Sułowicz W

Some Aspects of Cellular Immunity in Untreated and Maintenance Hemodialysis Patients

The cellular pattern of skin exudate in untreated uremic patients differed from that in healthy persons. The skin exudate composition in patients on maintenance hemodialysis approached normal values. Such normalization was, however, static: after sensitization with dinitrochlorobenzene--contrary to the control--both treated and untreated patients exhibited no changes in the cellular pattern of exudate. The activity of acid phosphatase in the cells of exudate was highly positive in control, almost normal in dialyzed, but weak in untreated uremic patients. Our investigations confirmed that cellular immunity in untreated and in maintenance hemodialysis patients is suppressed.

Effect of a hemodialysis session on plasma levels of endothelin-1 in hypertensive and normotensive subjects with end-stage renal failure.

Background: Elevated plasma endothelin-1 (ET-1) was found in end-stage renal failure (ESRF). However, there are discordant reports on the influence of hypertension on plasma ET-1 in ESRF and on the effect of hemodialysis on ET-1 concentrations. Aim: To compare the time course of plasma ET-1 during hemodialysis in hypertensive (HT) and normotensive (NT) ESRF patients. Methods: Plasma ET-1 and mean blood pressure (MP) were measured in 12 HT patients and 11 matched NT patients on maintenance hemodialysis at baseline (B), after a 2.5–3.5 h hemodialysis with ultrafiltration (P1) and after a subsequent 1 h isovolumic dialysis (P2). Results: In HT patients, plasma ET-1 increased at P1 with no further change after P2 (B vs. P1 and P2, p < 0.05). In NT patients, ET-1 levels were similar at B, P1 and P2. In HT, but not in NT subjects, volume loss correlated with change of ET-1 at P1. In HT patients, MP fell during P1 and tended to return towards baseline at P2. In NT patients, MP dropped after P1 and remained lower also at P2. Conclusion: Hypertensive ESRF subjects exhibit potentiated ET-1 release on hemodialysis, possibly stimulated by volume depletion with sympathetic activation, which may attenuate hypotensive hemodialysis effects thus contributing to hypertension in ESRF.

Relationship between aortic pulse wave velocity, selected proinflammatory cytokines, and vascular calcification parameters in peritoneal dialysis patients.

Introduction: Vascular calcification and arterial stiffening are cardiovascular risk factors among chronic kidney disease patients. Elevated aortic pulse wave velocity (AoPWV) is an independent predictor of increased cardiovascular morbidity and mortality. Objectives: The aim of the study was to analyze the relationships between inflammatory and vascular calcification parameters and arterial wall stiffness in chronic kidney disease (CKD) patients treated by peritoneal dialysis. Patients and methods: The study included 57 patients (27 women and 30 men) aged from 19 to 75 years (mean age 53 ± 13), treated by peritoneal dialysis during 4–100 months (mean 30.4 months). The concentrations of albumin, lipids, interleukin-6 (IL-6), IL-18, high-sensitive C-reactive protein, transforming growth factor-&bgr;1 (TGF-&bgr;1), osteocalcin, osteoprotegerin (OPG), fibroblast growth factor 23, fetuin A, parathyroid hormone (iPTH), total calcium (Ca), and phosphates (Pi) were measured. AoPWV was performed using a tonometric method, common carotid artery intima–media thickness (CCA-IMT) by ultrasonography evaluation, and calcium scoring (CaSc) with multirow spiral computed tomography (MSCT). Results: In univariate analysis, AoPWV correlated negatively with osteocalcin (R = −0.37; P = 0.005) and positively with OPG (R = 0.41; P = 0.002). Additionally, AoPWV was significantly positively associated with inflammatory parameters: IL-6 (R = 0.35; P = 0.009), TGF-&bgr;1 (R = 0.27; P = 0.047), and white blood cell (WBC) count (R = 0.33; P = 0.01). There were also positive correlations between AoPWV and imaging data: CCA-IMT (R = 0.32; P = 0.02) and CaSc (R = 0.38; P = 0.004). AoPWV did not correlate with calcium, phosphate, Ca × Pi index, or iPTH concentration. After multiple adjustments, osteocalcin was the only significant predictor of AoPWV. In logistic regression adjusted for age, hypertension, and mean arterial pressure at AoPWV evaluation, only osteocalcin was significantly associated with high (above median) AoPWV values [odds ratio 0.96 (0.92–0.99) per unit increase in osteocalcin]. Conclusion: OPG concentration and some inflammatory markers (WBC count, IL-6, TGF-&bgr;1) influenced the severity of arterial wall stiffness in CKD patients. Measurement of osteocalcin seems to be the best predictor of AoPWV.

Effect of Heparin and Prostacyclin/Heparin Infusion on Platelet Aggregation in Hemodialyzed Patients

The number of circulating platelet aggregates determined according to the method of Wu and Hoak and the platelet morphology revealed by scanning electron microscopy were investigated in 10 patients (8 males, 2 females) age 28-58 years) with end-stage renal failure treated by repeated hemodialysis. The examination was carried out twice: during a 4-hour hemodialysis session with the use of heparin alone and 1 week later during the course of another dialysis in the presence of both heparin and prostacyclin. During each dialysis session the platelet system was examined three times: prior to, after 90 min, and at the end of the procedure. As compared with the situation prior to dialysis, the number of platelet aggregates assessed after 90 min of dialysis and after its termination insignificantly rose following the treatment with heparin, but significantly fell after the use of the prostacyclin/heparin combination. The differences were also significant when the effects of both treatment types were compared. As revealed by scanning electron microscopy, during the course of hemodialysis with the use of heparin alone, the platelets showed signs of activation manifested by increases in number and length of cytoplasmic processes and by a tendency to aggregate. When both prostacyclin and heparin were used during dialysis, platelet activation was minimal or absent. Thus, the combined treatment with prostacyclin and heparin protects platelets from activation induced by their contact with artificial surfaces and may lower the risk of microthrombosis, making thereby hemodialysis safer and more effective.

Low-Sodium Versus Standard-Sodium Peritoneal Dialysis Solution in Hypertensive Patients: A Randomized Controlled Trial

BACKGROUND Peritoneal dialysis (PD) solutions with reduced sodium content may have advantages for hypertensive patients; however, they have lower osmolarity and solvent drag, so the achieved Kt/Vurea may be lower. Furthermore, the increased transperitoneal membrane sodium gradient can influence sodium balance with consequences for blood pressure (BP) control. STUDY DESIGN Prospective, randomized, double-blind clinical trial to prove the noninferiority of total weekly Kt/Vurea with low-sodium versus standard-sodium PD solution, with the lower confidence limit above the clinically accepted difference of -0.5. SETTING & PARTICIPANTS Hypertensive patients (≥ 1 antihypertensive drug, including diuretics, or office systolic BP ≥ 130 mmHg) on continuous ambulatory PD therapy from 17 sites. INTERVENTION 108 patients were randomly assigned (1:1) to 6-month treatments with either low-sodium (125 mmol/L of sodium; 1.5%, 2.3%, or 4.25% glucose; osmolarity, 338-491 mOsm/L) or standard-sodium (134 mmol/L of sodium; 1.5%, 2.3%, or 4.25% glucose; osmolarity, 356-509 mOsm/L) PD solution. OUTCOMES Primary end point: weekly total Kt/Vurea; secondary outcomes: BP control, safety, and tolerability. MEASUREMENTS Total Kt/Vurea was determined from 24-hour dialysate and urine collection; BP, by office measurement. RESULTS Total Kt/Vurea after 12 weeks was 2.53 ± 0.89 in the low-sodium group (n = 40) and 2.97 ± 1.58 in the control group (n = 42). The noninferiority of total Kt/Vurea could not be confirmed. There was no difference for peritoneal Kt/Vurea (1.70 ± 0.38 with low sodium, 1.77 ± 0.44 with standard sodium), but there was a difference in renal Kt/Vurea (0.83 ± 0.80 with low sodium, 1.20 ± 1.54 with standard sodium). Mean daily sodium removal with dialysate at week 12 was 1.188 g higher in the low-sodium group (P < 0.001). BP changed marginally with standard-sodium solution, but decreased with low-sodium PD solution, resulting in less antihypertensive medication. LIMITATIONS Broader variability of study population than anticipated, particularly regarding residual kidney function. CONCLUSIONS The noninferiority of the low-sodium PD solution for total Kt/Vurea could not be proved; however, it showed beneficial clinical effects on sodium removal and BP.

Vascular Effects of Advanced Glycation End-Products: Content of Immunohistochemically Detected AGEs in Radial Artery Samples as a Predictor for Arterial Calcification and Cardiovascular Risk in Asymptomatic Patients with Chronic Kidney Disease

Objectives. Our aim was to determine whether vascular deposition of advanced glycation end-products (AGEs) is associated with arterial calcification and cardiovascular mortality in chronic kidney disease (CKD) patients and to assess the relationships between vascular content of AGEs and selected clinical and biochemical parameters. Materials and Methods. The study comprised 54 CKD patients (33 hemodialyzed, 21 predialyzed). Examined parameters included BMI, incidence of diabetes, plasma fasting glucose, AGEs, soluble receptor for AGEs and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging, serum C-reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1), and fetuin-A. Fragments of radial artery obtained during creation of hemodialysis access were stained for calcifications using alizarin red. AGEs deposits were identified immunohistochemically and their relative content was quantified. Results. Vascular content of AGEs was positively correlated with BMI, hsCRP, fetuin-A, PAI-1, and DPPH scavenging in simple regression; only fetuin-A was an independent predictor in multiple regression. There was a significant positive trend in the intensity of AGEs immunostaining among patients with grades 1, 2, and 3 calcifications. AGEs immunostaining intensity predicted 3-year cardiovascular mortality irrespective of patients age. Conclusions. The present study demonstrates an involvement of AGEs in the development of medial arterial calcification and the impact of arterial AGE deposition on cardiovascular mortality in CKD patients.

Impaired Fasting Glucose and Diabetes as Predictors for Radial Artery Calcification in End Stage Renal Disease Patients

Objective. The objective of the study was to assess the relationship between selected clinical and biochemical parameters of end stage renal disease (ESRD) patients and arterial calcification. Materials and Methods. The study comprised 59 stage 5 chronic kidney disease patients (36 hemodialyzed and 23 predialysis). The examined parameters included common carotid artery intima-media thickness (CCA-IMT), BMI, incidence of diabetes and impaired fasting glucose (IFG), dyslipidemia, hypertension, and 3-year mortality. Plasma levels asymmetric dimethylarginine (ADMA), osteopontin (OPN), osteoprotegerin (OPG), and osteocalcin (OC) were also measured. Fragments of radial artery obtained during creation of hemodialysis access were stained for calcifications using von Kossa method and alizarin red. Results. Calcification of radial artery was significantly associated with higher prevalence of IFG and diabetes (P = 0.0004) and older age (P = 0.003), as well as higher OPG (P = 0.014) and ADMA concentrations (P = 0.022). Fasting glucose >5.6 mmol/l (IFG and diabetes) significantly predicted vascular calcification in multiple logistic regression. The calcification was also associated with higher CCA-IMT (P = 0.006) and mortality (P = 0.004; OR for death 5.39 [1.20–24.1] after adjustment for dialysis status and age). Conclusion. Combination of renal insufficiency and hyperglycemic conditions exerts a synergistic effect on vascular calcification and increases the risk of death.

Osteoprotegerin and osteoprotegerin/TRAIL ratio are associated with cardiovascular dysfunction and mortality among patients with renal failure

PURPOSE The high prevalence of cardiovascular morbidity and mortality among patients with chronic kidney disease (CKD) is observed especially in those undergoing dialysis. Osteoprotegerin (OPG) and its ligands, receptor activator of nuclear factor kappa-B ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have been associated with cardiovascular complications. Our aim was to study their role as cardiovascular risk factors in stage 5 CKD patients. PATIENTS AND METHODS OPG, RANKL and TRAIL concentrations were measured in 69 hemodialyzed CKD patients and 35 healthy volunteers. In CKD patients, cardiovascular dysfunction was assessed with aortic pulse wave velocity (AoPWV), carotid artery intima-media thickness (CCA-IMT), coronary artery calcium score (CACS) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum concentrations. Cardiovascular and overall mortality data were collected during a 7-years follow-up. RESULTS OPG plasma concentrations were higher in CKD patients comparing to controls. Total soluble RANKL was lower and OPG/RANKL ratio higher in patients. Soluble TRAIL concentrations did not differ between the groups and OPG/TRAIL ratio was higher in CKD patients. OPG and OPG/TRAIL positively predicted long-term mortality (all-cause and cardiovascular) in CKD patients. OPG positively correlated with AoPWV, CCA-IMT and NT-proBNP whereas OPG/TRAIL with AoPWV and NT-proBNP. Described relationships were independent of classical and non-classical cardiovascular risk factors, with exception of age. CONCLUSIONS Our study confirmed the role of OPG as a biomarker of cardiovascular dysfunction and a predictor of mortality in stage 5 CKD. OPG/TRAIL ratio can be proposed as a predictor of cardiovascular dysfunction and mortality.

Serum uromodulin concentrations correlate with glomerular filtration rate in patients with chronic kidney disease

INTRODUCTION Urinary uromodulin excretion has been associated with kidney diseases. However, serum uromodulin concentrations have not been extensively studied in patients with chronic kidney disease (CKD), and the results of published studies are inconsistent. OBJECTIVES The aims of the study were to evaluate serum uromodulin concentrations in patients with CKD and to assess the utility of serum uromodulin measurements for diagnosing CKD stages. PATIENTS AND METHODS This observational study included 170 patients with CKD stages 1 to 5, not treated by renal replacement therapy, and 30 healthy individuals. The serum levels of creatinine, cystatin C, and uromodulin were measured, and estimated glomerular filtration rate (eGFR) was calculated according to the 2012 CKD Epidemiology Collaboration cystatin‑creatinine equation. RESULTS Among patients with CKD, serum uromodulin concentrations were significantly lower than in controls, and were strongly negatively correlated with renal retention markers (ie, serum creatinine and cystatin C) and strongly positively correlated with eGFR. An inverse, hyperbolic relationship between serum creatinine and uromodulin levels was analogous to the well‑known association between serum creatinine concentrations and eGFR. A receiver‑operating characteristic curve analysis showed a high diagnostic accuracy of the measurement of serum uromodulin concentrations in the assessment of CKD stages. CONCLUSIONS Serum uromodulin concentrations are closely correlated with eGFR, which is the recommended measure of renal function. As uromodulin is produced exclusively by renal tubular cells, the assessment of uromodulin levels in patients with CKD may be an alternative method for evaluating the number of functioning nephrons.

Risk Stratification in Dialysis Patients: Coronary Artery Calcification Score Combined with High Sensitive C-Reactive Protein and Framingham Score for Cardiovascular Risk Prediction in Asymptomatic Subjects

Introduction: Vascular calcification independently predicts cardiovascular disease, the major cause of death in Chronic Kidney Disease (CKD) patients. Coronary Artery Calcium Score (CACS) is a marker for atherosclerotic plaque burden, vascular calcification and has been shown to be a predictor of incidence of myocardial infarction and death from Cardiovascular (CV) disease. Objectives: The aim of the study was to evaluate factors influencing CV mortality in a group of Peritoneal Dialysis (PD) patients during a six year observation period. Patients and methods: The study included 53 patients with no symptoms of CV disease (25 women, 28 men; mean age of 52 ± 12 years) treated with PD for a median period of 24 months. Baseline Framingham Risk Score (FRS) was assessed and CACS was measured using Multi-Row Spiral Computed Tomography (MSCT). Laboratory measurements included high sensitive C-reactive protein (hsCRP), osteoprotegerin (OPG), fibroblast growth factor 23 (FGF23), osteopontin (OPN), osteocalcin (OC), intact parathyroid hormone (iPTH), total calcium (Ca) and phosphates (Pi). The data concerning mortality was collected over a 6 year period. Results: During the six year observation period, 24 (45%) patients died, including 19 due to CV causes. Median overall survival was 72 months (lower quartile, 17 months). CACS was a significant predictor of all-cause and CV mortality both in simple analysis (HR=1.03 per 100 Agatston units, p=0.02 and HR=1.05, p=0.003), as well as in a multiple model adjusted for age of patients, dialysis duration, weekly creatinine clearance, Ca x Pi, iPTH, OPG, hsCRP and FRS (HR=1.04, p=0.02 and HR=1.05, p=0.01). The value of 800 Agatston units significantly differentiated the group into those with higher and lower risk for CV death (p=0.04). Age and FGF23 concentration were independent predictors of CACS. Also, hsCRP and FRS significantly predicted all-cause and CV mortality in simple Cox regression (HR=1.04, p=0.002 and HR=1.04, p=0.003; HR=1.14, p=0.047 and HR=1.23, p=0.01) as well as in a multiple model (HR=1.05, p=0.002 and HR=1.05, p=0.01; HR=1.23, p=0.01 and HR=1.33, p=0.004). Adding CACS to FRS and hsCRP significantly improved the prediction of cardiovascular mortality (p=0.02). Conclusions: Coronary calcium imaging is a non-invasive method of CV risk stratification that can accurately identify high-risk asymptomatic dialysis patients at the start of dialysis. The assessment of CACS together with inflammatory markers and conventional CV risk factors (FRS) may contribute to early diagnosis, prevention and reduction of deaths from CV disease in dialysis patients. Among the markers of bone disease, FGF-23 (a regulator of phosphorus metabolism) may be an early predictor of vascular calcification among dialysis patients.