Synergistic Renoprotective Effects of Green Tea Extract and Gemigliptin against Tacrolimus-Induced Nephrotoxicity in Mice

SUMMARY: Although tacrolimus (TAC) significantly reduces allograft rejection incidence in solid-organ transplantation, its long-term use is associated with an increased risk of TAC-induced nephrotoxicity. In this study, we investigated the renoprotective effects of green tea extract (GTE) with or without the dipeptidyl peptidase 4 inhibitor, gemigliptin, by assessing serum creatinine levels, the amount of proteinuria, and histopathology in TAC-induced nephrotoxicity. TAC-induced nephrotoxicity was induced by intraperitoneal TAC injection, GTE was administered via subcutaneous injection, and gemigliptin was administered orally. Mice with TAC-induced nephrotoxicity exhibited a significant increase in both serum creatinine levels and 24-hour urine protein. However, when treated with GTE via subcutaneous injection, mice showed a decrease in serum creatinine levels and the amount of proteinuria. When GTE was combined with gemigliptin, further renoprotective effects were observed in biochemical assessments, consistent with the attenuation of TAC-induced nephrotoxicity in histopathology. The expression of p53 protein was lower in the mice treated with the combination of GTE and gemigliptin compared to mice with TAC-induced nephrotoxicity. Our results demonstrate that the combination of GTE and gemigliptin treatment reveals synergistic renoprotective effects by decreasing the expression of p53 protein. These findings suggest that the combination of GTE and gemigliptin could potentially be used as a prophylactic or therapeutic strategy for TAC-induced nephrotoxicity.

Aunque tacrolimus (TAC) reduce significativamente la incidencia de rechazo de aloinjertos en trasplantes de órganos sólidos, su uso a largo plazo se asocia con un mayor riesgo de nefrotoxicidad inducida por TAC. En este estudio, investigamos los efectos renoprotectores del extracto de té verde (GTE) con o sin el inhibidor de la dipeptidil peptidasa 4, gemigliptina, mediante la evaluación de los niveles de creatinina sérica, la cantidad de proteinuria y la histopatología en la nefrotoxicidad inducida por TAC. La nefrotoxicidad inducida por TAC se indujo mediante inyección intraperitoneal de TAC, el GTE se administró mediante inyección subcutánea y la gemigliptina se administró por vía oral. Los ratones con nefrotoxicidad inducida por TAC mostraron un aumento significativo tanto en los niveles de creatinina sérica como en la proteína en orina de 24 horas. Sin embargo, cuando se trataron con GTE mediante inyección subcutánea, los ratones mostraron una disminución en los niveles de creatinina sérica y en la cantidad de proteinuria. Cuando se combinó GTE con gemigliptina, se observaron efectos renoprotectores adicionales en las evaluaciones bioquímicas, lo que concuerda con la atenuación de la nefrotoxicidad inducida por TAC en histopatología. La expresión de la proteína p53 fue menor en los ratones tratados con la combinación de GTE y gemigliptina en comparación con los ratones con nefrotoxicidad inducida por TAC. Nuestros resultados demuestran que la combinación de tratamiento con GTE y gemigliptina revela efectos renoprotectores sinérgicos al disminuir la expresión de la proteína p53. Estos hallazgos sugieren que la combinación de GTE y gemigliptina podría usarse potencialmente como estrategia profiláctica o terapéutica para la nefrotoxicidad inducida por TAC.

Prospective Protective Effects of Arthrospira platensis Against Acetaminophen Induced Hepato-Renal Toxicity in Rats / Efectos Protectores Prospectivos de Arthrospira platnesis Contra la Toxicidad Hepatorrenal Inducida por Paracetamol en Ratas

SUMMARY: The toxic effects of acetaminophen appear primarily in the liver and kidney. The protective effect of blue green alga Arthrospira platensis on hepato-renal toxicity caused by acetaminophen was evaluated in male rats. The obtained results showed that subcutaneous injection of acetaminophen at a dose 120 &240 սl acetaminophen/kg by weight resulted in an observed elevation in the enzyme activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Alkaline phosphatase (ALP), serum total lipids, total cholesterol, creatinine, total bilirubin, urea, nitric oxide (NO), L- malondialdehyde (MDA) and interleukins (IL-2 &IL-6). However, there is a decrease in the serum total protein, albumin and loss in antioxidant enzyme activities in liver including; superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GSH). This effect was found to be dose and time dependent. In spite of, pre- oral administration of Arthrospira platensis 1000 mg/kg .b. wt. prior acetaminophen injection succeeded to modulate the effect of the observed abnormalities caused by acetaminophen. Moreover, there were no remarkable changes in serum biomarkers of rats received Arthrospira platensis only at a dose of 1000 mg/kg by weight (group 2). The histopathological findings confirm the biochemical results that indicates the safety use of Arthrospira platensis at the selected dose in this study. Therefore, the present results clarified the protective effect of blue green alga Arthrospira platensis on oxidative stress, hepatic and nephrotoxicity induced by acetaminophen in male Wister rats.

Los efectos tóxicos del paracetamol aparecen principalmente en el hígado y el riñón. Se evaluó en ratas macho Wistar el efecto protector del alga verde azulada Arthrospira platensis sobre la toxicidad hepatorrenal causada por paracetamol. Los resultados obtenidos mostraron que la inyección subcutánea de paracetamol a dosis de 120 y 240 µl de paracetamol/kg, resultó en una elevación en las actividades enzimáticas de la aspartato aminotransferasa (AST), alanina aminotransferasa (ALT) y fosfatasa alcalina (ALP), lípidos séricos totales, colesterol total, creatinina, bilirrubina total, urea, óxido nítrico (NO), L- malondialdehído (MDA) e interleucinas (IL-2 e IL-6). Sin embargo, hay una disminución en la proteína sérica total, albúmina y pérdida en las actividades de las enzimas antioxidantes en el hígado, incluyendo; superóxido dismutasa (SOD), catalasa (CAT) y glutatión reductasa (GSH). Se encontró que este efecto era dependiente de la dosis y el tiempo. A pesar de la administración preoral de Arthrospira platensis 1000 mg/kg, la inyección previa de acetaminofeno logró modular el efecto de las anormalidades observadas causadas por el acetaminofeno. Además, no hubo cambios notables en los biomarcadores séricos de ratas que recibieron Arthrospira platensis solo a una dosis de 1000 mg/kg (Grupo 2). Los hallazgos histopatológicos confirman los resultados bioquímicos que indican la seguridad del uso de Arthrospira platensis a la dosis seleccionada en este estudio. Por lo tanto, los presentes resultados aclararon el efecto protector del alga verde azulada Arthrospira platensis sobre el estrés oxidativo, la toxicidad hepática y la nefrotoxicidad inducida por paracetamol en ratas Wistar macho.

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.

Síndrome de Fanconi por agentes quimioterapéuticos: serie de casos y revisión de la literatura

Introducción: múltiples agentes quimioterapéuticos que se usan comúnmente pueden causar síndrome de Fanconi (SF) completo o parcial. El SF es una tubulopatía proximal que produce alteraciones electrolíticas y ácido-básicas, donde se evidencia pérdida de glucosa, aminoácidos, calcio, fósforo, potasio, ácido úrico y se produce acidosis metabólica por pérdida de bicarbonato. El SF usualmente no es reportado y muchas veces no se realiza el diagnóstico. Objetivo: resaltar la importancia del monitoreo urinario y sérico en pacientes que estén sometidos a quimioterapia, así como describir la literatura reciente acerca de la asociación entre agentes quimioterapéuticos y síndrome de Fanconi parcial o completo. Presentación de los casos: se presenta una serie de casos de pacientes pediátricos oncológicos con función renal preservada, donde se produjeron diferentes manifestaciones de nefrotoxicidad tubular proximal secundaria a agentes quimioterapéuticos como antimetabolitos, agentes alquilantes y antraciclinas. Discusión y conclusión: el espectro del SF puede ir de una tubulopatía proximal generalizada o completa a alteraciones parciales en la reabsorción de electrolitos. Se debe reconocer la importancia del monitoreo sérico y urinario en pacientes con lesiones tumorales que van a ser sometidos a quimioterapias con agentes potencialmente nefrotóxicos; asimismo, tener en cuenta la dosis, la frecuencia y la combinación de agentes quimioterapéuticos, con el fin de prevenir y tratar complicaciones de toxicidad renal, incluyendo SF completo o parcial.

Introduction: Several commonly used chemotherapeutic agents can cause complete or partial Fanconi syndrome (FS). FS is a proximal tubulopathy that produces electrolyte and acid base disorders where there is loss of glucose, amino acids, calcium, phosphorus, potassium, uric acid and metabolic acidosis occurs due to loss of bicarbonate. FS is not usually reported, and the diagnosis is often misled. Purpose: To highlight the importance of urinary and serum monitoring in patients undergoing chemotherapy, as well as describe the recent literature about the association between chemotherapeutic agents and partial or complete Fanconi syndrome. Case presentation: A series of cases of pediatric oncology patients with preserved renal function is presented in which different manifestations of proximal tubular nephrotoxicity occurred secondary to chemotherapeutic agents such as antimetabolites, alkylating agents, and anthracyclines. Discussion and conclusion: The spectrum of FS can range from a generalized or complete proximal tubulopathy to partial alterations in electrolyte reabsorption. The importance of serum and urinary monitoring should be recognized in patients with tumor lesions who will undergo chemotherapies with potentially nephrotoxic agents; the dosage, frequency and combination of chemotherapeutic agents should be taken into account, in order to prevent and treat the complications of renal toxicity including complete or partial SF.

Nefrotoxicidad y hematotoxicidad un año después de cuatro ciclos de terapia con péptidos marcados con radionúclidos (PRRT) y su impacto en la planificación del tratamiento futuro. Un análisis retrospectivo / Nephrotoxicity and hematotoxicity one year after four cycles of peptide receptor radionuclide therapy (PRRT) and its impact on future treatment planning. A retrospective analysis

Introducción: La nefrotoxicidad y la hematotoxicidad después de la terapia con péptidos marcados con radionúclidos (PRRT) se han descrito en múltiples estudios usando diferentes actividades acumulativas, número de ciclos o péptidos marcados con radionúclidos. Aunque los tumores neuroendocrinos (NET) altamente diferenciados con metástasis tienen una larga supervivencia libre de progresión, pueden progresar. Analizamos los efectos secundarios a largo plazo en un esquema de tratamiento homogéneo en pacientes con PRRT y su impacto en el futuro tratamiento oncológico en caso de progresión. Métodos: De nuestra base de datos se analizaron 89 de 384 pacientes que recibieron la misma PRRT (Lu-177-DOTATATE o Y-90-DOTATOC) cuatro veces cada 10 a 12 semanas y un seguimiento a los 12 meses. Un paciente recibió tres y 11 pacientes recibieron dos veces cuatro ciclos de PRRT, lo que dio lugar a 102 casos. Se compararon el índice de filtrado glomerular estimado (FGe), la Hb, los glóbulos blancos y las plaquetas antes del primer ciclo de terapia y un año después del cuarto ciclo. La clasificación del FGe se realizó según la clasificación de la enfermedad renal crónica (ERC) y la clasificación de la hematotoxicidad según los Criterios Terminológicos Comunes para Eventos Adversos (CTCAE). También se evaluó el impacto de la edad, el sexo, la actividad acumulada y el tipo de PRRT en la toxicidad a largo plazo. Resultados: El grado 1-2 del FGe se redujo de 87/102 al inicio a 71 casos en el seguimiento (p < 0,001). Antes del tratamiento se encontró grado 3a en 13, grado 3b en 2, y en el seguimiento grado 3a en 25, grado 3b en cinco casos, y grado 4 en 1 caso. La anemia antes de la PRRT y en el seguimiento fue de grado 0 en 63 vs. 48 (p < 0,001), de grado 1 en 36 vs. 48, y de grado 2 en tres vs. seis casos. En el recuento de glóbulos blancos y plaquetas no se produjeron cambios significativos en la clasificación (AU)

Introduction: Nephro- and hematotoxicity after peptide receptor radionuclide therapy (PRRT) have been described in multiple studies with heterogeneous cumulative activities, number of cycles or radiolabelled peptides. Though highly differentiated metastasized neuroendocrine tumours (NET) have long progression free survival, they may progress. We analysed long-term side effects in a homogenous treatment schedule in PRRT-patients and their impact on future oncologic treatment in case of progression. Methods: From our database 89/384 patients receiving the same PRRT (Lu-177-DOTATATE or Y-90-DOTATOC) 4 times every 10 to 12 weeks and a follow-up at 12 months were analysed. One patient had three and 11 patients had two times four PRRT-cycles resulting in 102 cases. eGFR, Hb, WBC and platelets before the first and one year after the fourth therapy cycle were compared. eGFR-Grading was done according to chronic kidney disease classification (CKD) and grading of hematotoxicity according to Common Terminology Criteria for Adverse Events (CTCAE). Impact of age, gender, cumulative activity, type of PRRT on long-term-toxicity was also assessed. Results: eGFR grade 1-2 dropped from 87/102 at the baseline to 71 cases at follow-up (p<0.001). Before treatment grade 3a was found in 13, grade 3b in 2 cases, and at follow-up grade 3a in 25, grade 3b in 5, and grade 4 in 1 case. Anaemia prior to PRRT and at follow-up was grade 0 in 63 versus 48 (p<0.001), grade 1 in 36 versus 48, and grade 2 in three versus six cases. In white blood cell count and platelets, there were no significant changes in grading occurring. Subgroup analysis revealed that only in the age group 65 and older was there a higher incidence for anaemia (p=0.006) (AU)

Nephrotoxicity and hematotoxicity one year after four cycles of peptide receptor radionuclide therapy (PRRT) and its impact on future treatment planning - A retrospective analysis.

PURPOSE: Nephro- and hematotoxicity after peptide receptor radionuclide therapy (PRRT) have been described in multiple studies with heterogeneous cumulative activities, number of cycles or radiolabelled peptides. Though highly differentiated metastasized neuroendocrine tumours (NET) have long progression free survival, they may progress. We analysed long-term side effects in a homogenous treatment schedule in PRRT-patients and their impact on future oncologic treatment in case of progression. METHODS: From our database 89/384 patients receiving the same PRRT (Lu-177-DOTATATE or Y-90-DOTATOC) 4 times every 10-12 weeks and a follow-up at 12 months were analysed. One patient had three and 11 patients had two times four PRRT-cycles resulting in 102 cases. eGFR, Hb, WBC and platelets before the first and one year after the fourth therapy cycle were compared. eGFR-Grading was done according to chronic kidney disease classification (CKD) and grading of hematotoxicity according to CTCAE. Impact of age, gender, cumulative activity, type of PRRT on long-term-toxicity was also assessed. RESULTS: eGFR grade 1-2 dropped from 87/102 at the baseline to 71 cases at follow-up (p < 0.001). Before treatment grade 3a was found in 13, grade 3b in 2 cases, and at follow-up grade 3a in 25, grade 3b in 5, and grade 4 in 1 case. Anaemia prior to PRRT and at follow-up was grade 0 in 63 versus 48 (p < 0.001), grade 1 in 36 versus 48, and grade 2 in three versus six cases. In white blood cell count and platelets, there were no significant changes in grading occurring. Subgroup analysis revealed that only in the age group 65 and older was there a higher incidence for anaemia (p = 0.006). CONCLUSION: In roughly 20% of cases an increase in grading of nephro- or hematotoxicity is observed. In those patients, except in one, toxicity findings were mild or moderate one year after completion of four cycles of PRRT with either Y-90- or Lu-177-SST-analogues. In terms of safety, PRRT has no critical impact on further oncologic treatment options in the case of disease progression.

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.

Revisión sistemática sobre nuevas estrategias en la prevención de la Nefropatía Inducida por Contrastes / Systematic review of new strategies in the prevention of Contrast-Induced Nephropathy

La Nefropatía Inducida por Contrastes (NIC) es unapatología de elevada incidencia, asociada a la administración demedios de contraste. A pesar de los esfuerzos enfocados en prevenirsu desarrollo mediante actuaciones como la reducción del volumendel medio de contraste administrado, el uso de contrastes menostóxicos y la valoración previa de los factores de riesgo, esta patologíasigue siendo la tercera causa mundial de fallo renal agudo. Esto haceque sea imprescindible establecer un abordaje preventivo. En estetrabajo se han valorado las estrategias de prevención frente a la NICque se han evaluado en los últimos 10 años. La mayor parte de losestudios proponen la hidratación en combinación con antioxidantes,sin embargo, los resultados obtenidos no han sido concluyentes.Estrategias mas actuales como la administración de trimetazidina, unfármaco anti-isquémico; el tratamiento con el hongo Cordycepssinensis, con demostradas propiedades renoprotectoras; el oxígenopor vía inhalatoria; o las terapias basadas en el preacondicionamiento isquémico han resultado ser más eficaces en laprevención de la NIC, pero necesitan ser consolidadas con unaevidencia sólida y posiblemente adaptarse y orientarse de maneraindividual, en función de los factores de riesgo asociados a cadapaciente (AU)

Contrast-Induced Nephropathy (CIN) is a high-incidence pathologyassociated with the administration of contrast media. Despite effortsfocused on preventing its development through actions such asreducing the volume of the contrast medium administered, the use ofless toxic contrasts and the prior assessment of risk factors, thispathology continues to be the third world cause of acute kidneyfailure. This makes it essential to establish a preventive approach. Inthis work, prevention strategies for CIN studied in the last 10 yearshave been evaluated. Most of the studies propose hydration incombination with antioxidants, however, the results obtained havenot been conclusive. More current strategies such as theadministration of trimetazidine, an anti-ischemic drug; treatment withthe Cordyceps sinensis fungus, with proven renoprotectiveproperties; inhalational oxygen; or therapies based on ischemic preconditioning have proven to be more effective in the prevention ofCIN, but they need to be consolidated with solid evidence andpossibly adapted and oriented individually, depending on the riskfactors associated with each patient (AU)

Can magnesium sulfate prophylaxis reduce colistin nephrotoxicity? / ¿Puede la profilaxis con sulfato de magnesio reducir la nefrotoxicidad de la colistina?

The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin. Thirty Wistar Albino rats were divided into four groups: control, colistin, magnesium (Mg), and Mg+colistin. The drugs were administered to the groups for seven days. Urea-creatinine values were measured at the beginning (T0) and end (T1) of the study. Malondialdehyde (MDA) levels were measured in plasma and kidney tissue, glutathione (GSH) levels were analyzed in the erythrocyte and kidney tissues. At the end of the study, the semiquantitative score (SQS) was calculated by the histopathological examination of the kidneys. Urea values significantly decreased in Mg and Mg+colistin groups compared to the baseline (p=0.013 and p=0.001). At the time of T1, these groups had significantly lower urea values than the colistin and control groups. Creatinine value was significantly increased in the colistin group compared to baseline (p=0.005), the creatinine value in the colistin group was significantly higher than the Mg+colistin group (p=0.011). Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 (p<0.001). The Mg+colistin group had lower renal MDA levels than the colistin group. The colistin group had significantly higher renal tubular grade (p=0.035), renal affected area (p<0.001), and SQS (p=0.001) than the Mg+colistin group. The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin. (AU)

El objetivo del estudio fue investigar la función de la profilaxis con sulfato de magnesio en la nefrotoxicidad causada por la colistina. Se dividieron 30 ratas Wistar albinas en 4 grupos: control, colistina, magnesio (Mg) y Mg + colistina. Los fármacos se administraron a los grupos durante 7 días. Los valores de urea-creatinina se midieron al principio (T0) y al final (T1) del estudio. Se midieron los niveles de malondialdehído (MDA) en el plasma y el tejido renal, y se analizaron los niveles de glutatión (GSH) en los eritrocitos y el tejido renal. Al final del estudio, se calculó la puntuación semicuantitativa (semiquantitative score [SQS]) mediante el examen histopatológico de los riñones. Los valores de urea disminuyeron significativamente en los grupos de Mg y Mg + colistina en comparación con los valores iniciales (p = 0,013 y p = 0,001). En el momento del T1, estos grupos tenían valores de urea significativamente más bajos que los grupos de colistina y de control. El valor de creatinina se incrementó significativamente en el grupo de colistina en comparación con el valor inicial (p = 0,005); el valor de creatinina en el grupo de colistina fue significativamente mayor que en el grupo de Mg + colistina (p = 0,011). Los niveles de MDA en el plasma fueron significativamente más altos en el grupo de colistina en comparación con los otros grupos en el momento del T1 (p < 0,001). El grupo de Mg + colistina presentó niveles renales de MDA más bajos que el grupo de colistina. El grupo de colistina presentó un grado tubular renal (p = 0,035), un área renal afectada (p < 0,001) y una SQS (p = 0,001) significativamente mayores que el grupo de Mg + colistina. Los resultados del estudio indicaron que el sulfato de Mg puede tener un efecto reductor de la nefrotoxicidad de la colistina. (AU)

Nephrotoxicity and hematotoxicity one year after four cycles of peptide receptor radionuclide therapy (PRRT) and its impact on future treatment planning. A retrospective analysis. / Nefrotoxicidad y hematotoxicidad un año después de cuatro ciclos de terapia con péptidos marcados con radionúclidos (PRRT) y su impacto en la planificación del tratamiento futuro. Un análisis retrospectivo.

INTRODUCTION: Nephro- and hematotoxicity after peptide receptor radionuclide therapy (PRRT) have been described in multiple studies with heterogeneous cumulative activities, number of cycles or radiolabelled peptides. Though highly differentiated metastasized neuroendocrine tumours (NET) have long progression free survival, they may progress. We analysed long-term side effects in a homogenous treatment schedule in PRRT-patients and their impact on future oncologic treatment in case of progression. METHODS: From our database 89/384 patients receiving the same PRRT (Lu-177-DOTATATE or Y-90-DOTATOC) 4 times every 10 to 12 weeks and a follow-up at 12 months were analysed. One patient had three and 11 patients had two times four PRRT-cycles resulting in 102 cases. eGFR, Hb, WBC and platelets before the first and one year after the fourth therapy cycle were compared. eGFR-Grading was done according to chronic kidney disease classification (CKD) and grading of hematotoxicity according to Common Terminology Criteria for Adverse Events (CTCAE). Impact of age, gender, cumulative activity, type of PRRT on long-term-toxicity was also assessed. RESULTS: eGFR grade 1-2 dropped from 87/102 at the baseline to 71 cases at follow-up (p<0.001). Before treatment grade 3a was found in 13, grade 3b in 2 cases, and at follow-up grade 3a in 25, grade 3b in 5, and grade 4 in 1 case. Anaemia prior to PRRT and at follow-up was grade 0 in 63 versus 48 (p<0.001), grade 1 in 36 versus 48, and grade 2 in three versus six cases. In white blood cell count and platelets, there were no significant changes in grading occurring. Subgroup analysis revealed that only in the age group 65 and older was there a higher incidence for anaemia (p=0.006). CONCLUSIóN: In roughly 20% of cases an increase in grading of nephro- or hematotoxicity is observed. In those patients, except in one, toxicity findings were mild or moderate one year after completion of four cycles of PRRT with either Y-90- or Lu-177-SST-analogues. In terms of safety, PRRT has no critical impact on further oncologic treatment options in the case of disease progression.

Can magnesium sulfate prophylaxis reduce colistin nephrotoxicity?

The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin. Thirty Wistar Albino rats were divided into four groups: control, colistin, magnesium (Mg), and Mg+colistin. The drugs were administered to the groups for seven days. Urea-creatinine values were measured at the beginning (T0) and end (T1) of the study. Malondialdehyde (MDA) levels were measured in plasma and kidney tissue, glutathione (GSH) levels were analyzed in the erythrocyte and kidney tissues. At the end of the study, the semiquantitative score (SQS) was calculated by the histopathological examination of the kidneys. Urea values significantly decreased in Mg and Mg+colistin groups compared to the baseline (p=0.013 and p=0.001). At the time of T1, these groups had significantly lower urea values than the colistin and control groups. Creatinine value was significantly increased in the colistin group compared to baseline (p=0.005), the creatinine value in the colistin group was significantly higher than the Mg+colistin group (p=0.011). Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 (p<0.001). The Mg+colistin group had lower renal MDA levels than the colistin group. The colistin group had significantly higher renal tubular grade (p=0.035), renal affected area (p<0.001), and SQS (p=0.001) than the Mg+colistin group. The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin.

Nefrotoxicidad en pacientes ingresados a la UCI con monitorización de niveles de vancomicina

En el 2009 un grupo de tareas encabezado por la Sociedad Americana de Enfermedades Infecciosas (IDSA) recomendó niveles de vancomicina entre 15-20 mg/L para asegurar efectividad ante el aumento de las concentraciones mínimas inhibitorias del Staphylococcus aureus resistente a Meticilina (MRSA). No existe evidencia concluyente sobre el impacto de estos nuevos niveles terapéuticos en el riesgo de nefrotoxicidad. Objetivo: determinar si existe una asociación entre los niveles plasmáticos valle de vancomicina y el desarrollo de nefrotoxicidad, independientemente de la presencia o no de otros factores de riesgo para lesión renal. Metodología: se realizó un estudio de cohorte retrospectivo. Se estudiaron pacientes ingresados a UCI del Hospital Santo Tomás, entre el 01 de enero del 2018 y el 31 de diciembre del 2018, que fueron tratados con vancomicina. Se realizó análisis bivariado y multivariante. Resultados: 54 pacientes entraron al análisis; se inició la monitorización de niveles plasmáticos principalmente después de la cuarta dosis (77.78%); 13 pacientes (24.07%) desarrollaron nefrotoxicidad por vancomicina; en el análisis bivariado la única variable con una relación estadísticamente significativa con nefrotoxicidad fue tener niveles valle >15 mg/L (P=0.003). El análisis de regresión logística multivariante mostró que los niveles valle >15 mg/L tienen una asociación estadísticamente significativa con nefrotoxicidad (OR, 15.20 [95% IC, 1.48-156.11]; P=0.022), la cual es independiente de otros confusores. Conclusiones: Los niveles valle de vancomicina >15 mg/L se asociaron de forma independiente a nefrotoxicidad por vancomicina. Se deben realizar estudios prospectivos para definir la asociación de niveles valle de vancomicina con el desarrollo de nefrotoxicidad. (provisto por Infomedic International)

Can magnesium sulfate prophylaxis reduce colistin nephrotoxicity?

The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin. Thirty Wistar Albino rats were divided into four groups: control, colistin, magnesium (Mg), and Mg+colistin. The drugs were administered to the groups for seven days. Urea-creatinine values were measured at the beginning (T0) and end (T1) of the study. Malondialdehyde (MDA) levels were measured in plasma and kidney tissue, glutathione (GSH) levels were analyzed in the erythrocyte and kidney tissues. At the end of the study, the semiquantitative score (SQS) was calculated by the histopathological examination of the kidneys. Urea values significantly decreased in Mg and Mg+colistin groups compared to the baseline (p=0.013 and p=0.001). At the time of T1, these groups had significantly lower urea values than the colistin and control groups. Creatinine value was significantly increased in the colistin group compared to baseline (p=0.005), the creatinine value in the colistin group was significantly higher than the Mg+colistin group (p=0.011). Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 (p<0.001). The Mg+colistin group had lower renal MDA levels than the colistin group. The colistin group had significantly higher renal tubular grade (p=0.035), renal affected area (p<0.001), and SQS (p=0.001) than the Mg+colistin group. The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin.

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.

Melatonin ameliorates the drug induced nephrotoxicity: Molecular insights.

BACKGROUND: Drug-induced nephrotoxicity is a frequent adverse event that can lead to acute or chronic kidney disease and increase the healthcare expenditure. It has high morbidity and mortality incidence in 40-70% of renal injuries and accounts for 66% cases of renal failure in elderly population. OBJECTIVE: Amelioration of drug-induced nephrotoxicity has been long soughed to improve the effectiveness of therapeutic drugs. This study was conducted to review the melatonin potential to prevent the pathogenesis of nephrotoxicity induced by important nephrotoxic drugs. METHODS: We analyzed the relevant studies indexed in Pubmed, Medline, Scielo and Web of science to explain the molecular improvements following melatonin co-administration with special attention to oxidative stress, inflammation and apoptosis as key players of drug-induced nephrotoxicity. RESULTS: A robust consensus among researchers of these studies suggested that melatonin efficiently eradicate the chain reaction of free radical production and induced the endogenous antioxidant enzymes which attenuate the lipid peroxidation of cellular membranes and subcellular oxidative stress in drug-induced nephrotoxicity. This agreement was further supported by the melatonin role in disintegration of inflammatory process through inhibition of principle pro-inflammatory or apoptotic cytokines such as TNF-α and NF-κB. These studies highlighted that alleviation of drug-induced renal toxicity is a function of melatonin potential to down regulate the cellular inflammatory and oxidative injury process and to stimulate the cellular repair or defensive mechanisms. CONCLUSION: The comprehensive nephroprotection and safer profile suggests the melatonin to be a useful adjunct to improve the safety of nephrotoxic drugs.

Efecto nefroprotector del Camu Camu (Myrciaria dubia) en un modelo de nefrotoxicidad inducida por gentamicina en ratas / Nephroprotective effect of Camu Camu (Myrciaria dubia) in a model of nephrotoxicity induced by Gentamicin in rats

RESUMEN El objetivo del estudio fue determinar el efecto nefroprotector del extracto de camu camu en un modelo de nefrotoxicidad inducida por la gentamicina. Estudio de tipo experimental formado por 50 ratas Sprague Dawley que se dividieron aleatoriamente en cinco grupos de estudio: Al grupo control se le administró la solución salina, al grupo gentamicina se le indujo la nefrotoxicidad y a los grupos experimentales 1, 2 y 3 se les protegió con el extracto alcohólico de camu camu a diferentes dosis. La actividad nefroprotectora se evaluó por la cuantificación de la creatinina sérica, el peso y análisis histopatológico de los riñones. Los resultados evidenciaron una disminución significativa del nivel de creatinina en los grupos protegidos con el extracto alcohólico de camu camu con respecto al grupo gentamicina (p<0,05). Los grupos que recibieron camu camu presentaron un aumento gradual del peso de los riñones en una relación directa a la dosis del extracto (p<0,05). El análisis histológico evidenció pérdida epitelial, infiltrado inflamatorio intenso y congestión vascular en el grupo gentamicina, mientras que los grupos que recibieron camu camu con el extracto disminuyeron la gravedad del daño. Se concluye que el extracto de camu camu presentó una actividad nefroprotectora significativa en un modelo de nefrotoxicidad inducida por gentamicina.

ABSTRACT The aim of the study was to determine the nephroprotective effect of camu camu extract on a gentamicin-induced nephrotoxicity model. The study design was experimental using 50 Sprague Dawley rats randomly allocated into 1 of 5 five groups: a control group that was administered a saline solution, a gentamicin group in which nephrotoxicity was induced and experimental groups 1, 2 and 3 that were provided different doses of Camu Camu alcoholic extract. Nephroprotective activity was evaluated via quantification of seric creatinine, histopathological analysis and weighing of the kidneys. Results showed a significant decrease in creatinine levels between the group administered camu camu alcoholic extract and the gentamicin group (p<0.05). Groups who received camu camu presented a gradual increase in kidneys weight which corresponded directly to the extract dose (p<0.05). The histopathological analysis showed epithelial loss, intense inflammatory infiltrate and vascular congestion in the gentamicin group, while the groups who received the extract had a lower level of damage. Camu Camu extract provided a significant nephroprotective activity on a gentamicin-induced nephrotoxicity model.

Ocratoxinas y su potencial nefrótico / Ocratoxins and their nephrotoxic potential

Las ocratoxinas son metabolitos fúngicos que están presentes en una gran variedad de alimentos y sus subproductos. La nefrotoxicidad es su principal efecto tóxico, relacionado a su vez con distintos síndromes clínicos como la necrosis tubular o la nefropatía de los Balcanes. La mayor parte de la información que se conoce sobre estas sustancias proviene de reportes de casos, ensayos en animales o estudios experimentales in vitro. Este documento ofrece una visión general sobre las ocratoxinas, su mecanismo tóxico, su efecto nefrotóxico; así como un panorama sobre su regulación actual en Colombia.

Ochratoxins are fungal metabolites that are present in a wide variety of foods and their byproducts. Nephrotoxicity is its main toxic effect, related in turn to different clinical syndromes such as tubular necrosis or Balkan nephropathy. The information that is known about these substances comes from case reports, animal trials or in vitro experimental studies. This document offers an overview of ochratoxins, toxic mechanism, nephrotoxic effect, and a panorama of their current regulation in Colombia.

Sub-chronic administration of vincristine sulfate induces renal damage and apoptosis in rats via induction of oxidative stress and activation of Raf1-MEK1/2-Erk1/2 signal transduction / La administración subcrónica de sulfato de vincristina induce daño renal y apoptosis en ratas por inducción de estrés oxidativo y activación de la transducción de señales Raf1-MEK1/2-Erk1/2

SUMMARY: In spite of being one of the most powerful anti-cancer drug, the nephrotoxicity of Vincristine (VCR) is not well established in either animals or humans. Hence, this study evaluates the nephrotoxic effect of VCR in rats after sub-chronic long-term administration. Rats were divided into 2 groups (n=10/group) of either control and VCR treated rats (50 mg/kg). Treatments were carried out for 30 consecutive days, after which a series of biochemical and molecular experiments related to kidney function were evaluated. VCR administration significantly decreased the survival rate (69.8 %) and impaired renal function as evidenced by lowered creatinine (Cr) clearance (Ccr), high serum levels of urea and Cr, increased urinary protein levels and resulted in sever cortex pathological alterations, including glomerulus congestion and damage as well as vascular degenerations up to necrosis of both proximal and distal convoluted tubules. Mechanistically, VCR lowered renal antioxidant potential and ATP levels, enhanced lipid peroxidation and induced inflammation. In addition, VCR induced activation of Raf-1-MEK1/2-ERK1/2 signaling pathway leading to downregulation of Bcl2 and upregulation of P53, Bax, and cleaved caspase-3. In conclusion, these findings show a nephrotoxic effect of VCR sulfate in rats after sub-chronic administration and such effect was mediated by activation of ERK1/2 induced apoptosis.

RESUMEN: A pesar de ser uno de los medicamentos de mayor eficacia contra el cáncer, aún no se ha establecido la nefrotoxicidad de la vincristina (VCR) en animales y humanos. Por lo tanto, este estudio evalúa el efecto nefrotóxico de la VCR en ratas después de la administración subcrónica a largo plazo. Las ratas se dividieron en 2 grupos (n = 10 / grupo) de control y ratas tratadas con VCR (50 mg / kg). Los tratamientos se llevaron a cabo durante 30 días consecutivos, después de los cuales se evaluaron una serie de experimentos bioquímicos y moleculares relacionados con la función renal. La administración de VCR disminuyó significativamente la tasa de supervivencia (69,8 %), dificultó la función renal, lo que se observó además en los bajos niveles de creatinina (Cr) (Ccr), los niveles séricos elevados de urea y Cr, un nivel más alto de proteína urinaria, los que dieron lugar a alteraciones patológicas severas de la corteza, incluido el glomérulo congestión y daño, como también degeneraciones vasculares, incluyendo la necrosis de los túbulos contorneados proximales y distales. Mecánicamente, el VCR redujo el potencial antioxidante renal y los niveles de ATP, mejoró la peroxidación lipídica y la inflamación inducida. Además, la VCR indujo la activación de la vía de señalización Raf-1-MEK1 / 2-ERK1 / 2 que conduce a la regulación negativa de Bcl-2 y la regulación positiva de P53, Bax y la caspasa-3. En conclusión, estos hallazgos muestran un efecto nefrotóxico del sulfato de VCR en ratas después de la administración subcrónica. Dicho efecto fue mediado por la activación de la apoptosis inducida por ERK1 / 2.

Renal damage associated with heavy metals: review work / Daño renal asociado a metales pesados: trabajo de revisión

Abstract Catheter-associated infection is an entity with multiple complications, a condition that alters the quality of life of all patients Chronic kidney disease (CKD) represents an important health problem in the entire global population, where knowledge of the environmental factors associated with this disease is currently essential for its prevention. Several heavy metals are recognized, including Cadmium (Cd), Lead (Pb), Arsenic (As) and Mercury (Hg), which are clearly associated with renal damage and progression of CKD. Studies in animals and humans primarily demonstrate a clear association between exposure to these metals and the presence of chronic renal damage, where the pathophysiology of each of these metals is important in understanding the mechanism of renal damage. The present review aims to analyze the pathophysiology and clinical manifestations of the nephrotoxicity associated with these metals, as well as the different studies in both humans and animals that have been performed.

Resumen La enfermedad renal crónica (ERC) representa un importante problema de salud en todo el globo. Actualmente, es esencial para su prevención el conocimiento de los factores ambientales asociados con la enfermedad. Se reconocen diversos metales pesados, entre los que destacan el cadmio (Cd), plomo (Pb), arsénico (As) y mercurio (Hg), que están claramente asociados con la lesión renal y la progresión de la ERC. Estudios en animales y humanos demuestran, principalmente, una clara asociación entre la exposición a estos metales y la presencia de daño renal crónico, donde la fisiopatologia de cada uno de ellos es importante para entender el mecanismo de daño renal. La presente revisión tiene como objetivo analizar, tanto la fisiopatología y manifestaciones clínicas de la nefrotoxicidad asociada a dichos metales, como los diferentes estudios que se han realizado en humanos y animales.

Recommendations of everolimus use in liver transplant. / Recomendaciones de uso de everolimus en el trasplante hepático.

Mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVL) and sirolimus are immunosuppressive agents with a minor nephrotoxic effect, limited to the development of proteinuria in some cases. The combination of EVL and low-dose tacrolimus has proven to be as safe and effective as standard therapy with tacrolimus for the prevention of acute cellular rejection. Early initiation of EVL-based immunosuppressive regimens with reduced exposure to calcineurin inhibitors has been shown to significantly improve renal function of LT recipients during induction and maintenance phases, with comparable efficacy and safety profiles. In patients with established kidney failure, initiating EVL may enable clinicians to reduce calcineurin inhibitors exposure, thereby contributing to the improved renal function of these patients. Although there is not sufficient evidence to recommend their use to prevent the recurrence of hepatocellular carcinoma and the progression of de novo tumours, they are used in this context in routine clinical practice.