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End-stage renal disease (ESRD), or kidney failure, is a serious illness with significant health consequences and high-cost treatment options. Since the early 1980s, the number of Canadians with ESRD has more than quadrupled (CIHI, 2001), leading to questions about the current and future impact of the disease on public health, quality of life, health spending, and patients’ productivity. Using an economic burden of illness approach, this thesis estimates ESRD’s “direct” health care costs and “indirect” costs, such as productivity losses due to premature death and short- and long-term disability. It also projects future results under various alternative assumptions using a multi-state discrete time Markov model. The analysis suggests that, although less than 0.1% of Canadians have ESRD, it generated direct health care costs of $1.3 billion in 2000 or $51,099 per person with ESRD. That compares to $3,183 per capita for Canadians overall (CIHI, 2002b). Adding indirect morbidity and mortality costs brings the total to $1.9 billion. Rising ESRD numbers suggest higher costs in the future. Further analysis explored the effect of various assumptions about drivers of past trends, such as population growth, changes in the age structure, and the prevalence of conditions known to cause ESRD (e.g. diabetes). Projections were most sensitive to assumptions about the rate at which new cases are diagnosed. If current trends continue, the total economic burden of the disease can be expected to reach $7.9 billion by 2015 (year 2000 dollars). On the other hand, if the rate of new cases in 2000 were maintained, the economic burden of illness would be $5.7 billion in 2015. Nevertheless, under this and many other assumptions, there is likely to be a significant gap between available organs for transplant and the demand for transplantation. The likely effects of various options for addressing this gap are also explored. / Thesis / Doctor of Philosophy (PhD)

Les maladies cardiovasculaires (CV) représentent la première cause de mortalité lors de l'insuffisance rénale chronique (IRC). Cette morbidité apparat précocement lors de l'IRC et ne peut être explique par les facteurs de risque traditionnels. Le stress oxydant (SO), composante du cortège métabolique de l'IRC, représente un facteur de risque non traditionnel intriqué avec l'inflammation et la malnutrition. Le but de ce travail a été d'étudier la place du SO dans la survenue des complications CV au cours de l'IRC sur modale animal, puis de comparer le profil protéomique et la fonctionnalité des HDL in vitro entre sujets hémodialysés (HD) et témoins. Le SO au niveau CV a été étudié dans un modèle animal (adénine) d'IRC associé à la malnutrition. L'activité de la NADPH oxydase cardiaque est triple, alors que les activités des complexes de la chaîne respiratoire mitochondriale et de la SOD sont normales. Cette surproduction d'anion super oxyde est associé à une surexpression de l'ostéopontine et du pro-collagène de type I. L'étude protéomique des HDL de sujets HD et témoins a permis de préciser les anomalies qualitatives associées à la baisse des HDL induite par l'IRC. Les propriétés anti-oxydantes des HDL de ces mêmes sujets ont été étudiées in vitro sur un modèle d'oxydation des LDL au cuivre et sur un modèle cellulaire d'activation de la NADPH oxydase. En comparaison aux témoins, les HDL des sujets HD perdent leur capacité de protection des LDL contre l'oxydation. Par contre, la modulation de la NADPH oxydase sur modèle cellulaire est conservée avec les HDL de sujets HD mais serait moindre en présence d'une forte inflammation systémique. Ces résultats suggèrent que le SO est au cœur des complications cardiaques au cours de l'IRC. Parmi les mécanismes de défense endogènes, les propriétés anti-oxydantes des HDL sont en partie altérées chez le sujet HD. / Cardiovascular (CV) diseases are the first cause of mortality during chronic kidney disease (CKD) and cannot only be explained by traditional risk factors (age, gender, dyslipidemia, hypertension). Oxidative stress, which has been associated with CKD, appears as a non-traditional risk factor closely interconnected with inflammation and malnutrition.This study aimed at investigating oxidative stress in CV complications in uremic rats. Then, HDL proteomic profile and in vitro functionality of HDL were compared between hemodialyzed (HD) patients and control subjects.First, an animal model of CKD associated with malnutrition, the adenine-fed rats, was set up in order to study CV oxidative stress. NADPH oxidase activity was increased three-fold, but the maximal activity of mitochondrial respiratory chain complexes and SOD were not different between groups. Superoxide anion output was associated with accumulation of osteopontin and of pro-collagen type I. In a second part, HDL proteomic study from HD and control subjects was performed to characterize qualitative modifications associated with the decrease in HDL observed in CKD. HDL anti-oxidative activities from these subjects were studied in vitro in a model of copper-induced LDL oxidation and in a cellular model of NADPH oxidase activation. Compared to control, HDL from HD patients failed to protect LDL oxidation. By contrast, HDL modulation of NADPH activity is maintained in HD patients but could be impaired by elevated inflammation.These results suggest that oxidative stress is a key event in cardiac complications during CKD. Among protective endogenous mechanisms, HDL anti-oxidative properties could be impaired in HD patients.

End-stage renal disease (ESRD) introduces physical, psychological, social, emotional and spiritual challenges into patients’ lives. Spirituality has been found to contribute to improved health outcomes, mainly in the areas of quality of life (QOL) and well-being. No studies exist to explore the influences of spirituality on the health outcomes and general well-being in patients with end-stage renal disease receiving haemodialysis (HD) treatment in Scotland. This study was therefore carried out to examine and explore spirituality in the day-to-day lives of patients with ESRD receiving HD treatment and how it may influence their health outcomes and, in particular, QOL and general well-being. The study described in this thesis employed a sequential mixed method approach over two stages: quantitative and qualitative. Following ethical approval, a cross-sectional survey was conducted with 72 patients from 11 dialysis units recruited from four Health Boards in Scotland. The participants in the study were regular patients attending the dialysis units three times per week. Data on patients’ quality of life, general well-being, and spirituality were collected using self-administered questionnaires including demographic information: the Short Form Medical Outcome Study Questionnaire (SF-36v2), the General Health Questionnaire, and the Spiritual Well-Being Questionnaire. The data were analysed using the Predictive Analytics Software for Windows. The findings highlighted that patients’ quality of life was markedly lower than the United Kingdom general population average norms of 50. Increasing age was associated with better mental health but worse physical health. The survey also found that there were no significant associations between spirituality and patients’ quality of life and general well-being. However, it was considered important to complement and enrich the survey findings by gaining a deeper understanding of the influences of spirituality on patients’ health outcomes and general well-being by carrying out the qualitative component of the study. Qualitative data were collected using semi-structured interviews with a subsample of 21 patients from those who participated in the survey. A thematic approach using Framework Analysis informed the qualitative data analysis. Four main themes emerged from the qualitative interviews: ‘Emotional and Psychological Turmoil’, ‘Life is Restricted’, ‘Spirituality’ and ‘Other Coping Strategies’. The findings from the interviews confirmed that patients’ quality of life might be affected because of the physical challenges such as unremitting fatigue, disease unpredictability, or being tied down to a dialysis machine, or the emotional and psychological challenges imposed by the disease into their lives such as wholesale changes, dialysis as a forced choice and having a sense of indebtedness. The findings also revealed that spirituality was an important coping strategy for the majority of participants who took part in the qualitative component (n=16). Different meanings of spirituality were identified including connection with God or Supernatural Being, connection with the self, others and nature/environment. Spirituality encouraged participants to accept their disease and offered them a sense of protection, instilled hope in them and helped them to maintain a positive attitude to carry on with their daily lives, which may have had a positive influence on their health outcomes and general well-being. The findings also revealed that humour was another coping strategy that helped to diffuse stress and anxiety for some participants and encouraged them to carry on with their lives. The findings from this study contribute knowledge to increase our understanding of the influence of spirituality on the health outcomes and general well-being of patients with end-stage renal disease currently receiving haemodialysis treatment. Based on the findings from this thesis, recommendations are made for clinical practice, patient and nurse education and for future research.

L’insuffisance rénale chronique (IRC) terminale est une situation peu fréquente chez l’enfant mais a des conséquences importantes sur la survie et la qualité de vie. De nos jours, la majorité des enfants en IRC terminale en Europe vont recevoir une greffe de rein après un traitement de suppléance par dialyse ou de manière préemptive après un traitement conservateur de l’insuffisance rénale. Les objectifs de cette thèse sont de décrire l’épidémiologie de l’IRC chez l’enfant, d’évaluer les différences de pratiques et d’accès à la greffe rénale entre pays Européens, et d’investiguer le devenir clinique après transplantation, notamment la survie du greffon, la croissance, et la récidive de la maladie initiale sur le greffon. Premièrement, une revue de littérature sur l’épidémiologie de l’IRC chez l’enfant a été réalisée. Deuxièmement, nous avons mis en évidence par une enquête d’importantes variations de pratiques, de politiques d’allocation des greffons rénaux et d’accès à la greffe rénale pédiatrique à travers l’Europe. Des facteurs tels que le taux de greffe avec donneur vivant, la priorité nationale donnée aux enfants pour les donneurs décédés, ou un indicateur de richesse tel que le produit intérieur brut étaient associés à un meilleur accès à la greffe par pays. Troisièmement, l’étude du devenir après greffe par des études observationnelles a montré une amélioration de de la survie des greffons et de la taille à l’âge adulte après IRC terminale dans l’enfance. En utilisant l’oxalose comme exemple de maladie à haut risque de révidive, nous avons trouvé que le pronostic des enfants atteints d’oxalose en IRCT s’est amélioré au cours du temps. Il a été possible de déterminer quelles pratiques cliniques sont associées avec le meilleur devenir. L’ensemble de ces résultats suggère une augmentation de la prévalence et une meilleure prise en charge des enfants transplantés du rein en Europe. / Although end-stage renal disease (ESRD) is a rare condition in children, it has major consequences on their survival and quality of life. Most children with ESRD in Europe nowadays receive a renal transplant after variable periods of renal replacement therapy (RRT) with dialysis, or preemptively after conservative treatment of chronic kidney disease (CKD). The objectives of this thesis are to describe the epidemiology of CKD in children, to evaluate the differences of practices and access to transplant in Europe, and to investigate post transplant outcomes including graft survival, final height and disease recurrence. First, a literature review of the available data on pediatric CKD epidemiology was performed. Second, we analyzed the differences in transplantation practices, kidney allocation policies and access to transplantation between European countries in a survey study. Living donor transplant rate, national priority given to children, and an economic indicator like gross domestic product were found to be associated with a better access to transplantation by country. Third, we assessed post transplantation outcomes in longitudinal observational studies, including data from the European registry. We showed an improvement of graft survival and of adult height after childhood RRT over the years. Using oxalosis as an example of a rare disease with high risk of recurrence, we also found that the prognosis on RRT of children with such a disease improved over time. Some practices associated with better outcomes could be identified. Overall, our findings suggest an increasing prevalence and progress in the management of pediatric kidney transplant recipients in Europe.

Η τελικού σταδίου χρόνια νεφρική ανεπάρκεια (ΤΣΧΝΑ) είναι η αμετάκλητη απώλεια της νεφρικής λειτουργίας. Όταν η απώλεια της νεφρικής λειτουργίας φτάσει στο σημείο όπου οι νεφροί δεν μπορούν να συντηρήσουν τον ασθενή στην ζωή, τότε απαιτείται θεραπεία υποκατάστασης της νεφρικής λειτουργίας (ΘΥΝΛ). που είναι η αιμοκάθαρση (ΑΜΚ), η περιτοναϊκή κάθαρση, ή η μεταμόσχευση νεφρού. Η ενδονοσοκομειακή ΑΜΚ πραγματοποιείται 3 φορές την εβδομάδα και διαρκεί 3-5 ώρες. Η κατ' οίκον ΑΜΚ λαμβάνει χώρα στο σπίτι του ασθενούς, προσφέροντας ευελιξία στην επιλογή της συχνότητας (3-7 οορές εβδομάδα) και της διάρκειας της συνεδρίας ΑΜΚ (4-10 ώρες). Ειδικότερα η καθημερινή νυχτερινή κατ' οίκον ΑΜΚ, που πραγματοποιείται κατά την διάρκεια του ύπνου, προσφέρει σημαντικά κλινικά οφέλη, δυνατότητα κοινωνικής και επαγγελματικής αποκατάστασης, μείωση της φαρμακοληψίας, ελευθερία στην διατροφή και την πόση, καθώς και βελτίωση στην ποιότητα ζωής των ασθενών. Σύμφωνα με πρόσφατα στοιχεία, περισσότεροι από 10.000 Έλληνες ασθενείς υποφέρουν από ΤΣΧΝΑ και το 74% χρησιμοποιεί την ΑΜΚ ως θεραπεία υποκατάστασης, ενώ παράλληλα υπάρχει αυξανόμενη πίεση στις μονάδες ΑΜΚ, εξαιτίας της μεγάλης προσαύξησης του αριθμού των ασθενών τους. Για το 2004, η Ελλάδα παρουσίασε την μεγαλύτερη συχνότητα νεοεισαχθέντων ασθενών ανά εκατομμύριο πληθυσμού στην ΑΜΚ σε σύγκριση με 24 Ευρωπαϊκές χώρες και κατείχε την 3η θέση παγκοσμίως στην αντίστοιχη συχνότητα σε ΘΥΝΛ, μετά τις ΗΠΑ και την Ιαπωνία. Η κατάταξη της Ελλάδας στην 8η θέση, στην παγκόσμια σύγκριση του επιπολασμού σε ΘΥΝΛ, παρόλο που είναι ευνοϊκότερη, παραμένει πολύ υψηλή, υποδεικνύοντας το μέγεθος του αυξημένου αριθμού ΤΣΧΝΑ στην χώρα μας. Στους παράγοντες που συντελούν στην ύπαρξη του φαινομένου, είναι ο πολύ χαμηλός αριθμός μεταμοσχεύσεων νεφρού στην Ελλάδα, η οποία κατέχει την 20η θέση ανάμεσα σε 24 Ευρωπαϊκές χώρες, για το 2004, καθώς και η αύξηση της επιβίωσης των ασθενών σε ΘΥΝΛ. Η παρούσα διδακτορική διατριβή εστιάζεται στην αποτίμηση τεχνολογίας υγείας της κατ' οίκον αιμοκάθαρσης, στην μελέτη των παραγόντων που επιδρούν την υιοθέτηση της και στην αξιολόγηση της ποιότητας ζωής των αιμοκαθαιρομένων στην Ελλάδα. Συγκεκριμένοι στόχοι της είναι: i) Να εκτιμηθεί, πέρα από την ποιότητα ζωής, η προθυμία των Ελλήνων αιμοκαθαιρομένων να συμμετάσχουν σε πρόγραμμα κατ' οίκον ΑΜΚ και ii) Να διεξαχθεί βιβλιογραφική ανασκόπηση για να αποτιμηθεί αν η κατ' οίκον αιμοκάθαρση είναι πιο αποτελεσματική και με καλύτερο δείκτη κόστους -χρησιμότητας από την ενδονοσοκομειακή, καθώς και να συγκεντρωθούν και να αναλυθούν δεδομένα από την ερευνητική επίσκεψη σε έμπειρα κέντρα κατ' οίκον αιμοκάθαρσης του εξωτερικού. Η συγκέντρωση δεδομένων για την σχετιζόμενη με την υγεία ποιότητα ζωής 146 Ελλήνων αιμοκαθαιρομένων, πραγματοποιήθηκε σε 10 κέντρα ΑΜΚ της Ελλάδας, με ποσοστό απόκρισης 84%. Χρησιμοποιήθηκε το εξειδικευμένο στη νεφροπάθεια εργαλείο KDQOL-SF (που ενσωματώνει το εργαλείο γενικής υγείας SF-36) και ένα συμπληρωματικό ερωτηματολόγιο που συνοδευόταν από ενημερωτικό κείμενο για την* νυχτερινή κατ' οίκον ΑΜΚ, ώστε να συλλεχθούν δημογραφικά δεδομένα και να εκτιμηθεί η προθυμία συμμετοχής σε πρόγραμμα κατ' οίκον ΑΜΚ. Η συμπλήρωση των ερωτηματολογίων έγινε με επιτόπου συνέντευξη. Στην έρευνα συμμετείχαν 99 άνδρες και 47 γυναίκες, με μέση ηλικία 57 +/- 15,7 έτη. Παρόλο που το 61% των ερωτηθέντων ήταν σε παραγωγική ηλικία, μόνο το 23% είχαν παραμείνει στην εργασία τους και οι υπόλοιποι ήταν είτε άνεργοι, είτε σε άδεια ασθενείας, είτε είχαν συνταξιοδοτηθεί λόγω μερικής αναπηρίας, ενώ το 62% των ασθενών δήλωσε ετήσιο εισόδημα μικρότερο από 10.000€. Ο σακχαρώδης διαβήτης ήταν η πιο συχνά εμφανιζόμενη πρωτογενής αιτία νεφρικής ανεπάρκειας (20%) και η πλειοψηφία των ασθενών (73%) τελούν ΑΜΚ για λιγότερα από πέντε χρόνια. Τρεις ασθενείς αναγκάστηκαν να αλλάξουν τόπο διαμονής για να βρίσκονται πιο κοντά στην μονάδα ΑΜΚ, ενώ περίπου το 45% των αιμοκαθαιρομένων διανύουν συνολικά περισσότερα από 40km, 3 φορές την εβδομάδα, για κάθε συνεδρία ΑΜΚ. Από τις κλίμακες του KDQOL-SF, χαμηλότερες τιμές καταγράφηκαν στην εργασία, την σεξουαλική λειτουργία και τον φόρτο της νεοροπάθειας. Η σύγκριση των κλιμάκων SF-36 του δείγματος με τον Ελληνικό γενικό πληθυσμό παρουσίασε στατιστικά σημαντικές διαφορές (p<0,01) σε όλες τις κλίμακες, πλην του σωματικού πόνου. Επίσης, η σύνοψη συνιστωσών ψυχικής υγείας του δείγματος των αιμοκαθαιρουμένων ήταν ελαφρώς χαμηλότερη από του γενικού πληθυσμού, ενώ η σύνοψη συνιστωσών σωματικής υγείας ήταν αρκετά χαμηλότερη. Τα αποτελέσματα του δείγματος της παρούσας έρευνας (Ν=146) συγκρίθηκαν με αντίστοιχο δείγμα Ισπανών ασθενών ΤΣΧΝΑ (Ν=194) που συμπλήρωσαν το ίδιο ερωτηματολόγιο. Το γεγονός ότι και σ" αυτή την σύγκριση δεν εμφανίστηκε στατιστικά σημαντική διαφορά στην κλίμακα του σωματικού πόνου, ενδυναμώνει την εγκυρότητα της μέτρησης και υποδεικνύει ότι οι ασθενείς ΤΣΧΝΑ δεν υπέφεραν σημαντικά από σωματικό πόνο εξαιτίας της ασθένειας τους, σε σημείο τέτοιο, που να έχει αρνητική απήχηση στην αντίληψη τους για την σχετιζόμενη με την υγεία ποιότητα ζωής τους. Διάθεση συμμετοχής στην νυχτερινή κατ’ οίκον ΑΜΚ εξέφρασε το 84% των ασθενών και το 75% για την κατ΄ οίκον ΑΜΚ. Έντονη προθυμία σημειώθηκε στο 53% και το 38% των 146 ερωτηθέντων αντίστοιχα, ενώ διατεθειμένοι να δαπανήσουν κάποιο χρηματικό ποσό για να συμμετάσχουν ήταν το 38%. Στην ερευνητική επίσκεψη σε δύο μεγάλα και έμπειρα κέντρα κατ’ οίκον αιμοκάθαρσης του εξωτερικού, στο Lund και το Helsinki. συγκεντρώθηκαν πολύτιμα δεδομένα που αφορούν στην οργάνωση, την διεξαγωγή, την εμπειρία και την τεχνογνωσία τους. και τα οποία σχετίζονται με την δομή του προγράμματος, οικονομικές εκτιμήσεις, ιατρικά δεδομένα, στατιστικά αποτελέσματα, μεθόδους εκπαίδευσης και τα πιθανά ρίσκα ή προβλήματα που ενδέχεται να ανακύψουν, μαζί με τους τρόπους αποφυγής ή επίλυσης τους. Τα δημογραφικά δεδομένα σε συνδυασμό με το υψηλό κόστος, καθιστούν την ενδονοσοκομειακή αιμοκάθαρση μια από τις πιο δαπανηρές υγειονομικές παρεμβάσεις και διαπιστωμένα την πιο δαπανηρή μεταξύ των υπολοίπων μεθόδων ΘΥΝΛ. Το κόστος της στην Ελλάδα ξεπερνά το 2% των δαπανών της υγείας. Από την ανασκόπηση της παγκόσμιας βιβλιογραφίας, αλλά και από την μελέτη των κέντρων ΑΜΚ της Σκανδιναβίας, επιβεβαιώνεται ότι η κατ’ οίκον και η δορυφορική ΑΜΚ στοιχίζουν λιγότερο και έχουν καλύτερο δείκτη κόστους-αποτελεσματικότητας από την ενδονοσοκομειακή ΑΜΚ. ενώ παράλληλα εμφανίζουν αυξημένη επιβίωση και καλύτερη ποιότητα ζωής. Κατά συνέπεια, η ανάπτυξη αυτών των εναλλακτικών μεθόδων στην Ελλάδα θα μπορούσε να αμβλύνει την αύξηση του προβλεπόμενου συνολικού κόστους των μεθόδων ΘΥΝΛ στο υγειονομικό σύστημα, συμβάλλοντας και στην ανακούφιση από το πρόβλημα της αυξανόμενης πίεσης στις νοσοκομειακές μονάδες ΑΜΚ. αλλά και της έλλειψης του νοσηλευτικού προσωπικού, με την ταυτόχρονη βελτίωση της ποιότητας ζωής των αιμοκαθαιρομένων. Με την κατάλληλη οργάνωση και στελέχωση, η κατ* οίκον ΑΜΚ θα μπορούσε να γίνει εφικτή και στην Ελλάδα, αφού μεγάλη μερίδα ασθενών δηλώνουν πρόθυμοι να συμμετάσχουν, γεγονός που αποτελεί και την βασικότερη προϋπόθεση επιτυχίας ενός τέτοιου προγράμματος. Επιπρόσθετα, με δεδομένο ότι η Ελλάδα παρουσιάζει πολύ υψηλή συχνότητα νεοεισαχθέντων ασθενών ΤΣΧΝΑ, πρέπει να ενταθούν οι προσπάθειες για την συγκράτηση και τον περιορισμό αυτού του φαινομένου, μέσω προγραμμάτων ενημέρωσης και πρόληψης, που μαζί με την μεταμόσχευση παραμένουν οι αποτελεσματικότεροι τρόποι αντιμετώπισης του προβλήματος. / End stage renal failure is the irreversible loss of kidney function. When loss of kidney function reaches the point at which die kidneys fail to support life, then renal replacement therapy (RRT) is required, that is hemodialysis (HD), peritoneal dialysis or renal transplantation. Hospital hemodialysis is conducted 3 times per week and lasts 3-5 hours. Home hemodialysis takes places at patient’s home, offering flexibility in choosing the frequency (3-7 times Week) and the length of the hemodialysis session (4-10 hours). Daily nocturnal home hemodialysis in particular, which is conducted while the patient is asleep, offers significant clinical benefits, the opportunity of social and professional rehabilitation, reduction of drugs, freedom in diet and drinking intake, as well as improvement in patients' quality of life. According to recent records, more than 10.000 Greek patients suffer from end stage renal disease (ESRD) and 74% of them use hemodialysis as replacement therapy, while at die same time there is increasing pressure on hemodialysis units because of the growing number of patients who are receding hemodialysis. In 2004, Greece appeared to have the highest incidence per million population in hemodialysis, in comparison with 24 European countries and the 31 place in die world in the incidence per million population in RRT, after USA and Japan. The rating of Greece in the 8th place of global comparison in prevalence in RRT, although more propitious, remains very high suggesting die extent of the increasing number of ESRD m Greece. Among the factors that contribute to the existence of this phenomenon are the very low numbers of renal transplantation in Greece, which holds the 20th place among 24 European countries m 2004 and the increase of survival of patients on RRT. This doctoral thesis focuses on technology assessment of home HD, the study of the factors that affect its adoption and finally die evaluation of Greek hemodialysis patients' quality of life. The specific objectives are: i) To evaluate the quality of life of Greek hemodialysis patients, as well as their willingness to participate in a home HD program and ii) To conduct a review of the literature in order to assess whether home hemodialysis is more effective and with better cost-utility than hospital hemodialysis and to gather and analyze data taken from the inquiring visit in experienced home hemodialysis units of foreign countries. Data concerning die health related quality of life of 146 Greek hemodialysis patients were gathered from 10 HD units in Greece and the response rate was 84%. The renal disease specific instrument KDQOL-SF was used (which incorporates the general health instrument SF-36), accompanied with an additional questionnaire and an informative leaflet on nocturnal home hemodialysis, in order to gather demographic data and to evaluate the willingness of participation m a home hemodialysis progρam. Questionnaires were completed with on site interview. This study included 99 men and 47 women, with mean age 57 +/- 15,7 years. Although 61% of the participants were in productive age, only 23% were employed and the rest were either unemployed, on sick leave or receiving a disability pension, while 62% of the patients reported annual income less than l0.000 Euros. Diabetes mellitus was the most common primary kidney disease (20%) and the majority of patients were on hemodialysis for less than five years. Three patients were obliged to change place of residence so as to be closer to the hemodialysis unit, while almost 45% of the patients had to navel more than 40km, 3 times per week, for every HD session. The lowest scores in KDQOL-SF scales were found in work status, in sexual functioning and m the burden of kidney disease. The comparison of the SF-36 scales of die study sample with the Greek general population identified statistically significant differences (p<0.01) in all scales, except of the bodily pain scale. Moreover, the Mental Component Summary was slightly worse compared with the general population's, while the Physical Component Summary was quite lower. The results of the present study sample (N=146) were compared with an equivalent sample of Spanish ESRD patients (N=194) who completed the same questionnaire. The fact that m this comparison no statistically significant difference was found in the scale of bodily pain, strengthens the validity of the measurement and suggests that ESRD patients did not experience severe suffering from pain due to their disease that could worsen their perception of health related quality of life. Inclination to participate in nocturnal home HD was expressed by 84% of the patients and by 75% of the patients for home hemodialysis. Strong willingness was reported in 53% of the patients for nocturnal home HD and in the 38% for home HD respectively, while the 38% of the patients were also willing to contribute financially in order to participate. The inquiring visit in two experienced home hemodialysis units in Lund and Helsinki, provided valuable information concerning their organization, their waging, their experience and their know-how. which are related with the structure of the program, economical evaluations, medical data, statistical outcomes, methods of training and potential risks or problems that might emerge, together with advices on how to avoid or solve them. The demographical data in combination with the high cost renders hospital hemodialysis one of the most expensive medical interventions and certainly the most expensive among the other RRT methods. Hemodialysis cost in Greece absorbs more than 2% of total health expenditure. The review of the global literature and the study on the Scandinavian home HD units verified that both home and satellite hemodialysis are less costly and more cost-effective than hospital hemodialysis, while at the same time they present increased survival and better quality of life. Hence, the development of these alternative modalities of dialysis in Greece could mitigate the anticipated net cost increases of RRT to the health system. This could contribute to the alleviation of the increasing pressure on hospital HD units and the nursing shortage, with the simultaneous improvement of hemodialysis patients' quality of life. With the appropriate organization and staff, home hemodialysis could be feasible also in Greece, since big part of the patients are reporting willingness to participate and this fulfils the basic requirement for such a program to succeed. In addition, considering that Greece reports very high incidence, efforts must be intensified in order to restrain and reduce this phenomenon, through informing and prevention programs, which next to renal transplantation are the most effective ways to confront the problem.

Τα μέχρι σήμερα βιβλιογραφικά δεδομένα συνηγορούν υπέρ της ύπαρξης σύνδεσης μεταξύ της γονεϊκής νόσου και αυξημένης επίπτωσης συναισθηματικών και συμπεριφοριστικών προβλημάτων στα παιδιά Ωστόσο, στην Ελλάδα δεν υπάρχουν καθόλου βιβλιογραφικά δεδομένα, σχετικά με την σύνδεση της Χρόνιας Νεφρικής Ανεπάρκειας και ειδικότερα της θεραπείας ενδονοσοκομειακής αιμοκάθαρσης (ΑΜΚ) στους γονείς και της πιθανής εμφάνισης ψυχοπαθολογίας στα τέκνα αυτών. Εστία αυτής της μελέτης αποτέλεσε η συσχέτιση της ΧΝΑ και της ΑΜΚ στον γονέα με συγκεκριμένες διαγνωστικές κατηγορίες ή υποκατηγορίες Ψυχικών Διαταραχών στα παιδιά των ασθενών αυτών. Μελετήθηκαν προοπτικά 53 παιδιά, των οποίων ο πατέρας ή η μητέρα υποβαλλόταν σε ΑΜΚ, ηλικίας 6-21 ετών, με την χρήση των Ερωτηματολογίων της Achenbach για γονείς καθώς και με τη χρήση της Ημιδομημένης Ψυχιατρικής Διαγνωστικής Συνέντευξης για Παιδιά και Εφήβους K-SADS-PL. Επίσης εξετάσθηκε η ψυχική υγεία των ασθενών γονέων, με την χρήση της διαγνωστικής συνέντευξης SCID-I και SCID-II και των υγιών γονέων με την χρήση των ερωτηματολογίων ΗΑΜ-D και HAM-A. Διαπιστώθηκαν στατιστικά σημαντικές διαφορές σε όλες τις ομάδες συμπεριφορών της κλίμακας CBCL και στις δυο ηλικιακές ομάδες (6-18 & 18-21). Επίσης αναδείχθηκε ότι τα παιδιά της πειραματικής ομάδας παρουσίαζαν υψηλότερα ποσοστά ψυχοπαθολογίας, συγκριτικά με τους μάρτυρες ως προς την ψυχική υγεία των ασθενών γονέων ευρέθη ότι το 48.3% συμπλήρωναν τα κριτήρια για μια τουλάχιστον Ψυχική Διαταραχή, ενώ το αντίστοιχο ποσοστό στους μάρτυρες ήταν 20.7% (ΟR=6.7, 95% CI 2.0-28.7). Η μέση τιμή της βαθμολογίας που καταγράφηκε για την κατάθλιψη των συζύγων ασθενών ήταν 15.31 (SD=11.7) ενώ των συζύγων-μαρτύρων ήταν 3.19 (SD=3.65), διαφορά η οποία είναι στατιστικώς σημαντική (p<0.001). Τα υπό μελέτη παιδιά εμφανίζουν μεγαλύτερη ψυχοπαθολογία συγκριτικά με τους μάρτυρες, με επικρατέστερη της διαταραχή «Ειδική Φοβία» αλλά και την «Κατάθλιψη» και «Διαταραχή Διαγωγής». Επίσης, παρουσιάζουν περισσότερα συμπεριφορικά προβλήματα σε όλες τις επιμέρους Συμπεριφορές της κλίμακας CBCL, χαμηλότερες τιμές στο προφίλ ικανοτήτων, ενώ στα μεγαλύτερα σε ηλικία παιδιά ανεβρέθηκαν περισσότερα συναισθηματικά προβλήματα. Οι ασθενείς γονείς εμφανίζουν συντριπτικά υψηλότερα ποσοστά στις διαταραχές Διάθεσης, ενώ και στους υγιείς γονείς αναδείχτηκαν πολύ αυξημένα επίπεδα αγχώδους και καταθλιπτικής συμπτωματολογίας. Απαραίτητη είναι η διεξαγωγή προοπτικών μελετών, που θα αναδείξουν την ψυχοκοινωνική εξέλιξη των παιδιών αυτών στο χρόνο. / Bibliographic data up to today speak in favour of the existence of a strong connection between the parental illness and increased sentimental and behaviouristic problems in the children. However, in Greece no data exists. The aim of the present study was to explore the possible psychological impact on the children, who have a parent undergoing in-centre hemodialysis (HD) in Greece. We investigated 53 children, aged 6-21 years old, living at home, whose one parent was undergoing in-centre haemodialysis. The parents were recruited from 4 different haemodialysis centres in Southern Greece. Control subjects were matched with the study children for age, sex, place of residence, socioeconomic status and parental educational level. The data collection was carried out by filling the Child Behavior Checklist (CBCL) and the Adult Behavior Checklist (ABCL), with reports of the ill parent describing specific behavioral and emotional problems of the child, when the psychopathology of the children and their ill parents was studied according to DSM-IV criteria. Children of parents undergoing haemodialysis scored statistically significantly higher than the children in the control group (p<0.01, Wilcoxon signed-ranks test for paired data) on all aspects of trends in behavior (internalizing, externalizing, neither internalizing nor internalizing) on the CBCL and the ABCL scale. We found that this result would remain, even if it was tested with respect to sex (male/female) and age (6-18, 18-21). On the internalizing composite scale females aged 18-21 scored higher than males of same age. Also psychiatric disorders were by 1.8 -fold more frequent in the children of HD parents than in the control children. Ill parents suffered more from a psychiatric disorder (65.5%) in comparison with their controls (20%). The results of this study suggest that parental illness affects negatively the mental health of their dependent offspring aged 6-21 years old. Older children and mainly females seem to be more prone to depressive symptoms. Ill parents suffer greatly from psychiatric disorders and the most common is depression. Also it seems that parental mental health (both in the ill and the healthy parent) influence the mental health of the children. Essential is the conduct of prospective studies that will elect the psychosocial development of this population.

Depression is common in haemodialysis (HD) patients and is often unrecognised and undertreated, though associated with excess morbidity and mortality. Diagnosis is challenging due to symptom overlap with kidney failure, with fatigue being the most common overlapping symptom. Research on the effectiveness of antidepressant medication in this setting is sparse. A recent systematic review advocated well-designed Randomised Controlled Trials (RCTs) in this setting. The studies reported in this thesis had a number of aims. The main aim was to undertake a multicentre feasibility randomised, double blind, placebo-controlled trial of sertraline in patients on HD with Major Depressive Disorder (MDD). To identify suitable patients for this, a screening phase was required, which also allowed determination of the prevalence of depression in this setting and of the relative effectiveness of screening tools Patient Health Questionnaire-2 (PHQ-2), Patient Health Questionnaire-9 (PHQ-9), and Beck Depression Inventory-II (BDI-II). It also allowed examination of the relationships of fatigue in this setting (assessed mainly by the Multidimensional Fatigue Inventory (MFI), including those with a diagnosis, and management of depression. The finding, during screening, that a large proportion of the HD cohort was already on antidepressant treatment, presented the opportunity to study 'real-life' practice patterns in the management of antidepressant treatment in this setting. Recruitment into the RCT was difficult. 1,355 patients in five HD centres were considered for screening, but 243 of these were excluded, mainly because of their inability to read and understand English. Of the remaining 1,110 patients, 709 consented to screening. 231 of these screened positive for high depression symptoms but 130 were not considered for the trial phase, mainly because of concurrent treatment for depression (68 patients), and other contraindicated conditions and medication. In addition, 38 patients declined to take part in the psychiatric interview necessary for diagnosis of MDD. Of the 63 who underwent the diagnostic interview, 37 (58.7%) were diagnosed with MDD and 30 consented to enter the RCT and were randomised into sertraline or placebo groups. This was half of the anticipated recruitment into the RCT. Twenty-one patients (70%) completed the six-month study, eight of 15 in the sertraline group and 13 of 15 in the placebo group (p < 0.05). Drop out was mainly due to adverse or serious adverse events. Depression scores (BDI-II and Montgomery-Åsberg Depression Rating Scale (MADRS)) improved significantly in both the sertraline and placebo groups over six months but there were no significant differences between the treatment groups. There was a slight suggestion of more rapid improvement over the first two months on sertraline, but this was not significant. Fatigue scores were high in all sub-domains - with only a weak relationship with age and comorbidity. Mental fatigue was the strongest independent predictor of high depressive symptoms (BDI-II ≥16, PHQ-9 ≥8), while physical fatigue had the strongest relationship with dialysis recovery time, and survival. Distinguishing between these components of fatigue may have a role in refining the diagnosis and management of MDD. Forty-one of the 76 patients on antidepressant medication at screening were followed up for a mean of 14±5 months. Ten different antidepressant agents were being taken - the most common being Citalopram (39%). Most had been prescribed by GPs. Two-thirds of patients either deteriorated or failed to improve in terms of BDI-II scores during follow-up, many of whom had had no adjustment of medication during this time. Diagnostic evaluation at follow-up showed 37% to be suffering from current or recurrent major depressive episodes (MDE), 48% to have evidence of past MDE, and 15% to have no evidence of ever having been depressed. These empirical studies confirm that depression is very common in HD patients. Its diagnosis is complicated due to symptom overlap with the uraemic syndrome. Fatigue seems to be a key area of overlap with symptoms of depression with a complex relationship. There was no obvious benefit from antidepressants in this feasibility RCT and there was a high drop-out rate due to adverse events, particularly in the sertraline group. These findings raise concerns about the benefits and risks of antidepressants in patients on HD. Current practice patterns may be subjecting patients to substantial risk for little or no benefit. Identifying whether antidepressant medication is effective in this context is a major clinical need, hence the requirement for a definitive study. There is no doubt that to undertake a definitive study would pose considerable recruitment challenges. The findings presented here emphasise the importance of finding ways to overcome these challenges that might include efforts to incorporate patients already taking antidepressants.

Submitted by isabela.moljf@hotmail.com (isabela.moljf@hotmail.com) on 2017-06-19T12:43:50Z No. of bitstreams: 1 felipemartinsdovalle.pdf: 1212367 bytes, checksum: 1eb080fe9bb9c5ae3bdedfa118be339b (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-06-29T12:23:35Z (GMT) No. of bitstreams: 1 felipemartinsdovalle.pdf: 1212367 bytes, checksum: 1eb080fe9bb9c5ae3bdedfa118be339b (MD5) / Made available in DSpace on 2017-06-29T12:23:35Z (GMT). No. of bitstreams: 1 felipemartinsdovalle.pdf: 1212367 bytes, checksum: 1eb080fe9bb9c5ae3bdedfa118be339b (MD5) Previous issue date: 2017-02-22 / Introdução: O sedentarismo é altamente prevalente e aumenta a taxa de mortalidade por todas as causa em pacientes com doença renal crônica (DRC) em hemodiálise (HD). Em contraste, um estilo de vida mais ativo está associado a ganhos para esses pacientes. Assim, investigamos os efeitos do treinamento resistido intradialítico e supervisionado no nível de atividade física diária (NAFD), na capacidade funcional (CF), na qualidade de vida (QV) e na força muscular (FM) de pacientes com DRC em HD. Métodos: Vinte e quatro pacientes com DRC (54,2 ± 13,5 anos) em HD (6,0 ± 5,7 anos) foram randomizados para treinamento resistido de moderada intensidade ou controle. O treinamento resistido foi realizado durante as duas primeiras horas das sessões de HD, três vezes por semana, durante três meses. O NAFD foi avaliado por um acelerômetro pelo tempo gasto em diferentes atividades da vida diária (caminhando, em pé, sentado e deitado) e o número de passos. O acelerômetro foi utilizado por sete dias consecutivos (três dias dialíticos e quatro dias de não dialíticos). A CF, a QV e a FM foram avaliadas pelo teste de caminhada de seis minutos (TC6M), questionário SF-36 e pelo teste de contração isométrica voluntária máxima (CIVM), respectivamente. Os valores foram representados em deltas (pós-tratamento menos pré-tratamento). Resultados: Após três meses de treinamento resistido, não foi encontrada diferença significativa no tempo de caminhada (-1,2 ± 18,3 vs. -9,2 ± 13,1 min/dia), no tempo em pé (-10,2 ± 28,6 vs. ± 20,1 min/dia), no tempo sentado (20,8 ± 58,9 vs. -30,0 ± 53,0 min/dia), no tempo deitado (-9,3 ± 57,9 vs. 34,6 ± 54,0 min/dia) e no número de passos [-147 (1834) vs. -454 (2066)] entre os grupos exercício e controle, respectivamente. A distância percorrida no TC6M aumentou significativamente no grupo de treinamento em relação ao grupo controle (48,8 ± 35,9 vs. 6,9 ± 45,9 m, p=0,04). Não foi encontrada diferença significativa na FM (3,4 ± 7,2 vs. 0,5 ± 7,3 Kgf) entre os grupos treinamento e controle, respectivamente. Três domínios do SF-36 apresentaram aumento significativo no grupo treinamento em relação ao controle, respectivamente [capacidade funcional = 13,7 ± 9,9 vs. -12,5 ± 16,7, p=0,003; limitação por aspectos físicos = 0,0 (0,0) vs. -50,0 (93,7), p=0,03; estado geral da saúde = 6,6 ± 14,1 vs. -10,4 ± 21,4, p=0,01). O treinamento resistido intradialítico foi realizado com segurança por todos os participantes. Conclusão: O presente estudo demonstrou que o NAFD não foi modificado após três meses de treinamento resistido intradialítico em pacientes com DRC submetidos à HD. No entanto, esse programa de exercícios foi capaz de aumentar a CF e alguns domínios da QV nesses pacientes. / Background: Physical inactivity is highly prevalent and increases all causes of mortality in end-stage renal disease (ESRD) patients on hemodialysis (HD). In contrast, a more active lifestyle is associated with better outcomes in these patients. We therefore investigated the effects of supervised intradialytic resistance training on physical activities in daily life, physical capacity, quality of life and muscle strength in ESRD patients. Methods: Twenty four ESRD patients (54.2 ± 13.5 years) under HD (6.0 ± 5.7 years) were randomly assigned to either 3-month moderate-intensity resistance training or a control period. Resistance training was performed during the first two hours of HD sessions, three times a week, for three months. Physical activities in daily life was evaluated using an accelerometer regarding the time spent in different activities and positions of daily life (walking, standing, sitting and lying down), and the number of steps taken. The accelerometer was used for seven consecutive days (three dialysis days and four nondialysis days). Physical capacity, quality of life and muscle strength were evaluated by six-minute walking test (6MWT), SF-36 questionnaire and maximum voluntary isometric contraction test, respectively. The values were expressed as delta (post-pre treatment). Results: After three months of training, we didn’t find significant difference in walking time (-1.2 ± 18.3 vs. -9.2 ± 13.1 min/day), standing time (-10.2 ± 28.6 vs. 3.2 ± 20.1 min/day), sitting time (20.8 ± 58.9 vs. -30.0 ± 53.0 min/day), lying down time (-9.3 ± 57.9 vs. 34.6 ± 54.0 min/day) and number of steps taken [-147 (1834) vs. -454 (2066)] in training and control groups, respectively. The 6MWT distance increased significantly in training group when compared with control group (48.8 ± 35.9 vs. 6.9 ± 45.9 m, p=0.04). No significant difference was found in muscle strength (3.4 ± 7.2 vs. 0.5 ± 7.3 Kgf) in training and control groups, respectively. Three domains of the SF-36 showed significant increase in training group when compared with control group, respectively (physical functioning = 13.7 ± 9.9 vs. -12.5 ± 16.7, p=0.003; role physical = 0.0 (0.0) vs. -50.0 (93.7), p=0.03; general health = 6.6 ± 14.1 vs. -10.4 ± 21.4, p=0.01). Intradialytic resistance training was safely performed by all participants. Conclusions: The present study showed that daily life activities were not modified after three months of intradialytic resistance training in HD patients. However, the exercise program was able to increase the physical capacity and some domains quality of life in these patients.

Abstract The aim of this work was to evaluate the outcome of childhood Henoch-Schönlein purpura (HSP), the effectiveness of Cyclosporine A (CyA) for treating severe HSP nephritis (HSN), and more particularly the possibility for influencing the course of HSP disease by early prednisone treatment. A total of 47 adults who had had childhood HSP were evaluated after a mean of 24.1 years (16.4–35.6). The outcome was highly dependent on the renal symptoms at onset, since 7 out of 20 adults (20%) who had severe renal symptoms at onset had renal impairment as adults, compared with 2 out of 27 (7%) with mild or no renal symptoms at onset (relative risk 4.7; 95% CI 1.3–18.7). 70% of pregnancies in women after childhood HSN were complicated by hypertension or proteinuria. The annual incidence of HSN with nephrotic-range proteinuria was 2 per million children under 15 years. After a mean follow-up of 4.6 years, only three patients out of 19 were in complete remission. Kidney biopsy did not predict the outcome in these patients. CyA seemed to be promising for the treatment of severe HSN with nephrotic-range proteinuria, since four out of seven patients treated with CyA achieved stable remission and three had preserved their renal function after a mean follow-up of 6.0 years. Treatment at an early stage in the disease was associated with stable remission. The efficacy of early prednisone treatment was evaluated in a randomized double-blind trial involving 171 patients (84 prednisone, 87 placebo). Prednisone, given at a dose of 1 mg/kg/day for 2 weeks, with weaning over the next two weeks, was effective in reducing the intensity of abdominal pain (pain score 2.5 vs. 4.8; t-test p = 0.029) and shortening its duration (1.5 days vs. 2.7 days; t-test p = 0.028) compared with the placebo. The mean scores for joint pain were lower in the prednisone group (4.6 vs. 7.3; t-test p = 0.030) and the improvement from joint symptoms was faster (log rank p = 0.007). Prednisone did not prevent the development of renal symptoms but it was effective in treating them, since renal symptoms resolved in 61% of the prednisone patients after treatment compared with 34% of the placebo patients (difference 27%, 95% CI 3–47%, p = 0.024). Prednisone was most effective for children aged 6 or more with renal symptoms at onset, since only two patients needed to be treated in order to save one from renal involvement (95% CI's for NNT 2–6). The long-term outcome of HSP is dependent on renal symptoms. Severe renal symptoms indicate early immunosuppressive treatment for HSN, and patients with renal involvement at the acute phase need long-term follow-up, especially women during and after pregnancy. Early treatment with prednisone is effective in reducing the abdominal and joint symptoms involved in HSP and is also effective in altering, but not preventing, the course of renal involvement. / Tiivistelmä Väitöskirjatyön tarkoituksena oli selvittää lapsuusiän Henoch-Schönleinin purppuran (HSP) pitkäaikaisennustetta, Siklosporiini-A:n (CyA) tehoa vaikean HSP-nefriitin hoidossa ja tutkia varhain aloitetun prednisonihoidon hyötyä HSP-taudin oireisiin. HSP:n pitkäaikaisennustetta selvitettiin tarkastamalla 47:n lapsena HSP-taudin sairastaneen aikuisen terveystilanne keskimäärin 24.1 vuoden (16.4-35.6) seuranta-ajan jälkeen. HSP-taudin ennuste oli vahvasti riippuvainen munuaisoireen vaikeusasteesta: 20 % niistä, joilla taudin alussa oli vaikeat munuaisoireet, kärsi vielä aikuisiällä munuaisoireista; vastaava luku munuaisoireettomilla ja niillä, joilla oli ollut vain lievää veri- tai valkuaisvirtsaisuutta, oli 7 %, (RR 4.7; 95 % CI 1.3–18.7). Raskauskomplikaatiot olivat yleisiä lapsuusiällä HSP-taudin sairastaneilla naisilla, sillä 70 % raskauksista komplisoi korkea verenpaine tai valkuaisvirtsaisuus. Vuosittain 2 lasta miljoonasta sairastuu vaikeaan nefroottistasoiseen HSP-nefriittiin Suomessa. Vain kolme nefroottistasoiseen HSP-nefriittiin sairastuneesta 19 lapsesta oli 4.6 vuoden seurannan jälkeen parantunut oireettomaksi. Ensimmäisen munuaisbiopsian vaikeusaste ei ennakoinut selviytymistä. CyA näytti olevan lupaavan tehokas lääke vaikean HSP-nefriitin hoidossa, sillä neljä seitsemästä CyA-hoitoa saaneesta lapsesta, oli oireeton 6.0 vuoden seurannan jälkeen. Mitä aikaisemmin vaikean nefriitin hoito oli aloitettu, sen parempi hoitotulos oli. Varhain aloitetun prednisonihoidon hyötyä HSP-taudin oireisiin selvitettiin satunnaistetulla kaksoissokkotutkimuksella, johon satunnaistettiin 171 lasta (84 prednisoni, 87 lumelääke) saamaan joko prednisonia 1 mg/kg/päivä 2 viikon ajan tai lumelääkettä. Prednisoni vähensi tehokkaasti vatsa- ja nivelkipuja ja se lyhensi merkitsevästi myös niiden kestoa. Prednisoni ei estänyt munuaisoireen kehittymistä lapselle, mutta niiltä, joille se kehittyi, oireet hävisivät merkitsevästi nopeammin lumelääkitykseen verrattuna (61 % versus 34 %, 95 % CI 3–47 %, p = 0.024). Kaikkein tehokkainta prednisoni oli yli 6 vuotiaille lapsille, joilla oli munuaisoire heti taudin alussa (NNT 2, 95 % CI 2–6). Tutkimuksen perusteella voidaan sanoa, että lapsuusiällä HSP-nefriitin sairastaneet lapset tarvitsevat seurantaa aikuisiällä, erityisesti naiset raskauden aikana. HSP-nefriitin varhainen hoitaminen on tärkeää. Varhainen prednisonihoito ei estä munuaisoiretta, mutta hoitaa jo kehittynyttä nefriittiä ja vähentää vatsa- ja nivelkipuja tehokkaasti.