Small intestinal intussusception in five dogs with acute renal failure and suspected leptospirosis (L. australis)

OBJECTIVES This case series describes 5 dogs with small intestinal intussusception and acute kidney injury due to infection with Leptospira interrogans serovar Australis. CASE SERIES SUMMARY Small intestinal intussusception was observed in 4 dogs diagnosed with acute kidney injury due to leptospirosis presented between 1997 and 2005. Intussusception was diagnosed at initial presentation or later during hospitalization. An additional dog fulfilling our inclusion criteria was presented to a small animal specialty clinic nearby and was included. Upon admission, all dogs were severely azotemic and thrombocytopenic. All 5 dogs showed the strongest microscopic agglutination test serology reaction to L. interrogans serovar Australis. Two dogs survived with no apparent residual renal damage, 1 survived with subsequent mild chronic kidney disease, and 2 dogs were euthanized at the owners' request due to a guarded prognosis. NEW OR UNIQUE INFORMATION PROVIDED Intussusception can occur or may be seen in dogs with leptospirosis due to L. interrogans serovar Australis and patients should be monitored closely for this potential complication. As all 5 dogs described in this case series showed the highest titer for L. interrogans serovar Australis, these precautions may be especially applied in geographic areas where this particular serovar is seen.

Effects of dialysis modality on blood loss, bleeding complications and transfusion requirements in critically ill patients with dialysis-dependent acute renal failure.

Blood loss and bleeding complications may often be observed in critically ill patients on renal replacement therapies (RRT). Here we investigate procedural (i.e. RRT-related) and non-procedural blood loss as well as transfusion requirements in regard to the chosen mode of dialysis (i.e. intermittent haemodialysis [IHD] versus continuous veno-venous haemofiltration [CVVH]). Two hundred and fifty-two patients (122 CVVH, 159 male; aged 61.5±13.9 years) with dialysis-dependent acute renal failure were analysed in a sub-analysis of the prospective randomised controlled clinical trial-CONVINT-comparing IHD and CVVH. Bleeding complications including severity of bleeding and RRT-related blood loss were assessed. We observed that 3.6% of patients died related to severe bleeding episodes (between group P=0.94). Major all-cause bleeding complications were observed in 23% IHD versus 26% of CVVH group patients (P=0.95). Under CVVH, the rate of RRT-related blood loss events (57.4% versus 30.4%, P=0.01) and mean total blood volume lost was increased (222.3±291.9 versus 112.5±222.7 ml per patient, P <0.001). Overall, transfusion rates did not differ between the study groups. In patients with sepsis, transfusion rates of all blood products were significantly higher when compared to cardiogenic shock (all P <0.01) or other conditions. In conclusion, procedural and non-procedural blood loss may often be observed in critically ill patients on RRT. In CVVH-treated patients, procedural blood loss was increased but overall transfusion rates remained unchanged. Our data show that IHD and CVVH may be regarded as equivalent approaches in critically ill patients with dialysis-dependent acute renal failure in this regard.

Sphingosine: a mediator of acute renal tubular injury and subsequent cytoresistance.

The goal of this study was to determine whether sphingosine and ceramide, second messengers derived from sphingolipid breakdown, alter kidney proximal tubular cell viability and their adaptive responses to further damage. Adult human kidney proximal tubular (HK-2) cells were cultured for 0-20 hr in the presence or absence of sphingosine, sphingosine metabolites (sphingosine 1-phosphate, dimethylsphingosine), or C2, C8, or C16 ceramide. Acute cell injury was assessed by vital dye exclusion and tetrazolium dye transport. Their subsequent impact on superimposed ATP depletion/Ca2+ ionophore-induced damage was also assessed. Sphingosine (> or = 10 microM), sphingosine 1-phosphate, dimethylsphingosine, and selected ceramides (C2 and C8, but not C16) each induced rapid, dose-dependent cytotoxicity. This occurred in the absence of DNA laddering or morphologic changes of apoptosis, suggesting a necrotic form of cell death. Prolonged exposure (20 hr) to subtoxic sphingosine doses (< or = 7.5 microM) induced substantial cytoresistance to superimposed ATP depletion/Ca2+ ionophore-mediated damage. Conversely, neither short-term sphingosine treatment (< or = 8.5 hr) nor 20-hr exposures to any of the above sphingosine/ceramide derivatives/metabolites or various free fatty acids reproduced this effect. Sphingosine-induced cytoresistance was dissociated from the extent of cytosolic Ca2+ loading (indo-1 fluorescence), indicating a direct increase in cell resistance to attack. We conclude that sphingosine can exert dual effects on proximal renal tubular viability: in high concentrations it induces cell necrosis, whereas in low doses it initiates a cytoresistant state. These results could be reproduced in human foreskin fibroblasts, suggesting broad-based relevance to the area of acute cell injury and repair.

Erythropoietin protects against ischaemic acute renal injury

Erythropoietin (EPO) has recently been shown to exert important cytoprotective and anti-apoptotic effects in experimental brain injury and cisplatin-induced nephrotoxicity. The aim of the present study was to determine whether EPO administration is also renoprotectivein both in vitro and in vivo models ofischaemic acute renal failure Methods. Primary cultures of human proximal tubule cells (PTCs) were exposed to either vehicle or EPO (6.25–400 IU/ml) in the presence of hypoxia (1% O2), normoxia (21% O2) or hypoxia followed by normoxia for up to 24 h. The end-points evaluated included cell apoptosis (morphology and in situ end labelling [ISEL], viability [lactate dehydrogenase (LDH release)], cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA synthesis (thymidine incorporation). The effects of EPO pre-treatment (5000 U/kg) on renal morphology and function were also studied in rat models of unilateral and bilateral ischaemia–reperfusion (IR) injury. Results. In the in vitro model, hypoxia (1% O2) induced a significant degree of PTC apoptosis, which was substantially reduced by co-incubation with EPO at 24 h (vehicle 2.5±0.5% vs 25 IU/ml EPO 1.8±0.4% vs 200 IU/ml EPO 0.9±0.2%, n = 9, P

Caveolins in the repair phase of acute renal failure after oxidative stress

Ischaemia-reperfusion and toxic injury are leading causes of acute renal failure (ARF). Both of these injury initiators use secondary mediators of damage in oxygen-derived free radicals. Several recent publications about ischaemia-reperfusion and toxin-induced ARF have indicated that plasma membrane structures called caveolae, and their proteins, the caveolins, are potential participants in protecting or repairing renal tissues. Caveolae and caveolins have previously been ascribed many functions, a number of which may mediate cell death or survival of injured renal cells. This review proposes possible pathophysiological mechanisms by which altered caveolin-1 expression and localization may affect renal cell survival following oxidative stress.

Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure

Administration of human recombinant erythropoietin ( EPO) at time of acute ischemic renal injury ( IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa ( DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats ( N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation ( T0), or post-treated ( 6 h after the onset of reperfusion, T6) with EPO ( 5000 IU/kg), DPO ( 25 mu g/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.08 +/- 0.03mmol/l vs EPO-IRI 0.04 +/- 0.01mmol/l, P = 0.01). Delayed administration of DPO or EPO ( T6) also significantly abrogated subsequent renal dysfunction ( serum creatinine for IRI 0.17 +/- 0.05mmol/l vs DPO-IRI 0.06 +/- 0.01mmol/l vs EPO-IRI 0.03 +/- 0.03mmol/l, P = 0.01). There was also significantly decreased tissue injury ( apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.

Collagen XVIII/endostatin expression in experimental endotoxemic acute renal failure

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Epigastric Pain in Acute Renal Infarction: The Forgotten Presentation

Epigastric pain is a manifestation of several medical and surgical conditions. However, when persistent epigastric pain is associated with microscopic or frank haematuria and elevated lactate dehydrogenase (LDH), especially in patients with increased risk of thromboembolic events, acute renal infarction (ARI) should be considered. We report the case of a 77-year-old male patient who presented with sudden persistent epigastric pain and elevated LDH who was found to have atrial fibrillation. The patient was diagnosed with ARI. ARI is not usually a typical differential diagnosis in patients with persistent epigastric pain and elevated LDH in whom the risk of thromboembolic events is high. Thus, physicians should perform a contrast-enhanced CT scan as early as possible to rule out or confirm renal infarction.

Avaliação da disnatremia em pacientes com indicação de suporte renal em unidades de terapia intensiva

As disnatremias são os distúrbios hidroeletrolíticos mais comuns, sendo relatados em cerca de 30-40% dos pacientes hospitalizados. Quando presentes na admissão em Unidade de Tratamento Intensivo (UTI) são fatores de risco independentes de pior prognóstico, estando associadas à maior letalidade hospitalar. Mesmo disnatremias limítrofes (130 135 mEq/l na hiponatremia e 145 a 150 mEq/L na hipernatremia) têm sido associadas a um maior tempo de internação na UTI e a um aumento de letalidade hospitalar, independente da gravidade da doença de base. A concentração sérica do sódio é mantida por um fino controle, por meio da regulação renal do sal e da água. Pacientes com doença renal crônica (DRC) em tratamento conservador ou em terapia renal substitutiva, apresentam maior prevalência de disnatremia. Embora a hiponatremia seja mais frequente nessa população, o diagnóstico de hipo- ou hipernatremia tem sido associado a uma maior mortalidade. Não há relato claro na literatura da prevalência de disnatremias na injúria renal aguda (IRA), em especial nos casos mais graves, em que há indicação de suporte dialítico. O presente estudo teve como objetivos avaliar a prevalência da disnatremia e o seu impacto no prognóstico de pacientes gravemente enfermos com IRA e necessidade de suporte renal (SR) na UTI.Em um período de 44 meses (de dezembro de 2004 a julho 2008) foram incluídos de forma prospectiva todos os pacientes que iniciaram SR em 14 UTIs de 3 hospitais terciários do Rio de Janeiro. Dados clínicos e laboratoriais foram coletados prospectivamente e lançados em uma planilha eletrônica para posterior análise com o software R. Os desfechos de interesse foram letalidade na UTI e no hospital. As variáveis que, além do sódio, apresentavam associação com os desfechos de interesse na análise bivariada, foram selecionadas e incluídas no modelo de regressão logística múltipla.Um total de 772 pacientes foram incluídos no estudo. A mediana da idade foi de 75 [IIQ: 61-82 anos]; 81,5% (IC: 78,4%-84%) foram admitidos na UTI por complicações clínicas. A presença de pelo menos uma comorbidade (hipertensão, diabetes, doença coronariana, insuficiência cardíaca, doença pulmonar obstrutiva crônica ou cirrose) esteve presente em 84% dos pacientes. A maior parte dos pacientes (72,5%, IC: 69,2%-75,7%) apresentava o diagnóstico de sepse. Os principais fatores contribuinte para IRA foram sepse (72%) e isquemia/choque (66%). A mortalidade na UTI foi de 64,6% (IC: 61,1%-68%) e a hospitalar foi de 69,7% (IC: 66,3%-72,9%). O diagnóstico de disnatremia foi frequente, estando presente em 47,3% (IC: 43,7%-50,9%) dos pacientes. A hipernatremia foi significantemente mais frequente do que a hiponatremia (33,7% X 13,6%, p=0.001) na população estudada. Na análise multivariada, os pacientes mais idosos, a admissão clínica, o número de comorbidades e o número de disfunções orgânicas estiveram associados a uma maior letalidade hospitalar. Os paciente com hipernatremia grave (>155 mEq/l) apresentaram maior associação com o óbito na UTI e no hospital [odds ratio (OR) ajustado de 3.39 (1,48-7,8) e 2,87 (1,2-6,89), respectivamente], apesar de todos terem sido submetidos ao SR durante a internação na UTI. O estudo demonstrou que as disnatremias são altamente prevalentes em pacientes com IRA e necessidade de diálise na UTI. Diferente do que tem sido demonstrado na população de UTI e na com DRC, a hipernatremia é o distúrbio do sódio mais frequentemente observado na população estudada. A idade mais avançada, a admissão clínica, o número de comorbidades e o número de disfunções orgânicas e a hipernatremia grave estão associados a um pior desfecho na IRA com necessidade de SR na UTI.

Eficacia de la n-acetilcisteína en nefropatía inducida por contraste en pacientes con alteración renal previa: meta-análisis. (METACIAKI)

INTRODUCCIÓN: Se define lesión renal aguda inducida por contraste (CIAKI), al deterioro de la función renal en las 48 horas posteriores a la administración de radiofármacos. Para prevenir este evento se han estudiado diversas intervenciones clínicas, como la administración de N-Acetilcisteina (NAC), previa al procedimiento diagnóstico. Meta-análisis anteriores comparan diferentes intervenciones clínicas para prevenir CIAKI sin resultados concluyentes. El presente meta-análisis analiza la evidencia de la eficacia la administración de NAC previa al procedimiento diagnóstico para prevenir CIAKI en pacientes con nefropatía previa. METODOLOGÍA: Se analizaron por 3 revisores independientes estudios ECCA, en población con nefropatía, en inglés, español, portugués, italiano, alemán y francés tanto publicados como de literatura gris, en donde se comparara NAC versus hidratación o placebo. RESULTADOS: Los estudios encontrados fueron publicados entre el año 2000 y 2010. Se analizaron 37 reportes con 6.022 pacientes. La correlación intraclase para tres observadores fue kappa r=0.97 [IC95% 0.93-0.99]). Los pacientes con nefropatía a quienes se les administró NAC previo al procedimiento tuvieron un 34% menos de probabilidad de hacer falla renal aguda, con OR ajustado por sesgo de publicación de 0.66 [IC95% 0.50-0.88] con un p de 0.002. Al realizar análisis de sensibilidad por la escala de Jadad, se encuentra que los resultados en los estudios con baja calidad no son significativos (p=0.202). CONCLUSION: Los resultados soportan la asociación entre el tratamiento preventivo con N-Acetilcisteina y una menor frecuencia de lesión renal aguda inducida por medio de contraste en pacientes nefrópatas.

THE ROLE OF INNATE IMMUNITY IN SEPTIC ACUTE KIDNEY INJURIES

Acute kidney injury (AKI) is an important clinical syndrome characterized by abnormalities in the hydroelectrolytic balance. Because of high rates of morbidity and mortality (from 15% to 60%) associated with AKI, the study of its pathophysiology is critical in searching for clinical targets and therapeutic strategies. Severe sepsis is the major cause of AKI. The host response to sepsis involves an inflammatory response, whereby the pathogen is initially sensed by innate immune receptors (pattern recognition receptors [PRRs]). When it persists, this immune response leads to secretion of proinflammatory products that induce organ dysfunction such as renal failure and consequently increased mortality. Moreover, the injured tissue releases molecules resulting from extracellular matrix degradation or dying cells that function as alarmines, which are recognized by PRR in the absence of pathogens in a second wave of injury. Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are the best characterized PRRs. They are expressed in many cell types and throughout the nephron. Their activation leads to translocation of nuclear factors and synthesis of proinflammatory cytokines and chemokines. TLRs` signaling primes the cells for a robust inflammatory response dependent on NLRs; the interaction of TLRs and NLRs gives rise to the multiprotein complex known as the inflammasome, which in turn activates secretion of mature interleukin 1 beta and interleukin 18. Experimental data show that innate immune receptors, the inflammasome components, and proinflammatory cytokines play crucial roles not only in sepsis, but also in organ-induced dysfunction, especially in the kidneys. In this review, we discuss the significance of the innate immune receptors in the development of acute renal injury secondary to sepsis.

A role for regulatory T cells in renal acute kidney injury

Ischemia reperfusion injury (IRI) is a potential contributor for the development of chronic allograft nephropathy. T cells are important mediators of injury, even in the absence of alloantigens. We performed a depletion of TCD4(+)CTLA4(+)Foxp3(+) cells with anti-CD25(PC61), a treatment with anti-GITR (DTA-1) and rat-IgG, followed by 45 min of ischemia and 24/72 h of reperfusion, and then analyzed blood urea, kidney histopathology and gene expression in kidneys by QReal Time PCR. After 24 h of reperfusion, depletion of TCD4(+)CTLA4(+)Foxp3(+) cells reached 30.3%(spleen) and 67.8%(lymph nodes). 72 h after reperfusion depletion reached 43.1%(spleen) and 90.22%(lymph nodes) and depleted animals presented with significantly poorer renal function, while DTA-1 (anti-GITR)-treated ones showed a significant protection, all compared to serum urea from control group (IgG: 150.10 +/- 50.04; PC61: 187.23 +/- 31.38; DTA-1: 64.53 +/- 25.65, mg/dL, p<0.05). These data were corroborated by histopathology. We observed an increase of HO-1 expression in animals treated with DTA-1 at 72 h of reperfusion with significant differences. Thus, our results suggest that PC61 (anti-CD25) mAb treatment is deleterious, while DTA-1 (anti-GITR) mAb treatment presents a protective role in the renal IRI, indicating that some regulatory populations of T cells might have a role in IRI. (C) 2009 Elsevier B.V. All rights reserved.

Renal function and histology after acute hemorrhage in rats under dexmedetomidine action

OBJETIVO: Cerca de 50% de indicações de diálise em insuficiência renal aguda vêm de problemas do perioperatório. Alterações na hemodinâmica intra-operatória levam a vasoconstrição renal e hipoperfusão. Estudos prévios não definiram o papel renal da dexmedetomidina em hemorragia. Foram estudados os efeitos da dexmedetomidina na função e histologia renais, em ratos, após hemorragia aguda. MÉTODOS: Estudo encoberto com 20 ratos Wistar, anestesiados com pentobarbital sódico intraperitoneal, 50 mg. kg-1, divididos aleatoriamente em 2 grupos sob sangramento de 30% da volemia: GD - dexmedetomidina iv, 3 µg. kg-1 (10 min), e infusão contínua, 3 µg. kg-1. h-1; GC - pentobarbital. Para estimar depuração renal, administraram-se para-aminohipurato e iotalamato de sódio. Atributos estudados: freqüência cardíaca, pressão arterial média, temperatura retal, hematócrito, depuração de para-aminohipurato e iotalamato, fração de filtração, fluxo sangüíneo renal, resistência vascular renal, análise histológica dos rins. RESULTADOS: em GD, houve valores menores de freqüência cardíaca, pressão arterial média e resistência vascular, mas valores maiores de depuração de iotalamato e fração de filtração. A depuração de para-aminohipurato e o fluxo sangüíneo foram similares nos grupos. As alterações histológicas foram compatíveis com isquemia e houve maior dilatação tubular em GD. CONCLUSÃO: em ratos, após hemorragia aguda, a dexmedetomidina determinou melhor função renal, porém maior dilatação tubular.

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-kappa B and upregulating endothelial nitric oxide synthase

de Souza ACCP, Volpini RA, Shimizu MH, Sanches TR, Camara NOS, Semedo P, Rodrigues CE, Seguro AC, Andrade L. Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting nuclear factor-kappa B and upregulating endothelial nitric oxide synthase. Am J Physiol Renal Physiol 302: F1045-F1054, 2012. First published January 11, 2012; doi:10.1152/ajprenal.00148.2011.-The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-kappa B activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLP + EPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-L-arginine methyl ester (L-NAME) simultaneously with EPO administration (CLP + EPO + L-NAME). A fifth group (CLP + EPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLP + EPO rats presented significantly higher inulin clearance than did CLP and CLP + EPO + L-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLP + EPO rats; and inulin clearance was significantly higher in CLP + EPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLP + EPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-alpha activation, NF-kappa B activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-kappa B downregulation.