Acute kidney injury (AKI) may result from perioperative renal medullary hypoxia. Despite high oxygen delivery to the kidney, the medullary thick ascending limb (mTAL) in the outer renal medulla is susceptible to hypoxia because of its high oxygen consumption and relatively low rate of blood flow. The objective of this study was to evaluate the effect of a low pO2 (8% FiO2 for 5 h) on the major function of the mTAL and to develop a strategy to protect the mTAL in this setting. Evidence of hypoxia-induced reduction in mTAL function included low interstitial and urine osmolality but only a minimal rise in Na+ excretion; this was prevented by pre-treatment with desmopressin acetate (dDAVP), a vasopressin analogue which may increase tissue pO2. A decrease in urine osmolality may be of diagnostic value for hypoxic renal damage and dDAVP may prevent acute kidney injury in the perioperative setting.

Acute kidney injury (AKI) may result from perioperative renal medullary hypoxia. Despite high oxygen delivery to the kidney, the medullary thick ascending limb (mTAL) in the outer renal medulla is susceptible to hypoxia because of its high oxygen consumption and relatively low rate of blood flow. The objective of this study was to evaluate the effect of a low pO2 (8% FiO2 for 5 h) on the major function of the mTAL and to develop a strategy to protect the mTAL in this setting. Evidence of hypoxia-induced reduction in mTAL function included low interstitial and urine osmolality but only a minimal rise in Na+ excretion; this was prevented by pre-treatment with desmopressin acetate (dDAVP), a vasopressin analogue which may increase tissue pO2. A decrease in urine osmolality may be of diagnostic value for hypoxic renal damage and dDAVP may prevent acute kidney injury in the perioperative setting.

A doença de von Willebrand (DvW) é uma coagulopatia hereditária, causada por defeitos qualitativos ou quantitativos do fator de von Willebrand. O tratamento e a prevenção das intercorrências da DvW são bastante dispendiosos e, em geral, se baseiam na administração de concentrado de Fator VIII/FvW (CFVIII/FvW) e/ou da Desmopressina (DDAVP). Em muitas situações, o DDAVP é um tratamento eficaz que não expõe os pacientes aos riscos de contaminação viral e apresenta custo inferior quando comparado ao CFVIII/FvW. No entanto, a dificuldade de diagnóstico e classificação da DvW, bem como o baixo número de pacientes que se submetem ao teste para avaliação da resposta ao DDAVP, restringem a indicação do DDAVP como alternativa terapêutica para esses pacientes. O objetivo deste estudo foi avaliar retrospectivamente a indicação, o uso e o custo dos medicamentos no tratamento de pacientes com DvW com DDAVP e CFVIII/FvW no Hemocentro de Belo Horizonte no período entre 2011 a 2013. Este estudo incluiu 124 (24,22%) pacientes com DvW atendidos no hemocentro. Em 18 pacientes (14,52%) o diagnóstico de DvW não pode ser confirmado. Doze pacientes (9,68%) não puderam ser classificados e 73 foram classificados como tipo 1, 19 como tipo 2 e 2 pacientes como tipo 3. Oitenta e um pacientes fizeram o teste de DDAVP, sendo que 87,65% foram considerados responsivos. Nos pacientes tipo 1, a taxa de resposta ao DDAVP foi de 92%. Quase 32% dos pacientes tipo 1 não realizaram o teste. No período avaliado, foram utilizadas 3.794mcg de DDAVP (R$13.165,18) e 1.582.250 UI de CFVIII/FvW (R$1.075.930,00). Vinte por cento dos pacientes responsivos ao DDAVP utilizaram CFVIII/FvW em indicações onde o DDAVP poderia ter sido considerado (69.200UI de CFVIII/FvW versus 131 ampolas de DDAVP). Nos pacientes potencialmente responsivos ao DDAVP 108.700UI de CFVIII/FvW (R$73.916,00) poderiam ter sido substituídas por 247 ampolas de DDAVP (R$3.428,36). A escolha do DDAVP nessas situações poderia representar uma economia de 95,7% do valor gasto no tratamento do grupo de 27 pacientes responsivos e potencialmente responsivos ao DDAVP e 10,6% do valor total gasto para todo o tratamento dos pacientes no período do estudo. Estudos mais complexos de farmacoeconomia serão necessários para avaliar a magnitude da economia gerada com esse uso. O presente estudo mostrou que o DDAVP é uma alternativa terapêutica de menor custo, cuja indicação e utilização podem ser ampliadas no tratamento dos pacientes com DvW. Dessa maneira, a implementação de estratégias visando melhorar o diagnóstico, a classificação da doença, o acesso à testagem quanto à resposta ao DDAVP, bem como a conscientização dos profissionais de saúde e pacientes, quanto ao custo e segurança do DDAVP podem contribuir para o uso racional dos recursos destinados a essa parcela da população. / Von Willebrand disease (VWD) is a hereditary coagulopathy caused by qualitative or quantitative defects on von Willebrand factor. The treatment and the prevention of VWD complications is quite expensive and is generally based on the administration of vWF:FVIII Concentrates and/or Desmopressin (DDAVP). In many situations, DDAVP is an effective treatment that does not expose patients to viral contamination risks and presents a lower cost when compared to vWF:FVIII concentrates. However, the difficulty of diagnosis and classification of VWD, as well as the low number of patients tested to their responsiveness to DDAVP, restrict the use of DDAVP as an alternative treatment for these patients. The aim of this study was to evaluate retrospectively the clinical indications, the use and the cost of treatment of VWD patients with DDAVP and vWF:FVIII concentrates in the Blood Center of Belo Horizonte between 2011 and 2013. This study enrolled 124 (24.22%) VWD patients attended at the Blood Center.For18 (14.52%) patients, the diagnosis of VWD could not be confirmed. Twelve patients (9.68%) could not be classified and 73patients were classified as type 1, 19 as type 2 and 2 as type 3. Eighty-one patients were tested for DDAVP response and 87.65% (n=71) were considered responsive for the treatment. For type 1 VWD patients, the response rate to DDAVP was 92%. Almost 32% of type 1 VWD patients were not tested. In the period evaluated, 3,794mcg of DDAVP (R$ 13,165.18) and 1,582,250 IU of vWF:FVIII concentrates (R$ 1,075,930.00) were used. Between the cases with clinical indication of DDAVP use, 20% patients used vWF:FVIII concentrates (69.200UI of vWF:FVIII versus 131ampoules of DDAVP). In patients with good responsive to DDAVP, 108,700 IU of vWF:FVIII concentrates used (R$ 73,916.00) could be replaced by 247 ampoules of DDAVP (R$ 3,428.36). The choice of DDAVP in these situations could represent an economy of 95.7% of the value spent on the treatment of the 27 responsive and potentially responsive patients to DDAVP and 10.6% of the total value spent for the entire treatment of patients in the study period. More detailed studies of pharmacoeconomics are necessary to assess the magnitude of the economy generated by the use of DDAVP. This study demonstrated that DDAVP is a lower cost therapeutic alternative whose indication and use can be enhanced in the treatment of VWD patients. In this context, adoption of strategies to improve the differential diagnosis, expand the DDAVP responsiveness test, and aware health professionals and patients about the costs and safety use of DDAVP, could contribute to the rational use of resources designated to treatment of VWD.

A doença de von Willebrand (DvW) é uma coagulopatia hereditária, causada por defeitos qualitativos ou quantitativos do fator de von Willebrand. O tratamento e a prevenção das intercorrências da DvW são bastante dispendiosos e, em geral, se baseiam na administração de concentrado de Fator VIII/FvW (CFVIII/FvW) e/ou da Desmopressina (DDAVP). Em muitas situações, o DDAVP é um tratamento eficaz que não expõe os pacientes aos riscos de contaminação viral e apresenta custo inferior quando comparado ao CFVIII/FvW. No entanto, a dificuldade de diagnóstico e classificação da DvW, bem como o baixo número de pacientes que se submetem ao teste para avaliação da resposta ao DDAVP, restringem a indicação do DDAVP como alternativa terapêutica para esses pacientes. O objetivo deste estudo foi avaliar retrospectivamente a indicação, o uso e o custo dos medicamentos no tratamento de pacientes com DvW com DDAVP e CFVIII/FvW no Hemocentro de Belo Horizonte no período entre 2011 a 2013. Este estudo incluiu 124 (24,22%) pacientes com DvW atendidos no hemocentro. Em 18 pacientes (14,52%) o diagnóstico de DvW não pode ser confirmado. Doze pacientes (9,68%) não puderam ser classificados e 73 foram classificados como tipo 1, 19 como tipo 2 e 2 pacientes como tipo 3. Oitenta e um pacientes fizeram o teste de DDAVP, sendo que 87,65% foram considerados responsivos. Nos pacientes tipo 1, a taxa de resposta ao DDAVP foi de 92%. Quase 32% dos pacientes tipo 1 não realizaram o teste. No período avaliado, foram utilizadas 3.794mcg de DDAVP (R$13.165,18) e 1.582.250 UI de CFVIII/FvW (R$1.075.930,00). Vinte por cento dos pacientes responsivos ao DDAVP utilizaram CFVIII/FvW em indicações onde o DDAVP poderia ter sido considerado (69.200UI de CFVIII/FvW versus 131 ampolas de DDAVP). Nos pacientes potencialmente responsivos ao DDAVP 108.700UI de CFVIII/FvW (R$73.916,00) poderiam ter sido substituídas por 247 ampolas de DDAVP (R$3.428,36). A escolha do DDAVP nessas situações poderia representar uma economia de 95,7% do valor gasto no tratamento do grupo de 27 pacientes responsivos e potencialmente responsivos ao DDAVP e 10,6% do valor total gasto para todo o tratamento dos pacientes no período do estudo. Estudos mais complexos de farmacoeconomia serão necessários para avaliar a magnitude da economia gerada com esse uso. O presente estudo mostrou que o DDAVP é uma alternativa terapêutica de menor custo, cuja indicação e utilização podem ser ampliadas no tratamento dos pacientes com DvW. Dessa maneira, a implementação de estratégias visando melhorar o diagnóstico, a classificação da doença, o acesso à testagem quanto à resposta ao DDAVP, bem como a conscientização dos profissionais de saúde e pacientes, quanto ao custo e segurança do DDAVP podem contribuir para o uso racional dos recursos destinados a essa parcela da população. / Von Willebrand disease (VWD) is a hereditary coagulopathy caused by qualitative or quantitative defects on von Willebrand factor. The treatment and the prevention of VWD complications is quite expensive and is generally based on the administration of vWF:FVIII Concentrates and/or Desmopressin (DDAVP). In many situations, DDAVP is an effective treatment that does not expose patients to viral contamination risks and presents a lower cost when compared to vWF:FVIII concentrates. However, the difficulty of diagnosis and classification of VWD, as well as the low number of patients tested to their responsiveness to DDAVP, restrict the use of DDAVP as an alternative treatment for these patients. The aim of this study was to evaluate retrospectively the clinical indications, the use and the cost of treatment of VWD patients with DDAVP and vWF:FVIII concentrates in the Blood Center of Belo Horizonte between 2011 and 2013. This study enrolled 124 (24.22%) VWD patients attended at the Blood Center.For18 (14.52%) patients, the diagnosis of VWD could not be confirmed. Twelve patients (9.68%) could not be classified and 73patients were classified as type 1, 19 as type 2 and 2 as type 3. Eighty-one patients were tested for DDAVP response and 87.65% (n=71) were considered responsive for the treatment. For type 1 VWD patients, the response rate to DDAVP was 92%. Almost 32% of type 1 VWD patients were not tested. In the period evaluated, 3,794mcg of DDAVP (R$ 13,165.18) and 1,582,250 IU of vWF:FVIII concentrates (R$ 1,075,930.00) were used. Between the cases with clinical indication of DDAVP use, 20% patients used vWF:FVIII concentrates (69.200UI of vWF:FVIII versus 131ampoules of DDAVP). In patients with good responsive to DDAVP, 108,700 IU of vWF:FVIII concentrates used (R$ 73,916.00) could be replaced by 247 ampoules of DDAVP (R$ 3,428.36). The choice of DDAVP in these situations could represent an economy of 95.7% of the value spent on the treatment of the 27 responsive and potentially responsive patients to DDAVP and 10.6% of the total value spent for the entire treatment of patients in the study period. More detailed studies of pharmacoeconomics are necessary to assess the magnitude of the economy generated by the use of DDAVP. This study demonstrated that DDAVP is a lower cost therapeutic alternative whose indication and use can be enhanced in the treatment of VWD patients. In this context, adoption of strategies to improve the differential diagnosis, expand the DDAVP responsiveness test, and aware health professionals and patients about the costs and safety use of DDAVP, could contribute to the rational use of resources designated to treatment of VWD.

Le contrôle de la transcription constitue le principal niveau de la régulation de l'expression des gènes dans les cellules eucaryotes. Le laboratoire a identifié 6 familles indépendantes avec un diabète insipide néphrogénique (DIN) lié à l'X portant de grandes délétions en amont du gène de l'AVPR2. Dans chacune de ces familles, les gènes AVPR2 et AQP2 sont intacts et les hommes sont atteints de DIN lié à l'X dans sa forme rénale « classique ». Le séquençage et l'analyse de 61 kilobases en amont et en aval de l'AVPR2 ont permis l'identification de 6 zones délétées chez 6 familles indépendantes, dont 5 zones de taille supérieure à 7 kilo bases, et une zone, de 102 paires de bases, commune à l'ensemble des délétions. Chez le patient porteur de cette délétion, les récepteurs V2 ne sont pas exprimés dans le tubule collecteur mais le sont au niveau des cellules endothéliales. Notre travail est de tenter de comprendre les mécanismes régulateurs du locus de l'AVPR2, et d'étudier l'expression « tissu spécifique » de ce gène. Les études réalisées dans le système Hprt, confirment le rôle activateur de la séquence de 102 pb. Les expériences in vitro indiquent que cet effet dépende du contexte extracellulaire, de la nature des cellules, ainsi que du promoteur de l'AVPR2. Les protéines liant potentiellement l'une des extrémités de la délétion a révélé la présence, soit de protéines régulatrices, soit de séquences inconnues, toutes exprimées dans le rein. À terme, ces études, ainsi que celles en découlant, permettront de positionner l'AVPR2 comme une cible de choix dans le traitement des diabètes insipides, centraux et néphrogéniques, par thérapie génique.

La vasopressine (AVP), ou hormone antidiurétique, a deux effets majeurs : 1°) des effets sur la perméabilité à l'eau du canal collecteur rénal, médiés par les récepteurs V2, qui permettent la formation d'urine hyperosmotique et donc une économie d'eau ; 2°) des effets vasoconstricteurs sur le muscle lisse vasculaire, médiés par les récepteurs V1a, qui peuvent induire un effet presseur. L'idée que l'AVP puisse jouer un rôle dans l'hypertension artérielle par ses effets vasculaires est souvent avancée, mais les travaux explorant cette hypothèse n'ont pas été concluants. Par contre, peu de travaux ont été consacrés au fait que l'AVP puisse contribuer à l'hypertension de façon indirecte, par son action sur le rein. Pourtant, on sait que l'AVP stimule la réabsorption de sodium dans le canal collecteur en augmentant l'activité du canal sodium épithélial. Il est donc concevable que, dans certains cas, les effets de l'AVP puissent produire une rétention hydrosodée susceptible d'augmenter la pression artérielle. Le but de nos travaux a été d'étudier les relations entre l'excrétion d'eau et de sodium et la pression artérielle, en tenant compte notamment du débit urinaire, de la concentration de l'urine, de l'AVP et du rythme nycthéméral d'excrétion d'eau et de sodium en relation avec celui de la pression artérielle. Nous avons réalisé des travaux expérimentaux chez le rat normal, conscient, et chez des sujets participant à diverses investigations cliniques. Les principaux résultats obtenus sont les suivants. (1) En utilisant des agonistes et des antagonistes sélectifs des récepteurs V1a et V2 in vivo chez le rat, nous avons pu montrer que l'influence de l'AVP sur l'excrétion du sodium était biphasique, du fait d'effets opposés médiés par les récepteurs V1a et V2 et de leurs seuils de réponse différents. (2) Chez l'Homme, nous avons montré que des changements d'apport sodé entraînent des changements correspondants de la concentration urinaire de sodium (qui ne sont pas immédiats), sans modification du débit urinaire, contrairement à l'idée généralement acceptée. (3) Nous avons également montré que le niveau de concentration de l'urine est très variable d'un individu à l'autre mais qu'en moyenne, les hommes ont une osmolalité urinaire plus élevée que les femmes. D'autre part, les afro-américains ont une urine significativement plus concentrée et un volume urinaire plus faible que les caucasiens et un rythme nycthéméral atténué. Chez les hommes jeunes normotendus, la pression pulsée est positivement corrélée à la concentration de l'urine. Ceci suggère que l'AVP a une action plus intense chez certains sujets et pourrait jouer un rôle dans le contrôle de la pression artérielle par ses effets V2. (4) Parmi des sujets présentant des caractéristiques du syndrome métabolique, ceux qui ont un rythme nycthéméral d'excrétion d'eau et de sodium perturbé ont une chute nocturne de pression artérielle plus faible (or, on sait que c'est d'un mauvais pronostic). Ce travail a permis pour la première fois de mettre en évidence des relations entre l'excrétion d'eau et de sodium et la pression artérielle, relations qui sont variables selon la période du nycthémère considérée et dans lesquelles l'AVP est probablement impliquée. Nos études ouvrent ainsi de nouvelles pistes de recherche sur le rôle potentiel de cette hormone dans certaines pathologies cardiovasculaires et rénales qui pourraient, à terme, conduire à l'utilisation d'antagonistes des récepteurs V2 de l'AVP dans le traitement de ces pathologies.