Determinantes precoces en el desarrollo de injuria renal aguda durante la sepsis abdominal experimental / Early determinants of acute kidney injury during experimental intra-abdominal sepsis

Background: Sepsis-induced acute kidney injury (AKI) is an early and frequent organ dysfunction, associated with increased mortality. Aim: To evaluate the impact of macrohemodynamic and microcirculatory changes on renal function and histology during an experimental model of intra-abdominal sepsis. Material and Methods: In 18 anaesthetized pigs, catheters were installed to measure hemodynamic parameters in the carotid, right renal and pulmonary arteries. After baseline assessment and stabilization, animals were randomly divided to receive and intra-abdominal infusion of autologous feces or saline. Animals were observed for 18 hours thereafter. Results: In all septic animals, serum lactate levels increased, but only eight developed AKI (66%). These animals had higher creatinine and interleukin-6 levels, lower inulin and para-aminohippurate clearance (decreased glomerular filtration and renal plasma flow), and a negative lactate uptake. Septic animals with AKI had lower values of mean end arterial pressure, renal blood flow and kidney perfusion pressure, with an associated increase in kidney oxygen extraction. No tubular necrosis was observed in kidney histology. Conclusions: The reduction in renal blood flow and renal perfusion pressure were the main mechanisms associated with AKI, but were not associated with necrosis. Probably other mechanisms, such as microcirculatory vasoconstriction and inflammation also contributes to AKI development.

Lovastatin protects mithochondrial and renal function in kidney ischemia-reperfusion in rats / Lovastatina protege a função renal e mitocondrial na isquemia/reperfusão renal em ratos

PURPOSE: To investigate the effect of lovastatin on renal ischemia followed by reperfusion. METHODS: Thirty one Wistar rats submitted to left renal ischemia for 60 minutes followed by contralateral nephrectomy were divided into two groups: A (n =17, control, no treatment), and B (n=14, lovastatin 15 mg/kg/day p.o. ten days before ischemia). The animals were sacrificed at the end of ischemia, after 24 hours and at seven days after reperfusion. Survival, serum urea and creatinine levels and renal mitochondrial function were evaluated. RESULTS: Mortality was 29.4% in group A and 0.7% in group B. Urea and creatinine levels were increased in both groups, but the values were significantly lower in group B. Mitochondrial function showed decoupling in 83.4% of group A, as opposed to 38.4/% of group B. CONCLUSIONS: The result shows a protective action of renal function by lovastatin administered before ischemia/reperfusion. Since most of the mitochondrial fraction presented membranes with the ability to maintain ATP production in group B, stabilization of the mitochondrial membrane should be considered as part of the protective action of lovastatin on renal function in ischemia/reperfusion.

OBJETIVO: Investigar a ação da lovastatina na isquemia renal seguida de reperfusão. MÉTODOS: Trinta e um ratos Wistar submetidos à isquemia renal esquerda durante 60 minutos, seguida da nefrectomia contralateral, foram distribuídos em dois grupos: A (n=17, controle, sem tratamento) e B (n=14, recebendo 15 mg/Kg/dia de lovastatina via oral), durante os dez dias que antecederam a isquemia. Os animais foram mortos ao final da isquemia, e com 24 horas e sete dias após a reperfusão. Foram avaliadas a sobrevida, os valores séricos de uréia e creatinina e a função mitocondrial renal. RESULTADOS: A mortalidade foi 29,4% no grupo A e 0,7% no grupo B. Os níveis de uréia e creatinina elevaram-se nos dois grupos, mas foram significativamente menores no grupo B. No grupo A a função mitocondrial renal ficou desacoplada em 83,4% dos ensaios, enquanto que no grupo B isto ocorreu em apenas 38,4% dos ensaios. CONCLUSÕES: Os resultados mostram que a administração de lovastatina antes do episódio de isquemia protege a função renal. No grupo B, como a maior parte da fração mitocondrial isolada apresentou função acoplada à produção de ATP, deve-se também considerar a estabilização da membrana mitocondrial como parte da ação protetora da lovastatina na função renal durante isquemia e reperfusão.

Función renal en cirugía cardíaca con circulación extracorpórea: Pacientes valvulares y coronarios / Renal function during cardiac surgery with extracorporeal circulation

Background: Patients with valvular heart disease are at high risk of acute renal failure after surgery with extracorporeal circulation. Aim: To describe changes in renal function parameters during surgery with extracorporeal circulation in patients with valvular heart disease and compare them with those found in patients undergoing elective coronary surgery Material and Methods: Two groups of patients were studied. Group 1 was composed by twelve patients undergoing elective coronary surgery and group 2 was composed by eleven patients undergoing surgery for heart valve replacement. Glomerular filtration rate and effective renal plasma now were estimated from inulin and the 131 I-hippuran clearance respectively, at five different times, during surgery and the postoperative period. Sodium filtration fraction and fractional excretion were calculated. Alpha and pi-glutathione s-transferase in urine were measured as markers of tubular damage in the pre and postoperative periods. Results: Effective renal plasma flow was reduced in both groups before induction of anesthesia, did not change during surgery and decreased significantly in patients with valvular disease in the postoperative period. Glomerular filtration rates were normal during all the study period. There was a non significant reduction of filtration fraction during extracorporeal circulation. Alpha and pi glutathione s-transferases were normal and did not change. Fractional excretion of sodium increased significantly postoperatively Conclusions: In patients with valvular disease undergoing surgery with extracorporeal circulation, renal function does not deteriorate. No significant difference was found when compared with patients undergoing coronary surgery. No evidence of functional and cellular renal disfunction or damage was found in both study groups.

Comportamento da pressão arterial nos ratos SHR e Wistar-Kyoto expostos ao pneumoperitônio prolongado: estudo experimental com uso do dióxido de carbono para insuflação / Rats SHR and Wystar-Kyoto arterial blood pressure behavior during prolonged pneumoperitoneum exposure: trial study using carbon dioxide for insufflation

Para avaliar as repercussões da insuflação prolongada da cavidade peritoneal com gás carbônico sobre a hipertensão arterial essencial, utilizou-se ratos machos espontaneamente hipertensos (SHR) e como normotensos ratos machos Wistar-Kioto (WKY). No total foram utilizados 34 animais, sendo 22 SHRs e 12 WKYs, onde os ratos SHR foram distribuídos aleatoriamente aos grupos G1 e G3. O primeiro grupo (G1) com 12 animais SHRs e o segundo (G2) com 12 animais WKYs foram expostos a pneumoperitônio com dióxido de carbono por 120 minutos, enquanto que o terceiro grupo (G3) com 10 animais SHRs, passou por insuflação da cavidade peritoneal, seguida de punção com trocarte e esvaziamento do pneumoperitônio. Os animais deste grupo permaneceram anestesiados e com o abdome puncionado por 2 horas. Previamente a confecção do pneumoperitônio, a artéria e veia femorais direita foram dissecadas e canuladas. A artéria foi conectada ao transdutor de pressão para o registro contínuo da pressão arterial (PA), após a coleta inicial de 0,2 ml para dosagem da gasometria basal e 0,8 ml para as dosagens de uréia (U) e creatinina (Cr) basais. A veia femoral foi uttilizada para a expansão volêmica lenta com 10 ml de solução fisiológica após a coleta inicial de 1,0 ml de sangue arterial. Feito isto, procedeu-se a insuflação e punção abdominal mantendo ou não o pnemoperitônio, conforme o grupo. Foram feitas medidas da pressão arterial a cada 15 minutos e 5 minutos após o esvaziamento do abdome. Após a última aferição, foi colhido aproximandamente 3 ml de sangue arterial e 1 ml para a gasometria mais dosagem da U e Cr...

To assess the effects of prolonged peritoneal cavity insufflation with carbon dioxide on the essential hypertension, a experimental study was designed using male spontaneously hypertensive rats (SHR) and male normotensive Wistar-Kyoto (WKY). Thirty-four animals were used, 22 SHRs and 12 WKYs, where SHR rats were randomly assigned to groups G1 and G3. The first group (G1) with 12 animals SHRs and second group (G2) with 12 animals WKYs were exposed to pneumoperitoneum with carbon dioxide for 120 minutes, while the third group (G3) with 10 animals SHRs, had the peritoneal cavity insufflated, followed by puncture with trocarte and released the pneumoperitoneum. The animals of this group remained anesthetized and the abdomen punctured by 2 hours. Before making the pneumoperitoneum, right femoral artery and vein were dissected and cannulated. The artery was connected to the transducer pressure for the continuous recording of blood pressure (BP), after the initials blood samples: 0.2 ml for blood gases measurement and 0.8 ml for urea (U) and creatinine (Cr ). The femoral vein was used to volume expansion with 10 ml of saline solution after the initial sample of 1.0 ml arterial blood. Afterwards, a pnemoperitoneum insufflation and maintaining is done or not, depending on group. Blood pressure was recorded every 15 minutes and 5 minutes after pnemoperitoneum released. After last blood pressure record, a 3.0 ml blood sample was collected to measure plasma renin activity (PRA), and 1.0 ml for blood gases measurement, urea (U) and creatinine (Cr).

Acción novedosa de la aldosterona en la nefrotoxicidad por ciclosporina / Novel action of aldosterone in CsA nephrotoxicity

Calcineurin inhibitors are helpful ímmunosuppressíve agents in clinical practice. Thanks to their lower cost respect with new ímmunosuppressíve therapy, calcineurin inhibitors in our country continue being the most used treatment in solid organ transplant recipients or patients with autoimmune disease. In the 80's decade cyclosporine A (CsA) was introduced as the first calcineurin inhibitor transforming the immunosuppression therapy. Up to date, many articles evaluating beneficial and adverse effects of CsA have been published. In this review, basic aspects and actions of CsA are analyzed together with studies from our laboratory that pointed out the pathophysiological role of aldosterone as a mediator of functional and structural changes that are observed in CsA nephrotoxicity. Based in our findings, we proposed that in CsA nephrotoxicity, the aldosterone mediates renal vasoconstriction and enhances TGFJ3 expression promoting the development of nefrotoxicity. Finally, results from our laboratory and others allow us to suggest that aldosterone receptors blockade with spironolactone or eplerone could be a pharmacological therapy to reduce or prevent acute and chronic CsA nephrotoxicity in transplant recipients.

Los inhibidores de calcineurina son los agentes inmunosupresores más potentes con los que se cuenta en la práctica clínica, y gracias a su bajo costo respecto a las nuevas terapias inmunosupresoras, en nuestro país continúan siendo los agentes terapéuticos más utilizados para el manejo de pacientes con enfermedades autoinmunes o que reciben trasplantes. En la década de los 80's se introdujo la ciclosporina A (CsA) como primer inhibidor de calcineurina, lo cual revolucionó la terapia inmunosupresora. Desde entonces se han publicado muy variados artículos donde se han evaluado los efectos benéficos y deletéreos de estos inhibidores; específicamente nos enfocaremos a revisar las acciones de CsA y, en particular, los resultados de nuestro laboratorio que muestran el papel fisiopatológico que juega la aldosterona como mediador de los cambios funcionales y estructurales que se observan en la nefrotoxicidad por ciclosporina. Específicamente su participación en promover la vasoconstricción renal asociada a CsA y en el desarrollo de fibrosis al inducir la expresión de TGFβ. Por lo tanto, nuestros resultados y los de otros autores nos permiten proponer el bloqueo de los receptores de aldosterona con espironolactona o eplerone como un tratamiento farmacológico útil para reducir la incidencia de nefrotoxicidad aguda y crónica, inducida por CsA en pacientes con enfermedades autoinmunes o que reciben trasplante de órganos.

Efeitos do pneumoperitônio sobre a hemodinâmica e função renais de cães ventilados com volume e pressão controlados / Effects of pneumoperitoneum on renal hemodynamics and function of dogs under volume and pressure-controlled ventilation

JUSTIFICATIVA E OBJETIVOS: Não existem estudos que associem os efeitos determinados pelas modalidades ventilatórias às repercussões renais durante o pneumoperitônio. O objetivo deste trabalho foi avaliar as alterações na hemodinâmica e função renais determinadas pelo pneumoperitônio em cães com ventilação a volume e pressão controlados. MÉTODO: Dezesseis cães anestesiados com tiopental sódico e fentanil foram divididos em Grupo 1, volume controlado e Grupo 2, pressão controlada e submetidos a pneumoperitônio de 10 e 15 mmHg. Foram estudados fluxo sangüíneo renal, resistência vascular renal, depuração de para-aminohipurato de sódio, sódio plasmático, potássio plasmático, osmolalidade plasmática, depuração de creatinina, fração de filtração, volume urinário, osmolalidade urinária, depuração osmolar, depuração de água livre, depuração de sódio, excreção urinária de sódio, excreção fracionária de sódio, depuração de potássio, excreção urinária de potássio, excreção fracionária de potássio. Os dados foram coletados em 4 momentos. M1, antes do pneumoperitônio; M2, 30 minutos após pneumoperitônio com 10 mmHg; M3, 30 minutos após pneumoperitônio com 15 mmHg; M4, 30 minutos após a deflação do pneumoperitônio. RESULTADOS: As depurações de para-aminohipurato de sódio e creatinina permaneceram constantes em ambos os grupos durante o experimento. Os valores plasmáticos do sódio e do potássio não se alteraram. Ocorreu diminuição a partir de M2 da depuração e da excreção fracionária de potássio em ambos os grupos. CONCLUSÕES: As modalidades ventilatórias não determinaram diferenças na hemodinâmica renal entre os grupos estudados. O pneumoperitônio, ocasionando compressão do parênquima renal, pode ter determinado alterações na reabsorção e/ou secreção do potássio.

Assessment of renal and hepatic hemodynamics in cirrhosis of liver.

BACKGROUND AND OBJECTIVE: Investigators have documented an increase in renal artery resistance in cirrhotic patients. We studied the hepatic and renal hemodynamics by color Doppler in patients with liver cirrhosis in relation to the presence and severity of ascites. METHODS: A prospective study was carried out in a large public hospital on 33 patients with cirrhosis of liver and 11 healthy control subjects. Eleven patients had no ascites, 12 had diuretic-responsive ascites and 10 had refractory ascites. The resistance index (RI) of the hepatic artery was measured by color Doppler on its main branch and renal artery RI was measured on the main renal, interlobar and cortical arteries of the right kidney. RESULTS: Considering intraobserver variabilities, coefficient of variation for RI was 2.3%-7.8% (mean [SD] 4.2% [1.8%]). Hepatic artery RI were 0.68 (0.07), 0.68 (0.1), 0.81 (0.04), 1.0 (0.12) in control subjects and cirhotics with no ascites, responsive ascites and refractory ascites, respectively. Renal RI was significantly higher than in control subjects at all three levels in patients with responsive and refractory ascites, being higher in those with refractory than responsive ascites. Renal RI decreased from hilum towards the outer parenchyma, in cirrhotics with no ascites and responsive ascites but not in refractory ascites. CONCLUSION: Hepatic artery RI is higher in cirrhotics and is related to presence and severity of ascites. In control subjects and patients with no ascites or responsive ascites the renal RI decreased from hilum to the outer parenchyma.

Hepatorenal syndrome.

Hepatorenal syndrome is a life-threatening complication occurring commonly in cirrhosis liver and rarely in acute liver failure. It can be precipitated by shock, infection, surgery, large volume paracentesis or nephrotoxic drugs. Type I hepatorenal syndrome which usually develops over acute liver failure is rapidly progressive and has poor outcome. Type II hepatorenal syndrome is usually associated with refractory ascites and is slowly progressive with relatively good prognosis. Peripheral vasodilation with intrarenal vasoconstriction is the main pathophysiologic change. Diagnostic criteria, ascertained by international ascites club, is helpful to reach at a proper diagnosis. Management includes pharmacologic therapy to induce splanchnic vasoconstriction which improve renal circulation. Dopamine, vasopressin analogs (ornipressin and terlipressin), midodrine, noradrenaline have been used mainly as a bridge to the liver transplant or in anticipation of improvement in hepatic function. The molecular adsorbent recycling system (MARS) have been recently used in patients with hepatorenal syndrome. Transjugular intrahepatic portosystemic shunt is also another modality which has been used as a bridge to liver transplant in such patients.

The Usefulness of Pulsatile Flow Detection in Measuring Resistive Index in Renal Doppler US

OBJECTIVE: To assess the usefulness of pulsatile flow detection (PFD), a newly developed function of color Doppler US, in measuring resistive index (RI) in renal Doppler US and to compare it with conventional color Doppler (CCD). MATERIALS AND METHODS: Fifty-six kidneys in 31 patients were randomly selected and divided into two groups. In group A, RI was measured first with the aid of CCD, and then with PFD. In group B, data were obtained in the reverse order. The time required for each RI measurement was recorded in seconds. The quality of the Doppler spectral waveform was subjectively graded as 0, 1, or 2 and examination time and waveform quality were compared between PFD and CCD. RESULTS: The time required to measure RI with PFD (PFD time) was less than with CCD (CCD time) (mean 42.7 secs vs. mean 70.3 secs; p = 0.031). There was no significant difference in PFD time between group A and B, but CCD time was shorter in group B (70.3 secs vs. 24.6 secs; p = 0.0004). Spectral waveform quality was not significantly different between PFD and CCD. CONCLUSION: The time required to measure RI in kidneys can be shortened with the aid of the PFD function in color Doppler US without affecting the quality of the examination.

Bloqueio a selectinas em coelhos submetidos a isquemia e reperfusão hepática: produção de radicais livres, funções cardiovascular, repiratória, hepatica e renal / Selectin blockade in rabbit which underwent liver ischemia-reperfusion: production of free radicals, cardiovascular, respiratory and renal functions

Moléculas de adesão têm um importante papel na isquemia-reperfusão(I/R), e dentre elas, as selectinas, que são respónsaveis pela ativação e adesão dos neutrófilos. Estratégias dirigidas aos neutrófilos tem remduzido as lesões de I/R hepática, original em coelhos, foram estudados os efeitos do bloqueio a selectinas por um polissacarídeo. Em 26 coelhas,I/R hépatica parcial (85por cento) foi realizada, minimizando-se a hipertasão portal. No primeiro experimento, 20 coelhas foram divididas em dois grupos: anti-selectina (recebeu IV30mg/kg de um polisssacarídeo anti-selectina LX-2423 e controle ( recebeu NaCl-0,9por cento). Os animais foram submetidos a isquemia hepática parcial por 2h,hepatectomia do segmento não isquêmico, e reperfusão por 4h. No segundo experimento, seis coelhas foram randonizadas para os grupos anti-selecntina e controle. Após isquemia parcial de 1h e reperfusão de de 2 h, os animais foram submetidos a observação intravital da microcirculação hepática. Todos os animais receberam anti-selectina ou NaC1-0,9por cento 15 minutos antes da reperfusão. Comparado ao grupo controle, o grupo anti-selectina apresentou uma maior produção de bile(p<0,05) e sobrevida (p<0,05), menor resposta hipotensora (p<0,05) e melhor resposta ventilatória à reperfusão (p<0,02), menores níveis de creatinina (p<0,05) e lactato (p<0,05). A observação intravital pós-reperfusão mostrou significativa melhora na microcirculação hépatica do grupo anti-selectina. Uma menor produção de radicais livres, produzidos por leucócitos, estimulados com zimogênio, foi também encontrada no grupo anti-selectina (p<0,02). Em síntese, selectinas desempenham um importante papel na lesão de I/R hepática. O bloqueio a selectinas resulta em menor produção de radicais livres; melhora na microcirculação hepática; melhora nas funções cardiovascular, respiratória, hepática e renal, consequentemente, aumentando a sobrevida dos animais, frente a uma lesão de I/R hepática

Renal perfusion and disease progression.

The pathogenetic concept of renal hyperperfusion and hyperfiltration in inducing glomerular pathology and disease progression documented in the renal ablation model in experimental animals to mimic renal disease with reduced nephron mass has recently been challenged. In contrast to the above, the intrarenal hemodynamic study in a variety of chronic glomerulonephropathies reveals a unique characteristic of renal hypoperfusion rather than hyperperfusion. This is associated with an elevated renal arteriolar resistance and reductions in renal plasma flow and peritubular capillary blood flow. The magnitude of reduction in peritubular capillary blood flow is inversely proportional to the degree of tubulointerstitial disease and tubular dysfunction. A progressive reduction in the vascular space due to nonvascular expansion with disease progression supports the concept of hypoperfusion of a whole kidney as well as a single nephron. In accordance with the renal ablation model and early diabetes mellitus, a similar hypoperfusion pattern is also subsequently observed in the chronic stage of renal ablation model in animals and late diabetic nephropathy. The disparity between the hyperperfusion and hypoperfusion in inducing renal disease progression can be enlightened by the Noble Truth of Lord Buddha stating "The Middle Tract is The Balance of Nature". Further support of this conceptual view of renal hypoperfusion as a determinant of tubulointerstitial disease and disease progression is in accordance with the therapeutic benefit with an enhanced-renal-perfusion formula per se in a variety of chronic glomerulonephropathies.

Hemodinâmica glomerular renal no roedor Calomys callosus / Kidney glomerular hemodynamics in the rodent Calomys callosus

A funçäo renal do roedor Calomys callosus, envolvido no ciclo de transmissäo de diversos agentes patogênicos para o homem foi avaliada no animal intacto, através da técnica de depuraçäo e micropunçäo renal. Os resultados mostraram que este roedor apresenta níveis pressóricos, hematócrito e proteínas plasmáticas semelhantes aos dos ratos submetidos ao mesmo procedimento experimental. Os pesos corporal e renal, bem como a filtraçäo glomerular global e por nefro assemelham-se aops do camundngo. Surpreendentemente estes roedores apresentaram significante número de glomérulos superficiais por rim, permitindo a avaliaçäo da hemodinâmica glomerular. Apesar da pressäo arterial semelhante à dos ratos Munich-Wistar (MW), a pressäo hidr[aulica intraglomerular no Calomys callosus foi interiro. Esyta reduçäo foi conseqüente à menor risistência pós-glomerular quando comparada à dos ratos MW. O fluxo plasmático glomerular atingiu valor bastante elevado em relaçäo à filtraçäo glomerular por nefro, fato que näo só compensaria a reduzida pressäo intraglomerular, como também seria suficiente para elevar a filtraçäo (por g/rim) a níveis superiores neste roedor, pois o coeficiente de ultrafiltraçäo glomerular (Kf) foi semelhante ao do rato MW. O presente trabalho sugere que apesar das dificuldades técnicas que este animal impöe devido ao seu reduzido tamanho, o estudo da funçäo renal global bem como da hemodinâmica glomerular é factível, podendo portanto ser utilizado como modelo para estudo da funçäo...

Effect of disturbances in circulatory dynamics on perpetuation and pathogenesis of renal disease

Renal functions are affected by so many factors of which is renal circulatory dynamics. This latter factor affects membrane process, kidney filtration as well as different stresses on vessel wall. The following paper presents the possible pathways leading to renal disease without quantitative treatment. The suggested pathways constitute a conceptual scheme for the sequence of events that leads to renal disease. Each separate step is confirmed by literature or mathematical tools, yet, a few of them were suggested for the conceptual setting to be build up