Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.

BACKGROUND: Myasthenia 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. METHODS: We 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. RESULTS: We 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. DISCUSSION: Our 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.

Glomerular expression of matrix metalloproteinases in systemic lupus erythematosus in association with activity index and renal function.

PURPOSE: The aim of this study was to examine the expression of matrix metalloproteinases (MMPs) MMP-1, MMP-2, MMP-3, MMP-9, and their specific tissue inhibitor TIMP-1 in kidney biopsies of patients with lupus nephritis (LN) and to investigate the relationship between MMPs, activity index, and renal function at the time of kidney biopsy. METHODS: We performed immunohistochemistry with monoclonal antibodies against MMP-1, MMP-2, MMP-3, MMP-9, and TIMP-1 in 58 kidney-biopsy specimens with LN (according to the 2004 ISN/RPS classification) and eight specimens from normal kidney tissue. We used clinical data of 36 patients at the time of kidney biopsy to evaluate the association between MMPs expression and renal function. RESULTS: We found increased MMP-1, MMP-2, and MMP-3 expression in LN glomeruli and a significant correlation with the activity features, with higher activity index score and worse renal function (p < .001). In particular, we have noticed a significant correlation of MMP-1 with leukocyte influx (OR:16.5 95%CI 4.3-62.5 p < .001), and MMP-3 with glomerular hypercellularity (OR:18.6 95%CI 4.8-72.8 p < .001). Moreover, we found a strong correlation of MMP-2 expression with fibrinoid necrosis and cellular crescents formation (OR:17.1 95%CI 4.3-67.7 p < .001). CONCLUSIONS: MMP expression in renal biopsy of patients with LN is increased and directly related to a highly active inflammatory response. Moreover, stronger MMP expression is associated with higher activity index and a more profound renal dysfunction.

Endovascular Repair of an Inadvertent Right Vertebral Artery Rupture during Dialysis Catheter Insertion.

Central venous (CV) catheterization is not only an invaluable diagnostic modality but also an essential therapeutic tool for the treating physician, enabling rapid and reliable intravenous administration of drugs and fluids, providing venous access to patients undergoing long-term continuous or repeated intravenous treatment such as chemotherapy, or it can be used for hemodialysis in patients suffering from acute or chronic renal disease. On the other hand, CV catheterization can lead to a wide range of life-threatening complications for the patient especially if left untreated or become late-diagnosed. In particular, arterial injuries are among the most feared complications that require early clinical suspicion for prompt diagnosis and management. We report the case of a 79-year-old female dialysis patient who suffered from a vertebral artery (VA) injury complicated by a herald bleeding on the third postintervention day after an internal jugular vein dialysis catheter replacement. The patient initially presented neurological signs of a stroke and urgently treated endovascularly after immediate diagnosis of VA rupture was made. Imaging techniques are evidence-based tools that help minimize these mechanical complications, including inadvertent arterial puncture and therefore should be practiced and taught in training programs to avoid the potentially devastating consequences of CV catheterization.

Ambulatory aortic blood pressure, wave reflections and pulse wave velocity are elevated during the third in comparison to the second interdialytic day of the long interval in chronic haemodialysis patients.

BACKGROUND: Increased arterial stiffness and aortic blood pressure (BP) are independent predictors of cardiovascular outcomes in end-stage renal disease. The 3-day interdialytic interval is associated with elevated risk of cardiovascular morbidity and mortality in haemodialysis. This study investigated differences in ambulatory aortic BP and arterial stiffness between the second and third day of the long interdialytic interval. METHODS: Ambulatory BP monitoring with Mobil-O-Graph monitor (IEM, Stolberg, Germany) was performed in 55 haemodialysis patients during a 3-day interval. Mobil-O-Graph records oscillometric brachial BP and pulse waves and calculates aortic BP and augmentation index (AIx) as measure of wave reflections, and pulse wave velocity (PWV) as measure of arterial stiffness. RESULTS: Ambulatory aortic systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher during the third versus second interdialytic day (123.6 ± 17.0 versus 118.5 ± 17.1 mmHg, P < 0.001; 81.5 ± 11.8 versus 78 ± 11.9 mmHg, P < 0.001, respectively). Similar differences were noted for brachial BP. Ambulatory AIx and PWV were also significantly increased during the third versus second day (30.5 ± 9.9 versus 28.8 ± 9.9%, P < 0.05; 9.6 ± 2.3 versus 9.4 ± 2.3 m/s, P < 0.001, respectively). Differences between Days 2 and 3 remained significant when day-time and night-time periods were compared separately. Aortic SBP and DBP, AIx and PWV showed gradual increases from the end of dialysis session onwards. Interdialytic weight gain was a strong determinant of the increase in the above parameters. CONCLUSIONS: This study showed significantly higher ambulatory aortic BP, AIx and PWV levels during the third compared with the second interdialytic day. These findings support a novel pathway for increased cardiovascular risk during the third interdialytic day in haemodialysis.

Subcutaneous and total fat at L4-L5 and subcutaneous, visceral and total fat at L3-L4 are important contributors of fasting and postprandial adiponectin levels.

OBJECTIVES: Insulin resistance and central obesity have been implicated in the pathogenesis of hypoadiponectinemia in obesity. The aim of this study is to evaluate circulating post-prandial adiponectin in relation to glucose and insulin metabolism, indexes of insulin resistance and sensitivity and, indexes of body fat accumulation and distribution in obese men. METHODS: Twenty-eight non-diabetic men underwent an OGTT followed by an oral fat load and were studied at baseline and for 5 h post-prandially for serum adiponectin, glucose and insulin. Insulin resistance was estimated by Homeostasis model assessment (HOMA) and insulin sensitivity by Matsuda index. Body fat accumulation and distribution were evaluated by anthropometric indexes and multiple slices MRI of the abdomen and hip. RESULTS: Adiponectin was negatively correlated to insulin levels. Fasting and area under the curve (AUC) adiponectin levels were negatively correlated to HOMA (both p < 0.01) and positively to Matsuda index (both p < 0.05). Negative correlations between fasting adiponectin and total fat (r = -0.408, p < 0.05), AUC adiponectin and subcutaneous, visceral and total fat (r = -0.375, -0.413 and -0.475 respectively, all p < 0.05) at L3-L4 were found, and negative correlations between fasting adiponectin and subcutaneous (r = -0.402, p < 0.05) and total fat (r = -0.491, p < 0.05) and between AUC adiponectin and subcutaneous and total fat (r = -0.506 and -0.547, respectively, both p < 0.01) were present at L4-L5. CONCLUSIONS: Circulating adiponectin is inversely correlated to both visceral and subcutaneous fat in non-diabetic men, implying that both compartments are important for adiponectin levels. The best correlation is found at measurement site L4-L5.

Correlation of pre-existing radial artery macrocalcifications with late patency of primary radiocephalic fistulas in diabetic hemodialysis patients.

OBJECTIVE: The aim of this study was to evaluate the impact of pre-existing radial artery macrocalcification (Mönckeberg type of arteriosclerosis) on patency rates of radiocephalic fistulas (RCFs) in diabetic end-stage renal disease (ESRD) patients undergoing hemodialysis. METHODS: In this observational prospective study, the long-term patency rates (primary outcome measures) of RCFs in ESRD diabetics who had Mönckeberg radial (±brachial) artery disease (calcified [C] group) were compared with those obtained in ESRD diabetics who had healthy, noncalcified vessels before RCF construction (healthy [H] group). Vessel calcification was assessed by plain two-dimensional radiography. For inclusion in the C-group, uniform linear railroad track-type macrocalcifications of at least 6 cm in length, in the medial wall of the radial artery ipsilateral to RCF creation, were required. Patients were included in the H-group if the radial artery ipsilateral to the RCF creation was free of any macrocalcification, of either intima or media type. Any intimal-like plaque with irregular and patchy distribution was an exclusion criterion for both groups. Patients in both groups also were required to have suitable upper limb vascular anatomy on the basis of ultrasound imaging before RCF creation (cephalic vein of minimum diameter of 1.6 mm, without stenosis or thrombosis in all outflow areas, and radial artery of minimum diameter of 1.5 mm, without proximal hemodynamically significant stenosis). Secondary outcome measures included all-cause mortality. Kaplan-Meier statistics were used for comparison between groups. RESULTS: The arm radiograph at the site of possible fistula construction showed abnormality in 39 patients (C-group, 47 RCFs), whereas 33 patients had noncalcified ("healthy") vascular anatomy (H-group, 40 RCFs). Mean duration of the diabetic disease at the time of RCF creation was 8.9 ± 5.6 years (range, 2-25 years) for the H-group and 14 ± 9.9 years (range, 1-40 years) for the C-group (P = .018). The mean follow-up period for H-group and C-group was 51.9 ± 35.9 months (range, 0.1-126 months) and 26.1 ± 31.6 months (range, 0.1-144 months), respectively (P = .0006). Forty-four patients died during the follow-up period. Primary patency rates at 12, 24, 36, and 48 months for C-group vs H-group were 50.2% vs 80%, 36.5% vs 72.3%, 32.4% vs 67.9%, and 29.1% vs 59.3% (P = .0019). Respective values for secondary patency rates were 52.4% vs 87.5%, 40.9% vs 82.4%, 36.6% vs 78.1%, and 33.2% vs 72.8% (P = .00064). Patient survival rates at 24 and 48 months were 56.1% and 46.4% for C-group and 92.4% and 67.4% for H-group, respectively (P = .05). CONCLUSIONS: ESRD diabetics with radial artery Mönckeberg calcifications receiving RCFs had worse late clinical outcomes compared with ESRD diabetics with healthy distal arm vessels receiving the same access. The long-term benefit of RCFs may be lost in diabetics with extensively calcified vessels, and preferably the brachial artery should be used instead.

Recurrence of Idiopathic Membranous Nephropathy in the Kidney Allograft: A Systematic Review.

INTRODUCTION: The recurrence of idiopathic membranous nephropathy (iMN) after kidney transplantation is common, although its exact clinical significance remains unclear. This systematic review aims to elucidate the effects of iMN recurrence on graft survival. MATERIALS AND METHODS: A literature search was performed by systematically searching Medline, Scopus, Web of Science, and Google Scholar from inception. Cohort studies examining iMN recurrence after kidney transplantation were deemed eligible. Meta-analysis was performed by fitting random-effects models. RESULTS: Twelve (12) articles published from 1995 to 2016 reporting on 139 transplant patients with recurrent iMN were included. The median time of the diagnosis of recurrent iMN was 18 months during follow-up from 35 to 120 months. Risk factors for iMN recurrence in the renal allograft are a positive serum test for anti-PLA2R antibodies pretransplant, female sex, younger age, high proteinuria pretransplant, the longest interval from initial disease to end-stage chronic kidney disease, and the combination of alleles HLA DQA1 05:01 and HLA DQB1 02:01. In the pretransplant period, 37 (26.61%) patients had a positive serum test and 18 (12.94%) patients had a positive biopsy stain for anti-PLA2R antibodies. The sensitivity of the pretransplant positive serum test for these antibodies ranges from 57% to 85.30% and the specificity is 85.10-100%. A total of 81.80% of patients who received rituximab as treatment for iMN recurrence achieved complete and partial remission, while 18.20% had no response to treatment. iMN recurrence was not associated with significantly different rates of graft loss (odds ratio = 1.03, 95% CI: 0.52-2.04, p = 0.524, I2 = 0.00%). Recurrence of iMN was not associated with increased risk of graft loss independently of whether patients were treated with rituximab (OR: 0.98, 95% CI: 0.39-2.50, I2: 0%) or not (OR: 1.22, 95% CI: 0.58-2.59, I2: 3.8%). Patients with iMN recurrence who achieved remission had significantly reduced risk of graft loss (OR: 0.14, 95% CI: 0.03 to 0.73). CONCLUSION: The main outcome from this systematic review is that there is no statistically significant difference in graft survival in patients with iMN recurrence compared to those without recurrence in long-term follow-up. The achievement of remission is associated with significantly reduced risk of graft loss.

A nephrology trainee can define the fluid status through lung ultrasonography and inferior vena cava measurements in hemodialysis patients: an observational study in a single center.

AIMS: The determination of ideal weight in hemodialysis patients remains a common problem. The use of Lung Ultrasound (LUS) is an emerging method of assessing the hydric status of hemodialysis patients. LUS combined with Inferior Vena Cava (IVC) ultrasonography can define the fluid status in hemodialysis patients. METHODS: This study included 68 hemodialysis patients from the Dialysis Unit of Papageorgiou General Hospital in Thessaloniki. The patients underwent lung and IVC ultrasound 30 min before and after the end of the dialysis session by a nephrology trainee. Patients' ideal weight was modified based on daily clinical practice rather than ultrasound findings. The presence of B lines and ultrasound findings of the IVC were evaluated. RESULTS: The average B line score was 11.53 ± 5.02 before dialysis and became 5.57 ± 3.14 after the session. The average diameter of the IVC was 14.266 ± 0.846 mm before dialysis and 12.328 ± 0.879 mm after the session. The patients were categorized based on the magnitude of overhydration and the findings were evaluated. In addition, findings after the session showed a statistically significant correlation between the b line score and the diameter of the IVC adjusted for the body surface area. (p = 0.009 < 0.05). CONCLUSIONS: A high rate of hyperhydration was detected before the dialysis session (25%). While it is the first study conducted by a nephrology trainee highlighting that it is a feasible technique. Intervention studies should be carried out in the future to draw more precise conclusions.

Scanning more corresponds to more accuracy in hemodialysis patients: 28-zone protocol's superior findings from an observational study.

AIMS: Hypervolemia remains a problem in hemodialysis patients and is associated with hypertension, cardiovascular events and mortality. Lung Ultrasound (LUS) is a technique that detects hypervolemia via 4 different protocols depending on the number of sites checked on the chest wall. It has not been established which protocol should be preferred in the literature. METHODS: This study included 68 hemodialysis patients from one Dialysis Unit. All the patients underwent LUS with every single protocol 30 min before and after the end of the middle-week dialysis session by a nephrology trainee. Patients' ideal weight was modified based on daily clinical practice rather than ultrasound findings. RESULTS: Seventeen patients (25%) had ultrasound findings compatible with hypervolemia before the dialysis session, while eleven patients (16.2%) had still pulmonary congestion after the end of the session. These findings were similar to the number of patients considered hyperhydrated based on clinical criteria (10 patients). The rest protocols (8-zone, 6-zone and 4-zone protocol) considered fewer patients as hypervolemic. CONCLUSIONS: The 28-zone protocol can effectively detect hypervolemia and even classify the degree of it, although It is a time-consuming method. However, the other protocols can detect the hypervolemia in hemodialysis patients only when severe lung congestion exists. Their usefulness is limited in daily clinical practice in hemodialysis patients. More studies should be carried out for further and more reliable conclusions.

Evaluation of arteriovenous fistula maturation and early prediction of clinical eligibility, using ultrasound: The Fistula Maturation Evaluation (FAME) Study.

INTRODUCTION: The study of time-related alterations of ultrasound-determined parameters during maturation, and the assessment of time to hemodynamic maturation, enabling early prediction of clinical eligibility, of hemodialysis autologous arteriovenous fistulae (AVF). METHODS: This is an observational, prospective, study of only AVF-eligible patients referred for access creation, from 02/2019 to 02/2022 (ClinicalTrials.gov identifier: NCT0473687). Brachial artery diameter (dBA), access flow volume (FV), non-augmented efferent vein diameter (dEV), resistivity index (RI), and efferent vein total wall thickness (tEV), were assessed by ultrasound. Measurements were conducted daily in the first week and repeated on days 14, 21, 30, 60, and 90, postoperatively. The primary endpoint included the documentation of serial changes of flow and structural parameters related to AVF maturation in the first 90 days of the post-operative period and maturation early prediction. Secondary endpoints included the determination of factors affecting maturation. RESULTS: One hundred one participants (mean age, 67 ± 6 years; 76 males) were enrolled. Average dBA and FV reached maximum on day 60 (5.64 ± 0.85 mm) and 90 (1.172 ± 617 mL/min), respectively. Day 7 values of dBA (5.48 ± 0.73 mm) and FV (1.039 ± 531 mL/min) did not alter significantly during the follow-up period. Parameters indicative of clinical functionality, dEV (5.82 ± 0.90 mm) and tEV (0.493 ± 0.10 mm), reached approximately 90% of maximum (6.66 ± 1.42 mm and 0.526 ± 0.11 mm), by day 14. RI reached minimum on day 30 (0.46 ± 0.09), without significant changes after day 2 (0.48 ± 0.09, p = 0.284). A significant correlation was identified, between day 7 FV and day 60 dEV (r = 0.40, p = 0.0002). A FV cut-off value ⩾657.51 mL/min, on day 7, predicted successful fistula maturation with 85% sensitivity and 100% specificity. Multivariate analysis identified female gender, age >75, diabetes, and wrist access as independent predictors of decreased values of maturation parameters. CONCLUSION: Hemodynamic maturation is completed by the first postoperative week, while AVF is clinically functional, by the second. FV can be used for early prediction of maturation.

Differential effect of baseline adiponectin on all-cause mortality in hemodialysis patients depending on initial body mass index. Long-term follow-up data of 4.5 years.

OBJECTIVES: We sought to investigate the interaction of adiponectin levels and body mass index (BMI) for predicting all-cause mortality in a cohort of hemodialysis (HD) patients. DESIGN: Longitudinal, observational cohort study. SETTING: HD unit. SUBJECTS: Sixty patients (mean age: 64 ± 13 years, 39 men) with end-stage renal disease on maintenance HD followed up for 4.5 years represented the prospective study cohort. INTERVENTION: Associations between baseline plasma adiponectin levels and initial BMI with all-cause mortality were assessed taking into account the assumption of nonlinear correlations. The association between adiponectin, BMI, and serum levels of interleukin-10 (IL-10) and interleukin-6 (IL-6) with survival was determined cross-sectionally. MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: Nonlinear survival modeling showed that there was a U-shaped association of BMI with all-cause mortality, whereas there was an inverse U-shaped association for plasma adiponectin levels. Using a BMI of 24 kg/m(2) as a cutoff, an interaction effect of BMI on the association between adiponectin and mortality was observed (P = .045). In participants with BMI ≥ 24 kg/m(2), each 15 µg/mL increase in plasma adiponectin levels was associated with a decreased hazard of death (hazard ratio: 0.57, 95% CI: 0.32 to 0.99) in unadjusted analysis. In HD patients with BMI < 24 kg/m(2), no significant association was observed between adiponectin and mortality (P = .989). Cross-sectional analysis showed that in the subgroup of patients in whom the protective effect of adiponectin was observed (BMI ≥ 24 kg/m(2)), a positive linear association existed between adiponectin and IL-10 levels (r = 0.345, P = .027) as well as a negative association with IL-6 levels (r = -0.322, P = .040). No association was observed in patients with BMI < 24 kg/m(2), neither with IL-10 nor with IL-6. CONCLUSIONS: Obesity possibly modifies the effect of adiponectin on all-cause mortality in HD patients, thus explaining the published conflicting results in recent literature regarding the association of plasma adiponectin levels and mortality in chronic kidney disease patients.

Can dialysis modality influence quality of life in chronic hemodialysis patients? Low-flux hemodialysis versus high-flux hemodiafiltration: a cross-over study.

BACKGROUND: Hemodiafiltration with online preparation of the substitution [online high-flux hemodiafiltration (OHDF)] and hemodiafiltration with prepared bags of substitution (HDF) are important, recently widely used renal replacement therapies in patients with end-stage renal disease. However, there is little information on the comparative impacts of these modalities versus conventional low-flux hemodialysis (HD) on the quality of life (QoL) of HD patients. This study investigates the effect of dialysis modality on QoL in chronic HD patients. METHODS: In this prospective, randomized, cross-over, open label study, 24 patients were enrolled. Their age were 62 ± 13.34 years (mean ± SD), with the duration of dialysis of 31 ± 23.28 months (mean ± SD). Five of the patients were women. QoL was measured by the Short-Form Health Survey with 36 questions (SF-36) and subscale scores were calculated. Each patient received HD, OHDF, and HDF for 3 months, with the dialysis modality subsequently being altered. They completed the questionnaire of QoL at the end of each period. RESULTS: There were statistical significant differences in QoL for the total SF-36 [36.1 (26.7-45.7) and 40.7 (30.2-62.8)], for classic low-flux HD and high-flux hemodiafiltration, for bodily pain [45 (26.9-66.9) and 55 (35.6-87.5)], and for role limitations due to emotional functioning [0 (0-33.3) and 33.3 (0-100)], respectively. The scores did not differ significantly between the two types of hemodiafiltration. CONCLUSIONS: Our study indicates that QoL differs significantly among patients receiving low-flux HD and high-flux hemodiafiltration, on total SF-36, bodily pain, and role limitations due to emotional functioning. Convective modalities may offer better QoL than diffusive HD.

Results of a hemodialysis vascular access routine ultrasound surveillance protocol and frequency of surveillance guided pre-emptive access maintenance interventions.

BACKGROUND: To evaluate the implementation of routine surveillance using ultrasound on hemodialysis vascular access (VA) outcomes and determine the number and frequency of corrective, surveillance-guided procedures performed. METHODS: Multicenter, prospective, observational study that includes consecutive hemodialysis patients receiving therapy from native arteriovenous fistulae (AVF) or grafts (AVG). Participants were assigned to a routine VA Color Doppler ultrasound surveillance (DUS) protocol from January 2019 to December 2021. Patients were referred for corrective procedures (endovascular or surgical) based on clinical or DUS findings (pre-emptive procedures; PEP). Primary endpoint was the estimation of primary unassisted (PUP) and secondary patency (SP) rates. Secondary endpoints were the determination of the number and frequency of PEP and VA survival rates. RESULTS: In total, 223 patients with 243 VA (192 AVF and 51 AVG) were included. Access PUP and SP rates were 83% and 93% at 12 months, 75% and 88% at 24 months, and 72% and 83% at 36 months follow-up. Autologous fistulae PUP and SP were 89% and 96% at 12 months, 81% and 93% at 24 months, and 80% and 89% at 36 months, respectively. Graft PUP and SP were 56% and 80% at 12 months, 44% and 65% at 24 months, and 39% and 54% at 36 months, respectively. In total, 56 corrective procedures (38/56 PEP; 65.5%) were performed (0.13 procedures/year), of which 34 were in AVF patients (0.09 procedures/year) and 22 in AVG patients (0.40 procedures/year). Overall, 33 VA losses occurred (0.06 failures/year), 17 in AVF (0.04 failures/year), and 16 in AVG patients (0.20 failures/year). CONCLUSION: The use of DUS resulted in the timely diagnosis of dysfunction, satisfactory overall VA survival, and patency rates, with a low PEP frequency. Randomized controlled trials are required to establish the value of DUS surveillance on access patency and whether DUS-guided interventions could improve VA outcomes.

The Prognostic Role of Automated Office Blood Pressure Measurement in Hypertensive Patients with Chronic Kidney Disease.

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.

Dialysis Patients Respond Adequately to Influenza Vaccination Irrespective of Dialysis Modality and Chronic Inflammation.

(1) Background: Chronic inflammation and suboptimal immune responses to vaccinations are considered to be aspects of immune dysregulation in patients that are undergoing dialysis. The present study aimed to evaluate immune responses in hemodialysis (HD) and online hemodiafiltration (OL-HDF) patients to a seasonal inactivated quadrivalent influenza vaccine (IQIV). (2) Methods: We enrolled 172 chronic dialysis patients (87 on HD and 85 on OL-HDF) and 18 control subjects without chronic kidney disease in a prospective, cross-sectional cohort study. Participants were vaccinated with a seasonal IQIV, and antibody titers using the hemagglutination inhibition (HI) assay were determined before vaccination (month 0) and 1, 3, and 6 months thereafter. Demographics and inflammatory markers (CRP, IL-6, IL-1ß) were recorded at month 0. The primary endpoints were the rates of seroresponse (SR), defined as a four-fold increase in the HI titer, and seroprotection (SP), defined as HI titer ≥ 1/40 throughout the study period. Statistical analyses were conducted in R (version 3.6.3) statistical software. The differences between groups were analyzed using chi-square and t-test analyses for dichotomous and continuous variables, respectively. To identify independent determinants of SR and SP, generalized linear models were built with response or protection per virus strain as the dependent variable and group, age, sex, time (month 0, 1, 3, 6), diabetes, IL-6, dialysis vintage, HD access, and HDF volume as independent explanatory variables. (3) Results: SR and SP rates were similar between control subjects, and dialysis patients were not affected by dialysis modality. SP rates were high (> 70%) at the beginning of the study and practically reached 100% after vaccination in all study groups. These results applied to all four virus strains that were included in the IQIV. IL-6 levels significantly differed between study groups, with HD patients displaying the highest values, but this did not affect SP rates. (4) Conclusions: Dialysis patients respond to influenza immunization adequately and similarly to the general population. Thus, annual vaccination policies should be encouraged in dialysis units. OL-HDF reduces chronic inflammation; however, this has no impact on SR rates.

Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis.

Thrombosis is a common complication of end-stage renal disease, particularly in patients on hemodialysis. Although substantial progress has been made in preventing thrombotic complications in various other groups of patients, the mechanisms of thrombosis during hemodialysis require clarification. In this report, we demonstrate that complement activation triggered by hemodialysis biomaterials, and the subsequent generation of the complement anaphylatoxin C5a, results in the expression of functionally active tissue factor (TF) in peripheral blood neutrophils. Because TF is a key initiator of coagulation in vivo, we postulate that the recurring complement activation that occurs during long-term hemodialysis contributes to thrombosis in dialyzed end-stage renal disease patients. Furthermore, we found that complement contributed to the induction of granulocyte colony-stimulating factor, which has been implicated in the pathogenesis of thrombosis in patients treated with the recombinant form of this molecule. Importantly, the inhibition of complement activation attenuated the TF expression and granulocyte colony-stimulating factor induction in blood passing through a hemodialysis circuit, suggesting that the complement system could become a new therapeutic target for preventing thrombosis in patients with chronic renal failure who are maintained on hemodialysis.

The effect of bicarbonate peritoneal dialysis solutions on cardiac structural and functional alterations.

BACKGROUND: The systemic effects of absorbed glucose degradation products (GDPs) contained within the conventional peritoneal dialysis solutions (cPDS) are largely unknown, while they appear to affect also cardiovascular function. The aim of the present study was to evaluate if the new bicarbonate-based less bioincompatible new peritoneal dialysis solutions ameliorate cardiac structural and functional status as well as the peritoneal net ultrafiltration (UF) and residual renal function. Patients and methods. This is a single centre, prospective cohort study of 12 stable continues ambulatory peritoneal dialysis patients (four women, eight men) mean aged 71.3 ± of 6.01 years and mean peritoneal dialysis (PD) duration 31.9 ± 21.33 months, treated with the usual cPDS (Medital Bieffe®, with increased GDPs, low pH and lactate as a buffer system). The patients changed for a 6-month period to the newer biocompatible PD solutions (BicaVera, Fresenius® low GDPs, normal pH, bicarbonate as a buffer) and at the end of this time, they returned to their previous schema of conventional solutions, for another 6 months. During the study period, the left ventricle ejection fraction (EF), left ventricle end systolic and diastolic diameter (LVESD, LVEDD), left ventricle mass index (LVMI), glyoxal serum and peritoneal concentrations, net UF and 24 h urine volume were repeatedly estimated: at the beginning of the study (T0), after 6 months with the biocompatible solutions (T6) and at the end of study (T12), after the 6-month period using again the cPDS. The UF volume and glyoxal concentrations were estimated at end of a 4 h dwell of an exchange with a PD solution of 2.27 % glucose. RESULTS: There was a statistically significant difference between the mean levels of EF, LVESD, LVEDD, LVMI, UF and glyoxal serum and peritoneal concentrations at the beginning (T0) and in the middle of the study (T6) (for serum glyoxal P = 0.005, for peritoneal glyoxal P = 0.0004, for EF P = 0.0004, for LVESD P = 0.023, for LVEDD P = 0.002, for LVMI P = 0.0005 and for UF P = 0.005) as well as between the mean values in the middle (T6) and at the end of the evaluation period (T12) (for serum glyoxal P = 0.043, for peritoneal glyoxal P = 0.006, for EF P = 0.00009, for LVESD P = 0.012, for LVEDD P = 0.00014, for LVMI P = 0.00013 and for UF P = 0.048). On the other hand, no statistically significant difference was revealed between the T0 and T12 mean values of glyoxal (serum and peritoneal), EF, LVESD, LVEDD, LVMI and UF. During the study period, there was no statistically significant difference in daily urine volume and glomerular filtration rate. CONCLUSIONS: The use of bicarbonate-based PDS induced a statistically significant improvement of left ventricle structure (LVESD, LVEDD and LVMI) and functional (EF) indicators. These beneficial effects on left ventricle in combination with the improvement of net UF may designate a protective role of the newer bicarbonate peritoneal solutions on cardiovascular function morbidity and mortality risk of PD patients.

Impact of C-reactive protein on absolute reticulocyte count in haemodialysis patients: the role of iron status.

BACKGROUND: The exact mechanisms by which the effects of inflammation on erythropoiesis occur are still to be determined. We aimed to examine the relation between C-reactive protein (CRP) and erythropoiesis as quantified by the absolute reticulocyte count (RTC) and the possible effect of iron status on this relationship. METHODS: As part of a study that follows the changes of haematologic parameters after the intravenous (IV) administration of iron in 93 stable haemodialysis (HD) patients, we made a cross-sectional analysis of baseline measurements and an analysis of changes in RTC 1 week after baseline measurements and iron administration. RESULTS: Multiple linear regression analysis revealed that RTC had a positive correlation with CRP; RTC had a negative correlation with reticulocyte haemoglobin content (CHr). An interaction was also found between CRP and CHr in that CRP had a significant relation to RTC only in those patients whose CHr was more than 31.2 pg. At lower values of CHr, the correlation between CRP and RTC was not significant. Five days after the IV administration of 200 mg iron sucrose, a significant increase of RTC was observed, only in those patients with elevated baseline CRP levels who also showed an increase in CHr levels from ≤ 31.2 pg at baseline to ≥ 31.2 pg post-administration, supporting the presence of an independent positive correlation between CRP and RTC when iron is adequate. CONCLUSIONS: It is indicated that, in HD patients, elevated CRP values are associated with increased erythroid production only when CHr is quite satisfactory.

Variants in clock genes could be associated with lower risk of type 2 diabetes in an elderly Greek population.

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.

Pivotal role of paricalcitol in the treatment of calcific uremic arteriolopathy in the presence of a parathyroid adenoma.

Calcific uremic arteriolopathy, or calciphylaxis, is a serious and life-threatening complication of end-stage renal disease. Its pathogenesis is not yet fully elucidated and treatment is controversial. In the presence of severe hyperparathyroidism, parathyroidectomy should be considered. We report a case of a woman on maintenance hemodialysis therapy with calciphylaxis and parathyroid adenoma who refused to undergo parathyroidectomy. She was treated successfully with a combination of noncalcium phosphate binders, cinacalcet, and paricalcitol. Subcutaneous plaques disappeared, and the necrotic lesion was healed. Discontinuation of paricalcitol led to an increase in serum parathyroid hormone levels and reappearance of the patient's symptoms, whereas its reintroduction resulted in complete remission of the clinical picture. Paricalcitol, a less calcemic vitamin D analogue, is also a selective vitamin D receptor activator with a number of nonclassic actions (such as inhibition of inflammation and ossification-calcification) that could prove beneficial in cases of calciphylaxis.