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Objective: To investigate the clinicopathological features of renal leukocyte chemokine type 2 amyloidosis (ALECT2). Methods: The prevalence, clinical characteristics, renal histopathological features, and renal outcome of 15 patients with ALECT2 by kidney biopsy were collected in the Department of Kidney Pathology, Shanxi Medical University Second Hospital, Taiyuan, China from January 1993 to December 2023. Immunohistochemistry and mass spectrometry for amyloid proteins were carried out. Results: Fifteen patients with ALECT2 were included in the study, representing 12.93% (15/116) of the renal biopsy-proven amyloidosis cases. There were 5 males and 10 females. The median age at diagnosis was 61 years. All patients had various degrees of proteinuria; 7 patients had nephrotic syndrome; 3 patients had renal insufficiency; 7 patients had microscopic hematuria. Renal biopsy showed that strongly orangophilic amyloid proteins distributed mainly in the renal cortical interstitium, vascular walls, the glomerular mesangium and/or glomerular basement membrane. Eight cases were diagnosed with ALECT2 alone and 7 cases combined with other renal diseases, including 4 cases with membranous nephropathy, 2 cases with IgA nephropathy, and 1 case with subacute tubular interstitial nephropathy. ALECT2 patients with concurrent renal disease showed a higher proteinuria level than those without (3.48 g/24 h versus 4.58 g/24 h). All patients were corroborated by immunohistochemistry to exhibit the specific location of LECT2 in the amyloid fibrils. Mass spectrometry analysis revealed LECT2 polypeptide in 9 patients. Except two patients with worsening renal function, the others showed stable renal function during the mean follow-up period of 12.5 months. Conclusions: ALECT2 is the second common type of renal amyloidosis in our center. The majority of ALECT2 patients show concurrent renal diseases, with a high rate of membranous nephropathy. Amyloid deposits distribute mainly in the cortical interstitium of the kidney, the glomerular mesangium and vascular walls. Mass spectrometry is the most sensitive and specific method for detecting LECT2 amyloidosis.
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Amiloidosis , Enfermedades Renales , Riñón , Síndrome Nefrótico , Humanos , Masculino , Amiloidosis/metabolismo , Amiloidosis/patología , Amiloidosis/diagnóstico , Femenino , Persona de Mediana Edad , Síndrome Nefrótico/metabolismo , Síndrome Nefrótico/patología , Riñón/patología , Enfermedades Renales/patología , Enfermedades Renales/metabolismo , Proteinuria , Biopsia , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Glomerulonefritis Membranosa/patología , Glomerulonefritis Membranosa/metabolismo , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/metabolismo , Anciano , Hematuria/etiología , Insuficiencia Renal/metabolismoRESUMEN
Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of ß-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.
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Calcimiméticos , Calcitriol , Osteoblastos , Hormona Paratiroidea , Animales , Calcitriol/farmacología , Ratas , Calcimiméticos/farmacología , Calcimiméticos/uso terapéutico , Hormona Paratiroidea/farmacología , Masculino , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/metabolismo , Huesos/metabolismo , Huesos/efectos de los fármacos , Ratas Wistar , Insuficiencia Renal/tratamiento farmacológico , Insuficiencia Renal/metabolismo , Osteogénesis/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/complicaciones , Diferenciación Celular/efectos de los fármacos , Calcio/metabolismoRESUMEN
OBJECTIVE: There is limited information on favipiravir pharmacokinetics in critically ill patients and no studies on pharmacokinetics in patients with moderate and severe kidney dysfunction. The aim was to determine favipiravir pharmacokinetics (oral, 1,600 mg, q12h on day 1, then 600 mg, q12h for 4 days) in critically ill COVID-19 patients with kidney dysfunction and to compare those with observations reported in healthy adults. MATERIALS AND METHODS: In a descriptive study, blood samples taken from patients meeting the relevant criteria (estimated glomerular filtration rate < 60 mL/min) were collected and analyzed. Analysis of blood samples was done by high performance liquid chromatography (HPLC), and the maximal concentration (Cmax), the time of maximal concentration (tmax), half-life (T1/2) and area under the curve (AUC0-12h) of favipiravir were calculated (WinNonlin) and compared to reported data in healthy subjects after first administration. RESULTS: Based on analysis of samples collected in 7 patients, the Cmax (29.99 vs. 64.5 µg/mL) of favipiravir was decreased, T1/2 (5.8 vs. 4.8 hours) longer, tmax delayed, while total exposure was lower (AUC0-12: 192.53 vs. 446.09 µg/mL) compared to reported data in healthy subjects after first administration. Exposure remained lower up to day 5. CONCLUSION: In patients with kidney dysfunction related to COVID-19, favipiravir did not reach the expected exposure. This may be due to poorer and delayed absorption, and subsequent altered disposition. Population pharmacokinetic and mechanistic studies are needed to better explore the relevant covariates and to determine the optimal dose in these patients, as this drug is likely of relevance for other indications.
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Amidas , Antivirales , Tratamiento Farmacológico de COVID-19 , Pirazinas , Humanos , Amidas/farmacocinética , Pirazinas/farmacocinética , Pirazinas/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , Anciano , Antivirales/farmacocinética , Antivirales/administración & dosificación , Enfermedad Crítica , Semivida , COVID-19/complicaciones , Área Bajo la Curva , Adulto , SARS-CoV-2 , Tasa de Filtración Glomerular , Insuficiencia Renal/metabolismo , Insuficiencia Renal/complicaciones , Índice de Severidad de la EnfermedadRESUMEN
The recruitment of a parallel, healthy participants (HPs) arm in renal and hepatic impairment (RI and HI) studies is a common strategy to assess differences in pharmacokinetics. Limitations in this approach include the underpowered estimate of exposure differences and the use of the drug in a population for which there is no benefit. Recently, a method was published by Purohit et. al. (2023) that leveraged prior population pharmacokinetic (PopPK) modeling-based simulation to infer the distribution of exposure ratios between the RI/HI arms and HPs. The approach was successful, but it was a single example with a robust model having several iterations of development and fitting to extensive HP data. To test in more studies and models at different stages of development, our catalogue of RI/HI studies was searched, and those with suitable properties and from programs with available models were analyzed with the simulation approach. There were 9 studies included in the analysis. Most studies were associated with models that would have been available at the time (ATT) of the study, and all had a current, final model. For 3 studies, the HP PK was not predicted well by the ATT (2) or final (1) models. In comparison to conventional analysis of variance (ANOVA), the simulation approach provided similar point estimates and confidence intervals of exposure ratios. This PopPK based approach can be considered as a method of choice in situations where the simulation of HP data would not be an extrapolation, and when no other complicating factors are present.
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Simulación por Computador , Voluntarios Sanos , Modelos Biológicos , Humanos , Estudios Retrospectivos , Farmacocinética , Hepatopatías/metabolismo , Enfermedades Renales , Preparaciones Farmacéuticas/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Insuficiencia Renal/metabolismoRESUMEN
Precision dosing strategies require accounting for between-patient variability in pharmacokinetics (PK), affecting drug exposure, and in pharmacodynamics (PD), affecting response achieved at the same drug concentration at the site of action. Although liquid biopsy for assessing different levels of molecular drug targets has yet to be established, individual characterization of drug elimination pathways using liquid biopsy has recently been demonstrated. The feasibility of applying this approach in conjunction with modeling tools to guide individual dosing remains unexplored. In this study, we aimed to individualize physiologically-based pharmacokinetic (PBPK) models based on liquid biopsy measurements in plasma from 25 donors with different grades of renal function who were previously administered oral midazolam as part of a microdose cocktail. Virtual twin models were constructed based on demographics, renal function, and hepatic expression of relevant pharmacokinetic pathways projected from liquid biopsy output. Simulated exposure (AUC) to midazolam was in agreement with observed data (AFE = 1.38, AAFE = 1.78). Simulated AUC variability with three dosing approaches indicated higher variability with uniform dosing (14-fold) and stratified dosing (13-fold) compared with individualized dosing informed by liquid biopsy (fivefold). Further, exosome screening revealed mRNA expression of 532 targets relevant to drug metabolism and disposition (169 enzymes and 361 transporters). Data related to these targets can be used to further individualize PBPK models for pathways relevant to PK of other drugs. This study provides additional verification of liquid biopsy-informed PBPK modeling approaches, necessary to advance strategies that seek to achieve precise dosing from the start of treatment.
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Hígado , Midazolam , Modelos Biológicos , Prueba de Estudio Conceptual , Humanos , Midazolam/farmacocinética , Midazolam/administración & dosificación , Masculino , Femenino , Biopsia Líquida/métodos , Hígado/metabolismo , Persona de Mediana Edad , Anciano , Insuficiencia Renal/metabolismo , Adulto , Área Bajo la Curva , Exosomas/metabolismo , Medicina de Precisión/métodosRESUMEN
OBJECTIVES: To establish a rat model that accurately replicates the clinical characteristics of male infertility (MI) with Liver Depression and Kidney Deficiency (LD & KD) and investigate the pathogenesis. METHODS: After subjecting the rats to chronic restraint stress (CRS) and adenine treatment, a series of tests were conducted, including ethological assessments, evaluations of reproductive characteristics, measurements of biochemical parameters, histopathological examinations, and analyses of urinary metabolites. Additionally, bioinformatics predictions were performed for comprehensive analysis. RESULTS: Compared to the control, the model exhibited significant manifestations of MI with LD & KD, including reduced responsiveness, diminished frequency of capturing estrous female rats, and absence of mounting behavior. Additionally, the kidney coefficient increased markedly, while the coefficients of the testis and epididymis decreased significantly. Sperm counts and viabilities decreased notably, accompanied by an increase in sperm abnormalities. Dysregulation of reproductive hormone levels in the serum was observed, accompanied by an upregulation of proinflammatory cytokines expressions in the liver and kidney, as well as exacerbated oxidative stress in the penile corpus cavernosum and testis. The seminiferous tubules in the testis exhibited a loose arrangement, loss of germ cells, and infiltration of inflammatory cells. Furthermore, utilizing urinary metabolomics and bioinformatics analysis, 5 key biomarkers and 2 crucial targets most closely linked to MI were revealed. CONCLUSION: The study successfully established a clinically relevant animal model of MI with LD & KD. It elucidates the pathogenesis of the condition, identifies key biomarkers and targets, and provides a robust scientific foundation for the prediction, diagnosis, and treatment of MI with LD & KD.
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Biomarcadores , Modelos Animales de Enfermedad , Infertilidad Masculina , Animales , Masculino , Ratas , Biomarcadores/metabolismo , Infertilidad Masculina/metabolismo , Infertilidad Masculina/etiología , Testículo/metabolismo , Testículo/patología , Riñón/metabolismo , Riñón/patología , Ratas Sprague-Dawley , Hígado/metabolismo , Hígado/patología , Estrés Oxidativo , Hepatopatías/metabolismo , Hepatopatías/patología , Insuficiencia Renal/metabolismo , Insuficiencia Renal/patología , Insuficiencia Renal/etiologíaRESUMEN
One of the key pharmacokinetic properties of most small molecule drugs is their ability to bind to serum proteins. Unbound or free drug is responsible for pharmacological activity while the balance between free and bound drug can impact drug distribution, elimination, and other safety parameters. In the hepatic impairment (HI) and renal impairment (RI) clinical studies, unbound drug concentration is often assessed; however, the relevance and impact of the protein binding (PB) results is largely limited. We analyzed published clinical safety and pharmacokinetic studies in subjects with HI or RI with PB assessment up to October 2022 and summarized the contribution of PB results on their label dose recommendations. Among drugs with HI publication, 32% (17/53) associated product labels include PB results in HI section. Of these, the majority (9/17, 53%) recommend dose adjustments consistent with observed PB change. Among drugs with RI publication, 27% (12/44) of associated product labels include PB results in RI section with the majority (7/12, 58%) recommending no dose adjustment, consistent with the reported absence of PB change. PB results were found to be consistent with a tailored dose recommendation in 53% and 58% of the approved labels for HI and RI section, respectively. We further discussed the interpretation challenges of PB results, explored treatment decision factors including total drug concentration, exposure-response relationships, and safety considerations in these case examples. Collectively, comprehending the alterations in free drug levels in HI and RI informs treatment decision through a risk-based approach.
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Etiquetado de Medicamentos , Unión Proteica , Humanos , Insuficiencia Renal/metabolismo , Relación Dosis-Respuesta a Droga , Preparaciones Farmacéuticas/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Hepatopatías/metabolismo , Hepatopatías/tratamiento farmacológico , Proteínas Sanguíneas/metabolismo , Cálculo de Dosificación de DrogasRESUMEN
This study observed the effects of Notoginseng Radix et Rhizoma on the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin complex 1(mTORC1) signaling pathway and mitochondrial energy metabolism in the rat model of adriamycin-induced renal fibrosis with blood stasis syndrome to explore the mechanism of Notoginseng Radix et Rhizoma in protecting the kidney. Thirty male rats with adriamycin-induced renal fibrosis were randomized into model, low-, medium-, and high-dose Notoginseng Radix et Rhizoma, and positive control groups(n=6). Six clean SD male rats were selected into the normal group. The normal group and model group were administrated with normal saline, and other groups with corresponding drugs. After 8 weeks of treatment, the renal function, renal pathology, adenosine triphosphate(ATP) levels, Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase activities, and the protein levels of ATP5B, mTORC1, 70 kDa ribosomal protein S6 kinase(P70S6K), P85, Akt, p-Akt, and SH2-containing inositol phosphatase(SHIP2) in the renal tissue were determined. Compared with the normal group, the model group showed elevated levels of blood urea nitrogen(BUN) and serum creatinine(SCr)(P<0.01). Compared with the model group, Notoginseng Radix et Rhizoma and the positive control lowered the levels of BUN and SCr, which were significant in the medium-and high-dose Noto-ginseng Radix et Rhizoma groups and the positive control group(P<0.05). Compared with the model group, Notoginseng Radix et Rhizoma and the positive control alleviated the pathological changes in the renal tissue, such as vacuolar and fibroid changes, glomerulus atrophy, cystic expansion of renal tubules, and massive infiltration of inflammatory cells. Compared with the normal group, the model group showed decreased mitochondrial ATP content and Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase activities in the renal tissue(P<0.05), and medium-and high-dose Notoginseng Radix et Rhizoma and positive control mitigated such decreases(P<0.05). Compared with the model group, medium-and high-dose Notoginseng Radix et Rhizoma and the positive control up-regulated the protein levels of ATP5B and SHIP2 and down-regulated the protein levels of mTORC1, P70S6K, P85, Akt, and p-Akt(P<0.05 or P<0.01 or P<0.001). Notoginseng Radix et Rhizoma may exert an anti-fibrosis effect by inhibiting the activation of the PI3K/Akt/mTORC1 pathway to restore mitochondrial energy metabolism, thus protecting the kidney.
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Medicamentos Herbarios Chinos , Metabolismo Energético , Diana Mecanicista del Complejo 1 de la Rapamicina , Mitocondrias , Panax notoginseng , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Animales , Masculino , Ratas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Panax notoginseng/química , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Metabolismo Energético/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Rizoma/química , Humanos , Transducción de Señal/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Insuficiencia Renal/tratamiento farmacológico , Insuficiencia Renal/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Icodec is a once-weekly insulin being developed to provide basal insulin coverage in diabetes mellitus. This study evaluated the effects of renal or hepatic impairment on icodec pharmacokinetics. METHODS: Two open-label, parallel-group, single-dose (1.5 U/kg subcutaneously) trials were conducted. In a renal impairment trial, 58 individuals were allocated to normal renal function (measured glomerular filtration rate ≥ 90 mL/min), mild (60 to < 90 mL/min), moderate (30 to < 60 mL/min) or severe (< 30 mL/min) renal impairment or end-stage renal disease. In a hepatic impairment trial, 25 individuals were allocated to normal hepatic function or mild (Child-Pugh Classification grade A), moderate (grade B) or severe (grade C) hepatic impairment. Blood was sampled frequently for a pharmacokinetic analysis until 35 days post-dose. RESULTS: The shape of the icodec pharmacokinetic profile was not affected by renal or hepatic impairment. Total icodec exposure was greater for mild (estimated ratio [95% confidence interval]: 1.12 [1.01; 1.24]), moderate (1.24 [1.12; 1.37]) and severe (1.28 [1.16; 1.42]) renal impairment, and for end-stage renal disease (1.14 [1.03; 1.28]), compared with normal renal function. It was also greater for mild (1.13 [1.00; 1.28]) and moderate (1.15 [1.02; 1.29]) hepatic impairment versus normal hepatic function. There was no statistically significant difference between severe hepatic impairment and normal hepatic function. Serum albumin levels (range 2.7-5.1 g/dL) did not statistically significantly influence icodec exposure. CONCLUSIONS: The clinical relevance of the slightly higher icodec exposure with renal or hepatic impairment is limited as icodec should be dosed according to individual need. No specific icodec dose adjustment is required in renal or hepatic impairment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03723785 and NCT04597697.
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Hipoglucemiantes , Humanos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Adulto , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/administración & dosificación , Hepatopatías/metabolismo , Insulina de Acción Prolongada/farmacocinética , Insulina de Acción Prolongada/administración & dosificación , Tasa de Filtración Glomerular , Esquema de Medicación , Insuficiencia Renal/metabolismoRESUMEN
ZFYVE21 is an ancient, endosome-associated protein that is highly expressed in endothelial cells (ECs) but whose function(s) in vivo are undefined. Here, we identified ZFYVE21 as an essential regulator of vascular barrier function in the aging kidney. ZFYVE21 levels significantly decline in ECs in aged human and mouse kidneys. To investigate attendant effects, we generated EC-specific Zfyve21-/- reporter mice. These knockout mice developed accelerated aging phenotypes including reduced endothelial nitric oxide (ENOS) activity, failure to thrive, and kidney insufficiency. Kidneys from Zfyve21 EC-/- mice showed interstitial edema and glomerular EC injury. ZFYVE21-mediated phenotypes were not programmed developmentally as loss of ZFYVE21 in ECs during adulthood phenocopied its loss prenatally, and a nitric oxide donor normalized kidney function in adult hosts. Using live cell imaging and human kidney organ cultures, we found that in a GTPase Rab5- and protein kinase Akt-dependent manner, ZFYVE21 reduced vesicular levels of inhibitory caveolin-1 and promoted transfer of Golgi-derived ENOS to a perinuclear Rab5+ vesicular population to functionally sustain ENOS activity. Thus, our work defines a ZFYVE21- mediated trafficking mechanism sustaining ENOS activity and demonstrates the relevance of this pathway for maintaining kidney function with aging.
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Envejecimiento , Caveolina 1 , Células Endoteliales , Riñón , Óxido Nítrico Sintasa de Tipo III , Óxido Nítrico , Transducción de Señal , Animales , Humanos , Masculino , Ratones , Envejecimiento/metabolismo , Envejecimiento/fisiología , Caveolina 1/metabolismo , Caveolina 1/genética , Células Endoteliales/metabolismo , Aparato de Golgi/metabolismo , Riñón/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Fenotipo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas de Unión al GTP rab5/metabolismo , Proteínas de Unión al GTP rab5/genética , Insuficiencia Renal/metabolismo , Insuficiencia Renal/fisiopatología , Insuficiencia Renal/genéticaRESUMEN
Dersimelagon is an orally administered selective melanocortin-1 receptor agonist being investigated for treatment of erythropoietic protoporphyria, X-linked protoporphyria, and diffuse cutaneous systemic sclerosis. Dersimelagon is extensively metabolized in the liver, and potential recipients may have liver dysfunction. Further, effects of renal impairment on pharmacokinetic properties should be established in drugs intended for chronic use. Two separate studies (ClinicalTrials.gov: NCT04116476; NCT04656795) evaluated the effects of hepatic and renal impairment on dersimelagon pharmacokinetics, safety, and tolerability. Participants with mild (n = 7) or moderate (n = 8) hepatic impairment or normal hepatic function (n = 8) received a single oral 100-mg dersimelagon dose. Participants with mild (n = 8), moderate (n = 8), or severe (n = 8) renal impairment or normal renal function (n = 8) received a single 300-mg dose. Systemic exposure to dersimelagon was comparable with mild hepatic impairment but higher with moderate hepatic impairment (maximum observed plasma concentration, 1.56-fold higher; area under the plasma concentration-time curve from time 0 extrapolated to infinity, 1.70-fold higher) compared with normal hepatic function. Maximum observed plasma concentration and area under the plasma concentration-time curve from time 0 extrapolated to infinity were similar with moderate renal impairment but higher with mild (1.86- and 1.87-fold higher, respectively) and severe (1.17- and 1.45-fold higher, respectively) renal impairment versus normal renal function. Dersimelagon was generally well tolerated.
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Receptor de Melanocortina Tipo 1 , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Administración Oral , Receptor de Melanocortina Tipo 1/metabolismo , Receptor de Melanocortina Tipo 1/agonistas , Anciano , Hepatopatías/metabolismo , Área Bajo la Curva , Insuficiencia Renal/metabolismo , Adulto Joven , alfa-MSH/análogos & derivados , alfa-MSH/farmacocinética , alfa-MSH/administración & dosificación , alfa-MSH/efectos adversos , alfa-MSH/farmacología , Índice de Severidad de la EnfermedadRESUMEN
AIMS: To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). METHODS: An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL). RESULTS: A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438). CONCLUSIONS: Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m2) in a subsequent larger study.
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Diabetes Mellitus Tipo 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Masculino , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Persona de Mediana Edad , Femenino , Anciano , Tasa de Filtración Glomerular/efectos de los fármacos , Glucemia/efectos de los fármacos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Glucósidos/farmacocinética , Glucósidos/uso terapéutico , Glucósidos/farmacología , Glucósidos/efectos adversos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Adulto , Nefropatías Diabéticas/tratamiento farmacológico , Hemoglobina Glucada/análisis , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Insuficiencia Renal/metabolismo , Transportador 2 de Sodio-Glucosa , Glucosuria/inducido químicamente , BenzofuranosRESUMEN
Lenacapavir is a novel, first-in-class, multistage inhibitor of HIV-1 capsid function approved for the treatment of multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced people with HIV. Two Phase 1, open-label, parallel-group, single-dose studies assessed the pharmacokinetics (PK) of lenacapavir in participants with moderate hepatic impairment [Child-Pugh-Turcotte (CPT) Class B: score 7-9] or severe renal impairment [15 ≤ creatinine clearance (CLcr) ≤29 mL/min] to inform lenacapavir dosing in HIV-1-infected individuals with organ impairment. In both studies, a single oral dose of 300 mg lenacapavir was administered to participants with normal (n = 10) or impaired (n = 10) hepatic/renal function who were matched for age (±10 years), sex, and body mass index (±20%). Lenacapavir exposures [area under the plasma concentration-time curve from time 0 to infinity (AUCinf) and maximum concentration (Cmax)] were approximately 1.47- and 2.61-fold higher, respectively, in participants with moderate hepatic impairment compared to those with normal hepatic function, whereas lenacapavir AUCinf and Cmax were approximately 1.84- and 2.62-fold higher, respectively, in participants with severe renal impairment compared to those with normal renal function. Increased lenacapavir exposures with moderate hepatic or severe renal impairment were not considered clinically meaningful. Lenacapavir was considered generally safe and well tolerated in both studies. These results support the use of approved lenacapavir dosing regimen in patients with mild (CPT Class A: score 5-6) or moderate hepatic impairment as well as in patients with mild (60 ≤ CLcr ≤ 89 mL/min), moderate (30 ≤ CLcr ≤ 59 mL/min), and severe renal impairment.
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Hepatopatías , Insuficiencia Renal , Humanos , Área Bajo la Curva , Insuficiencia Renal/metabolismo , Riñón/metabolismo , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismoRESUMEN
Renal impairment is a common complication in patients with short bowel syndrome with intestinal failure (SBS-IF). Glucagon-like peptide-2 analogs, such as apraglutide, have been developed as a treatment option for SBS-IF. This study assessed the potential for apraglutide overexposure in individuals with severely impaired renal function versus healthy volunteers with normal renal function. In this phase 1, open-label, multicenter, nonrandomized, parallel-group study, a single dose of apraglutide 5 mg was administered subcutaneously to individuals with severely impaired renal function (<30 mL/min/1.73 m2) and healthy volunteers with normal renal function (≥90 mL/min/1.73 m2). Primary pharmacokinetic endpoints were maximum observed concentration (Cmax) and exposure to apraglutide (area under the curve [AUC] from time 0 to infinity [AUCinf], and AUC from time 0 to the last quantifiable concentration [AUClast]). Each group comprised 8 individuals. Results show that patients with severe renal impairment do not have increased apraglutide exposure. Apraglutide achieved a lower Cmax and AUCinf in individuals with severe renal impairment versus those with normal renal function (Cmax = 36.9 vs 59.5 ng/L; AUCinf = 3100 vs 4470 h · ng/mL, respectively). The respective geometric mean ratios were 0.620 and 0.693 for Cmax and AUCinf, and the upper bound of their 90% confidence intervals were <2, indicating patients with severe renal impairment were not overexposed to apraglutide versus those with normal renal function. Adverse events were mild or moderate in severity. Apraglutide does not require dose reduction for any degree of renal impairment and could be used in a broader patient population of renally impaired patients without dose adjustment.
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Área Bajo la Curva , Insuficiencia Renal , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Insuficiencia Renal/metabolismo , Anciano , Péptido 2 Similar al Glucagón/farmacocinética , Péptido 2 Similar al Glucagón/administración & dosificación , Péptido 2 Similar al Glucagón/efectos adversos , Síndrome del Intestino Corto/tratamiento farmacológico , Síndrome del Intestino Corto/fisiopatologíaRESUMEN
Vancomycin (VCM) is the first-line antibiotic for severe infections, but nephrotoxicity limits its use. Leonurine (Leo) has shown protective effects against kidney damage. However, the effect and mechanism of Leo on VCM nephrotoxicity remain unclear. In this study, mice and HK-2 cells exposed to VCM were treated with Leo. Biochemical and pathological analysis and fluorescence probe methods were performed to examine the role of Leo in VCM nephrotoxicity. Immunohistochemistry, q-PCR, western blot, FACS, and Autodock software were used to verify the mechanism. The present results indicate that Leo significantly alleviates VCM-induced renal injury, morphological damage, and oxidative stress. Increased intracellular and mitochondrial ROS in HK-2 cells and decreased mitochondrial numbers in mouse renal tubular epithelial cells were reversed in Leo-administrated groups. In addition, molecular docking analysis using Autodock software revealed that Leo binds to the PPARγ protein with high affinity. Mechanistic exploration indicated that Leo inhibited VCM nephrotoxicity via activating PPARγ and inhibiting the TLR4/NF-κB/TNF-α inflammation pathway. Taken together, our results indicate that the PPARγ inhibition and inflammation reactions were implicated in the VCM nephrotoxicity and provide a promising therapeutic strategy for renal injury.
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Ácido Gálico/análogos & derivados , Insuficiencia Renal , Vancomicina , Ratones , Animales , Vancomicina/metabolismo , Vancomicina/farmacología , Vancomicina/uso terapéutico , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , PPAR gamma/metabolismo , Receptor Toll-Like 4/metabolismo , Simulación del Acoplamiento Molecular , Riñón/patología , Insuficiencia Renal/metabolismo , Inflamación/tratamiento farmacológicoRESUMEN
The current study investigated the ameliorating impact of GA water extract (GAE) on CCl4-induced nephrotoxicity in renal cells and tissue by comparing its effectiveness with the Ketosteril (Ks) drug in restoring oxidative stress and necroinflammation. The cell morphology, necrosis, and redox state were evaluated in Vero cells. The influence of GAE on CCl4-induced oxidative stress, inflammation, and necrosis was examined in rats. The predicted inhibitory mechanism of GAE phenolic constituents against COX-2 and iNOS was also studied. The results revealed that GAE contains crucial types of phenolic acids, which are associated with its antiradical activities. GAE improved CCl4-induced Vero cell damage and restored renal architecture damage, total antioxidant capacity, ROS, TBARS, NO, GSH, GPX, SOD, and MPO in rats. GAE downregulated the gene expression of renal NF-κB, TNF-α, iNOS, and COX-2, as well as kidney injury molecule-1 (KIM-1) in rats. The GAE improved blood urea, creatinine, cholesterol, and reducing power. The computational analysis revealed the competitive inhibitory mechanism of selected phenolic composites of GAE on COX-2 and iNOS activities. The GAE exhibited higher potency than Ks in most of the studied parameters, as observed by the heatmap plots. Thus, GAE is a promising extract for the treatment of kidney toxicity.
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FN-kappa B , Insuficiencia Renal , Chlorocebus aethiops , Ratas , Animales , FN-kappa B/metabolismo , Tetracloruro de Carbono/toxicidad , Goma Arábiga , Células Vero , Ciclooxigenasa 2/metabolismo , Antioxidantes/farmacología , Estrés Oxidativo , Insuficiencia Renal/metabolismo , Oxidación-Reducción , Riñón/metabolismo , Necrosis/metabolismoRESUMEN
Receptor interacting protein kinase 3 (RIPK3) is an intracellular kinase at the crossroads of cell death and inflammation. RIPK3 contains a RIP homotypic interaction motif (RHIM) domain which allows interactions with other RHIM-containing proteins and a kinase domain that allows phosphorylation of target proteins. RIPK3 may be activated through interaction with RHIM-containing proteins such as RIPK1, TRIF and DAI (ZBP1, DLM-1) or through RHIM-independent mechanisms in an alkaline intracellular pH. RIPK3 mediates necroptosis and promotes inflammation, independently of necroptosis, through either activation of NFκB or the inflammasome. There is in vivo preclinical evidence of the contribution of RIPK3 to both acute kidney injury (AKI) and chronic kidney disease (CKD) and to the AKI-to-CKD transition derived from RIPK3 deficient mice or the use of small molecule RIPK3 inhibitors. In these studies, RIPK3 targeting decreased inflammation but kidney injury improved only in some contexts. Clinical translation of these findings has been delayed by the potential of some small molecule inhibitors of RIPK3 kinase activity to trigger apoptotic cell death by inducing conformational changes of the protein. A better understanding of the conformational changes in RIPK3 that trigger apoptosis, dual RIPK3/RIPK1 inhibitors or repurposing of multiple kinase inhibitors such as dabrafenib may facilitate clinical development of the RIPK3 inhibition concept for diverse inflammatory diseases, including kidney diseases (AU)
La proteína quinasa 3 que interactúa con el receptor (RIPK3) es una quinasa intracelular que se encuentra a medio camino entre la muerte celular y la inflamación. La RIPK3 contiene un dominio motivo de interacción homotípica de RIP (RHIM), que permite las interacciones con otras proteínas que contienen RHIM, y un dominio de quinasa que permite la fosforilación de las proteínas diana. La RIPK3 puede ser activada a través de la interacción con las proteínas que contienen RHIM tales como RIPK1, TRIF y DAI (ZBP1, DLM-1), o a través de mecanismos independientes de RHIM en un pH intracelular alcalino. La RIPK3 media en la necroptosis y promueve la inflamación, independientemente de la necroptosis, bien a través de la activación de NFκB, o del inflamasoma. Existe evidencia preclínica in vivo de la contribución de RIPK3 a la insuficiencia renal aguda (IRA) y la enfermedad renal crónica (ERC), así como a la transición IRA-ERC derivada de ratones con deficiencia de RIPK3 o del uso de pequeñas moléculas inhibidoras de RIPK3. En dichos estudios, el tener a RIPK3 como objetivo redujo la inflamación, pero la nefropatía mejoró solo en algunos contextos. La traducción clínica de estos hallazgos se ha demorado debido al potencial de ciertas pequeñas moléculas inhibidoras de la actividad de la quinasa RIPK3 para activar la muerte celular induciendo cambios conformacionales de la proteína. Comprender mejor los cambios conformacionales de RIPK3 activadores de la apoptosis, los inhibidores duales RIPK3/RIPK1 o la reconversión de múltiples inhibidores de la quinasa tales como dabrafenib podría facilitar el desarrollo clínico del concepto de la inhibición de RIPK3 para diversas enfermedades inflamatorias, incluyendo las enfermedades renales (AU)
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Humanos , Insuficiencia Renal/metabolismo , Inflamación , Concentración Osmolar , Proteína Quinasa 3 Activada por Mitógenos , Enfermedad AgudaRESUMEN
ABSTRACT: In both medical and forensic autopsy, the kidneys may be overlooked grossly and histologically. As both acute and chronic kidney dysfunction have major implications on morbidity and mortality, it is essential to consider the kidneys as a pathologic source for both immediate and proximate cause of death. For decades, vitreous humor has been used as a measure of postmortem electrolyte analysis to help understand ionic disturbances carried over from the antemortem period. Renal insufficiency from both acute and chronic kidney dysfunction can be ascertained from vitreous investigations and should be a consideration for cause of death. Here, we present 4 cases in which vitreous analysis was used to determine the cause of death. In highlighting these cases, we support the use of biochemical testing in autopsy while demonstrating how it can help elucidate an often overlooked means of mortality. Importantly, it can help with the formulation of clinicopathologic correlations between antemortem and postmortem findings.
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Electrólitos , Cuerpo Vítreo , Humanos , Cuerpo Vítreo/química , Cuerpo Vítreo/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Anciano , Insuficiencia Renal/metabolismo , Potasio/metabolismo , Potasio/análisis , Sodio/metabolismo , Sodio/análisis , Adulto , Patologia Forense , Anciano de 80 o más AñosRESUMEN
The use of conventional gadolinium(Gd)-based contrast agents in magnetic resonance imaging (MRI) poses a significant risk of Nephrogenic Systemic Fibrosis (NSF) syndrome in patients with impaired renal function (grades 4 and 5). To address this issue, a new study has introduced a novel metabolic Gadolinium oxide nanoparticle (Gd2O3 NPs) coated with ß-cyclodextrin (ßCD). The study aims to investigate NSF syndrome by quantifying tissue Gd deposition biodistribution in renal impairment rats using MR molecular imaging. This is the first study of its kind to use this approach. A group of 20 rats were divided into four groups, each containing five rats that underwent 5/6 nephrectomy. The rats received 12 intravenous injections of a novel homemade synthesized gadolinium oxide polycyclodextrin (Gd2O3@PCD) at a dose of 0.1 mmol/kg, conventional contrast agents (CAs) drugs of Omniscan (Gd-DTPA-BMA) and Dotarem (Gd-DOTA), at a dose of 2.5 mmol/kg, and 250 µl saline for two injections per week during six weeks. T1-weighted MR imaging was performed before the injections and once a week for six weeks to quantify Gd deposition in four different organs (skin, liver, heart, and lung) in rats using inductively coupled plasma mass spectrometry (ICP-MS). The relationship between Signal-to-Noise Ratio (SNR) and biodistribution of Gd deposition due to NSF-induced syndrome was also calculated. The results of the study showed that the Gd concentrations in tissues were significantly higher in the Gd2O3@PCD group compared to the other groups, without any significant histopathological changes (P < 0.05). In the Gd2O3@PCD group, Gd was mainly deposited in the skin, followed by the liver, lung, and heart, without any symptoms of thickening or hardening of the skin. The Gd concentrations in the skin, liver, lung, and heart were significantly lower in the Dotarem group than in the Omniscan group (P < 0.05). In the histopathological examinations, the Omniscan group showed increased cellularity in the dermis. A significant hyperintensity was observed in the Gd2O3@PCD-treated rats compared to the Dotarem and Omniscan groups in the liver, heart, and lung. Compared to conventional Gd-based CAs, the novel metabolically Gd2O3@PCD with increased SNR, biosafety, and a considerably lower probability of developing NSF, has potential applicability for diagnosing patients with renal diseases in clinical MR Molecular Imaging (MRMI).
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Meglumina , Nanopartículas , Dermopatía Fibrosante Nefrogénica , Compuestos Organometálicos , Insuficiencia Renal , beta-Ciclodextrinas , Humanos , Ratas , Animales , Medios de Contraste/efectos adversos , Dermopatía Fibrosante Nefrogénica/inducido químicamente , Gadolinio/efectos adversos , Ratas Wistar , Distribución Tisular , Gadolinio DTPA , Insuficiencia Renal/inducido químicamente , Insuficiencia Renal/metabolismo , Insuficiencia Renal/patología , beta-Ciclodextrinas/efectos adversos , Imagen por Resonancia Magnética , Imagen MolecularRESUMEN
BACKGROUNDS: Tacrolimus (TAC) concentration in peripheral blood mononuclear cells (PBMCs) is regarded as a better predictor of its immunosuppressive effect than the TAC concentration in whole blood. However, whether the exposure of TAC in PBMCs or WB was altered in post-transplant recipients with renal impairment remains unclear. METHODS: We investigated the relationship of trough TAC concentration in WB and PBMCs with renal functions in post-transplant recipients. The pharmacokinetic profiles of TAC in PBMCs and WB in the two chronic kidney disease (CKD) rat models were examined using UPLC-MS/MS. Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to analyze the expression of proteins and mRNAs related to TAC metabolism and transport, respectively. In addition, the effects of uremic toxins on human PBMCs were investigated using whole-transcriptome sequencing (RNA sequencing [RNA-seq]). RESULTS: We observed a decrease in the trough TAC concentration in PBMCs in the recipients with estimated glomerular filtration rate (eGFR) < 90 mL/min, compared with those of recipients with eGFR > 90 mL/min, but there was no difference in blood based on TAC concentrations (C0Blood). In a 150-patient post-transplant cohort, no significant relationship was observed between PBMCs and WB concentrations of TAC, and the eGFR value was correlated with TAC C0PBMCs but not with TAC C0Blood. In two CKD rat models, the TAC pharmacokinetic profile in the PBMCs was significantly lower than that in the control group; however, the blood TAC pharmacokinetic profiles in the two groups were similar. Transcriptome results showed that co-incubation of human PBMCs with uremic toxins upregulated the expression of AHR, ABCB1, and ABCC2. Compared to control rats, plasma IS increased by 1.93- and 2.26-fold and the expression of AHR, P-gp, and MRP2 in PBMCs was higher in AD and 5/6 nephrectomy (NX) rats, without modifying the expression of other proteins related to TAC exposure. CONCLUSION: The pharmacokinetics of TAC in PBMCs changed with a decline in renal function. Uremic toxins accumulate during renal insufficiency, which activates AHR, upregulates the expression of P-gp and MRP2, and affects their intracellular concentrations. Our findings suggest that monitoring TAC concentrations in PBMCs is more important than monitoring WB concentrations in post-transplant recipients with renal impairment.