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.

Decreased Levels of Soluble Developmental Endothelial Locus-1 Are Associated with Thrombotic Microangiopathy in Pregnancy.

HELLP (Hemolysis, Elevated Liver enzymes and Low Platelets) syndrome is a life-threatening complication of pregnancy, which is often secondary to preeclampsia. To date, there is no biomarker in clinical use for the early stratification of women with preeclampsia who are under increased risk of HELLP syndrome. Herein, we show that the levels of circulating developmental endothelial locus-1 (DEL-1), which is an extracellular immunomodulatory protein, are decreased in patients with HELLP syndrome compared to preeclampsia. DEL-1 levels are also negatively correlated with the circulating levels of kidney injury molecule-1 (KIM-1), which is a biomarker for disorders associated with kidney damage. Receiver-operating characteristic curve analysis for DEL-1 levels and the DEL-1 to KIM-1 ratio demonstrates that these values could be used as a potential biomarker that distinguishes patients with HELLP syndrome and preeclampsia. Finally, we show that placental endothelial cells are a source for DEL-1, and that the expression of this protein in placenta from patients with HELLP syndrome is minimal. Taken together, this study shows that DEL-1 is downregulated in HELLP syndrome both in the circulation and at the affected placental tissue, suggesting a potential role for this protein as a biomarker, which must be further evaluated.

Prognostic Factors of Fatal and Nonfatal Cardiovascular Events in Patients With Type 2 Diabetes: The Role of Renal Function Biomarkers.

In this study, 158 patients with different degrees of renal function were followed for 7 years to assess the prognostic value of various risk factors, including carotid intima-media thickness (cIMT) and biomarkers of renal function, for incident cardiovascular morbidity and mortality in patients with type 2 diabetes. The investigators found that estimated glomerular filtration rate, albuminuria, and history of cardiovascular disease (CVD) can be used for prognosis of CVD, whereas cIMT adds little to the accuracy of this prediction.

Fibroblast Growth Factor 23 and α-Klotho Protein Are Associated with Adverse Clinical Outcomes in Non-Dialysis CKD Patients.

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.

The Association of dp-ucMGP with Cardiovascular Morbidity and Decreased Renal Function in Diabetic Chronic Kidney Disease.

We aimed to investigate the possible association of the inactive, dephosphorylated, uncarboxylated matrix Gla protein (dp-ucMGP) with oxidized low-density lipoprotein (ox-LDL) and all-cause/cardiovascular (CV) mortality and renal function in diabetic chronic kidney disease (CKD). Ox-LDL and dp-ucMGP were determined in 66 diabetic CKD patients. All patients were prospectively followed for seven years, or until the occurrence of death, or a composite renal outcome of 30% estimated glomerular filtration rate (eGFR) reduction or progression to end-stage renal disease (ESRD) requiring dialysis occurred. Secondary outcomes were the occurrence of CV events. Kaplan-Meier curves showed that patients with plasma dp-ucMGP levels above the median (≥656 pM) had a significantly higher risk for all study endpoints. After adjustment for several well-known cofounders, multivariate Cox analysis showed that high plasma dp-ucMGP levels were associated with all-cause mortality (Hazard ratio-HR = 2.63, 95% Confidence Interval-CI = 1.17-5.94, p = 0.02), CV mortality (HR = 2.82, 95% CI = 1.07-7.49, p = 0.037) and progression of CKD (HR = 4.02, 95% CI = 1.20-13.46, p = 0.024). Circulating dp-ucMGP is associated with mortality and decreased renal function in diabetic CKD.

Histological grading in primary membranous nephropathy is essential for clinical management and predicts outcome of patients.

AIMS: Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment. METHODS AND RESULTS: Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re-evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15-85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage ≥1 in 52% and 51.4%, respectively. The follow-up period was 122.3 (112-376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow-up (P = 0.004, P < 0.0001, P < 0.0001 and P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation. CONCLUSIONS: The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long-term follow-up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.

Carotid intima-media thickness is an independent predictor of all-cause mortality and cardiovascular morbidity in patients with diabetes mellitus type 2 and chronic kidney disease.

BACKGROUND: Intima-Media-Thickness of the carotid artery wall (cIMT) is a strong predictor of cardiovascular (CV) disease. The aim of this study was to investigate the significance of cIMT as an independent prognostic factor for CV morbidity and mortality in patients with chronic kidney disease (CKD) and diabetes mellitus type 2 (DM2). METHODS: The study included 142 diabetic patients in different stages of CKD. Patients were categorized into two groups according to low (≤0.86 mm) or high cIMT (>0.86 mm), respectively. CV events and death from all causes were registered during a seven-year follow-up. RESULTS: Mean age, BMI and duration of diabetes were 68 years (range: 45-90), >30 kg/m2 and 15 years (range: 5-40), respectively. Patients with increased cIMT were older, suffered from a lower estimated glomerular filtration rate (eGFR), peripheral atherosclerosis and plaque presence in either carotid artery. Increased BMI (beta= -0.29, p = .01), lower eGFR (beta = 0.353, p = .003) and male gender (beta= -0.339, p = .005) were found to predict increased cIMT. Predictors of all-cause mortality in Cox proportional hazard models were low eGFR and high cIMT with HR = 0.96 (CI = 0.94-0.98), p < .001 and HR = 2.9 (CI = 1.03-7.99), p = .04, respectively. The risk of future CV event was determined by albuminuria and cIMT with HR = 1 (CI = 1.0-1.0), p < .001 and HR = 2.04 (CI = 1.1-3.78), p = .02, respectively. Patients with high cIMT presented significantly higher all-cause mortality and a new CV event (p = .005/p = .018, respectively). CONCLUSIONS: cIMT is a strong and independent predictor of CV morbidity and mortality, and should be considered a valuable tool for the stratification of CV risk in patients with CKD and DM2.

A Comparative Study of Short-Term Blood Pressure Variability in Hemodialysis Patients with and without Intradialytic Hypertension.

BACKGROUND: Short-term blood pressure (BP) variability (BPV) is associated with increased cardiovascular risk in hemodialysis. Patients with intradialytic hypertension have high risk of adverse outcomes. Whether BPV is increased in these patients is not clear. The purpose of this study was to compare short-term BPV in patients with and without intradialytic hypertension. METHODS: Forty-one patients with and 82 patients without intradialytic hypertension (intradialytic SBP rise ≥10 mm Hg to > 150 mm Hg) matched in a 1: 2 ratio for age, sex, and hemodialysis vintage were included. All subjects underwent 48-h ambulatory BP monitoring during a regular hemodialysis and the subsequent interdialytic interval. Brachial and aortic BPV were calculated with validated formulas and compared between the 2 groups during the 48-h and the 44-h periods and during the 2 daytime and nighttime periods respectively. RESULTS: During 48-h or 44-h periods and daytime or nighttime, brachial SBP/DBP and aortic SBP/DBP were significantly higher in cases than in controls. All brachial SBP/DBP BPV indexes [SD, weighted SD (wSD), coefficient-of-variation (CV) and average-real-variability (ARV)] were not significantly different between groups during the 48- or 44-h periods (48-h: SBP-ARV 11.59 ± 3.05 vs. 11.70 ± 2.68, p = 0.844, DBP-ARV: 8.60 ± 1.90 vs. 8.90 ± 1.63, p = 0.357). Analysis stratified by day or night between days 1 and 2 revealed, in general, similar results. No significant differences in dipping pattern were observed between groups. Analysis of aortic BPV had similar findings. CONCLUSIONS: BPV is similar between those with and without intradialytic hypertension. However, those with intradialytic hypertension have a sustained increase in systolic and diastolic BP during the entire interdialytic interval.

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.

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.

The association of home blood pressure with all-cause mortality in hemodialysis patients: A prospective observational study.

INTRODUCTION: Prior observational studies conducted in the hemodialysis population have suggested a reverse association between dialysis-unit blood pressure (BP) and mortality. The present study aimed to investigate the prognostic association of home versus dialysis-unit BP with all-cause mortality in hemodialysis patients. METHODS: At baseline, 146 patients receiving maintenance hemodialysis underwent assessment of their BP with the following methods: (i) 2-week averaged routine predialysis and postdialysis BP measurements; (ii) home BP monitoring for 1 week that included duplicate morning and evening BP measurements with the use of validated devices. RESULTS: Over a median follow-up period of 38 months (interquartile range [IQR]: 22-54), 44 patients (31.1%) died. In Kaplan-Meier curves, predialysis and postdialysis systolic BP (SBP) was not associated with all-cause mortality, while home SBP appeared to be of prognostic significance (log rank p = 0.029). After stratifying patients into quartiles, all-cause mortality was lowest when home SBP was ranging from 128.1 to 136.8 mmHg (quartile 2). In univariate Cox regression analysis, using quartile 2 as a referent category, the risk of all-cause mortality was 3.32-fold higher in quartile 1, 1.53-fold higher in quartile 3 and 3.25-fold higher in quartile 4. The risk-association remained unchanged after adjustment for several confounding factors (adjusted hazard ratio: 4.79, 1.79, 3.63 for quartiles 1, 3, and 4 of home systolic BP, respectively). CONCLUSION: Our findings suggest that among hemodialysis patients, 1-week averaged home SBP is independently associated with all-cause mortality. In sharp contrast, SBP recorded either before or after dialysis over 2 weeks is not prognostically informative.

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.

Sleep quality in caregivers of patients with end-stage renal disease.

The aim of this study was to evaluate the self-reported quality of sleep among caregivers of patients who are receiving hemodialysis (HD) and peritoneal dialysis (PD). In 64 caregivers of patients of the University General Hospital of Evros in Northeastern Greece, who were receiving HD and PD, the following instruments were administered: Pitsburgh Sleep Quality Index (PSQI), Zung Depression Rating Scale (ZDRS), Self-Anxiety Scale (SAS), Well - Being Index (WHO- 5). The mean PSQI value of caregivers was 5.27 ±3.40 and 39% of them had poor sleep quality. "Poor sleepers" had significantly lower levels of quality of life (p=0.02), elevated levels of anxiety (p=0.006) and higher scores in the depression scale (p=0.009) compared to "good sleepers". In the regression analysis depression was found to have the greatest contribution to the variability of 'sleep quality' (standardized beta = 0.62, p<0.001) and quality of sleep seemed to improve as years of dialysis that the patient underwent increased (standardized beta = -0.28, p=0.007). Physicians should screen caregivers' sleep quality, especially during the first stages of the illness.

Mutual effect modification between adiponectin and HDL as risk factors of cardiovascular events in Type 2 diabetes individuals: a cohort study.

PURPOSE: We aimed to assess whether high-density lipoprotein (HDL) cholesterol modifies the association between adiponectin and incident cardiovascular (CV) morbidity and mortality in Type 2 Diabetes Mellitus (T2DM) and vice versa. METHODS: At baseline, 106 T2DM participants with various degrees of renal function were enrolled and followed up over a period of 7 years with fatal/nonfatal CV events as outcome. RESULTS: During the follow-up, 49 participants experienced incident CV events (28 fatal, 21 nonfatal). On univariate Fine and Gray sub-hazard models, HDL cholesterol was a strong modifier of the association between adiponectin and CV outcomes both on crude (P = 0.011) and gender- and eGFR-adjusted models (P = 0.010). The protective effect for CV events portended by a fixed increase in adiponectin (1 µg/ml) was progressively higher across increasing values of HDL cholesterol. Moreover, plasma adiponectin also modified the protective effect of HDL on CV outcomes both in crude and multivariate analyses. We found a mutual effect modification between adiponectin and HDL as risk factors of CV events in participants with T2DM. CONCLUSION: Our results are coherent with the hypothesis that HDL cholesterol might play a pivotal role in the interpretation of the association between adiponectin and the risk of adverse CV outcomes in this population.

Oxidized LDL Is Associated with eGFR Decline in Proteinuric Diabetic Kidney Disease: A Cohort Study.

Diabetic kidney disease (DKD) is a highly heterogenous disease, including the proteinuric and the nonproteinuric pattern. Oxidized low-density lipoprotein (ox-LDL) is progressively increased in DKD and causes direct damage to kidney tubular epithelial cells through a mechanism similar to that underlying the deleterious effect of lipid peroxides in the vascular endothelium. We aimed to examine the association between plasma ox-LDL cholesterol and clinical endpoints in DKD patients. Ninety-one patients with established proteinuric DKD and diabetic retinopathy were enrolled and prospectively followed for 10 years or the occurrence of death, or at least 30% decline in eGFR, or progression to end-stage kidney disease (ESKD) requiring renal replacement therapy (primary outcome). At the end of the study, both eGFR and proteinuria were reassessed. Secondary outcomes of the study were the percentage change in eGFR and proteinuria over time for each patient. At baseline, patients were divided into 2 groups according to the median ox-LDL value (i.e., below or equal and above 66.22 U/L). Both Kaplan-Meier curves (p = 0.001, log-rank test) and univariate Cox regression analysis showed that high ox-LDL was associated with the primary outcome (HR = 3.42, 95%CI = 1.55 - 7.56, p = 0.002). After adjustment for various well-known cofounders, multivariate Cox analysis showed that the association between increased circulating ox-LDL levels and the composite kidney endpoint remained significant (HR = 2.87, 95%CI = 1.14-7.20, p = 0.025). Regarding the secondary outcome of eGFR decline, the assessment of areas under the curves (AUC) showed that ox-LDL outperformed several cofounding factors (AUC 71%, 95%CI = 0.59 - 0.83, p = 0.001) and had better accuracy to predict deterioration of eGFR over time than baseline proteinuria (AUC 67%, 95%CI = 0.54 - 0.79, p = 0.014). Increased ox-LDL might be associated with disease progression in proteinuric DKD.

Oxidized LDL Modifies the Association between Proteinuria and Deterioration of Kidney Function in Proteinuric Diabetic Kidney Disease.

Proteinuria is characterized by low accuracy for predicting onset and development of diabetic kidney disease (DKD) because it is not directly associated with molecular changes that promote DKD, but is a result of kidney damage. Oxidized low-density lipoprotein (ox-LDL) reflects oxidative stress and endothelial dysfunction, both underlying the development of proteinuria and loss of kidney function in DKD. We aimed to investigate whether ox-LDL modifies the association between proteinuria and progression of DKD in a cohort of 91 patients with proteinuric DKD and diabetic retinopathy, followed for 10 years. The primary endpoint was a combined kidney outcome of eGFR decline ≥30% or progression to end-stage kidney disease. After the end of the study, we considered the percentage change of eGFR over time as our secondary outcome. Proteinuria was associated with both outcomes, and ox-LDL amplified the magnitude of this link (p < 0.0001 for primary and p < 0.0001 for secondary outcome, respectively). After adjustment for duration of diabetes, history of cardiovascular disease and serum albumin, ox-LDL remained a significant effect modifier of the association between proteinuria and eGFR decline over time (p = 0.04). Our study shows that in proteinuric DKD, circulating ox-LDL levels amplified the magnitude of the association between proteinuria and progression of DKD.

Association of rs11780592 Polymorphism in the Human Soluble Epoxide Hydrolase Gene (EPHX2) with Oxidized LDL and Mortality in Patients with Diabetic Chronic Kidney Disease.

Soluble epoxide hydrolase 2 (EPHX2) is an enzyme promoting increased cellular apoptosis through induction of oxidative stress (OS) and inflammation. The EPHX2 gene which encodes soluble EPHX2 might be implicated in the pathogenesis and development of OS and atherosclerosis. We aimed to assess the possible association between two functional polymorphisms of the EPHX2 gene (rs2741335 and rs11780592) with oxidized LDL (ox-LDL), carotid atherosclerosis, mortality, and cardiovascular (CV) disease in 118 patients with diabetic chronic kidney disease (CKD). At baseline, ox-LDL and carotid intima-media thickness (cIMT) were evaluated and all patients were followed for seven years with outcomes all-cause mortality and CV events. rs11780592 EPHX2 polymorphism was associated with ox-LDL, cIMT, albuminuria, and hypertension. Compared to AG and GG, AA homozygotes had higher values of albuminuria, ox-LDL, and cIMT (p = 0.046, p = 0.003, and p = 0.038, respectively). These associations remained significant, even after grouping for the G allele. After the follow-up period, 42/118 patients died (30/60 with AA genotype, 11/42 with AG genotype, and 1/12 with GG genotype) and 49/118 experienced a new CV event (fatal or nonfatal). The Kaplan-Meier analysis revealed that patients with the AA genotype exhibited a significantly higher mortality risk, compared to patients with AG and GG genotypes (p = 0.006). This association became even stronger, when AG and GG genotypes were grouped (AA vs. AG/GG, p = 0.002). AA homozygotes were strongly associated with all-cause mortality in both univariate (hazard ratio (HR) = 2.74, confidence interval (CI) = 1.40-5.35, p = 0.003) and multivariate Cox regression analysis (HR = 2.61, CI = 1.32-5.17, p = 0.006). In conclusion, our study demonstrated that genetic variations of EPHX2 gene were associated with increased circulating ox-LDL, increased cIMT, and all-cause mortality in diabetic CKD. Since EPHX2 regulates the cholesterol efflux and the oxidation of LDL in foam cells and macrophages, our study suggests that a genetic basis to endothelial dysfunction and OS might be present in diabetic CKD.

Oxidative Stress Genes in Diabetes Mellitus Type 2: Association with Diabetic Kidney Disease.

Diabetic type 2 patients compared to nondiabetic patients exhibit an increased risk of developing diabetic kidney disease (DKD), the leading cause of end-stage renal disease. Hyperglycemia, hypertension, oxidative stress (OS), and genetic background are some of the mechanisms and pathways implicated in DKD pathogenesis. However, data on OS pathway susceptibility genes show limited success and conflicting or inconclusive results. Our study is aimed at exploring OS pathway genes and variants which could be associated with DKD. We recruited 121 diabetes mellitus type 2 (DM2) patients with DKD (cases) and 220 DM2, non-DKD patients (control) of Greek origin and performed a case-control association study using genome-wide association data. PLINK and EIGENSOFT were used to analyze the data. Our results indicate 43 single nucleotide polymorphisms with their 21 corresponding genes on the OS pathway possibly contributing or protecting from DKD: SPP1, TPO, TTN, SGO2, NOS3, PDLIM1, CLU, CCS, GPX4, TXNRD2, EPHX2, MTL5, EPX, GPX3, ALOX12, IPCEF1, GSTA, OXR1, GPX6, AOX1, and PRNP. Therefore, a genetic OS background might underlie the complex pathogenesis of DKD in DM2 patients.