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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Red Blood Cell Distribution Width Is Associated with Deterioration of Renal Function and Cardiovascular Morbidity and Mortality in Patients with Diabetic Kidney Disease.

We sought to investigate the possible association between Red Blood Cell Distribution Width (RDW), vascular calcification, oxidative stress and renal function and all-cause/cardiovascular (CV) mortality, CV events and progression of kidney disease in a cohort of patients with Diabetic Kidney Disease (DKD). Carotid intima media thickness (cIMT) and oxidized low-density cholesterol were measured in 104 Type 2 Diabetes Mellitus (T2DM) patients with established DKD, distributed in all five stages of kidney disease and 38 diabetics with normal renal function. All patients were followed for 7 years with end-points all-cause and CV mortality, CV events and progression to End-Stage Renal Disease (ESRD). RDW was positively correlated with diabetes duration (r = 0.19, p = 0.023) and albuminuria (r = 0.29, p = 0.002). Multivariate regression analysis revealed that RDW was a strong, independent predictor of cIMT value (ß = 0.031, p = 0.012). Kaplan-Meier curves and Cox proportional hazard models revealed that after adjustment for several cofounders, RDW was a significant and independent predictor for all-cause mortality, CV mortality, CV event and progression to ESRD (HR 1.75, p = 0.001, HR 2.03, p = 0.001, HR = 1.66, p < 0.0001 and HR 2.14, p = 0.001 respectively). RDW predicts mortality, CV events and deterioration of renal function in DKD, probably reflecting atherosclerosis.

Genetic variation in CARD8, a gene coding for an NLRP3 inflammasome-associated protein, alters the genetic risk for diabetic nephropathy in the context of type 2 diabetes mellitus.

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.

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.

Intradialytic Cardiovascular Exercise Training Alters Redox Status, Reduces Inflammation and Improves Physical Performance in Patients with Chronic Kidney Disease.

Redox status (RS) perturbations and inflammation are fundamental features of chronic kidney disease (CKD) that are substantially exacerbated in end-stage renal disease (ESRD). This study aimed at investigating the efficacy of a 6-month intradialytic exercise training program on RS, inflammation and physical performance in patients with ESRD. Twenty hemodialysis (HD) patients (17 males, three females) were randomly assigned to either an intradialytic training (bedside cycling) group (TR; n = 10) or a control group (CON; n = 10) for 6 months. Anthropometrics [body mass and height, body mass index (BMI), body composition], physical performance (VO2peak), functional capacity [North Staffordshire Royal Infirmary (NSRI) walk test, sit-to-stand test (STS-60)], quality of life (short form-36 (SF-36) as well as RS [thiobarbituric acid reactive substances (TBARS), protein carbonyls (PC), reduced (GSH) and oxidized (GSSG) glutathione, GSH/GSSG, total antioxidant capacity (TAC), catalase activity (CAT)] and high-sensitivity C-reactive protein (hs-CRP) were assessed at baseline and after the 6-month intervention. Peak oxygen consumption (VO2peak) increased by 15% only in TR (p < 0.01). Performance in NSRI, STS-60 and SF-36 improved by 4-13% only in TR (p < 0.01). Exercise training reduced TBARS (by 28%), PC (by 31%) and hs-CRP (by 15%), and elevated GSH (by 52%), GSH/GSSG (by 51%), TAC (by 59%) and CAT (by 15%) (p < 0.01). These findings suggest that engagement in chronic intradialytic cardiovascular exercise alters RS, reduces inflammation and improves performance in patients with ESRD.

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.