RESUMEN
The kidney injury molecule (KIM)-1 is shed from proximal tubular cells in acute kidney injury (AKI), relaying tubular epithelial proliferation. Additionally, KIM-1 portends complex immunoregulation and is elevated after exposure to lipopolysaccharides. It thus may represent a biomarker in critical illness, sepsis, and sepsis-associated AKI (SA-AKI). To characterise and compare KIM-1 in these settings, we analysed KIM-1 serum concentrations in 192 critically ill patients admitted to the intensive care unit. Irrespective of kidney dysfunction, KIM-1 serum levels were significantly higher in patients with sepsis compared with other critical illnesses (191.6 vs. 132.2 pg/mL, p = 0.019) and were highest in patients with urogenital sepsis, followed by liver failure. Furthermore, KIM-1 levels were significantly elevated in critically ill patients who developed AKI within 48 h (273.3 vs. 125.8 pg/mL, p = 0.026) or later received renal replacement therapy (RRT) (299.7 vs. 146.3 pg/mL, p < 0.001). KIM-1 correlated with markers of renal function, inflammatory parameters, hematopoietic function, and cholangiocellular injury. Among subcomponents of the SOFA score, KIM-1 was elevated in patients with hyperbilirubinaemia (>2 mg/dL, p < 0.001) and thrombocytopenia (<150/nL, p = 0.018). In univariate and multivariate regression analyses, KIM-1 predicted sepsis, the need for RRT, and multi-organ dysfunction (MOD, SOFA > 12 and APACHE II ≥ 20) on the day of admission, adjusting for relevant comorbidities, bilirubin, and platelet count. Additionally, KIM-1 in multivariate regression was able to predict sepsis in patients without prior (CKD) or present (AKI) kidney injury. Our study suggests that next to its established role as a biomarker in kidney dysfunction, KIM-1 is associated with sepsis, biliary injury, and critical illness severity. It thus may offer aid for risk stratification in these patients.
Asunto(s)
Lesión Renal Aguda , Biomarcadores , Enfermedad Crítica , Receptor Celular 1 del Virus de la Hepatitis A , Sepsis , Humanos , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Sepsis/sangre , Sepsis/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Anciano , Lesión Renal Aguda/sangre , Lesión Renal Aguda/etiología , Lesión Renal Aguda/diagnóstico , Biomarcadores/sangre , Índice de Severidad de la Enfermedad , Insuficiencia Multiorgánica/sangre , Insuficiencia Multiorgánica/etiología , Unidades de Cuidados Intensivos , AdultoRESUMEN
BACKGROUND: Some markers of inflammation-TNF receptors 1 and 2 (TNFR1 and TNFR2)-are independently associated with progressive CKD, as is a marker of proximal tubule injury, kidney injury molecule 1 (KIM-1). However, whether an episode of hospitalized AKI may cause long-term changes in these biomarkers is unknown. METHODS: Among adult participants in the Chronic Renal Insufficiency Cohort (CRIC) study, we identified 198 episodes of hospitalized AKI (defined as peak/nadir inpatient serum creatinine values ≥1.5). For each AKI hospitalization, we found the best matched non-AKI hospitalization (unique patients), using prehospitalization characteristics, including eGFR and urine protein/creatinine ratio. We measured TNFR1, TNFR2, and KIM-1 in banked plasma samples collected at annual CRIC study visits before and after the hospitalization (a median of 7 months before and 5 months after hospitalization). RESULTS: In the AKI and non-AKI groups, we found similar prehospitalization median levels of TNFR1 (1373 pg/ml versus 1371 pg/ml, for AKI and non-AKI, respectively), TNFR2 (47,141 pg/ml versus 46,135 pg/ml, respectively), and KIM-1 (857 pg/ml versus 719 pg/ml, respectively). Compared with matched study participants who did not experience AKI, study participants who did experience AKI had greater increases in TNFR1 (23% versus 10%, P<0.01), TNFR2 (10% versus 3%, P<0.01), and KIM-1 (13% versus -2%, P<0.01). CONCLUSIONS: Among patients with CKD, AKI during hospitalization was associated with increases in plasma TNFR1, TNFR2, and KIM-1 several months after their hospitalization. These results highlight a potential mechanism by which AKI may contribute to more rapid loss of kidney function months to years after the acute insult.
Asunto(s)
Lesión Renal Aguda , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Insuficiencia Renal Crónica , Adulto , Biomarcadores , Creatinina , Humanos , Receptores Tipo II del Factor de Necrosis Tumoral , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapiaRESUMEN
BACKGROUND: Repeated administration of cisplatin causes CKD. In previous studies, we reported that the kidney-secreted survival protein renalase (RNLS) and an agonist peptide protected mice from cisplatin-induced AKI. METHODS: To investigate whether kidney-targeted delivery of RNLS might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a RNLS agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of RNLS, single-cell RNA sequencing analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma RNLS in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy. RESULTS: In mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney RNLS; genetic deletion of RNLS was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA sequencing analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature and suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma RNLS levels trended lower at day 14 post-treatment. CONCLUSIONS: Kidney-targeted delivery of RNLS agonist RP81-MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.
Asunto(s)
Cisplatino/efectos adversos , Monoaminooxidasa/metabolismo , Insuficiencia Renal Crónica/inducido químicamente , Insuficiencia Renal Crónica/prevención & control , Secuencia de Aminoácidos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Línea Celular , Cisplatino/administración & dosificación , Creatinina/sangre , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Tasa de Filtración Glomerular , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monoaminooxidasa/deficiencia , Monoaminooxidasa/genética , Nanocápsulas/administración & dosificación , Péptidos/administración & dosificación , Péptidos/genética , Insuficiencia Renal Crónica/patologíaRESUMEN
BACKGROUND: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. METHODS: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. RESULTS: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. CONCLUSIONS: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.
Asunto(s)
Biomarcadores/sangre , Nefropatías Diabéticas/genética , Fallo Renal Crónico/genética , Insuficiencia Renal Crónica/genética , Adulto , Anciano , Quimiocina CCL2/sangre , Proteína 1 Similar a Quitinasa-3/sangre , Estudios de Cohortes , Nefropatías Diabéticas/sangre , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Humanos , Fallo Renal Crónico/sangre , Masculino , Persona de Mediana Edad , Fenotipo , Prevalencia , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , Insuficiencia Renal Crónica/sangre , Riesgo , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium-glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS). METHODS: Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression. RESULTS: In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p < 0.01), 2.7 (95% CI 2.0, 3.6; p < 0.01) and 1.5 (95% CI 1.2, 1.8; p < 0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p < 0.01), 1.9% (95% CI 3.5%, 0.2%; p = 0.03) and 26.7% (95% CI 30.7%, 22.7%; p < 0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p = 0.02] and 0.9 [95% CI 0.9, 1.0; p < 0.01] respectively), independent of other patient characteristics. The baseline and 1 year change in biomarkers did not associate with cardiovascular or heart failure outcomes. CONCLUSIONS/INTERPRETATION: Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin.
Asunto(s)
Biomarcadores/sangre , Canagliflozina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Anciano , Glucemia/metabolismo , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Femenino , Tasa de Filtración Glomerular , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Transportador 2 de Sodio-Glucosa/sangreRESUMEN
Coronavirus disease 2019 (COVID-19) is one of the most pressing health problems of this century, but our knowledge of the disease is still limited. In this study, we aimed to examine serum-soluble urokinase plasminogen activator receptor (suPAR) and kidney injury molecule 1 (KIM-1) levels based on the clinical course of COVID-19. Our study included 102 patients over the age of 18 who were diagnosed as having COVID-19 between September 2020 and December 2020 and a control group of 50 health workers over the age of 18 whose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR results were negative. KIM-1 was measured by ELISA and suPAR by suPARnostic™ assay. Analysis of previously identified variables of prognostic significance in COVID-19 revealed high neutrophil to lymphocyte ratio, lactose dehydrogenase, prothrombin time, C-reactive protein, PaO2 /FiO2 , D-dimer, ferritin, and fibrinogen levels in patients with severe disease (p < 0.05 for all). KIM-1 and suPAR levels were significantly higher in COVID-19 patients compared to the control group (p = 0.001 for all). KIM-1 level was higher in severe patients compared to moderate patients (p = 0.001), while suPAR level was lower (p = 0.001). KIM-1, which is believed to play an important role in the endocytosis of SARS-CoV-2, was elevated in patients with severe COVID-19 and may be a therapeutic target in the future. SuPAR may have a role in defense mechanism and fibrinolysis, and low levels in severe patients may be associated with poor prognosis in the early period.
Asunto(s)
COVID-19/sangre , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , SARS-CoV-2 , Adulto , Anciano , Biomarcadores/sangre , COVID-19/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: The aim of this study was to investigate if there is a causal relationship between circulating levels of TIM-1 (T-cell immunoglobulin and mucin domain 1) and incidence of stroke. Approach and Results: Plasma TIM-1 was analyzed in 4591 subjects (40% men; mean age, 57.5 years) attending the Malmö Diet and Cancer Study. Incidence of stroke was studied in relation to TIM-1 levels during a mean of 19.5 years follow-up. Genetic variants associated with TIM-1 (pQTLs [protein quantitative trait loci]) were examined, and a 2-sample Mendelian randomization analysis was performed to explore the role of TIM-1 in stroke using summary statistics from our pQTLs and the MEGASTROKE consortium. A total of 416 stroke events occurred during follow-up, of which 338 were ischemic strokes. After risk factor adjustment, TIM-1 was associated with increased incidence of all-cause stroke (hazards ratio for third versus first tertile, 1.44 [95% CI, 1.10-1.87]; P for trend, 0.004), and ischemic stroke (hazards ratio, 1.42 [95% CI, 1.06-1.90]; P for trend, 0.011). Nineteen independent lead SNPs, located in three genomic risk loci showed significant associations with TIM-1 (P<5×10-8). A 2-sample Mendelian Randomization analysis suggested a causal effect of TIM-1 on stroke (ß=0.083, P=0.0004) and ischemic stroke (ß=0.102, P=7.7×10-5). CONCLUSIONS: Plasma level of TIM-1 is associated with incidence of stroke. The genetic analyses suggest that this could be a causal relationship.
Asunto(s)
Receptor Celular 1 del Virus de la Hepatitis A/genética , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/genética , Biomarcadores/sangre , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Humanos , Incidencia , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Fenotipo , Pronóstico , Estudios Prospectivos , Sitios de Carácter Cuantitativo , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnóstico , Suecia/epidemiología , Factores de TiempoRESUMEN
BACKGROUND: After accounting for known risk factors for CKD progression in children, clinical outcomes among children with CKD still vary substantially. Biomarkers of tubular injury (such as KIM-1), repair (such as YKL-40), or inflammation (such as MCP-1, suPAR, TNF receptor-1 [TNFR-1], and TNFR-2) may identify children with CKD at risk for GFR decline. METHODS: We investigated whether plasma KIM-1, YKL-40, MCP-1, suPAR, TNFR-1, and TNFR-2 are associated with GFR decline in children with CKD and in subgroups defined by glomerular versus nonglomerular cause of CKD. We studied participants of the prospective CKiD Cohort Study which enrolled children with an eGFR of 30-90 ml/min per 1.73 m2 and then assessed eGFR annually. Biomarkers were measured in plasma collected 5 months after study enrollment. The primary endpoint was CKD progression, defined as a composite of a 50% decline in eGFR or incident ESKD. RESULTS: Of the 651 children evaluated (median age 11 years; median baseline eGFR of 53 ml/min per 1.73 m2), 195 (30%) had a glomerular cause of CKD. Over a median follow-up of 5.7 years, 223 children (34%) experienced CKD progression to the composite endpoint. After multivariable adjustment, children with a plasma KIM-1, TNFR-1, or TNFR-2 concentration in the highest quartile were at significantly higher risk of CKD progression compared with children with a concentration for the respective biomarker in the lowest quartile (a 4-fold higher risk for KIM-1 and TNFR-1 and a 2-fold higher risk for TNFR-2). Plasma MCP-1, suPAR, and YKL-40 were not independently associated with progression. When stratified by glomerular versus nonglomerular etiology of CKD, effect estimates did not differ significantly. CONCLUSIONS: Higher plasma KIM-1, TNFR-1, and TNFR-2 are independently associated with CKD progression in children.
Asunto(s)
Receptor Celular 1 del Virus de la Hepatitis A/sangre , Inflamación/sangre , Túbulos Renales/patología , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Insuficiencia Renal Crónica/sangre , Adolescente , Biomarcadores , Quimiocina CCL2/sangre , Niño , Proteína 1 Similar a Quitinasa-3/sangre , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Túbulos Renales/metabolismo , Masculino , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , Insuficiencia Renal Crónica/patologíaRESUMEN
BACKGROUND: The kidney injury molecule-1 (KIM-1) has previously been associated with kidney function in rodents and humans. Yet its role as a predictive marker for future decline in kidney function has remained less clear. METHODS: At baseline (1991-1994), fasting plasma KIM-1 (p-KIM-1) was measured in 4739 participants of the population-based Malmö Diet and Cancer Study. Creatinine and cystatin C were used to calculate estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Collaboration 2012 creatinine-cystatin C equation at baseline and follow-up examination (2007-2012). Incident CKD was defined as an eGFR <60 mL/min/1.73 m2 at follow-up. RESULTS: During a mean follow-up time of 16.6 years, high p-KIM-1 levels were associated with a greater decline in eGFR (quartile 1 -1.36 versus quartile 4 -1.54 mL/min/1.73 m2; P < 0.001). In multivariate analyses, the risk for incident CKD at the follow-up examination was higher among participants with baseline p-KIM-1 levels in the highest quartile {odds ratio [OR] 1.45 [95% confidence interval (CI) 1.10-1.92]} compared with those within the lowest quartile. The relative impact of baseline p-KIM-1 on incidence of CKD [OR 1.20 (95% CI 1.08-1.33) per 1 standard deviation (SD) increase in p-KIM-1] was comparable to those of age and systolic blood pressure (SBP) [OR 1.55 (95% CI 1.38-1.74) and OR 1.21 (95% CI 1.09-1.35) per 1 SD increase, respectively]. Adding p-KIM-1 to a conventional risk model resulted in significantly improved C-statistics (P = 0.04) and reclassified 9% of the individuals into the correct risk direction (continuous net reclassification improvement P = 0.02). Furthermore, the risk for hospitalization due to impaired renal function increased with increasing baseline p-KIM-1 [hazard ratio per 1 SD 1.43; (95% CI 1.18-1.74)] during a mean follow-up time of 19.2 years. CONCLUSION: Our results show that p-KIM-1 predicts the future decline of eGFR and risk of CKD in healthy middle-aged participants. Whether p-KIM-1 can be used to prioritize preventive action that needs to be further investigated.
Asunto(s)
Biomarcadores/sangre , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/patología , Creatinina/sangre , Cistatina C/sangre , Femenino , Tasa de Filtración Glomerular , Humanos , Incidencia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/sangre , Suecia/epidemiologíaRESUMEN
Objectives: The use of kidney function and injury markers for early detection of drug-related glomerular or tubular kidney injury in infants, children and adolescents requires age-specific data on reference intervals in a pediatric healthy population. This study characterizes serum values for eight kidney function and injury markers in healthy infants, children and adolescents. Methods: A single center prospective observational study was conducted between December 2018 and June 2019. Serum samples from 142 healthy infants, children and adolescents aged between 0 and ≤15 years were collected. Statistical analyses for eight markers (albumin (ALB), ß2-microglobulin (B2M), ß-trace protein (BTP), creatinine (SCR), cystatin C (CYSC), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), uromodulin (URO)) were performed to obtain reference intervals and associations with age, sex and weight were investigated (Pearson correlation, linear and piecewise regression). Results: ALB and SCR increased with age (p<0.01), whereas B2M, BTP and KIM-1 values decreased with advancing age (p<0.05) in this healthy pediatric study population. CYSC showed dependency on sex (lower concentration in females) and decreased with age until reaching approximately 1.8 years; thereafter an increase with age was seen. NGAL and URO did not show any age-dependency. Conclusions: This study provides age appropriate reference intervals for key serum kidney function and injury markers determined in healthy infants, children and adolescents. Such reference intervals facilitate the interpretation of changes in kidney function and injury markers in daily practice, and allow early detection of glomerular and tubular injury in infancy, childhood and adolescence.
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Lesión Renal Aguda/diagnóstico , Biomarcadores/sangre , Pruebas de Función Renal/métodos , Adolescente , Albúminas/análisis , Niño , Preescolar , Creatinina/sangre , Cistatina C/sangre , Femenino , Tasa de Filtración Glomerular , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Humanos , Lactante , Recién Nacido , Oxidorreductasas Intramoleculares/sangre , Riñón , Lipocalina 2/sangre , Lipocalinas/sangre , Masculino , Valores de Referencia , Uromodulina/sangre , Microglobulina beta-2/sangreRESUMEN
BACKGROUND Sepsis causes acute kidney injury (AKI) in critically ill patients. Roflumilast, a phosphodiesterases-4 (PDE4) inhibitor, has been shown to be therapeutically effective in sepsis-induced organ injury. However, the function of roflumilast in sepsis-induced AKI is not clearly understood. The present study aimed to explore the protective effect of roflumilast on sepsis-induced AKI in mice. MATERIAL AND METHODS A sepsis model was established by cecal ligation and puncture surgery. Roflumilast (1 mg/kg and 3 mg/kg) was used once daily for 7 consecutive days for treatment. Kidney tissues were pathologically examined by hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining. The levels of kidney injury markers including blood urea nitrogen (BUN), creatinine (Cre), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), and inflammatory cytokines including interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and IL-1ß were detected by their corresponding test kits. The protein expression was measured using western blot and cell apoptosis of kidney tissue was determined by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay. RESULTS Roflumilast was demonstrated to alleviate sepsis-induced AKI by reducing histopathological changes and decreasing the levels of kidney injury markers in a concentration-dependent way. The production of TNF-alpha, IL-6, and IL-1ß was significantly suppressed by roflumilast. Besides, roflumilast inhibited the activation of NLRP3 (nucleotide-binding domain (NOD)-like receptor protein 3) and NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells). Additionally, roflumilast inhibited cell apoptosis and changes in expression of apoptosis related proteins induced by sepsis. Finally, high concentration of roflumilast (3 mg/kg) did not have an adverse effect on liver, heart, lung, or spleen. CONCLUSIONS Our study indicated that roflumilast could ameliorate AKI induced by sepsis through restraining inflammatory response and apoptosis of the kidney, providing a molecular basis for a novel medical treatment of septic AKI.
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Lesión Renal Aguda/tratamiento farmacológico , Aminopiridinas/farmacología , Benzamidas/farmacología , Aminopiridinas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Benzamidas/metabolismo , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Ciclopropanos/metabolismo , Ciclopropanos/farmacología , Citocinas/sangre , Femenino , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Inflamación/metabolismo , Riñón/patología , Lipocalina 2/sangre , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Inhibidores de Fosfodiesterasa 4/metabolismo , Inhibidores de Fosfodiesterasa 4/farmacología , Sepsis/complicacionesRESUMEN
AIM: Acute kidney injury (AKI) is often underdiagnosed due to several limitations of the renal marker creatinine. Tubular urinary biomarkers may substantially contribute to diagnose AKI early. For early detection of AKI, we evaluated for the first time N-acetyl-ß-d-glucosaminidase (NAG), Kidney-injury-molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in acute chest pain. METHODS: We included 402 chest pain patients aged 18 to 95 years seen in the emergency department. From 311 subjects, blood and urine samples were collected. RESULTS: Thirty-three patients developed an AKI and showed a significant increase in all three tubular markers compared to patients without AKI (each P < .001). According to receiver operating characteristic (ROC) analysis, combining NAG and creatinine showed a significantly increased area under the curve (AUC) compared to creatinine alone (AUC: 0.75 vs 0.87; P < .001). KIM-1, NGAL and cystatin C showed no significant differences in AUC compared to creatinine. In 120 individuals with blood and urine sampling before contrast media exposure, ROC analysis showed a significantly improved diagnostic performance for the combination of both (AUC: 0.83 vs creatinine AUC: 0.66; P = .004). AKI occurrence showed no dependency from CM volume. NAG presented as an independent AKI predictor beside creatinine, age, the diagnosis of myocardial infarction and mean arterial pressure. Regarding the prognostic value for renal replacement therapy, the combination of NAG and creatinine showed a significantly lager AUC than creatinine (AUC: 0.95 vs AUC: 0.85; P < .001). CONCLUSION: NAG presented as a promising marker of impending AKI and the necessity of renal replacement therapy.
Asunto(s)
Acetilglucosaminidasa/sangre , Lesión Renal Aguda , Dolor en el Pecho , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Lipocalina 2/sangre , Lesión Renal Aguda/sangre , Lesión Renal Aguda/diagnóstico , Biomarcadores/sangre , Dolor en el Pecho/sangre , Dolor en el Pecho/diagnóstico , Dolor en el Pecho/etiología , Diagnóstico Precoz , Servicios Médicos de Urgencia/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Terapia de Reemplazo Renal/métodos , Tiempo de TratamientoRESUMEN
AIMS/HYPOTHESIS: As part of the Surrogate Markers for Micro- and Macrovascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) programme we previously reported that large panels of biomarkers derived from three analytical platforms maximised prediction of progression of renal decline in type 2 diabetes. Here, we hypothesised that smaller (n ≤ 5), platform-specific combinations of biomarkers selected from these larger panels might achieve similar prediction performance when tested in three additional type 2 diabetes cohorts. METHODS: We used 657 serum samples, held under differing storage conditions, from the Scania Diabetes Registry (SDR) and Genetics of Diabetes Audit and Research Tayside (GoDARTS), and a further 183 nested case-control sample set from the Collaborative Atorvastatin in Diabetes Study (CARDS). We analysed 42 biomarkers measured on the SDR and GoDARTS samples by a variety of methods including standard ELISA, multiplexed ELISA (Luminex) and mass spectrometry. The subset of 21 Luminex biomarkers was also measured on the CARDS samples. We used the event definition of loss of >20% of baseline eGFR during follow-up from a baseline eGFR of 30-75 ml min-1 [1.73 m]-2. A total of 403 individuals experienced an event during a median follow-up of 7 years. We used discrete-time logistic regression models with tenfold cross-validation to assess association of biomarker panels with loss of kidney function. RESULTS: Twelve biomarkers showed significant association with eGFR decline adjusted for covariates in one or more of the sample sets when evaluated singly. Kidney injury molecule 1 (KIM-1) and ß2-microglobulin (B2M) showed the most consistent effects, with standardised odds ratios for progression of at least 1.4 (p < 0.0003) in all cohorts. A combination of B2M and KIM-1 added to clinical covariates, including baseline eGFR and albuminuria, modestly improved prediction, increasing the area under the curve in the SDR, Go-DARTS and CARDS by 0.079, 0.073 and 0.239, respectively. Neither the inclusion of additional Luminex biomarkers on top of B2M and KIM-1 nor a sparse mass spectrometry panel, nor the larger multiplatform panels previously identified, consistently improved prediction further across all validation sets. CONCLUSIONS/INTERPRETATION: Serum KIM-1 and B2M independently improve prediction of renal decline from an eGFR of 30-75 ml min-1 [1.73 m]-2 in type 2 diabetes beyond clinical factors and prior eGFR and are robust to varying sample storage conditions. Larger panels of biomarkers did not improve prediction beyond these two biomarkers.
Asunto(s)
Biomarcadores/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/patología , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Microglobulina beta-2/sangre , Anciano , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Riñón/patología , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Oportunidad RelativaRESUMEN
Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we utilized proteomics, metabolomics and lipidomics panel assay measurements in baseline plasma samples from the multinational PROVALID study (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers) of patients with incident or early chronic kidney disease (median follow-up 35 months, median baseline eGFR 84 mL/min/1.73 m2, urine albumin-to-creatinine ratio 8.1 mg/g). In an accelerated case-control study, 258 individuals with a stable eGFR course (median eGFR change 0.1 mL/min/year) were compared to 223 individuals with a rapid eGFR decline (median eGFR decline -6.75 mL/min/year) using Bayesian multivariable logistic regression models to assess the discrimination of eGFR trajectories. The analysis included 402 candidate predictors and showed two protein markers (KIM-1, NTproBNP) to be relevant predictors of the eGFR trajectory with baseline eGFR being an important clinical covariate. The inclusion of metabolomic and lipidomic platforms did not improve discrimination substantially. Predictions using all available variables were statistically indistinguishable from predictions using only KIM-1 and baseline eGFR (area under the receiver operating characteristic curve 0.63). Thus, the discrimination of eGFR trajectories in patients with incident or early diabetic kidney disease and maintained baseline eGFR was modest and the protein marker KIM-1 was the most important predictor.
Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Tasa de Filtración Glomerular , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Insuficiencia Renal Crónica/sangre , Anciano , Teorema de Bayes , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Ischemic injury is a primary contributor to the initiation of renal tubular epithelial cell damage in sickle cell disease (SCD). In this study, we investigated the effects of bilateral ischemia-reperfusion injury, which is a common type of acute kidney injury (AKI), in male and female genetic mouse model of SCD. Bilateral occlusion of both renal hila for 21â¯min led to a significantly higher detection of established serum markers of AKI (creatinine, KIM-1 and NGAL) compared to sham-operated male SCD mice. Severe damage to the outer medullary tubules was determined in the ischemia-reperfision injury (IRI)-treated SCD male mice. In female SCD mice with a longer ischemic time (23â¯min), the serum markers of AKI were not as highly elevated compared to their male counterparts, and the extent of outer medullary tubular injury was less severe. To assess the potential benefit in the use of hydroxyurea (50â¯mg/kg IP) following bilateral renal IRI, we observed that the serum markers of AKI and the outer medullary tubular damage were markedly improved compared to male SCD mice that were not treated with hydroxyurea. In this study, we confirmed that male SCD mice were more susceptible to increased tubular damage and a loss in renal function compared to female SCD mice, and that hydroxyurea may partially prevent the extent of tubular injury following severe ischemia-reperfusion injury in SCD.
Asunto(s)
Lesión Renal Aguda/fisiopatología , Anemia de Células Falciformes/tratamiento farmacológico , Hidroxiurea/farmacología , Túbulos Renales/efectos de los fármacos , Daño por Reperfusión/fisiopatología , Lesión Renal Aguda/sangre , Anemia de Células Falciformes/sangre , Animales , Antidrepanocíticos/farmacología , Biomarcadores/sangre , Creatinina/sangre , Modelos Animales de Enfermedad , Femenino , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Túbulos Renales/metabolismo , Túbulos Renales/patología , Lipocalina 2/sangre , Masculino , Ratones , Daño por Reperfusión/sangreRESUMEN
BACKGROUND: Kidney injury is common in patients with cardiovascular disease. OBJECTIVES: We determined whether blood measurement of kidney injury molecule-1 (KIM-1), would predict kidney outcomes in patients undergoing angiographic procedures for various indications. METHODS: One thousand two hundred eight patients undergoing coronary and/or peripheral angiography were prospectively enrolled; blood was collected for KIM-1 measurement. Peri-procedural acute kidney injury (AKI) was defined as AKI within 48 hours of contrast exposure. Non-procedural AKI was defined as AKI beyond 48 hours. Development of chronic kidney disease (CKD) was defined as progression to an estimated glomerular filtration rate (eGFR) <60 milliliters/minute/1.73 m2 by study conclusion. Univariate and multivariable Cox proportional hazards models were used to identify predictors of non-procedural AKI, while univariate and multivariable logistic regression analysis was used to evaluate peri-procedural AKI and predictors of progression to CKD. RESULTS: During mean follow up of 4 years, peri-procedural AKI occurred in 5.0%, non-procedural AKI in 27.3%, and 12.4% developed new reduction in eGFR <60 mL/min/1.73 m2. Higher KIM-1 concentrations were associated with prevalent comorbidities associated with risk in cardiovascular disease and worse left ventricular function. In adjusted analyses, elevated pre- and post-procedural KIM-1 concentrations predicted not only peri-procedural AKI (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.09-2·18, Pâ¯=â¯.01 and OR 1.54, 95% CI 1.10-2.15, Pâ¯=â¯.01, respectively) and non-procedural AKI (hazard ratio [HR] 1·49, 95% CI 1·24-1·78, Pâ¯<â¯.001 and HR 1.46, 95% CI 1.23-1.74, Pâ¯<â¯.001, respectively), but also progression to CKD (OR 1.99, 95% CI 1.32-2.99, Pâ¯=â¯.001 and OR 2·02, 95% CI 1·35-3·03, Pâ¯=â¯.001, respectively). CONCLUSIONS: In a typical at-risk population undergoing coronary and/or peripheral angiography, blood concentrations of KIM-1 may predict incident peri-procedural and non-procedural AKI, as well as progression to CKD.
Asunto(s)
Enfermedades Cardiovasculares/diagnóstico , Catéteres , Angiografía Coronaria/efectos adversos , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Insuficiencia Renal Crónica/sangre , Anciano , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/fisiopatologíaRESUMEN
OBJECTIVES: The occupational exposure limit for trichloroethylene (TCE) in different countries varies from 1 to 100 ppm as an 8-hour time-weighted average (TWA). Many countries currently use 10 ppm as the regulatory standard for occupational exposures, but the biological effects in humans at this level of exposure remain unclear. The objective of our study was to evaluate alterations in immune and renal biomarkers among workers occupationally exposed to low levels of TCE below current regulatory standards. METHODS: We conducted a cross-sectional molecular epidemiology study of 80 healthy workers exposed to a wide range of TCE (ie, 0.4-229 ppm) and 96 comparable unexposed controls in China, and previously reported that TCE exposure was associated with multiple candidate biological markers related to immune function and kidney toxicity. Here, we conducted further analyses of all of the 31 biomarkers that we have measured to determine the magnitude and statistical significance of changes in the subgroup of workers (n=35) exposed to <10 ppm TCE compared with controls. RESULTS: Six immune biomarkers (ie, CD4+ effector memory T cells, sCD27, sCD30, interleukin-10, IgG and IgM) were significantly decreased (% difference ranged from -16.0% to -72.1%) and one kidney toxicity marker (kidney injury molecule-1, KIM-1) was significantly increased (% difference: +52.5%) among workers exposed to <10 ppm compared with the control group. These associations remained noteworthy after taking into account multiple comparisons using the false discovery rate (ie, <0.20). CONCLUSION: Our results suggest that occupational exposure to TCE below 10 ppm as an 8-hour TWA may alter levels of key markers of immune function and kidney toxicity.
Asunto(s)
Biomarcadores/análisis , Tricloroetileno/efectos adversos , Adulto , Proteínas Reguladoras de la Apoptosis/análisis , Proteínas Reguladoras de la Apoptosis/sangre , Biomarcadores/sangre , Ligando CD30/análisis , Ligando CD30/sangre , Recuento de Linfocito CD4/métodos , China , Estudios Transversales , Femenino , Receptor Celular 1 del Virus de la Hepatitis A/análisis , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Humanos , Inmunoglobulina G/análisis , Inmunoglobulina G/sangre , Inmunoglobulina M/análisis , Inmunoglobulina M/sangre , Interleucina-10/análisis , Interleucina-10/sangre , Masculino , Exposición Profesional/efectos adversos , Exposición Profesional/análisis , Tricloroetileno/sangreRESUMEN
BACKGROUND: Acute renal dysfunction still constitutes a highly significant obstacle to renal transplantation outcome. Kidney injury molecule-1 is highly upregulated in proximal tubular cells and shed into the urine and blood circulation following kidney injury. The aim of current cohort study was to evaluate the urine KIM-1 (uKIM-1) mRNA expression level and its protein concentration in blood and urine samples to determine whether sequential monitoring of KIM-1 in renal allograft recipients is a reliable biomarker for predicting the clinical status and outcome. METHODS: Both uKIM-1 mRNA expression level and the level of serum and uKIM-1 protein concentration in the 52 renal transplant recipients were respectively quantified using real-time PCR and ELISA methods at 2, 90 and 180 days after transplantation. RESULT: KIM-1 mRNA and protein expression level in the blood and urine samples of patients with graft dysfunction was significantly higher than patients with well-functioning graft on days 2, 90 and 180 after transplantation. Receiver-operating characteristic curve analysis of mRNA and protein expression levels showed that urinary and blood KIM-1 at months 3 and 6 could predict acute renal dysfunction at 6 months and 1 year after transplantation. CONCLUSION: Sequential monitoring of uKIM-1 mRNA expression level and its protein concentration in the serum and urine samples of renal transplant patients suggests that KIM-1 could be a sensitive and specific biomarker for early diagnosis and prognosis of kidney allograft injury.
Asunto(s)
Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Trasplante de Riñón , Adulto , Anciano , Biomarcadores , Estudios de Cohortes , Diagnóstico Precoz , Femenino , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/metabolismo , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , ARN Mensajero/sangre , ARN Mensajero/genética , ARN Mensajero/orina , Sensibilidad y Especificidad , Resultado del TratamientoRESUMEN
The concentration of kidney injury molecule-1 (KIM-1) was measured in blood plasma of 99 patients with clear-cell carcinoma and 14 patients with benign renal tumors using a Human Serum TIM-1/KIM-1/HAVCR Quantikine ELISA kit. The control group consisted of 15 healthy male and 14 healthy female subjects. KIM-1 levels in blood plasma of patients with cancer or benign renal tumors were significantly higher than in the control (p<0.00001 and p<0.01, respectively). In patients with benign tumors, this parameter was significantly lower than in patients with cancer (p<0.0001). KIM-1 level significantly increased with disease stage (p<0.0001), and even in stage I cancer, it was higher than in the control group (p<0.0001) or in patients with benign tumors (p<0.01). The best sensitivity/specificity ratio for stage I renal cancer detection (81 and 83% respectively) was achieved at cut-off level 77 pg/ml, the sensitivity of detection of for stages II-IV being 97%. Plasma level of KIM-1 increased with increasing the size and area of the primary tumor (T). This parameter was higher in patients with metastasis in regional lymph nodes irrespective of their number (N1 or N2) in comparison with patients without regional metastasis (N0). It is also higher in patients with distant metastasis (M+). In patients with grade III-IV cancer, KIM-1 level was 7-fold higher than in patients with grade I-II tumor (p<0.0001). Thus, KIM-1 can be regarded as a highly sensitive marker for early detection of clear-cell carcinoma.
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Biomarcadores de Tumor/sangre , Carcinoma de Células Renales/sangre , Receptor Celular 1 del Virus de la Hepatitis A/sangre , Neoplasias Renales/sangre , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/patología , Detección Precoz del Cáncer/métodos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/patologíaRESUMEN
Animal models of kidney transplantation (KTX) are widely used in studying immune response of hosts to implanted grafts. Additionally, KTX can be used in generating kidney-specific knockout animal models by transplantation of kidneys from donors with global knockout of a gene to wild-type recipients or vice versa. Dual-kidney transplantation (DKT) provides a more physiological environment for recipients than single-kidney transplantation (SKT). However, DKT in mice is rare due to technical challenges. In this study, we successfully performed DKT in mice and compared the hemodynamic response and graft function with SKT. The surgical time, complications, and survival rate of DKT were not significantly different from SKT, where survival rates were above 85%. Mice with DKT showed less injury and quicker recovery with lower plasma creatinine (Pcr) and higher glomerular filtration rate (GFR) than SKT mice (Pcr = 0.34 and 0.17 mg/dl in DKT vs. 0.50 and 0.36 mg/dl in SKT at 1 and 3 days, respectively; GFR = 215 and 131 µl/min for DKT and SKT, respectively). In addition, the DKT exhibited better renal functional reserve and long-term outcome of renal graft function than SKT based on the response to acute volume expansion. In conclusion, we have successfully generated a mouse DKT model. The hemodynamic responses of DKT better mimic physiological situations with less kidney injury and better recovery than SKT because of reduced confounding factors such as single nephron hyperfiltration. We anticipate DKT in mice will provide an additional tool for evaluation of renal significance in physiology and disease.