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BACKGROUND AND AIMS Patients with intradialytic hypertension (IDH) have higher mean 44-h ambulatory blood pressure (BP) levels than patients without the phenomenon. IDH is associated with an increased risk of cardiovascular and all-cause mortality. Whether the excess risk for mortality in patients with IDH depends on the BP rise during dialysis per se or on elevated 44-h ambulatory BP is not known. This is the first study evaluating the association of IDH with cardiovascular events and all-cause mortality before and after adjustment for ambulatory BP and other cardiovascular risk factors. METHOD A total of 242 haemodialysis patients underwent 48-h ABPM with Mobil-O-Graph-NG and were followed for a median of 45.7 months. IDH was defined as: SBP rise ≥ 10 mmHg from pre- to post-dialysis and post-dialysis SBP ≥ 150 mmHg. The primary end-point was all-cause mortality; the secondary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, resuscitation after cardiac arrest, hospitalization for heart failure, coronary or peripheral revascularization procedures. RESULTS During follow-up, a total of 122 patients died; 69 due to cardiovascular causes. Cumulative freedom from both the primary and secondary endpoints was significantly lower for patients with IDH (log rank-P = 0.048/0.022, respectively). The risk for all-cause mortality was significantly higher for patients with IDH [HR = 1.566, 95% confidence interval (95% CI) (1.001, 2.450)]; similarly, the risk for the combined cardiovascular endpoint was higher for these individuals [HR = 1.675, 95% CI (1.071, 2.620)]. The observed associations attenuated after adjustment for 44-h SBP [all-cause mortality: HR = 1.529, 95% CI (0.952, 2.457)] and combined cardiovascular endpoint: HR = 1.388 95% CI (0.866, 2.225). After additional adjustment for age, interdialytic weight gain, dialysis vintage, 44-h pulse wave velocity, history of coronary artery disease, diabetes mellitus and heart failure the respective HRs were 1.409 [95% CI (0.851, 2.332)] and 1.435 [95% CI (0.879, 2.343)]. CONCLUSION Patients with IDH presented higher risk for death and cardiovascular outcomes. Sustained high BP levels during the 44-h interdialytic period and not only intradialytic BP rise per se may be participating in the excess risk of this condition.

Background: The pathophysiology of renal disease progression in autosomal-dominant polycystic kidney disease (ADPKD) involves not only cystogenesis but also endothelial dysfunction, leading to the activation of inflammatory and fibrotic pathways. This study evaluated the levels of biomarkers related to osmoregulation, immune system activation, and tubular injury in ADPKD patients with impaired or preserved renal function. Methods: This study included 26 ADPKD patients with modestly impaired renal function (estimated glomerular filtration rate [eGFR] 45–70 mL/min/1.73 m2; Group A), 26 age- and sex-matched ADPKD patients with relatively preserved renal function (eGFR >70 mL/min/1.73 m2; Group B), and 26 age- and sex-matched controls (Group C). Serum levels of copeptin, the inflammasome nucleotide-binding and oligomerization domain-like receptors pyrin domain-containing protein 3 (NLRP3), and soluble urokinase-type plasminogen activator receptor (suPAR) were measured with ELISA techniques. Results: Patients in Group A had higher levels of copeptin (median [interquartile range]: 50.44 [334.85] pg/mL), NLRP3 (5.86 [3.89] ng/mL), and suPAR (390.05 [476.53] pg/mL) compared to patients in Group B (32.38 [58.33], p = 0.042; 2.42 [1.96], p < 0.001; and 313.78 [178.85], p = 0.035, respectively) and Group C (6.75 [6.43]; 1.09 [0.56]; and 198.30 [28.53], respectively; p < 0.001 for all comparisons). Levels of all studied markers were also significantly higher in Group B patients compared to controls (p < 0.001), despite having similar eGFR. In patients with ADPKD, all studied biomarkers were correlated positively with asymmetric-dimethylarginine (ADMA) and endocan levels, and negatively with eGFR. ADMA and endocan levels were the only parameters independently associated with increased copeptin levels. Conclusions: This study showed that ADPKD patients with impaired and preserved renal function had higher copeptin, NLRP3, and suPAR levels than controls. Such findings support that cystogenesis and inflammation are associated with endothelial dysfunction, even in the early stages of ADKPD.

Η ΑΕΠΚΝ είναι η πιο συχνά εμφανιζόμενη κληρονομική διαταραχή που προκαλεί ΧΝΝ παγκοσμίως, οδηγώντας περίπου 5% των ασθενών στο τελικό στάδιο, τόσο στην Ευρώπη όσο και στη Βόρειο Αμερική. Η ΧΝΝ αποτελεί τη σοβαρότερη κλινική εκδήλωση με σημαντική αύξηση της θνητότητας και της θνησιμότητας. Οι μηχανισμοί πρόκλησης και εξέλιξης της ΧΝΝ δεν έχουν διευκρινιστεί πλήρως και εξακολουθούν να αποτελούν αντικείμενο έρευνας.Η γνωστή θεωρία είναι ότι ελαττώνεται το φυσιολογικό παρέγχυμα από την πίεση των νεφρικών κύστεων καθώς αυτές αυξάνονται σε μέγεθος. Ωστόσο σε πειραματικές μελέτες έχει φανεί ότι η αποσυμπίεση με την παροχέτευση των κύστεων δε βελτίωσε τη νεφρική λειτουργία, ούτε καθυστέρησε την εξέλιξη της νεφρικής βλάβης. Επίσης η μελέτη CRISP διαπίστωσε ότι η νεφρική ροή αίματος (δηλαδή η αγγειακή αντίσταση) είναι ανεξάρτητος προγνωστικός δείκτης, τονίζοντας τη σημασία της αγγειασύσπασης και της αγγειακής αναδιαμόρφωση.Ιστολογικά χαρακτηρίζεται από προοδευτικά επιδεινούμενη αγγειακή σκλήρυνση του προσαγωγού και του μεσολοβίδιων αρτηριών καθώς και από διάμεση φλεγμονή και διάμεση ίνωση. Ακόμα σε ασθενείς με φυσιολογική ή σχεδόν φυσιολογική νεφρική λειτουργία η αγγειοδιαστολή που εξαρτάται από τη δράση του NO στο ενδοθήλιο είναι ελαττωματική στα μικρά υποδόρια αγγεία σε σύγκριση με υγιείς ίδιας ηλικίας. Η ελάττωση της βιοδιαθεσιμότητας του NO οδηγεί προφανώς σε χρόνια αγγειοσύσπαση και επακόλουθη αρτηριοσκλήρυνση.Φαίνεται αρκετά πιθανό ότι η ανεπάρκεια του NO συνεισφέρει στην εξέλιξη της νεφρικής βλάβης και τελικά οδηγεί σε νεφροσκλήρυνση και τελικό στάδιο ΧΝΝ. Μεγάλο ενδιαφέρον αναπτύσσεται τα τελευταία χρόνια γύρω από τις μεθυλαργινίνες και ιδιαίτερα την ADMA. Αποτελεί ενδογενή αναστολέα των συνθετασών του NO και βλάπτει την εξαρτώμενη από το ενδοθήλιο διαστολή των αγγείων.Υπάρχει ένας μεγάλος αριθμός δεδομένων που συνδέουν την ADMA με τη πρωτεϊνουρία και την υπέρταση, οι οποίοι αποτελούν κλασσικούς παράγοντες εξέλιξης της νεφρικής βλάβης. Υπάρχουν επίσης αρκετά στοιχεία που αποδεικνύουν ότι η ADMA εμπλέκεται άμεσα στην εξέλιξη της ΧΝΝ. Η ADMA ενδέχεται να κατέχει αιτιολογικό ρόλο στην εξέλιξη της νεφρικής νόσου.Ο σκοπός της παρούσας μελέτης ήταν ο προσδιορισμός των επιπέδων ADMA σε δύο ομάδες ασθενών με ΑΕΠΚΝ, με διατηρημένη νεφρική λειτουργία (eGFR>70ml/min) και επηρεασμένη νεφρική λειτουργία (eGFR=45-70ml/min) και η σύγκρισή τους τόσος με ενήλικες ιδίων δημογραφικών χαρακτηριστικών χωρίς ΑΕΠΚΝ καθώς και η συσχέτισή τους με τα επίπεδα νεφρικής λειτουργίας και τα επίπεδα του οξειδωτικού stress. Στόχος μας ήταν η διερεύνηση αιτιολογικής σύνδεσης της ADMA με την ελάττωση της νεφρικής λειτουργίας ως πιθανός παθογενετικός μηχανισμός πρόκλησης νεφρικής βλάβης και εξέλιξης της ΧΝΝ σε αυτή των κατηγορία ασθενών.Η πρωτοτυπία της παρούσας μελέτης έγκειται στην διερεύνηση της παρουσίας αυξημένης ADMA από τα αρχικά στάδια της ΑΕΠΚΝ ως πιθανής μηχανιστικής οδού για της πρόκληση και εξέλιξη της νεφρικής βλάβης. Επίσης η διερεύνηση της παρουσίας ενδοθηλιακής δυσλειτουργίας από αρχικά στάδια, που φαίνεται να αποτελεί ειδικό χαρακτηριστικό γνώρισμα. Τέλος η διερεύνηση της παρουσίας αυξημένου οξειδωτικού stress από τα αρχικά στάδια που πιθανότατα εμπλέκεται στην παθοφυσιολογία της ενδοθηλιακής δυσλειτουργίας και της νεφρικής βλάβης.Από την ανάλυση των αποτελεσμάτων προέκυψαν τα κάτωθι συμπεράσματα. α) Αυξημένα επίπεδα ADMA εμφανίζεται από πολύ νωρίς στους ασθενείς με ΑΕΠΚΝ. β) Τα επίπεδα ADMA συσχετίζονται θετικά με το εμφανιζόμενο από νωρίς οξειδωτικού stress και αυξάνονται περαιτέρω με την επιδείνωση του. γ) Η παρούσα έρευνα ενισχύει την άποψη ότι η ADMA συμμετέχει στους μηχανισμούς πρόκλησης και εξέλιξης της νεφρικής βλάβης στην ΑΕΠΚΝ.

Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent inherited kidney disease, characterized by growth of bilateral renal cysts, hypertension, and multiple extrarenal complications that eventually can lead to renal failure. It is caused by mutations in PKD1 or PKD2 genes encoding the proteins polycystin-1 and polycystin-2, respectively. Over the past few years, studies investigating the role of primary cilia and polycystins, present not only on the surface of renal tubular cells but also on vascular endothelial cells, have advanced our understanding of the pathogenesis of ADPKD and have shown that mechanisms other than cyst formation also contribute to renal functional decline in this disease. Among them, increased oxidative stress, endothelial dysfunction, and hypoxia may play central roles because they occur early in the disease process and precede the onset of hypertension and renal functional decline. Endothelial dysfunction is linked to higher asymmetric dimethylarginine levels and reduced nitric oxide bioavailability, which would cause regional vasoconstriction and impaired renal blood flow. The resulting hypoxia would increase the levels of hypoxia-inducible-transcription factor 1α and other angiogenetic factors, which, in turn, may drive cyst growth. In this review, we summarize the existing evidence for roles of endothelial dysfunction, oxidative stress, and hypoxia in the pathogenesis of ADPKD.

Background and Aims Hypertension is highly prevalent in hemodialysis patients. Current recommendations suggest the use of ambulatory-BP-monitoring (ABPM) as the gold-standard for hypertension diagnosis and management in these subjects. This study assessed the accuracy of peridialytic, intradialytic and scheduled interdialytic recordings in diagnosing high 44-h interdialytic BP. Method A total of 242 hemodialysis patients that underwent valid 48-h ABPM were included in the analysis. We used ambulatory BP as reference standard and tested the accuracy of the following BP metrics: Pre- and post-dialysis, Intradialytic, Intradialytic plus pre/post-dialysis readings and Scheduled interdialytic BP (out-of-dialysis day: readings at 8:00 am, 8:00 pm or their average). Results 44-h SBP/DBP levels had significant differences with and pre- or post-dialysis BP, but no or minor differences with any of the other BP metrics. 44-h SBP and DBP correlated strongly with Intradialytic (r=0.713/0.753, p Conclusion In contrast to pre- and post-dialysis BP, the average of intradialytic, intradialytic plus pre/post-dialysis or scheduled interdialytic BP recordings show reasonable agreement with ambulatory BP and may be used for hypertension diagnosis and management in hemodialysis.

BACKGROUND: Evidence suggests that the anti-aging protein a-Klotho is a central modulator of mineral homeostasis. Circulating a-Klotho exerts endocrine activity and has been implicated in the process of vascular calcification, which is accelerated in patients with chronic kidney disease (CKD) and portends an unfavorable overall prognosis. However, the role of a-Klotho in this process remains unclear. The purpose of this study was to investigate the possible interaction between a-Klotho and the calcification of the aortic valve and coronary arteries in patients with CKD. METHODS: In this study we enrolled a total of 60 adult patients with CKD. Group 1 included 30 participants with CKD stage V and group 2 included 30 participants with CKD stage III. RESULTS: Participants in group 1 had lower levels of circulating a-Klotho compared to group 2 (390; 280–590 vs. 722; 501–897 pg/mL; P=0.001), were of younger age (55.5; 45–63 vs. 69; 62–74 years; P

Background: Intradialytic hypertension occurs in 5–15% of hemodialysis patients and is associated with increased cardiovascular risk, but the responsible mechanisms remain unknown. This study examined the effects of nebivolol and irbesartan on ambulatory central blood pressure (BP), arterial stiffness, and wave-reflection parameters in patients with intradialytic hypertension. Methods: This is a prespecified analysis of a single-blind, randomized, cross-over study in 38 hemodialysis patients with intradialytic hypertension. Patients were randomized to nebivolol 5 mg followed byirbesartan 150 mg, or vice versa. In a non-randomized manner, the first half of the patients (n = 19) received a single drug dose 1 h prior to dialysis session and the remaining received the drugs for a whole week before the evaluation. Ambulatory central BP, arterial stiffness, and wave-reflection parameters were estimated with Mobil-O-Graph NG device, during a midweek dialysis day. Results: Intake of a single dose of nebivolol or irbesartan resulted in lower postdialysis central systolic BP (c-SBP) (baseline: 140.9 ± 15.4; nebivolol: 130.3 ± 19.5, p = 0.009; irbesartan: 127.3 ± 24.4 mm Hg, p = 0.007). Single-dose nebivolol also produced marginally lower 24-h c-SBP (p = 0.064) and lower 24-h central diastolic BP (c-DBP) (p = 0.029). Weekly administration of both drugs reduced postdialysis c-SBP (baseline: 144.1 ± 15.3; nebivolol: 131.8 ± 14.1, p = 0.014; irbesartan: 126.4 ± 17.8, p = 0.001) and 24-h c-SBP and c-DBP (baseline: 135.5 ± 10.3/91.9 ± 9.2; nebivolol: 126.4 ± 8.4/86.6 ± 7.2, p < 0.001/p = 0.002; irbesartan: 128.7 ± 11.6/87.0 ± 9.4, p = 0.061/p = 0.051 mm Hg). Single-dose intake of both drugs did not affect heart rate-adjusted augmentation index [AIx(75)], but decreased postdialysis pulse wave velocity (PWV). Importantly, weekly administration of both drugs reduced 24-h PWV (baseline: 10.0 ± 2.5; nebivolol: 9.7 ± 2.5, p = 0.012; irbesartan: 9.7 ± 2.7, p = 0.041). In between drug-group comparisons, no significant differences were noted. Conclusions: This is the first randomized evaluation on the effects of pharmacological interventions on central BP and PWV in patients with intradialytic hypertension. Weekly administration of both nebivolol and irbesartan reduced 24-h central BP and PWV, but not AIx(75).

Deoxynivalenol (DON) is a mycotoxin produced by certain Fusarium species and found in a high percentage of wheat and maize grains cultured worldwide. Although not so toxic as other mycotoxins, it exhibits both chronic and acute toxicity, and therefore methods for its fast and accurate on-site determination are highly desirable. In the current work, we employ an optical immunosensor based on White Light Reflectance Spectroscopy (WLRS) for the fast and sensitive immunochemical label-free determination of DON in wheat and maize samples. The assay is completed in 12 min and has a quantification limit of 2.5 ng/mL in buffer corresponding to 125 mu g/kg in whole grain which is lower than the maximum allowable concentrations set by the regulatory authorities for grains intended for human consumption. Several extraction protocols have been compared, and the highest recovery (>90%) was achieved employing distilled water. In addition, identical calibration curves were received in buffer and wheat/maize extraction matrix providing the ability to analyze the grain samples using calibrators in buffer. Recoveries of DON from spiked wheat and maize grain samples ranged from 92.0(+/- 4.0) to 105(+/- 4.0)%. The analytical performance of the WLRS immunosensor, combined with the short analysis time and instrument portability, supports its potential for on-site determinations.

Background Population-specific consensus documents recommend that the diagnosis of hypertension in haemodialysis patients be based on 48-h ambulatory blood pressure (ABP) monitoring. However, until now there is just one study in the USA on the prevalence of hypertension in haemodialysis patients by 44-h recordings. Since there is a knowledge gap on the problem in European countries, we reassessed the problem in the European Cardiovascular and Renal Medicine working group Registry of the European Renal Association-European Dialysis and Transplant Association. Methods A total of 396 haemodialysis patients underwent 48-h ABP monitoring during a regular haemodialysis session and the subsequent interdialytic interval. Hypertension was defined as (i) pre-haemodialysis blood pressure (BP) ≥140/90 mmHg or use of antihypertensive agents and (ii) ABP ≥130/80 mmHg or use of antihypertensive agents. Results The prevalence of hypertension by 48-h ABP monitoring was very high (84.3%) and close to that by pre-haemodialysis BP (89.4%) but the agreement of the two techniques was not of the same magnitude (κ statistics = 0.648; P Conclusions The prevalence of hypertension in haemodialysis patients assessed by 48-h ABP monitoring is very high. Pre-haemodialysis BP poorly reflects the 48 h-ABP burden. About a third of the haemodialysis population has white coat or masked hypertension. These findings add weight to consensus documents supporting the use of ABP monitoring for proper hypertension diagnosis and treatment in this population.

Background Multiple myeloma and other related monoclonal gammopathies are frequently encountered conditions associated with renal damage, especially in elderly population. They are arising from clonal proliferation of plasma cells in bone marrow producing various quantities of abnormal monoclonal immunoglobulins, or their components/fragments. Summary These abnormal proteins differ from normal immunoglobulins in the amino acid sequence and in the three-dimensional structure of the molecule, which may determine their toxicity. Kidney seems to be a target organ as a major catabolic site. The pathology of renal disease is highly heterogeneous involving a variety of different mechanisms, which are divided into immunoglobulin dependent and immunoglobulin independent mechanisms. The Ig-dependent mechanisms may involve the four components of the kidney parenchyma, and the primary structure of these proteins determine the pattern of renal disease. Key message This review summarizes the existing literature in the pathobiology of multiple myeloma, and the pathological properties of the M-proteins, focusing on the mechanisms of the renal manifestations related to these abnormal proteins, especially glomerular injury. Also it supports the opinion that monoclonal gammopathy of undetermined significance (MGUS) should not be used in cases where there is proven renal impairment due to these proteins, even if it is mild and does not meet the current criteria.

Hypertension and progressive decline of renal function are among the common clinical manifestations in autosomal dominant polycystic kidney disease (ADPKD). At present, cyst formation in ADPKD patients is still considered the main pathogenic mechanism for the onset of these manifestations. However, the presence of polycystins in the vessels and the cilia of the endothelial cells and vascular smooth muscle cells, as well as development of hypertension prior to renal function decline and its prognostic role for the latter, indicate that polycystins may have an important role for endothelial damage in several vascular beds. Pathological polycystins induce intracellular calcium abnormalities, which affect various cellular organelles and functions and possibly lead not only to several abnormal biochemical reactions within endothelial cells, but also to an imbalance between oxidant and antioxidant capacity. Among the consequences of this process is accumulation of asymmetric-dimethylarginine, which not only participates in the induction and progression of renal damage, but also interferes with the normal vascular response due to nitric oxide (NO) inhibition. Reduced NO bioavailability would result in the long-run in relative vasoconstriction, impaired renal blood flow and vascular remodelling. This review summarizes the existing data from studies supporting that mechanisms other than cyst formation also contribute to the pathogenesis of hypertension and renal function decline in ADPKD.

Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid found in tissues and cells that circulates in plasma and is excreted in urine. It inhibits nitric oxide synthases (NOs) and produces considerable cardiovascular biological effects. Several studies have suggested that plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. In animal and in population studies ADMA has been associated with progression of CKD. Several mechanisms may be involved in this association, such as compromise of the integrity of the glomerular filtration barrier and development of renal fibrosis. This review summarizes the existing literature on the biology and physiology of ADMA focusing on its role in the progression of renal disease.

Wave reflections and arterial stiffness are independent cardiovascular risk factors in ESRD. Previous studies in this population included only static recordings before and after dialysis. This study investigated the variation of these indices during intra- and interdialytic intervals and examined demographic, clinical, and hemodynamic variables related to arterial function in patients undergoing hemodialysis.Between February 2013 and May 2014, a total of 153 patients receiving maintenance hemodialysis in five dialysis centers of northern Greece underwent ambulatory BP monitoring with the newly introduced Mobil-O-Graph device (IEM, Stolberg, Germany) over a midweek dialysis session and the subsequent interdialytic period. Mobil-O-Graph is an oscillometric device that records brachial BP and pulse waves and estimates, via generalized transfer function, aortic BP, augmentation index (AIx) as a measure of wave reflections, and pulse wave velocity (PWV) as an index of arterial stiffness.AIx was lower during dialysis than in the interdialytic period of dialysis-on day (Day 1) (mean±SD, 24.7%±9.7% versus 26.8%±9.4%; P0.001). In contrast, PWV remained unchanged between these intervals (9.31±2.2 versus 9.29±2.3 m/sec; P=0.60). Both AIx and PWV increased during dialysis-off day (Day 2) versus the out-of-dialysis period of Day 1 (28.8%±9.8% versus 26.8%±9.4% [P0.001] and 9.39±2.3 versus 9.29±2.3 m/sec [P0.001]). Older age (odds ratio [OR], 1.09; 95% confidence interval [95% CI], 1.02 to 1.15), female sex (OR, 7.56; 95% CI, 1.64 to 34.81), diabetic status (OR, 8.84; 95% CI, 1.76 to 17.48), and higher mean BP (OR, 1.17; 95% CI, 1.09 to 1.27) were associated with higher odds of high AIx; higher heart rate was associated with lower odds (OR, 0.71; 95% CI, 0.63 to 0.80) of high AIx. Older age (OR, 2.04; 95% CI, 1.61 to 2.58) and higher mean BP (OR, 1.15; 95% CI, 1.05 to 1.27) were independent correlates of high PWV.This study showed a gradual interdialytic increase in AIx, whereas PWV was only slightly elevated during Day 2. Future studies are needed to elucidate the value of these ambulatory measures for cardiovascular risk prediction in ESRD.

Asymmetric dimethylarginine (ADMA) is a naturally occurring amino acid found in tissues and cells that circulates in plasma and is excreted in urine. It inhibits nitric oxide synthases (NOs) and produces considerable cardiovascular biological effects. Several studies have suggested that plasma concentrations of ADMA provide a marker of risk for endothelial dysfunction and cardiovascular disease. In animal and in population studies ADMA has been associated with progression of CKD. Several mechanisms may be involved in this association, such as compromise of the integrity of the glomerular filtration barrier and development of renal fibrosis. This review summarizes the existing literature on the biology and physiology of ADMA focusing on its role in the progression of renal disease.