LDLR gene polymorphism (rs688) affects susceptibility to cardiovascular disease in end-stage kidney disease patients.

BACKGROUND: The low-density lipoprotein receptor (LDLR) plays a significant role in maintaining the cellular cholesterol homeostasis. Mutations in the LDLR gene can lead to a significant rise in plasma LDL levels that may result in an increased risk of atherosclerosis and coronary heart disease. The purpose of this study was to assess the potential association of the LDLR rs688 polymorphism with cardiovascular disease (CVD) in patients with end-stage kidney disease (ESKD) undergoing hemodialysis. METHODS: In this case-control study the polymorphism was genotyped by the allele specific PCR method in 800 patients with ESKD and 500 healthy controls. The genotype and allele distribution was compared in subgroups of patients with CVD (552) versus those without CVD (248). RESULTS: A significant difference was observed in genotype distribution among ESKD patients and healthy controls. The frequencies of the T allele and TT genotype in ESKD group were significantly higher, with OR (95% CI) 2.2 (1.87-2.6), p <  0.0001 and 5.84 (3.94-8.65), p <  0.0001, respectively. In the he ESKD cohort the distribution of the rs688 was compared between CVD+ and CVD- subgroups. A strong association of the polymorphism with the CVD risk was observed in this analysis. The frequencies of the T allele and TT genotype were significantly higher in CVD+ subgroup, with OR (95% CI) 3.4 (2.71-4.26), p <  0.0001 and 13.2 (7.87-22.09), p <  0.0001, respectively. A multivariate logistic regression analysis was performed to estimate the association between rs688 T variant and risk of CVD. After adjustment for age, sex, BMI, hypertension and diabetes, both CT and TT genotypes were associated with an increased risk of developing CVD in the dominant, recessive and codominant models of inheritance. No significant differences in serum LDL cholesterol levels were found when compared between genotypes. CONCLUSIONS: The present study is the first to demonstrate the association of the LDLR gene polymorphism with increased susceptibility to cardiovascular disease in ESKD patients. This finding needs further investigation to confirm that LDLR rs688 might be a novel genetic risk factor with some prognostic capacity for CVD in ESKD patients.

Correction: Quantification of Dialytic Removal and Extracellular Calcium Mass Balance during a Weekly Cycle of Hemodialysis.

[This corrects the article DOI: 10.1371/journal.pone.0153285.].

Interleukin-4 Gene Intron 3 VNTR Polymorphism in Type 2 Diabetes Patients with Peripheral Neuropathy.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) is one of late complications of diabetes mellitus. The aim of this study was to evaluate the association between variable number tandem repeat (VNTR) polymorphism in intron 3 of interleukin-4 gene and risk of DPN. METHODS: We examined 926 T2DM patients and 420 healthy controls. In the patient group, 44% had DPN. Genomic DNA was isolated from all subjects and genotyped for the IL-4 VNTR polymorphism by polymerase chain reaction (PCR). RESULTS: No significant difference was observed in the frequency of minor P1 allele between T2DM patients and controls (OR 1.00, 95% CI 0.81-1.23, p = 0.988). The distribution of IL-4 VNTR polymorphism was compared between patients with DPN and those without it. The polymorphism was not significantly associated with DPN in studied subjects. In comparison of 406 T2DM patients with DPN and 520 patients without it, the OR (95% CI) for P1 allele was 0.82 (0.65-1.04), p = 0.10 and for P1P1 genotype 1.00 (0.53-1.89), p = 0.991. When two subgroups of patients with DPN, those with cardiovascular disease (CVD) and without CVD, were compared, subgroup with coexisting CVD had significantly higher frequency of P1 allele than patients without CVD, with odds ratio for the P1 allele 3.27 (95% CI 1.83-5.83), p = 0.0001. CONCLUSION: Our results demonstrated that VNTR polymorphism in the IL-4 gene is associated with DPN in type 2 diabetes patients with coexisting CVD.

Pro198Leu Polymorphism in the Glutathione Peroxidase 1 Gene Contributes to Diabetic Peripheral Neuropathy in Type 2 Diabetes Patients.

Glutathione peroxidase 1 (Gpx1) is an endogenous antioxidant enzyme. The T allele of the Pro198Leu polymorphism in the Gpx1 (rs1050450, 198C > T) gene is associated with reduced enzyme activity. The aim of this study was to evaluate the association between Pro198Leu polymorphism and risk of diabetic peripheral neuropathy (DPN). We examined 1244 T2DM patients and 730 healthy controls. In the patient group, 33 % had diabetic peripheral neuropathy. All subjects were genotyped for the Gpx1 Pro198Leu polymorphism by polymerase chain reaction and restriction analysis. A significant increase in the T allele and TT genotype frequencies was observed in DPN patients compared to those without DPN (OR 1.55, 95 % CI 1.30-1.85 and 1.89, 95 % CI 1.30-2.74, respectively). The association remained significant after correction for age, disease duration, HbA1c and BMI. When distribution of T allele was compared between DPN+ and DPN- subgroups and controls, OR was 1.54 for DPN+ and 1.00 for DPN- patients. In conclusion, our findings suggest that Gpx1 Pro198Leu genotypes are significantly associated with the risk of diabetic peripheral neuropathy in patients with T2DM. The study provides new clinically relevant information regarding genetic determinants of susceptibility to diabetic neuropathy.

Syndecan-4 Is an Independent Predictor of All-Cause as Well as Cardiovascular Mortality in Hemodialysis Patients.

BACKGROUND: Left ventricular hypertrophy is associated withincreased mortality in hemodialysis (HD) patients.Syndecan-4 plays a role in many processes that are involved in the heart fibrosis and hypertrophy.We designed this study to prospectively determine whether syndecan-4 was predictive of mortality in a group of HD patients. METHODS: In total, 191 HD patients were included. Clinical, biochemical and echocardiographic parameters were recorded. HD patients were followed-up for 23.18 ± 4.02 months. RESULTS: Syndecan-4 levels correlated strongly with geometrical echocardiographic parameters and ejection fraction. Relations with pressure-related parameters were weak and only marginally significant. Using the receiver operating characteristics the optimal cut-off points in predicting all-cause as well as cardiovascular (CV) mortality were evaluated and patients were divided into low and high syndecan-4 groups. A Kaplan-Meier analysis showed that the cumulative incidences of all-cause as well as CV mortality were higher in high serum syndecan-4 group compared with those with low serum syndecan-4 (p<0.001 in both cases).A multivariate Cox proportional hazards regression analysis revealed syndecan-4 concentration to be an independent and significant predictor of all-cause (hazard ratio, 2.99; confidence interval, 2.34 to 3.113; p<0.001)as well as CV mortality (hazard ratio, 2.81;confidence interval, 2.28to3.02; p<0.001). CONCLUSIONS: Serum syndecan-4 concentration reflects predominantly geometrical echocardiographic parameters. In HD patients serum syndecan-4 concentration is independently associated with all-cause as well as CV mortality.

Association between functional variant of inflammatory system gene (PSMA6) and end-stage kidney disease.

BACKGROUND: The proteasome system is involved in several disorders. The 5' untranslated region of PSMA6 gene contains a single nucleotide polymorphism (SNP) -8 C/G, associated with diabetes, myocardial infarction and coronary artery disease. METHODS: We examined 584 patients with end-stage kidney disease (ESKD) and 430 controls. All were genotyped for -8 C/G SNP by polymerase chain reaction and restriction analysis. RESULTS: We observed lower frequency of CG + GG genotypes in patients than in controls (20 vs. 42 %, p = 0.0038). The odds ratio of 0.34 (95 % CI 0.26-0.45) suggests association of CG + GG with decreased risk of ESKD. We investigated the association between PSMA6 polymorphism and LVH present in 54 % of patients. There was a significant association of CG + GG genotype with LVH, with over 75 % of CG + GG in patients with LVH. This effect was independent from other common causes of LVH-age (OR 1.12, p = 0.643) and hypertension (OR 1.72, p = 0.422). CONCLUSION: We demonstrated for the first time that PSMA6 polymorphism might be a protective factor for ESKD. On the other hand, CG + GG genotypes are independently related to LVH in ESKD patients.

Effect of balance Solution on the Peritoneal Membrane in Automated Peritoneal Dialysis.

Interference of conventional peritoneal dialysis fluids (cPDFs) with peritoneal membrane cell functions may be attributed to the dialysis fluid's low pH, high glucose concentration, and/or the presence of glucose degradation products (GDPs), the last of which leads to higher levels of advanced glycation end-products (AGEs). It has been suggested that the peritoneal membrane might be better preserved by using biocompatible solutions, including cancer antigetn 125 (CA125). This prospective, open-label, multicentre, randomized, controlled, cross-over phase IV study compared the in vivo biocompatibility of a neutral-pH, low-GDP peritoneal dialysis (PD) solution (balance) with a cPDF in automated PD (APD) patients. Our study revealed a significantly increased appearance rate and concentration of CA125 in the peritoneal effluent of APD patients treated with the neutral-pH, low-GDP solution balance versus a conventional PD solution.

Coexistence of granulomatosis with polyangiitis (GPA) and Crohn's disease or multiorgan manifestation of the same disease?

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis of unknown aetiology, often related to the antineutrophil cytoplasmic antibody (ANCA). GPA was previously named Wegener's granulomatosis (WG). The disease frequently has multisystemic presentation, targeting mainly the respiratory tract and kidneys, but gastrointestinal involvement is uncommon. Crohn's disease (CD) is an inflammatory bowel disease (IBD) with many extraintestinal manifestations. Clinically, symptoms of WG and CD can mimic each other. In this paper a case of GPA manifested initially by severe multiorgan damage including colitis, regarded to be coexistent CD, is presented. The case illustrates the difficulties in establishing the diagnosis when symptoms of the diseases mimic each other.

Phosphate Kinetics in Hemodialysis: Application of Delayed Pseudo One-Compartment Model.

BACKGROUND/AIMS: Various body-regulating mechanisms try to counteract rapid changes in serum phosphate levels during hemodialysis (HD). Neither recently proposed nor other existing standard compartment models are able to capture clinically observed intradialytic serum phosphate rebound. METHODS: Phosphate serum concentration was frequently measured during 75 HD sessions in 25 patients. Time delay was introduced into the standard pseudo one-compartment model in order to reflect the time needed for the body-regulating mechanism to affect serum phosphate level. RESULTS: Measured serum phosphate concentration at the end of 4 h dialysis session was on average larger than 1 h earlier (p value = 0.015). The model with time delay reproduced successfully 19 out of 21 and 9 out of 10 sessions with and without recorded intradialytic rebound, respectively. CONCLUSION: The intradialytic serum phosphate rebound is associated with the time delay reflecting efficacy of body-regulating mechanisms, that is, the larger the delay the larger is the intradialytic rebound.

Quantification of Dialytic Removal and Extracellular Calcium Mass Balance during a Weekly Cycle of Hemodialysis.

OBJECTIVES: The removal of calcium during hemodialysis with low calcium concentration in dialysis fluid is generally slow, and the net absorption of calcium from dialysis fluid is often reported. The details of the calcium transport process during dialysis and calcium mass balance in the extracellular fluid, however, have not been fully studied. METHODS: Weekly cycle of three dialysis sessions with interdialytic breaks of 2-2-3 days was monitored in 25 stable patients on maintenance hemodialysis with calcium concentration in dialysis fluid of 1.35 mmol/L. Total and ionic calcium were frequently measured in blood and dialysate. The volume of fluid compartments was measured by bioimpedance. RESULTS: Weekly dialytic removal of 12.79 ± 8.71 mmol calcium was found in 17 patients, whereas 9.48 ± 8.07 mmol calcium was absorbed per week from dialysis fluid in 8 patients. Ionic calcium was generally absorbed from dialysis fluid, whereas complexed calcium (the difference of total and ionic calcium in dialysis fluid) was removed from the body. The concentration of total calcium in plasma increased slightly during dialysis. The mass of total and ionic calcium in extracellular fluid decreased during dialysis in patients with the dialytic removal of calcium from the body and did not change in patients with the absorption of calcium from dialysis fluid. CONCLUSIONS: We conclude that about one third of patients on dialysis with calcium 1.35 mmol/L in dialysis fluid may absorb calcium from dialysis fluid and therefore individual prescriptions of calcium concentration in dialysis fluid should be considered for such patients.

Rs10887800 renalase gene polymorphism is associated with an increased risk of coronary artery disease in hemodialyzed patients.

PURPOSE: Coronary artery disease (CAD) is common in patients with end-stage renal disease (ESRD). Recent studies have suggested that renalase, a novel FAD-dependent amine oxidase, may play an important role in the pathogenesis of cardiovascular complications in ESRD patients. The aim of the study was to investigate the association between renalase gene polymorphisms and a risk of CAD in patients on hemodialysis. METHODS: In a case-control study, a total of 309 hemodialyzed patients (107 with and 202 without CAD) were genotyped for two SNPs in the renalase gene (rs10887800 and rs2576178) using the PCR-RFLP method. RESULTS: By multivariate logistic regression analysis, we found that rs10887800GG genotype was associated with an increased risk of CAD under the codominant model [GG vs AA; adjusted OR 2.66 (95 % CI, 1.19-5.94), p = .017] and under the recessive model [GG vs AG + AA; adjusted OR 2.10 (95 % CI, 1.10-4.02), p = .025]. The rs2576178 polymorphism did not influence the risk of CAD. CONCLUSION: The study suggested for the first time that the rs10887800 renalase gene polymorphism may be involved in the pathogenesis of CAD in hemodialyzed patients and thus could be considered a new genetic risk factor for CAD in this population.

Effect of G(-174)C polymorphism in interleukin-6 gene on cardiovascular disease in type 2 diabetes patients.

Interleukin-6 (IL-6) is an important pro-inflammatory cytokine of relevance to cardiovascular diseases. The aim of this case-control study was to evaluate the association between the G(-174)C functional polymorphism in the IL-6 gene and risk of cardiovascular disease (CVD) in type 2 diabetes patients. We examined 1090 patients with T2DM and 612 controls. All subjects were genotyped for the G(-174)C polymorphism by polymerase chain reaction (PCR) and restriction analysis. There were no significant differences in the distribution of genotypes and alleles between T2DM patients and healthy controls. Significantly higher C allele frequency was observed in CVD+ patients compared to CVD- subgroup (53% vs. 32%, p<0.0001). The odds ratio for C allele was 2.4 (95% CI 1.99-2.9, p<0.0001) and for CC genotype 4.55 (95% CI 3.12-6.63, p<0.000). When the distribution of G(-174)C polymorphism was compared in subgroups with different clinical phenotypes of CVD, a significant association of CC genotype with myocardial infarction was observed. Forty eight percent of patients with MI had the CC genotype compared to 22% of patients without MI (p<0.0001). In conclusion, type 2 diabetes patients carrying the C allele of the IL-6 G(-174)C polymorphism have a significantly increased risk of CVD.

[Acquired perforating dermatosis in the patient with chronic kidney disease ­ case report and literature review].

Acquired perforating dermatosis (APD) represents a heterogenous group of skin disorders characterized histopathologically by transepithelial elimination (TEE) of dermal structures. APD is manifested clinically as multi-localized, papulo-nodular skin lesions accompanied by a refractory pruritus. APD typically coexists with long-term disorders, most often diabetic kidney disease (DKD). The paper presents a case of a 56-year-old male patient with chronic kidney disease (CKD) and concomitant acquired reactive perforating collagenosis (ARPC), which is a subtype of APD. Etiological theories of ARPC as well as current diagnostic and treatment principles in dermatosis were described. On the basis of the presented case report and the literature review attention was paid to diagnostic difficulties associated with APD. The assumption was made that APD can be an underdiagnosed disease and thus it is not treated correctly. According to the authors' opinion, this is an important circumstance to popularize the knowledge about APD.

Receptor for advanced glycation end products (RAGE) gene polymorphism and cardiovascular disease in end-stage renal disease patients.

BACKGROUND/OBJECTIVES: Receptor for advanced glycation end products (RAGE) contributes to the pathogenesis of vascular and inflammatory diseases. We investigated whether the functional polymorphism in the promoter region of the RAGE gene (-374 T/A) influences development of cardiovascular disease in the end-stage renal disease (ESRD) patients. METHODS: The cohorts of 1866 ESRD patients and 1143 healthy subjects were genotyped by polymerase chain reaction (PCR) for the RAGE variant rs1800624. RESULTS: The genotype and allele frequencies did not differ significantly between ESRD patients and controls. There was no significant difference in the genotype distribution when patients with CVD were compared to those without it (p for A allele = 0.62). After stratifying CVD patients according to CVD clinical phenotype, the ESRD patients with stroke had a lower frequency of A allele than patients without CVD (0.12 vs. 0.21, p = 0.027). To confirm this finding, we genotyped 163 patients with ischemic stroke but without renal disease. In this group, the AA/TA genotypes were also significantly associated with lower risk of stroke (OR 0.46, p = 0.0002). CONCLUSION: Our data suggest that the presence of the A allele of -374 T/A polymorphism in the RAGE gene has a protective effect against stroke.

Matrix Metalloproteinase-9 (MMP-9) Gene Polymorphism in Stroke Patients.

Matrix metalloproteinases (MMPs), endopeptidases degrading extracellular matrix, play an important role in the pathogenesis of atherosclerosis and vascular disease. The aim of this study was to evaluate the association between the C(-1562)T functional polymorphism in the MMP-9 gene and risk of stroke. We examined 322 patients with stroke and 410 controls. In the patient group, 52 % had type 2 diabetes. All subjects were genotyped for the C(-1562)T polymorphism by polymerase chain reaction and restriction analysis. A significant increase in T allele and CT + TT genotype frequencies was observed in patients compared with controls (OR 1.73, 95 % CI 1.34-2.23 and 1.89, 95 % CI 1.39-2.56, respectively). The T allele carriers were younger at the onset of stroke (63.5 ± 11.7 years) than patients with CC genotype (71 ± 14.1 years) (p = 0.0002). The comparison between patients with T2DM and without it showed that the T allele and CT + TT genotype were more frequent in T2DM patients (OR 1.48, 95 % CI 1.03-2.12 for T allele and 1.44, 95 % CI 1.93-2.24 for CT + TT genotype). In conclusion, our findings suggest that MMP-9 C(-1562)T polymorphism is significantly associated with risk of stroke in patients with and without T2DM.

Matrix metalloproteinase-2 (MMP-2) gene polymorphism and cardiovascular comorbidity in type 2 diabetes patients.

OBJECTIVE: Matrix metalloproteinases (MMPs) play an important role in pathogenesis of atherosclerosis and vascular disease. We hypothesized that MMP-2 might be a susceptibility gene for cardiovascular disease (CVD) in diabetes. The aim of this study was to evaluate the association between C(-1306)T functional polymorphism in the MMP-2 gene and risk of CVD in type 2 diabetes patients. METHODS: We examined 1090 patients with T2DM and 612 controls. All subjects were genotyped for the C(-1306)T polymorphism by polymerase chain reaction (PCR) and restriction analysis. RESULTS: A significant decrease of T allele frequency was observed in patients with CVD versus those with no CVD (OR 0.44, 95% CI 0.36-0.52, p<0.0001). In contrast, OR for CC genotype was 2.19 (1.79-2.68, p<0.0001), conferring 2-fold greater odds for CVD. When the distribution of C(-1306)T was compared in subgroups with different clinical phenotypes of CVD, patients with stroke had the lowest frequency of T allele (6% vs. 11%), compared to entire CVD+ group (p<0.05). CONCLUSIONS: T2DM patients carrying the T allele of MMP-2 C(-1306)T polymorphism have a significantly reduced risk of CVD. The C(-1306)T polymorphism is associated with susceptibility to stroke in T2DM patients.

Phosphate Kinetics During Weekly Cycle of Hemodialysis Sessions: Application of Mathematical Modeling.

Both hyperphosphatemia and hypophosphatemia are associated with increased morbidity and mortality among patients on dialysis. The control of serum phosphate concentration is a considerable clinical problem. Our study aimed to improve understanding of phosphate kinetics in patients on dialysis using mathematical modeling. Three consecutive hemodialysis sessions with breaks of 2-2-3 days were monitored in 25 patients. Phosphate concentration was measured every hour and 45 min after the end of dialysis in blood serum and every 30 min in dialysate during each session. Volume of fluid compartments and body composition were assessed by bioimpedance. The pseudo one-compartment model was applied to describe the profile of phosphate in blood serum during intra- and interdialytic periods of 1-week cycle of three hemodialysis sessions. Model parameters, such as phosphate internal clearance (KM ) and the rate of phosphate mobilization (RM ), were correlated with the reduction of serum phosphate concentration during dialysis (Cpost /Cpre ) and with equivalent continuous clearance (ECC) for phosphate. KM correlated negatively with predialysis serum phosphate concentration. There was significant positive correlation between RM and age. Postdialysis volume of phosphate central compartment was lower than, but correlated to, extracellular water volume. Parameters of the pseudo one-compartment model, phosphate internal clearance, and the rate of phosphate inflow to the central compartment (the one accessible for dialysis) from other phosphate body reservoirs correlated with the indices of dialysis adequacy, such as reduction of serum phosphate and ECC. The pseudo one-compartment model can be successfully extended from a single hemodialysis to the standard weekly cycle of sessions and the model parameters strongly correlate with the adequacy parameters of dialytic removal of phosphate.

The prognostic value of positive T-wave in lead aVR in hemodialysis patients.

BACKGROUND: Given that cardiac disease is the leading cause of mortality in hemodialysis (HD) patients, identification of patients at risk for cardiac mortality is crucial. The aim of this study was to determine if positive T-wave amplitude in lead aVR (TaVR) was predictive of cardiovascular (CV) mortality and sudden cardiac death (SCD) in a group of HD patients. METHODS AND RESULTS: After exclusion, 223 HD patients were prospectively followed-up for 25.43 ± 3.56 months. Patients were divided into TaVR negative (n = 186) and TaVR positive (n = 37) groups. Myocardial infarction, diabetes and beta-blocker therapy were more frequent in positive TaVR patients. Patients with upright TaVR were older, had higher left ventricular mass index, lower ejection fraction, higher calcium × phosphate product, higher troponin T level, higher prevalence of ST-T abnormalities, and increased width of QRS complex and QT interval, compared with patients with negative TaVR. A Kaplan-Meier analysis showed that the cumulative incidences of CV mortality as well as SCD were higher in patients with positive TaVR compared with those with negative TaVR (log-rank, p < 0.001 in both cases). A multivariate analysis selected age [hazard ratio (HR) 1.71, p < 0.001], heart rate (HR 1.42, p = 0.016), and positive TaVR (HR 2.21, p = 0.001) as well as age (HR 1.88, p < 0.001), and positive TaVR (HR 1.53, p = 0.014) as independent predictors of CV mortality and SCD, respectively. CONCLUSION: In HD patients, positive TaVR is an independent and powerful predictor of CV mortality as well as SCD. This simple ECG parameter provides additional information beyond what is available with other known traditional risk factors and allows the identification of patients most at risk of CV events.

Phosphate, urea and creatinine clearances: haemodialysis adequacy assessed by weekly monitoring.

BACKGROUND: The specific distribution of phosphate and the control mechanisms for its plasma level makes phosphate kinetics during haemodialysis (HD) considerably different from those of urea and creatinine and makes the quantitative evaluation of adequacy of phosphate removal difficult. We propose the application of equivalent continuous clearance (ECC) as a phosphate adequacy parameter and compare it with ECC for creatinine and urea. METHODS: Three consecutive dialysis sessions were evaluated for 25 patients on maintenance HD. Concentrations of phosphate, urea and creatinine in plasma were measured every 1h during the treatment and 45 min after, and every 30 min in dialysate. ECC was calculated using the removed solute mass assessed in dialysate and weekly solute profile in plasma. Similar calculations were performed also for the midweek dialysis session only. Different versions of the reference concentration for ECC were applied. RESULTS: ECC with peak average reference concentration was 5.4 ± 1.0 for phosphate, 7.0 ± 1.0 for urea and 4.7 ± 1.0 mL/min for creatinine. ECC for urea and creatinine were well correlated in contrast to the correlations of ECC for phosphate versus urea and creatinine. Midweek ECC were higher than weekly ECC, but they were well correlated for urea and creatinine, but only weakly for phosphate. CONCLUSIONS: HD adequacy monitoring for phosphate may be performed using ECC, but it is less predictable than similar indices for urea and creatinine. The values of ECC for phosphate are within the range expected for its molecular size compared with those for urea and creatinine.