A nefropatia induzida por contraste (NIC) é uma lesão renal aguda (LRA) tóxica, que consiste em vasoconstrição intra-renal, toxicidade tubular direta com liberação de espécies reativas de oxigênio (EROs). A NIC está diretamente associada a doenças crônicas que comprometem a oxigenação da região da medula renal, como a disfunção renal preexistente, o Diabetes Mellitus (DM) e insuficiência cardíaca congestiva. Esse estudo investigou os mecanismos fisiopatológicos que caracterizam a NIC em ratos diabéticos. Foram utilizados ratos Wistar, adultos e machos. No protocolo DM foi realizada a nefrectomia unilateral esquerda (Nefré) no 1º dia, para potencializar o efeito tóxico da hiperglicemia crônica no rim. O DM foi induzido pela administração intravenosa (i.v.) de 65 mg/kg de estreptozotocina (STZ, diluída com citrato) no 20º dia, e o contraste iodado (CI) ioxitalamato de meglumina, 6 ml/kg, foi administrado (intraperitoneal, i.p.) no 85º dia. Foram realizados os seguintes grupos: Citrato (controle); Nefré+Citrato; DM; Nefré+DM; DM+CI; Nefré+DM+CI. Foram avaliados parâmetros fisiológicos (ingestão de ração e água, peso, glicemia capilar, peso do rim e peso relativo do rim); a albuminúria (método de imunodifusão), a função renal (FR) (clearance de creatinina, método de Jaffé), a lesão oxidativa (peróxidos urinários-PU, FOX-2; substâncias reativas com o ácido tiobarbitúrico-TBARS, tióis no tecido renal) e análise histológica renal (lesão tubulointersticial). Observou-se que os grupos diabéticos apresentaram polifagia, polidipsia, hiperglicemia e redução do peso corporal (p<0,05), além de redução do clearance de creatinina com elevação de PU e TBARS, manutenção de tióis e elevação da albuminúria. O tratamento com CI nos animais diabéticos determinou redução da FR, elevação dos PU e TBARS e redução dos tióis. Quanto à histologia renal, demonstrou-se que apenas o grupo Nefré+DM+CI apresentou lesão tubulointersticial. Os achados dessa investigação confirmaram o efeito tóxico do CI dose única sobre a função renal de ratos com hiperglicemia crônica, pressupondo que o DM seja fator de risco para essa nefropatia. / Contrast-Induced Nephropathy (CIN) is a toxic acute kidney injury (AKI) that consists in intrarenal vasoconstriction, direct tubular toxicity with generation of reactive oxygen species (ROS). The CIN is associated with the decreased tissue oxygen tension in renal medula in preexisting renal dysfunction, Diabetes Mellitus (DM) and congestive heart failure. This study investigated the pathophysiologic mechanisms in the CIN in diabetic rats. Adult, male, Wistar rats were used. It was performed left uninephrectomy (Nx) on the 1st day in the DM group to potentialize the toxic effect of the chronic hyperglycemia. The DM was induced by a single dose of intravenous streptozotocin (65mg/kg i.v.) in sodium citrate buffer, on the 20th day and the iodine contrast (IC) meglumine ioxithalamate 6 ml/kg was administrated (intraperitoneal, i.p.) on the 85th day. Animals were divided into the following groups: Citrate (control); Nx+Citrate; DM; Nx+DM; DM+IC; Nx+DM+IC. Physiological parameters (water and food intake, body weight, blood glucose, kidney weight and relative kidney weight); renal function (creatinine clearance, Jaffé method); urine albumin (imunodifusion method); oxidative injury (urinary peroxides, FOX-2, tiobarbituric acid reactive substances-TBARS and thiols in renal tissue) and kidney histological analysis (tubulointerstitial injury) were evaluated. In the diabetic groups, polyphagia, polydipsia, increased blood glucose and reduced body weight were observed (p<0.05). The relative kidney weight was increased in the Nx and IC animals (p<0.05). The renal function was reduced; urinary peroxides and TBARS were increased in the diabetic and IC animals. The decrease in thiols levels in the diabetic and IC groups demonstrated the endogenous substrate consumption. The Nx animals that received IC presented tubular cells vacuolization and edema with moderate injury. The data has described the pathophysiology of CIN in diabetic rats involving oxidative injury that resulted of association of chronic high blood glucose and IC toxicity, suggesting that DM can be pointed out as a risk factor for CIN.

Orientador: Marilda Mazzali / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-09T16:38:38Z (GMT). No. of bitstreams: 1 Beraldo_FelipeCaetano_M.pdf: 4477461 bytes, checksum: 2e940e62a8ea6158326013aef37b29e0 (MD5) Previous issue date: 2007 / Resumo: A lesão renal causada pela isquemia é a principal causa de insuficiência renal aguda [IRA] em rins nativos e transplantados. A fisiopatologia da IRA induzida por isquemia/reperfusão [I/R] envolve alterações na hemodinâmica renal, lesão de células endoteliais e tubulares e os processos inflamatórios, que resultam na ativação e lesão de células endoteliais, aumento da adesão entre células endoteliais e leucócitos, migração de leucócitos para o tecido afetado e comprometimento microvascular. Dentre as células inflamatórias envolvidas no modelo I/R, estudos demonstram a participação de macrófagos e leucócitos. Os mastócitos, apesar de participarem ativamente do processo de fibrose intersticial renal, são pouco estudados neste modelo. Estudos anteriores demonstraram que a presença de mastócitos em transplantes renais humanos com necrose tubular aguda [NTA] apresentou correlação com o desenvolvimento de fibrose intersticial. Assim, o presente estudo tem como hipótese que a presença de mastócitos no modelo de I/R seria um fator de risco para o desenvolvimento de nefropatia crônica. Para tanto, animais [ratos Wistar machos] foram submetidos ao procedimento clássico de isquemia/reperfusão e sacrificados a períodos variáveis de 0 a 14 dias. Ao final de cada período foram analisadas a função renal [creatinina sérica], a presença de células inflamatórias [macrófagos, mastócitos, linfócitos T], a proliferação celular, a expressão de fatores pró-inflamatórios [osteopontina], de diferenciação epititélio-mesenquimal [vimentina] e pró-fibróticos [alfa-actina] através de imunohistoquímica. Os animais desenvolveram IRA, confirmada pela presença de elevação de creatinina sérica a partir de D1 e pela presença de alterações degenerativas tubulares, especialmente em camada medular externa. A partir do D7 pós reperfusão teve início o processo regenerativo tubular, com redução dos níveis séricos de creatinina e aumento do número de túbulos com regeneração celular. O infiltrado inflamatório medular, detectado por aumento de expressão de células PCNA + apresentou pico em D3. Os mastócitos foram as primeiras células a apresentar aumento de expressão (D1), seguidas de linfócitos e macrófagos em D3. Entretanto, enquanto o infiltrado de macrófagos e linfócitos diminuiu a partir de D7, o número de mastócitos permaneceu crescente, com pico em D14. A expressão de osteopontina em camada medular foi precoce (D1) e constante até D7, enquanto vimentina apresentou elevação a partir de D3, com pico em D5-7. Em D14, tanto a expressão de osteopontina como de vimentina foram menos intensas, porém ainda significativamente superiores às dos animais controle (Sham). Miofibroblastos, identificados através de imunohistoquímica para alfa actina apresentaram aumento significativo a partir de D3, e persistiram elevados até o período final do estudo (D14). Estes dados sugerem que os mastócitos participam do processo de resposta renal à isquemia, com infiltração precoce e persistência durante o processo de regeneração/cicatrização. A associação com macrófagos e linfócitos sugere sua participação no processo inflamatório inicial. Entretanto, a persistência de mastócitos e a associação com expressão de vimentina e de alfa actina sugerem que estas células também tem participação no processo de regeneração e de cicatrização tecidual / Abstract: Renal ischemia is the main cause of acute renal failure in both native and transplanted kidneys. Ischemia/reperfusion lesion includes changes in renal hemodynamic, endothelial and tubular cell lesion, and inflammatory process, resulting in endothelial cell activation, increased adhesion of endothelial cells and leukocytes, migration of circulating cells to damaged tissue and microvascular dysfunction. While macrophages and T cells are usually analyzed in this model, mast cells, another group of inflammatory cells, are forgotten. Previous studies have shown that mast cells are involved in renal fibrosis, but its participation in the acute phase of renal injury remains unknown. In this study we hypothesized that the presence of mast cells in response to ischemia reperfusion lesion could be a risk factor for the development of renal fibrosis. Male Wistar rats undergone bilateral renal artery clamping for 45 minutes, and were sacrificed from 0 to 14 days after reperfusion. At each study point, renal function, (serum creatinine) and renal morphology (PAS staining), presence of cell proliferation (PCNA), inflammatory cells (macrophages, T cells and mast cells), as well as the expression of pro inflammatory (osteopontin), de-differentiation (vimentin) and pro fibrotic (a smooth muscle cell actin- aSMA ) markers were analyzed. All studied animals developed acute renal failure, confirmed by the increase in serum creatinine and presence of degenerative tubular cell lesions in outer medulla, from D1. Seven days after reperfusion the regenerative process started, with decrease in serum creatinine levels and increase in number of regenerative tubular cells. Interstitial inflammatory response in medulla, analyzed by PCNA stained, peaked at D3. Mast cells was the early detected cell type (D1), followed by both macrophages and T cells at D3.However, while macrophages and T cells infiltrates decreased from D7, mast cell remained in medullar interstitium, with a peak in D14. Osteopontin expression in medulla was observed at early points (D1), and remained constant till D7. Vimentin increased from D3, peaking from D5-D7. Despite a reduction of osteopontin and vimentin expression was observed at D14, these values were still higher than in control animals (Sham). Myofibroblasts, identified by aSMA staining were observed in medulla from D3, and persisted until the end of study period (D14). These data suggests that mast cells are involved in the tissue response to ischemic injury, with an early infiltration and persisting during the repare/scare phase. Association with macrophages and T cells suggests the participation of mast cells in the early inflammatory response. However, its persistence and association with vimentin and myofibroblasts suggests the participation in both renal repare and scarring process / Mestrado / Ciencias Basicas / Mestre em Clinica Medica

Thrombotic microangiopathies (TMA) are disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microthrombi leading to organ dysfunction. Atypical hemolytic uremic syndrome (aHUS) is a rare subtype of TMA mediated by complement dysregulation. We present a case of a 59-year-old female who presented with acute kidney injury and mild thrombocytopenia but with normal hemoglobin. We highlight the importance of prompt diagnosis of aHUS and initiating appropriate treatment with eculizumab.

Dissertation (MD)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: Acute renal failure still is, with the exception of cardiac deaths, the most important pathological process associated with perioperative mortality in patients operated for abdominal aortic aneurysms. The intraoperative change in renal blood flow (RBF) and glomerular function have been investigated in human and animal models, particularly over the past 15 years. Despite large variation in study populations, measurement techniques and study designs in general, a significant body of evidence has developed which suggests infrarenal aortic clamp-induced renal ischemia to be the cause of postoperative acute renal failure when this complication does occur. It is rather surprizing then that, despite some recent studies which have reported on various pharmacological interventions to prevent intraoperative renal ischemia (with variable success), very little has apparently been done to unravel the pathogenesis and exact pathophysiology of this potentially lethal complication. Although a number of investigators suggest the possibility of hormonal involvement (particularly reninangiotensin, antidiuretic hormone (ADH) and catecholamines) in the process, the exact role of these mediators have not been explored (or reported) in a structured fashion. In an initial human study, renal hemodynamics and function were measured from the preoperative period, during the intraoperative phase and at least until 4 hours after aortic unclamping. To investigate the possibility of a temporal relationship between renal changes and fluctuations in hormonal concentrations, plasma concentrations of relevant hormones were determined at every sampling period where renal parameters were measured. The decrease in RBF and glomerular filtration rate (GFR) which we demonstrated to coincide with infrarenal aortic cross clamping, is consistent with results previously published. We demonstrated persistence of the impairment of these parameters as long as 4 hours into the postoperative phase; which has previously only been reported for the period until immediately after aortic unclamping with the abdomen still open. The persistence of a depressed GFR until the time of discharge of patients is cause for concern, particularly in patients with compromised renal function prior to surgery. Of the measured hormones with a potential influence on RBF and nephron function, renin was the only mediator where changes in plasma concentrations coincided with the depression of RBF and GFR after aortic cross clamping. The design of our study did not allow us to conclude whether the concomitant increase in angiotensin II was primarily responsible for the change in renal hemodynamics, or whether the raised renin (and angiotensin) levels were stimulated by the decrease in RBF induced by another mechanism. In another patient group, we demonstrated that the combination of mannitol and dopamine provided no protection against the deleterious effects of aortic cross clamping. In fact, the high urine volumes produced under the influence of these agents (which did not correlate with RBF at the corresponding periods), is likely to prompt a false sense of security. Given the lack of any objective benefit afforded by these agents, their use in these clinical circumstances should be discouraged. The animal studies were aimed at elucidation of the exact role of angiotensin in the pathogenesis and pathophysiology of the renal changes associated with infrarenal aortic clamping, as well as the interaction of angiotensin with other modulators for which an interactive relationship had been described previously under other experimental and/or clinical circumstances. The first study showed that, although renin (and thus angiotensin) concentrations were high after aortic unclamping, the hormone had no pathogenic or pathophysiological role of significance in the observed renal changes during this period (since blocking angiotensin II activation by the prevention of renin release, or by inhibiting the conversion enzyme, did not prevent a substantial decrease in RBF or GFR during that period). Preventing angiotensin II activation did, however, prevent renal changes during aortic clamping. This beneficial effect did not establish a primary role for angiotensin during that period, since the favourable influence could also (at least partially) be explained by prevention of the permissive influence of angiotensin on other vasoconstrictors and/or other vasodilatory influences of ACE inhibition and [1- blockade which are unrelated to angiotensin. This study did indicate that (at least partially) different mechanisms are responsible for the renal changes seen during aortic clamping, and after aortic unclamping. The second study explored the role of calcium in the renal pathophysiological changes during aortic clamping and after unclamping. The protective influence effected by the administration of a Ca2 + -blocker suggest the dependence of the renal vasoconstrictive and glomerular pathophysiological process( es) on the cellular influx of Ca2 + through voltage-gated channels. It unfortunately provides no definitive insight into the primary instigators of these processes. However, it does offer a clinically useful method of preventing these changes and protecting the kidney against ischemic injury during abdominal aortic surgery. The third component of the animal studies demonstrates the importance of the protective effect of renal prostaglandins during the specific experimental (and probably also the clinical) circumstances. Again, it does not provide definitive information on the mediators responsible for the renal changes, since the deleterious effects of numerous endogenous substances have previously been shown to be counterbalanced by intrarenal synthesis of prostaglandins under various experimental and clinical circumstances. The extent of the pathophysiological and ultrastructural changes which occurred under the influence of a NSAID does, however, suggest that these drugs should not be used under these clinical circumstances. The last component of the study provides evidence that angiotensin only plays a secondary/supplementary role in the renal pathophysiological process even during aortic clamping. This may explain the contradictory evidence regarding the potential beneficial effect of ACE inhibition (on renal hemodynamics and glomerular function) during abdominal aortic surgery (Licker et al. 1996, Colson et al. 1992a). Based on our studies, ACE inhibition can not be supported for this purpose. / AFRIKAANSE OPSOMMING: Akute nierversaking is met die uitsondering van kardiale sterftes, steeds die belangrikste patologiese proses wat geassosieer is met perioperatiewe mortaliteit in pasiënte wat opereer word vir abdominale aorta aneurismes. Die intraoperatiewe veranderinge in renale bloedvloei (NBV) en glomerulêre funksie is die afgelope 15 jaar ondersoek en gerapporteer in pasiënte- sowel as diere-modelle. Ten spyte van groot variasies in studie-populasies, meettegnieke en ontwerp van studies in die algemeen, dui 'n wesenlike hoeveelheid getuienis daarop dat infrarenale klemming van die aorta renale isgemie induseer, wat die oorsaak is van postoperatiewe akute nierversaking wanneer hierdie komplikasie voorkom. Dit is verbasend dat, ten spyte van sommige onlangse studies wat rapporteer oor 'n verskeidenheid farmakologiese ingrepe om intraoperatiewe renale isgemie te voorkom (met wisselende sukses), baie min oënskynlik gedoen is om die patogenese en die presiese patofisiologie van hierdie potensieel dodelike komplikasie te ontrafel. Hoewel verskeie outeurs die moontlikheid van hormonale betrokkenheid (veral renienangiotensien, antidiuretiese hormoon en katekolamiene) in hierdie proses suggereer, is die presiese rol van hierdie mediators nog nie op 'n gestruktureerde wyse ondersoek (of rapporteer) nie. In ons aanvanklike pasiënte-studie is renale hemodinamika en -funksie gemeet vanaf die preoperatiewe periode, gedurende die intra-operatiewe fase en tot minstens vier uur na ontklemming van die aorta. Serumkonsentrasies van relevante hormone is bepaal tydens elke metingsperiode waar renale parameters gemeet is, ten einde die moontlikheid van 'n temporale verwantskap tussen renale veranderinge en variasies in hormoonkonsentrasies te ondersoek. Die vermindering in NBV en glomerulêre filtrasiespoed (GFS) wat ons aangetoon het om saam te val met infrarenale aortaklemming, stem ooreen met resultate wat tevore deur ander navorsers publiseer is. Ons het aangetoon dat die inkorting van hierdie parameters voortduur tot minstens vier uur na aorta-ontklemming. Hierdie veranderinge is tevore slegs rapporteer vir periodes tot kort na aorta-ontklemming voor sluiting van die buikwond. Die feit dat die GFS steeds verlaag is met ontslag van hierdie pasiënte, skep rede tot kommer, veral in pasiënte wat alreeds ingekorte nierfunksie het voor die chirurgiese prosedure. Van die gemete hormone wat moontlik 'n invloed sou kon uitoefen op NBV eh nefronfunksie, was renien die enigste waarvan verandering in plasmakonsentrasies saamgeval het met die onderdrukking van NBV en GFS na aortaklemming. Die ontwerp van ons studie het ons nie toegelaat om 'n besliste uitspraak te maak of die geassosieerde verhoging in angiotensien II primêr verantwoordelik was vir die verandering in renale hemodinamika, of dat die verhoogde renien (en angiotensien) bloedvlakke moontlik sekondêr stimuleer is deur die verandering in NBV wat deur 'n ander meganisme induseer is. In 'n ander pasiëntegroep het ons aangetoon dat die kombinasie van mannitol en dopamien geen beskerming verleen het teen die nadelige effekte van aorta-klemming nie. Die groot volumes uriene wat uitgeskei is onder die invloed van hierdie middels (wat nie korreleer het met NBV tydens ooreenstemmende periodes nie), het inderwaarheid 'n ontoepaslike gerustheid uitgelok. Weens die ooglopende gebrek aan objektiewe voordeel wat verleen word deur hierdie middels, behoort hulle gebruik tydens hierdie kliniese omstandighede ontmoedig te word. Die doel van die diere studies was die identifisering van die presiese rol van angiotensien in die patogenese en patofisiologie van die renale veranderinge geassosieer met infrarenale aortaklemming, sowel as die interaksie van angiotensien met ander modulators waarvoor 'n interaktiewe verwantskap voorheen beskryf is onder eksperimentele en/of kliniese omstandighede. Die eerste studie het getoon dat alhoewel renien (en dus angiotensien) konsentrasies hoog was na aorta-ontklemming, die hormone geen betekenisvolle patogenetiese of patofisiologiese rol in die waargenome renale veranderinge gedurende hierdie periode het nie (aangesien blokkade van angiotensien aktivering deur voorkoming van renien vrystelling, of deur inhibisie van angiotensien omsettingsensiem (AOE), nie 'n daling in NBV of GFS kon voorkom nie). Voorkoming van angiotensien II aktivering het egter wel renale verandering voorkom gedurende aortaklemming. Dié voordelige effek het nie 'n primêre rol vir angiotensien gedurende die periode bevestig nie, aangesien die gunstige invloed ook (ten minste gedeeltelik) verduidelik kon word deur die voorkoming van die fassiliterende invloed van angiotensien op ander vasokonstriktore en/of ander vasodilator-invloede van die onderdrukking van AOE en ïs-blokkers (wat geen verband het met angiotensien of die blokkade daarvan nie). Die studie het aangetoon dat (ten minste gedeeltelik) verskillende meganismes verantwoordelik is vir renale veranderinge wat gesien is gedurende aortaklemming en na -ontklemming. Die tweede studie het die rol van kalsium in die renale patofisiologiese veranderinge gedurende aortaklemming en na ontklemming ondersoek. Die beskermende invloed wat deur die toediening van Ca2 + -blokkers bewerkstellig is, het bevestig dat die renale vasokonstriktoriese en glomerulêre patofisiologiese prosesse afhanklik is van sellulêre influks van kalsium deur spannings-afhanklike kannale. Dit het ongelukkig geen definitiewe insig verleen ten opsigte van die primêre inisieerders van die proses nie. Dit verskaf nogtans 'n bruikbare kliniese metode om daardie veranderinge te voorkom en die niere teen isgemiese besering gedurende abdominale aorta-chirurgie te beskerm. Die derde komponent van die diere-studies demonstreer die belangrikheid van die beskermende effek van renale prostaglandiene tydens die spesifieke eksperimentele (en waarskynlik ook die kliniese) omstandighede. Weereens gee dit nie definitiewe inligting oor die bemiddelaars wat verantwoordelik is vir die renale veranderinge nie, aangesien die skadelike effekte van verskeie endogene stowwe voorheen aangetoon is om beperk of voorkom te word deur die intrarenale vrystelling van prostaglandiene. Die omvang van die patofisiologiese en ultrastrukturele veranderinge wat ontstaan het onder die invloed van nie-steroïed anti-inflammatoriese middels (wat gebruik is om prostaglandien sintese te inhibeer), dui aan dat hierdie middels vermy moet word onder soortelyke kliniese omstandighede. Die laaste komponent van die studie verskaf 'n sterk aanduiding dat angiotensien slegs 'n sekondêre/aanvullende rol speel in die renale patofisiologiese proses, selfs gedurende aortaklemming. Dit mag die weersprekende getuienis oor die potensiële voordeel van AOE onderdrukking (op renale hemodinamika en glomerulêre funksie) gedurende abdominale aortachirurgie (Licker et al. 1996, Colson et al. 1992a) verklaar. Gebaseer op ons studies, kan AOE onderdrukking nie ondersteun word vir hierdie doel nie.

A ventilação mecânica (VM) tem sido recentemente associada ao desenvolvimento de falências orgânicas distais, como um fator contribuinte para a falência renal em pacientes com trauma e fator de risco para diálise e mortalidade em unidade de terapia intensiva (UTI). A estratégia ventilatória adotada pode influenciar estes efeitos. O objetivo do presente estudo é explorar a hipótese de que a estratégia de ventilação mecânica adotada pode influenciar na função renal. Delineamento: Randomizado, investigação animal experimental. Casuística: Ratos machos Wistar, anestesiados, paralisados e ventilados mecanicamente. Intervenção: Dois grupos com seis animais cada foram randomizados para receberem ventilação mecânica com volume corrente (VT) de 8ml/kg (VT8) ou 27ml/kg (VT27). Os parâmetros ajustados para grupo foram: a) VT 8ml/kg; Freqüência respiratória (FR) 60±7 rpm; pressão positiva expiratória final (PEEP) 3 cmH2O; Pico de pressão inspiratória (Pwap) 11.8±2 cmH2O; Pressão média de vias aéreas (Pawm) 6,33±0,22 e b) VT 27ml/kg; FR 30±5 rpm; PEEP 0 cmH2O; Pwap 22.7±4 cmH2O; Pawm 6,50±0,22. Mensurações e Resultados: O grupo VT27 apresentou redução significativa no clearance de inulina após 60 minutos de VM, indicando insuficiência renal aguda (0.6±0.05 ml/min/100g de peso corporal (PC)), e ainda mais acentuada após 90 minutos de VM (0.45±0.05 ml/min/100g de PC) comparada aos valores basais (0.95±0.07 ml/min/100g de PC), p<0.001. Nenhum dos dois grupos sofreram variações significativas em relação as variáveis hemodinâmicas e gasométricas. Conclusões: Observamos que o ritmo de filtração glomerular (RFG) mensurado pelo clearance de inulina é afetado pela estratégia de volume corrente empregado após 60 minutos de VM com 27ml/kg e caindo a valores mais baixo após 90 minutos de VM / Mechanical Ventilation (MV) has been recently associated with development of distal organ failure and it is also a contributor factor for renal failure in trauma patients, and risk factor for dialysis and mortality rate in intensive care unit. The ventilatory strategy adopted might be influenced this effect. The aim of the present study was to explore the hypothesis that mechanical ventilatory strategy may contribute to decreased renal function. Design: Randomized animal laboratory investigation. Subjects: Anesthetized, paralyzed, and mechanically ventilated male Wistar rats. Interventions: Two groups of six rats each were randomized to receive tidal volume of either 8ml/kg or 27 ml/kg. Ventilation strategies for the two groups were as follows: a) 8ml/kg; frequency 60±7 beats/min; positive endexpiratory pressure, 3.0 cm H2O; and peak inspiratory airway pressure (Pawp), 11.8±2 cm H2O; and b) 27ml/kg; frequency 30±5 beats/min; positive end-expiratory pressure, 0 cm H2O; and peak inspiratory airway pressure (Pawp), 22.7±4 cm H2O; Both groups with the same mean airway pressure (Pawm), 6,33±0,21 and 6,5±0,22, respectively. Measurements and main Results: Rats ventilated with high tidal volume (27ml/kg) presented significantly decreased inulin clearance after 60 minutes of mechanical ventilation, indicating acute renal insufficiency (0.6±0.05 ml/min/BW) in comparison with basal values (0.95±0.07 ml/min/BW), p<0.001. We observed decreased in inulin clearance in rats that received high tidal volume, after 60 minutes of ventilation and even more significant at 90 minutes of ventilation (0.45±0.05 ml/min/BW) compared with basal values. No inulin clearance alteration was observed in control ventilation group (0.8±0.05 ml/min/BW basal vs. 0.72±0.03 ml/min/BW 120 min of MV). Conclusion: We concluded that GFR is affected by different strategies of mechanical ventilation, and after 60 minutes of high tidal volume (27ml/kg) ventilation the renal function marked decreased, getting worse after 90 minutes

A high-performance liquid chromatography was developed to assay levofloxacin and vancomycin. Fluorescence polarization immunoassay was to assay amikacin. The oseltamivir carboxylate and telavancin concentrations were assayed by high-performance liquid chromatography coupled with tandem mass spectrometry. / An in vitro model was utilized to examine adsorption of antibiotics onto haemofilters. In order to test antibiotics from a range of classes, levofloxacin, amikacin, vancomycin, telavancin, and oseltamivir carboxylate were studied. / In summary, the antibiotic adsorption by haemofilters is a complex process. Both characteristics of antibiotics and haemofilters may determine adsorption. Among the studied antibiotics, in vitro adsorption of amikacin by PAN filters may have clinical significance, thus the routine monitoring of amikacin peak concentration in vivo during CRRT is recommended. / In the in vitro model, blood was pumped from an agitated, glass mixing chamber (heated using an automatic water bath), around a circuit and returned to the mixing chamber using a haemofiltration machine. Ultrafiltrate was also returned to the mixing chamber to constitute a closed circuit. As a result any decrease in drug concentration could only be due to adsorption to the filter and extracorporeal circuit, spontaneous degradation or metabolism by red cells. / The main findings were: (1) low adsorption of levofloxacin and vancomycin by haemofilters at clinically relevant concentrations; (2) significant absolute adsorption of amikacin by polyacrylonitrile haemofilters; (3) the adsorption of antibiotics was membrane-material dependent with greater adsorption by polyacrylonitrile filters; (4) lack of relationship between membrane surface area and amikacin adsorption; (5) the adsorption of levofloxacin is reversible, contrary to irreversibility of vancomycin and amikacin; (6) sieving coefficient of oseltamivir is very near to 1.0. / This thesis investigated: (1) the extent of antibiotic adsorption (levofloxacin, vancomycin, amikacin, telavancin and oseltamivir carboxylate) by haemofilters; (2) the time course of antibiotic adsorption by haemofilters; (3) the effects of plasma albumin concentration, initial dosage, pH, filter membrane material, filter membrane surface area and repeated dosing on adsorption; (4) the reversibility or irreversibility of adsorption; (5) clearance of oseltamivir carboxylate and telavancin by ultrafiltration. / Up to 25% of critically ill patients develop acute renal failure with sepsis being the most common cause. Outside of North and South America, these patients usually receive continuous renal replacement therapy (CRRT) which utilizes high flux haemofilter membranes. Thus it is common for these patients to be concurrently receiving antibiotics and CRRT. However, information about the adsorptive capacity of various haemofilters for most drugs is lacking. / "September 2007." / Advisers: Charles Gomersall; Tony Gin. / Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4659. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 147-164). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract in English and Chinese. / School code: 1307.

Introdução: A anfotericina B é a droga de escolha para o tratamento de doenças fúngicas severas, estando associada, no entanto, a alta incidência de nefrotoxicidade. O uso de anfotericinas modificadas está associado a elevado custo. Em grupos de baixo risco o uso de sobrecarga hidrossalina pode ser suficiente para evitar perda severa de função renal. Métodos: Foram estudados prospectivamente pacientes internados em hospital universitário, com idade superior a 12 anos, e que estavam dentro das primeiras 24 horas de uso de anfotericina B. Foram excluídos pacientes em centros de terapia intensiva e que estivessem em uso de drogas vasoativas. Solução salina 0,9% (500 ml) foi infundida antes e após a anfotericina B. Foram coletados exames na inclusão e no término do tratamento. A dosagem de creatinina sérica foi repetida após 30 dias do término do tratamento. Resultados: Foram estudados 48 pacientes. A média de elevação da creatinina sérica foi de 0,3 (0,18-0,41) mg/dl., representando um decréscimo médio de 25 (12,8-36,9) ml/min na depuração de creatinina endógena (DCE). Insuficiência renal aguda (IRA), definida pela elevação maior do que 50% da creatinina basal, ocorreu em 15 pacientes (31,3%). Pacientes que utilizaram antibióticos e aqueles em status pós-quimioterapia ou submetidos a transplante de medula óssea foram os que apresentaram maior risco de desenvolverem IRA. A creatinina e a DCE após 30 dias do término do tratamento não diferiram de seus valores basais. Conclusão: Em pacientes de baixo risco, o uso de anfotericina B com adminstração profilática de solução fisiológica foi associado à alteração pequena e reversível da função renal. Devido ao alto custo, o uso de métodos mais dispendiosos nestes pacientes não parece justificado no momento. Ensaios clínicos randomizados são necessários nesta população. / Background: Amphotericin B is the drug of choice for treatment of severe fungal illnesses. It is, however, associated with a high incidence of nephrotoxicity. The use of modified amphotericins has a high economic cost. It is possible that in low-risk patients, saline loading is enough to prevent significant loss of renal function induced by the use of amphotericin B. Methods: Patients were prospectively enrolled in the study. They were older then 12 years, were within the first 24 hours of treatment with amphotericin B and had normal renal function. Patients at intensive care units or using vasoactive drugs were excluded. Sodium chloride 0.9% (500 ml) was infused before and after the amphotericin B. Blood and urine analysis were done for the evaluation of the renal function in the beginning and in the end of the treatment. Serum creatinine was repeated 30 days after the end of the amphotericin B treatment. Results: Forty-eight patients were studied. The mean rise of the serum creatinine was of 0.3 (0.18- 0.41) mg/dl, representing a mean decrease of 25 (12.8-36.9) ml/min of the creatinine clearance (CrCl). Acute renal failure (ARF), defined as a rise higher than 50% of the baseline creatinine, occurred in 15 patients (31.3%). Patients that were on antibiotics, in post-chemotherapy status or those submitted to bone marrow transplantation had the higher risk of developing ARF. Mean serum creatinine and the CrCl were no different from baseline values after 30 days. Conclusion: In low-risk patients, the use of amphotericin B with prophylactic sodium chloride loading was associated with a small and reversible decrease of the renal function. Due to its high cost the use of more expensive therapies in this group of patients does not seem to be justified at the moment. Prospective randomized trials are necessary in the low-risk population.

Introdução: A anfotericina B é a droga de escolha para o tratamento de doenças fúngicas severas, estando associada, no entanto, a alta incidência de nefrotoxicidade. O uso de anfotericinas modificadas está associado a elevado custo. Em grupos de baixo risco o uso de sobrecarga hidrossalina pode ser suficiente para evitar perda severa de função renal. Métodos: Foram estudados prospectivamente pacientes internados em hospital universitário, com idade superior a 12 anos, e que estavam dentro das primeiras 24 horas de uso de anfotericina B. Foram excluídos pacientes em centros de terapia intensiva e que estivessem em uso de drogas vasoativas. Solução salina 0,9% (500 ml) foi infundida antes e após a anfotericina B. Foram coletados exames na inclusão e no término do tratamento. A dosagem de creatinina sérica foi repetida após 30 dias do término do tratamento. Resultados: Foram estudados 48 pacientes. A média de elevação da creatinina sérica foi de 0,3 (0,18-0,41) mg/dl., representando um decréscimo médio de 25 (12,8-36,9) ml/min na depuração de creatinina endógena (DCE). Insuficiência renal aguda (IRA), definida pela elevação maior do que 50% da creatinina basal, ocorreu em 15 pacientes (31,3%). Pacientes que utilizaram antibióticos e aqueles em status pós-quimioterapia ou submetidos a transplante de medula óssea foram os que apresentaram maior risco de desenvolverem IRA. A creatinina e a DCE após 30 dias do término do tratamento não diferiram de seus valores basais. Conclusão: Em pacientes de baixo risco, o uso de anfotericina B com adminstração profilática de solução fisiológica foi associado à alteração pequena e reversível da função renal. Devido ao alto custo, o uso de métodos mais dispendiosos nestes pacientes não parece justificado no momento. Ensaios clínicos randomizados são necessários nesta população. / Background: Amphotericin B is the drug of choice for treatment of severe fungal illnesses. It is, however, associated with a high incidence of nephrotoxicity. The use of modified amphotericins has a high economic cost. It is possible that in low-risk patients, saline loading is enough to prevent significant loss of renal function induced by the use of amphotericin B. Methods: Patients were prospectively enrolled in the study. They were older then 12 years, were within the first 24 hours of treatment with amphotericin B and had normal renal function. Patients at intensive care units or using vasoactive drugs were excluded. Sodium chloride 0.9% (500 ml) was infused before and after the amphotericin B. Blood and urine analysis were done for the evaluation of the renal function in the beginning and in the end of the treatment. Serum creatinine was repeated 30 days after the end of the amphotericin B treatment. Results: Forty-eight patients were studied. The mean rise of the serum creatinine was of 0.3 (0.18- 0.41) mg/dl, representing a mean decrease of 25 (12.8-36.9) ml/min of the creatinine clearance (CrCl). Acute renal failure (ARF), defined as a rise higher than 50% of the baseline creatinine, occurred in 15 patients (31.3%). Patients that were on antibiotics, in post-chemotherapy status or those submitted to bone marrow transplantation had the higher risk of developing ARF. Mean serum creatinine and the CrCl were no different from baseline values after 30 days. Conclusion: In low-risk patients, the use of amphotericin B with prophylactic sodium chloride loading was associated with a small and reversible decrease of the renal function. Due to its high cost the use of more expensive therapies in this group of patients does not seem to be justified at the moment. Prospective randomized trials are necessary in the low-risk population.

Introdução: A anfotericina B é a droga de escolha para o tratamento de doenças fúngicas severas, estando associada, no entanto, a alta incidência de nefrotoxicidade. O uso de anfotericinas modificadas está associado a elevado custo. Em grupos de baixo risco o uso de sobrecarga hidrossalina pode ser suficiente para evitar perda severa de função renal. Métodos: Foram estudados prospectivamente pacientes internados em hospital universitário, com idade superior a 12 anos, e que estavam dentro das primeiras 24 horas de uso de anfotericina B. Foram excluídos pacientes em centros de terapia intensiva e que estivessem em uso de drogas vasoativas. Solução salina 0,9% (500 ml) foi infundida antes e após a anfotericina B. Foram coletados exames na inclusão e no término do tratamento. A dosagem de creatinina sérica foi repetida após 30 dias do término do tratamento. Resultados: Foram estudados 48 pacientes. A média de elevação da creatinina sérica foi de 0,3 (0,18-0,41) mg/dl., representando um decréscimo médio de 25 (12,8-36,9) ml/min na depuração de creatinina endógena (DCE). Insuficiência renal aguda (IRA), definida pela elevação maior do que 50% da creatinina basal, ocorreu em 15 pacientes (31,3%). Pacientes que utilizaram antibióticos e aqueles em status pós-quimioterapia ou submetidos a transplante de medula óssea foram os que apresentaram maior risco de desenvolverem IRA. A creatinina e a DCE após 30 dias do término do tratamento não diferiram de seus valores basais. Conclusão: Em pacientes de baixo risco, o uso de anfotericina B com adminstração profilática de solução fisiológica foi associado à alteração pequena e reversível da função renal. Devido ao alto custo, o uso de métodos mais dispendiosos nestes pacientes não parece justificado no momento. Ensaios clínicos randomizados são necessários nesta população. / Background: Amphotericin B is the drug of choice for treatment of severe fungal illnesses. It is, however, associated with a high incidence of nephrotoxicity. The use of modified amphotericins has a high economic cost. It is possible that in low-risk patients, saline loading is enough to prevent significant loss of renal function induced by the use of amphotericin B. Methods: Patients were prospectively enrolled in the study. They were older then 12 years, were within the first 24 hours of treatment with amphotericin B and had normal renal function. Patients at intensive care units or using vasoactive drugs were excluded. Sodium chloride 0.9% (500 ml) was infused before and after the amphotericin B. Blood and urine analysis were done for the evaluation of the renal function in the beginning and in the end of the treatment. Serum creatinine was repeated 30 days after the end of the amphotericin B treatment. Results: Forty-eight patients were studied. The mean rise of the serum creatinine was of 0.3 (0.18- 0.41) mg/dl, representing a mean decrease of 25 (12.8-36.9) ml/min of the creatinine clearance (CrCl). Acute renal failure (ARF), defined as a rise higher than 50% of the baseline creatinine, occurred in 15 patients (31.3%). Patients that were on antibiotics, in post-chemotherapy status or those submitted to bone marrow transplantation had the higher risk of developing ARF. Mean serum creatinine and the CrCl were no different from baseline values after 30 days. Conclusion: In low-risk patients, the use of amphotericin B with prophylactic sodium chloride loading was associated with a small and reversible decrease of the renal function. Due to its high cost the use of more expensive therapies in this group of patients does not seem to be justified at the moment. Prospective randomized trials are necessary in the low-risk population.

A ventilação mecânica (VM) tem sido recentemente associada ao desenvolvimento de falências orgânicas distais, como um fator contribuinte para a falência renal em pacientes com trauma e fator de risco para diálise e mortalidade em unidade de terapia intensiva (UTI). A estratégia ventilatória adotada pode influenciar estes efeitos. O objetivo do presente estudo é explorar a hipótese de que a estratégia de ventilação mecânica adotada pode influenciar na função renal. Delineamento: Randomizado, investigação animal experimental. Casuística: Ratos machos Wistar, anestesiados, paralisados e ventilados mecanicamente. Intervenção: Dois grupos com seis animais cada foram randomizados para receberem ventilação mecânica com volume corrente (VT) de 8ml/kg (VT8) ou 27ml/kg (VT27). Os parâmetros ajustados para grupo foram: a) VT 8ml/kg; Freqüência respiratória (FR) 60±7 rpm; pressão positiva expiratória final (PEEP) 3 cmH2O; Pico de pressão inspiratória (Pwap) 11.8±2 cmH2O; Pressão média de vias aéreas (Pawm) 6,33±0,22 e b) VT 27ml/kg; FR 30±5 rpm; PEEP 0 cmH2O; Pwap 22.7±4 cmH2O; Pawm 6,50±0,22. Mensurações e Resultados: O grupo VT27 apresentou redução significativa no clearance de inulina após 60 minutos de VM, indicando insuficiência renal aguda (0.6±0.05 ml/min/100g de peso corporal (PC)), e ainda mais acentuada após 90 minutos de VM (0.45±0.05 ml/min/100g de PC) comparada aos valores basais (0.95±0.07 ml/min/100g de PC), p<0.001. Nenhum dos dois grupos sofreram variações significativas em relação as variáveis hemodinâmicas e gasométricas. Conclusões: Observamos que o ritmo de filtração glomerular (RFG) mensurado pelo clearance de inulina é afetado pela estratégia de volume corrente empregado após 60 minutos de VM com 27ml/kg e caindo a valores mais baixo após 90 minutos de VM / Mechanical Ventilation (MV) has been recently associated with development of distal organ failure and it is also a contributor factor for renal failure in trauma patients, and risk factor for dialysis and mortality rate in intensive care unit. The ventilatory strategy adopted might be influenced this effect. The aim of the present study was to explore the hypothesis that mechanical ventilatory strategy may contribute to decreased renal function. Design: Randomized animal laboratory investigation. Subjects: Anesthetized, paralyzed, and mechanically ventilated male Wistar rats. Interventions: Two groups of six rats each were randomized to receive tidal volume of either 8ml/kg or 27 ml/kg. Ventilation strategies for the two groups were as follows: a) 8ml/kg; frequency 60±7 beats/min; positive endexpiratory pressure, 3.0 cm H2O; and peak inspiratory airway pressure (Pawp), 11.8±2 cm H2O; and b) 27ml/kg; frequency 30±5 beats/min; positive end-expiratory pressure, 0 cm H2O; and peak inspiratory airway pressure (Pawp), 22.7±4 cm H2O; Both groups with the same mean airway pressure (Pawm), 6,33±0,21 and 6,5±0,22, respectively. Measurements and main Results: Rats ventilated with high tidal volume (27ml/kg) presented significantly decreased inulin clearance after 60 minutes of mechanical ventilation, indicating acute renal insufficiency (0.6±0.05 ml/min/BW) in comparison with basal values (0.95±0.07 ml/min/BW), p<0.001. We observed decreased in inulin clearance in rats that received high tidal volume, after 60 minutes of ventilation and even more significant at 90 minutes of ventilation (0.45±0.05 ml/min/BW) compared with basal values. No inulin clearance alteration was observed in control ventilation group (0.8±0.05 ml/min/BW basal vs. 0.72±0.03 ml/min/BW 120 min of MV). Conclusion: We concluded that GFR is affected by different strategies of mechanical ventilation, and after 60 minutes of high tidal volume (27ml/kg) ventilation the renal function marked decreased, getting worse after 90 minutes