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Objective:To explore the role and mechanism of nuclear receptor subfamily 4 group A member 1 ( NR4A1) in suppressing cisplatin nephrotoxicity. Methods:The expression of NR4A1 gene in renal cell subpopulations was analyzed using the "Tabula-muris" single cell transcriptome sequencing database. NR4A1 gene was over-expressed by lentivirus infection in HK-2 cell line and primary renal proximal tubular epithelial cells. Cell counting kit-8 was used to detect the cytotoxicity of cisplatin. The cell death ratio was analyzed using propidium iodide (PI) staining by flow cytometry. The expression of NR4A1 and nuclear factor erythroid 2-related factor 2 ( NRF2) was detected by real-time fluorescent quantitative PCR and Western blotting. Ferroptosis was analyzed by detecting the contents of malondialdehyde (MDA), oxidized glutathione (GSSG) and lipid reactive oxygen species (ROS). Results:The single cell transcriptome sequencing database showed that NR4A1 gene was the lowest expression in renal proximal tubular epithelial cell subsets. Cisplatin (50 μmol/L or 100 μmol/L) could significantly induce MDA, GSSG and lipid ROS production in renal proximal tubular epithelial cells (all P<0.01), and higher cisplatin concentration accompanied with a more increase of MDA, GSSG and lipid ROS. Compared with the control HK-2 cells, the lipid ROS content and iron ion content of HK-2 cells over-expressing NR4A1 were significantly lower (all P<0.01), and the over-expression of NR4A1 inhibited cisplatin-induced cytotoxicity and ferroptosis in renal proximal tubular epithelial cells. Mechanistically, NR4A1 up-regulated the expression of anti-ferroptosis gene NRF2 in proximal renal tubular epithelial cells ( P<0.01). Furthermore, single cell data analysis showed that, similar to the expression of NR4A1 in renal tissue subsets, NRF2 was also the lowest in renal proximal tubular epithelial cells. Conclusions:Cisplatin can induce ferroptosis of renal proximal tubular epithelial cells in a dose-dependent manner. NR4A1 can inhibit cisplatin-induced ferroptosis by up-regulating NRF2 in renal proximal tubular epithelial cells, thereby alleviating the cytotoxicity of cisplatin.
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The aim of this study was to elucidate the protective effect of arbutin on cisplatin (Cis) induced renal tubular epithelial cell injury and its mechanism. Cell counting kit-8 was used to detect the viability of renal tubular epithelial cells. The toxicity of arbutin on renal tubular epithelial cells at different concentrations and the appropriate concentration of arbutin to protect cells against cisplatin were observed. The renal tubular epithelial cells were divided into control group, arbutin group, Cis group and arbutin+Cis group. Flow cytometry, quantitative real-time PCR and Western blotting were used to detect the levels of apoptosis and inflammation. The results showed that arbutin had no significant toxic effect on renal tubular epithelial cells in the mentioned concentration range (0-200 μmol/L). When the concentration of arbutin exceeded 100 μmol/L, it showed a protective effect on renal tubular epithelial cells. Arbutin intervention significantly reduced cisplatin-induced apoptosis of renal tubular epithelial cells and the increase of inflammation-related molecules p-p65 and interleukin-18. In addition, arbutin intervention reversed the cisplatin-induced reduction of Bcl-2 in renal tubular epithelial cells. These findings suggest that arbutin can attenuate cisplatin-induced renal tubular epithelial cell injury through anti-apoptotic and anti-inflammatory responses, which may be expected to be a new potential therapeutic drug for acute kidney injury.
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Abstract Polymyxins are antibiotics developed in the 1950s. Polymyxin-induced neurotoxicity has been often described in medical literature. The same cannot be said of nephrotoxicity or tubulopathy in particular. This report describes the case of a patient prescribed polymyxin B to treat a surgical wound infection, which led to significant increases in fractional excretion of calcium, magnesium, and potassium and subsequent persistent decreases in the levels of these ions, with serious consequences for the patient. Severe hypocalcemia, hypomagnesemia, and hypokalemia may occur during treatment with polymyxin. Calcium, magnesium and potassium serum levels must be monitored during treatment to prevent life-threatening conditions.
Resumo Polimixinas são um grupo de antibióticos desenvolvidos na década de 1950. Seus efeitos neurotóxicos são comumente descritos na literatura, porém há menos relatos sobre seus efeitos nefrotóxicos, especialmente tubulopatias. O objetivo deste relato é descrever o uso de polimixina B em uma paciente para tratamento de infecção de ferida operatória, promovendo grande aumento das frações de excreção de cálcio, magnésio e potássio e acarretando reduções graves e persistentes desses íons, com sérias consequências para a paciente. Hipocalcemia, hipomagnesemia e hipocalemia severas podem ocorrer durante terapia com polimixina e é sugerido que sejam monitorizadas as concentrações séricas desses eletrólitos durante o tratamento como forma de evitar condições de risco à vida.
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Abstract Introduction: Tubular damage is common in glomerular diseases (GD). Glycosuria is a marker of tubular dysfunction and may be used to detect tubular lesion and CKD progression. The aim of this study was to evaluate the prevalence and prognostic value of glycosuria at the time of diagnosis in primary glomerulopathies (PG). Methods: We conducted a 24-month retrospective study in patients diagnosed with PG in our center between 2009 and 2020. We excluded diabetic patients, use of SGLT2 inhibitors, transplant patients, and secondary GD. Patients were divided in two groups according to their glycosuria status at diagnosis. Results: We studied 115 patients. Global prevalence of glycosuria was 10% (n=11) and membranous nephropathy (MN) had the highest prevalence (n=5, 17.9%). We found that patients with glycosuria had higher serum creatinine (2.4 vs. 1.2 mg/dL, p=0.030), higher albuminuria (4.8 vs. 1.9 g/g, p=0.004), and lower serum albumin (2.3 vs. 3.2 g/dL, p=0.021). We did not find association with histological prognostic factors. At the end of follow-up, patients with glycosuria had higher prevalence of the composite outcome of stage 5D CKD or 50% increase in basal SCr (45.5% vs. 17.3%, p=0.037). In patients with MN, results were similar but we were able to find an association of glycosuria with more severe interstitial fibrosis and tubular atrophy (25.0 vs. 0.0 %, p=0.032). Conclusion: Ten percent of our patients with PG have glycosuria. Glycosuria at the time of diagnosis was associated with more severe clinical presentation and worst renal outcome. The association with higher albuminuria suggests that tubular function has an impact on the severity and outcomes of PG.
Resumo Introdução: Danos tubulares são comuns em doenças glomerulares (DG). Glicosúria é um marcador de disfunção tubular e pode detectar lesão tubular e progressão da DRC. O objetivo deste estudo foi avaliar a prevalência e o valor prognóstico da glicosúria no diagnóstico em glomerulopatias primárias (GP). Métodos: Realizamos estudo retrospectivo de 24 meses em pacientes diagnosticados com GP em nosso centro entre 2009-2020. Excluímos pacientes diabéticos, uso de inibidores de SGLT2, pacientes transplantados e DG secundárias. Os pacientes dividiram-se em dois grupos de acordo com seu estado de glicosúria no diagnóstico. Resultados: Estudamos 115 pacientes. A prevalência global de glicosúria foi de 10% (n=11) e a nefropatia membranosa (NM) teve maior prevalência (n=5, 17,9%). Constatamos que pacientes com glicosúria apresentavam creatinina sérica mais elevada (2,4 vs. 1,2 mg/dL, p=0,030), albuminúria mais alta (4,8 vs. 1,9 g/g, p=0,004), e albumina sérica mais baixa (2,3 vs. 3,2 g/dL, p=0,021). Não encontramos associação com fatores prognósticos histológicos. Ao final do acompanhamento, pacientes com glicosúria tiveram maior prevalência do desfecho composto de DRC estágio 5D ou aumento de 50% na CrS basal (45,5% vs. 17,3%, p=0,037). Em pacientes com NM, os resultados foram semelhantes, mas encontramos uma associação de glicosúria com fibrose intersticial mais grave e atrofia tubular (25,0 vs. 0,0 %, p=0,032). Conclusão: 10% de nossos pacientes com GP têm glicosúria. A glicosúria no diagnóstico foi associada a uma apresentação clínica mais grave e pior desfecho renal. A associação com albuminúria mais elevada sugere que a função tubular tem um impacto na gravidade e nos desfechos da GP.
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Objective:To investigate the effects of Klotho on autophagy of human renal tubule cells under high glucose through AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase (ERK) pathways.Methods:Human renal tubular epithelial cells cultured in vitro were divided into control group and high glucose group (HG group, added with 30 mmol/L glucose); According to the transfection of pcDNA3.1-vector or pcDNA3.1-Klotho, they were divided into two groups: Vector group and Klotho group; According to whether AMPK inhibitor compound C or ERK inhibitor curcumin was added after pcDNA3.1-Klotho transfection and high glucose stimulation, they were divided into four groups: HG+ Vector group, HG+ Klotho group, HG+ Klotho+ compound C group and HG+ Klotho+ curcumin group. The expression of Klotho was detected by real-time fluorescent quantitative polymerase chain reaction (qRT-PCR) and Western blot; The relative expression of LC3-Ⅱ/LC3-Ⅰ and p-AMPK/AMPK and p-ERK/ERK were detected by Western blot; Changes of autophagosome in human renal tubular epithelial cells observed by transmission electron microscope. Results:The protein and mRNA expression of Klotho in human renal tubular epithelial cells of HG group was significantly lower than that in the control group (all P<0.05); The LC3-Ⅱ/LC3-Ⅰ in Klotho group was significantly higher than that in Vector group ( P<0.05); The number of autophagosomes in Klotho group was also significantly higher than that in Vector group ( P<0.05); p-AMPK/AMPK in Klotho group was significantly higher than that in Vector group ( P<0.05), while p-ERK/ERK in Klotho group was significantly lower than that in Vector group ( P<0.05). The protein relative expression of p-AMPK/AMPK in HG+ Klotho+ compound C group (0.44±0.04) was significantly lower than that in HG+ Klotho group (0.79±0.08) ( P<0.01); The protein relative expression of p-ERK/ERK in HG+ Klotho+ curcumin group (1.05±0.12) was significantly higher than that in HG+ Klotho group (0.56±0.05) ( P<0.01). The relative expression of LC3-Ⅱ/LC3-Ⅰ protein in HG+ Klotho+ compound C group and HG+ Klotho+ curcumin group (0.79±0.12; 0.68±0.09) were significantly lower than that in HG+ Klotho group (1.65±0.20) (all P<0.01). Conclusions:Klotho can enhance autophagy of human renal tubular epithelial cells under high glucose condition by activating AMPK and inhibiting ERK pathway.
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Objective:Clamping bilateral renal arteries with refined surgical methods to establish the rat renal ischemia-reperfusion injury (RIRI) model, and study the protective mechanism of ischemic preconditioning renal (IPC) tubular cell-derived exosomes in RIRI.Methods:25 female Sprague Dawley (SD) rats were divided into sham group, model group, inactivated group, normoxic group, IPC group. In the sham operation group, after bilateral renal arteries were dissociated, the back incision was disinfected and closed. The model group established RIRI model; RIRI models were established in inactivated group, normoxia group and IPC group, and then 200 μg of inactivated exosomes, normal exosomes and IPC exosomes were injected into the caudal vein 24 hours after operation. Serum creatinine (Scr) and urea nitrogen (BUN) levels were detected. The pathological changes of renal tissue were observed under light microscope. Transmission electron microscopy (TEM) was used to observe the shape and size of renal tubular exosomes. Nanoparticle tracking analysis (NTA)was used to detect the concentration and size of renal tubular exosomes.Results:Compared with the sham group, the Scr and BUN levels in the model group were significantly elevated ( P<0.01). Renal pathological changes in the model group showed damaged of the tubular structure, necrosis and shedding of tubular epithelial cells, and a large number of inflammatory cells accumulated in the renal interstitial tissue with varying degrees of edema. Compared with the inactivated group, the Scr and BUN levels significantly decreased in the normoxic group and IPC group ( P<0.01). Renal pathological changes in the normoxic group and IPC group showed that the renal tubular cell necrosis alleviated, inflammatory was reduced, the improved edema. Compared with the normoxic group, the Scr and BUN levels in the IPC group were further reduced ( P<0.01). Renal pathological changes in the IPC group showed that the inflammatory cells were significantly reduced, the cell edema was significantly improved, and the cell apoptosis was significantly reduced. Conclusions:Clamping bilateral renal arteries with refined surgical methods is the main and optimal way to build a rat model of RIRI. IPC tubular cell-derived exosomes have protective and repair effects on RIRI.
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The modern era has brought an appreciation that renal cell carcinoma (RCC) includes diverse subtypes derived from the various parts of the nephron, each with its distinctive genetic basis and tumor biology. Carcinoma of the collecting ducts of Bellini (CDC) is a rare subtype of RCC, with a predictably poor prognosis. This rare subtype represents less than 1% of all kidney carcinomas. It derives from presumably numerous chromosomal losses. It is of chief importance to differentiate CDC from other types of renal cell cancer. Typically, it is characterized by a firm, centrally located tumor with infiltrative borders. Regarding the histopathologic characteristics, we can find complex, highly infiltrative cords with inflamed (desmoplastic) stroma, with high-grade nuclei and mitoses. Most reported cases of CDC had been high grade, advanced stage, and unresponsive to conventional therapies. This rare form of disease highlights the importance of multidisciplinary teams in the management of cancer patients.
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Humans , Female , Adult , Carcinoma, Renal Cell/pathology , Kidney Neoplasms/pathology , Kidney Tubules, CollectingABSTRACT
Objective:To observe the expression of sirtuin 3 (Sirt3) and mitochondrial damage-associated proteins in lipopolysaccharide (LPS)-induced acute kidney injury mouse model and renal tubular epithelial cells, and to explore the role of Sirt3 in LPS-induced abnormal mitochondrial dynamics in renal tubular epithelial cells.Methods:Eighteen specific pathogen free (SPF) male C57BL/6 mice were randomly assigned to control group, LPS 24 h group and LPS 48 h group. The control group was intraperitoneally injected with physiological saline (0.1 ml/10 g), and LPS 24 h group and LPS 48 h group were intraperitoneally injected with LPS (10 mg/kg) solution. Renal functional indexes of mice were analyzed by automatic biochemical analyzer. The pathological change of the kidney was observed by HE staining, and the expressions of dynamin-related protein-1 (Drp1), optic atrophy type 1 (Opa1) and Sirt3 were evaluated by Western blotting. Expression and distribution of Sirt3 in kidney was assessed by immunohistochemistry. Human renal tubular epithelial cells (HK-2) were exposed to 10 μg/ml LPS for 24 h, and the expression of Drp1, Opa1 and Sirt3 were detected by Western blotting. Cell apoptosis was assessed by Hoechst-33342 staining. After transfection to HK-2 cells with pcDNA3.1-Sirt3 recombinant plasmid, the expressions of Sirt3, Drp1, Opa1 and cell apoptosis were detected by the same methods as above.Results:(1) The levels of blood urea nitrogen and serum creatinine in LPS group were significantly higher than those in control group (both P<0.05), and the pathological changes of kidney were obvious. (2) Compared with the control group, the expression of mitochondrial fission-associated protein Drp1 in renal tissue of LPS group was significantly higher ( P<0.05), and the expression of mitochondrial fusion associated protein Opa1 was significantly lower ( P<0.05). (3) Compared with the control group, the expression of Sirt3 in LPS group was significantly lower ( P<0.05), and immunohistochemistry results showed that Sirt3 was mainly expressed in glomerular vascular endothelial cells and renal tubular epithelial cells. (4) In vitro, LPS stimulation induced increased Drp1 expression in HK-2 cells ( P<0.05), decreased Opa1 and Sirt3 expression (both P<0.05), and increased apoptosis ( P<0.05). (5) LPS-induced mitochondrial dynamics disturbance and apoptosis were alleviated by pcDNA3.1-Sirt3 recombinant plasmid transfection. Conclusions:LPS can induce down-regulation of Sirt3 expression and disturbance of mitochondrial dynamics, and Sirt3 may play a protective role in LPS-induced acute kidney injury by regulating mitochondrial dynamics.
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Objective:To evaluate the effect of hydrogen-rich saline on serine threonine protein kinase (Akt) /nuclear factor E2-related factor 2 (Nrf2) signaling pathway during hypoxia/reoxygenation (H/R) injury to human renal tubular epithelial cells.Methods:Human renal tubular epithelial cell line were seeded in 96-well plates at a density of 1.5×10 4 cells/ml (200 μl/well) or in 6-well plates at a density of 2×10 5 cells/ml (2 ml/well) were divided into 5 groups( n=30 each) using a random number table method: control group (group C), hydrogen-rich group (group H), group H/R, H/R plus hydrogen-rich saline group (group H/R+ H) and H/R plus hydrogen-rich saline plus Akt inhibitor uprosertib group (group H/R+ H+ U) .In group C, the cells were incubated for 28 h in an incubator filled with normoxia at 37 ℃ (5%CO 2-21%O 2-74%N 2). In group H, cells were added to the medium containing 0.6 mmol/L hydrogen-rich saline, and then incubated for 28 h in an incubator filled with normoxia at 37 ℃.In group H/R, the cells were incubated in an anaerobic chamber (37 ℃, 5%CO 2-1%O 2-94 %N 2) for 24 h, and then incubated for 4 h in an incubator filled with normoxia at 37 ℃.In group H/R+ H, the cells were incubated in an anaerobic chamber for 24 h, and then incubated for 4 h in an incubator containing 0.6 mmol/L filled with normoxia at 37 ℃.In group H/R+ H+ U, the cells were incubated for 1 h in the culture medium containing uprosertib 10 μmol/L (final concentration) and the other treatments were similar to those previously described in group H/R+ H. After treatment in each group, the cell viability was measured by MTT assay, cell apoptosis was measured using flow cytometry, superoxide dismutase (SOD) activity was measured using xanthine oxidase method), malondialdehyde (MDA) content was detected by thiobarbituric acid method, the expression of Akt, phosphorylated Akt (p-Akt), total Nrf2, nuclear Nrf2 and activated caspase-3 was detected by Western blot, and the expression of Nrf2 mRNA was detected by Real-time PCR. Results:Compared with group C, the cell viability and activity of SOD were significantly decreased, the apoptosis rate and content of MDA were increased, and the expression of p-Akt, nuclear Nrf2, total Nrf2, activated caspase-3 protein and Nrf2 mRNA was up-regulated in group H/R and group H/R+ H ( P<0.05). Compared with group H/R, the cell viability and activity of SOD were significantly increased, the apoptosis rate and content of MDA were decreased, the expression of p-Akt, nuclear Nrf2, total Nrf2 and Nrf2 mRNA was up-regulated and expression of activated caspase-3 protein was down-regulated in group H/R+ H ( P<0.05). Compared with group H/R+ H, the cell viability and activity of SOD was significantly decreased, the apoptosis rate and content of MDA were increased, the expression of p-Akt, nuclear Nrf2, total Nrf2 protein and Nrf2m RNA was down-regulated, and the expression of activated caspase-3 protein was up-regulated in group H/R+ H+ U ( P<0.05). Conclusion:The mechanism by which hydrogen-rich saline attenuates H/R injury to human renal tubular epithelial cells is related to improving activation of Akt/Nrf2 signaling pathway, decreasing oxidative stress response and inhibiting cell apoptosis.
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Objective:To compare aging models for renal tubular epithelial cells induced by different drugs.Methods:Different concentrations of D-galactose(D-gal), hydrogen peroxide(H 2O 2)and cisplatin(CDDP)were administered to the human proximal tubular epithelial cell line(HK2). Cell activity and the half maximal inhibitory concentration(IC50)were measured by the CCK-8 assay; cell senescence was assessed by senescence-related β-galactosidase staining(SA-β-gal); senescence-related gene expression was detected by Western blotting; cell cycle distribution and apoptosis were determined by flow cytometry.Pathological changes in renal tubules and interstitial tissues were examined in D-gal-induced and naturally aging mice using HE staining, and p16 expression was detected using immunohistochemistry. Results:CCK-8 assay results showed that HK2 cell activity was inhibited treatment with each of the three compounds.The 48-hour IC50 values were(365.8±9.7)mmol/L for D-gal, (385.4±20.8)μmol/L for H 2O 2 and(8.4±1.6)μmol/L for CDDP.Light microscopic observation revealed slowed growth of HK2 cells in the three groups.The rate of SA-β-gal-positive cells increased, compared with the control group( P<0.05). Treatment resulted in an increase in G0/G1 phase cells by(22.9±1.0)% in the 400 mmol/L D-gal group and by(13.0±4.4)% in the 400 μmol/L H 2O 2 group, while G2/M phase cells increased by(14.4±1.9)%( t=48.07, 6.40, 16.53, P<0.05)in the 8 μmol/L CDDP group, compared with the control group.Also, compared with the control group, HK2 cell apoptosis increased by(50.3±1.0)% in the 400 μmol/L H 2O 2 group and by(41.9±2.0)% in the 8 μmol/L CDDP group, which was significantly higher than(7.7±0.4)% in the 400 mmol/L D-gal group( t=77.47, 33.73, 28.35, all P<0.05). Western blotting results indicated that the expression of CCND1 was down-regulated after any of the three drugs reached a certain concentration.The expression of p16 in the D-gal group was up-regulated( F=92.88, P<0.05), but there was no statistical difference in the expression of p16 after H 2O 2 or CDDP treatment.Mice of the D-gal model showed a decline in renal tubular cells, thickened basement membrane, widened interstitial spaces and increased expression of p16 in renal tubules similar to those observed in naturally aging mice. Conclusions:For HK2 cell senescence models induced by three different drugs, the renal tubular epithelial cell senescence model induced by D-gal is relatively close to the natural senescence model.
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The kidney plays a key role in hepatitis B virus (HBV) infection of liver cells. The pathogenesis of HBV-associated glomerulonephritis (HBV-GN) remains unclear, and the mechanism of HBV directly causing the injury of renal tubules has been taken seriously in recent years. HBV can induce the apoptosis of renal tubular cells by regulating cell cycle and activating related signaling pathways including NF-κB and thus lead to the progression of HBV-GN. At present, there are still no drugs targeting the kidney in the treatment of HBV-GN. This article summarizes the research advances in the key factors for HBV infection of cells and the injury of renal tubular cells caused by HBV and elaborates on the possible mechanism of direct infection of renal tubular cells by HBV, so as to provide new ideas for the treatment of HBV-GN.
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Resumen La acidosis tubular renal distal es causada por un defecto en la excreción de iones de hidrogeno a nivel tubular distal, lo que aumenta el pH de la orina y disminuye el pH plasmático; esta es una enfermedad con varias manifestaciones clínicas asociadas. En este artículo se hace una revisión profunda sobre la acidosis tubular renal distal y se presenta el caso de tres hermanos (dos hombres y una mujer) con la entidad, siendo este uno de los primeros casos familiares reportados en Colombia. Los tres pacientes recibieron el diagnóstico durante el período de lactancia, presentaron nefrocalcinosis y tuvieron buena respuesta a la terapia con álcali iniciada de forma temprana, logrando eventualmente su suspensión. De manera curiosa, uno de los pacientes también presentó deficiencia de mevalonato quinasa con hiperinmunoglobulinemia D, una alteración no descrita con anterioridad. Esta asociación y la aparente falta de necesidad de continuar el manejo con álcali son atípicas a la luz del conocimiento actual, mereciendo especial consideración.
Abstract The distal renal tubular acidosis presents due to a defect in the excretion of hydrogen ions at the distal tubular level, causing an increase in the pH of the urine and a decrease in the plasma pH, with several associated clinical manifestations. This article makes a thorough review of distal renal tubular acidosis and presents the case of three siblings with the entity, two men and one woman, this being one of the first family cases reported in Colombia. All three received the diagnosis during the lactation period, presented nephrocalcinosis and good response to the alkali therapy started early, eventually achieving their suspension. Interestingly, one of them also presented deficiency mevalonate-kinase with hiperinmunoglobulinemia D, alteration not previously described. This association and the apparent lack of need for continued management with alkali are atypical in the light of current knowledge, deserving special consideration.
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Humans , Male , Female , Acidosis, Renal Tubular , Patients , Colombia , Siblings , Genetics , NephrocalcinosisABSTRACT
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.
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Humans , Drug-Related Side Effects and Adverse Reactions , Acute Kidney Injury/chemically induced , Risk Factors , Acute Kidney Injury/epidemiology , Nephrotic Syndrome/chemically induced , Nephrotic Syndrome/epidemiologyABSTRACT
Objective@#To clarify the relationship between the hemoglobin level and renal tubular atrophy/interstitial fibrosis (T) in the Oxford stage of renal pathology in IgA nephropathy (IgAN) patients.@*Methods@#Patients diagnosed with IgAN by renal biopsy from January 1st 2010 to December 31st 2015 in Shenzhen Second People's Hospital with complete laboratory and imaging data were retrospectively analyzed. Patients were divided into anemic group and non-anemic group. The relationship between hemoglobin level and renal tubular atrophy/interstitial fibrosis was determined by logistic regression analysis. The possible curve relationship between hemoglobin and renal tubular atrophy/interstitial fibrosis was analyzed by smooth curve fitting analysis. The diagnostic value of hemoglobin for renal tubular atrophy/interstitial fibrosis was analyzed by the receiver operating curve (ROC).@*Results@#A total of 630 patients with IgAN were included in this study, 130 patients in the anemia group (20.63%) and 500 patients in the non-anemia group (79.37%). There was no statistically significant difference in age between the two groups, but the difference of the gender was statistically significant (male 35.38% vs 53.80%, χ2=10.740, P<0.001). Compared with the non-anemia group, the anemia group had a higher proportion of tubular atrophy/interstitial fibrosis (χ2=62.586, P<0.001), higher 24 h urinary protein quantification (Z=-6.082, P<0.001), and lower eGFR (t=7.126, P<0.001). Multivariate logistic regression analysis showed that increasing hemoglobin level was an independent protective factor for reducing the risk of renal tubular atrophy/interstitial fibrosis (OR=0.973, 95%CI 0.958-0.987, P<0.001). Smooth curve fitting analysis showed that there was a linear negative correlation between hemoglobin and tubular atrophy/interstitial fibrosis. The ROC curve suggested that the best threshold of hemoglobin was 120.5 g/L when renal tubular atrophy/interstitial fibrosis occurred. That was, when hemoglobin was above 120.5 g/L, the severity level of renal tubular atrophy interstitial fibrosis might be reduced.@*Conclusion@#The incidence of renal tubular atrophy/interstitial fibrosis is higher in IgAN patients with anemia, and hemoglobin>120.5 g/L may reduce the risk of tubular atrophy/interstitial fibrosis.
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Objective@#To investigate the effects of insulin-like growth factor 1 receptor (IGF-1R) inhibitor on tubulopathy in diabetic kidney disease (DKD) mice.@*Methods@#C57BL/6J male mice were randomly divided into normal control group (n=10) and DKD model group (n=30), by giving a single intraperitoneal injection of STZ 150 mg/kg to establish a DKD model. After established successfully, the mice in DKD model group were randomly divided into DKD group (n=10), benazepril group (n=10) and IGF-1R inhibitor group (n=10). IGF-1R inhibitor group was given intraperitoneal injection of IGF-1R inhibitor (30 mg·kg-1·d-1) and benazepril group was given intraperitoneal injection of benazepril (30 mg·kg-1·d-1). Normal control group and DKD group were given an equal amount of normal saline. After 8 weeks of feeding, mice were euthanatized. Body weight and kidney weight were recorded. Blood, urine and kidney samples were collected. Biochemical tests such as blood glucose and urine albumin were measured by automatic biochemical instruments and albumin excretion rate was calculated. Pathological changes of mice were observed by hematoxylin-eosin staining (HE) and periodic acid-schiff staining (PAS). Phosph (p) IGF-1R expression level was determined by immunohistochemistry and Western blotting.@*Results@#Compared with the normal control group, blood glucose, kidney weight/body weight and urinary albumin excretion rate were significantly higher in DKD group (all P<0.01). In DKD mice, glomerular expansion, tubular stenosis, tubular swelling and tubular atrophy were significantly detected. Meanwhile, the number of proximal tubular epithelial (PTE) cells was decreased, and the renal tubular injury scores, the average glomerular volume, and pIGF-1R protein expression were increased (all P<0.05). Compared with the DKD group, albumin excretion rate was significantly reduced (P<0.01), the above pathological changes were alleviated and the effect of IGF-1R inhibitor was more significant. Compared with the DKD group, the pIGF-1R protein expression was reduced in IGF-1R inhibitor group (P<0.05). Compared with the benazepril group, the pIGF-1R protein expression was reduced in IGF-1R inhibitor group (P<0.05).@*Conclusion@#IGF-1R inhibitor has better effect than benazepril on alleviating the tubulopathy of DKD mice.
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Drugs are a common cause of acute and chronic kidney disease and contribute to patient morbidity and increased healthcare utilization. Drug-induced nephrotoxicity is approximately 14% to 26% in adults and tends to increase among certain patients and/or with complex clinical conditions. Unfortunately, apart from conservative management, including drug withdrawal, no effective treatment is known for this condition. Therefore, in order to reduce the frequency of drug-induced nephrotoxicity, early recognition of renal toxicity and appropriate prevention strategies, such as understanding the exact mechanisms of renal injury, patient and drug-related risk factors, and preemptive measures are needed. In this review, we will present the mechanisms of drug-induced nephrotoxicity and general preventive strategies for clinical physicians.
Subject(s)
Adult , Humans , Delivery of Health Care , Kidney Tubules , Pharmaceutical Preparations , Renal Insufficiency , Renal Insufficiency, Chronic , Risk FactorsABSTRACT
Objective To investigate the effects of insulin-like growth factor 1 receptor (IGF-1R) inhibitor on tubulopathy in diabetic kidney disease (DKD) mice.Methods C57BL/6J male mice were randomly divided into normal control group (n=10) and DKD model group (n=30),by giving a single intraperitoneal injection of STZ 150 mg/kg to establish a DKD model.After established successfully,the mice in DKD model group were randomly divided into DKD group (n=10),benazepril group (n=10) and IGF-1R inhibitor group (n=10).IGF-1R inhibitor group was given intraperitoneal injection of IGF-1R inhibitor (30 mg· kg-1· d-1) and benazepril group was given intraperitoneal injection of benazepril (30 mg· kg-1· d-1).Normal control group and DKD group were given an equal amount of normal saline.After 8 weeks of feeding,mice were euthanatized.Body weight and kidney weight were recorded.Blood,urine and kidney samples were collected.Biochemical tests such as blood glucose and urine albumin were measured by automatic biochemical instruments and albumin excretion rate was calculated.Pathological changes of mice were observed by hematoxylin-eosin staining (HE) and periodic acid-schiff staining (PAS).Phosph (p) IGF-1R expression level was determined by immunohistochemistry and Western blotting.Results Compared with the normal control group,blood glucose,kidney weight/body weight and urinary albumin excretion rate were significantly higher in DKD group (all P ＜ 0.01).In DKD mice,glomerular expansion,tubular stenosis,tubular swelling and tubular atrophy were significantly detected.Meanwhile,the number of proximal tubular epithelial (PTE) cells was decreased,and the renal tubular injury scores,the average glomerular volume,and plGF-1R protein expression were increased (all P ＜ 0.05).Compared with the DKD group,albumin excretion rate was significantly reduced (P ＜ 0.01),the above pathological changes were alleviated and the effect of IGF-1R inhibitor was more significant.Compared with the DKD group,the pIGF-1R protein expression was reduced in IGF-1R inhibitor group (P ＜ 0.05).Compared with the benazepril group,the pIGF-1R protein expression was reduced in IGF-1R inhibitor group (P ＜ 0.05).Conclusion IGF-1R inhibitor has better effect than benazepril on alleviating the tubulopathy of DKD mice.
ABSTRACT
Objective To evaluate the effect of resveratrol on mitochondrial function in renal tubular epithelial cells of rats with sepsis-induced acute kidney injury.Methods Ninety-six healthy SpragueDawley rats of both sexes,aged 5-7 weeks,weighing 180-220 g,were divided into 4 groups (n =24 each) using a random number table method:sham operation group (Sham group),sepsis group (group Sep),sepsis plus vehicle group (Sep+Ⅴ group) and sepsis plus resveratrol group (Sep+R group).Sepsis was induced by cecal ligation and puncture (CLP).Normal saline 0.5 ml,vehicle 0.5 ml and resveratrol 10 mg/kg were intraperitoneally injected at 6,12 and 18 h after CLP in Sep,Sep+Ⅴ and Sep+R groups,respectively.At 24 h after CLP,serum concentrations of creatinine (Cr) and blood urea nitrogen (BUN) were measured,and kidney tissues were obtained for examination of the pathological changes (using transmission electron microscopy),and the damage to the renal tubules was scored.The renal tubular epithelial cells (RTECs) were isolated from the kidney cortex at 24 h after CLP for determination of mitochondrial transmembrane potential (by flow cytometry with the fluorescent probe JC-1),intracellular ATP content,mitochondrial permeability transition pore (mPTP) opening,lipid peroxide (LPO) content,and lysosomal membrane permeability.Results Compared with group Sham,the serum concentrations of Cr and BUN,renal tubular damage score,mPTP opening,LPO content and lysosomal membrane permeability were significantly increased,and mitochondrial transmembrane potential and ATP content were decreased in Sep and Sep+Ⅴ groups (P＜0.01).Compared with Sep and Sep+Ⅴ groups,the serum concentrations of Cr and BUN,renal tubular damage score,mPTP opening,LPO content and lysosomal membrane permeability were significantly decreased,and mitochondrial transmembrane potential and ATP content were increased in group Sep+R (P＜0.05).Conclusion Resveratrol improves mitochondrial function in renal tubular epithelial cells of rats with sepsis and reduces acute kidney injury,and the mechanism may be related to inhibiting oxidative stress and decreasing the lysosomal membrane permeability.
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Objective To investigate effects of albumin overload on mitochondrial membrane potential and ultrastructural changes in renal tubular epithelial cells (HK-2).Methods Vitrocultured HK-2 cells were treated with different concentrations of albumin.The mitochondrial membrane potential in HK-2 cells was detected by fluorescence probe JC-1,and the electron microscopy was used to detect the mitochondrial ultrastructure of cells.Results JC-1-detected red/green ratio was 2.34 ± 0.21 at 0 g/L of albumin treatment,0.83 ± 0.09 at 4 g/L,0.41 ± 0.07 at 8 g/L,0.38± 0.08 at 16 g/L albumin overload,which showed a gradually decreased red and green fluorescence intensity ratio along with increased albumin overload(F =162.794,P ＜0.001),and with significant differences in the ratio among groups (all P ＜ 0.05).Albumin overload-induced mitochondrial abnormality in transmission electron microscope included mitochondrial swelling,disordered cristae arrangement,cristae lysis and cavitation,and the increase of bilayer membrane structures in HK-2 cells.Conclusions Albumin overload can induce the decline of mitochondrial membrane potential,mitochondrial damage and autophagy in renal tubular epithelial cells,which suggest that mitochondrial damage and autophagy may be one of the mechanisms of albumin overloadinduced renal tubular epithelial cell injury.
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Objective@#To study the pathological features, immunophenotypes, differential diagnoses and prognostic parameters of collecting duct carcinoma of the kidney (CDC).@*Methods@#Clinical imaging, histopathology, immunohistochemistry, and survival data of 10 patients at First Affiliated Hospital of Nanjing Medical University from January 2009 to August 2017 were retrospectively analyzed along with a review of literatures.@*Results@#The clinical symptoms of CDC were not specific, and image examinations showed space-occupying mass lesions. Tumors were mainly located in renal medulla with grey and firm cut face and the presence of focal hemorrhage and necrosis. Microscopically, there were predominant tubular or tubular-papillary structures with associated focal sarcomatoid areas, desmoplastic stromal reaction and lymphoplasmacytic cells infiltration. Tumor cells had marked cytological atypia with high grade nuclei, conspicuous nucleolus and numerous mitoses. Immunohistochemically, tumor cells were strongly positive for CK19, E-cadherin, vimentin, HCK, CK7 and PAX8. The main treatment was radical nephrectomy in the patients. Seven cases died of CDC with median survival of 10 months.@*Conclusions@#CDC is a rare, highly aggressive malignancy of kidney with poor prognosis. Definitive diagnosis should be made by histology and immunohistochemistry. Differential diagnoses include papillary renal cell carcinoma(type Ⅱ), renal medullary carcinoma, infiltrating high grade urothelial carcinoma, renal pelvis adenocarcinoma and metastatic adenocarcinomas.