Interferons are known cytokines that display antiviral, anti-proliferative and immuno-modulatory functions in the host. Interferon-gamma (Ifnγ) is the only type II family interferon that binds to the heterodimeric receptor consisting of two subunits, IfnγR1 and IfnγR2. This specific interaction between Ifnγ and its receptor triggers the activation of Janus Kinase (Jak) – Signal Transducer and Activator of Transcription (Stat) pathway. This triggers a cascade of events leading to modulation of a wide variety of genes resulting in a plethora of responses including antimicrobial activities, induction of Major Histocompatibility Complex encoded molecules etc. The impact of Ifnγ in regulating host defense is observed in patients who lack functional IFNγ or its receptor as they succumb to less virulent strains of intracellular bacteria such as Mycobacterium and Salmonella. Also, mice lacking important downstream signaling components such as Stat1 and Interferon Regulated Factor 1 (Irf1) are known to be highly susceptible to a variety of bacterial and viral infections. Consequently, studies on uncharacterized signaling and regulatory molecules downstream to Ifnγ are of great interest. The modulatory functions of Ifnγ have been attributed to its ability to regulate the expression of a vast number of genes in a Stat1 and Irf1 dependent manner. Also, gene regulation in response to Ifnγ in a target cell such as mouse hepatoma cell line, H6, can be categorized broadly into two subsets: Reactive Oxygen Species (ROS) - Reactive Nitrogen Intermediates (RNI) dependent (e.g. Nos2, Catalase, Id2 etc.) as well as ROS – RNI independent (e.g. Tap1, Lmp2 etc.). However, the effect of Ifnγ induced ROS and RNI in the regulation of the expression of genes at the level of transcriptome and how these could impact cellular and host responses are not well characterized. To investigate these questions, we standardized an in vitro Ifnγ responsive primary cell culture system using mouse adherent peritoneal macrophages (PMs). It needs to be highlighted that this study has, primarily, utilized unstimulated resident PMs. The adherent cells from the peritoneal cavity were positive for macrophage markers such as F4/80 and CD11b, but negative for granulocyte marker Gr1. Also, PMs were resistant to Ifnγ induced cell death, unlike cell lines such as the mouse fibroblast cell line L929, for the time points studied. There are three distinct parts to this study involving the system of PMs: I. To understand the contribution of Nitric Oxide (NO) in regulating the expression of novel Ifnγ responsive genes, PMs from C57BL/6 mice and mice lacking nitric oxide synthase 2 (Nos2-/-), the enzyme isoform responsible for the generation of NO in PMs, were stimulated with Ifnγ for 8 h and microarray analysis was performed. Detailed analysis led to identification of several annotated genes that were uniquely regulated in C57BL/6 and Nos2-/- PMs. Further analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database identified several differentially regulated pathways. Interestingly, a large number of metabolism related pathways, Butirosin and neomycin, Galactose, Phenylalanine and glyoxylate and dicarboxylate, were specifically up-regulated in the C57BL/6 PMs treated with Ifnγ. Similarly, other metabolism related pathways were differentially regulated by Ifnγ in PMs from C57BL/6 and Nos2-/- mice. One of the pathways that was up regulated in a Nos2 dependent manner in the C57BL/6 PMs upon Ifnγ treatment was that of circadian rhythm, which consisted of genes Per1, Bhlhb2 and Bhlhb3. All three are known circadian rhythm regulators, with Bhlhb2 and Bhlhb3 being transcriptional repressors that bind to E-box consensus sequence (CANNTG) as heterodimers, using the basic helix-loop-helix (bHLH) domains, along with other transcriptional regulators. Both Bhlhb2 and Bhlhb3 were up regulated at RNA and protein levels in a kinetic manner upon Ifnγ treatment in L929 cells. Studies with inhibitors to ROS and RNI revealed that up regulation of Bhlhb2 and Bhlhb3 was RNI, but not ROS, dependent in response to Ifnγ. Interestingly, the RNI inhibitor, NG-Methyl-L-Arginine (LNMA) rescued Ifnγ induced ROS. On the other hand, ROS inhibitors, e.g. Apocyanin and polyethylene glycol Catalase (PEG-Catalase), did not affect the nitrite amounts in the supernatant. These experiments suggested that RNI was upstream to ROS in L929 cells and both contributed to Ifnγ induced cell death. The knockdown of Bhlhb3 using specific siRNAs in the untreated L929 cells increased Bhlhb2 amounts, but not vice versa. This observation is consistent with the fact that Bhlhb3 is a known repressor of Bhlhb2. However, this repression of Bhlhb2 by Bhlhb3 was not detected upon Ifnγ treatment in L929 cells possibly because of heterodimerization of Bhlhb3 with other Ifnγ induced transcriptional modulators. Finally, knockdown of either of the proteins did not affect induced nitrite but decreased ROS amounts resulting in significant rescue of Ifnγ induced cell death of L929 cells. Thus, Bhlhb2 and Bhlhb3 are novel Ifnγ induced proteins that are NO dependent and contribute to Ifnγ induced cell death. Ifnγ and Nos2 are known to elicit antibacterial defense in the host. Interestingly, recent studies have implicated circadian rhythm to regulate bacterial infection in mice. Therefore, regulation of both Bhlhb2 and Bhlhb3 upon Ifnγ treatment and during Salmonella enterica Serovar Typhimurium (S. typhimurium) infection in the bone marrow derived macrophages (BMDMs) was performed. Both Bhlhb2 and Bhlhb3 were induced in a Nos2 dependent manner upon Ifnγ addition in BMDMs. Similar to L929 cells, Bhlhb3 repressed Bhlhb2 in the untreated BMDMs. Also, infection of BMDMs with S. typhimurium increased the protein amounts of Bhlhb2, while repressing Bhlhb3. Importantly, knockdown of Bhlhb2 resulted in higher colony forming units (CFU), whereas knockdown of Bhlhb3 reduced CFU in BMDMs 18 h post infection with S. typhimurium. Thus, Bhlhb2 induced whereas Bhlhb3 repressed antibacterial defense in BMDMs. The exact mechanism downstream to these two proteins and their inter-relationship in regulating S. typhimurium infection is of considerable interest and will be studied in future. II. Macrophages are known to produce a large number of different cytokines and chemokines upon activation. To identify novel cytokines and chemokines that may be differentially regulated in response to Ifnγ, a protein array was performed using the supernatants of C57BL/6 PMs treated with and without Ifnγ. Chemokine Ccl3 was found to be repressed by Ifnγ in the supernatant of PMs. Further analysis using Enzyme Linked Immuno-Sorbent Assay (ELISA) revealed that both Ccl3 and Ccl4, highly homologous proteins that chemo-attract almost all types of leukocytes, were repressed upon Ifnγ treatment. This response was ligand and cell specific as Lip polysaccharide (LPS) stimulation of PMs and Ifnγ stimulation of thioglycollate elicited PMs did not result in repression of Ccl3 and Ccl4. Also, studies with fludarabine, an inhibitor to Stat1, revealed that the repression of Ccl3 and Ccl4 as well as induction of Cxcl10 in response to Ifnγ was Stat1 dependent. Importantly, the use of LNMA as well as PMs from Nos2-/- mice established the role of Nos2 in the repression of Ccl3 and Ccl4, but not Cxcl10 induction, in response to Ifnγ. Furthermore, activation of p38 Mapk, but not Jnk, was downstream to Nos2 activation and contributed functionally to the repression of Ccl3 and Ccl4 in response to Ifnγ. Finally, the transcriptional repressor, Activating Transcription Factor 3 (Atf3), was induced in a Stat1-Nos2-p38 Mapk dependent manner and knockdown of Atf3 using siRNAs established the functional role of the same in the repression of Ccl3 and Ccl4 in response to Ifnγ. Further, to understand the regulation of Ccl3 and Ccl4, their modulation upon S. typhimuirum infection of BMDMs was performed. Apart from regulating the CFU in BMDMs, Ifnγ and Nos2 functionally repressed Ccl3 and Ccl4 upon S. typhimurium infection. Oral infection of mice with S. typhimurium was performed and mice lacking Ifnγ and Nos2 were found to have greater CFU in their organs as well as more leukocytes in the infected liver sections in comparison to the infected C57BL/6 mice. Importanly, absence of Ifnγ as well as Nos2 increased the amounts of Ccl3 and Ccl4 in the sera upon S. typhimurium infection in comparison to the C57BL/6 infected mice. Overall, this part of the study identified Ifnγ and Nos2 to repress chemokines Ccl3 and Ccl4 in macrophages and in mice upon S. typhimurium infection. III. While working on the above mentioned studies, it was noticed that addition of Ifnγ to PMs induced in a dose and time dependent manner aggregation of cells. Experiments with LPS, TG PECs and BMDMs established that Ifnγ induced aggregation of PMs was ligand and cell type specific. A panel of cell surface integrins and selectins were screened for regulation upon Ifnγ addition, namely Icam1, Lfa1, CD11b, P-selectin and E-selectin. Most of the cell surface integrins were repressed by Ifnγ in a kinetic manner. Interestingly, CD11b as well as E-Selectin co-localized to the sites of interactions between the PMs upon Ifnγ treatment. Studies with Reopro, a purified F(ab’)2 to glycoprotein GPIIb that is also known to functionally block CD11b, revealed the functional contribution of CD11b during Ifn induced aggregation of PMs. Further, studies with specific inhibitors identified RNI, but not ROS, to contribute to Ifnγ induced PM aggregation. Also, lack of Nos2 in PMs upon Ifnγ treatment resulted in minimal aggregation together with morphological changes, e.g. flattening of cells. Since differences in the morphology of PMs was observed in the absence of Nos2 upon Ifnγ treatment, the regulation and roles of cytoskeleton proteins, Actin and tubulin, during Ifnγ induced aggregation of PMs was studied. Upon Ifnγ stimuli, actin and tubulin get stabilized. On the other hand, the absence of Nos2 leads to depolymerization of actin, while tubulin failed to stabilize to the membrane, in response to Ifnγ. Further, addition of actin and tubulin depolymerizing agents, Cytochalasin D and Colcemid respectively, decreased Ifnγ induced aggregation of PMs. Live cell imaging studies revealed that PMs needed actin, but not tubulin or CD11b, for mobility. Upon Ifnγ treatment, PMs from C57BL/6 mice exhibited reduced mobility and aggregated with each other. The Nos2-/- PMs exhibited lower mobility compared to C57BL/6 PMs and, upon Ifnγ treatment, underwent morphological changes with time, e.g. flattening. On the other hand, Nos2 is important for endogenous mobility and maintaining the cellular morphology in response to Ifnγ. To understand the physiological relevance of our observations, oral infection of C57BL/6 and Nos2-/- mice with S. typhimurium was performed. Four days post infection, no significant differences in the number of peritoneal cells were found. Importantly, PMs from infected Nos2-/- mice had higher CFU in comparison to C57BL/6 mice. However, the amounts of cytokines such as Ifnγ, Tnfα, Il6 and Il1β in the peritoneal lavage were not significantly different between the two infected strains. Interestingly, PMs isolated from infected Nos2-/- mice displayed distinct morphology, e.g. flattening. In comparison, infected C57BL/6 PMs aggregated when cultured for 24 h in vitro. In the future, it will be interesting to address the functional roles of aggregates of macrophages during physiologically relevant responses such as combating intracellular bacterial infection. This part of the study adds a new dimension to the ability of Ifnγ in the regulation of macrophage-macrophage interactions and their roles during intracellular bacterial infections. Overall, the present study has elucidated hitherto uncharacterized roles of Nos2 and mechanisms involved in regulation of novel functional responses of PMs to Ifnγ and during S. typhimurium infection.

Les objectifs sont d’évaluer l’efficience (survie, qualité de vie et le coût) des deux techniques de dialyse de rechercher les déterminants qui orientent le choix vers l’une ou l’autre des techniques de dialyse et d’évaluer le parcours de soins des patients en dialyse. La première partie de ce travail de thèse à analyser les données de la région PACA issues du registre REIN. Cette analyse est descriptive et porte sur le profil des patients démarrent un traitement en dialyse (HD et DP). Une analyse de survie a été réalisée selon la technique de dialyse initiale et selon le parcours de soins. Dans une seconde partie, le coût et sur la qualité de vie ont été évalués selon les différentes techniques de dialyse afin d’évaluer l’efficience de ces modalités à partir des données recueillies dans un PHRC régional. Dans une troisième partie, les facteurs liés au choix initial de la technique de dialyse, DP ou HD ont été recherchés. Ce travail a fait l’objet d’une étude ciblée auprès de patients et de néphrologues au sein de 4 structures de dialyse. La survie et la qualité de vie des patients sont similaires entre HD et DP. Le changement de technique, de la DP vers l'HD, a un impact positif sur la survie. La DP est moins coûteuse que l’HD. Les contre-indications médicales à la DP ne concernaient que 26,7% des patients inclus. En absence de contre-indications, la préférence du patient et les pratiques des professionnelles (information et pratiques de centre) sont les deux principaux facteurs liés au choix initial de la technique de dialyse, notamment par la DP. Une meilleure information pourrait contribuer à augmenter le choix de la DP. / The objectives of this work were to assess and compare the efficiency (survival, quality of life and cost) of patients initially treated with peritoneal dialysis (PD) or hemodialysis (HD), to search determinants that guide the initial choice towards either dialysis techniques and to assess the trajectory between dialysis modalities. The first part of this thesis was to analyze the database, from the PACA region (2004 – 2014), issue from the French REIN registry. This analysis was descriptive and focused to analyze main characteristics and outcome (survival) of dialysis patients (initial dialysis and switching) and to identify risk factors. The second part of this thesis was to measure and compare dialysis patient quality of life and health’s care costs between dialysis modalities (HD and PD). Database was issued from PHRC. The third part was to search the factors related to the initial choice of dialysis technique, PD or HD. This work was the subject of a targeted survey of patients and neurologists in a dialysis structure. The survival and the quality of life were similar between hemodialysis and peritoneal dialysis. Switching to HD may improve positively the survival compared to those who remained on PD, whereas, switching to PD was not. The DP is less expensive than HD. Medical contraindications to the PD were for 26.7%. In the absence of contraindications, patient preference and professional practices (information and practical center) are the two main factors related to the initial choice of dialysis technique, in particular to choice of PD. Better information could help to increase the choice of DP

This thesis deals with the profitability of sales of the dialysis care provider. The main aim of the work was to optimise the dialysis care in Jindrichuv Hradec hospital. Mentioned proposed solution concerns personnel and technical aspects and particular elimination methods. Another aim of the work was to clarify the reimbursement system of the particular dialysis methods, to compare economic results with the profitability of the dialysis care in the years 2006 and 2007. The author endeavoured to create possible ways of the development based on the knowledge of the number of patients and the insurance company reimbursement system. Necessary data and information were acquired from Jindrichuv Hradec hospital reports. This work is thought to contribute to enrich the practical usage and its results can be used by the hospital management or anybody interested in the dialysis care and its economic aspects.

La douleur abdominale post chirurgicale reste une douleur difficile à gérer. Cette douleur présente 2 composantes : (1) une composante pariétale liée à l’agression des muscles de la paroi abdominale et du péritoine pariétal et (2) une composante viscérale liée à l’agression du péritoine viscérale et des viscères. La douleur pariétale est bien systématisée, elle correspond à des métamères bien identifiés. Par contre la douleur viscérale est souvent mal localisée, irradiée ou transférée à un site cutané. Les AL administrés par l’intermédiaire d’un cathéter d’infiltration pariétal, d’un bloc de la paroi abdominale ou par voie systémique montrent une efficacité clinique dans l’analgésie post opératoire d’une chirurgie abdominale. Cependant le mécanisme d’action des AL en fonction de leurs voies d’administration n’est pas bien élucidé. Le but de nos études est d’explorer l’effet des AL sur les deux composantes de la douleur abdominale dans un modèle animal en fonction de leur voie d’administration. Nous avons réalisé 3 études expérimentales :1-Dans l’étude 1 nous avons comparé l’effet de la ropivacaïne administrée par voie systémique ou par un cathéter pré péritonéal sur la douleur pariétale et viscérale dans un modèle de laparotomie chirurgicale chez le rat.. 2-Dans l’étude 2 nous avons validé un bloc de la paroi abdominale chez le rat.. 3-Dans l’étude 3 nous avons comparé l’effet de la bupivacaïne par voie systémique à l’effet obtenu par l’administration de la bupivacaïne par un bloc de la paroi abdominale. Nous avons également comparé l’effet des Al par voie systémique à une vagotomie chimique préventive. L’ensemble de ces travaux montrent que lors d’une laparotomie, les AL sont efficaces dans le traitement de la nociception aussi bien par voie systémique que par voie locorégionale. Nous avons démontré qu’un bloc de la paroi abdominale, ainsi qu’une infiltration pré péritonéale diminuaient la transmission de la nociception viscérale vers le SNC par action directe sur les terminaisons nerveuses pariétales. De plus, lors d’une laparotomie, l’administration systémique d’AL montre une efficacité dans l’inhibition de la transmission de la nociception viscérale vers le SNC associée à un effet anti inflammatoire local et systémique supérieure à celui d’une administration locorégionale. / The abdominal post surgical pain has two components : (1) a parietal component due toaggression of the abdominal wall muscles and the parietal peritoneum and (2) a visceralcomponent due to aggression of the visceral peritoneum and viscera. Parietal pain is welllocalized; it corresponds to identified dermatomes. Otherwhise, visceral pain is often badlylocalized. Local anesthetics injected through a parietal catheter of infiltration, an abdominal wall blockor by a systemic administration show clinical efficiency in post operative analgesia afterabdominal surgery. However, the action mechanisms of local anesthetics according to theiradministration route are not well clarified. The purpose of our studies is to explore localanesthetics effect on both components of the abdominal pain in an animal model according totheir administration route.In this purpose we realized three experimental studies :1- In the first study, we compared the effect of systemic administration or through a preperitoneal catheter of ropivacaïne on parietal and visceral pain in a model of surgicallaparotomy in the rat. 2- In the second study, we established a block of the abdominal wall in the rat. 3- In the third study, parietal and peritoneal inflammation were induced by carrageenaninjection in the abdominal wall or in the peritoneal cavity in the rat according to theexperimental group. Then, we compared the effect of a systemic administration of bupivacaïneto its administration by an abdominal wall block. Furthermore, the systemic effect of localanesthetics was compared to a preventive chemical vagotomy. These works showed that during laparotomy, local anesthetics are effective in thetreatment of the nociception as well as by systemic or locoregional administration. We showedthat an abdominal wall block as well as a pre peritoneal administration decreased thetransmission of the visceral nociception towards the central nervous system by direct action onthe parietal nerve endings. Furthermore, during a laparotomy, systemic administration of localanesthetics inhibited the transmission of visceral nociception towards the central nervoussystem associated with a local and systemic anti inflammatory effects. This anti inflammatoryeffect was higher than that what we showed by locoregional administration of bupivacaïne.

Bakgrund: Njursvikt innebär en nedsatt filtreringsförmåga och delas in i två tillstånd, akut och kronisk. Akut njursvikt utvecklas inom kort tid med kraftigt reducerad glomerulär filtration och leder till ett allvarligt tillstånd, medan vid kronisk njursvikt försämras kapaciteten långsamt under en längre tid och i det senare skedet krävs kontinuerlig dialysbehandling. Personer som drabbas av njursvikt behöver dialysbehandling för att uppehålla livet. Många väljer en behandlingsform med hembaserad dialys som innefattar både hemodialys (HD) och peritonealdialys (PD). Det krävs mycket självhantering vid utförandet av dialys i hemmet, och för att leva med sjukdomen behöver personen har förståelse för egenvård och samarbete med sjukvården.    Syfte: Att belysa personers upplevelser av att leva med hembaserad dialysbehandling vid kronisk njursvikt. Metod: Litteraturöversikten baserades på tio vetenskapliga artiklar med kvalitativa ansatser.  Artiklarna hämtades från databaserna CINAHL complete och PubMed med års begränsning 2009-2019. Resultat: Fyra teman framkom kring upplevelser att leva med dialys i hemmet: En förändrad livssituation påverkar självbild och kroppsuppfattning, Behov av stöd och hjälp vid egenvård, Upplevelser av begränsningar och anpassning och En känsla av frihet och ökad livskvalitet. Diskussion: I metoddiskussionen diskuteras styrkor och svagheter i hur studien har genomförts. Resultatet diskuteras mot Orems egenvårdteori, tidigare forskning och riktlinjer. En stor del av diskussionen understryker betydelsen av personers egenvårdsförmåga i samband med livsförändring och anpassningsprocess samt betydelsen av stöd och hjälp från sjukvården och närstående. / Background: Kidney failure includes reduced filtration ability and can be categorised into an acute and a chronic form. Acute renal failure develops within a short timeperiod and comes with a heavily reduced glomerular filtration whereas chronic kidney failure progresses slowly during a longer period of time and in the later stages, continuous dialysis treatment becomes necessary. Individuals afflicted by renal failure need dialysis treatment to survive. Many people choose a home-based dialysis including both haemodialysis and peritoneal dialysis. Home -based dialysis necessitates much individual efforts and to live with the disease there is a need for understanding selfcare as well as collaborating with national health care. Aim: To review individual experiences from living with home-based dialysis with chronic renal failure. Method: A literature review was based on ten scientific articles with qualitative methodology. The articles were obtained from the databases CINAHL complete and PUBMed covering 2009 to 2019. Results: Four themes associated with the experiences from living with home-dialysis emerged: A changed self - and body image, Need of support and help during selfcare, Experiences from limitations and adjustments, A sense of freedom and increased quality of life. Discussion: In the discussion on methodology, strength and weaknesses of the study is discussed. The results are discussed in the context of the self-care theory of Orem, previous research and guidelines.  A major part of the discussion underlines the importance of the self-care ability of the individual in the context of lifestyle changes and in the process of adjustment. Also the importance of support and help by the health-care system and relatives is emphasised.

No description available.

INTRODUÇÃO: Os distúrbios minerais e ósseos da doença renal crônica (DMO-DRC) são influenciados por vários fatores, como idade, etiologia da DRC, toxinas urêmicas e modalidade dialítica. Os DMO-DRC são bem descritos em pacientes tratados com hemodiálise (HD). No entanto, na diálise peritoneal (DP) os estudos são escassos e, na maioria deles, não há dados de histologia óssea. OBJETIVOS: caracterizar os DMO-DRC em uma coorte de pacientes em DP; comparar os resultados com aqueles obtidos da HD; e analisar o desempenho de marcadores séricos para o diagnóstico das doenças de alto e baixo remodelamento ósseo. MÉTODOS: quarenta e um pacientes tratados com DP submeteram-se a avaliação clínica, bioquímica e biópsia óssea. RESULTADOS: a doença óssea adinâmica (DOA) foi o tipo de osteodistrofia renal (OR) predominante, correspondendo a 49% da amostra. Ao se analisar separadamente diabéticos e não diabéticos, a prevalência de DOA foi de 77,7% no primeiro grupo e 26% no segundo (p=0,001). Na comparação entre DP e HD, observou-se que os pacientes do primeiro grupo apresentavam 25(OH) vitamina D mais baixa, mineralização óssea mais comprometida e melhor volume ósseo. A fosfatase alcalina óssea (FAO) apresentou a melhor sensibilidade e especificidade tanto para o diagnóstico de alto, quanto de baixo remodelamento ósseo. CONCLUSÕES: a DOA é o tipo de OR mais prevalente na DP. No entanto, a influência do diabetes como fator de risco parece ser maior do que a própria modalidade dialítica / INTRODUCTION: Chronic kidney disease - mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins and dialysis modality. CKD-MBD has been extensively studied in hemodialysis (HD) patients. However, for peritoneal dialysis (PD), only a few, older studies exist, most of which contain no bone biopsy data. The present study sought to: characterize CKD-MBD in a cohort of prevalent PD patients; compare the results with that obtained from HD patients; and analyse performance of bone turnover serum markers to make the diagnosis of high or low bone turnover disease in PD patients. METHODS: Forty-one PD patients underwent to a clinical evaluation, biochemical analysis and bone biopsy. RESULTS: The most prevalent pattern of renal osteodystrophy (ROD) was adynamic bone disease (ABD), comprising 49% of the sample population. When we separately analyzed diabetic and non-diabetic patients, the ABD prevalence was 77.7% in the former group and 26% in the latter group (p=0.001). The comparison between DP and HD patients revealed low 25(OH) vitamin D level, worst bone mineralization and better bone volume parameters in the former group. Bone alkaline phosphatase (BAP) demonstrated the best sensitivity and specificity values to detect both high and low turnover disease. CONCLUSION: ABD is the most frequent type of ROD. However, the effect of diabetes on the development of ABD is more important than the dialysis modality itself

INTRODUÇÃO: Os distúrbios minerais e ósseos da doença renal crônica (DMO-DRC) são influenciados por vários fatores, como idade, etiologia da DRC, toxinas urêmicas e modalidade dialítica. Os DMO-DRC são bem descritos em pacientes tratados com hemodiálise (HD). No entanto, na diálise peritoneal (DP) os estudos são escassos e, na maioria deles, não há dados de histologia óssea. OBJETIVOS: caracterizar os DMO-DRC em uma coorte de pacientes em DP; comparar os resultados com aqueles obtidos da HD; e analisar o desempenho de marcadores séricos para o diagnóstico das doenças de alto e baixo remodelamento ósseo. MÉTODOS: quarenta e um pacientes tratados com DP submeteram-se a avaliação clínica, bioquímica e biópsia óssea. RESULTADOS: a doença óssea adinâmica (DOA) foi o tipo de osteodistrofia renal (OR) predominante, correspondendo a 49% da amostra. Ao se analisar separadamente diabéticos e não diabéticos, a prevalência de DOA foi de 77,7% no primeiro grupo e 26% no segundo (p=0,001). Na comparação entre DP e HD, observou-se que os pacientes do primeiro grupo apresentavam 25(OH) vitamina D mais baixa, mineralização óssea mais comprometida e melhor volume ósseo. A fosfatase alcalina óssea (FAO) apresentou a melhor sensibilidade e especificidade tanto para o diagnóstico de alto, quanto de baixo remodelamento ósseo. CONCLUSÕES: a DOA é o tipo de OR mais prevalente na DP. No entanto, a influência do diabetes como fator de risco parece ser maior do que a própria modalidade dialítica / INTRODUCTION: Chronic kidney disease - mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins and dialysis modality. CKD-MBD has been extensively studied in hemodialysis (HD) patients. However, for peritoneal dialysis (PD), only a few, older studies exist, most of which contain no bone biopsy data. The present study sought to: characterize CKD-MBD in a cohort of prevalent PD patients; compare the results with that obtained from HD patients; and analyse performance of bone turnover serum markers to make the diagnosis of high or low bone turnover disease in PD patients. METHODS: Forty-one PD patients underwent to a clinical evaluation, biochemical analysis and bone biopsy. RESULTS: The most prevalent pattern of renal osteodystrophy (ROD) was adynamic bone disease (ABD), comprising 49% of the sample population. When we separately analyzed diabetic and non-diabetic patients, the ABD prevalence was 77.7% in the former group and 26% in the latter group (p=0.001). The comparison between DP and HD patients revealed low 25(OH) vitamin D level, worst bone mineralization and better bone volume parameters in the former group. Bone alkaline phosphatase (BAP) demonstrated the best sensitivity and specificity values to detect both high and low turnover disease. CONCLUSION: ABD is the most frequent type of ROD. However, the effect of diabetes on the development of ABD is more important than the dialysis modality itself

Objectif: Le traitement de la carcinose péritonéale (CP) d’origine appendiculaire récidivante demeure sous-étudié. L’objectif est d’évaluer le traitement à offrir aux patients présentant une récidive de la maladie. Méthodologie: Depuis 2003, les données de tous les patients avec CP d’origine appendiculaire traités dans notre centre ont été recueillies. Le traitement de la maladie primaire consistait en une cytoréduction chirurgicale complète de la CP suivie d’une chimiothérapie hyperthermique intra-péritoneale (CHIP) à l’oxaliplatine. Lors d’une récidive, une deuxième cytoréduction avec une CHIP à la mitomycine C était offerte aux patients rencontrant certains critères de sélection. Résultats: Un total de 58 patients ont subi une cytoréduction complète suivie d’une CHIP avec l’oxaliplatine. Durant la période de suivi, 22 patients démontrèrent une maladie récidivante (39%). Le péritoine était le site de récidive le plus fréquent. Les survies sans maladie étaient statistiquement différentes selon le grade histopathologique et le degré de complétude de la cytoréduction. Parmi ces 22 patients, huit patients ont reçu une deuxième cytoréduction suivie d’une CHIP à la mitomycine C, un patient a subi une cytoréduction complète seule et 13 patients avaient une maladie non résécable. La survie globale moyenne des patients ayant reçu un deuxième traitement fut de 28 mois. Les taux de morbidité et de mortalité suite à une deuxième cytoréduction suivie d’une CHIP furent de 25% et 0%, respectivement. Conclusion: Une cytoréduction suivie d’une CHIP demeure une intervention possible chez les patients qui présentent une maladie récidivante, mais certains critères doivent être appliqués afin de maximiser la survie et minimiser la morbidité et la mortalité de cette approche. / Background: Additional treatment in patients presenting recurrent peritoneal carcinomatosis (PC) has been much overlooked in the literature. The aim of this study is to assess the effects of additional treatment in patients with recurrent disease despite a first CRS with HIPEC. Methods: Since 2003, data from all patients with PC arising from the appendix treated in our center were prospectively collected. Treatment of primary disease consisted in CRS followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin. When recurrent disease occurred, second CRS followed by HIPEC with mitomycin C were offered to patients meeting some selection criteria. Results: A total of 58 patients underwent CRS followed by HIPEC with oxaliplatin. During follow-up, 22 patients developed recurrent disease (39%). Peritoneum was the most common site of treatment failure. In the entire series, histologic grades and completeness of CRS were significant independent predictors of disease-free survival. Among patients with recurrent disease (n=22), eight patients underwent second CRS followed by HIPEC with mitomycin C, one patient received a CRS alone, and thirteen patients had unresectable disease. Mean overall survival for patients who received a second treatment (n=8) was 28 months. Morbidity and mortality rates following second CRS and HIPEC were 25% and 0%, respectively. Conclusions: CRS followed by HIPEC remains a possible intervention in patients with recurrent disease, but some selection criteria should be applied in order to maximise survival and minimise morbidity and mortality of this approach.

Depuis 20 ans, certains patients porteurs d’une carcinose péritonéale sont traités par une chirurgie de cytoréduction combinée avec une chimiohyperthermie intrapéritonéale (CHIP). Bien que l’oxaliplatine (OX) soit couramment utilisée lors de CHIP, une telle utilisation chez l’humain n’est supportée que par des études de phase II et il n’y a pas d’études précliniques caractérisant les propriétés de l’OX dans le contexte d’administration intrapéritonéale. L’objectif de ce projet de maîtrise est d’étudier l’effet de la température sur l’absorption tissulaire et systémique de l’OX administrée par voie intrapéritonéale chez le rat. Nous avons procédé à une perfusion intrapéritonéale de 3 différentes doses d’OX à 3 différentes températures pendant 25 minutes chez une total 35 rats Sprague-Dawley, puis effectué le dosage des concentrations d’OX dans différents compartiments. Nous avons observé une augmentation linéaire (p<0,05) entre la dose d’OX administrée et sa concentration dans tous les compartiments (péritoine, mésentère, sang portal et systémique). De plus, avec l’augmentation de la température de perfusion, nous avons observé une augmentation de la concentration d’OX dans le péritoine mais une diminution de sa concentration dans les compartiments systémique et portal (p<0,05). Ces résultats démontrent donc que la dose et l’hyperthermie augmentent indépendamment la pénétration tissulaire de l’OX et que l’hyperthermie limite son absorption systémique. Ces observations suggèrent que l’hyperthermie pourrait réduire la toxicité systémique de l’OX. Pour connaître la cinétique de l’OX, des études subséquentes doivent être faites. / Over the last twenty years, certain patients afflicted with peritoneal carcinomatosis have been treated with a combination of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion. Supported by phase II studies only, Oxaliplatin (OX) is commonly used in this context. However, pre-clinical studies to characterize its properties in such conditions are lacking. The purpose of this project is to study the effect of temperature on tissue and systemic absorption of OX when administered by intraperitoneal route in the rat. By intraperitoneal route, we administered 3 different doses of OX at 3 different temperatures for 25 minutes on 35 Sprague-Dawley rats. Samples from selected compartments were harvested and OX concentration was measured using high performance liquid chromatography. We obtained a linear correlation (p<0.05) between OX dose and tissue concentration in every compartments analyzed (peritoneum, mesentery, systemic and portal blood). With hyperthermia, we observed an increase in peritoneum and mesentery concentration of OX, but a decrease it its systemic and portal concentration (p<0.05). Intraperitoneal administration of OX leads to high concentration of drug in local tissues. Hyperthermia enhances tissue absorption and minimizes systemic absorption suggesting it could reduce systemic toxicity. Additional studies are needed to further define the pharmacokinetics of OX administered by intraperitoneal route.