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.

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.

Thrombophilia in hemodialysis patients: Transfer to peritoneal dialysis is life saving.

The majority of vascular access thrombosis episodes in hemodialysis patients are due to anatomic abnormalities. Thrombophilias are inherited, acquired or mixed disorders which also predispose to venous thromboembolism. They include protein C, protein S and antithrombin deficiencies, as well as gene mutations for prothrombin and factor V Leiden. The most important of the mixed cases is hyperhomocysteinemia, which includes both a genetic and an acquired substrate. We report two patients undergoing hemodialysis who suffered from multiple thrombotic events, the first due to factor V Leiden heterozygosity and the second because of hyperhomocysteinemia due to homozygosity for MTHFR C677T mutation. As no site for vascular access was left, transfer to peritoneal dialysis for both patients improved solute clearance and quality of life with no additional thrombotic events noted.

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.

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.

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.

N-Acetylcysteine: more than preventing contrast-induced nephropathy in uremic patients-focus on the antioxidant and anti-inflammatory properties.

Oxidative stress (OS) has been recognized as a pathophysiologic mechanism underlying the development and progression of chronic kidney disease (CKD). OS, which results from the disturbance of balance among pro-oxidants and antioxidants favoring the pro-oxidants, is present even in early CKD and increases progressively along with deterioration of kidney function to end-stage kidney disease (ESKD). In ESKD, OS is further exacerbated mainly due to dialysis procedures per se and predisposes to increased cardiovascular morbidity and mortality. Therefore, since OS plays a pivotal role in the pathogenesis and progression of atherosclerosis in uremic patients, several strategies aiming to ameliorate OS in these patients have been proposed. Among those, N-acetylcysteine (NAC), a thiol-containing antioxidant agent, has attracted special attention due to its pleiotropic functions and beneficial effect in various OS-related entities including paracetamol overdose and prevention of contrast-induced nephropathy. In this review, we present the currently available literature on the antioxidant and anti-inflammatory properties of NAC in CKD, including hemodialysis and peritoneal dialysis.

Effects of Home-Based Exercise Training on Cardiac Autonomic Neuropathy and Metabolic Profile in Diabetic Hemodialysis Patients.

Background: This study aimed to investigate the effects of a home-based exercise training program on Cardiac Autonomic Neuropathy (CAN) and metabolic profile in Diabetic Kidney Disease (DKD) patients undergoing maintenance hemodialysis (HD). Method: Twenty-eight DKD patients undergoing hemodialysis were randomly assigned into two groups. The exercise (EX) group followed a 6-month combined exercise training program at home, while the control (CO) group remained untrained. All participants at baseline and the end of the study underwent cardiopulmonary exercise testing (CPET), biochemical tests for glucose and lipid profile, and 24-h electrocardiographic monitoring for heart rate variability (HRV) analysis and heart rate turbulence (HRT). Results: At the end of the study, compared to the CO, the EX group showed a significant increase in serum high-density lipoprotein (HDL) by 27.7% (p = 0.01), peak oxygen uptake (VO2peak) by 9.3% (p < 0.05), the standard deviation of R-R intervals (SDNN) by 34.3% (p = 0.03), percentage of successive RR intervals higher than 50ms (pNN50) by 51.1% (p = 0.02), turbulence slope (TS) index by 18.4% (p = 0.01), and decrease in (glycated hemoglobin) HbA1c by 12.5% (p = 0.04) and low-frequency power LF (ms2) by 29.7% (p = 0.01). Linear regression analysis after training showed that VO2peak was correlated with SDNN (r = 0.55, p = 0.03) and HF (r = 0.72, p = 0.02). Multiple regression analysis indicated that the improvement of sympathovagal balance and aerobic capacity depended on patients' participation in exercise training. Conclusion: In conclusion, a 6-month home-based mixed-type exercise program can improve cardiac autonomic function and metabolic profile in DKD patients on HD.

The effect of a 6-month intradialytic exercise program on hemodialysis adequacy and body composition: a randomized controlled trial.

BACKGROUND/AIM: End-stage kidney disease (ESKD) is strongly associated with factors that aggravate the physical activity level and body composition status of hemodialysis patients (HD). Even though exercise in HD patients have shown remarkable benefits on hemodialysis adequacy, it is yet inconclusive if exercise can positively affect body composition parameters or if dialysis adequacy may affect body composition status. This study aimed to investigate the effect of a 6-month intradialytic exercise training program on dialysis adequacy indices and body composition parameters in HD patients. STUDY DESIGN: A total of 24 HD patients were randomly assigned into two equally sized groups. The exercise group (EX group) participated in a 6-month intradialytic moderate-intensity aerobic exercise training program at the beginning of the HD sessions, three times a week for 60 min, and maintained a Borg's Rating of Perceived Exertion score between 13 and 14. The Control group (C group) remained untrained. At baseline, during, and at the end of the 6-month study, we assessed single-pool Kt/V, urea reduction ratio (URR), and body composition parameters, such as extracellular water (ECW)/ intracellular water (ICW) ratio, body mass index (BMI) and lean tissue mass (LTM). In all patients, the 6-min-walking test (6MWT) was performed as a marker of physical performance. RESULTS: A significant increase of both Kt/V (increase by 19%, p = 0.01), and URR (increase by 7%, p = 0.03) values has been observed in the EX group after the 6-month training program. Similarly, a statistically significant increase in 6MWT distance (from 442 ± 67 m to 481 ± 68 m, p = 0.02) in the EX group has also been found, compared to the C group (from 393 ± 59 m to 427 ± 81 m, p = 0.06). Neither EX nor C group has shown significant changes in body composition parameters. After training, linear regression analysis revealed a strong positive correlation between Kt/V and 6MWT changes (r = 0.74, p = 0.04) in the EX group. CONCLUSIONS: Six months of intradialytic aerobic exercise might increase dialysis adequacy, by increasing Kt/V and URR, and physical performance, regardless of changes in body composition indices.

VItamin K In PEritonial DIAlysis (VIKIPEDIA): Rationale and study protocol for a randomized controlled trial.

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

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.

Cardiovascular Benefits of Extended-Time Nocturnal Hemodialysis.

Hemodialysis (HD) remains the most utilized treatment for End-Stage Kidney Disease (ESKD) globally, mainly as conventional HD administered in 4 h sessions thrice weekly. Despite advances in HD delivery, patients with ESKD carry a heavy cardiovascular morbidity and mortality burden. This is associated with cardiac remodeling, left ventricular hypertrophy (LVH), myocardial stunning, hypertension, decreased heart rate variability, sleep apnea, coronary calcification and endothelial dysfunction. Therefore, intensive HD regimens closer to renal physiology were developed. They include longer, more frequent dialysis or both. Among them, Nocturnal Hemodialysis (NHD), carried out at night while asleep, provides efficient dialysis without excessive interference with daily activities. This regimen is closer to the physiology of the native kidneys. By providing increased clearance of small and middle molecular weight molecules, NHD can ameliorate uremic symptoms, control hyperphosphatemia and improve quality of life by allowing a liberal diet and free time during the day. Lastly, it improves reproductive biology leading to successful pregnancies. Conversion from conventional to NHD is followed by improved blood pressure control with fewer medications, regression of LVH, improved LV function, improved sleep apnea, and stabilization of coronary calcifications. These beneficial effects have been associated, among others, with better extracellular fluid volume control, improved endothelial- dependent vasodilation, decreased total peripheral resistance, decreased plasma norepinephrine levels and restoration of heart rate variability. Some of these effects represent improvements in outcomes used as surrogates of hard outcomes related to cardiovascular morbidity and mortality. In this review, we consider the cardiovascular effects of NHD.

Vitamin K for the Treatment of Cardiovascular Disease in End-Stage Renal Disease Patients: Is there Hope?

In Chronic Kidney Disease, vascular calcification (VC) is highly prevalent even at early stages and is gradually enhanced, along with disease progression to End-Stage Renal Disease (ESRD). The calcification pattern in uremia includes all types of mineralization and contributes to the heavy cardiovascular (CV) burden that is common in these patients. Ectopic mineralization is the result of the imbalance between inhibitors and promoters of vascular calcification, with the latter overwhelming the former. The most powerful, natural inhibitor of calcification is Matrix Gla Protein (MGP), a small vitamin K dependent protein, secreted by chondrocytes and vascular smooth muscle cells. In uremia, MGP was reported as the only molecule able to reverse VC by "sweeping" calcium and hydroxyapatite crystals away from the arterial wall. To become biologically active, this protein needs to undergo carboxylation and phosphorylation, reactions highly dependent on vitamin K status. The inactive form of MGP reflects the deficiency of vitamin K and has been associated with CV events and mortality in ESRD patients. During the past decade, vitamin K status has emerged as a novel risk factor for vascular calcification and CV disease in various populations, including dialysis patients. This review presents evidence regarding the association between vitamin K and CV disease in ESRD patients, which are prone to atherosclerosis and atheromatosis.

Could Antioxidant Supplementation Delay Progression of Cardiovascular Disease in End-Stage Renal Disease Patients?

In end-stage renal disease patients, the leading causes of mortality are of cardiovascular (CV) origin. The underlying mechanisms are complex, given that sudden heart failure is more common than acute myocardial infarction. A contributing role of oxidative stress is postulated, which is increased even at early stages of chronic kidney disease, is gradually augmented in parallel to progression to endstage renal disease and is further accelerated by renal replacement therapy. Oxidative stress ensues when there is an imbalance between reactive pro-oxidants and physiologically occurring electron donating antioxidant defence systems. During the last decade, a close association of oxidative stress with accelerated atherosclerosis and increased risk for CV and all-cause mortality has been established. Lipid peroxidation has been identified as a trigger for endothelial dysfunction, the first step towards atherogenesis. In order to counteract the deleterious effects of free radicals and thereby ameliorate, or delay, CV disease, exogenous administration of antioxidants has been proposed. Here, we attempt to summarize existing data from studies that test antioxidants for CV protection, such as vitamins E and C, statins, omega-3 fatty acids and N-acetylcysteine.

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.

APD or CAPD: one glove does not fit all.

The use of Automated Peritoneal Dialysis (APD) in its various forms has increased over the past few years mainly in developed countries. This could be attributed to improved cycler design, apparent lifestyle benefits and the ability to achieve adequacy and ultrafiltration targets. However, the dilemma of choosing the superior modality between APD and Continuous Ambulatory Peritoneal Dialysis (CAPD) has not yet been resolved. When it comes to fast transporters and assisted PD, APD is certainly considered the most suitable Peritoneal Dialysis (PD) modality. Improved patients' compliance, lower intraperitoneal pressure and possibly lower incidence of peritonitis have been also associated with APD. However, concerns regarding increased cost, a more rapid decline in residual renal function, inadequate sodium removal and disturbed sleep are APD's setbacks. Besides APD superiority over CAPD in fast transporters, the other medical advantages of APD still remain controversial. In any case, APD should be readily available for all patients starting PD and the most important indication for its implementation remains patient's choice.

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.