Does Metabolic Syndrome and Its Components Have Prognostic Significance for Renal and Cardiovascular Outcomes in IgA Nephropathy?

BACKGROUND: Patients with IgA nephropathy (IgAN), a chronic kidney disease (CKD), are significantly more likely to have cardiovascular (CV) mortality and morbidity than the general population. The occurrence of metabolic syndrome (MetS) and metabolic risk factors are independent risk factors for CV disease and renal progression. The purpose of this study was to determine how metabolic characteristics in a homogeneous population of CKD patients relate to prognosis. METHODS: A total of 145 patients with CKD stages 1-4 diagnosed with IgA nephropathy (92 men and 53 women, aged 54.7 ± 13 years) were examined and monitored for a median of 190 months. All-cause mortality and any CV event, such as stroke, myocardial infarction, revascularization (CV), end-stage renal disease, and renal replacement therapy (renal), have been included in the composite endpoints (CV and renal). RESULTS: Patients with MetS had significantly more primary endpoint events (23/65 patients vs. 15/60 patients, p < 0.001) compared to the non-MetS group. The MetS group had a statistically significant increase in both primary renal and CV endpoints (18/65 vs. 10/60, p = 0.001), and in CV endpoint events (7/65 vs. 6/60, p = 0.029) among the secondary endpoints (CV and renal separately). Based on Cox regression analysis, the main endpoint independent predictors of survival were dyslipidemia, eGFR, hemoglobin, urine albuminuria, and diabetes mellitus. Independent predictors of secondary renal endpoints were dyslipidemia, hemoglobin, urine albumin, and eGFR. Predictors of secondary cardiovascular endpoints were gender, BMI, and diabetes. When Kaplan-Meier curves were analyzed at the combined endpoints (CV and renal) or each endpoint independently, significant differences were seen between MetS and non-MetS. With more MetS components, the primary endpoint rate increased significantly (MetS comp. 0 vs. MetS comp. 2+, primary endpoints, p = 0.012). CONCLUSIONS: Our results show that the metabolic profile has a prognostic role not only for renal endpoints but also for CV endpoints in IgAN. BMI, hyperuricemia, hypertension, and diabetes have a predictive value for the prognosis of IgA nephropathy.

Are Platelet-Related Parameters Prognostic Predictors of Renal and Cardiovascular Outcomes in IgA Nephropathy?

Background: IgA nephropathy (IgAN) is associated with chronic inflammation. Platelet-related parameters, such as the platelet (PLT) count, platelet-to-albumin ratio (PAR), and platelet-to-lymphocyte ratio (PLR), were examined as potential prognostic indicators for renal and cardiovascular (CV) outcomes in IgAN. We were interested in whether platelet-related parameters are risk factors for ESKD and CV events in IgAN patients. Methods: In a monocentric retrospective study, 124 IgAN patients were divided into two groups based on the cut-off value of the PAR. All-cause mortality, major CV events, and end-stage renal disease were the primary combined endpoints. Secondary endpoints, such as CV or renal endpoints, were also analyzed separately. Results: The patients' mean age was 43.7 ± 13.5 years, and the follow-up time was 124 ± 67 months. The K-M curve showed that the PLR, PAR, and PLT were strongly associated with primary combined (p = 0.002, p = 0.004, p = 0.001) and renal outcomes (p < 0.001, p < 0.001, p < 0.001), but not with CV outcomes in IgAN. However, when combined with left ventricular hypertrophy (LVH) or metabolic syndrome (MetS), the PAR was found to be a significant predictor of both primary (p < 0.001, p < 0.001) and secondary outcomes (p = 0.001 and p = 0.038; p = 0.001 and p = 0.015). Additionally, the PLR correlated with albuminuria (r = -0.165, p = 0.033) and LVH (r = -0.178, p = 0.025), while PLT correlated with eGFR (r = 0.158, p = 0.040). Conclusions. Elevated PARs and PLRs may predict progression to end-stage kidney disease, but in combination with LVH and MetS, they were related to CV events in IgAN. The determination of PARs and PLRs can be useful and cost-effective parameters for assessing both cardiovascular and renal risks in IgAN.

Renal and cardiovascular prognostic significance of echocardiographic early diastolic mitral annular velocity in IgA nephropathy.

In chronic kidney disease (CKD), as in IgA nephropathy (IgAN), cardiovascular (CV) mortality and morbidity are many times higher than in the general population, and diastolic dysfunction (LVDD) has prognostic significance as well. Tissue Doppler Echocardiography (TDI) is another method for measuring myocardial contractility and determining diastolic dysfunction. 79 IgAN patients (age 46 ± 11 years) with CKD stages 1-3 were investigated and followed for 70 ± 28.7 months. Doppler echocardiography was used to measure the E (early) and A (late) waves, as well as the E wave deceleration time (EDT) during mitral inflow. TDI was used to measure early (Ea) and late (Aa) diastolic velocities (lateral and septal basal wall fragment average). From these, we calculated the E/Ea and Ea/Aa ratios. The primary combined endpoints were total mortality, major CV events, and end-stage renal disease, and the secondary endpoints were cardiovascular or renal (eGFR decreased below 15 ml/min/1.73 m2 or renal replacement therapy was started). Patients with decreased Ea (< 13 cm/s) had significantly more endpoints (20/42 vs. 3/37; p = 0.001) than patients with higher Ea (≥ 13 cm/s). The secondary renal endpoints were also significantly higher (p = 0.004). In a multivariate model, the eGFR showed independent correlation with the E/A ratio (r = 0.466; p < 0.01), EDT (r = - 0.270; p < 0.01), Ea/Aa ratio (r = 0.455; p < 0.01), and decreased Ea (r = 0.544; p < 0.01). Independent factors influencing Ea were only EDT by uni- and multivariate regression but age and albuminuria by logistic regression. Decreased Ea measured by TDI seems to be an eligible factor to predict the prognosis of IgA nephropathy. The decreased Ea may be a helpful parameter to identify high-risk CKD patients.

Acute Vascular Response to Hemodialysis as Measured by Serum Syndecan-1 and Endothelin-1 Levels as Well as Vascular Stiffness.

BACKGROUND: Chronic hemodialysis (HD) patients have a very high cardiovascular risk. Acute vascular changes during dialysis mediated by factors of the endothelium may have a crucial role in this. The aim of this article is to study the acute vascular changes during HD. METHODS: In 29 consecutive chronic HD patients (age: 65.6 ± 10.4 years), their pre-, mid-, and post-HD plasma syndecan-1 (SDC-1) and endothelin-1 (ET-1) levels were measured. Applanation tonometry was performed before HD. RESULTS: Their SDC-1 levels increased during HD (p = 0.004). Males had higher ET-1 levels. The patients were divided into two groups based on their pre-HD pulse wave velocity (PWV): PWV ≥ 12 m/s and PWV < 12 m/s. The pre-HD and mid-HD SDC-1 levels were higher in the group with a PWV ≥ 12 m/s (10.174 ± 2.568 vs. 7.928 ± 1.794 ng/mL, p = 0.013, and 10.319 ± 3.482 vs. 8.248 ± 1.793 ng/mL, p = 0.044, respectively). The post-HD ET-1 levels were higher in the patient group with a PWV ≥ 12 m/s (10.88 ± 3.00 vs. 8.05 ± 3.48 pg/l, p = 0.027). Patients with a PWV ≥ 12 m/s had higher pre-HD peripheral and aortic systolic blood pressures (p < 0.05). The total cholesterol correlated with the SDC-1 decrease during HD (r = 0.539; p = 0.008). The pre-, mid-, and post-HD SDC-1 correlated with ultrafiltration (r = 0.432, p = 0.019; r = 0.377, p = 0.044; and r = 0.401, p = 0.012, respectively). CONCLUSION: SDC-1 and ET-1 contribute to the vascular changes observed during HD, and they have correlations with some cardiovascular risk factors.

Relationship between arterial stiffness, left ventricular diastolic function, and renal function in chronic kidney disease.

AIM: In chronic kidney disease, IgA nephropathy, and left ventricular diastolic dysfunction have prognostic significance as well. However, the relationship between diastolic dysfunction, arterial stiffness, and renal function has not been fully elucidated. METHODS: 79 IgA nephropathy patients (aged 46 ± 11 years) and 50 controls were investigated. Tissue Doppler imaging was used to measure early (Ea) and late (Aa) diastolic velocities. Arterial stiffness was measured by a photoplethysmographic (stiffness index (SI)) and an oscillometric method (aortic pulse wave velocity (PWVao)). RESULTS: We compared the IgAN patients to a similar cardiovascular risk group with a preserved eGFR. A strong correlation was found between Ea/Aa and SI (p < 0.001), also with PWVao (p < 0.001), just in IgAN, and with eGFR (p < 0.001) in both groups. IgAN patients were divided into groups CKD1-2 vs. CKD3-5. In the CKD 3-5 group, the incidence of diastolic dysfunction increased significantly: 39% vs. 72% (p = 0.003). Left ventricle rigidity (LVR) was calculated, which showed a close correlation with SI (p = 0.009) and eGFR (p = 0.038). By linear regression analysis, the independent predictors of SI were age, E/A, and E/Ea; SI was the predictor of LVR; and E/A and hypertension were the predictors of eGFR. CONCLUSION: In chronic kidney disease, increased cardiac rigidity and vascular stiffness coexist with decreased renal function, which is directly connected to diastolic dysfunction and vascular stiffness. On the basis of comparing the CKD group to the control group, vascular alterations in very early CKD can be identified.

The Role of Two Heart Biomarkers in IgA Nephropathy.

Cardiovascular mortality is a leading cause of death in chronic kidney disease (CKD), as is IgA nephropathy (IgAN). The purpose of this study is to find different biomarkers to estimate the outcome of the disease, which is significantly influenced by the changes in vessels (characterized by arterial stiffness) and the heart. In our cross-sectional study, 90 patients with IgAN were examined. The N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was measured as a heart failure biomarker by an automated immonoassay method, while the carboxy-terminal telopeptide of collagen type I (CITP) as a fibrosis marker was determined using ELISA kits. Arterial stiffness was determined by measuring carotid-femoral pulse wave velocity (cfPWV). Renal function and routine echocardiography examinations were performed as well. Based on eGFR, patients were separated into two categories, CKD 1-2 and CKD 3-5. There were significantly higher NT-proBNP (p = 0.035), cfPWV (p = 0.004), and central aortic systolic pressure (p = 0.037), but not CITP, in the CKD 3-5 group. Both biomarker positivities were significantly higher in the CKD 3-5 group (p = 0.035) compared to the CKD 1-2 group. The central aortic systolic pressure was significantly higher in the diastolic dysfunction group (p = 0.034), while the systolic blood pressure was not. eGFR and hemoglobin levels showed a strong negative correlation, while left ventricular mass index (LVMI), aortic pulse pressure, central aortic systolic pressure, and cfPWV showed a positive correlation with NT-proBNP. cfPWV, aortic pulse pressure, and LVMI showed a strong positive correlation with CITP. Only eGFR was an independent predictor of NT-proBNP by linear regression analysis. NT-proBNP and CITP biomarkers may help to identify IgAN patients at high risk for subclinical heart failure and further atherosclerotic disease.

Left ventricular myocardial mass index associated with cardiovascular and renal prognosis in IgA nephropathy.

INTRODUCTION: In chronic kidney disease (CKD), like in IgA nephropathy (IgAN), cardiovascular (CV) mortality and morbidity are many times higher than in the general population, and left ventricular hypertrophy (LVH) is an independent risk factor for CV disease. This follow-up study investigated the association between left ventricular mass index (LVMI) and renal or cardiovascular outcomes. METHODS: We examined 118 IgAN patients prospectively. LVMI and LV geometry was investigated using echocardiography. The primary combined endpoints were total mortality, major CV events, and end-stage renal disease. Secondary endpoints, i.e.-cardiovascular or renal endpoints,-were also examined separately. RESULTS: Sixty seven percent were males, mean age 53.5 ± 13.5. Mean follow-up time: 184 months. LVMI inversely correlated with eGFR (corr. coefficient: -0.365; p < 0.01). We divided the patients into two groups based on the LVMI cut-off suggested by the literature. The presence of LVH caused a worse prognosis in primary (p < 0.001), renal endpoints (p = 0.01), and also in CV endpoints (p = 0.001). The higher LVMI in men significantly worsened the prognosis in all endpoints. Concentric hypertrophy meant a worse prognosis. Independent predictors of LVMI were gender and eGFR in uni- and multivariate regression and hemoglobin levels only in logistic regression. Independent predictors of the primary endpoint were LVMI, eGFR, gender, obesity, HT, DM, and metabolic syndrome in Cox regression analysis. CONCLUSION: Increased LVMI may predict the progression to end-stage renal disease and CV events in IgAN. Determining LVMI may be a useful parameter not only in CV risk but also in the stratification of renal risk in CKD.

Efficacy of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis of KALM-1 and KALM-2 Phase 3 Studies.

Rationale & Objective: Chronic kidney disease-associated pruritus (CKD-aP) in patients treated by hemodialysis (HD) impairs quality of life (QoL). Difelikefalin, a selective κ-opioid receptor agonist, decreased the intensity of CKD-aP in patients undergoing HD. This pooled analysis evaluated difelikefalin's efficacy and the itch-related QoL overall and in subgroups defined by demographics or disease characteristics. Study Design: In KALM-1 and KALM-2, participants were randomized (1:1) to receive intravenous difelikefalin or placebo 3 times/wk for 12 weeks, followed by a 52-week open-label extension. Setting & Participants: Adults with moderate to severe CKD-aP treated by HD in North America, Europe, and the Asia-Pacific region. Intervention: Intravenous difelikefalin at 0.5 mcg/kg or placebo. Outcomes: Itch intensity (Worst Itching Intensity Numerical Rating Scale [WI-NRS]) and itch-related QoL (Skindex-10 and 5-D Itch questionnaires). Results: 851 participants were randomized (difelikefalin, n = 426; placebo, n = 425). This pooled analysis demonstrated early     (week 1), sustained difelikefalin efficacy, with significantly greater achievement of ≥3-point WI-NRS reduction with difelikefalin (51.1%) versus placebo (35.2%; P < 0.001). Achievement of a ≥4-point WI-NRS reduction was significantly greater with difelikefalin (38.7%) versus placebo (23.4%; P < 0.001). Difelikefalin reduced itch intensity in subgroups based on age, sex, anti-itch medication use, the presence of specific medical conditions, and gabapentin or pregabalin use. More participants receiving difelikefalin versus placebo achieved clinically meaningful decreases of ≥15 points on the Skindex-10 scale (55.5% vs 40.5%, respectively; P < 0.001) and ≥5 points on the 5-D Itch scale (52.1% vs 42.3%, respectively; P = 0.01), with sustained 5-D Itch effects up to 64 weeks. Limitations: Subgroup samples were small. The WI-NRS, Skindex-10, and 5-D Itch are not used in routine clinical care of dialysis patients; therefore, findings may not reflect the real-world effectiveness of difelikefalin. Conclusions: Difelikefalin demonstrated rapid, sustained efficacy, with consistent results in diverse populations of patients treated by HD. Funding: Cara Therapeutics, Inc. Trial Registration: The KALM-1 trial is registered as NCT03422653 and the KALM-2 trial is registered as NCT03636269.

Cardiometabolic Effects of Irisin in Patients with End-Stage Renal Disease on Regular Hemo- or Peritoneal Dialysis.

INTRODUCTION: Data on the role of irisin in vascular calcification in patients with end-stage renal diseases on regular dialysis are inconsistent, and the underlying mechanisms are not clearly defined. The present study was designed to explore the association of serum irisin with vascular stiffness and with the impact of well-established risk factors. METHODS: The clinical study enrolled 52 hemodialysis (HD) and 15 continuous ambulatory peritoneal dialysis (PD) patients with an age of >18 years receiving dialysis therapy for >3 months. Patients who had major pathologies affecting carbohydrate, lipid, and bone metabolism and those who had acute cardiovascular events were excluded. Thirty-seven healthy subjects matched for age and sex served as controls. Routine biochemical parameters were measured in fasting serum samples by standard methods. Serum irisin was determined using the commercial ELISA kit (BioVendor Laboratory Medicine Inc., Brno, Czech Republic). Arterial stiffness parameters - carotid-femoral pulse wave velocity (cf PWV) and augmentation index (Aix) - were measured using applanation tonometry (SphygmoCor System; AtCor Medical, Sydney, Australia). Body composition was assessed by segmental bioelectric impedance (InBody 2.0; Biospace Co. Ltd., Seoul, Korea). RESULTS: It was demonstrated that serum irisin levels were markedly depressed (p < 0.05), while the cf PWV significantly increased (p < 0.05) in HD/PD patients as compared to controls. Serum irisin proved to be independent of serum insulin, glucose, and HOMA-IR. However, it was inversely related to HbA1c (ß = -0.544, p = 0.035), iPTH (ß = -0.260, p = 0.035), and alkaline phosphatase (r = -0.325, p = 0.007). Furthermore, significant negative relationships were found of irisin to serum triglyceride and indices of body fat mass. Retrospective analysis at a follow-up period of 40 months revealed a direct relationship of irisin to all-cause mortality (p = 0.039). CONCLUSIONS: Our study demonstrated that serum irisin levels are reduced in uremic patients on regular HD/PD but failed to establish significant associations of irisin deficiency with vascular stiffness. However, the significant negative relationship of irisin to HbA1c, iPTH, and alkaline phosphatase suggests that it improves insulin sensitivity, inhibits bone resorption, mitigates bone-vascular interaction, and protects vascular function.

The prognostic role of heart rate recovery after exercise and metabolic syndrome in IgA nephropathy.

BACKGROUND: Cardiovascular (CV) morbidity and mortality are higher in chronic kidney disease (CKD) than in the general population. Reduced heart rate recovery (HRR) is an independent risk factor for CV disease. The aim of the study was to determine the prognostic role of HRR in a homogenous group of CKD patients. METHODS: One hundred and twenty-five IgA nephropathy patients (82 male, 43 female, age 54.7 ± 13 years) with CKD stage 1-4 were investigated and followed for average 70 months. We performed a graded exercise treadmill stress test. HRR was derived from the difference of the peak heart rate and the heart rate at 1 min after exercise. Patients were divided into two groups by the mean HRR value (22.9 beats/min). The composite (CV and renal) endpoints included all-cause mortality and any CV event such as stroke, myocardial infarction, revascularisation (CV) and end-stage renal disease, renal replacement therapy (renal). RESULTS: Patients with reduced HRR (< 23 bpm) had significantly more end point events (22/62 patients vs. 9/53 patients, p = 0.013) compared to the higher HRR (≥23 bpm). Of the secondary the endpoints (CV or renal separately) rate of the renal endpoint was significantly higher in the lower HRR group (p = 0.029), while there was no significant difference in the CV endpoint between the two HRR groups (p = 0.285). Independent predictors of survival were eGFR and diabetes mellitus by using Cox regression analysis. Kaplan-Meier curves showed significant differences in metabolic syndrome and non-metabolic syndrome when examined at the combined endpoints (cardiovascular and renal) or at each endpoint separately. The primary endpoint rate was increased significantly with the increased number of metabolic syndrome component (Met.sy. comp. 0 vs. Met. sy. comp. 2+, primary endpoints, p = 0.012). CONCLUSION: Our results showed that reduced HRR measured by treadmill exercise test has a predictive value for the prognosis of IgA nephropathy. The presence of metabolic syndrome may worsen the prognosis of IgA nephropathy.

Roxadustat for the Maintenance Treatment of Anemia in Patients with End-Stage Kidney Disease on Stable Dialysis: A European Phase 3, Randomized, Open-Label, Active-Controlled Study (PYRENEES).

INTRODUCTION: Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for the treatment of anemia of chronic kidney disease (CKD). This European, phase 3, randomized, open-label, active-controlled study investigated efficacy and safety of roxadustat in patients with end-stage kidney disease on dialysis for at least 4 months. METHODS: Patients were randomized to switch from an erythropoiesis-stimulating agent (ESA) (epoetin alfa or darbepoetin alfa) to roxadustat three times/week or to continue their previous ESA. Roxadustat and ESA doses were adjusted to maintain hemoglobin within 10.0-12.0 g/dL during the treatment period (day 1 up to 52-104 weeks). Primary endpoints were hemoglobin change from baseline (CFB) to the average of weeks 28-36 without rescue therapy and hemoglobin CFB to the average of weeks 28-52 regardless of rescue therapy. Treatment-emergent adverse events (TEAEs) were assessed descriptively. RESULTS: Of 1081 screened patients, 836 were randomized and received treatment (roxadustat, n = 415; ESA, n = 421). The least squares means (95% CI) of the treatment difference (roxadustat - ESA) for hemoglobin CFB to weeks 28-36 (without rescue therapy) and CFB to weeks 28-52 (regardless of rescue therapy) were 0.235 (0.132, 0.339) g/dL and 0.171 (0.082, 0.261) g/dL, respectively, demonstrating non-inferiority of roxadustat to ESA (non-inferiority margin of - 0.75 g/dL). The proportions of patients who achieved target hemoglobin without rescue therapy during weeks 28-36 were 84.2% (roxadustat) and 82.4% (ESA). Roxadustat was superior to ESA in decreasing LDL cholesterol from baseline to the average of weeks 12-28. Serious TEAEs occurred in 50.7% (roxadustat) and 45.0% (ESA) of patients. Common TEAEs in both treatment groups included hypertension, arteriovenous fistula thrombosis, headache, and diarrhea. CONCLUSION: Roxadustat was non-inferior to ESAs in maintaining hemoglobin levels in this cohort of patients with anemia of CKD on dialysis for at least 4 months who were previously treated with ESAs. Observed TEAEs were consistent with previous studies.

Efficacy and Cardiovascular Safety of Roxadustat in Dialysis-Dependent Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies.

INTRODUCTION: This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients. METHODS: Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using least-squares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. RESULTS: In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE+ in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE+ : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE+ (HR 1.13, 95% CI 0.95-1.34). TEAEs were generally comparable between groups. CONCLUSION: Roxadustat improved hemoglobin similarly to ESA while demonstrating comparable cardiovascular and overall safety profiles in a wide spectrum of dialysis-dependent patients with anemia of CKD. Roxadustat represents an oral alternative to ESAs for achieving a target hemoglobin for anemia of CKD in dialysis-dependent patients.

Pro- and anti-inflammatory factors, vascular stiffness and outcomes in chronic hemodialysis patients.

OBJECTIVE: In this observational study we addressed accelerated arteriosclerosis (AS) in patients with chronic renal failure (CRF) on hemodialysis (HD) by measuring vascular stiffness (VS) parameters and attempted to relate them to pro-inflammatory and protective factors. PATIENTS: 96 consecutive patients receiving regular HD were included. 20 adult patients without major renal, cardiovascular or metabolic morbidities served as controls. METHODS: AS parameters (carotid-femoral pulse wave velocity - PWV, aortic augmentation index - Aix) were measured by using applanation tonometry (SphygmoCor, AtCor Medical, Sidney). In addition to routine laboratory tests 25(OH) vitamin D3 (vitamin D3) and high-sensitivity C-reactive protein (hsCRP) were quantified by immunometric assay; whereas fetuin-A, α-Klotho, tumor necrosis factor-α (TNF-α) and transforming growth factor-ß1 (TGF-ß1) were determined by ELISA. RESULTS: Pro-inflammatory biomarkers (hsCRP, TNF-α and TGF-ß1) were markedly elevated (P < 0.01), while anti-inflammatory factors (fetuin-A: P < 0.05, α-Klotho: P < 0.01, vitamin D3: P < 0.01) significantly depressed in HD patients when compared to controls. PWV was significantly affected only by total cholesterol, fetuin-A and dialysis time. Multiple linear regression analyses revealed that several clinical and laboratory parameters were associated with pro- and anti-inflammatory biomarkers rather than VS. The impact of baseline clinical and biochemical variables on outcome measures were also analyzed after three-year follow-up, and it was demonstrated that low levels of vitamin D, α-Klotho protein and fetuin-A were related to adverse cardiovascular outcomes, whereas all-cause mortality was associated with elevated hsCRP and depressed vitamin D. CONCLUSIONS: Our results provide additional information on the pathomechanism of accelerated AS in patients with CRF, and documented direct influence of pro- and anti-inflammatory biomarkers on major outcome measures.

Locking Hemodialysis Catheters With Trimethoprim-Ethanol-Ca-EDTA to Prevent Bloodstream Infections: A Randomized, Evaluator-blinded Clinical Trial.

BACKGROUND: Central line-associated bloodstream infections (CLABSIs) often result from intraluminal microbial colonization and are associated with morbidity, mortality, and substantial costs. The use of antimicrobial catheter lock solutions may reduce the incidence of CLABSI. METHODS: Patients undergoing hemodialysis (HD) through a prevalent central venous catheter (CVC) were randomly assigned to have their CVC locked between dialysis sessions with an antimicrobial catheter lock solution that contained trimethoprim 5 mg/mL, ethanol 25%, and Ca-EDTA 3% (investigational medical device [IMD]) or heparin 5000 U/mL active control heparin (ACH). Exit site care was standardized by protocol-driven use of skin antiseptics and occlusive dressings. The composite primary endpoint consisted of the incidence of CLABSI and intracatheter thrombolytic treatment (TT). Given the viscosity and odor of the IMD, blinding was impossible. Therefore, a blinded endpoint committee adjudicated the incidence of CLABSI. RESULTS: A total of 270 patients on HD were enrolled and followed for 43738 CVC-days. Despite the low CLABSI incidence of 0.41/1000 CVC-days in patients randomized to ACH, the IMD further reduced the incidence 4.56-fold to 0.09/1000 CVC-days (P < .03). The product was well tolerated, and the frequency and severity of adverse events were comparable between groups. Intracatheter instillation of thrombolytics was more frequent in patients who received the IMD (12% ACH, 40% IMD; P < .001), but rates of catheter removal did not differ (13% ACH, 11% IMD). Overall, dialysis adequacy was comparable between groups. CONCLUSIONS: In patients on chronic HD, a trimethoprim, ethanol, and Ca-EDTA lock solution significantly reduced the incidence of CLABSI. CLINICAL TRIALS REGISTRATION: NCT01989091.

The Impact of Osteocalcin, Osteoprotegerin and Osteopontin on Arterial Stiffness in Chronic Renal Failure Patients on Hemodialysis.

BACKGROUND/AIMS: This cross-sectional study was designed to assess the relationship between vascular stiffness (VS) and bone-related proteins involved in the development of arteriosclerosis in patients on regular hemodialysis (HD). METHODS: 68 consecutive patients in stable clinical condition who received regular HD in the FMC Dialysis Center, Pécs were included. VS parameters (carotid-femoral pulse wave velocity - PWV, aortic augmentation index - AIx) were determined by applanation tonometry (SphygmoCor, AtCor Medical, Sidney) and the routine latoratory test were completed with measurements of osteocalcin (OC), osteopontin (OP) and osteoprotegerin (OPG) by using commercially available ELISA kits. 35 heathcare workers served as controls. RESULTS: In patients on regular HD PWV markedly increased and there was several-fold elevation in the interrelated bone-specific proteins (OC, OP, OPG). PWV was found to be independently associated only with OC (ß:-0.25, p<0.029) and age (r=0.411,p<0.000), but risk factors for arterial calcification had significant impact on OC (systolic blood pressure, hsCRP, BMI), OPG (age, BMI) and OP (LDL-cholesterol). CONCLUSION: Except for OC, our results failed to document direct association of vascular lesion with OP and OPG, therefore their high circulating levels may be an epiphenomenon or they may have counter-regulatory role to attenuate the uremic calcification process.

Association of plasma ortho-tyrosine/para-tyrosine ratio with responsiveness of erythropoiesis-stimulating agent in dialyzed patients.

Objectives Patients with end-stage renal failure (ESRF) treated with erythropoiesis-stimulating agents (ESAs) are often ESA-hyporesponsive associated with free radical production. Hydroxyl free radical converts phenylalanine into ortho-tyrosine, while physiological isomer para-tyrosine is formed enzymatically, mainly in the kidney. Production of 'para-tyrosine' is decreased in ESRF and it can be replaced by ortho-tyrosine in proteins. Our aim was to study the role of tyrosines in ESA-responsiveness. Methods Four groups of volunteers were involved in our cross-sectional study: healthy volunteers (CONTR; n = 16), patients on hemodialysis without ESA-treatment (non-ESA-HD; n = 8), hemodialyzed patients with ESA-treatment (ESA-HD; n = 40), and patients on continuous peritoneal dialysis (CAPD; n = 21). Plasma ortho-, para-tyrosine, and phenylalanine levels were detected using a high performance liquid chromatography (HPLC)-method. ESA-demand was expressed by ESA-dose, ESA-dose/body weight, and erythropoietin resistance index1 (ERI1, weekly ESA-dose/body weight/hemoglobin). Results We found significantly lower para-tyrosine levels in all groups of dialyzed patients when compared with control subjects, while in contrast ortho-tyrosine levels and ortho-tyrosine/para-tyrosine ratio were comparatively significantly higher in dialyzed patients. Among groups of dialyzed patients the ortho-tyrosine level and ortho-tyrosine/para-tyrosine ratio were significantly higher in ESA-HD than in the non-ESA-HD and CAPD groups. There was a correlation between weekly ESA-dose/body weight, ERI1, and ortho-tyrosine/para-tyrosine ratio (r = 0.441, P = 0.001; r = 0.434, P = 0.001, respectively). Our most important finding was that the ortho-tyrosine/para-tyrosine ratio proved to be an independent predictor of ERI1 (ß = 0.330, P = 0.016). In these multivariate regression models most of the known predictors of ESA-hyporesponsiveness were included. Discussion Our findings may suggest that elevation of the ratio of ortho-tyrosine/para-tyrosine could be responsible for decreased ESA-responsiveness in dialyzed patients.

An archived serum sample as a clue for identifying the primary source of a nosocomial hepatitis C virus outbreak in a haemodialysis unit.

Due to an unexpected technical error, patients at a dialysis unit who were seronegative for hepatitis C virus (HCV) were temporarily transferred to another dialysis unit next to a ward reserved for HCV-seropositive patients. In the following 7 months, 17 patients were diagnosed as anti-HCV positive. The aim of the study was to reveal the cause of this nosocomial infection. Anti-HCV-positive sera were further tested by molecular methods. Data collection and on-site epidemiologic inspections were carried out. The source of the nosocomial infection proved to be a seropositive patient treated at the unit, who died before the outbreak was recognized. The exact date of the infection was determined.

Age-dependent parathormone levels and different CKD-MBD treatment practices of dialysis patients in Hungary--results from a nationwide clinical audit.

BACKGROUND: Achieving target levels of laboratory parameters of bone and mineral metabolism in chronic kidney disease (CKD) patients is important but also difficult in those living with end-stage kidney disease. This study aimed to determine if there are age-related differences in chronic kidney disease-mineral and bone disorder (CKD-MBD) characteristics, including treatment practice in Hungarian dialysis patients. METHODS: Data were collected retrospectively from a large cohort of dialysis patients in Hungary. Patients on hemodialysis and peritoneal dialysis were also included. The enrolled patients were allocated into two groups based on their age (<65 years and ≥65 years). Characteristics of the age groups and differences in disease-related (epidemiology, laboratory, and treatment practice) parameters between the groups were analyzed. RESULTS: A total of 5008 patients were included in the analysis and the mean age was 63.4±14.2 years. A total of 47.2% of patients were women, 32.8% had diabetes, and 11.4% were on peritoneal dialysis. Diabetes (37.9% vs 27.3%), bone disease (42.9% vs 34.1%), and soft tissue calcification (56.3% vs 44.7%) were more prevalent in the older group than the younger group (p<0.001 for all). We found an inverse relationship between age and parathyroid hormone (PTH) levels (p<0.001). Serum PTH levels were lower in patients with diabetes compared with those without diabetes below 80 years (p<0.001). Diabetes and age were independently associated with serum PTH levels (interaction: diabetes × age groups, p=0.138). Older patients were more likely than younger patients to achieve laboratory target ranges for each parameter (Ca: 66.9% vs 62.1%, p<0.001; PO4: 52.6% vs 49.2%, p<0.05; and PTH: 50.6% vs 46.6%, p<0.01), and for combined parameters (19.8% vs 15.8%, p<0.001). Older patients were less likely to receive related medication than younger patients (66.9% vs 79.7%, p<0.001). CONCLUSIONS: The achievement of laboratory target ranges for bone and mineral metabolism and clinical practice in CKD depends on the age of the patients. A greater proportion of older patients met target criteria and received less medication compared with younger patients.

Effect of hemodialysis session on the dynamics of carnitine ester profile changes in L-carnitine pretreated end-stage renal disease patients.

PURPOSE: Carnitine deficiency is common in end-stage renal disease (ESRD) patients receiving hemodialysis (HD) treatment. We investigated the effects of L-carnitine supplementation on acyl carnitine (AC) profile and the changes of distinct ACs during a single HD session in long-term L-carnitine pretreated ESRD patients. METHODS: Twenty non-diabetic adult patients and 37 healthy controls were studied. Blood samples were drawn before and after 12 weeks of carnitine supplementation, then hourly during an HD session, as well as 30 min after the end of the session. Free and individual AC plasma levels were determined by using ESI MS/MS technique. RESULTS: HD patients showed lower free- and total carnitine levels and elevated ACs and acyl/free carnitine ratio before carnitine supplementation. The L-carnitine supplementation resulted in dramatic elevation of all carnitine esters. The HD session induced a progressive decline in free, short-chain, and dicarboxylic ACs (~80 % of pre-HD amount was washed out); the decrease of medium-chain ACs proved to be more moderate (~60 % washed out), whereas the long-chain ACs remained unaffected. Already 30 min after HD, a substantial increase was seen in free carnitine concentration (reaching 26 % of predialysis level) and the ACs also started to replenish (to 21-52 % of predialysis levels), without further exogenous carnitine load. CONCLUSIONS: The washout induced by HD session results in variable depletion of short-, medium-, and long-chain carnitine esters in carnitine-pretreated patients; the recovery of the circulating carnitine esters from the body stores occurs within 30 min after the cessation of the HD procedure.

Dramatic decrease of carnitine esters after interruption of exogenous carnitine supply in hemodialysis patients.

L-carnitine supplementation is extensively used in patients on maintenance hemodialysis (HD) to improve dialysis-related clinical symptoms. In a series of studies, we investigated the dynamics of carnitine pool in carnitine-supplemented HD patients; here we report dramatic decrease with special changes of the ester profile due to interruption of the exogenous intake after the last HD session. Serum samples were collected from 18 L-carnitine-repleted end-stage renal disease (ESRD) patients before the L-carnitine supplementation, after completion of a carnitine supplementation period treatment (12 weeks, 1 g/IV/HD), right before the HD session, and 44 h after the dialysis. Levels of free carnitine (FC) and the individual esters were determined using electrospray MS/MS technique. Normally, L-carnitine supplementation causes significant elevation of all carnitine compounds to supraphysiological levels, which reaches a standard steady-state-like profile. In this study we found a dramatic decrease in the level of FC, and in short- and medium-chain acylcarnitines (ACs) 44 h after the last dialysis. At the end of this interdialytic period, FC levels increased to only 65% of the predialysis level, whereas the amounts of C2 and C3 esters recovered to only 50%. The level of C6 was 65% of the predialysis level, whereas the amount of C8 chain length ACs returned to 72% of the predialysis level. No significant change was seen in AC concentrations above C10 chain length. Omission of one single dosage of supplemental carnitine in long-term administration schemes results in dramatic decrease and reprofiling of carnitine esters even after the usual 44 h of interdialytic period.