The Key Role of Hepcidin-25 in Anemia in Multiple Myeloma Patients with Renal Impairment.

Background and objectives: Anemia is common in multiple myeloma (MM) and is caused by a complex pathomechanism, including impaired iron homeostasis. Our aim is to evaluate the biomarkers of iron turnover: serum soluble transferrin receptor (sTfR) and hepcidin-25 in patients at various stages of MM in relation with markers of anemia, iron status, inflammation, renal impairment and burden of the disease and as predictors of mortality. Materials and methods: Seventy-three MM patients (six with smoldering and 67 with symptomatic disease) were recruited and observed for up to 27 months. Control group included 21 healthy individuals. Serum sTfR and hepcidin were measured with immunoenzymatic assays. Results: MM patients with and without anemia had higher sTFR compared to controls, while only anemic patients had higher hepcidin-25. Both hepcidin-25 and sTfR were higher in anemic than non-anemic patients. Higher hepcidin-25 (but not sTfR) was associated with increasing MM advancement (from smoldering to International Staging System stage III disease) and with poor response to MM treatment, which was accompanied by lower blood hemoglobin and increased anisocytosis. Neither serum hepcidin-25 nor sTfR were correlated with markers of renal impairment. Hepcidin-25 predicted blood hemoglobin in MM patients independently of other predictors, including markers of renal impairment, inflammation and MM burden. Moreover, both blood hemoglobin and serum hepcidin-25 were independently associated with patients' 2-year survival. Conclusions: Our results suggest that hepcidin-25 is involved in anemia in MM and its concentrations are not affected by kidney impairment. Moreover, serum hepcidin-25 may be an early predictor of survival in this disease, independent of hemoglobin concentration. It should be further evaluated whether including hepcidin improves the early diagnosis of anemia in MM.

Transgelin-2 in Multiple Myeloma: A New Marker of Renal Impairment?

Transgelin is a 22-kDa protein involved in cytoskeletal organization and expressed in smooth muscle tissue. According to animal studies, it is a potential mediator of kidney injury and fibrosis, and moreover, its role in tumorigenesis is emerging in a variety of cancers. The study included 126 ambulatory patients with multiple myeloma (MM). Serum transgelin-2 concentrations were measured by enzyme-linked immunoassay. We evaluated associations between baseline transgelin and kidney function (serum creatinine, estimated glomerular filtration rate-eGFR, urinary markers of tubular injury: cystatin-C, neutrophil gelatinase associated lipocalin-NGAL monomer, cell cycle arrest biomarkers IGFBP-7 and TIMP-2) and markers of MM burden. Baseline serum transgelin was also evaluated as a predictor of kidney function after a follow-up of 27 months from the start of the study. Significant correlations were detected between serum transgelin-2 and serum creatinine (R = 0.29; p = 0.001) and eGFR (R = -0.25; p = 0.007). Transgelin significantly correlated with serum free light chains lambda (R = 0.18; p = 0.047) and serum periostin (R = -0.22; p = 0.013), after exclusion of smoldering MM patients. Patients with decreasing eGFR had higher transgelin levels (median 106.6 versus 83.9 ng/mL), although the difference was marginally significant (p = 0.05). However, baseline transgelin positively correlated with serum creatinine after the follow-up period (R = 0.37; p < 0.001) and negatively correlated with eGFR after the follow-up period (R = -0.33; p < 0.001). Moreover, higher baseline serum transgelin (beta = -0.11 ± 0.05; p = 0.032) significantly predicted lower eGFR values after the follow-up period, irrespective of baseline eGFR and follow-up duration. Our study shows for the first time that elevated serum transgelin is negatively associated with glomerular filtration in MM and predicts a decline in renal function over long-term follow-up.

Renal Impairment Detectors: IGFBP-7 and NGAL as Tubular Injury Markers in Multiple Myeloma Patients.

Background and Objectives: Urine insulin-like growth factor-binding protein 7 (IGFBP-7), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), and neutrophil gelatinase-associated lipocalin (NGAL) monomer are novel tubular kidney injury biomarkers. In multiple myeloma (MM), immunoglobulin free light chains (FLCs) play an integral role in renal impairment. This study aimed to investigate the correlation between new biomarkers and acclaimed parameters of renal failure, MM stage, and prognosis. Materials and Methods: The examined parameters included: urinary and serum cystatin-C, IGFBP-7, and TIMP-2, and urinary NGAL monomer in 124 enrolled patients. Results: Urinary and serum IGFBP-7 and urinary NGAL were higher among patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, and positively correlated with urine light chains. Serum and urine IGFBP-7 and urine NGAL were greater among patients with a higher disease stage. In the whole study group, urinary concentrations of the studied markers were positively correlated with each other. In multiple linear regression, urinary IGFBP-7 and NGAL were associated with lower eGFR, independently of other urinary markers. Conclusions: Urinary IGFBP-7 and NGAL monomer may be useful markers of tubular renal damage in patients with MM. Biomarker-based diagnostics may contribute to earlier treatment that may improve renal outcomes and life expectancy in MM.

Evaluating the Relationship of GDF-15 with Clinical Characteristics, Cardinal Features, and Survival in Multiple Myeloma.

Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor-ß superfamily, participates in processes associated with myeloma development and its end-organ complications. It plays a significant role in both physiological and abnormal erythropoiesis and regulates iron homeostasis through modulation of hepcidin. It is abnormally secreted in marrow stromal cells of patients with multiple myeloma (MM), which may reflect the tumor microenvironment. We analyzed the associations of serum GDF-15 with clinical characteristics of 73 MM patients (including asymptomatic MM) and the laboratory indices of renal function, anemia, and inflammation. Baseline serum GDF-15 was studied as the predictor of two-year survival. We defined five clinically relevant subgroups of patients (symptomatic MM only, patients with and without remission, patients on chemotherapy, and without treatment). Increased GDF-15 concentrations were associated with more advanced MM stage, anemia, renal impairment (lower glomerular filtration and higher markers of tubular injury), and inflammation. Most of the results were confirmed in the subgroup analysis. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin were associated with GDF-15 independently of other variables. In the studied MM patients, GDF-15 did not significantly predict survival (p = 0.06). Our results suggest that serum GDF-15 reflects myeloma burden and shares a relationship with several markers of prognostic significance, as well as major manifestations.

Angiogenic factor screening in women with mild preeclampsia - New and significant proteins in plasma.

INTRODUCTION: The aim of this study was to analyse a panel of 60 angiogenic factors (pro-angiogenic and antiangiogenic) in the plasma of women with mild preeclampsia. MATERIALS AND METHODS: We recruited 21 women between 25 and 40 weeks gestation with diagnosed mild preeclampsia into the study group and 27 healthy women with uncomplicated pregnancies of corresponding gestational age to that of the study to the control group. We used a quantitative protein macroarray method that allowed for analysis of 60 angiogenic proteins per sample simultaneously. RESULTS: We showed a statistically significant increase in the concentration of 8 proteins, interferon gamma (IFN-γ), interleukin 6 (IL-6), leukaemia inhibitory factor (LIF), heparin-binding EGF-like growth factor (HB-EGF), hepatocyte growth factor (HGF), C-X-C motif chemokine 10 (IP-10), leptin and platelet-derived growth factor BB (PDGF-BB), as well as a significant decrease in the concentration of 3 proteins, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and follistatin, in the plasma of women with preeclampsia. CONCLUSION: Based on our findings, it seems that protein factors may play an important role in the pathogenesis of preeclampsia, and there are many proteins that have not been studied in PE to date. There are no previous studies assessing the LIF, follistatin, HGF, HB-EGF and PDGF-BB concentrations in the plasma of women with PE; therefore, our obtained results indicate that these proteins are new factors that can play an important role in the pathomechanisms of PE.

Effects of 17ß-estradioland raloxifene on endothelial OPG and RANKL secretion.

OBJECTIVES: This study aims to asses the effects of estradiol vs. raloxifene on the levels of osteoprotegerin and soluble Receptor Activator of Nuclear Factor kB Ligand (sRANKL) in Human Umbilical Vein Endothelial Cells (HUVEC) culture in standard and calcifying medium. MATERIAL AND METHODS: Human Umbilical Vein Endothelial Cells were isolated from human umbilical vein by standard method. The supernatant concentrations of osteoprotegerin (OPG) and sRANKL (ELISA) were determined after incubation with glicerophosphate, estradiol , raloxifene, glicerophoshate and estradiol, glicerophosphate and raloxifene in comparison with control group at four designated time points (0, 1, 2 and 4 days of incubation). RESULTS: Incubation of estradiol with HUVEC colony lowered the OPG level significantly after day 2 and 4. Meantime, the level of sRANKL was stable. Raloxifene added to standard growth medium also significantly lowered OPG concentration after day 4 only, with no impact on sRANKL concentration. When added to calcifying medium, both estradiol and raloxifene significantly changed OPG level during the experiment. In all treated groups OPG levels were lower than in groups exposed to calcifying medium only. Neither estradiol, nor raloxifene changed sRANKL levels during the experiment. CONCLUSIONS: Estradiol and raloxifene affect OPG secretion from endothelial cells in vitro which may suggest their modifying role in pathogenesis of vascular calcification in postmenopausal women.

Plasma C16-Cer levels are increased in patients with preterm labor.

INTRODUCTION: The pathogenesis of preterm labor is fragmentarily explained. The most widely accepted theory points out to infection and inflammation as possible causes, which can be mediated by potentially different factors, including sphingolipid mediators. Sphingolipids are a class of lipids that have been shown as important mediators in various cell processes such as: proliferation, growth, apoptosis, stress response, necrosis and inflammation. The aim of the study was to assess plasma concentrations of selected sphingolipids in patients with preterm labor. MATERIAL AND METHODS: We used ultra-high performance liquid chromatography with triple mass spectrometry (UHPLC-ESI-MS/MS) to assess plasma concentrations of the 11 sphingolipids in patients presenting with symptoms of preterm labor (n=61) and threatened preterm labor (n=40). RESULTS: We observed a statistically significant increase (p-value<0.004) in plasma concentrations of C16-Cer in patients with preterm labor as compared to the control group. We also found C16-Cer to be the best predictor of preterm labor in the group of patients with symptoms occurring after 32 weeks of gestation. CONCLUSIONS: Our findings show a possible involvement of selected sphingolipids, especially C16-Cer, in the pathogenesis of preterm labor. Their role as predictors of preterm delivery needs to be validated in the future on larger group of patients.

Iron Status and Inflammation in Early Stages of Chronic Kidney Disease.

BACKGROUND/AIMS: One of the most common causes of anemia of chronic disease (ACD) is chronic kidney disease. The main pathomechanism responsible for ACD is subclinical inflammation. The key element involved in iron metabolism is hepcidin, however, studies on new indices of iron status are in progress.The aim of the study was to assess the iron status in patients in early stages of chronic kidney disease, iron correlation with inflammation parameters and novel biomarkers of iron metabolism. METHODS: The study included 69 patients. Standard laboratory measurements were used to measure the iron status, complete blood count, fibrinogen, prothrombin index, C-reactive protein concentration (CRP), creatinine, urea, uric acid. Commercially available kits were used to measure high-sensitivity CRP, interleukin 6 (IL-6), hepcidin-25, hemojuvelin, soluble transferrin receptor (sTfR), growth differentiation factor-15 (GDF-15) and zonulin. RESULTS: Absolute iron deficiency was present in 17% of the patients, functional iron deficiency was present in 12% of the patients. Functional iron deficiency was associated with significantly higher serum levels of fibrinogen, ferritin, transferrin saturation, total iron binding capacity, hepcidin and older age relative to patients with absolute iron deficiency. In comparison with patients without iron deficiency, patients with functional iron deficiency were older, with lower prothrombin index, higher fibrinogen, CRP, hsCRP, sTfR, GDF-15, urea and lower eGFR. Hepcidin was predicted by markers of inflammation:ferritin, fibrinogen and IL-6. CONCLUSION: Inflammation is correlated with iron status. Novel biomarkers of iron metabolism might be useful to distinguish iron deficiency anemia connected with inflammation and absolute iron deficiency.

Iron status in patients with chronic heart failure.

AIMS: The changes in iron status occurring during the course of heart failure (HF) and the underlying pathomechanisms are largely unknown. Hepcidin, the major regulatory protein for iron metabolism, may play a causative role. We investigated iron status in a broad spectrum of patients with systolic HF in order to determine the changes in iron status in parallel with disease progression, and to associate iron status with long-term prognosis. METHODS AND RESULTS: Serum concentrations of ferritin, transferrin saturation (Tsat), soluble transferrin receptor (sTfR), and hepcidin were assessed as the biomarkers of iron status in 321 patients with chronic systolic HF [age: 61 ± 11 years, men: 84%, left ventricular ejection fraction: 31 ± 9%, New York Heart Association (NYHA) class: 72/144/87/18] at a tertiary cardiology centre and 66 age- and gender-matched healthy subjects. Compared with healthy subjects, asymptomatic HF patients had similar haematological status, but increased iron stores (evidenced by higher serum ferritin without distinct inflammation, P < 0.01) with markedly elevated serum hepcidin (P < 0.001). With increasing HF severity, patients in advanced NYHA classes had iron deficiency (ID) (reduced serum ferritin, low Tsat, high sTfR), iron-restricted erythropoiesis (reduced haemoglobin, high red cell distribution width), and inflammation (high serum high-sensitivity-C-reactive protein and interleukin 6), which was accompanied by decreased circulating hepcidin (all P < 0.001). In multivariable Cox models, low hepcidin was independently associated with increased 3-year mortality among HF patients (P < 0.001). CONCLUSIONS: Increased level of circulating hepcidin characterizes an early stage of HF, and is not accompanied by either anaemia or inflammation. The progression of HF is associated with the decline in circulating hepcidin and the development of ID. Low hepcidin independently relates to unfavourable outcome.

GDF15 is related to anemia and hepcidin in kidney allograft recipients.

UNLABELLED: Anemia is more prevalent in renal transplant recipients than in GFR-matched chronic kidney disease patients. Hepcidin is a small defensin-like peptide whose production by hepatocytes is modulated in response to anemia, hypoxia or inflammation. Growth differentiation factor 15 (GDF15) was recently identified as a hepcidin-suppression factor that is expressed at high levels in patients with ineffective erythropoiesis. The aim of the study was to assess GDF15 levels with relation to iron parameters in 62 stable kidney allograft recipients maintained on triple immunosuppressive therapy. METHODS: Complete blood count, urea, creatinine, and iron status were assessed by standard methods. We measured GDF15, hepcidin, hemojuvelin, IL-6 and NGAL with commercially available assays. RESULTS: Mean levels of GDF15, NGAL, hepcidin and hemojuvelin were significantly higher in kidney allograft recipients when compared to the control group (p < 0.001 for all). GDF15 was significantly higher in patients with anemia according to the WHO definition when compared to their nonanemic counterparts (p < 0.05). GDF15 levels were not dependent on the type of immunosuppressive therapy. In univariate analysis GDF15 was related to kidney function (creatinine r = 0.39, p < 0.01, eGFR by MDRD r = -0.37, p < 0.01), urea (r = 0.39, p < 0.01), uric acid (r = 0.42, p < 0.01), hepcidin (r = -0.32, p < 0.01), IL-6 (r = 0.28, p < 0.05), hemoglobin (r = -0.32, p < 0.05), and NGAL (r = -0.35, p < 0.01). GDF15 was not related to serum iron, or ferritin. In multivariate analysis, hepcidin was found to be a predictor of GDF15. In conclusion, our preliminary data may suggest possible mutual relations between GDF15 and hepcidin in patients with kidney disease and that GDF15 might be involved in the pathogenesis of anemia in kidney allograft recipients. However, the role of inflammation should be also elucidated.

Circulating levels of renalase, norepinephrine, and dopamine in dialysis patients.

BACKGROUND: hRenalase may degrade catecholamines and regulate sympathetic tone and blood pressure (BP). The aim of the study was to assess dopamine (DA), norepinephrine (NE), and renalase in 75 hemodialysis (HD) and 26 peritoneal dialysis (PD) patients and their correlations with heart rate (HR), BP, a type of hypotensive therapy, and residual renal function. METHODS: Renalase, DA, NE were studied using commercially available assays. RESULTS: Renalase and NE were higher and DA was lower in dialyzed groups comparing to healthy volunteers. Hemodialysis patients had lower NE and higher renalase level. Norepinephrine was higher in anuric patients in HD group. Renalase correlated with dialysis vintage and inversely with residual diuresis. Dopamine correlated with residual diuresis in the whole study cohort, with HR in PD patients, with renalase in HD patients. Norepinephrine correlated with aortic diameter in PD patients. Norepinephrine was significantly higher in patients with coronary artery disease (CAD) in HD group. Hemodialysis population with CAD had lower NE and higher DA and renalase level than their PD counterparts. In the follow up, 27% of HD group died. Cardiac death was diagnosed in 17% and there was higher renalase level than in noncardiac death. CONCLUSIONS: Elevated level of circulating renalase in dialysis patients is rather related to kidney function and the sympathetic nervous system hyperactivity found in this population. The real excess of renalase in the pathogenesis of cardiovascular disorders in patients with chronic kidney disease still remains to be proven. If confirmed, it may give a new way for pathophysiological therapy.

VAP-1 in peritoneally dialyzed patients.

VAP-1 (vascular adhesion protein-1) possesses semicarbazide-sensitive amine oxidase (SSAO) activity. It has also been found that serum VAP-1 was elevated in acute and chronic hyperglycemia and in patients with diabetes as well as in chronic kidney disease. Renalase, with possible monoamine oxidase activity, which breaks down catecholamines such as SSAO, is expressed in the endothelium as well as in the kidney. The aim of the study was to assess serum VAP-1 levels in peritoneally dialyzed (PD) patients and factors explaining its variability. This pilot study was performed on 25 peritoneally dialyzed patients, including 4 patients with type 2 diabetes. We found that the mean VAP-1 was significantly higher in chronic ambulatory peritoneal dialysis (CAPD) patients when compared to the control group (p<0.05). Dopamine was significantly lower in PD patients when compared to the healthy volunteers (p<0.05), whereas noradrenaline was significantly higher in PD patients relative to the healthy volunteers (p<0.01). There was a significant difference in the VAP-1 concentration in the group with and without residual renal function (p<0.05) as well as between 10 patients with hyperglycemia when compared to patients with normoglycemia (p<0.05). There was no effect of gender on the serum VAP-1 levels. In PD patients VAP-1 correlated with systolic blood pressure (r=-0.4, p<005), residual renal function (r=-0.62, p<0.05), and glucose (=0.54, p<0.05). We concluded that VAP-1, elevated in patients on PD, was predominantly dependent on residual kidney function and glucose level, factors both linked to endothelial damage and cardiovascular complications.

An Array SPRi Biosensor for the Determination on PARP-1 in Blood Plasma.

A biosensor was developed for the quantification of poly(ADP-ribose) polymerase-1 (PARP-1) in body fluids. An antibody specific for PARP-1 was placed on a chip with cysteamine (linker) and a gold layer. This biosensor has a linear response range (10-1000 pg∙mL-1) under appropriate pH conditions and with an antibody ligand concentration of 5 ng∙mL-1. Plasma samples were diluted with PBS buffer in appropriate quantities so that they fell within the linear range of the calibration curve. The biosensor exhibited suitable precision and accuracy, and good recovery (at levels from 95% to 105%). The method was validated by means of PARP-1 determinations in plasma samples from patients with endometriosis and a control group, using surface plasmon resonance imaging (SPRi) biosensors and an enzyme-linked immunosorbent assay (ELISA) test. The Spearman correlation coefficient was close to 1. PARP-1 may be a marker providing information about pathological changes in the body during endometriosis.

Plasma and Peritoneal Fluid Annexin A2 Levels in Patients with Endometriosis.

Introduction: Endometriosis is an inflammatory-related reproductive age disease characterized by the presence of endometrial cells outside the uterine cavity. Current laboratory practice does not provide specific markers for detecting and assessing the advancement of endometriosis in either plasma or peritoneal fluid. The severity of disease is assessed in stages from I to IV based on the results of laparoscopic inspection. The protein annexin A2 (ANXA2) has been reported to be associated with inflammatory processes. Aim of the Study: The study aimed to investigate and compare ANXA2 protein concentration using the ELISA method in plasma and peritoneal fluid in a group of women with endometriosis compared to controls. Materials and Methods: Biological material was collected during a multicenter, cross-sectional study, which was conducted at eight departments during elective laparoscopy from 53 women with and 40 women without endometriosis. Patients were divided by endometriosis stage and infertility status, and then compared with subgroups. Analysis included the Chi-square test for categorical variables, Mann-Whitney U-test and two-sided Wilcoxon rank-sum test for continuous variables. Results: Women with endometriosis had significantly elevated plasma ANXA2 levels compared to women without endometriosis (mean concentrations 28.69 vs 19.61 ng/L, p=0.01). Differences in peritoneal fluid ANXA2 levels were statistically insignificant (mean concentrations of 23.7 vs 22.97 ng/L, p=0.06). Plasma concentrations in patients with stage III and IV endometriosis were significantly higher compared to controls (mean concentrations of 24.19 vs 19.71 ng/L, p=0.03). No such differences were observed in plasma when comparing stages I-II vs III-IV, and stages I-II vs controls (mean concentrations of 33.82 vs 24.19 ng/L, p=0.72 and 33.82 vs 19.71 ng/L, p=0.12, respectively). Comparison of samples from patients with or without infertility, primary or secondary infertility, endometriosis with or without infertility, and non-endometriosis with or without infertility showed no significant differences in the plasma nor in the peritoneal fluid concentrations. Conclusion: ANXA2 is possibly involved in the pathogenesis of endometriosis, especially in advanced stages. Due to the limited group of tested samples, further studies are needed to confirm its role.

VAP-1, a novel molecule linked to endothelial damage and kidney function in kidney allograft recipients.

BACKGROUND/AIMS: VAP-1 (vascular adhesion protein-1) is a copper-containing SSAO (semicarbazide sensitive amine oxidase) secreted by vascular smooth muscle cells, adipocytes, endothelial cells with functional monoamine oxidase activity. The oxidation process generates harmful products that may be involved in atherosclerosis and vascular damage. Elevation of SSAO activity is observed in atherosclerosis, diabetes mellitus and obesity. On the other hand, renalase, with possible monoamine oxidase activity, which breaks down catecholamines like SSAO, is also expressed in the endothelium as well as in the kidney. The aim of the study was to assess VAP-1 levels and its correlations with endothelial injury markers and renalase in 50 kidney allograft recipients. METHODS: Hemoglobin, urea, creatinine, rate were studied by standard laboratory method in the hospital central laboratory. We assessed markers of endothelial function/injury: vWF, thrombomodulin, ICAM, VCAM, CD40L, CD44, CD146, inflammation: hsCRP, and IL-6 and adipocytokines: leptin, adiponectin, visfatin, apelin with commercially available assays. RESULTS: The mean serum VAP-1 in Tx was significantly higher comparing to the control group. In kidney transplant recipients VAP-1 correlated with BMI (r=0.39, p<0.01), CD44 (r=0.27, p<0.05), hsCRP (r=0.28, p<0.05), serum creatinine (r=0.29, p<0.05), eGFR (CKD-EPI formula r=-0.27, p<0.05, MDRD r=-0.27,p<0.05, Cockcroft-Gault r=-0.35,p<0.01), serum urea (r=0.27, p<0.05), CD146 (r=0.49, p<0.001), CD40L (r=0.26, p<0.06), and renalase (r=0.34, p<0.05). In multiple regression analysis VAP-1 was predicted 80% by serum creatinine (beta value 0.33, p=0.01), and CD146 (beta value 43, p=0.0005). CONCLUSION: VAP-1, elevated in kidney transplant recipients, is predominantly dependent on endothelial damage and kidney function, which deteriorated with time after kidney transplantation.

Renalase, a novel enzyme involved in blood pressure regulation, is related to kidney function but not to blood pressure in hemodialysis patients.

UNLABELLED: Renalase, secreted by the kidney, degrades catecholamines and may play a role in the regulation of sympathetic tone and blood pressure. The aim of this study was to assess serum renalase levels in hemodialysis patients and their relationship to blood pressure control, type of antihypertensive therapy and the presence of residual renal function. RESULTS: The mean serum renalase in the study cohort was significantly higher than in the control group (27.53 ± 7.18 vs. 3.86 ± 0.73 µg/ml, p < 0.001). The serum renalase concentration was significantly lower in patients with residual renal function when compared to the anuric patients. The type of hypotensive treatment (ß-blockers, ACE inhibitors or AT1 receptor blockers) did not affect renalase levels. There was a significant inverse correlation between the serum renalase and age (r = -0.28, p = 0.023) and residual renal function (r = -0.327, p = 0.001). Renalase was not related to blood pressure, heart rate or hemodialysis vintage. CONCLUSION: Elevated renalase levels in HD patients may be due to impaired kidney function. Further studies are needed to prove or disprove the possible role of renalase in the pathogenesis of hypertension in patients with kidney diseases.

Renalase, stroke, and hypertension in hemodialyzed patients.

INTRODUCTION: Hypertension and kidney disease have been associated with increased incidence of stroke. Renalase, a newly discovered hormone, is secreted by the kidney and circulates in blood. The aim of this study was to assess possible correlations between renalase, blood pressure, stroke, and cardiovascular status in prevalent hemodialyzed patients. METHODS: Renalase was assessed using commercially available assay. Echocardiography was performed in each patient. RESULTS: Serum renalase was significantly lower in patients with a history of stroke (21%) than in patients without it. Similarly, renalase was significantly lower in hypertensive patients (82%) when compared with normotensives. Serum renalase correlated with creatinine, residual renal function, and transferrin saturation. The only predictor of renalase in multiple regression analysis was the presence of hypertension explaining 90% of the renalase variations. CONCLUSIONS: Our preliminary results suggest that renalase, probably due to the sympathetic nervous system hyperactivity, could be associated with hypertension and cardiovascular complications, including stroke in hemodialyzed patients. However, further studies are needed to establish the possible role of renalase in these complications. Renalase is "a new postulated therapeutic target."

Factors Influencing Longevity of Humoral Response to SARS-CoV-2 Vaccination in Patients with End Stage Kidney Disease Receiving Renal Replacement Therapy.

COVID-19 has severely affected the population of patients with end stage renal disease. Current data have proved a two-dose vaccination schedule against SARS-CoV-2 to be effective among dialyzed patients. There are limited data on the longevity and modulating factors of humoral response after vaccination. We performed a prospective longitudinal cohort study to determine longevity of the humoral response after SARS-CoV-2 vaccine. The study included 191 adult patients on hemodialysis and peritoneal dialysis. All participants had been vaccinated with three doses, either with BNT162b2 (Pfizer-BioNTech) (n = 109) or mRNA-1273 (Moderna) (n = 82). Anti-spike protein receptor-binding domain antibodies (anti-S IgG) were assessed using SARS-CoV-2 (RBD) IgG ELISA EIA-6150 IVD assay at baseline, on the 21st day and 43rd day, before a booster dose and two weeks thereafter. We found that before vaccination, 37.7% of the cohort had anti-S IgG titres concordant with seroconversion. After two-dose vaccination, seroconversion occurred in 97% of patients. The booster dose evoked a ~12-fold increase in antibody level. Obesity increased more than two-fold the odds for a decrease in anti-S IgG. Previous COVID-19 infection enhanced longevity of the humoral response following vaccination. In patients with previous COVID-19 infection, the BNT162b2 vaccine was associated with a higher odds of anti-S IgG waning compared to the mRNA-1273 vaccine. In conclusion, we report that obesity predisposes patients to protective antibody waning, hybrid immunity enhances odds for higher anti-S IgG concentrations and vaccine efficacy may be influenced by previous SARS-CoV-2 infection. The results might provide a rationale for vaccination protocol design.

Plasma and Peritoneal Poly (ADP-Ribose) Polymerase Levels in Patients with Endometriosis.

The evidence of poly (ADP-ribose) polymerase (PARP) association with the immune response could be coherent with the immunological theory of endometriosis and suggests the possibility of a new research direction. The aim of the study was to evaluate the levels of PARP in plasma and peritoneal fluid of patients with and without endometriosis. It was a multicenter, cross-sectional study. Plasma and peritoneal fluid samples were collected from patients with and without endometriosis during planned laparoscopic procedures in eight clinical centers. In total, 84 samples of plasma and 84 samples of the peritoneal fluid were included in the final analyses. Double-antibody sandwich enzyme-linked immunosorbent assay was performed in order to assess levels of PARP in collected samples. No statistically significant differences regarding the detected levels of PARP in plasma and peritoneal fluid comparing patients with and without endometriosis were observed. Patients with a history of infertility had significantly higher plasma PARP concentrations (p = 0.04). We have not observed the potential role of PARP concentration levels in plasma nor peritoneal fluid as an endometriosis biomarker. We have determined an association between a higher plasma PARP concentration and a history of infertility.

Plasma and Peritoneal Fluid ZEB Levels in Patients with Endometriosis and Infertility.

Zinc finger E-box-binding homeobox 1 (ZEB1) and zinc finger E-box-binding homeobox 2 (ZEB2) are transcription factors that regulate epithelial−mesenchymal transformation (EMT). The aim of this study was to compare levels of ZEB1 and ZEB2 in the peritoneal fluid and plasma between patients with and without endometriosis in order to assess their utility in the diagnostic process. Plasma and peritoneal fluid samples were collected from 50 patients with and 48 without endometriosis during planned surgical procedures in eight clinical centers. Quantitative ZEB1 and ZEB2 levels analyses were performed using a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). No significant differences were observed in ZEB1 levels in any of the subanalyses nor any differences regarding ZEB2 levels between patients with and without endometriosis. Plasma ZEB2 levels were significantly higher among patients with infertility compared to fertile women (16.07 ± 12.70 ng/L vs. 12.07 ± 11.92 ng/L; p < 0.04). Both ZEB1 and ZEB2 do not seem to have a significant value in the initial diagnosis of endometriosis as a single marker. The differences in ZEB2 plasma levels between patients with and without infertility indicate the possibility of EMT dysregulation in the pathogenesis of adverse fertility outcomes.