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Background and Aim: Placental Growth Factor (PlGF) plays a crucial role in angiogenesis and was identified as a potential prognostic biomarker in various types of cancer. Therefore, we evaluated the diagnostic accuracy and prognostic value of PlGF serum concentration in patients with clear cell renal cell carcinoma (ccRCC). Patients and Methods: A total of 49 patients subjected to partial or radical nephrectomy for ccRCC [localized without relapse (lccRCC; n=31), localized with later relapse (rccRCC; n=8), primary metastatic cancer (mccRCC; n=10); median of follow-up 4.4 years] were enrolled in a prospective study to assess the significance of PlGF serum concentration. PlGF was measured prior to surgery and 3 months postoperatively. Our control group consisted of 38 healthy subjects. Results: PlGF serum concentration was significantly higher in ccRCC compared to controls (P=0.002). The cut-off value of PlGF concentration for the risk of ccRCC was determined at 12.71 pg/mL (AUC=0.729; P=0.0001). Prior to surgery, among ccRCC subgroups, significantly higher PlGF concentration was detected in mccRCC compared to lccRCC (P=0.002). Postoperatively, we observed a tendency to higher PlGF serum concentration in rccRCC compared to lccRCC subgroup, however without significance (P=0.17). The cut-off value for the risk of relapse was 11.41 pg/mL (AUC=0.792; P=0.0003). In subjects with localized ccRCC with PlGF concentration below 11.41 pg/mL 3-years cancer specific survival was 93% compared to 61% in subject with concentration above the cut-off value (P=0.018). Conclusion: Based on our findings, PlGF serum concentration seems to be a useful biomarker in diagnostics and prediction of prognosis in ccRCC.

Osteopontin (OPN) is an extracellular matrix glycoprotein that plays a role in a variety of cellular activities associated with inflammatory and fibrotic responses. Increased OPN levels in myocardium and plasma have been demonstrated in patients with dilated cardiomyopathy (DCM). However, nothing is known about OPN levels in patients with hypertrophic cardiomyopathy (HCM). Therefore, the aim of our study was to compare plasma OPN levels in patients with these two most common cardiomyopathies. We examined plasma OPN as well as creatinine, C‑reactive protein (CRP), brain-type natriuretic peptide (BNP), and troponin I levels in 64 patients with DCM, 43 patients with HCM, and 75 control subjects. Transthoracic echocardiography was also performed on all cardiomyopathy patients. Plasma OPN levels were significantly elevated in patients with DCM compared with HCM patients (95 ± 43 vs. 57 ± 21 ng/ml; p < 0.001) and control subjects (54 ± 19 ng/ml; p < 0.001); however, there was no difference between HCM patients and control subjects. New York Heart Association (NYHA) class III or IV disease was more frequently present in DCM patients than in HCM subjects (44 % vs. 2 %, p < 0.0001). In multivariate analysis, BNP and CRP levels together with NYHA class were found to be significant predictors of plasma OPN levels in DCM patients (p = 0.002, p = 0.029, and p < 0.001 for BNP, CRP, and NYHA, respectively). Plasma OPN levels were associated with overall heart failure severity rather than with specific cardiomyopathy subtype in patients suffering from DCM or HCM, respectively.

Background/aim Proteinase pregnancy-associated plasma protein A (PAPP-A) modulates the cell growth and carcinogenesis process. Its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to evaluate the significance of PAPP-A serum concentration in diagnosis, follow-up and prognosis of ccRCC patients. Materials and methods In a prospective study including 121 patients who underwent radical or partial nephrectomy for ccRCC [localized ccRCC without relapse (n=80), localized ccRCC with later relapse (n=26), primary metastatic cancer (n=15)] PAPP-A serum concentration was assessed preoperatively and in certain subgroups also postoperatively. Results PAPP-A serum concentration showed no statistically significant difference between ccRCC and controls and among ccRCC subgroups, respectively. Disease stage and Fuhrman's grade were not shown to affect PAPP-A concentration. The dynamics of postoperative PAPP-A concentrations did not reveal any significance and PAPP-A was not a prognostic factor for cancer related or overall survival. Conclusion PAPP-A serum concentration does not seem to be a useful biomarker in ccRCC.

Pregnancy associated plasma protein A2 (PAPP-A2) is a metalloproteinase that plays multiple roles in fetal development and post-natal growth. Here we present a novel surface plasmon resonance (SPR) biosensor for the rapid and quantitative detection of PAPP-A2 in blood samples. This biosensor uses a single surface referencing approach and a sandwich assay with functionalized gold nanoparticles for signal enhancement. We demonstrate that this SPR biosensor enables the detection of PAPP-A2 in 30 % blood plasma at levels as low as 3.6 ng/mL. We also characterize the performance of the biosensor and evaluate its cross-reactivity to a PAPP-A analogue. Finally, we utilize this SPR biosensor for the detection of PAPP-A2 in blood serum from two groups of subjects: pregnant women and healthy non-pregnant women and men. Graphical Abstract Temporal sensor response corresponding to respective steps of the assay for detection of PAPP-A2 in buffer.

BACKGROUND GDF-15 is a protein belonging to the transforming growth factor beta superfamily that has a role in regulating inflammatory and apoptotic pathways. High level GDF-15 in tumor tissues and plasma correlate with an increased risk of recurrence and reduced overall survival. OBJECTIVE The aim of this study was to screen GDF-15 capacity to detecting metastatic CRC and compare it with standard tumor markers CEA and CA19-9. METHODS We collected serum samples from 97 patients with metastatic colorectal cancer and 79 samples from healthy controls. Serum levels of GDF-15, CEA and CA19-9 were measured by immunochemically. A Kaplan-Meier curve was applied for analysis of survival rates, and a log-rank was used for univariate analysis. RESULTS Serum levels of GDF-15 were significantly higher in patients with colorectal cancer compared to healthy controls (p< 0.001). In addition, serum levels of GDF-15 correlated with extent of liver involvement and patients with higher GDF-15 levels had significantly worse outcome (p< 0.0001). CONCLUSIONS Our results show GDF-15 as an effective biomarker in patients with metastatic colorectal cancer with the same sensitivity as CEA. In addition, GDF-15 levels strongly correlate with extension of liver involvement in contrast with CEA.

Aim To assess the prognostic importance of serum levels of retinol, retinol-binding protein 4 (RBP4) and vitamin E at the time of diagnosis in patients with renal cell carcinoma (RCC). Patients and methods In this prospective study, in a cohort of 102 renal cell carcinoma patients, relationships between serum levels of the aforementioned markers and recurrence-free survival (RFS), overall survival (OS), as well as cancer-specific survival (CSS), were evaluated. The vitamin A and vitamin E levels were determined by high-performance liquid chromatography (HPLC), while the RBP4 level by enzyme-linked immunosorbent assay (ELISA). Results The median follow-up period was 39 months. Renal cell carcinoma recurred in 9 patients; 23 patients died with 12 of them from RCC. The preoperative vitamin E level was associated to RFS (p=0.02). We found a significant relationship between OS and the level of RBP4 (p=0.002), retinol (p=0.037) and vitamin E (p=0.007). The CSS period was significantly associated with the level of RBP4 (p=0.0001) and retinol (p=0.0003). Patients with an RBP4 level less than 21.0 mg/l at the time of diagnosis had a 13.5-times higher risk of death due to RCC progression; this risk was up to 7.7-times higher with vitamin A levels under 0.52 mg/l. Conclusion Low levels of vitamin A, E and RBP4 at the time of RCC diagnosis are associated with a poorer prognosis after surgery.

Endothelial activation and dysfunction may play a significant role in the progression of breast cancer. In our study we examined markers of endothelial activation (soluble ICAM-1, P-selectin, E-selectin) in 98 young patients with breast cancer (< 40 years). In 50 of them (and 20 age-matched controls) we also measured flow mediated vasodilation. Patients with breast cancer had significantly higher serum levels of soluble E-selectin, P-selectin and ICAM-1, P-selectin was higher in patients with larger tumors, node involvement and seemed to be apredictor of poor outcome. We were unable to find significant difference in the parameters of flow mediated vasodilation between patients with breast cancer and healthy subjects, although both peak blood flow (PBF) and flow mediated vasodilation (FMD) seemed to be skewed compared to healthy subjects toward mean and lower levels. Cluster analysis enabled us to distinguish several larger groups of patients with different degree of endothelial activation and function and different outcome. Group of patients with high E-selectin, high ICAM-1 (higher endothelial activation) and low VEGF (putative endothelial damage) had more frequently negative estrogen receptors and had worse outcome compared to the group of patients with lower E-selectin, lower ICAM-1 and mostly positive estrogen receptors. Further studies of larger groups of patients should help to identify the panel of endothelial markers which could help in predicting the outcome of young patients with breast cancer.

Objectives EN-RAGE is extracellular newly identified receptor for advanced glycation end-products binding protein playing a role in inflammation. The aim was to test the relationship of EN-RAGE to prognosis of long-term hemodialysis patients (HD). Design and methods This is a prospective observational cohort study in 261 HD patients followed up for five years. Laboratory parameters were measured at the beginning of the study. Results EN-RAGE was slightly but unsignificantly increased in HD patients compared with healthy controls and correlated significantly with inflammatory markers. Univariate Cox analysis demonstrated EN-RAGE as a significant predictor for mortality due to infection (HR (95%CI): 1.305 (1.063–1.602), per standard deviation, p = 0.01), but this significance disappeared in multivariate Cox analysis when CRP was included into the model. Conclusions Our study demonstrates EN-RAGE as an inflammatory biomarker. It is related to mortality of HD patients due to infection, but in our study, it did not provide additional information to CRP.

Background. Dialysis patients are at high risk of cardiovascular complications. Pregnancy-associated plasma protein A (PAPP-A) as well as sRAGE (soluble receptor for advanced glycation end products) are new biomarkers related to cardiovascular disease. The aim of our study was to describe their intra- and inter-individual variability. Methods. The studied group consisted of 21 chronic hemodialysis patients. PAPP-A, sRAGE and selected routine parameters were measured monthly during a 1-year prospective study. Results. Our results show high intra-individual variability of both PAPP-A and sRAGE. Both PAPP-A and sRAGE were closely linked to serum transferrin levels. Additionally, sRAGE was significantly associated with leukocyte count and haemoglobin. Conclusion. Our study demonstrates high intra-individual variability of PAPP-A and sRAGE in stable clinical status. This finding could be helpful for further evaluation of the significance of PAPP-A and sRAGE in chronic kidney disease.

The aim of the study was to investigate genetic and biochemical background of PAPP-A (pregnancy-associated plasma protein A) in patients with risk pregnancies.Five PAPP-A gene polymorphisms and PAPP-A maternal serum levels were studied together in 165 women in third trimester pregnancies complicated with threatening preterm labor (n=98), preeclampsia (n=35), intrauterine growth restriction (n=34) and ICP (intrahepatic cholestasis of pregnancy) (n=15). 114 healthy pregnant women served as controls.Preeclamptic patients had significantly higher frequency of TT genotype of Cys327Cys polymorphism compared to controls (p0.01). Patients with ICP had increased serum levels of PAPP-A compared to controls and correlation analysis showed significant relationship between PAPP-A and CRP (C-reactive protein) in the patients with intrauterine growth restriction (r=0.49, p=0.007).Our study indicates the association of TT genotype of Cys327Cys polymorphism of the PAPP-A gene with preeclampsia. However, further study with larger groups of preeclamptic patients is needed to confirm our results.

Background/Aims: Pregnancy-associated plasma protein A (PAPP-A) is a biomarker related to vascular damage. The aim of the study was to focus on PAPP-A and related parameters and their relationship to the prognosis of long-term hemodialysis (HD) patients. Methods: This is a prospective observational cohort study which included 261 long-term HD patients followed up for 5 years and 66 healthy subjects. PAPP-A, placental growth factor (PlGF), matrix metalloproteinase 2 and 9 (MMP-2, MMP-9), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein-4 (IGFBP-4), and cardiac, nutritional and inflammatory parameters were measured at the beginning of the study and tested as predictors of mortality. Results: PAPP-A, PlGF, IGF-1, IGFBP-4 and MMP-2 were significantly increased in HD patients compared to controls (PAPP-A 27.6 ± 15.5 mIU/l in HD vs. 9.4 ± 2.5 mIU/l in controls, p < 0.001). Increased PAPP-A was a significant independent predictor of overall mortality and mortality due to infection in the multivariate Cox analysis [HR (95% CI): 1.237 (1.060–1.444), p = 0.007, and 1.416 (1.115–1.798), p = 0.004, per standard deviation, respectively]. PAPP-A was not related to cardiovascular mortality. Conclusion: Increased PAPP-A is a significant independent predictor of overall mortality and mortality due to infection but it was not related to cardiovascular mortality in this study.

Advanced glycation end products (AGEs) are associated with cardiovascular diseases. Whether the AGE levels change during myocardial reperfusion injury is currently unknown. The aim of our study was to investigate the dynamics of AGEs in myocardial reperfusion injury and to discuss potential reasons for these changes. The dynamics of AGEs, pentosidine and neopterin in the plasma of patients with acute myocardial infarction (AMI) treated using thrombolysis (n = 40) were analyzed. In addition, AGEs were measured in patients with open heart surgery (n = 12) and rabbits with induced AMI (n = 9). In all three studies of myocardial reperfusion injury, a significant decrease of AGEs was observed (by 26 ± 19% in patients with AMI, by 23 ± 14% in patients with open heart surgery and by 39 ± 10% in rabbits with AMI within 1 day of reperfusion; p 0.05 in all studies). In additional studies, an association between lower AGEs and an activated immune system (R (2) = 0.09; p 0.01) and fasting (decrease by 38%; p 0.01) was shown. AGEs decrease in reperfusion injury of the heart. Indices pointing towards the involvement of immune system activation and fasting are presented. Further studies focusing on the underlying mechanism and on the clinical value of the observed dynamics of AGEs are needed.

Background: The calcium-binding protein S100A12 (EN-RAGE) causes inflammation through interaction with the multiligand receptor for advanced glycation end products (RAGE). The aim of the study was to determine S100A12 levels and describe their relationship to inflammatory markers in patients with decreased renal function. Methods: The studied group consisted of 46 patients with various degrees of chronic renal insufficiency (CHRI), 31 long-term hemodialysis (HD) patients and 24 healthy controls. S100A12 and soluble RAGE were assessed immunochemically (ELISA), and routine biochemical parameters were measured. Results: S100A12 levels were not different in CHRI (166 ± 140 ng/ml) and HD patients (127 ± 101 ng/ml) compared to controls (126 ± 106 ng/ml; p = 0.20, n.s.). In CHRI patients, S100A12 correlated with C-reactive protein (CRP) levels, orosomucoid, and inversely with α2-macroglobulin. In HD patients, S100A12 correlated with age, CRP, orosomucoid, fibrinogen and leukocyte levels. In multivariate regression analysis after adjustment for age, S100A12 levels remained correlated with: orosomucoid in CHRI patients; CRP, leukocytes, fibrinogen and negatively with sRAGE in HD patients; and leukocytes in controls. Conclusions: Although S100A12 levels were not elevated in patients with decreased kidney function, a relation to markers of inflammation was found. Further studies are required to demonstrate the significance of S100A12 in patients with decreased renal function.

Background: Diabetic retinopathy (DR) is characterized by blood-retina barrier breakdown induced by local changes in the retina and systemic factors. We investigated vitreous and serum levels of glucose and uric acid (UA) in patients with DR and aimed to describe their correlation with the grade of DR. Methods: Prospective study of 81 patients with DR and 48 non-diabetic controls. Biochemical analysis of vitreous and serum samples was performed. Results: UA and glucose concentrations in vitreous and serum were significantly higher in diabetic patients than in controls. Absolute ratios (vitreous level/serum level) of UA and glucose were higher in proliferative compared with non-proliferative DR. Conclusions: The results suggest that, apart from glucose, increased levels of UA in diabetic patients may also be involved in the pathogenesis and progression of DR.

Malnutrition, inflammation, and oxidative stress are inter-related mechanisms linked to the progression of cardiovascular disease and prognosis of long-term hemodialysis (HD) patients. In this study, we focus on antioxidant vitamins and trace elements and the relationship of their serum levels to the prognosis of long-term HD patients.Prospective observational cohort study.261 long-term HD patients prospectively followed up for 5 years (2003-2008). The control group consisted of 66 healthy participants.Retinol, alpha-tocopherol, retinol-binding protein 4 (RBP-4), and the trace elements zinc and selenium.Mortality and cardiovascular mortality. During follow-up, 146 patients (56%) died, and for 71 of these, death was due to cardiovascular causes.Retinol, alpha-tocopherol, RBP-4, zinc, selenium, and basic nutritional and inflammatory parameters measured at the beginning of the study.Retinol and RBP-4 levels were significantly increased, whereas retinol:RBP-4 ratio and alpha-tocopherol, selenium, and zinc levels were decreased in HD patients compared with controls (retinol, 168.1 +/ 64.4 microg/dL in HD patients vs 99.1 +/-23.3 [corrected] microg/dL in controls; P0.001). Lower retinol level was found to be a significant independent predictor of overall and cardiovascular mortality in multivariate Cox analysis (HR, 0.733 [95% CI, 0.599-0.896], P=0.002, and 0.694 [95% CI, 0.511-0.942], P=0.02, per 1 SD, respectively). The worst prognoses for patients with lower retinol levels were observed when these were combined with low albumin levels.Sample size, investigation of prevalent, not incident, dialysis patients.This is the first study showing a lower retinol level as an independent predictor of overall and cardiovascular mortality in HD patients. It has to be elucidated whether the beneficial effects of higher serum retinol levels should be attributed to only better nutritional support or also to retinol's role in immune response and differentiation.

The main objective was to examine the relationship between the soluble receptor for advanced glycation end products (sRAGE) and calprotectin concentrations in faeces and serum of patients with inflammatory bowel diseases (IBD) during biological treatment with infliximab.A total of 29 IBD patients treated with infliximab were evaluated. Calprotectin and sRAGE in serum and faeces and serum IL-6 and CRP were measured during the induction regimen of infliximab treatment at weeks (W) 0, 2 and 10.At W0, a significant increase in faecal calprotectin was found in IBD compared to healthy persons (690 +/- 696 microg/g and 23 +/- 7 microg/g, respectively, p0.001). No clear difference was found in serum sRAGE levels in IBD cohort compared to healthy controls (772 +/- 274 pg/mL and 720 +/- 107 pg/mL, respectively, p = 0.159); however, a significant negative correlation was found between faecal calprotectin levels and serum concentrations of sRAGE in the active IBD cohort (r = -0.518, p = 0.004). In the stool eluates, sRAGE levels were non-measurable. In the group of responders-to-treatment, the initial surge in both faecal and serum calprotectin levels as well as CRP and IL-6 was followed by a significant decrease on W10. Surprisingly, no significant changeovers were seen in serum sRAGE concentrations in responders neither in W2 nor in W10.Unlike other examined local and systemic inflammatory markers, serum sRAGE did not change during the infliximab treatment, despite the initial correlation with the degree of mucosal inflammation.

Objective The receptor for advanced glycation end products, RAGE, has been implicated in pathogenesis of many diseases. Soluble RAGE, sRAGE, extracellular domain of RAGE, is new biomarker. The aim of the study was to determine sRAGE levels in physiological pregnancy and their changes in pregnancies complicated by preterm labor or preeclampsia. Design and methods Serum levels of sRAGE were determined in 79 healthy pregnant women, 42 pregnant women in preterm labor or with preeclampsia and 24 non-pregnant controls. Results sRAGE serum levels are decreased in physiological pregnancy compared to healthy non-pregnant controls (p

Background: Advanced glycation end products (AGEs) belong to uremic toxins and some pathological effects of AGEs are linked to RAGE (receptor for AGEs). Their precursors are detoxified by the glyoxalase (GLO) system. The A419C (E111A) polymorphism of the GLO I gene is associated with vascular disease in hemodialysis (HD) patients and some RAGE gene polymorphisms are implicated in various pathological states. Aim: To study the relationship of A419C GLO I and four RAGE polymorphisms (–429T/C, –374T/A, 2184A/G and Gly82Ser) in the prognosis of HD patients. Methods: The group studied consisted of 214 chronic HD patients prospectively followed up for 43 months. 100 patients died, 48 due to cardiovascular causes. Results: The Kaplan-Meier analysis showed a higher mortality rate in patient-mutated homozygotes for RAGE –429CC, RAGE 2184GG and GLO I 419CC. A higher hazard risk was confirmed by the Cox proportional hazards model when wild-type homozygotes were taken as reference: RAGE –429CC 2.28 (95% CI 1.04–4.99), RAGE 2184GG 3.16 (95% CI 1.44–6.93), and GLO I 419CC 1.75 (95% CI 1.08–2.86). Both RAGE polymorphisms were also associated with cardiovascular mortality: RAGE –429CC 3.54 (95% CI 1.37–9.14) and RAGE 2184GG 5.04 (95% CI 1.93–13.11). Conclusion: In summary, our study shows for the first time a link between RAGE and GLO polymorphisms in the prognosis of HD patients.

Background: Cardiovascular disease caused by atherosclerosis remains a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD). We evaluated the potential association of cardiovascular risk factors including asymmetric dimethyl L-arginine (ADMA) and the soluble receptor for advanced glycation end products (sRAGE) with preclinical atherosclerosis in patients undergoing kidney transplantation. Patients and Methods: In 92 males and 47 females undergoing the first cadaveric renal transplantation, ADMA, sRAGE and common risk factors including lipid parameters were evaluated as potential predictors of preclinical atherosclerosis defined as the Belcaro score (focused on advanced atherosclerotic changes) measured by ultrasound. Results: The prevalence of atherosclerotic changes was approximately 70% in men and women. In logistic regression, age, history of smoking, presence of diabetes mellitus, and plasma triglycerides were the strongest independent predictors for advanced atherosclerosis in the whole group. In unadjusted analyses advanced atherosclerosis was also associated with sRAGE in men and with the atherogenic index of plasma in women. Conclusion: Apart from traditional cardiovascular risk factors, plasma triglycerides were found to be strong and independent predictors of advanced atherosclerosis in patients with ESRD. In addition, sRAGE was associated with atherosclerosis in men and the atherogenic index of plasma in women.

Objectives The purpose of this study was to assess whether low serum levels of fetuin-A are potential biochemical predictor of early and/or late survival in chronic hemodialysis (HD) patients. Design and methods We measured serum levels of fetuin-A in 67 patients on chronic HD, and correlated it to 3, 12, and 24 months mortality. Results Cumulative death rate was 7%, 19%, and 37% deaths at 3, 12, and 24 months. Serum fetuin-A was significantly lower in 3 months and 12 months non-survivals (p

Background: High cardiovascular risk in patients with chronic kidney disease (CKD) may be related to mineral disorder and microinflammation. Fibroblast growth factor 23 (FGF-23) is a phosphatonin and inhibitor of calcitriol synthesis, which is associated with poor prognosis in CKD patients starting dialysis. Matrix-metalloproteinases (MMP-2, MMP-9) contribute to myocardial remodeling and arterial calcification. FGF-23 and MMPs levels are altered in CKD, however, little is known about their association and relation to cardiovascular (CV) disease. Methods: Standard laboratory parameters, plasma levels of MMP-2, MMP-9, FGF-23, PAPP-A and CV disease history were assessed in 80 patients with CKD 1–5 and 44 healthy control subjects. Results: FGF-23 and MMP-2 (assessed by ELISA) were higher in CKD patients compared to controls. FGF-23 increased from CKD 3, whereas MMP-2 increased only in CKD 5. FGF-23 was positively associated with MMP-2, adjusted to age, eGFR, phosphatemia, calcitriol and parathormone. FGF-23 independently correlated with parathormone and inversely with calcitriol, whereas MMP-2 was related to phosphatemia. FGF-23 was higher in subjects with a history of CV disease compared to those free of such history (559.0 vs.184.0 RU/ml), adjusted to age and eGFR. Conclusion: Our data suggest a possible relationship between FGF-23, MMP-2 and CV disease in CKD. Potential causality of this association remains to be elucidated.

BACKGROUND During routine haemodialysis (HD) body temperature increases, which contributes to haemodynamic instability. The relative roles of increased heat production and/or incomplete heat transfer are not fully elucidated. Concomitant measurement of heat production and heat transfer may help to assess the factors determining thermal balance during HD. METHODS Thirteen stable non-diabetic maintenance HD patients were investigated during two HD procedures (isothermic, dT = 0, no change of body temperature; thermoneutral, dE = 0, no energy transfer between blood and dialysate), using a blood temperature monitor (BTM) in active mode. Energy transfer, blood and dialysate temperature, and relative blood volume change (dBV) were continuously recorded, and resting energy expenditure (REE; Deltatrac Datex) was measured repeatedly during each procedure. Fourteen healthy persons served as controls for REE comparison. RESULTS In isothermic HD, median energy removal was 218 kJ/4 h HD (= heat flow -15.1 W). This cooling correlated with dBV induced by ultrafiltration (rho = 0.731, P < 0.01). There was no difference in dBV between isothermic (7.7%) and thermoneutral (8.1%) HD. Predialysis REE was 82.8 W/1.73 m(2), not different from controls. No variation in REE during HD was observed, except a small and transient increase after a light meal (5 and 4%). In the time course of REE, no difference between the procedures was found. CONCLUSIONS Our findings suggest that stable maintenance HD patients have REE not different from healthy controls, that HD procedure per se does not significantly increase REE and that neither isothermic nor thermoneutral regimen has any influence on metabolic rate. Therefore, body temperature elevation during routine HD may rather be due to decreased heat removal. With the use of BTM in active mode, body temperature can be kept stable (isothermic HD), which requires active cooling. This negative energy transfer is proportional to decrease in blood volume induced by ultrafiltration.

Receptor for advanced glycation end products (RAGE) may be involved in the pathogenesis of the cancer progression and metastasis. Pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE), so the higher sRAGE levels may confer the patients with cancer with better outcome. The aim was to study sRAGE and RAGE gene polymorphisms in patients with breast cancer. The authors studied sRAGE and RAGE polymorphisms in 120 patients with breast cancer (subdivided based on the clinical stage, histologic grading, expression of hormonal and Her2/neu receptors) and in 92 healthy controls. Despite higher serum concentrations of AGEs, serum concentrations of sRAGE were lower in patients with breast cancer compared to healthy controls (1581 +/- 777 versus 1803 +/- 632 ng/mL, p < 0.05). Serum levels of sRAGE were higher in patients with advanced breast cancer (stage III), lower grade and positive estrogen receptors, and intermediate positivity of Her2/neu receptors and were also influenced genetically (Gly82Ser and 2184 AG polymorphisms of the RAGE gene). Decreased sRAGE levels in patients with breast cancer may contribute to the progression of the disease. Patients with better outcome (low grade and positive estrogen receptors) have higher sRAGE levels. Progression of the disease, may, however, increase sRAGE levels, possibly as a compensatory mechanism to counteract further progression.

Objective. This study was designed to evaluate vitamin D status with separate determination of 25-OH D2and 25-OH D3and its relationship to vitamin D binding protein (VDBP) in patients with chronic kidney disease (CKD) and long-term haemodialysis patients (HD).Methods. 45 CKD patients, 103 HD patients, and 25 controls (C) were included. Plasma vitamin D concentrations were determined using chromatography and VDBP in serum and urine in CKD using enzyme immunoassay.Results. Plasma vitamin D levels were lower in CKD (30.16 ± 16.74 ng/mL) and HD (18.85 ± 15.85 ng/mL) versus C (48.72 ± 18.35 ng/mL),P<0.0001. 25-OH D3was the dominant form of vitamin D. Serum VDBP was higher in CKD (273.2 ± 93.8 ug/mL) versus C (222 ± 87.6 ug/mL) and HD (213.8 ± 70.9 ug/mL),P=0.0003. Vitamin D/VDBP ratio was the highest in C and the lowest in HD; however, there was no correlation between vitamin D and VDBP. Urinary concentration of VDBP in CKD (0.25 ± 0.13 ug/mL) correlated with proteinuria(r=0.43,P=0.003).Conclusions. Plasma levels of vitamin D are decreased in CKD patients and especially in HD patients. 25-OH D3was the major form of vitamin D. Despite urinary losses of VDBP, CKD patients had higher serum VDBP concentrations, indicating compensatory enhanced production. Vitamin D binding protein is not involved in vitamin D deficiency.

Advanced glycation end products (AGEs) accumulate in patients with decreased renal function and exert various toxic effects through the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) is a naturally occurring inhibitor of AGE-RAGE action. The aim of the study is to describe the relationship of sRAGE to renal function and dialysis modalities.The studied group consisted of 81 patients: 25 patients with various degrees of decreased renal function, 20 long-term hemodialysis (HD) patients, 15 peritoneal dialysis (PD) patients, and 21 healthy age-matched subjects. sRAGE was assessed immunochemically (enzyme-linked immunosorbent assay), and routine biochemical parameters were measured by means of certified methods.sRAGE level correlates positively with serum creatinine concentration (r = 0.50; P0.05), and its relationship to creatinine clearance is hyperbolic. sRAGE levels are elevated significantly, mainly in patients with end-stage renal disease (3,119.0 +/- 968.4 pg/mL in HD patients and 3,652.7 +/- 1,677.7 pg/mL in PD patients versus 1,405.1 +/- 426.1 pg/mL in controls; both P0.001 versus controls). In PD patients, sRAGE is detectable in spent dialysate (median, 75.8 pg/mL), correlates with its serum levels (r = 0.67; P0.05), and is related to protein losses in dialysate. In HD patients, sRAGE levels increase by 50% (P0.001) from 0 to 15 minutes during both HD and hemodiafiltration, and then decrease until the end of the session.Serum sRAGE levels increase in patients with decreased renal function, mainly patients with end-stage renal disease. It remains to be elucidated whether the increase is caused just by decreased renal function or whether sRAGE is upregulated to protect against toxic effects of AGEs.

Bioincompatibility of hemodialysis (HD) membranes is responsible for neutrophil activation leading to oxidative stress, which can be further increased by intravenous (IV) iron (Fe) administration. The aim of our study was to monitor neutrophil respiratory burst during HD and to find out whether this process is influenced by IV Fe and oral vitamin E administration.Within four HD sessions, blood samples were taken from seven chronic HD patients at time 0 (before HD), 60, 70, and 130 min of HD session. Neutrophil respiratory burst was assessed by luminol-enhanced chemiluminescence (CL). Plasma advanced oxidation protein products (AOPP) concentration was measured spectrophotometrically. During the second and the fourth HD, 62.5 mg of sodium ferric gluconate was applied IV in the 65th minute of HD. Before the last two HD, the patients were given orally 200 mg of vitamin E daily for 7 days. Patient's results were compared with healthy controls.Predialysis CL is higher in patients than in controls (1,926 +/- 436 vs. 1,083 +/- 325 RLU, p.01). CL decreases in the 60th min of HD (1,926 +/- 436 vs. 1,220 +/- 599 RLU, p.05); thereafter, it remains stable. After Fe application, CL increases at time 130 compared with CL at time 60 (1,303 +/- 269 vs. 877 +/- 292 RLU, p.05). AOPP concentration is higher in patients than in controls (137.5 +/- 42.7 vs. 88.9 +/- 24.8 micromol/L, p.01) and remains unaffected by vitamin E supplementation. After vitamin E intake, predialysis CL remains significantly higher than in controls, and changes in CL during HD are minimal despite Fe administration.HD patients' neutrophils generate more oxygen radicals than in healthy individuals. This production decreases during HD and then increases after IV Fe administration. Short-term vitamin E administration attenuates this fluctuation of neutrophil oxidative metabolism, without affecting the total degree of oxidative stress.

Background: The aim of the study was to determine pregnancy-associated plasma protein-A (PAPP-A), which was recently described as a new marker of cardiovascular events, in patients with chronic renal insufficiency/failure and to find out its relationship to renal function and to prominent markers of oxidative stress (advanced oxidation protein products – AOPP) and inflammation (C-reactive protein – CRP). Methods: The studied group consisted of 36 chronic hemodialysis patients (HD), 10 patients treated with continuous ambulatory peritoneal dialysis (CAPD) and 38 patients with chronic renal insufficiency (CHRI) not yet dialyzed. PAPP-A was measured by Time Resolved Amplified Cryptate Emission technology. Determination of AOPP is based on a spectrophotometric method. Results: PAPP-A levels are statistically significantly elevated in the both groups of dialyzed patients in comparison with healthy subjects (27.0 ± 16.5 mIU/l in HD and 14.07 ± 6.73 mIU/l in CAPD vs. 8.22 ± 2.7 mIU/l in the control group, p < 0.0001 and p < 0.001, respectively, p < 0.05 HD vs. CAPD). The mean serum PAPP-A levels in the CHRI patients not yet dialyzed were not significantly higher in comparison with the control group (9.72 ±4.44 vs. 8.22 ± 2.7 mIU/l, n.s.). In the CHRI not dialyzed patients, we found a significant positive correlation between serum creatinine and PAPP-A levels (r = 0.68, p < 0.05). In comparison with controls, AOPP and CRP levels were significantly higher in HD patients [AOPP 155.0 ± 37.9 µmol/l, p < 0.0001 vs. controls, CRP 10.0 (4.6– 26.9) mg/l (median, interquartile range), p < 0.0001 vs. controls], CAPD patients [AOPP 118.5 ± 25.8 µmol/l, p < 0.0001 vs. controls, CRP 7.7 (2.0–18.8) mg/l, p < 0.01 vs. controls] and AOPP levels in chronic renal failure patients not yet dialyzed (98.5 ± 43.24 µmol/l, p < 0.01 vs. controls). The correlations between PAPP-A and AOPP (r = 0.49, p < 0.05) and PAPP-A and CRP (r = 0.48, p < 0.05) serum concentration were statistically significant in HD patients. In CAPD patients, neither a correlation between PAPP-A and AOPP nor a correlation between PAPP-A and CRP were found. Conclusion: We can conclude that serum PAPP-A levels sensitively reflect the changes in renal function, depend on dialysis modality, and may represent a novel marker associated with inflammation and oxidative stress in chronic renal failure patients.

Objectives: To determine the combination of urinary protein markers for noninvasive detection of primary and recurrent urothelial bladder carcinomas. Methods: Urinary concentrations of 27 biomarkers (NSE, ATT, AFABP, Resistin, Midkine, Clusterin, Uromodulin, ZAG2, HSP27, HSP 60, NCAM1/CD56, Angiogenin, Calreticulin, Chromogranin A, CEACAM1, CXCL1, IL13Ra2, Progranulin, VEGFA, CarbAnhydIX, Annexin-V, TIM4, Galectin1, Cystatin B, Synuclein G, ApoA1 and ApoA2) were assessed by enzyme-linked immunosorbent assay or by electrochemiluminiscence immunoassay. Results: During the primary diagnostics, a group of 70 patients with primary occurrence of bladder cancer and 49 healthy control subjects were compared. For this clinical situation, the most accurate combination proved to be the combination of cytology with markers Midkine and Synuclein G (sensitivity 91.8%, specificity 97.5%). During the monitoring of patients with non-muscle invasive bladder cancer (NMIBC), a group of 44 patients with cancer recurrence was compared with the group of 61 patients with a history of NMIBC without current disease. For this clinical situation, the most accurate combination proved to be the combination of cytology and erythrocytes count in urine sediment with markers Midkine, ZAG2, CEACAM1, and Synuclein G (sensitivity 92.68%, specificity 90.16%). A lower accuracy of the diagnostic panel and the necessity to use more markers in the case of recurrence was connected with a different structure of patients. Conclusions: Multi-marker test can significantly improve the bladder cancer detection both during the primary diagnostics and monitoring of patients with NMIBC. This outcome should result in other, larger studies.

Intraperitoneal glucose degradation products (GDP) load influences systemic advanced glycation end products (AGEs) but the effects on soluble receptor for AGEs (s-RAGE) and its proinflammatory ligands: extracellular newly identified receptor for advanced glycation end-products binding protein(EN-RAGE) and high mobility group box-1 protein (HMGB-1) are unknown. We aimed to compare plasma and peritoneal s-RAGE, EN-RAGE and HMGB-1 between three peritoneal dialysis (PD) prescription regimens with different intraperitoneal GDP loads. High GDP load (glucose-lactate PD fluid, D; N = 8) was compared with a low (glucose-bicarbonate/lactate with icodextrin for overnight dwell, E; N = 9) and a very low GDP load (glucose-bicarbonate/lactate, P; N = 16). D group demonstrated higher plasma EN-RAGE, 77.8 ng/mL, vs. both E, 11.2, P 0.001 and P, 27.0, P 0.001 as well as higher plasma HMGB-1, 2.2 ng/mL vs. both E, 1.1, P 0.01 and P, 1.5, P 0.01. Plasma s-RAGE, which did not differ between D, E and P, correlated with its effluent levels. Patients with faster peritoneal transport (D/Pcr0.65) tended to have higher plasma s-RAGE compared to slow transporters (2300 vs. 1762 pg/mL, P = 0.056). Peritoneal clearance of s-RAGE and EN-RAGE was higher with E compared to both D and P (P 0.001 resp. P 0.01). Subgroup of PD patients with CRP above median demonstrated higher plasma HMGB-1 and EN-RAGE, P 0.05 for both. A lower intraperitoneal GDP load is associated with decreased plasma levels of EN-RAGE and HMGB-1. Peritoneal transport, microinflammation and the capability of icodextrin to increase peritoneal clearance of middle molecular weight substances might also exert an effect on plasma s-RAGE and its proinflammatory ligands levels.

Pregnancy-associated plasma protein A (PAPP-A) is a key regulator of insulin-like growth factor bioavailability essential for normal fetal development. In maternal blood, this protein increases with gestational age and then rapidly decreases after delivery. It is routinely used for Down syndrome screening in the first trimester of pregnancy, and its decrease compared to a normal pregnancy indicates an increased risk for both chromosomal anomalies and adverse pregnancy outcomes. It belongs to a group of biomarkers that predict later preeclampsia development, primarily early onset preeclampsia; however, it should be combined with a Doppler ultrasonography of the uterine artery (pulsatile index) and other biochemical and maternal factors to achieve a higher detection rate with an acceptable false positivity rate. Some studies have demonstrated an even more pronounced decrease of PAPP-A in the early second trimester of pregnancy in women who subsequently develop preeclampsia compared with women who do not develop preeclampsia. Conversely, during the last trimester of pregnancy, its concentration increases even more in patients with preeclampsia than in patients without. It is also detectable at very low levels in nonpregnant individuals, and a higher concentration indicates an adverse effect in patients with acute coronary syndromes or stable atherosclerotic disease and in patients with end-stage renal disease who are being treated with hemodialysis.

Recent discoveries suggest that T-regulatory lymphocytes (Treg) might play an important role in the pathophysiology of preterm labor. The aim of this study was to assess the relationship among the levels of maternal circulating Treg cells, uterine cervical length, and the risk of preterm labor. Sixty women with regular contractions and/or cervical incompetence at 24-32 weeks' gestation were recruited into a prospective study. Each patient underwent transvaginal ultrasound examination of the cervical length, and regulatory T cells were quantified in peripheral blood samples by flow cytometry. Patients with cervical incompetence were prescribed vaginal progesterone until birth. Measurements of Treg levels and cervical length correlated with the timing of labor. The risk of preterm labor happening within 48 h of testing was demonstrated to be almost 35 times higher (OR=35.21, CI 13.3; 214, p0.001) in the group with simultaneously low Treg values (0.031 × 10(9)/L) and a shortened uterine cervix (17.5mm), compared with the situation where both of these values were normal. Similar results were found in predicting preterm delivery before 34 weeks, or between 34 and 37 weeks. A statistically nonsignificant trend toward increased cervical length and increased Treg count was noted in the women on progesterone treatment. We show for the first time that the combined assessment of Treg cell count and cervical length is a much better predictor of preterm delivery than either parameter used on its own. This combined approach may offer clinical application in patients who present with risk factors for preterm labor.

Objective Pregnancy-associated plasma protein A (PAPP-A) has prognostic impact in pregnancy and acute coronary syndrome. Patients with chronic kidney disease have an excessive cardiovascular risk. In an effort to identify novel risk factors for cardiovascular disease, we investigated the relationship of PAPP-A with specific outcomes in diabetic patients undergoing dialysis. Methods PAPP-A was measured in 1098 diabetic hemodialysis patients, who participated in the German Diabetes and Dialysis Study and followed-up for a median of 4 years. By Cox regression analysis, we assessed the association of baseline levels of PAPP-A with all-cause mortality, combined cardiovascular events and the specific outcomes of sudden death, stroke, myocardial infarction and infectious mortality. Results Patients had a mean age of 66 ± 8 years (54% male) and median PAPP-A concentration of 17 mIU/L (IQR 13.4–20.9 mIU/L). Per standard deviation increase in PAPP-A the adjusted risk of sudden cardiac death increased by 23% (HR 1.23, 95%CI 1.12–1.36). Categorical analyses showed that the patients in the 4th PAPP-A quartile had an adjusted 2.6 fold increased risk of sudden death and 2.8 fold increased risk of stroke as compared to the patients in the 1st quartile. Similarly, the risk of combined cardiovascular events was significantly elevated by the factor 1.5 in patients of the 4th quartile. Additionally, PAPP-A levels were associated with infectious deaths and all-cause mortality. Conclusions PAPP-A is associated with sudden death, stroke and infectious complications in diabetic dialysis patients. PAPP-A may be useful for risk assessment and monitoring in populations at high risk of cardiovascular events.

Background Placental growth factor [PlGF) is a cardiovascular (CV) risk marker, which is related to left ventricle hypertrophy (LVH) in animal models. Currently there are no data available regarding the possible relationship of PlGF and the development of LVH or diastolic dysfunction in patients with chronic kidney disease (CKD) and the relationship of PlGF to other CV risk factors in CKD patients. The aim of our study was to determine the possible association of PlGF and several other CV risk markers to echocardiographic parameters in CKD population. Methods We prospectively examined selected laboratory (PlGF, fibroblast growth factor-23 -FGF23, vitamin D, parathyroid hormone, extracellular newly identified RAGE-binding protein - EN-RAGE, B-type natriuretic peptide - BNP) and echocardiographic parameters in 62 patients with CKD 2–4. Mean follow-up was 36 ±10 months. Laboratory and echocardiographic data were collected 2–3 times, at the shortest interval of 12 months apart. Multivariate regression analysis was used to detect independent correlations of variables. Results Increased left ventricular mass index (LVMI, g/m2.7) was found in 29% patients with CKD 2–4, left ventricular (LV) diastolic dysfunction was detected in 74.1% patients (impaired LV relaxation in 43.5% patients and pseudonormal pattern in 30.6% patients). After 36 ± 10 months increased LVMI was found in 37.1% patients with CKD 2–4, LV diastolic dysfunction was detected in 75.8% patients (impaired LV relaxation in 43.5% patients and pseudonormal pattern in 32.3% patients). Following independent correlations were found: LVMI was related to PlGF, cholesterol, BNP, systolic blood pressure and serum creatinine. EN-RAGE correlated positively with left atrial diameter and inversely with E/A ratio. During the follow-up we found a significant increase in LVMI and left atrial diameter, whereas a significant decrease in LVEF was noted. Conclusion According to our data, PlGF is independently related to increased LV mass in CKD, whereas EN-RAGE is more likely related to diastolic dysfunction in this population.

Matrix metalloproteinase-2 (MMP-2) and pregnancy-associated plasma protein-A (PAPP-A) have been implicated in chronic kidney disease (CKD) and cardiovascular disease (CVD). However, the serum determinants of MMP-2 and PAPP-A in CKD are unknown. The aim of the present study is to evaluate the clinical significance of MMP-2 and PAPP-A and their determinants in patients with CKD.The studied group consisted of 203 subjects: 159 patients with chronic kidney disease stages 1 - 5 (CKD 1 - 5), and 44 healthy control subjects. MMP-2 levels were assessed immunochemically using ELISA (enzyme linked immunosorbent assay), PAPP-A levels were determined immunochemically with TRACE (time-resolved amplified cryptate emission), and routine biochemical parameters were measured using standard methods.Compared with healthy controls, CKD patients (3 - 5) had no significant changes in MMP-2 levels. MMP-2 levels (195 +/- 76 vs. 255 +/- 77 ng/mL, p0.0001) were significantly lower in CKD patients (1 - 2) and PAPP-A levels (12.1 +/- 8.5 vs. 9.3 +/- 2.2 mIU/L, p = 0.001) were significantly higher in CKD 4 compared to control subjects. Multivariate analysis revealed that PAPP-A (p0.0001), proteinuria (p = 0.002), alpha-2-macroglobulin (p = 0.01), and negatively albumin (p = 0.02) and haemoglobin (p = 0.0002), were independent correlates of MMP-2 after adjustment for age and glomerular filtration rate. Proteinuria (p = 0.02), creatinine (p0.0001), and negatively albumin (p = 0.01), were independent correlates of PAPP-A adjusted for age and glomerular filtration rate.The present study demonstrated that serum MMP-2 and PAPP-A were independent correlates of proteinuria, albumin, and other examined parameters. Our results suggest the possibility that circulating MMP-2 and PAPP-A be used as indicators for renal damage in CKD patients on conservative treatment.

To assess levels of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) in follicular fluids and sera of female patients undergoing in vitro fertilization (IVF) treatment, and discover the role of MMPs in IVF outcome prediction.Sera and follicular fluids were obtained from 58 female patients treated for infertility by IVF. Twenty-nine of them became pregnant after the embryo-transfer; another 29 were not successful in IVF and did not conceive. Forty female non-pregnant blood donors and 38 healthy pregnant patients in the first trimester after the physiological conception were examined as control groups. MMP-2 and MMP-9 were quantitively assessed using enzyme-linked immunosorbent assay.IVF females successfully conceiving after the IVF have shown the highest MMP-9 concentrations in sera (833.5 {686.0;958.7} ng/mL) and follicular fluids (9.6 {6.0; 17.0} ng/mL) compared to all other examined cohorts. Different behavior of MMP-2 and MMP-9 during the artificial ovulation was confirmed, because only MMP-9 has shown a vast difference between serum and follicular concentrations.MMP-9 could be a good predictor of the successful IVF outcome (pregnancy), which was proven for serum as well as follicular MMP-9 levels.

Background: Specific changes and imbalanced con- centrations of matrix metalloproteinases (MMPs) and pregnancy-associated plasma protein-A (PAPP-A) may reflect the pathophysiology of various nephropa- thies (GN). We compared MMP-2, MMP-9 and PAPP-A levels in patients with GN, with those found in healthy controls. Methods: We studied 45 controls and 128 patients with GN, defined by kidney biopsy: IgA nephropathy (IgAN, n=33), membranous glomerulonephritis (MN, n=23), minimal change nephrotic syndrome (MCNS, n=7), focal segmental glomerular sclerosis (FSGS, n=11), lupus nephritis (LN, n=22) and ANCA-associated glo- merulonephritis (AAV, n=32). MMP-2 and MMP-9 levels were assessed using enzyme-linked immunosorbent assay; PAPP-A levels were determined with time-re- solved amplified cryptate emission, and routine bio- chemical parameters were measured. Results: Compared with controls, IgAN patients ex- hibited a significant decrease in levels of MMP-2 contrasted with increased MMP-9 and unchanged PAPP-A levels. LN patients exhibited a parallel de- crease in MMP-2, MMP-9 and PAPP-A levels. In the MCNS/FSGS and AAV patients, MMP-2, MMP-9 and PAPP-A levels were unchanged. In MN patients, in- creased MMP-9 levels contrasted with unchanged MMP-2 and PAPP-A levels (all p

Objectives The aim of the study was to analyze polymorphisms of receptor for advanced glycation end products (RAGE) gene, and glyoxalase I gene and soluble RAGE, sRAGE, in physiological and pathological pregnancy. Design and methods Polymorphisms of RAGE gene (− 429 T/C, − 374 T/A, 557 G/A, 2184 A/G) and glyoxalase I gene (A419C) and sRAGE serum levels were determined in 284 women with pathological and physiological pregnancy. Results No differences in distribution of genotype and allelic frequencies of studied polymorphisms were found. GA genotype of RAGE 557 G/A polymorphism (known as Gly82Ser) is associated with lower sRAGE serum levels in healthy pregnant women compared to GG genotype (483 ± 104 vs. 692 ± 262 pg/mL, p = 0.008). sRAGE correlates negatively with ALT in patients with pregnancy intrahepatic cholestasis (r = − 0.536, p = 0.05). Conclusions We did not show any association of RAGE and glyoxalase I gene polymorphisms with pathological pregnancy, however further studies are needed to confirm the results.

Pregnancy-associated plasma protein A (PAPP-A) is a biomarker routinely used in screening for Down syndrome in the first trimester of pregnancy. It is also present in very small amounts in men and non-pregnant women. PAPP-A is a key regulator of local insulin-like growth factor (IGF) bioavailability – IGFs are essential for normal body size during fetal development, but they are associated with aging and age-related diseases. Measurement of circulating PAPP-A can provide valuable information not only in pregnant women (chromosomal anomalies and adverse pregnancy outcomes) but also in patients with coronary artery disease (contribution to diagnosis, prognostic value) and in patients with kidney diseases. PAPP-A is associated with renal function and proteinuria, is increased mainly in dialysis patients and decreases after kidney transplantation. It is an independent mortality predictor of hemodialysis patients and indicator of adverse outcome of transplanted patients. PAPP-A levels can be influenced by various chemicals and drugs, among them mainly heparin. Various assays for PAPP-A exist and the type of assay used in a study should be considered. This article reviews the data summarizing basic information about PAPP-A with a particular focus on the significance of PAPP-A in renal diseases.

To analyze the relation of the fertility and pregnancy of women of childbearing age to the intracellular (IC) production of tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and interleukins 2 and 4 (IL-2 and IL-4).Intracellular cytokine production in peripheral blood CD3(+) CD4(+) lymphocytes was analyzed by flow cytometry in 185 women being treated for infertility and 50 fertile women of childbearing age. Infertile women have a significantly higher IC production of TNF-α, IFN-γ, IL-2, and IL-4 and higher ratios of TNF-α/IL-2, TNF-α/IL-4, and TNF-α/IFN-γ compared to the fertile women.Cytokines produced by Th lymphocytes are important in orchestrating the immune response during conception, and Th-cell dysregulation could be a reason for infertility.

Advanced glycation end product (AGE) levels are elevated in patients with decreased renal function and may contribute to the excessive cardiovascular disease in this population. However, their relation to nutrition, anemia, and micro inflammation is not well characterized. The aim of this study is to determine their relationship in patients with chronic kidney disease (CKD).The studied group consisted of 203 subjects: 159 patients with CKD 1-5 and 44 healthy control subjects. AGE levels were assessed by spectrofluorimetry, and routine biochemical parameters were measured using standard methods.AGE levels were significantly increased in CKD patients compared with controls (3.9 ± 1.7 × 105 AU in CKD 1-5 patients vs. 3.2 ± 0.48 × 105 AU in controls, p0.0001). AGE levels increased from CKD 3. AGE levels were positively associated with age, albumin, prealbumin, and orosomucoid, and were negatively associated with hemoglobin and estimated glomerular filtration rate. In multiple regression analysis, after adjustment to age and glomerular filtration rate, AGE levels remained independently correlated with albumin and prealbumin and negatively correlated with hemoglobin.This study is the demonstration that nutrition markers, albumin and prealbumin, are the positive determinants and hemoglobin is the negative determinant of serum AGE levels in patients with CKD.

To investigate inflammatory processes during ovarian hyperstimulation, we have studied the soluble receptor for advanced glycation end products (sRAGE) levels in sera and follicular fluids of women undergoing in vitro fertilisation (IVF) cycle.A total of thirty-three women undergoing IVF treatment were recruited, the number of follicles in investigated IVF cycles was 18 +/- 10 (mean +/- SD), oocytes 12 +/- 8, and the clinical pregnancy rate was 42% (14/33). The control group of serum samples was comprised of 35 healthy female blood donors. Sera and follicular fluids were examined for sRAGE levels by enzyme-linked immunosorbent assay (sRAGE ELISA, Quantikine, RD Systems).Serum levels of sRAGE in women after ovarian hyperstimulation and induction of ovulation (1039 +/- 493 pg/mL) were significantly lower than in healthy blood donors (1535 +/- 438 pg/mL), p = 0.045. Follicular sRAGE levels (4355 +/- 1100 pg/mL) were significantly higher than serum levels (1039 +/- 493 pg/ml), p0.001. Serum sRAGE levels showed significant negative correlation with the number of stimulated follicles (r = -0.71, p = 0.01) and retrieved oocytes (r = -0.54, p = 0.048). Women who successfully conceived after the IVF showed significantly higher sRAGE levels in follicular fluid (4595 +/- 925 pg/mL) compared to women who did not conceive (3986 +/- 806 pg/mL), p = 0.031.Concentration of sRAGE in follicular fluid is several-fold higher compared to serum and most other biological fluids investigated until this time. It supports the hypothesis that mammalian ovulation can be compared to an inflammatory event. A significant negative correlation of serum sRAGE with the yield of follicles and oocytes, together with the high follicular sRAGE levels, in particular in women who conceive after the IVF, could be explained by the essential outflow of sRAGE to the follicular compartment.

Objectives: To assess the relationship between maternal and umbilical serum concentrations of matrix metalloproteinases (MMP)-2,8,9, the soluble receptor for advanced glycation end products (sRAGE) and IL-10 0 and premature delivery and fetal inflammation. Methods: Maternal serum levels of MMPs, sRAGE, IL-10 and C-reactive protein (CRP) were determined in 67 women with preterm labor and in 38 healthy pregnant women of similar gestational age (GA). In the group with preterm labor we also determined umbilical concentrations of MMPs, IL-6 and sRAGE. The group with preterm labor was additionally divided based on the presence of funisitis and elevations of fetal umbilical IL-6 concentrations. Results: Maternal serum levels of MMP-2 and sRAGE were significantly lower in women with preterm labor compared to women with normal pregnancy. Additionally, within the group of women with preterm labor, maternal serum MMP-2 concentrations were significantly lower in the subgroup with funisitis and in the subgroup with elevated umbilical concentration of IL-6. Conclusion: Our results demonstrate significantly different serum concentrations of MMP-2 and sRAGE in women with preterm labor compared to healthy pregnant patients of the same GA.

Cardiovascular mortality in hemodialysis (HD) patients remains high despite improvements in HD technique such as dialysis adequacy, dialysis fluid purity, and membrane biocompatibility. Optimal fluid balance to maintain optimal hemodynamic stability during hemodialysis (HD) procedure is essential. At the present time, hemodynamic stability is conventionally assessed as stability of macrocirculation, especially as maintenance of systemic blood pressure with no attention paid to peripheral perfusion. Peripheral ischemic vascular disease represents a serious problem with high mortality and morbidity. We estimated skin microcirculation changes during HD using new device, Laser Doppler Line Scanner (Moor Instruments, Devon, UK).The aims were to introduce the novel method of detection of skin perfusion changes during hemodialysis and to evaluate possible relationship of these to ultrafiltration as well as to selected biochemical characteristics.In 36 hemodynamically stable patients, we performed paired measurements of skin blood flow in both hands before and during HD with registering the time of dialysis and the total ultrafiltration achieved.We found a significant decrease in a majority of the evaluated areas. However, the skin blood flow change was not homogenous as it decreased more on the fingers.To our knowledge, this is the first study when the microcirculatory changes during hemodialysis are demonstrated and evaluated in large skin surface area, and showing not only a decrease in a majority of areas but also the heterogeneity of the changes.

The receptor for advanced glycation end-products (RAGE) takes part in the pathogenesis of many diseases, including diabetes mellitus and cancer. AGE-precursors are detoxified by glyoxalase (GLO). sRAGE, soluble RAGE, is an inhibitor of pathological effects mediated via RAGE. The aim was to study sRAGE and polymorphisms of RAGE (AGER) and GLO genes in patients with pancreas cancer (PC).The studied group consisted of 51 patients with PC (34 with impaired glucose tolerance-IGT, 17 without IGT), 34 type 2 DM and 154 controls. For genetic analysis, the number of patients was increased to 170. Serum sRAGE was measured by ELISA and all polymorphisms (RAGE -429T/C, -374T/A, 2184A/G, Gly82Ser and GLO A419C) were determined by PCR-RFLP and confirmed by sequencing.Soluble RAGE is decreased in patients with PC compared to patients with DM and controls (975+/-532 vs. 1416+/-868 vs. 1723+/-643pg/mL, p0.001). Patients with PC and IGT have lower sRAGE levels compared to patients with PC without IGT (886+/-470 vs. 1153+/-616pg/mL, p0.05). No relationship of sRAGE to the stage was found. We did not show any difference in allelic and genotype frequencies in all RAGE and GLO polymorphisms among the studied groups.This is the first study demonstrating decreased sRAGE in patients with pancreas cancer. Its levels are even lower than in diabetics and are lowest in patients with PC and IGT. Our study supports the role of glucose metabolism disorder in cancerogenesis. Further studies are clearly warranted, especially with respect to potential preventive and therapeutic implications.

Objective Levels of high-density lipoprotein (HDL) cholesterol as well as its functional roles are suppressed in chronic kidney disease because of ongoing chronic microinflammatory state. We hypothesized that intervention aimed at reducing inflammation may improve the levels and activity of HDL cholesterol as well as survival of our patients. Methods In this prospective follow-up study, we selected 67 patients (33 women, 34 men) on chronic hemodialysis (23.5 months [range, 10 to 34], aged 67.5 years [range, 39 to 90 years]). Targeted examination for asymptomatic infective foci or poor function of arterio-venous (AV)-fistula was carried out after a detailed initial clinical examination in all patients. Individual intervention was performed according to examination results. Blood was drawn for analysis of HDL cholesterol; interleukin-6, its soluble receptor, monocyte chemoattractant protein 1 (MCP-1), total iron binding capacity, and high sensitivity C-reactive protein at the beginning of the study and after 3 months. The patients were then closely followed up for 2 years during which the occurrence and cause of death was registered. Results A significant decrease of inflammatory parameters (Interleukin-6: 4.9 vs. 1.1 pg/mL, P > .001 and MCP-1: 397 vs. 310 pg/mL, P = .02) and increase of HDL cholesterol (1.22 ± 0.55 vs. 1.33 ± 0.55; P = .003) was seen in the entire study population. No difference in survival was found between the different interventional groups. The 2-year death rate was 37%. On using Kaplan–Meier analysis, a significantly better survival in patients with increase of HDL cholesterol (77% vs. 50%; P = .013) and/or a decrease of MCP-1 (81% vs. 53%; P = .04) was found after 3 months of intervention. Conclusions It was concluded that individually aimed intervention may improve levels of HDL cholesterol and MCP-1. Changes in these 2 parameters can predict the 2-year survival rates of patients.

Background: Fetuin-A is a major inhibitor of ectopic calcium phosphate precipitation and an acute phase reactant. Its deficiency, common in end-stage renal disease, has been suggested to be associated with cardiovascular complications. The aim of this study was to monitor fetuin-A levels in the early period after renal transplantation. Methods: 30 deceased donor kidney recipients treated with calcineurin inhibitor-based immunosuppression were followed prospectively for the first 3 months and the association of fetuin-A levels with clinical and laboratory parameters was evaluated. Results: Despite a correlation of fetuin-A levels with creatinine clearance (r = 0.348, p < 0.01) and estimated GFR (r = 0.331, p < 0.01), no significant increase in fetuin-A levels over the first 3 months was observed. Moreover, a significant decrease in serum fetuin-A levels was noted at 2 weeks (p < 0.001). Subsequently, fetuin-A levels increased (p < 0.001) reaching pretransplant values at month 3. Conclusions: In this study there was no increase of fetuin-A levels during the first 3 months, but a decrease 2 weeks after transplantation was observed.

Effect of advanced glycation end products (AGEs) in the pathogenesis of cancer could be diminished by interaction with soluble RAGE or by reducing AGE-precursors via glyoxalase I. Glu111Ala polymorphism of glyoxalase I gene, AGEs, and sRAGE serum levels were studied in 113 breast cancer patients and in 58 controls. Higher frequency of the mutated C allele was found in patients with negative estrogen receptors and in patients in clinical stage III compared to controls (P< 0.05). The presence of the C allele could represent a negative prognostic factor; however, further studies are needed to confirm this hypothesis.

Objective: The aim of this study was to analyse the dynamics of advanced glycation end products (AGEs) after acute myocardial infarction (MI). Subjects and Methods: Blood samples were taken from 20 non-diabetic patients with acute MI on the 1st, 2nd, 3rd and 5th day after the onset of symptoms. Serum AGE levels were estimated spectrofluorometrically. Results: A marked decrease in the AGE-specific fluorescence was observed, especially between the 1st and the 2nd days after MI. Conclusion: The findings of this study tend to contradict the suggestion that AGEs are relatively stable markers of carbonyl stress. Although the reason for this is currently unknown, this observation may have implications for ongoing studies of AGEs in cardiovascular diseases.

OBJECTIVE The receptor for advanced glycation end products, RAGE, plays an important role in the pathogenesis of several diseases. sRAGE, soluble receptor for advanced glycation end products, is an inhibitor of the pathological effect mediated via RAGE. The aim of this study was to assess the usefulness of measuring sRAGE concentration in pregnant women with threatening preterm labor. METHODS Serum levels of sRAGE, interleukin-6 (IL-6) and routine markers of inflammation were determined in 46 pregnant women with threatening preterm labor, 35 healthy pregnant women and 15 non-pregnant controls. RESULTS Serum levels of sRAGE in healthy pregnant women were significantly lower than in non-pregnant controls (669+/-296 vs. 1929+/-727 pg/mL, P