Metformin Inhibits ROS/TNF-alpha Axis-Mediated Chronic Kidney Disease Induced by TAA Independent of Leukocyte Infiltration in Association with the Inhibition of Kidney Injury Biomarkers / La Metformina Inhibe la Enfermedad Renal Crónica Mediada por el Eje ROS/TNF-alfa Inducida por TAA Independientemente de la Infiltración de Leucocitos en Asociación con la Inhibición de Biomarcadores de Lesión Renal

SUMMARY: The toxic effects of thioacetamide (TAA) and carbon tetrachloride on the human body are well recognized. In this study, we examined whether TAA intoxication can induce kidney leukocyte infiltration (measured as leukocyte common antigen CD45) associated with the augmentation of the reactive oxygen species (ROS)/tumor necrosis factor-alpha (TNF-α) axis, as well as biomarkers of kidney injury with and without metformin treatment. Rats were either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being sacrificed after 10 weeks (experimental group) or were pre-treated with metformin (200 mg/kg) daily for two weeks prior to TAA injections and continued receiving both agents until the end of the experiment, at week 10 (protective group). Using basic histology staining, immunohistochemistry methods, and blood chemistry analysis, we observed profound kidney tissue injury such as glomerular and tubular damage in the experimental group, which were substantially ameliorated by metformin. Metformin also significantly (p0.05) increase in kidney expression of CD45 positive immunostaining cells. In conclusion, we found that TAA induces kidney injury in association with the augmentation of ROS/TNF-α axis, independent of leukocyte infiltration, which is protected by metformin.

Son bien conocidosos los efectos tóxicos de la tioacetamida (TAA) y el tetracloruro de carbono en el cuerpo humano. En este estudio, examinamos si la intoxicación por TAA puede inducir la infiltración de leucocitos renales (medida como antígeno leucocitario común CD45) asociada con el aumento de las especies reactivas de oxígeno (ROS)/factor de necrosis tumoral-alfa (TNF-α), así como biomarcadores de daño renal con y sin tratamiento con metformina. A las ratas se les inyectó TAA (200 mg/kg; dos veces por semana durante 8 semanas) antes de sacrificarlas a las 10 semanas (grupo experimental) o se les pretrató con metformina (200 mg/kg) diariamente durante dos semanas antes de las inyecciones de TAA y continuaron recibiendo ambos agentes hasta el final del experimento, en la semana 10 (grupo protector). Usando tinción histológica básica, métodos de inmunohistoquímica y análisis químico de la sangre, observamos una lesión profunda del tejido renal, como daño glomerular y tubular en el grupo experimental, que mejoraron sustancialmente con la metformina. La metformina también inhibió significativamente (p0,05) en la expresión renal de células de inmunotinción positivas para CD45. En conclusión, encontramos que el TAA induce la lesión renal en asociación con el aumento del eje ROS/TNF-α, independientemente de la infiltración de leucocitos, que está protegida por metformina.

Investigation of the protective effect of boric acid against hepatotoxic and nephrotoxic injury induced by acrylamide in rats / Investigación del efecto protector del ácido bórico contra lesiones hepatotóxicas y nefrotóxicas inducidas por acrilamida en ratas

SUMMARY: To investigate if the administration of boric acid (BA) would exert any protective effect against possible nephrotoxicity and hepatotoxicity induced by the exposure to acrylamide (ACR) in rats. In our study, we used a total of 28 rats that were divided into four equal groups. Group 1: the control group which was not treated with any procedure. Group 2: the ACR group that was administered ACR 50 mg/kg/day via intraperitoneal (i.p) route for 14 days. Group 3: the BA group that was administered BA 200 mg/kg/ day via gavage via peroral (p.o) route for 14 days. Group 4: the ACR+BA group that was administered BA simultaneously with ACR. Total antioxidant and oxidant (TAS/TOS) capacities were measured in all groups at the end of the experiment. In addition, the specimens obtained were evaluated with histopathological examination. Studies showed that the ACR and ACr+BA groups were not significantly different in terms of hepatic TAS level while the TOS level was higher in the ACR group than the ACR+BA group. The groups did not show any significant difference regarding renal TAS and TOS levels. In the histopathological examination of the hepatic tissue, the histopathological injury score of the ACR group was significantly higher than those of the other groups whereas it was significantly lower in the ACR+BA group than the ACR group. Our study concluded that Boric acid had a protective effect against acrylamide- induced hepatotoxicity, but not against nephrotoxicity.

El objetivo de este estudio fue investigar si la administración de ácido bórico (BA) ejercería algún efecto protector frente a la posible nefrotoxicidad y hepatotoxicidad inducida por la exposición a acrilamida (ACR) en ratas. En nuestro estudio, utilizamos un total de 28 ratas que se dividieron en cuatro grupos iguales. Grupo 1: grupo control que no fue tratado. Grupo 2: grupo ACR al que se le administró ACR 50 mg/kg/día por vía intraperitoneal (i.p) durante 14 días. Grupo 3: grupo BA al que se le administró BA 200 mg/kg/día por sonda por vía peroral (p.o) durante 14 días. Grupo 4: grupo ACR+BA al que se administró BA simultáneamente con ACR. Las capacidades antioxidantes y oxidantes totales (TAS/TOS) se midieron en todos los grupos al final del experimento. Además, los especímenes obtenidos fueron evaluados con examen histopatológico. Los estudios demostraron que los grupos ACR y ACr+BA no fueron significativamente diferentes en términos del nivel hepático de TAS, mientras que el nivel de TOS fue mayor en el grupo ACR que en el grupo ACR+BA. Los grupos no mostraron ninguna diferencia significativa con respecto a los niveles renales de TAS y TOS. En el examen histopatológico del tejido hepático, la puntuación de lesión histopatológica del grupo ACR fue significativamente mayor que la de los otros grupos, mientras que fue significativamente menor en el grupo ACR+BA que en el grupo ACR. Nuestro estudio concluyó que el ácido bórico tiene un efecto protector contra la hepatotoxicidad inducida por acrilamida, pero no contra la nefrotoxicidad.

Minimal fresh gas flow sevoflurane anesthesia and postoperative acute kidney injury in on-pump cardiac surgery: a randomized comparative trial

Abstract Background Compound A is generated by sevoflurane when it reacts with carbon dioxide absorbers with strong bases at minimal fresh gas flow (FGF) and is nephrotoxic in animals. No conclusive data has shown increased risk in humans. The aim of this study was to investigate if minimal FGF promotes an increase in the incidence of acute kidney injury (AKI) when compared to high FGF in patients undergoing on-pump cardiac surgery under sevoflurane anesthesia. Methods Two hundred and four adult patients scheduled for on-pump cardiac surgery under sevoflurane anesthesia were randomly allocated to two groups differentiated by FGF: minimal FGF (0.5 L.min−1) or high FGF (2.0 L.min−1). Baseline creatinine measured before surgery was compared daily to values assayed on the first five postoperative days, and 24-hour urinary output was monitored, according to the KDIGO (Kidney Disease Improving Global Outcomes) guideline to define postoperative cardiac surgery-associated acute kidney injury (CSA-AKI). Creatinine measurements were also obtained 20 and 120 days after hospital discharge. Results Postoperative AKI occurred in 55 patients, 26 patients (29.5%) in the minimal FGF group and 29 patients (31.5%) in the high FGF group (p= 0.774). Twenty days after discharge, 11 patients (6.1%) still had CSA-AKI and 120 days after discharge only 2 patients (1.6%) still had CSA-AKI. Conclusions When compared to high FGF, minimal FGF sevoflurane anesthesia during on-pump cardiac surgery is not associated with increased risk of postoperative AKI in this population at high risk for renal injury.

Research progress on animal models of contrast-induced acute kidney injury / 中南大学学报(医学版)

Contrast-induced acute kidney injury (CI-AKI) refers to acute kidney injury that occurs after intravascular contrast media is applied. It is the third most common cause for acute renal failure in hospitalized patients and can cause severe renal impairment and adverse cardiovascular outcomes. In severe cases, it can even lead to the death of the patient. Due to its complicated pathogenesis, the pathogenesis of CI-AKI has not yet been elucidated. Therefore, it is of great significance to further study the pathogenesis for the prevention of CI-AKI. Moreover, a good animal model of CI-AKI is an important tool for in-depth research on the pathogenesis of acute kidney injury induced by contrast agents.

Nephroprotective effects of Lippia sidoides ethanolic extract against ischemia/reperfusion-induced acute kidney injury

Abstract Ischemia/reperfusion injury (I/R) is commonly related to acute kidney injury (AKI) and oxidative stress. Antioxidant agents are used to treat this condition. Lippia sidoides is a brazillian shrub with anti-inflammatory and anti-oxidative properties. Thus, the aim of this study is to evaluate the effect of Lippia sidoides ethanolic extract (LSEE) on in vivo and in vitro models of AKI induced by I/R. Male Wistar rats were submitted to unilateral nephrectomy and ischemia on contralateral kidney for 60 min via clamping followed by reperfusion for 48 h. They were divided into four groups: Sham, LSEE (sham-operated rats pre-treated with LSEE), I/R (rats submitted to ischemia) and I/R-LSEE (rats treated with LSEE before ischemia). Kidney tissues homogenates were used to determine stress parameters and nephrin expression. Plasma and urine samples were collected for biochemical analysis. I/R in vitro assays were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and flow cytometry assays in Rhesus Monkey Kidney Epithelial Cells (LLC-MK2). The LSEE treatment prevented biochemical and nephrin expression alterations, as well as oxidative stress parameters. In the in vitro assay, LSEE protected against cell death, reduced the reactive oxygen species and increased mitochondrial transmembrane potential. LSEE showed biotechnological potential for a new phytomedicine as a nephroprotective agent.

Green coffee bean extract attenuates gentamicin induced acute nephrotoxicity in rats / El extracto de grano de café verde atenúa la nefrotoxicidad aguda inducida por gentamicina en ratas

Gentamicin induced acute nephrotoxicity (GIAN) is considered as one of the important causes of acute renal failure. In recent years' great effort has been focused on the introduction of herbal medicine as a novel therapeutic agent for prevention of GIAN. Hence, the current study was designed to investigate the effect of green coffee bean extract (GCBE) on GIAN in rats. Results of the present study showed that rat groups that received oral GCBE for 7 days after induction of GIAN(by a daily intraperitoneal injection of gentamicin for 7days), reported a significant improvement in renal functions tests when compared to the GIAN model groups. Moreover, there was significant amelioration in renal oxidative stress markers (renal malondialdehyde, renal superoxide dismutase) and renal histopathological changes in the GCBE-treated groups when compared to GIAN model group. These results indicate that GCBE has a potential role in ameliorating renal damage involved in GIAN.

La nefrotoxicidad aguda inducida por gentamicina (GIAN) se considera una de las causas importantes de insuficiencia renal aguda. En los últimos años, el gran esfuerzo se ha centrado en la introducción de la medicina herbal como un nuevo agente terapéutico para la prevención de GIAN. Por lo tanto, el estudio actual fue diseñado para investigar el efecto del extracto de grano de café verde (GCBE) sobre la GIAN en ratas. Los resultados del presente estudio mostraron que los grupos de ratas que recibieron GCBE oral durante 7 días después de la inducción de GIAN (mediante una inyección intraperitoneal diaria de gentamicina durante 7 días), informaron una mejora significativa en las pruebas de función renal en comparación con los grupos del modelo GIAN. Además, hubo una mejora significativa en los marcadores de estrés oxidativo renal (malondialdehído renal, superóxido dismutasa renal) y cambios histopatológicos renales en los grupos tratados con GCBE en comparación con el grupo del modelo GIAN. Estos resultados indican que GCBE tiene un papel potencial en la mejora del daño renal involucrado en GIAN.

Can paricalcitol increase the effectiveness of n-acetylcysteine in contrast induced acute kidney prophylaxis in rats? A biochemical and histopathological study / ¿Puede el paricalcitol aumentar la eficacia de la n-acetilcisteína en la profilaxis renal aguda inducida por contraste en ratas? Un estudio bioquímico e histopatológico

SUMMARY: N-Acetylcysteine (NAC) is used for contrast induced acut kidney injury (CI-AKI) prophylaxis because of its antioxidant effects. Paricalcitol, which has reno-protective effects, is likely to provide a more effective prophylaxis when added to NAC treatment. The study was designed based on this hypothesis. The study was organised to include 4 groups each consisting of 7 rats. Group 1 was the control group, and Group 2 included rats with CI-AKI. Rats in Group 3 were administered NAC at a dose of 100 mg/kg via oral gavage once a day for 5 days. Rats in group 4 were administered paricalcitol at a dose of 0.4 mcg/kg once a day for 5 days in addition to NAC. CI-AKI was induced after the treatments in both groups. The study was terminated on the sixth day. Samples were collected from the rats' sera and kidney tissues to study oxidant and antioxidant parameters; kidney function tests were also studied. There were significant differences between the contrast nephropathy group (Group 2) and NAC and NAC+paricalcitol groups with respect to serum urea and creatinine levels. When the same groups were compared regarding oxidant (TOS-MDA) and antioxidant (TAC-Paraoxonase) parameters, we observed that the oxidant parameters increased in serum and kidney tissue samples with NAC use, and that effect was strengthened by the addition of paricalcitol to NAC treatment. However, despite increased antioxidant effectiveness, we observed no decrease in urea and creatinine levels when paricalcitol was added for CI-AKI in rats. There was no significant difference between Group 3 and Group 4. Paricalcitol provides a more potent antioxidant effect in both serum and kidney tissue samples when added to NAC treatment in rats with CI-AKI. Despite increased antioxidant parameters, however, paricalcitol does not provide a significant decrease in urea and creatinine levels.

RESUMEN: Debido a sus efectos atioxidantes la N- acetilcisteína (NAC) se usa para la profilaxis de la lesión renal aguda inducida por contraste (CI-AKI). Es probable que el paricalcitol, que tiene efectos renoprotectores, proporcione una profilaxis más eficaz cuando se agrega al tratamiento con NAC. En base a esta hipótesis el estudio fue diseñado para incluir cuatro grupos cada uno compuesto por siete ratas. El grupo 1 fue el grupo control y el grupo 2 incluyó ratas con CI-AKI. A las ratas del Grupo 3 se les administró NAC con una dosis de 100 mg/kg por sonda oral una vez al día, durante 5 días. A las ratas del grupo 4 se les administró paricalcitol a una dosis de 0,4 mcg/kg una vez al día durante 5 días, además de NAC. Se indujo CI-AKI después de los tratamientos en ambos grupos. El estudio finalizó el sexto día. Se recolectaron muestras de suero y tejidos renales de ratas para estudiar los parámetros oxidantes y antioxidantes; También se estudiaron las pruebas de función renal. Hubo diferencias significativas entre el grupo de nefropatía por contraste (Grupo 2) y los grupos NAC y NAC+paricalcitol con respecto a los niveles séricos de urea y creatinina. Cuando se compararon los mismos grupos con respecto a los parámetros oxidantes (TOS-MDA) y antioxidantes (TAC-Paraoxonase), observamos que los parámetros oxidantes aumentaron en muestras de suero y tejido renal con el uso de NAC, y ese efecto se vio reforzado por la adición de paricalcitol a tratamiento NAC. Sin embargo, a pesar de una mayor eficacia antioxidante, no observamos una disminución en los niveles de urea y creatinina cuando se agregó paricalcitol para CI-AKI en ratas. No hubo diferencias significativas entre el Grupo 3 y el Grupo 4. El paricalcitol proporciona un efecto antioxidante más potente tanto en muestras de suero como de tejido renal cuando se agrega al tratamiento con NAC en ratas con CI-AKI. Sin embargo, a pesar del aumento de los parámetros antioxidantes, el paricalcitol no proporciona una disminución sig- nificativa en los niveles de urea y creatinina.

Rapidly progressive glomerulonephritis and acute kidney injury associated with cocaine use - Case report / Glomerulonefrite rapidamente progressiva e lesão renal aguda associada ao uso de cocaína - Relato de caso

ABSTRACT A wide spectrum of renal complications can occur with acute and chronic use of cocaine. Most cases are related to rhabdomyolysis, but other mechanisms are malignant hypertension, renal ischemia, and rapidly progressive glomerulonephritis (RPGN) associated-ANCA vasculitis. In recent years, the use of cocaine adulterated with levamisole has been associated with ANCA vasculitis and pauci-immune RPGN. RPGN is clinically manifested as a nephritic syndrome with a rapid and progressive decline in renal function, and its histopathological finding is the presence of crescents in more than 50% of the glomeruli. We report a case of a 38-year-old man chronic user of cocaine, alcohol, and cigarettes who had red urine, oliguria, swollen legs and eyelids, as well as the uremic symptoms anorexia, emesis, and mental confusion. He was admitted with acute kidney injury and performed six hemodialysis sessions during the first 16 days of hospitalization and then was transferred to a tertiary hospital for diagnostic investigation. Tests of ANF (antinuclear factor), ANCA, anti-DNA, serology for hepatitis B, C, and HIV virus were negative. A renal percutaneous biopsy revealed crescentic glomerulonephritis with mild tubular atrophy. The patient underwent pulse therapy with methylprednisolone (for 3 days) and cyclophosphamide. Then he maintained daily prednisone and monthly intravenous cyclophosphamide and evolved with progressive improvement of renal function.

RESUMO Um amplo espectro de complicações renais pode ocorrer com o uso agudo e crônico de cocaína. A maioria dos casos está relacionada à rabdomiólise, mas outros mecanismos são hipertensão maligna, isquemia renal e glomerulonefrite rapidamente progressiva (GNRP) associada à vasculite por ANCA. Nos últimos anos, o uso de cocaína adulterada com levamisol tem sido associado à vasculite por ANCA e GNRP pauci-imune. A GNRP se manifesta clinicamente como uma síndrome nefrítica, com um declínio rápido e progressivo da função renal, e seu achado histopatológico é a presença de crescentes em mais de 50% dos glomérulos. Relatamos um caso de um homem de 38 anos, usuário crônico de cocaína, álcool e cigarros que apresentava urina vermelha, oligúria, pernas e pálpebras inchadas, além dos sintomas urêmicos, anorexia, êmese e confusão mental. Foi internado com lesão renal aguda e realizou seis sessões de hemodiálise durante os primeiros 16 dias de internação, e depois foi transferido para um hospital terciário para investigação diagnóstica. Os testes de ANF (fator antinuclear), ANCA, anti-DNA, sorologia para vírus da hepatite B, C e HIV foram negativos. Uma biópsia percutânea renal revelou glomerulonefrite crescente, com leve atrofia tubular. O paciente foi submetido à pulsoterapia com metilprednisolona (por 3 dias) e ciclofosfamida. Em seguida, ele manteve a prednisona diária e a ciclofosfamida intravenosa mensal e evoluiu com melhora progressiva da função renal.

Poisoning in domestic cats in Brazil: toxicants, clinical signs, and therapeutic approaches / [Intoxicação em gatos domésticos no Brasil: toxicantes, sinais clínicos e abordagens terapêuticas]

This study evaluated the most common toxic agents affecting domestic cats, the clinical signs of toxicity, and the therapeutic approaches for recovery. A survey on poisoning in cats was conducted among small animal veterinary practitioners from 2017 to 2018. Of the 748 completed questionnaires, 543 (72.6%) were evaluated. Pesticides and household cleaning supplies were the most common causes of poisoning in cats. The toxicant groups included pesticides and household cleaning supplies (organophosphates), human drugs (acetaminophen), plants/plant derivatives (lily), and veterinary drugs (tramadol). The major clinical signs for these four groups of toxicants were (1) acetaminophen poisoning, which caused oxidative erythrocyte damage; (2) muscarinic and nicotinic cholinergic syndrome, which resulted from organophosphate poisoning; (3) acute kidney injury, which resulted from intoxication of lily; and (4) serotonin syndrome, which resulted from tramadol toxicosis. Interventions for treating poisoning in cats were based on the clinical presentation of animals. In the present study, the significant toxins identified to be dangerous for cats were characterized using the obtained data in Brazil as well as the main associated clinical signs and therapy recommended by veterinarians.(AU)

Objetiva-se com este trabalho caracterizar os principais toxicantes para gatos domésticos, bem como os prevalentes sinais clínicos e a terapêutica associada. Uma pesquisa sobre envenenamento em gatos foi realizada entre médicos veterinários no período de 2017 a 2018. Dos 748 questionários preenchidos, 543 (72,6%) foram avaliados. Pesticidas e domissanitários foram os principais causadores de intoxicação em gatos. Entre os grupos tóxicos, destacaram-se, na categoria pesticidas e domissanitários (organofosforados), medicamentos humanos (acetaminofeno), plantas e derivados de planta (lírio) e medicamentos veterinários (tramadol). Os principais sinais clínicos para os quatro grupos de substâncias tóxicas foram: (1) intoxicação por acetaminofeno, que causou dano eritrocitário oxidativo; (2) síndrome colinérgica muscarínica e nicotínica, resultante do envenenamento por organofosforado; (3) lesão renal aguda, causada pela intoxicação por lírio; e (4) síndrome serotoninérgica, resultante da exposição ao tramadol. As intervenções realizadas para o tratamento dos envenenamentos foram justificáveis mediante a apresentação clínica dos animais. Por meio dos dados obtidos, puderam-se caracterizar os principais tóxicos para gatos no Brasil, bem como os principais sinais clínicos associados e a terapêutica preconizada pelos médicos veterinários.(AU)

Desenlaces asociados con solución salina normal versus lactato de ringer en sepsis y choque séptico o hipovolémico / Outcomes associated with normal saline solution vs lactated ringer´s solution in sepsis and septic or hypovelemic shock

Introducción: los cristaloides son medicamentos usados en pacientes críticamente enfermos, con resultados ambiguos cuando se utilizan soluciones balanceadas versus solución salina normal. Objetivo: conocer si existen diferencias al usar solución salina 0.9% vs. lactato de Ringer en pacientes críticamente enfermos con sepsis y choque séptico o hipovolémico, en cuanto a mortalidad, lesión renal aguda y tiempo de estancia hospitalaria. Métodos: estudio observacional de tipo cohorte retrospectiva en mayores de 18 años con diagnóstico de sepsis, choque séptico o hipovolémico. Se excluyeron aquellos con enfermedad renal crónica en diálisis, las hospitalizadas por ginecología/obstetricia y aquellos con diagnóstico de muerte encefálica o donantes de órganos. Se evaluaron los desenlaces primarios de mortalidad, lesión renal aguda y estancia hospitalaria. Resultados y discusión: se incluyeron 314 pacientes, 158 en el grupo expuesto a solución salina al 0.9% y 156 con lactato de Ringer. Se presentó lesión renal aguda en 22.7% con solución salina y 25.8% con lactato de Ringer (OR 1.18 IC 95%:0.7-2). La mortalidad con solución salina fue de 49%, y en lactato 49% (OR 1.01 IC 95%:0.63-1.63). Los factores de riesgo identificados para mortalidad fueron uso de soporte vasopresor (OR 35 IC 95% 12-83) y lesión renal aguda (1.3 IC 95% 1.01-1.69). Conclusiones: en el paciente críticamente enfermo con sepsis, choque séptico o hipovolémico el uso desolución salina 0.9% no representa diferencias al compararlo con lactato de Ringer en cuanto a mortalidad, lesión renal aguda o estancia hospitalaria. La elección de un cristaloide debe ser individualizada, teniendo en cuenta las comorbilidades, la presencia de hipercloremia o hiperpotasemia.

Objective: crystalloids are drugs used in critically ill patients, with ambiguous results when balanced solutions versus normal saline solution (NS) are used. The objective of this study is to determine if there are differences when NS (0.9%) vs. lactated Ringer ́s (LR) solution are given to critically ill patients in sepsis or septic or hypovolemic shock, in terms of mortality, acute renal injury and length of hospital stay. Methods: a retrospective observational cohort study in patients over 18 years old with sepsis or septic or hypovolemic shock. Patients with chronic renal disease on dialysis, those hospitalized by gynecology/obstetrics and those diagnosed with brain death or organ donors were excluded. The primary mortality outcomes, acute renal injury and hospital stay were evaluated. Results: 314 patients were included, 158 in the NS group and 156 in the LR group. Acute renal injury occurred in 22.7% in the NS group and 25.8% in the LR group (OR 1.18 IC 95%:0.7-2). Mortality rate was 49% in the NS group and 49% in the LR group (OR 1.01 95%: CI 0.63-1.63). Mortality risk factors included the use of vasopressor support (OR 35 95% CI 12-83) and acute renal injury (1.3 95% CI 1.01-1.69). Conclusions: no difference was found with the use of NS in critically ill patients with sepsis or septic or hypovolemic shock when compared with LR in terms of mortality, acute renal injury or hospital stay. The choice of which crystalloid to administer should be individualized, based on the comorbidities and the presence of hyperchloremia or hyperkalemia.

The renoprotective effects of Heme Oxygenase-1 during contrast-induced acute kidney injury in preclinical diabetic models

OBJECTIVES: Contrast-induced acute kidney injury (CI-AKI) is an important clinical problem that can be aggravated by diabetes mellitus, a major risk factor. However, heme oxygenase-1 (HO-1), a promising therapeutic target, can exert antioxidant effects against CI-AKI. Thus, we investigated the role of HO-1 in CI-AKI in the presence of diabetes mellitus. METHODS: Twenty-eight male Wistar rats weighing 250-300g were subjected to left uninephrectomy, and concomitantly, diabetes induced by streptozotocin (65 mg/kg). After 12 weeks, iodinated contrast (meglumine ioxithalamate, 6 mL/kg) and hemin (HO-1 inducer-10 mg/k) were administered 60 min before iodinated contrast treatment. The rats were randomly divided into four groups: control, diabetes mellitus (DM), DM iodinated contrast (DMIC), and DMIC hemin (DMICH). Kidney function, albuminuria, oxidative profile, and histology were assessed. All experimental data were subjected to statistical analyses. RESULTS: CI-AKI in preclinical diabetic models decreased creatinine clearance and increased urinary neutrophil gelatinase-associated lipocalin (NGAL) levels and the degree of albuminuria. Additionally, the levels of oxidative and nitrosative stress metabolites (urinary peroxides, thiobarbituric acid-reactive substances, and NO) were elevated, while thiol levels in kidney tissue were reduced. Kidney histology showed tubular cell vacuolization and edema. HO-1 inducer treatment improved kidney function and reduced urinary the NGAL levels. The oxidative profile showed an increase in the endogenous thiol-based antioxidant levels. Additionally, the tubular injury score was reduced following HO-1 treatment. CONCLUSIONS: Our findings highlight the renoprotective effects of HO-1 in CI-AKI and preclinical diabetic models. Therefore, HO-1 ameliorates kidney dysfunction, reduces oxidative stress, and prevents cell necrosis.

Impacto do uso de drogas nefrotóxicas em pacientes pediátricos graves / Impact of the use of nephrotoxic drugs in critically ill pediatric patients

RESUMO Objetivo: Avaliar a associação entre uso de drogas nefrotóxicas e lesão renal aguda em pacientes pediátricos graves. Métodos: Estudo de coorte retrospectivo envolvendo todas as crianças internadas na unidade de terapia intensiva de um hospital pediátrico durante o período de 1 ano. A lesão renal aguda foi definida pela classificação KDIGO. Foram incluídos pacientes com tempo de internação maior que 48 horas e idade entre 1 mês e 14 anos. Foram excluídos aqueles com nefropatia aguda ou crônica, uropatia, cardiopatia congênita ou adquirida, uso crônico de drogas nefrotóxicas, rabdomiólise e síndrome de lise tumoral. Os pacientes foram classificados quanto ao uso de drogas nefrotóxicas durante internação na unidade de terapia intensiva pediátrica. Resultados: A amostra foi composta por 226 crianças, sendo que 37,1% fizeram uso de drogas nefrotóxicas, 42,4% desenvolveram lesão renal aguda e 7,5% morreram. As medicações que, isoladamente, apresentaram associação com lesão renal aguda foram aciclovir (p < 0,001), vancomicina (p < 0,001), furosemida (p < 0,001) e ganciclovir (p = 0,008). O uso concomitante de duas ou mais drogas nefrotóxicas foi caracterizado como marcador independente de disfunção renal (p < 0,001). Após alta da unidade de terapia intensiva pediátrica, o acompanhamento da função renal na enfermaria foi inadequado em 19,8% dos casos. Conclusão: É necessário que o médico intensivista tenha conhecimento das principais drogas nefrotóxicas, de modo a prever, reduzir ou evitar danos a seus pacientes.

Abstract Objective: To evaluate the association between the use of nephrotoxic drugs and acute kidney injury in critically ill pediatric patients. Methods: This was a retrospective cohort study involving all children admitted to the intensive care unit of a pediatric hospital during a 1-year period. Acute kidney injury was defined according to the KDIGO classification. Patients with a length of hospital stay longer than 48 hours and an age between 1 month and 14 years were included. Patients with acute or chronic nephropathy, uropathy, congenital or acquired heart disease, chronic use of nephrotoxic drugs, rhabdomyolysis and tumor lysis syndrome were excluded. Patients were classified according to the use of nephrotoxic drugs during their stay at the pediatric intensive care unit. Results: The sample consisted of 226 children, of whom 37.1% used nephrotoxic drugs, 42.4% developed acute kidney injury, and 7.5% died. The following drugs, when used alone, were associated with acute kidney injury: acyclovir (p < 0.001), vancomycin (p < 0.001), furosemide (p < 0.001) and ganciclovir (p = 0.008). The concomitant use of two or more nephrotoxic drugs was characterized as an independent marker of renal dysfunction (p < 0.001). After discharge from the pediatric intensive care unit, renal function monitoring in the ward was inadequate in 19.8% of cases. Conclusion: It is necessary for intensivist physicians to have knowledge of the main nephrotoxic drugs to predict, reduce or avoid damage to their patients.

Quercetin protects against acetaminophen-induced acute nephrotoxicity associated with the inhibition of biomarkers of acute kidney injury in rats / La quercetina protege contra la nefrotoxicidad aguda inducida por acetaminofén asociada con la inhibición de biomarcadores de lesión renal aguda en ratas

Acetaminophen (also called paracetamol, or APAP) causes acute kidney injury after accidental or intentional ingestion of a toxic dose of the drug. We tested whether the antioxidant and anti-inflammatory agent, quercetin (QUR) given alone can protect against acute nephrotoxicity induced by APAP overdose in a rat model of APAP-induced acute kidney injury. Rats were either given a single dose of APAP (2 g/kg) before being sacrificed after 24 hours or were pre-treated for 7 days with QUR (50 mg/kg) before being given a single dose of APAP and then sacrificed 24 hours post APAP ingestion. Kidneys were examined by light microscopy after staining with hematoxylin and eosin (H&E) and collected blood samples were assayed for biomarkers of oxidative stress, inflammation, and kidney injury. H&E stained sections of kidney from the model group of rats (APAP) showed substantial damage to the kidney architecture as demonstrated by widening of Bowman's space, tubular dilatation, vacuolization of tubular epithelium, and congested dilated blood vessels, which were partially protected by QUR. In addition, APAP significantly (p<0.05) increased blood levels of urea, creatinine, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-a), and interleukin-6 (IL-6), which were significantly (p<0.05) reduced by QUR. These results indicate that quercetin partially protects against APAP-induced acute kidney injury in rats, which is associated with the inhibition of biomarkers of oxidative stress and inflammation and kidney injury.

El acetaminofeno (también llamado paracetamol o DCI) causa daño renal agudo después de la ingestión accidental o intencional de una dosis tóxica del medicamento. En el estudio analizamos si el agente antioxidante y antiinflamatorio, la quercetina (QUR) administrada sola, puede proteger contra la nefrotoxicidad aguda inducida por sobredosis de DCI en un modelo de rata. Las ratas recibieron una dosis única de DCI (2 g / kg) antes de ser sacrificadas después de 24 horas o fueron pretratadas durante 7 días con QUR (50 mg / kg) antes de recibir una dosis única de DCI y luego sacrificadas 24 horas post ingestión. Los riñones se examinaron mediante microscopía óptica después de la tinción con hematoxilina y eosina (H&E) y las muestras de sangre recolectadas se analizaron para detectar biomarcadores de estrés oxidativo, inflamación y daño renal. Las secciones de riñón teñidas con H&E del grupo modelo de ratas (DCI) mostraron un daño sustancial a la arquitectura del riñón, como lo demuestra la ampliación del espacio de Bowman, la dilatación tubular, la vacuolización del epitelio tubular y los vasos sanguíneos dilatados congestionados, que estaban parcialmente protegidos por QUR. Además, DCI aumentó significativamente (p <0,05) los niveles sanguíneos de la urea, creatinina, malondialdehído (MDA), factor de necrosis tumoral alfa (TNF-a) e interleucina-6 (IL-6), los que fueron reducidos significativamente (p < 0,05) por QUR. Estos resultados indican que la quercetina protege parcialmente contra la lesión renal aguda inducida por DCI en ratas, asociada con la inhibición de biomarcadores de estrés oxidativo, inflamación y lesión renal.

Vitamin D Toxicity / Toxicidade da Vitamina D

Abstract Fortification of food products with vitamin D was central to the eradication of rickets in the early parts of the 20th century in the United States. In the subsequent almost 100 years since, accumulating evidence has linked vitamin D deficiency to a variety of outcomes, and this has paralleled greater public interest and awareness of the health benefits of vitamin D. Supplements containing vitamin D are now widely available in both industrialized and developing countries, and many are in the form of unregulated formulations sold to the public with little guidance for safe administration. Together, this has contributed to a transition whereby a dramatic global increase in cases of vitamin D toxicity has been reported. Clinicians are now faced with the challenge of managing this condition that can present on a spectrum from asymptomatic to acute life-threatening complications. This article considers contemporary data on vitamin D toxicity, and diagnostic and management strategies relevant to clinical practice.

Resumo A suplementação de produtos alimentares com vitamina D foi fundamental para a erradicação do raquitismo no início do século XX nos Estados Unidos. Nos quase 100 anos subsequentes, o acúmulo de evidências vinculou a deficiência de vitamina D a uma variedade de desfechos, e isso tem levantado grande interesse público e conscientização dos benefícios à saúde da vitamina D. Os suplementos que contêm vitamina D estão agora amplamente disponíveis tanto nos países desenvolvidos quanto naqueles em desenvolvimento, e muitos estão na forma de formulações não regulamentadas, vendidas ao público com poucas orientações para uma administração segura. Juntos, isso contribuiu para uma transição na qual um aumento global dramático nos casos de toxicidade da vitamina D tem sido relatado. Médicos agora enfrentam o desafio de tratar essa condição que pode apresentar um espectro de complicações assintomáticas a agudas, com risco de vida. Este artigo considera dados atualizados sobre a toxicidade da vitamina D e estratégias de diagnóstico e manejo relevantes para a prática clínica.

Ameliorative effect of vitamin E on biochemical and ultrastructural changes in artemether-induced renal toxicity in rats / Efecto paliativo de la vitamina E sobre los cambios bioquímicos y ultraestructurales en la toxicidad renal inducida por arteméter en ratas

This experiment was designed to study the administration of normal doses of one of recent antimalarial drug and coadministration of vitamin E on the kidney tissue. A total twenty-four adult male albino rats were used and divided into four groups: the first one served as a control, the second received artemether orally for three days consecutively. The rats of the third and fourth groups received the same dose of artemether concomitantly with 50 and 100 mg/kg vitamin E orally daily for 2 weeks. After the last dose, the rats were sacrificed and the kidney tissues with blood samples obtained and processed for light, electron microscopic and biochemical analysis. Histologically, artemether treated kidneys showed atrophied glomeruli with widened urinary space and kidney tubules were degenerated with disturbed contour and some vacuoles inside it. Ultrastructurally, the glomeruli of this group showed hypertrophic endothelial cells, irregularity of its basement membrane, disrupted foot processes and filtration slits. The kidney tubule cells showed loss of basal infoldings, cytoplasmic vacuolation, polymorphic damaged swollen mitochondria a loss of its microvilli towards its capillary lumen. Artemether plus vitamin E of the rat kidney groups showed improvement of morphological changes compared to the changes seen in artemether alone. These data were confirmed by biochemical findings with marked improvement of blood urea and creatinine levels and increase of anti-oxidant enzyme activities of glutathione peroxidase and superoxide dismutase in the vitamin E treated groups. The results of this study revealed that vitamins E can improve the adverse changes of artemether of rat renal tissue.

Este proyecto fue diseñado para estudiar la administración de dosis normales de uno de los medicamentos antipalúdicos y de la administración de vitamina E en el tejido renal. Se utilizaron 24 ratas albinas machos adultas divididas en cuatro grupos: el primero sirvió como control, el segundo recibió arteméter por vía oral durante tres días consecutivos. Las ratas del tercer y cuarto grupos recibieron la misma dosis de arteméter concomitantemente con 50 y 100 mg / kg de vitamina E por vía oral diariamente durante 2 semanas. Después de la última dosis, las ratas fueron sacrificadas y se obtuvo el tejido renal de cada muestra los cuales fueron procesados para análisis con microscopías de luz y electrónica, además de exámenes bioquímicos. Histológicamente, los riñones tratados con arteméter mostraron atrofia glomerular con espacio urinario ensanchado y túbulos renales degenerados con contorno alterado y algunas vacuolas en su interior. Ultraestructuralmente, los glomérulos de este grupo mostraron células endoteliales hipertróficas, irregularidad de su membrana basal, procesos alterados del pie y hendiduras de filtración. Las células del túbulo renal mostraron pérdida de inflexiones basales, vacuolación citoplasmática, mitocondrias dañadas y pérdida de sus microvellosidades hacia la luz capilar. Arteméter más vitamina E en los grupos de riñón de rata mostraron una mejora de los cambios morfológicos, en comparación con los cambios observados en arteméter solamente. Estos datos fueron confirmados por hallazgos bioquímicos con una marcada mejoría de los niveles de urea y creatinina en sangre y un aumento de las actividades enzimáticas antioxidantes de la glutatión peroxidasa y la superóxido dismutasa en los grupos tratados con vitamina E. Los resultados de este estudio revelaron que la vitamina E puede mejorar los cambios adversos del arteméter del tejido renal de la rata.

Prevalência de nefropatia induzida por contraste em pacientes cardíacos de um setor de hemodinâmica / Prevalence of contrast-induced nephropathy in cardiac patients in a hemodynamic sector / Prevalencia de nefropatía inducida por contraste en pacientes cardíacos de un sector de hemodinámica

Objetivo: Determinar a prevalência da nefropatia induzida por contraste em pacientes cardiopatas submetidos a procedimentos angiográficos de diagnóstico e/ou tratamento. Método: Estudo prospectivo, quantitativo, realizado no setor de hemodinâmica de um hospital de grande porte, situado na região norte do Rio Grande do Sul, Brasil. A amostra foi constituída por 79 participantes através do cálculo de tamanho amostral. Resultados: A amostra foi formada por 52 (65,8%) homens e 27 (34,2%) mulheres. A idade média foi de 65,9 ± 9,52 anos. A incidência de nefropatia induzida por contraste foi de 30,38%, totalizando 24 pacientes. Conclusão: Foi evidenciada uma alta prevalência de nefropatia por contraste, apesar dos pacientes apresentarem poucos fatores de risco, o que ressalta a necessidade de medidas preventivas e redução do volume de contraste

Objective: To determine the prevalence of contrast-induced nephropathy in cardiac patients undergoing diagnostic and / or treatment angiographic procedures. Method: A prospective, quantitative study in the hemodynamics sector of a large hospital, located in the northern region of Rio Grande do Sul, Brazil. The sample consisted of 79 participants through the calculation of sample size. Results: The sample consisted of 52 (65.8%) men and 27 (34.2%) women. The mean age was 65.9 ± 9.52 years. The incidence of contrast-induced nephropathy was 30,38%, totaling 24 patients. Conclusion: A high prevalence of contrast nephropathy was evidenced, despite the fact that patients presented few risk factors, which highlights the need for preventive measures and reduction of contrast volume

Objetivo: Determinar la prevalencia de la nefropatía inducida por contraste en pacientes cardiopatas sometidos a procedimientos angiográficos de diagnóstico y / o tratamiento. Método: Estudio prospectivo, cuantitativo, realizado en el sector de hemodinámica de un hospital de gran porte, situado en la región norte de Rio Grande do Sul, Brasil. La muestra fue constituida por 79 participantes a través del cálculo de tamaño muestral. Resultados: La muestra fue formada por 52 (65,8%) hombres y 27 (34,2%) mujeres. La edad media fue de 65,9 ± 9,52 años. La incidencia de nefropatía inducida por contraste fue del 30,38%, totalizando 24 pacientes. Conclusión: Se evidenció una alta prevalencia de nefropatía por contraste, a pesar de que los pacientes presentaban pocos factores de riesgo, lo que resalta la necesidad de medidas preventivas y reducción del volumen de contraste

Drug-induced nephrotoxicity

SUMMARY Acute kidney injury is a very common diagnosis, present in up to 60% of critical patients, and its third main cause is drug toxicity. Nephrotoxicity can be defined as any renal injury caused directly or indirectly by medications, with acute renal failure, tubulopathies, and glomerulopathies as common clinical presentations. Some examples of drugs commonly associated with the acute reduction of glomerular filtration rate are anti-inflammatories, antibiotics, such as vancomycin and aminoglycosides, and chemotherapeutic agents, such as cisplatin and methotrexate. Cases of tubulopathy are very common with amphotericin B, polymyxins, and tenofovir, and cases of glomerulopathies are common with VEGF inhibitors, bisphosphonates, and immunotherapy, and it is also common to have more than one clinical presentation related to a single agent. Early diagnosis is essential for the good evolution of the patient, with a reduction of renal exposure to the toxic agent, which requires knowing the risk factors and biomarkers. General measures such as correcting hydroelectrolytic disorders and hypovolemia, monitoring the serum level, avoiding combinations with the synergy of renal injury, and looking for similar options that are less toxic are the foundations for the treatment of complications that are still common and often preventable.

RESUMO A lesão renal aguda é um diagnóstico muito comum, presente em até 60% dos pacientes críticos, e sua terceira maior causa é a toxicidade de medicamentos. A nefrotoxicidade pode ser definida como qualquer lesão renal causada por medicamentos, direta ou indiretamente, tendo a insuficiência renal aguda, tubulopatias e glomerulopatias como apresentações clínicas comuns. Alguns exemplos de drogas comumente associadas à redução aguda da taxa de filtração glomerular são anti-inflamatórios, antibióticos, como a vancomicina e aminoglicosídeos, e agentes quimioterápicos, tais como cisplatina e metotrexato. Casos de tubulopatia são muito comuns com anfotericina B, polimixinas e tenofovir, já casos de glomerulopatias são comuns com inibidores de VEGF, bisfosfonatos e imunoterapia; também é comum ocorrer mais de uma apresentação clínica relacionada a um único agente. O diagnóstico precoce é essencial para a boa evolução do paciente, com a redução da exposição ao agente tóxico, o que requer conhecimento dos fatores de risco e biomarcadores. Medidas gerais, tais como a correção de distúrbios hidreletrolíticos e da hipovolemia, o monitoramento do nível sérico, evitar combinações com sinergia de lesão renal e procurar opções semelhantes e menos tóxicas são os alicerces do tratamento de complicações que são comuns e, muitas vezes, evitáveis.

Suppression of monosodium glutamate-induced acute kidney injury and renal ultrastructural damage in rats by vitamin E / Supresión de lesiones renales agudas inducidas por glutamato monosódico y daño ultraestructural renal en ratas por vitamina E

Food additives and flavour enhancers used in the food industry are potential health risks. We tested the hypothesis that the food additive and flavour enhancer, monosodium glutamate (MSG), which is the sodium salt of glutamic acid can induce ultrastructural alterations to the kidney, and the antioxidant vitamin E can protect against acute kidney injuries induced by a toxic dose of MSG in a rat model of the disease. The model group of rats received a daily dose of MSG (4 gm/kg) for 7 days, whereas the protective groups were either received a 100 mg/kg vitamin E plus MSG or 300 mg/kg vitamin E plus MSG for 7 days. Rats were then sacrificed on day 8. Transmission and light microscopy images revealed substantial kidney damage induced by MSG in the model group as demonstrated by degenerated epithelial cells with Pyknotic nuclei, swollen mitochondria, damaged brush margins, dilated tubules, and widening of Bowman's space with shrinkage and deformity of some glomeruli. Treatment of the model group with vitamin E showed a substantial protection of kidney tissue and renal ultrastructure by 300 mg/kg vitamin E compared to a partial protection by 100 mg/kg vitamin E. In addition, MSG significantly (p<0.05) increased serum levels of urea and creatinine, which were significantly (p<0.05) decreased with vitamin E. However, for serum creatinine, high doses of vitamin E (300 mg/kg) were more effective than lower doses (100 mg/kg) of vitamin E. These results indicate that vitamin E at 300 mg/kg effectively protects against MSG-induced acute kidney injury in rats.

Los aditivos alimentarios y los potenciadores del sabor utilizados en la industria alimentaria son riesgos potenciales para la salud. Probamos la hipótesis de que el aditivo alimentario y el potenciador del sabor, glutamato monosódico (MSG), la sal sódica del ácido glutámico, puede inducir alteraciones ultraestructurales del riñón, y que las propiedades antioxidantes de la vitamina E, pueden proteger contra las lesiones renales inducidas por una dosis tóxica de MSG en un modelo de rata. El grupo modelo de ratas recibió una dosis diaria de MSG (4 g / kg) durante 7 días, mientras que los grupos protectores recibieron una dosis de 100 mg / kg de vitamina E más MSG o 300 mg / kg de vitamina E más MSG durante 7 días. Las ratas se sacrificaron el día 8. Las imágenes de microscopía óptica y de transmisión revelaron un daño renal sustancial inducido por el MSG en el grupo modelo, como lo demuestran las células epiteliales degeneradas con núcleos picnóticos, mitocondrias hinchadas, bordes dañados, túbulos dilatados y ensanchamiento del espacio de Bowman, además de la deformidad de algunos glomérulos. El tratamiento del grupo modelo con vitamina E mostró una protección sustancial del tejido renal y la ultraestructura renal de 300 mg / kg de vitamina E en comparación con una protección parcial de 100 mg / kg de vitamina E. Además, el MSG aumentó significativamente (p <0,05) en el suero los niveles de urea y creatinina, disminuyeron significativamente (p <0,05) con la vitamina E. Sin embargo, para la creatinina sérica, las dosis altas de vitamina E (300 mg / kg) fueron más efectivas que las dosis más bajas (100 mg / kg) de vitamina E. Estos resultados indican que la vitamina E a 300 mg / kg protege eficazmente contra la lesión renal aguda inducida por MSG en ratas.