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Patients on hemodialysis show dysregulated immunity, basal hyperinflammation and a marked vulnerability to COVID-19. We evaluated the immune profile in COVID-19 hemodialysis patients and the changes associated with clinical deterioration after the hemodialysis session. Recruited patients included eight hemodialysis subjects with active, PCR-confirmed SARS-CoV-2 infection, five uninfected hemodialysis patients and five healthy controls. In SARS-CoV-2-infected hemodialysis patients TNF-α, IL-6 and IL-8 were particularly increased. Lymphopenia was mostly due to reduction in CD4+ T, B and central memory CD8+ T cells. There was a predominance of classical and intermediate monocytes with reduced HLA-DR expression and enhanced production of pro-inflammatory molecules. Immune parameters were analysed pre- and post-hemodialysis in three patients with COVID-19 symptoms worsening after the hemodialysis session. There was a higher than 2.5-fold increase in GM-CSF, IFN-γ, IL-1ß, IL-2, IL-6, IL-17A and IL-21 in serum, and augmentation of monocytes-derived TNF-α, IL-1ß and IL-8 and CXCL10 (p < 0.05). In conclusion, COVID-19 in hemodialysis patients associates with alteration of lymphocyte subsets, increasing of pro-inflammatory cytokines and monocyte activation. The observed worsening during the hemodialysis session in some patients was accompanied by augmentation of particular inflammatory cytokines, which might suggest biomarkers and therapeutic targets to prevent or mitigate the hemodialysis-related deterioration during SARS-CoV-2 infection.
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COVID-19 , Fallo Renal Crónico , Humanos , SARS-CoV-2/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-6 , Interleucina-8 , Citocinas/metabolismo , Fallo Renal Crónico/terapia , Diálisis RenalRESUMEN
Recurrent and massive intravascular haemolysis induces proteinuria, glomerulosclerosis, and progressive impairment of renal function, suggesting podocyte injury. However, the effects of haemoglobin (Hb) on podocytes remain unexplored. Our results show that cultured human podocytes or podocytes isolated from murine glomeruli bound and endocytosed Hb through the megalin-cubilin receptor system, thus resulting in increased intracellular Hb catabolism, oxidative stress, activation of the intrinsic apoptosis pathway, and altered podocyte morphology, with decreased expression of the slit diaphragm proteins nephrin and synaptopodin. Hb uptake activated nuclear factor erythroid-2-related factor 2 (Nrf2) and induced expression of the Nrf2-related antioxidant proteins haem oxygenase-1 (HO-1) and ferritin. Nrf2 activation and Hb staining was observed in podocytes of mice with intravascular haemolysis. These mice developed proteinuria and showed podocyte injury, characterized by foot process effacement, decreased synaptopodin and nephrin expression, and podocyte apoptosis. These pathological effects were enhanced in Nrf2-deficient mice, whereas Nrf2 activation with sulphoraphane protected podocytes against Hb toxicity both in vivo and in vitro. Supporting the translational significance of our findings, we observed podocyte damage and podocytes stained for Hb, HO-1, ferritin and phosphorylated Nrf2 in renal sections and urinary sediments of patients with massive intravascular haemolysis, such as atypical haemolytic uraemic syndrome and paroxysmal nocturnal haemoglobinuria. In conclusion, podocytes take up Hb both in vitro and during intravascular haemolysis, promoting oxidative stress, podocyte dysfunction, and apoptosis. Nrf2 may be a potential therapeutic target to prevent loss of renal function in patients with intravascular haemolysis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Lesión Renal Aguda/metabolismo , Anemia Hemolítica/metabolismo , Apoptosis , Hemoglobinas/metabolismo , Podocitos/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Adulto , Anemia Hemolítica/genética , Anemia Hemolítica/patología , Animales , Línea Celular , Modelos Animales de Enfermedad , Endocitosis , Femenino , Ferritinas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hemólisis , Humanos , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 1 Relacionado con NF-E2/genética , Factor 1 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Fosforilación , Podocitos/ultraestructura , Receptores de Superficie Celular/metabolismo , Adulto JovenRESUMEN
Glomerular hematuria is a cardinal symptom of renal disease. Glomerular hematuria may be classified as microhematuria or macrohematuria according to the number of red blood cells in urine. Recent evidence suggests a pathological role of persistent glomerular microhematuria in the progression of renal disease. Moreover, gross hematuria, or macrohematuria, promotes acute kidney injury (AKI), with subsequent impairment of renal function in a high proportion of patients. In this pathological context, hemoglobin, heme, or iron released from red blood cells in the urinary space may cause direct tubular cell injury, oxidative stress, pro-inflammatory cytokine production, and further monocyte/macrophage recruitment. The aim of this manuscript is to review the role of glomerular hematuria in kidney injury, the role of inflammation as cause and consequence of glomerular hematuria, and to discuss novel therapies to combat hematuria.
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Glomerulonefritis/complicaciones , Glomerulonefritis/fisiopatología , Hematuria/etiología , Hematuria/orina , Glomérulos Renales/fisiopatología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/fisiopatología , Animales , Biomarcadores , Glomerulonefritis/diagnóstico , Glomerulonefritis/etiología , Hematuria/diagnóstico , Humanos , Riñón/patología , Riñón/fisiopatología , Estrés Oxidativo , Fenotipo , PronósticoRESUMEN
Background: Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis in the world, but there is little epidemiological data about possible changes in its presentation over the years. Available information about the influence of age on the form of clinical presentation is also scarce. Methods: The aim of the study was to analyse all renal biopsies performed between 1994 and 2013 and recorded in the Spanish Registry of Glomerulonephritis with a histological diagnosis of IgAN. The study was divided into five 4-year periods (1994-97, 1998-2001, 2002-05, 2006-09 and 2010-13) and patients were divided into four age groups: ≤16, 17-44, 45-64 and ≥65 years. Results: From 20.974 renal biopsies recorded, 2961 (14.1%) corresponded to IgAN. The prevalence of IgAN remained stable, but a significant increase in age [from 37.6 (SD 17.7) in 1994-97 to 44.9 (SD 16.8) years in 2010-13; P = 0.001] and worse renal function at presentation [from serum creatinine (SCr) 1.9 (SD 1.9) in 1994-97 to 2.3 (SD 2.1) mg/dL in 2010-13; P = 0.001] were observed over the years. Nephrotic-range proteinuria and acute kidney injury (AKI) as forms of presentation were significantly more common among patients ≥65 years (17.7% and 43.2%, respectively) as compared with the other age groups [≤16 (11.4% and 13.1%, respectively), 17-44 (13.1% and 13%, respectively) and 45-64 (12.1% and 21.3%, respectively)]. Blood pressure, SCr and proteinuria were also significantly higher at presentation among elderly patients. Conclusions: Although the prevalence of IgAN in Spain has remained stable over the years, patients are significantly older and present with significantly worse renal function in the last years. The incidence of nephrotic-range proteinuria (17.7%) and AKI (43.2%) as forms of presentation is remarkable among patients ≥65 years of age.
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Lesión Renal Aguda/diagnóstico , Glomerulonefritis por IGA/diagnóstico , Proteinuria/diagnóstico , Lesión Renal Aguda/cirugía , Adolescente , Adulto , Anciano , Biopsia , Diagnóstico Diferencial , Femenino , Glomerulonefritis por IGA/cirugía , Humanos , Masculino , Persona de Mediana Edad , Proteinuria/cirugía , Sistema de Registros , España , Adulto JovenRESUMEN
Hematuria is a cardinal symptom in IgA nephropathy, but its influence on the risk of disease progression has been scarcely investigated. We followed a cohort of 112 patients with IgA nephropathy for a mean±SEM period of 14±10.2 years, during which clinical and analytic risk factors (including urine sediment examination) were regularly recorded. According to the magnitude of time-averaged hematuria, we classified patients as those with persistent hematuria and those with negative or minimal hematuria. We also classified patients according to the magnitude of time-averaged proteinuria (>0.75 or ≤0.75 g/d). The proportion of patients reaching ESRD or a 50% reduction of renal function was significantly greater among patients with persistent hematuria than patients with minimal or negative hematuria (30.4% and 37.0% versus 10.6% and 15.2%, respectively; P=0.01). Multivariable analysis revealed time-averaged hematuria, time-averaged proteinuria, renal function at baseline, and the presence of tubulointerstitial fibrosis on renal biopsy as independent predictors of ESRD. After hematuria disappearance, which occurred in 46% of the patients, the rate of renal function decline changed from -6.45±14.66 to -0.18±2.56 ml/min per 1.73 m2 per year (P=0.001). Patients with time-averaged proteinuria >0.75 g/d had significantly poorer renal survival than those with time-averaged proteinuria ≤0.75 g/d. However, on further classification by time-averaged hematuria, only those patients with time-averaged proteinuria >0.75 g/d and persistent hematuria had significantly worse renal survival than those in the other three groups. In conclusion, remission of hematuria may have a significant favorable effect on IgA nephropathy outcomes.
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Glomerulonefritis por IGA/orina , Hematuria/etiología , Riñón/fisiopatología , Adulto , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Proteinuria/etiología , Remisión Espontánea , Factores de Riesgo , Adulto JovenRESUMEN
Haematuria has long been considered to be a benign condition associated with glomerular diseases. However, new evidences suggest that haematuria has a pathogenic role in promoting kidney disease progression. An increased risk for end-stage renal disease has been reported in adolescents and young adults with persistent microscopic haematuria. A persistent impairment of renal function has been also reported following macroscopic haematuria-associated acute kidney injury in immunoglobulin A nephropathy. Haematuria-induced renal damage has been related to oxidant, cytotoxic and inflammatory effects induced by haemoglobin or haem released from red blood cells. The pathophysiological origin of haematuria may be due to a more fragile and easily ruptured glomerular filtration barrier, as reported in several glomerular diseases. In this review we describe a number of the key issues associated with the epidemiology and pathogenesis of haematuria-associated diseases, provide an update of recent knowledge on the role of haematuria on renal function outcome and discuss specific therapeutic approaches in this setting. KEY SUMMARY POINTS: 1. Glomerular haematuria is a common observation in a number of renal diseases that may lead to persistent renal injury. 2. Haematuria in children differs from that in adults in specific aspects, particularly in the frequency of glomerular diseases and renal disease outcome. 3. Regular follow-up of renal function in children with isolated microhaematuria may be recommended.
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Glomerulonefritis/complicaciones , Hematuria/etiología , Riñón/fisiopatología , Insuficiencia Renal Crónica/etiología , Animales , Progresión de la Enfermedad , Glomerulonefritis/diagnóstico , Glomerulonefritis/fisiopatología , Glomerulonefritis/terapia , Hematuria/diagnóstico , Hematuria/fisiopatología , Hematuria/terapia , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/prevención & control , Pronóstico , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/prevención & control , Factores de RiesgoRESUMEN
OBJECTIVE: No consensus has been established as to which is the best fourth-line agent in patients with resistant hypertension (RHT). The aim of the present study was to assess the effect of intensifying diuretic treatment with loop diuretic (furosemide) or aldosterone antagonist (spironolactone) on blood pressure (BP) control in RHT. METHODS: The study population comprised 30 patients with RHT who were divided into two treatment arms. Fifteen patients received furosemide 40 mg/day and 15 patients received spironolactone 25 mg/day. Ambulatory BP monitoring was performed baseline, 3 and 6 months. RESULTS: Baseline BP was 162 ± 8/90 ± 6 mmHg, 70% men, mean age 63.3 ± 9.1 years 56.1% diabetic and estimated glomerular filtration rate (eGFR) 55.8 ± 16.5 mL/min per 1.73 m(2) . There were no significant differences between groups at baseline in age, gender, percentage diabetics, eGFR, BP, number of antihypertensive drugs, or aldosterone levels. At 6 months, systolic BP decreased by 24 ± 9.2 mmHg (from 163.6 ± 8.6 to 139.6 ± 8.1 mmHg) in the spironolactone group, compared with 13.8 ± 2.8 mmHg (from 162 ± 7.9 to 148 ± 6.4 mmHg) in the furosemide group (P < 0.01). Diastolic BP fell 11 ± 8.1 mmHg in the spironolactone group compared with 5.2 ± 2.2 mmHg in the furosemide group (P < 0.01). Significant reduction in urinary albumin creatinine ratio (from 173 ± 268 to 14 ± 24 mg/g, P < 0.01) was observed in the spironolactone group at 6 months. Multiple regression analysis showed that only treatment with spironolactone was associated with control of BP < 140/90 mmHg at 6 months. No severe adverse events were recorded. CONCLUSION: Spironolactone is more effective than furosemide for control of BP in RHT patients, with a positive added effect on albuminuria. Spironolactone is safe in patients with mild kidney impairment, although serum potassium should be closely monitored, especially in diabetics.
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Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Resistencia a Medicamentos , Furosemida/uso terapéutico , Hipertensión/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/uso terapéutico , Espironolactona/uso terapéutico , Anciano , Antihipertensivos/efectos adversos , Monitoreo Ambulatorio de la Presión Arterial , Quimioterapia Combinada , Femenino , Furosemida/efectos adversos , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Estudios Prospectivos , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/efectos adversos , Espironolactona/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The response to erythropoiesis-stimulating agents (ESA) in patients with chronic kidney disease (CKD) is variable. The body mass index (BMI) variations can modify the response to ESA. The objective was to assess the effect of body composition on the response to ESA in dialysis patients. METHODS: This is an observational cross-sectional study. Prevalent hemodialysis and peritoneal dialysis (PD) patients were selected. In the same day, a single blood test, a body composition analysis using bioimpedance spectroscopy and anthropometric measurements were performed. We collected ESA doses. We analyzed erythropoietin resistance index (ERI). The ERI was calculated dividing the weekly weight-adjusted (kg) dose of ESA (IU) by the hemoglobin level (g/dL). RESULTS: The study was comprised of 218 patients (58% men; age 65 (16) years old; 80% hemodialysis, 20% PD). There was an inverse correlation between ERI and BMI (p=0.01), fat tissue index (FTI) (p=0.01) and prealbumin (p=0.04). We found an independent association between higher ERI levels and lower FTI and prealbumin values. CONCLUSION: Response to ESA is influenced by body composition. Fat tissue favors the body's response to ESA.
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Anemia/prevención & control , Composición Corporal , Eritropoyetina/uso terapéutico , Hematínicos/uso terapéutico , Fallo Renal Crónico/complicaciones , Anciano , Anemia/etiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Background: Endothelial damage and cardiovascular disease complicate chronic kidney disease (CKD). The increased atherogenicity observed in patients with CKD can be linked to microinflammation and endothelial damage. Circulating endothelial glycocalyx degradation products, such as perlecan and decorin, tend to be elevated in CKD. We aimed to explore the association between the plasma perlecan and decorin levels and this pro-inflammatory and atherogenic state by studying monocyte subpopulations and intracellular adhesion molecule (ICAM)-1 expression in patients with CKD. Methods: We studied 17 healthy controls, 23 patients with advanced CKD, 25 patients on haemodialysis, 23 patients on peritoneal dialysis and 20 patients who underwent kidney transplantation. Perlecan and decorin levels were evaluated using enzyme-linked immunosorbent assays, and the monocyte phenotype was analysed using direct immunofluorescence and flow cytometry. Results: The plasma perlecan levels were higher in patients with CKD than in the healthy controls. These levels were associated with a higher prevalence of ICAM-1+ monocytes. Conversely, patients with advanced CKD (pre-dialysis) had higher plasma decorin levels, which were associated with a reduced ICAM-1 expression per monocyte. Conclusions: Elevated perlecan levels in CKD may be associated with a higher prevalence of ICAM-1+ monocytes and a pro-inflammatory phenotype. Elevated decorin levels may act as a negative regulator of ICAM-1 expression in monocytes. Therefore, perlecan and decorin may be related to inflammation and monocyte activation in CKD and may act as potential markers of endothelial damage.
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Oxidative stress plays a key role in the pathophysiology of chronic kidney disease (CKD). Most studies have investigated peripheral redox state focus on plasma, but not in different immune cells. Our study analyzed several redox state markers in plasma and isolated peripheral polymorphonuclear (PMNs) and mononuclear (MNs) leukocytes from advanced-CKD patients, also evaluating differences of hemodialysis (HD) and peritoneal dialysis (PD) procedures. Antioxidant (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH)) and oxidant parameters (xanthine oxidase (XO), oxidized glutathione (GSSG), malondialdehyde (MDA)) were assessed in plasma, PMNs and MNs from non-dialysis-dependent-CKD (NDD-CKD), HD and PD patients and healthy controls. Increased oxidative stress and damage were observed in plasma, PMNs and MNs from NDD-CKD, HD and PD patients (increased XO, GSSG and MDA; decreased SOD, CAT, GPX and GSH; altered GSSG/GSH balance). Several oxidative alterations were more exacerbated in PMNs, whereas others were only observed in MNs. Dialysis procedures had a positive effect on preserving the GSSG/GSH balance in PMNs. Interestingly, PD patients showed greater oxidative stress than HD patients, especially in MNs. The assessment of redox state parameters in PMNs and MNs could have potential use as biomarkers of the CKD progression.
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BACKGROUND: Chronic kidney disease (CKD) is increasing in patients older than 65 years and is related to morbidity, frailty, and dependence. Peritoneal dialysis (PD) has classically been associated with young patients with an active life. HYPOTHESIS: PD should be offered to patients over 65 years. We search for any unfavorable results that may advice not to recommend PD therapy for this group. OBJECTIVE: To describe PD treatment and outcomes in patients > 65 years, to compare their results with patients < 65 years and to identify areas with room for improvement in a real-life study. STUDY: Prospective, observational, and multicenter study performed in incident PD patients, from January 2003 until January 2018. RESULTS: We included 2,435 PD patients, 31.9% were older than 65 years; there was a difference of 25 years between both groups. Median follow up was 2.1 years. Older than 65 years group had more comorbidity: Diabetes (29.5% vs 17.2%; p < 0.001), previous CV events 34.5% vs 14.0%; p < 0.001), Charlson index (3.8 vs 3.0; p < 0.001). We did not find differences in efficacy and PD adequacy objectives fulfillment, anaemia management or blood pressure during follow-up. Peritonitis rate was higher in older 65 years group (0.65 vs 0.45 episodes/patient/year; p < 0.001), but there was not differences in germs, admission rate and follow up. Mortality was higher in older 65 years group (28.4% vs 9.4%) as expected. PD permanence probability was similar (2.1 years). The main cause of PD withdrawal was transplant in group < 65 years (48.3%) and transfer to HD in group > 65 years. The main reason was caregiver or patient fatigue (20.2%), and not technique failure (7.3%). Multivariate Cox regression analysis showed a relation (HR [95%CI]) between mortality and age > 65 years 2.4 [1.9-3.0]; DM 1.6 [1.3-2.1]; CV events 2.1 [1.7-2.7]. Multivariate Cox regression analysis identify a relation between technique failure and age > 65 years 1.5 [1.3-1.9]; DM 1.6 [1.3-1.9] and previous transplant 1.5 [1.2-2.0]. CONCLUSION: Patients older than 65 years fulfilled PD adequacy criteria during the follow up. We believe PD is a valid option for patients older 65 years. It is necessary to try to prevent infections and patient/caregiver fatigue, to avoid HD transfer for reasons not related to technique failure.
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Fallo Renal Crónico , Diálisis Peritoneal , Insuficiencia Renal Crónica , Anciano , Fatiga/complicaciones , Humanos , Fallo Renal Crónico/terapia , Diálisis Peritoneal/métodos , Estudios Prospectivos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapiaRESUMEN
Kidney transplantation is the best option for patients with end-stage renal disease. Despite the improvement in cardiovascular burden (leading cause of mortality among patients with chronic kidney disease), cardiovascular adverse outcomes related to the inflammatory process remain a problem. Thus, the aim of the present study was to characterize the immune profile and microvesicles of patients who underwent transplantation. We investigated the lymphocyte phenotype (CD3, CD4, CD8, CD19, and CD56) and monocyte phenotype (CD14, CD16, CD86, and CD54) in peripheral blood, and endothelium-derived microvesicles (annexin V+CD31+CD41-) in plasma of patients with advanced chronic kidney disease (n = 40), patients with transplantation (n = 40), and healthy subjects (n = 18) recruited from the University Hospital "12 de Octubre" (Madrid, Spain). Patients with kidney transplantation had B-cell lymphopenia, an impairment in co-stimulatory (CD86) and adhesion (CD54) molecules in monocytes, and a reduction in endothelium-derived microvesicles in plasma. The correlations between those parameters explained the modifications in the expression of co-stimulatory and adhesion molecules in monocytes caused by changes in lymphocyte populations, as well as the increase in the levels of endothelial-derived microvesicles in plasma caused by changes in lymphocyte and monocytes populations. Immunosuppressive treatment could directly or indirectly induce those changes. Nevertheless, the particular characteristics of these cells may partly explain the persistence of cardiovascular and renal alterations in patients who underwent transplantation, along with the decrease in arteriosclerotic events compared with advanced chronic kidney disease. In conclusion, the expression of adhesion molecules by monocytes and endothelial-derived microvesicles is related to lymphocyte alterations in patients with kidney transplantation.
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Massive intravascular hemolysis is associated with acute kidney injury (AKI). Nuclear factor erythroid-2-related factor 2 (Nrf2) plays a central role in the defense against oxidative stress by activating the expression of antioxidant proteins. We investigated the role of Nrf2 in intravascular hemolysis and whether Nrf2 activation protected against hemoglobin (Hb)/heme-mediated renal damage in vivo and in vitro. We observed renal Nrf2 activation in human hemolysis and in an experimental model of intravascular hemolysis promoted by phenylhydrazine intraperitoneal injection. In wild-type mice, Hb/heme released from intravascular hemolysis promoted AKI, resulting in decreased renal function, enhanced expression of tubular injury markers (KIM-1 and NGAL), oxidative and endoplasmic reticulum stress (ER), and cell death. These features were more severe in Nrf2-deficient mice, which showed decreased expression of Nrf2-related antioxidant enzymes, including heme oxygenase 1 (HO-1) and ferritin. Nrf2 activation with sulforaphane protected against Hb toxicity in mice and cultured tubular epithelial cells, ameliorating renal function and kidney injury and reducing cell stress and death. Nrf2 genotype or sulforaphane treatment did not influence the severity of hemolysis. In conclusion, our study identifies Nrf2 as a key molecule involved in protection against renal damage associated with hemolysis and opens novel therapeutic approaches to prevent renal damage in patients with severe hemolytic crisis. These findings provide new insights into novel aspects of Hb-mediated renal toxicity and may have important therapeutic implications for intravascular hemolysis-related diseases.
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Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body. However, because of their chemical structure, these molecules can exert harmful effects when they are released massively into the bloodstream, as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis. Once in the plasma, these haem proteins can be filtered and can accumulate in the kidney, where they become cytotoxic, particularly for the tubular epithelium, inducing acute kidney failure and chronic kidney disease. In this review, we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins, their relation to both acute and chronic loss of renal function, the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions. Finally, we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets, with particular emphasis on the numerous clinical trials that are currently ongoing.
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Lesión Renal Aguda/etiología , Hemoproteínas/metabolismo , Riñón/metabolismo , Insuficiencia Renal Crónica/etiología , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/terapia , Proteínas Sanguíneas/fisiología , Ensayos Clínicos como Asunto , Drogas en Investigación/uso terapéutico , Hemólisis , Humanos , Quelantes del Hierro/uso terapéutico , Túbulos Renales/metabolismo , Túbulos Renales/patología , Estrés Oxidativo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/terapia , Rabdomiólisis/complicaciones , Rabdomiólisis/metabolismo , Bicarbonato de Sodio/uso terapéutico , Terapias en InvestigaciónRESUMEN
Chronic malnutrition is a common problem in patients with end-stage renal disease on hemodialysis. Some studies have reported albumin loss into dialysis fluid during postdilution online hemodiafiltration (OL-HDF). The aim of the study was to assess the nutritional status of patients on high-volume OL-HDF and to demonstrate that higher convective clearances are not associated with malnutrition due to possible loss of nutrients with ultrafiltration. Demographic and clinical data, corporal composition with bioimpedance spectroscopy, dialysis features, albumin loss into dialysis fluid and laboratory parameters were collected in twenty-eight patients with ESRD undergoing postdilution OL-HDF with stable convective volumes over 28 L/session. Convective volume (CV) in the last six months was 32.51 ± 3.52 L per session. Cross-sectional analysis of dialysis features showed 32.7 ± 3.34 L of CV and high reduction rates of beta-2-microglobulin (84.2 ± 3.8%) and cystatin-C (81.6 ± 3.47%). Beta-2-microglobulin reduction showed a positive correlation with prealbumin levels (P = 0.048). CV was only correlated with cystatin-C reduction (P = 0.025). Estimated albumin loss into dialysis fluid (1.82 ± 1.05 g/session) was not related to laboratory or bioimpedance nutritional parameters, or to CV. Among patients with higher CV, serum albumin levels maintained more stability during the observational period. High volume OL-HDF results in better convective clearances and is not associated with malnutrition. Albumin and nutrients loss into dialysis fluid should not be a limiting factor of the substitution volume.
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Hemodiafiltración , Fallo Renal Crónico/terapia , Desnutrición/epidemiología , Estado Nutricional , Anciano , Enfermedad Crónica , Estudios Transversales , Cistatina C , Soluciones para Diálisis , Femenino , Humanos , Masculino , Desnutrición/etiología , Persona de Mediana Edad , Albúmina Sérica/metabolismo , Microglobulina beta-2/metabolismoRESUMEN
BACKGROUND: Sevelamer is a phosphate binder widely used in chronic kidney disease (CKD) patients. Sevelamer, as well as other resin-based binders, can crystallize leading to the formation of concretions. Sevelamer crystals (SC) have been associated with gastrointestinal (GI) mucosal injury. We describe three new cases of GI lesions associated with SC and review previously reported cases. METHODS: We describe three new cases of GI lesions associated with SC and review previously reported cases. RESULTS: We found 16 previously reported cases of SC-induced GI lesions. The mean patient age was 61 years (interquartile range 51.5-71.75), 62.5% were females and 10 patients were diabetic. In 13 cases, SC was found inside the GI mucosa. Six patients had history of major abdominal surgery. GI bleeding was the most common clinical symptom (n = 7), with three patients presenting with acute abdomen requiring surgical intervention. Although, SC-induced lesions were observed in all GI segments, intestine was involved in 81% of the cases. Endoscopic examination revealed mainly erosions and ulcerations (n = 7) and pseudoinflammatory polyps (n = 5). No association between sevelamer doses and the severity of GI lesions was found. However, diabetics patients seemed to develop GI lesions with smaller doses of sevelamer as compared with non-diabetic patients, in spite of their fewer GI comorbidities. CONCLUSIONS: SC-induced GI lesions should be considered in CKD patients treated with sevelamer who present GI symptoms, especially lower GI bleeding, once other causes have been ruled out. Diabetics seem more prone to develop SC- associated GI lesions. Sevelamer therapy should be avoided if possible in patients with a history of major abdominal surgery or chronic constipation, because of the high risk of serious GI complications.
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Recent studies suggest a pathogenic role for glomerular haematuria among renal function. However, there is no data on the prevalence of haematuria from a large renal biopsy registry. We analysed the prevalence of gross (GH) and microscopic (mH) haematuria in 19,895 patients that underwent native renal biopsies from the Spanish Registry of Glomerulonephritis. Haematuria's overall incidence was 63% (GH 8.6% and mH 55.1%), being more frequent in males (64.7% vs. 62.4%). GH was more prevalent in patients <18 years (21.3% vs. 7.7%). The commonest clinical presentation associated with GH was acute kidney injury (31.5%) and IgA Nephropathy (IgAN) (33.6%) was the most frequent histological finding. GH patients showed a significantly (p < 0.05) lower eGFR and proteinuria levels as compared with patients with mH and without haematuria. Moreover, mH was more prevalent in adults (56.3%). Nephrotic syndrome was the commonest clinical presentation in mH patients (32.2%) and IgAN (18.5%) the most frequent histological finding. In conclusion, haematuria, is a frequent urinalysis finding in patients underwent native renal biopsy. The most frequent histological finding in both GH and mH is IgAN. Whereas, GH is more frequent in young males with acute kidney injury, mH is commoner among adults with nephrotic syndrome.
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Lesión Renal Aguda/epidemiología , Glomerulonefritis/epidemiología , Hematuria/epidemiología , Sistema de Registros , Lesión Renal Aguda/complicaciones , Lesión Renal Aguda/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Estudios de Seguimiento , Glomerulonefritis/complicaciones , Glomerulonefritis/fisiopatología , Hematuria/complicaciones , Hematuria/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , España/epidemiologíaRESUMEN
The objective of the present study was to analyze the characteristics and survival of patients from our hospital who started home hemodialysis. We analyzed all patients receiving home hemodialysis from 1969 to 2015 (51 patients; age 45 ± 23 years; men 77%). We collected characteristics, hospital admission, and mortality. After a median follow-up of 43 (22-76) months, we found 0-1 hospital admissions per year. Sixty-nine percent received a kidney transplant, and the global mortality was 10%. Survival at 5 years was 96%. Mean equivalent renal urea clearance was 15.6 ± 4.2 mL/min, the ß-2 microglobulin reduction rate was 67 ± 18%, the number of antihypertension drugs was 0.7 ± 0.3, and the erythropoietin resistance index was 3.7 ± 2.1 IU/kg/week/g/dL. Daily home hemodialysis is a viable option for renal replacement therapy and should be offered alongside other therapies.
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Hemodiálisis en el Domicilio/métodos , Fallo Renal Crónico/terapia , Trasplante de Riñón/estadística & datos numéricos , Adulto , Anciano , Femenino , Estudios de Seguimiento , Hemodiálisis en el Domicilio/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , España , Análisis de Supervivencia , Adulto JovenRESUMEN
Escenario: La prevalencia de enfermedad renal crónica (ERC) aumenta en población mayor de 65años y asocia morbilidad, dependencia y fragilidad. La diálisis peritoneal (DP) se ha considerado una técnica de paciente joven y vida activa. Hipótesis: La DP puede ser adecuada en pacientes de edad avanzada. Buscamos resultados desfavorables que contravengan esta hipótesis. Objetivo: Describir el tratamiento con DP en mayores de 65años, evaluar su evolución clínica comparada con los menores de 65 e identificar áreas de mejora asistencial. Estudio: Prospectivo, observacional y multicéntrico en incidentes en DP, seguimiento hasta evento o fin del estudio (ene-2003 a ene-2018).Resultados: Se incluyen 2.435 pacientes; el 31,9% (777) eran mayores de 65 años. El tiempo medio de seguimiento fue de 2,1años para ambos grupos. El grupo de edad avanzada era 25años mayor, con más comorbilidad: diabetes (29,5% vs. 17,2%; p<0,001), evento CV previo (34,5% vs. 14,0%; p<0,001) e índice de Charlson sin edad (3,8 vs. 3,0; p<0,001). No encontramos diferencias en cumplimiento de objetivos intermedios de eficacia de DP, control de anemia o hipertensión durante el seguimiento. La tasa de peritonitis fue mayor en la cohorte mayor de 65años (0,65 vs. 0,45 episodios/paciente-año; p<0,001), aunque la distribución gérmenes, tasa de ingreso y evolución final fue similar en ambos grupos. Lógicamente, registramos mayor mortalidad en el grupo mayor de 65años (28,4% vs. 9,4%), aunque el tiempo de permanencia en DP fue similar (2,1años). La principal causa de salida fue el trasplante renal en jóvenes (48,3%), mientras que en los pacientes de mayor edad fue el paso a hemodiálisis, principalmente por cansancio de cuidador/autocuidado (20,2%) y no por fallo de la técnica (7,3%). (AU)
Background: Chronic kidney disease (CKD) is increasing in patients older than 65years and is related to morbidity, frailty, and dependence. Peritoneal dialysis (PD) has classically been associated with young patients with an active life. Hypothesis: PD should be offered to patients over 65years. We search for any unfavorable results that may advice not to recommend PD therapy for this group. Objective: To describe PD treatment and outcomes in patients >65years, to compare their results with patients <65years and to identify areas with room for improvement in a real-life study. Study: Prospective, observational, and multicenter study performed in incident PD patients, from January 2003 until January 2018. Results: We included 2,435 PD patients, 31.9% were older than 65years; there was a difference of 25years between both groups. Median follow up was 2.1years. Older than 65years group had more comorbidity: Diabetes (29.5% vs 17.2%; p<0.001), previous CV events 34.5% vs 14.0%; p<0.001), Charlson index (3.8 vs 3.0; p<0.001). We did not find differences in efficacy and PD adequacy objectives fulfillment, anaemia management or blood pressure during follow-up. Peritonitis rate was higher in older 65years group (0.65 vs 0.45 episodes/patient/year; p<0.001), but there was not differences in germs, admission rate and follow up. Mortality was higher in older 65years group (28.4% vs 9.4%) as expected. PD permanence probability was similar (2.1years). The main cause of PD withdrawal was transplant in group <65years (48.3%) and transfer to HD in group >65years. The main reason was caregiver or patient fatigue (20.2%), and not technique failure (7.3%). (AU)
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Humanos , Masculino , Femenino , Anciano , Anciano de 80 o más Años , Diálisis Peritoneal , Insuficiencia Renal Crónica/tratamiento farmacológico , Estudios Prospectivos , Insuficiencia Renal Crónica/mortalidad , FragilidadRESUMEN
Macrophages play an important role in rhabdomyolysis-acute kidney injury (AKI), although the molecular mechanisms involved in macrophage differentiation are poorly understood. We analyzed the expression and regulation of CD163, a membrane receptor mainly expressed by anti-inflammatory M2 macrophages, in rhabdomyolysis-AKI and developed targeted probes for its specific detection in vivo by MRI. Intramuscular injection of glycerol in mice promoted an early inflammatory response, with elevated proportion of M1 macrophages, and partial differentiation towards a M2 phenotype in later stages, where increased CD163 expression was observed. Immunohistological studies confirmed the presence of CD163-macrophages in human rhabdomyolysis-AKI. In cultured macrophages, myoglobin upregulated CD163 expression via HO-1/IL-10 axis. Moreover, we developed gold-coated iron oxide nanoparticles vectorized with an anti-CD163 antibody that specifically targeted CD163 in kidneys from glycerol-injected mice, as determined by MRI studies, and confirmed by electron microscopy and immunological analysis. Our findings are the first to demonstrate that CD163 is present in both human and experimental rhabdomyolysis-induced AKI, suggesting an important role of this molecule in this pathological condition. Therefore, the use of probes targeting CD163-macrophages by MRI may provide important information about the cellular composition of renal lesion in rhabdomyolysis.