Capturing Scientific Knowledge on Medical Risk Factors

In this paper, we describe a model for representing scientific knowledge of risk factors in medicine in an explicit format which enables its use for automated reasoning. The resulting model supports linking the conclusions of up-to-date clinical research with data relating to individual patients. This model, which we have implemented as an ontology-based system using Linked Data, enables the capture of risk factor knowledge and serves as a translational research tool to apply that knowledge to assist with patient treatment, lifestyle, and education. Knowledge captured using this model can be disseminated for other intelligent systems to use for a variety of purposes, for example, to explore the state of the available medical knowledge

Oxidative Stress in Patients Undergoing Peritoneal Dialysis: A Current Review of the Literature

Peritoneal dialysis (PD) patients manifest excessive oxidative stress (OS) compared to the general population and predialysis chronic kidney disease patients, mainly due to the composition of the PD solution (high-glucose content, low pH, elevated osmolality, increased lactate concentration and glucose degradation products). However, PD could be considered a more biocompatible form of dialysis compared to hemodialysis (HD), since several studies showed that the latter results in an excess accumulation of oxidative products and loss of antioxidants. OS in PD is tightly linked with chronic inflammation, atherogenesis, peritoneal fibrosis, and loss of residual renal function. Although exogenous supplementation of antioxidants, such as vitamins E and C, N-acetylcysteine, and carotenoids, in some cases showed potential beneficial effects in PD patients, relevant recommendations have not been yet adopted in everyday clinical practice

Oxidative Stress in Hemodialysis Patients: A Review of the Literature

Hemodialysis (HD) patients are at high risk for all-cause mortality and cardiovascular events. In addition to traditional risk factors, excessive oxidative stress (OS) and chronic inflammation emerge as novel and major contributors to accelerated atherosclerosis and elevated mortality. OS is defined as the imbalance between antioxidant defense mechanisms and oxidant products, the latter overwhelming the former. OS appears in early stages of chronic kidney disease (CKD), advances along with worsening of renal failure, and is further exacerbated by the HD process per se. HD patients manifest excessive OS status due to retention of a plethora of toxins, subsidized under uremia, nutrition lacking antioxidants and turn-over of antioxidants, loss of antioxidants during renal replacement therapy, and leukocyte activation that leads to accumulation of oxidative products. Duration of dialysis therapy, iron infusion, anemia, presence of central venous catheter, and bioincompatible dialyzers are several factors triggering the development of OS. Antioxidant supplementation may take an overall protective role, even at early stages of CKD, to halt the deterioration of kidney function and antagonize systemic inflammation. Unfortunately, clinical studies have not yielded unequivocal positive outcomes when antioxidants have been administered to hemodialysis patients, likely due to their heterogeneous clinical conditions and underlying risk profile

Red Blood Cell Distribution Width Is Associated with Deterioration of Renal Function and Cardiovascular Morbidity and Mortality in Patients with Diabetic Kidney Disease

We sought to investigate the possible association between Red Blood Cell Distribution Width (RDW), vascular calcification, oxidative stress and renal function and all-cause/cardiovascular (CV) mortality, CV events and progression of kidney disease in a cohort of patients with Diabetic Kidney Disease (DKD). Carotid intima media thickness (cIMT) and oxidized low-density cholesterol were measured in 104 Type 2 Diabetes Mellitus (T2DM) patients with established DKD, distributed in all five stages of kidney disease and 38 diabetics with normal renal function. All patients were followed for 7 years with end-points all-cause and CV mortality, CV events and progression to End-Stage Renal Disease (ESRD). RDW was positively correlated with diabetes duration (r = 0.19, p = 0.023) and albuminuria (r = 0.29, p = 0.002). Multivariate regression analysis revealed that RDW was a strong, independent predictor of cIMT value (β = 0.031, p = 0.012). Kaplan-Meier curves and Cox proportional hazard models revealed that after adjustment for several cofounders, RDW was a significant and independent predictor for all-cause mortality, CV mortality, CV event and progression to ESRD (HR 1.75, p = 0.001, HR 2.03, p = 0.001, HR = 1.66, p < 0.0001 and HR 2.14, p = 0.001 respectively). RDW predicts mortality, CV events and deterioration of renal function in DKD, probably reflecting atherosclerosis

Unfavorable Effects of Peritoneal Dialysis Solutions on the Peritoneal Membrane: The Role of Oxidative Stress

One of the main limitations to successful long-term use of peritoneal dialysis (PD) as a renal replacement therapy is the harmful effects of PD solutions to the structure and function of the peritoneal membrane (PM). In PD, the PM serves as a semipermeable membrane that, due to exposure to PD solutions, undergoes structural alterations, including peritoneal fibrosis, vasculopathy, and neoangiogenesis. In recent decades, oxidative stress (OS) has emerged as a novel risk factor for mortality and cardiovascular disease in PD patients. Moreover, it has become evident that OS plays a pivotal role in the pathogenesis and development of the chronic, progressive injury of the PM. In this review, we aimed to present several aspects of OS in PD patients, including the pathophysiologic effects on the PM, clinical implications, and possible therapeutic antioxidant strategies that might protect the integrity of PM during PD therapy

Association of Red Blood Cell Distribution Width and Neutrophil-to-Lymphocyte Ratio with Calcification and Cardiovascular Markers in Chronic Kidney Disease

We aimed to investigate the association between Red Blood Cell Distribution Width (RDW) and Neutrophil-to-Lymphocyte Ratio (NLR), simple, rapidly assessed markers from the complete blood count with vascular calcification (VC)/stiffness and cardiovascular disease (CVD) in chronic kidney disease (CKD). Dephosphorylated, uncarboxylated matrix Gla-protein (dp-ucMGP), and central/peripheral hemodynamics’ parameters were measured in 158 CKD patients, including Hemodialysis and Peritoneal Dialysis. Spearman’s rho analysis showed that RDW correlated with C-reactive protein (CRP) (r = 0.29, p < 0.001), dp-ucMGP (r = 0.43, p = < 0.0001), central diastolic blood pressure (DBP) (r = −0.19, p = 0.02), and albuminuria (r = −0.17, p = 0.03). NLR correlated with the duration of CVD (r = 0.32, p < 0.001), CRP (r = 0.27, p = 0.01), dp-ucMGP (r = 0.43, p < 0.0001), central DBP (r = −0.32, p < 0.0001) and eGFR (r = −0.25, p = 0.04). In multiple regression models, circulating dp-ucMGP was an independent predictor of RDW (β = 0.001, p = 0.001) and NLR (β = 0.002, p = 0.002). In CKD patients, RDW and NLR are associated with traditional and novel markers of VC and CVD

Evaluation of factors involved in vascular calcification in patients with diabetic nephropathy

Vascular calcification is highly prevalent in patients with chronic kidney disease (CKD) and predicts a variety of cardiovascular disease (CVD) events. CVD is the leading cause of morbidity and mortality in patients with kidney failure on dialysis, with a 30-fold higher mortality than the general population, despite adjustment for traditional CVD risk factors. Furthermore, type 2 diabetes mellitus (T2DM) patients present a high prevalence of CVD events due to accelerated vascular calcification, while the underlying pathogenic mechanisms are not completely understood. Thus, it is widely known that high calcification burden is seen in diabetic nephropathy (DN), even in early stages.Genetic and biochemical studies have established matrix Gla protein (MGP) as the first known protein that both in vitro and in vivo acts as a powerful calcification inhibitor. MGP is a vitamin K-dependent protein of 84 amino acids with a molecular weight of 12 kDa, expressed by hypertrophic chondrocytes and vascular smooth muscle cells in the arterial wall. The function of MGP depends on a post-translational γ-glutamyl carboxylation, an essential activation step that rely on the availability of vitamin K. Furthermore, to be fully biologically active, after γ-carboxylation, MGP must undergo phosphorylation on three serine residues. Vitamin K availability is maintained through the vitamin K cycle. In deficiency of vitamin K, MGP is neither carboxylated, nor phosphorylated and therefore remains inactive. The circulating, inactive dephosphorylated, uncarboxyalted form of MGP (dpucMGP) has been repeatedly associated with increased vascular calcification. Moreover, plasma levels of dpucMGP increased progressively with deterioration of renal function in a cohort of patients at different stages of CKD.Several studies have demonstrated that both dietary and genetic factors involved in a set of sequential reactions that guarantee recycling of vitamin K (the vitamin K cycle) can lead to poor vitamin K status and subsequently to reduced function of MGP. Single nucleotide polymorphisms (SNPs) in the key enzyme responsible for the recycling of vitamin K (VKORC1 -vitamin K epoxide reductase complex subunit 1) gene appear to be associated with accelerated calcification of the aorta. More detailed pharmacogenetic studies have demonstrated that carriers of the A allele of VKORC1 -1639G>A polymorphism presented higher function and levels of VKORC1 and subsequently increased vitamin K status and increased function of MGP. Another factor affecting the levels of vitamin K is apolipoprotein E (apoE), which plays an important role in receptor mediated clearance of lipoprotein particles-chylomicron (known carriers of vitamin K) from plasma. The gene encoding MGP has eight SNPs in its promoter and coding regions. Several studies have revealed the importance of the T-138C polymorphism, which lies in a region of the promoter that is essential for transcription in vascular smooth muscle cells.There is a growing body of evidence supporting that higher levels of dp-ucMGP, reflecting vitamin K insufficiency, are strong and independent predictors of adverse outcomes and increased risk for all-cause mortality and both fatal/non-fatal cardiovascular events in various groups of patients.We sought to determine the association between apoE, VKORC1 -1639G > A and MGP T-138C polymorphisms and the plasma levels of the inactive dpucMGP, as well as their effect on carotid intima-media thickness (cIMT) in patients with diabetic nephropathy. We also investigated the distribution of MGP T-138C polymorphism in this group of patients and the predictive value of dpucMGP and MGP T-138C polymorphism in relation to all- cause mortality, cardiovascular mortality and cardiovascular events in patients with DN.VKORC1 -1639G > A, apoE and MGP T-138C polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 40 diabetic patients without nephropathy and 118 patients at different stages of diabetic nephropathy including subjects on hemodialysis. Measurements of cIMT were performed using real-time B-mode ultrasonography. Plasma levels of dpucMGP were determined in a subgroup of 67 patients by ELISA.Mortality and cardiovascular events were assessed during a 7 year follow up. Plasma dpucMGP levels and cIMT values increased significantly with severity of diabetic nephropathy (P A and apoE polymorphisms were not associated with cIMT, MGP T-138C polymorphism was associated with cIMT in the total population. TT homozygotes for the MGP T-138C polymorphism had higher values of cIMT compared to combined TC and CC genotypes (P=0.006). MGP T-138C polymorphism was a strong independent predictor of cIMT (P646 pM are independent risk factor for all-cause mortality [HR 2.97, 95% CI 1.27-6.95, P=0.012], CV mortality - (HR 5.49, 95% CI 1.85-16.33, P=0.002) and non-fatal CV event- (HR 2.07 95% CI 1.00-4.20, P=0.047). Since MGP is an important inhibitor of tissue and VC our study suggests that there may a genetic basis to tissue and VC in diabetic nephropathy.Η Χρόνια Νεφρική Νόσος (ΧΝΝ) αποτελεί ένα σημαντικό επιδημιολογικό πρόβλημα, με αυξανόμενη συχνότητα και επιπολασμό και υψηλό κόστος στα εθνικά συστήματα υγείας, παγκοσμίως. Η κυριότερη αιτία της ραγδαίας αύξησης του επιπολασμού της νεφρικής νόσου την τελευταία εικοσαετία είναι η αύξηση του επιπολασμού του Σακχαρώδη Διαβήτη Τύπου 2 (ΣΔΤ2), της συχνότερης αιτίας της νεφροπάθειας. Στους ασθενείς με διαβητική νεφροπάθεια (ΔΝ), ακόμα και στα αρχικά στάδια, παρατηρείται επιταχυνόμενη επασβέστωση των αγγείων και συνεπώς η καρδιαγγειακή νόσος αποτελεί την πρώτη αιτία θνητότητας και νοσηρότητας.Η Matrix Gla Protein (MGP) αποτελεί την πρώτη πρωτεΐνη που αναγνωρίστηκε in vitro και in vivo ως ισχυρός αναστολέας αγγειακής επασβέστωσης (ΑΕ). Πρόκειται για μία βιταμινο-Κ εξαρτώμενη πρωτεΐνη 84 αμινοξέων, μοριακού βάρους 12 kDa, που εκφράζεται από τα χονδροκύτταρα και τα λεία μυϊκά κύτταρα του αγγειακού τοιχώματος. Για να γίνει βιολογικά δραστική η MGP πρέπει να υποστεί γ-καρβοξυλίωση και φωσφορυλίωση, διαδικασίες που εξαρτώνται από τις διαθέσιμη ποσότητα βιταμίνης Κ. Η ανενεργός, μη-καρβοξυλιωμένη, μη-φωσφορυλιωμένη μορφή της MGP (dpucMGP) έχει σχετιστεί επανειλημμένως με ανάπτυξη ΑΕ, αλλά και με εξέλιξη της ΧΝΝ.Αρκετές μελέτες έχουν δείξει πως εκτός από διαιτητικούς, εμπλέκονται και γενετικοί παράγοντες στον κύκλο της βιταμίνης Κ (ανακύκλωση της βιταμίνης Κ) και μπορούν να οδηγήσουν σε μειωμένη δραστικότητα της MGP και συνεπώς σε ΑΕ. Η υπομονάδα 1 του συμπλόκου της αναγωγάσης του εποξειδίου της βιταμίνης Κ (Vitamin K Epoxide Reductase Complex Subunit 1 – VKORC1) είναι βασικό συστατικό του κύκλου της βιταμίνης Κ, καθώς είναι το υπεύθυνο ένζυμο για την ολοκλήρωση της μετατροπής του εποξειδίου της βιταμίνης Κ σε βιταμίνη Κ και συνεπώς, της ανακύκλωσής της. Μονονουκλεοτιδικοί γονιδιακοί πολυμορφισμοί (single nucleotide polymorphisms, SNPs) στο γονίδιο που κωδικοποιεί το υπεύθυνο ένζυμο για την ανακύκλωση της βιταμίνης Κ έχουν συσχετιστεί με επιταχυνόμενη ΑΕ της αορτής. Στην περιοχή του υποκινητή του γονιδίου VKORC1 έχει ταυτοποιηθεί ο πολυμορφισμός -1639G>A. Φορείς του G αλληλομόρφου εμφανίζουν αυξημένη κατά 44% δραστικότητα του υποκινητή και αυξημένα επίπεδα ενζύμου VKORC1. Ένας άλλος παράγοντας που επηρεάζει τα επίπεδα της βιταμίνης Κ είναι η απολιποπρωτεϊνη Ε (apoE) η οποία διευκολύνει την κυτταρική πρόσληψη των χυλομικρών που αποτελούν το φορέα μεταφοράς της βιταμίνης Κ στο αίμα. Τα τρία συνηθισμένα αλληλόμορφα της apoE διαφέρουν στην ικανότητά τους να διευκολύνουν την κάθαρση των πλούσιων σε βιταμίνη Κ λιποπρωτεϊνών από την κυκλοφορία με αποτέλεσμα τα επίπεδα πλάσματος της βιταμίνης Κ να μεταβάλλονται στους φορείς των τριών αλληλομόρφων της apoE. Το γονίδιο που κωδικοποιεί την MGP έχει οκτώ SNPs στον υποκινητή και στις περιοχές κωδικοποίησης. O πολυμορφισμός T-138C (rs 1800802) βρίσκεται σε περιοχή του υποκινητή που είναι απαραίτητος για τη μεταγραφή στα λεία μυϊκά κύτταρα των αγγείων. Αρκετοί ερευνητές έχουν δείξει πως η κυκλοφορούσα dpucMGP είναι ανεξάρτητος παράγοντας κινδύνου για ολική και ΚΑ θνητότητα σε διάφορους πληθυσμούς.Στην παρούσα μελέτη, σε διαβητικούς ασθενείς με ΔΝ και σε διαβητικούς χωρίς ΔΝ, μετρήθηκαν τα επίπεδα της κυκλοφορούσας dpucMGP, το πάχος του Ε-ΜΧΚ -ως υποκλινικού δείκτη αθηροσκλήρωσης-, και εκτιμήθηκε η επίδραση γενετικών πολυμορφισμών των γονιδίων των MGP, VKORC1 και apoE σε σχέση με το πάχος του Ε-ΜΧΚ και τα επίπεδα της dpucMGP. Επίσης αξιολογήθηκε η επίδραση των παραπάνω παραγόντων στην ολική και ΚΑ θνητότητα, τα ΚΑ επεισόδια και την εξέλιξη της νεφρικής νόσου στον πληθυσμό αυτό.Η γονοτύπηση των πολυμορφισμών του VKORC1-1639G>A, της MGP -138 T>C και της apoE πραγματοποιήθηκε με τη μέθοδο PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) σε 40 ασθενείς με ΣΔΤ2 και φυσιολογική νεφρική λειτουργία (ομάδα ελέγχου) και 118 ασθενείς με διάφορα στάδια διαβητικής ΧΝΝ (1-5, συμπεριλαμβανομένων ασθενών υπό αιμοκάθαρση με τεχνητό νεφρό- ΤΝ). Τα επίπεδα της dp-ucMGP του πλάσματος υπολογίστηκαν με τη μέθοδο ELISA (enzyme-linked immunosorbent assay). Σε όλους τους ασθενείς της μελέτης μετρήθηκε υπερηχογραφικά το πάχος του έσω-μέσου χιτώνα της κοινής καρωτίδας αρτηρίας (Ε-ΜΧΚ), με υψηλής ευκρίνειας υπερηχογραφικό μηχάνημα Doppler. Ο πληθυσμός της μελέτης παρακολουθήθηκε για μια 7ετία, με καταληκτικά σημεία την ολική θνητότητα, την ΚΑ θνητότητα και τα ΚΑ συμβάντα (θανατηφόρα και μη).Τα επίπεδα πλάσματος dpucMGP και η τιμή του πάχους Ε-ΜΧΚ σχετίστηκαν στατιστικά σημαντικά με την εξέλιξη της ΔΝ (P A και apoE δε σχετίστηκαν, ο πολυμορφισμός MGP T-138C σχετίστηκε με το πάχος του Ε-ΜΧΚ. Οι TT ομοζυγώτες εμφάνιζαν υψηλότερες πάχους Ε-ΜΧΚ συγκριτικά με τους γονότυπους TC και CC μαζί (P=0,006). Ο MGP T-138C ήταν ανεξάρτητος προγνωστικός παράγοντας του πάχους Ε-ΜΧΚ, μετά από προσαρμογή για αρκετούς παράγοντες κινδύνου για ΑΕ (P 646 pM είναι ανεξάρτητος παράγοντας κινδύνου για ολική θνητότητα – [HR 2,97, 95% CI 1,27-6,95, P=0,012], KA θνητότητα - (HR 5,49, 95% CI 1,85-16,33, P=0,002) και εμφάνιση ΚΑ συμβάματος- (HR 2,07 95% CI 1,00-4,20, P=0,047) συγκριτικά με τους ασθενείς στην ομάδα της χαμηλής dpucMGP.Καθώς η MGP αποτελεί σημαντικό αναστολέα της ιστικής και αγγειακής επασβέστωσης, η μελέτη μας υποδεικνύει ότι μάλλον υπάρχει γενετική βάση στην επασβέστωση των ασθενών με διαβητική νεφροπάθεια. Θα μπορούσαμε να υποθέσουμε ότι ο πολυμορφισμός T-138C της MGP ίσως προδιαθέτει γενετικά στην έκφραση της αγγειακής επασβέστωσης

Dietary Antioxidant Supplements and Uric Acid in Chronic Kidney Disease: A Review

Increased serum levels of uric acid have been associated with the onset and development of chronic kidney disease (CKD), cardiovascular disease, and mortality, through several molecular pathogenetic mechanisms, such as inflammation and oxidative stress. Oxidative stress is present even in the early stages of CKD, progresses parallelly with the deterioration of kidney function, and is even more exacerbated in end-stage renal disease patients undergoing maintenance hemodialysis. Although acting in the plasma as an antioxidant, once uric acid enters the intracellular environment; it behaves as a powerful pro-oxidant. Exogenous intake of antioxidants has been repeatedly shown to prevent inflammation, atherosclerosis and oxidative stress in CKD patients. Moreover, certain antioxidants have been proposed to exert uric acid-lowering properties. This review aims to present the available data regarding the effects of antioxidant supplements on both oxidative stress and uric acid serum levels, in a population particularly susceptible to oxidative damage such as CKD patients