MG risk locus and replicate previously reported susceptibility loci, including HLA,TNFRSF11A, and CTLA4. Our analysis also supports the existence of a different genetic architecture in EOMG vs LOMG and identifies a region betweenSRCAPandFBRSas a novel EOMG risk locus. Additionally, through HLA fine-mapping, we observe different HLA genes implicated in EOMG vs LOMG (HLA-BandHLA-DRB1respectively). Finally, we detect positive genetic correlation of MG with other autoimmune disorders including Type 1 Diabetes, Rheumatoid Arthritis, and late-onset Vitiligo, suggesting a shared genetic basis across them.Implications of all the available evidenceOur study sheds light into the etiology of MG identifyingAGRNas a novel risk locus.AGRNencodes agrin, a protein with a significant role in the formation of the neuromuscular junction and mutations in this gene have been associated with congenital myasthenic syndrome. Our findings hint to an intriguing hypothesis of symbiotic processes underlying MG pathogenesis and points to muscle growth and development in EOMG and steroid hormones synthesis in LOMG. The observed genetic correlations between MG and certain other autoimmune disorders could possibly underlie comorbidity patterns across this group of disorders.

Background: Fibroblast growth factor 23 (FGF-23) and α-Klotho protein appear to have an important role in the pathogenesis of CKD-mineral and bone disorders. The aim of this study was to investigate the association of FGF-23 and α-Klotho levels with adverse clinical outcomes in patients with non-dialysis CKD. Materials and Methods: We conducted a prospective cohort study, enrolling participants with non-dialysis CKD from a single center in Greece. At enrollment, glomerular filtration rate (GFR) was measured (mGFR) and plasma levels of carboxyl terminal FGF-23 (cFGF-23) and soluble α-Klotho (sKlotho) were determined by enzyme-linked immunoassay. Participants were followed for up to 5 years or until the occurrence of the primary endpoint of initiation of renal replacement therapy or death. Multivariate regression tree analysis was used to identify informative baseline parameters in order to categorize participants. Also, using median values of cFGF-23 and sKlotho, participants were categorized into 4 groups, in whom survival was compared using Kaplan-Meier and Cox regression analysis. Results: 128 participants were enrolled with a median mGFR of 41.5 mL/min/1.73 m2 (IQR = 28.2). Baseline mGFR correlated with cFGF-23 and sKlotho (r = −0.54 and r = 0.49, respectively; p < 0.0001 for both). cFGF-23 and sKlotho levels correlated negatively (r = −0.24, p = 0.006). Multivariate regression tree analysis resulted in 3 groups defined by cutoff values of mGFR (60.9 mL/min/1.73 m2) and phosphate (3.7 mg/dL). These groups correlated with CKD stage, cFGF-23, and sKlotho (p < 0.0001 for all). During a median follow-up of 36 months (IQR = 22), 40 (31.2%) participants reached the primary endpoint (31 initiated renal replacement therapy, 9 died). Survival to primary endpoint differed among the 4 groups formed using median values of both biomarkers, with the low FGF-23/high Klotho and high FGF-23/low Klotho having the longest and shortest survival, respectively. High FGF-23/low Klotho group, compared to the opposite one, had a significantly elevated risk of the primary outcome (HR, 6.8; 95% CI, 2.3–19.6; p = 0.0004). Conclusions: In patients with CKD stages 1–5, the combination of higher cFGF-23 and lower sKlotho levels along with mGFR and serum phosphate was associated with adverse clinical outcomes. The utility of combinations of traditional and novel biomarkers to predict outcomes warrants further study.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Background and Aims Peritoneal protein loss (PPL) through peritoneal effluent has been a well-recognized detrimental result of peritoneal dialysis (PD). The amount of protein lost will depend on dialysis time, protein size, its serum concentration and other factors including patients’ clinical status. Peritoneal protein loss may be a manifestation of endothelial dysfunction, as with another type of capillary protein leakage, microalbuminuria, a recognized endothelial dysfunction marker. The aim of this study was to retrospectively evaluate the influence of PPL on cardiovascular mortality of peritoneal dialysis patients Method This is a single center retrospective study of 84 PD patients (m=54, f=30) with mean age of 65.2±17 years, mean PD duration of 43.2±24.9 months conducted for the time period from 2006 to 2019 (13 years). The patients were divided into two groups according to the amount of protein excreted during the modified Peritoneal Equilibration Test (PET) procedure using PD solution of 3.86% DW, 2 Lt infusion volume for total time of 4 hours. The total amount of proteins excreted was calculate from PET by multiplying the concentration of proteins at the end of the test with the total volume of PD fluid at the same time. Group A excreted a total amount of proteins < 1.55 gr (median value) at the end of PET test and Group B > 1.55 gr. The cumulative all-cause and cardiovascular survival of the PD patients was calculated by Kaplan Meier while the possible effect of any parameter in survival rates was evaluated by using Cox Regression analysis Results There was not any statistically significant difference between the two groups according to PD duration, age, dialysis adequacy targets, Residual Renal Function(RRF), BMI, ultrafiltration volume during PET and their transport status. The cumulative all-cause survival using Kaplan-Meier analysis revealed no statistically significant deference between the two groups (Log Rank p=0.55) even though mortality risk was adjusted for several factors (Cox Regression). When cardiovascular survival, using Cox Regression analysis, was adjusted for age, sex, Diabetes, PD modality, dialysis Kt/V and RRF we found that Group A (with protein excretion < 1.55 gr) had statistically significant better cardiovascular survival (p=0.029) compared to Group B. We confirm these results while trying to find among the total of our patients the possible risk factors for cardiovascular mortality. Using Cox Regression analysis, the amount of protein excreted during PET procedure and the type of PD solutions (high or low in GDPs) used were statistically significant (p=0.019 and p=0.04 respectively) independent risk factors for cardiovascular survival in our patients. Conclusion These results indicate that protein loss during peritoneal dialysis procedure has negative impact on cardiovascular mortality and survival of PD patients. Additionally, the use of PD solutions with low Glucose Degradation Products (GDPs) and AGEs may improve PD patient’s cardiovascular survival. Randomized interventional studies are encouraged to address the pathological concern of PPL in the future, namely its effects on cardiovascular conditions or its role as marker and effort to reduce PPL using ACE inhibitors or vit D should be considered only if it diminishes cardiovascular morbidity or mortality.