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PURPOSE: The clinical outcomes of kidney transplantation from deceased donors have seen significant improvements with the use of machine perfusion (MP), now a standard practice in transplant centers. However, the use of perfusate biomarkers for assessing organ quality remains a subject of debate. Despite this, some centers incorporate them into their decision-making process for donor kidney acceptance. Recent studies have indicated that lactate dehydrogenase (LDH), glutathione S-transferase, interleukin-18, and neutrophil gelatinase-associated lipocalin (NGAL) could predict post-transplant outcomes. MATERIALS AND METHODS: Between August 2016 and June 2017, 31 deceased-donor after brain death were included and stroke was the main cause of death. Pediatric patients, hypersensitized recipients were excluded. 43 kidneys were subjected to machine perfusion. Perfusate samples were collected just before the transplantation and stored at -80ºC. Kidney transplant recipients have an average age of 52 years, 34,9% female, with a BMI 24,6±3,7. We employed receiver operating characteristic analysis to investigate associations between these perfusate biomarkers and two key clinical outcomes: delayed graft function and primary non-function. RESULTS: The incidence of delayed graft function was 23.3% and primary non-function was 14%. A strong association was found between NGAL concentration and DGF (AUC=0.766, 95% CI, P=0.012), and between LDH concentration and PNF (AUC=0.84, 95% CI, P=0.027). Other perfusate biomarkers did not show significant correlations with these clinical outcomes. CONCLUSION: The concentrations of NGAL and LDH during machine perfusion could assist transplant physicians in improving the allocation of donated organs and making challenging decisions regarding organ discarding. Further, larger-scale studies are required.
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Biomarcadores , Funcionamiento Retardado del Injerto , Trasplante de Riñón , Lipocalina 2 , Preservación de Órganos , Perfusión , Humanos , Femenino , Biomarcadores/análisis , Masculino , Persona de Mediana Edad , Perfusión/métodos , Adulto , Lipocalina 2/análisis , Preservación de Órganos/métodos , Donantes de Tejidos , Curva ROC , Resultado del Tratamiento , Factores de Tiempo , L-Lactato Deshidrogenasa/análisis , Valores de Referencia , Valor Predictivo de las PruebasRESUMEN
Spontaneous rupture of the patellar (PTR) and quadriceps (QTR) tendon is infrequent. Systemic diseases such as diabetes mellitus, CKD, and secondary hyperparathyroidism (SHPT) are risk factors. The present cohort study aimed to evaluate risk factors associated with tendon rupture in hemodialysis (HD) patients with SHPT, as well as outcomes including surgical complications, re-ruptures, and fracture. Baseline clinical, laboratorial data, and radiographs were analyzed. Patients were followed up from March 2012 to March 2020. One-hundred thirty-one patients (≥18 yr of age, on HD ≥ 6 mo, with SHPT) were included. Incidence rates of PTR and QTR were 2.3 and 1.7/10000 HD patients/yr, respectively. The mean age of patients with tendon rupture was 44.0 ± 11.2 yr. These patients exhibited higher serum levels of phosphorus (6.3 ± 1.5 mg/dL vs 5.6 ± 1.1 mg/dL; P = .005), PTH (2025.7 ± 667.6 pg/mL vs 1728.4 ± 684.8 pg/mL; P = .035), and C-reactive-protein (35.4 ± 32.9 mg/dL vs 17 ± 24.5 mg/dL; P = .002) compared to the group without tendon rupture. The mean follow-up was 56.7 ± 27.1 mo. No patient required a new surgical approach or experienced re-rupture. Of all patients, 31% experienced hip fracture: 50% in the group with rupture (29.5 ± 17.4 mo after the tendon rupture) vs 26% without tendon rupture (P = .015). After adjustment, the hazard ratio for hip fracture was 2.87 (95% CI, 1.27-6.49; P = .012). Patients with SHPT and high levels of phosphorus, PTH, and inflammatory markers were at greater risk for tendon rupture. Surgical complication rates were low. However, results suggest that tendon rupture of knee extensor mechanism in HD patient with SHPT should be regarded as a "red flag" for future hip fracture.
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Vitamin E is a lipid-soluble nutrient found mainly in vegetable oils and oilseeds. It is divided into eight homologous compounds; however, only α-tocopherol exhibits vitamin activity. Many advantages are related to these compounds, including cellular protection through antioxidant and anti-inflammatory activity, and improving lipid metabolism. Physiopathology of many diseases incepts with reduced antioxidant defense, characterized by an increased reactive oxygen species production and activation of transcription factors involved in inflammation, such as nuclear factor-kappa B (NF-κB), that can be linked to oxidative stress. Moreover, disorders of lipid metabolism can increase the risk of cardiovascular diseases. In addition, intestinal dysbiosis plays a vital role in developing chronic non-communicable diseases. In this regard, vitamin E can be considered to mitigate those disorders, but data still needs to be more conclusive. This narrative review aims to elucidate the mechanisms of action of vitamin E and if supplementation can be beneficial in a disease scenario regarding non-communicable diseases.
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Enfermedades no Transmisibles , Vitamina E , Humanos , Antioxidantes/uso terapéutico , Antioxidantes/farmacología , Estrés Oxidativo , alfa-TocoferolRESUMEN
BACKGROUND & AIMS: Turmeric (a source of curcumin) is an excellent food to modulate oxidative stress, inflammation, and gut dysbiosis in patients with chronic kidney disease (CKD). However, no studies report the benefits of curcumin in patients undergoing peritoneal dialysis (PD). This study aims to evaluate the effects of curcuminoid supplementation on oxidative stress, inflammatory markers, and uremic toxins originating from gut microbiota in patients with CKD undergoing PD. METHODS: This longitudinal, randomized, single-blind, placebo-controlled trial evaluated 48 patients who were randomized into two groups: Curcumin (three capsules of 500 mg of Curcuma longa extract, with 98.42 % total curcuminoids) or placebo (three capsules of 500 mg of starch) for twelve weeks. In the peripheral blood mononuclear cells (PBMCs), the transcriptional expression levels of Nrf2, HOX-1 and NF-κB were evaluated by quantitative real-time PCR. Oxidative stress was evaluated by malondialdehyde (MDA) and total Thiol (T-SH). TNF-α and IL-6 plasma levels were measured by ELISA. P-cresyl sulphate plasma level, a uremic toxin, was evaluated by high-performance liquid chromatography (HPLC) with fluorescent detection. RESULTS: Twenty-four patients finished the study: 10 in the curcumin group (57.5 ± 11.6 years) and 14 in the placebo group (56.5 ± 10.0 years). The plasma levels of MDA were reduced after 12 weeks in the curcumin group (p = 0.01), while the placebo group remained unchanged. However, regarding the difference between the groups at the endpoint, no change was observed in MDA. Still, there was a trend to reduce the p-CS plasma levels in the curcumin group compared to the placebo group (p = 0.07). Likewise, the concentrations of protein thiols, mRNA expression of Nrf2, HOX-1, NF-κB, and cytokines plasma levels did not show significant changes. CONCLUSION: Curcuminoid supplementation for twelve weeks attenuates lipid peroxidation and might reduce uremic toxin in patients with CKD undergoing PD. This study was registered on Clinicaltrials.gov as NCT04413266.
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Curcumina , Diálisis Peritoneal , Insuficiencia Renal Crónica , Uremia , Humanos , Curcumina/farmacología , Curcumina/uso terapéutico , FN-kappa B/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Leucocitos Mononucleares/metabolismo , Método Simple Ciego , Inflamación , Estrés Oxidativo , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Diarilheptanoides/farmacología , Diarilheptanoides/uso terapéutico , Suplementos Dietéticos , Uremia/tratamiento farmacológicoRESUMEN
Chronic kidney disease (CKD) has long been recognized as a state of progressive decline in renal function. Morbidity and mortality are well correlated to the stage of renal function decline. Approximately one million deaths are estimated to be related to CKD worldwide. They are mostly associated with cardiovascular disease as a result of concurrent hypertension, accelerated atherosclerosis, and volume overload. Even with the best current treatment, disease progression is the general rule with a small fraction who reach CKD stage 5 requiring kidney transplantation or dialysis. Transplant patients show substantial reductions in mortality and cardiovascular events, as well as improvements in quality of life. However, the capacity of health systems to deliver kidney transplantation varies worldwide with worse indicators in low-income countries. Consequently, exploring novel and better therapeutic options for CKD is mandatory. Cell-based therapy is a promising strategy for treating CKD in preclinical models, and several clinical trials involving kidney disease exhibit a favorable safety profile. This chapter aims to provide an overview of CKD and the recent results of clinical trials of cell therapy in kidney diseases.
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Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Progresión de la Enfermedad , Calidad de Vida , Diálisis Renal , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/complicaciones , Ciencia Traslacional BiomédicaRESUMEN
Patients with end-stage renal disease develop changes in bone quality and quantity, which can be assessed using different methods. This study aimed to compare and to correlate bone parameters obtained in vivo using high-resolution peripheral quantitative computed tomography (HR-pQCT) with those obtained by bone biopsy using histomorphometry and microcomputed tomography (microCT) analysis of the iliac crest core, and to evaluate if HR-pQCT is helpful in aiding with categorization of those with high turnover. Twenty hemodialysis patients, 13 females (7 postmenopausal), underwent bone biopsy from 2018 to 2020. The mean age was 48.5 ± 10.6 years, and the mean hemodialysis vintage was 15 years. Histomorphometry identified mineralization defects, low turnover, and high turnover in 65%, 45%, and 35% of the patients, respectively. The highest values of trabecular bone volume (BV/TV) were obtained by histomorphometry, while the highest values of cortical thickness (Ct.Th) were obtained by HR-pQCT at the distal tibia. Moderate correlations were found between BV/TV values obtained by microCT of the bone core and HR-pQCT at the distal radius (r = 0.531, p = 0.016) and at the distal tibia (r = 0.536, p = 0.015). BV/TV values obtained from the bone core by histomorphometry and microCT were also significantly correlated (r = 0.475, p = 0.04). Regarding Ct.Th, there was a strong correlation between the radius and tibia HR-pQCT (r = 0.800, p < 0.001), between bone core microCT and the distal radius HR-pQCT (r = 0.610, p < 0.01), as between histomorphometry and microCT (r = 0.899, p < 0.01). In groups classified by bone turnover, patients with high turnover presented lower BV/TV, Tb.N, Tb.Th, and Ct.Th than those with low turnover in peripheral sites using HR-pQCT. By this method, it was possible to identify low turnover from tibia BV/TV > 12,4% plus Tb.Sp ≤ 0.667 mm (AUC 0.810, 95% CI 0.575 to 0.948) and high turnover from total bone mineral density (BMD) ≤ 154.2 mg HA/cm3 (AUC 0.860, 95% CI 0.633 to 0.982, p < 0.001) and cortical BMD ≤ 691.6 mg HA/cm3 (AUC 0.840, 95% CI 0.609 to 0.963, p < 0.001). In conclusion, HR-pQCT had significant correlation with iliac crest bone in BV/TV and Ct.Th, which are known to provide bone strength. This method is quick and non-invasive and may be helpful in categorizing those with high versus low turnover in hemodialysis patients.
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INTRODUCTION: Vascular calcification related to severe secondary hyperparathyroidism (SHPT) is an important cause of cardiovascular and bone complications, leading to high morbidity and mortality in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD). The present study aimed to analyze whether ankle-brachial index (ABI), a non-invasive diagnostic tool, is able to predict cardiovascular outcomes in this population. METHODS: We selected 88 adult patients on HD for at least 6 months, with serum iPTH>1,000pg/mL. We collected clinical data, biochemical and hormonal parameters, and ABI (sonar-Doppler). Calcification was assessed by lateral radiography of the abdomen and by simple vascular calcification score (SVCS). This cohort was monitored prospectively between 2012 and 2019 for cardiovascular outcomes (death, myocardial infarction (MI), stroke, and calciphylaxis) to estimate the accuracy of ABI in this setting. RESULTS: The baseline values were: iPTH: 1770±689pg/mL, P: 5.8±1.2 mg/dL, corrected Ca: 9.7±0.8mg/dL, 25(OH)vit D: 25.1±10.9ng/mL. Sixty-five percent of patients had ABI>1.3 (ranging from 0.6 to 3.2); 66% had SVCS≥3, and 45% aortic calcification (Kauppila≥8). The prospective evaluation (51.6±24.0 months), provided the following cardiovascular outcomes: 11% of deaths, 17% of nonfatal MI, one stroke, and 3% of calciphylaxis. After adjustments, patients with ABI≥1.6 had 8.9-fold higher risk of cardiovascular events (p=0.035), and ABI≥1.8 had 12.2-fold higher risk of cardiovascular mortality (p=0.019). CONCLUSION: The presence of vascular calcifications and arterial stiffness was highly prevalent in our population. We suggest that ABI, a simple and cost-effective diagnostic tool, could be used at an outpatient basis to predict cardiovascular events in patients with severe SHPT undergoing HD.
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Enfermedades Cardiovasculares , Hiperparatiroidismo Secundario , Infarto del Miocardio , Adulto , Índice Tobillo Braquial , Enfermedades Cardiovasculares/etiología , Humanos , Hiperparatiroidismo Secundario/complicaciones , Diálisis Renal , Factores de RiesgoRESUMEN
BACKGROUND: Previous study showed that purinergic P2X7 receptors (P2X7R) reach the highest expression in the first week after unilateral ureteral obstruction (UUO) in mice, and are involved in the process of inflammation, apoptosis and fibrosis of renal tissue. We, herein, document the role of purinergic P2X7 receptors activation on the third day of UUO, as assessed by means of BBG as its selective inhibitor. METHODS: We investigated the effects of brilliant blue G (BBG), a P2X7R antagonist, in the third day of kidney tissue response to UUO in rats. For this purpose, male Wistar rats submitted to UUO or sham operated, received BBG or vehicle (V), comprising four groups: UUO-BBG, UUO-V, sham-BBG and sham-V. The kidneys were harvested on day 3 UUO and prepared for histology, immunohistochemistry (P2X7R, PCNA, CD-68, α-sma, TGF-ß1, Heat-shock protein-47, TUNEL assay), quantitative real-time PCR (IL-1ß, procollagens type I, III, and IV) for mRNA quantification. RESULTS: The group UUO-V presented an enhancement in tubular cell P2X7-R expression, increase influx of macrophages and myofibroblasts, HSP-47 and TGF- ß1 expression. Also, upregulation of procollagen types I, III, and IV, and IL-1ß mRNAs were seen. On the other hand, group UUO-BBG showed lower expression of procollagens and IL-1ß mRNAs, as well as less immunoreactivity of HSP-47, TGF-ß, macrophages, myofibroblasts, and tubular apoptosis. This group also presented increased epithelial cell proliferation. CONCLUSION: BBG, a known highly selective inhibitor of P2X7R, attenuated renal inflammation, collagen synthesis, renal cell apoptosis, and enhanced renal cell proliferation in the early phase of rat model of UUO.
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Proliferación Celular/efectos de los fármacos , Riñón/patología , Nefritis/tratamiento farmacológico , Antagonistas del Receptor Purinérgico P2X/uso terapéutico , Colorantes de Rosanilina/uso terapéutico , Obstrucción Ureteral/complicaciones , Actinas/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Apoptosis/efectos de los fármacos , Movimiento Celular , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Colágeno Tipo IV/genética , Fibrosis , Proteínas del Choque Térmico HSP47/metabolismo , Interleucina-1beta/genética , Riñón/metabolismo , Túbulos Renales/patología , Macrófagos/fisiología , Masculino , Miofibroblastos/fisiología , Nefritis/etiología , Antagonistas del Receptor Purinérgico P2X/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Colorantes de Rosanilina/farmacología , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Chronic kidney disease (CKD) patients develop metabolic acidosis when approaching stages 3 and 4, a period in which accelerated atherogenesis may ensue. Studies in vitro show that low pH may increase low-density lipoprotein (LDL) oxidation, suggesting a role for chronic metabolic acidosis in atherosclerosis. The present study attempted to evaluate the effects of conservative care using oral sodium bicarbonate (NaHCO3) supplementation on the electronegative LDL [LDL(-)], a minimally oxidized LDL, plasma levels in CKD patients. METHODS: Thirty-one CKD patients were followed by a multidisciplinary team during 15 months of care in which 1.0 mmol/kg/day oral NaHCO3 supplementation was first given in the third month. Blood samples were collected 3 months before the initiation of oral NaHCO3 supplementation (T1), at the time of the beginning of supplementation (T2), and thereafter, each 4 months (T3, T4 and T5) until month 15 of care. Blood parameters and LDL(-) were measured from these collections. RESULTS: After 12 months of conservative care, creatinine clearance (MDRD) was kept stable, and serum bicarbonate (HCO3-) increased from 20.5 ± 2.9 to 22.6 ± 1.1 mM (p < 0.003). LDL(-) plasma levels declined from 4.5 ± 3.3 to 2.1 ± 0.9 U/L (p < 0.007) after reaching mean serum HCO3- levels of 22.6 ± 1.1 mM. CONCLUSIONS: Conservative care using oral NaHCO3 supplementation was able to stabilize renal function and decrease serum levels of LDL(-), a modified proatherogenic lipoprotein, only when mean serum HCO3- levels approached 22 mM. This study constitutes evidence that alkali therapy, in addition to its beneficial effect on renal disease progression, might serve as a preventive strategy to attenuate atherogenesis in CKD patients.
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INTRODUCTION: Patients on hemodialysis (HD) present high mortality from cardiovascular complications and high morbidity, including decreasing functional capacity and quality of life. OBJECTIVE: To analyze clinical and laboratory responses of patients in HD to intradialytic cardiopulmonary rehabilitation on an outpatient basis. METHODS: We evaluated 14 patients in a prospective study for 8 months using cardiopulmonary rehabilitation protocol (CRehab) consisted of intradialytic aerobic exercise with a cycle ergometer. We analyzed heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP), peripheral oxygen saturation (SpO2) and modified Borg scale. We evaluated cardiac function by echocardiogram, functional capacity by six minutes walk test (6MWT), and quality of life by SF-36 survey, before and after CRehab. Biochemical data and KT/Vsp were collected form medical records. RESULTS: During CRehab, the results of HR, SBP, DBP, SpO2 and Borg scale showed no significant changes. 6MWT test showed progressive increase in the distance covered (p < 0.001) as well as a reduction in the scale of Borg post-6MWT (p = 0.009). There was no significant change in any biochemical data or in KT/Vsp. There was increase in left ventricular ejection from 65.7 ± 10.2% to 73.6 ± 10.1% (p = 0.028) and in left ventricular diastolic diameter (p = 0.027). According to SF-36 survey, patients showed improvement in three areas: physical role functioning (p = 0.012), bodily pain (p = 0.007) and vitality (p = 0.009). CONCLUSION: The intradialytic CRehab applied in this population was safe and allowed objective improvement of functional capacity and exercise tolerance, subjective improvement in the perception of effort, significant increase in cardiac function and better quality of life in different domains.
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Ejercicio Físico , Fallo Renal Crónico/terapia , Diálisis Renal , Rehabilitación Cardiaca , Prueba de Esfuerzo , Tolerancia al Ejercicio , Femenino , Pruebas de Función Cardíaca , Humanos , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de VidaRESUMEN
Hyperparathyroidism, vitamin D deficiency, increased fibroblast growth factor-23 (FGF-23), and metabolic acidosis promote bone fragility in chronic kidney disease (CKD). Although useful in predicting fracture risk in the general population, the role of dual-energy X-ray absorptiometry (DXA) in CKD remains uncertain. This cross-sectional study included 51 men aged 50-75 yr with moderate CKD. The stage 4 CKD patients had higher levels of parathyroid hormone (p<0.001), FGF-23 (p=0.029), and lowest 25-hydroxyvitamin D (p=0.016), bicarbonate (p<0.001), total femur (p=0.003), and femoral neck (p=0.011) T-scores compared with stage 3 CKD patients. Total femur and femoral neck T-scores were directly correlated with serum bicarbonate (p=0.003, r=0.447 and p=0.005, r=0.427, respectively) and estimated glomerular filtration rate (p=0.024, r=0.325 and p=0.003, r=0.313, respectively) but were not significantly associated with parathyroid hormone, 25-hydroxyvitamin D, or FGF-23. Only 3.9% of the participants had osteoporosis on DXA scan, whereas 31.4% reported a low-impact fracture. Our data point to a pivotal role of metabolic acidosis for bone impairment and to the inadequacy of DXA to evaluate bone fragility in CKD patients.
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Acidosis , Densidad Ósea , Fémur , Fracturas Osteoporóticas , Insuficiencia Renal Crónica , Absorciometría de Fotón/métodos , Acidosis/etiología , Acidosis/metabolismo , Anciano , Brasil , Estudios Transversales , Fémur/diagnóstico por imagen , Fémur/metabolismo , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Tasa de Filtración Glomerular , Humanos , Hiperparatiroidismo/etiología , Hiperparatiroidismo/metabolismo , Masculino , Persona de Mediana Edad , Fracturas Osteoporóticas/etiología , Fracturas Osteoporóticas/metabolismo , Valor Predictivo de las Pruebas , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Reproducibilidad de los Resultados , Índice de Severidad de la Enfermedad , Estadística como Asunto , Deficiencia de Vitamina D/etiología , Deficiencia de Vitamina D/metabolismoRESUMEN
PURPOSE: To evaluate nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappaB (NF-κB) mRNA expression in nondialysis chronic kidney disease (CKD) patients, comparing with data from hemodialysis (HD) patients and healthy individuals. METHODS: Twenty nondialysis CKD patients (62.0 ± 8.1 years old, 11 men, estimated glomerular filtration rate of 36.8 ± 13.6 mL/min/1.73 m(2)), twenty HD patients (55.0 ± 15.2 years old, 13 men, and dialysis vintage of 76.5 ± 46.3 months) and eleven healthy individuals (50.9 ± 8.0 years old, 6 men) were enrolled in the study. The peripheral blood mononuclear cells were isolated and processed for the evaluation of expression of NF-κB and Nrf2 by quantitative real-time polymerase chain reaction. RESULTS: Nrf2 mRNA expression was significantly higher in nondialysis (1.12 ± 0.57) when compared to HD patients (0.58 ± 0.35, p = 0,006) but similar to healthy individuals (1.13 ± 0.64). Inversely, NF-κB mRNA expression was lower in nondialysis (1.21 ± 0.71) when compared to HD patients (2.08 ± 0.7, p < 0.0001) and similar to healthy individuals (1.04 ± 0.22). Nrf2 mRNA was positively correlated with NF-κB mRNA expression in nondialysis CKD patients (r = 0.52, p = 0.02) and healthy individuals (r = 0.77, p < 0.006). By contrast, Nrf2 mRNA was inversely correlated with NF-κB mRNA expression (r = -0.65, p = 0.003) in HD patients. CONCLUSION: Nondialysis CKD patients may conserve regular homeostatic balance between Nrf2 and NF-κB expressions, being comparable to healthy individuals. However, HD patients seem to have Nrf2 downregulation and NF-κB upregulation. Thus, the association among Nrf2 and NF-κB expressions and nutritional status, kidney disease progression or immune deregulation deserve further investigation.
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Factor 2 Relacionado con NF-E2/genética , FN-kappa B/genética , ARN Mensajero/sangre , Insuficiencia Renal Crónica/genética , Adulto , Anciano , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Estudios Transversales , Femenino , Expresión Génica , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Diálisis Renal , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/terapia , Factor de Necrosis Tumoral alfa/sangreRESUMEN
AIM: The focus in renal transplantation is to increase long-term allograft survival. One of the limiting factors is calcineurin inhibitor (CNI)-induced fibrosis. This study attempted to examine the histological aspect of interstitial fibrosis and the modulation of the transforming growth factor-ß (TGF-ß) canonical signalling pathway following early withdrawal of CNI from sirolimus-based immunosuppressive therapy. METHODS: Forty-five kidney transplant recipients with low-medium immunologic risk were randomized and underwent protocol biopsies obtained at the time of transplantation and at 3 and 12 months thereafter. The recipients were taking tacrolimus, sirolimus and prednisone. After the 3rd month, patients were randomized into two groups: sirolimus (SRL) (removed CNI and increased sirolimus) and tacrolimus (TAC) (maintained CNI). Renal biopsies were analyzed according to Banff's 2007 criteria. The sum of Banff's ct and ci constituted the chronicity index. Fibrosis was evaluated by the histomorphometrical analysis of the total collagen and myofibroblast deposition. Immunohistochemical characterization and quantification of TGF-ß, TGF-ß receptor 1 (TGF-ß-R1), receptor 2 (TGF-ß-R2) and phospho-Smad2/3 (p-Smad2/3) were performed. RESULTS: Maintenance of CNI was associated with the increase of the surface density of collagen and α-smooth muscle actin (α-SMA), (P = 0.001). Furthermore, increased TGF-ß (P = 0.02), TGF-ß-R1 (P = 0.02), p-Smad2/3 (P = 0.03) and stabilized TGF-ß-R2. On the other hand, the removal of CNI with increase in the dose of sirolimus limited the enhancement of the chronicity index at 12 m (SRL, 2.18 vsâ TAC, 3.12, P = 0.0007), diminished the deposition of fibrosis and promoted the stabilization of TGF-ß, TGF-ß-R2, p-Smad2/3 and myofibroblasts as well as the reduction of TGF-ß-R1 (P = 0.01). CONCLUSION: The early withdrawal of CNI limited the fibrosis progression through the stabilization of chronicity index and of the canonical TGF-ß signalling pathway.
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Inhibidores de la Calcineurina/administración & dosificación , Rechazo de Injerto/prevención & control , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Riñón/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sirolimus/administración & dosificación , Tacrolimus/administración & dosificación , Factor de Crecimiento Transformador beta/metabolismo , Adulto , Biopsia , Brasil , Inhibidores de la Calcineurina/efectos adversos , Colágeno/metabolismo , Esquema de Medicación , Quimioterapia Combinada , Femenino , Fibrosis , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/inmunología , Rechazo de Injerto/metabolismo , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunohistoquímica , Inmunosupresores/efectos adversos , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patología , Estudios Prospectivos , Sirolimus/efectos adversos , Tacrolimus/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Heparanase-1 activation, albuminuria, and a decrease in glomerular heparan sulfate (HS) have been described in diabetic nephropathy (DN). Glycosaminoglycan (GAG)-based drugs have been shown to have renoprotective effects in this setting, although recent trials have questioned their clinical effectiveness. Here, we describe the effects of fucosylated chondroitin sulfate (FCS), a novel GAG extracted from a marine echinoderm, in experimentally induced DN compared to a widely used GAG, enoxaparin (ENX). METHODS: Diabetes mellitus (DM) was induced by streptozotocin in male Wistar rats divided into three groups: DM (without treatment), FCS (8 mg/kg), and ENX (4 mg/kg), administered subcutaneously. After 12 weeks, we measured blood glucose, blood pressure, albuminuria, and renal function. The kidneys were evaluated for mesangial expansion and collagen content. Immunohistochemical quantifications of macrophages, TGF-ß, nestin and immunofluorescence analysis of heparanase-1 and glomerular basement membrane (GBM) HS content was also performed. Gene expression of proteoglycan core proteins and enzymes involved in GAG assembly/degradation were analyzed by TaqMan real-time PCR. RESULTS: Treatment with GAGs prevented albuminuria and did not affect the glucose level or other functional aspects. The DM group exhibited increased mesangial matrix deposition and tubulointerstitial expansion, and prevention was observed in both GAG groups. TGF-ß expression and macrophage infiltration were prevented by the GAG treatments, and podocyte damage was halted. The diabetic milieu resulted in the down-regulation of agrin, perlecan and collagen XVIII mRNAs, along with the expression of enzymes involved in GAG biosynthesis. Treatment with FCS and ENX positively modulated such changes. Heparanase-1 expression was significantly reduced after GAG treatment without affecting the GBM HS content, which was uniformly reduced in all of the diabetic animals. CONCLUSIONS: Our results demonstrate that the administration of FCS prevented several pathological features of ND in rats. This finding should stimulate further research on GAG treatment for this complication of diabetes.
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Sulfatos de Condroitina/farmacología , Sulfatos de Condroitina/uso terapéutico , Citoprotección/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Riñón/efectos de los fármacos , Albuminuria/metabolismo , Animales , Colágeno/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Glicosaminoglicanos/farmacología , Glicosaminoglicanos/uso terapéutico , Riñón/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Ratas , Ratas Wistar , EstreptozocinaRESUMEN
Primary Sjögren's syndrome (pSS) is an important cause of renal tubular dysfunction in adults, mainly due to acquired type 1 distal renal tubular acidosis (RTA 1) and concentration defects (CD). This cross-sectional study evaluated renal tubular function of patients with pSS, by detecting proximal tubular injury (through measurements of urinary ß2 microglobulin and albumin), RTA 1 (through an acidification protocol using furosemide and fludrocortisone), and CD (through water deprivation test, WDT). A total of 25 patients with pSS were evaluated and despite a preserved renal function (eGFR 92.5 ± 26.3 mL/min/1.73 m(2)), 24% were diagnosed as RTA 1. On the other hand, CD was diagnosed in 28% of the patients who presented worse renal function (eGFR 68.6 ± 27.7 mL/min/1.73 m(2)). Increased ß2 microglobulin was found in 16% of the patients, and all of them had impaired renal function (eGFR 39.5 ± 11.9 mL/min/1.73 m(2)). These data showed a high prevalence of tubular dysfunction, mainly RTA 1 and CD, in patients with pSS, and suggest that patients with this disorder should be evaluated by the acidification protocol used in this study and WDT for proper diagnosis. Proximal tubular injury was less common, and probably associated with worsening of renal function.
Asunto(s)
Acidosis Tubular Renal/epidemiología , Túbulos Renales/fisiopatología , Síndrome de Sjögren/epidemiología , Acidosis Tubular Renal/diagnóstico , Acidosis Tubular Renal/fisiopatología , Albuminuria/epidemiología , Albuminuria/fisiopatología , Análisis de Varianza , Biomarcadores/orina , Brasil/epidemiología , Distribución de Chi-Cuadrado , Estudios Transversales , Tasa de Filtración Glomerular , Humanos , Capacidad de Concentración Renal , Prevalencia , Pronóstico , Factores de Riesgo , Síndrome de Sjögren/diagnóstico , Microglobulina beta-2/orinaRESUMEN
BACKGROUND: Heparins from porcine and bovine intestinal mucosa differ in their structure and also in their effects on coagulation, thrombosis and bleeding. However, they are used as undistinguishable drugs. METHODS: We compared bovine and porcine intestinal heparin administered to patients undergoing a particular protocol of haemodialysis. We compared plasma concentrations of these two drugs and also evaluated how they affect patients and the dialyzer used. RESULTS: Compared with porcine heparin, bovine heparin achieved only 76% of the maximum plasma concentration as IU mL⻹. This observation is consistent with the activities observed in the respective pharmaceutical preparations. When the plasma concentrations were expressed on weight basis, bovine heparin achieved a maximum concentration 1.5 fold higher than porcine heparin. The reduced anticoagulant activity and higher concentration, on weight basis, achieved in the plasma of patients under dialysis using bovine instead of porcine heparin did not affect significantly the patients or the dialyzer used. The heparin dose is still in a range, which confers security and safety to the patients. DISCUSSION: Despite no apparent difference between bovine and porcine intestinal heparins in the haemodialysis practice, these two types of heparins should be used as distinct drugs due to their differences in structure and biological effects. CONCLUSIONS: The reduced anticoagulant activity achieved in the plasma of patients under dialysis using bovine instead of porcine heparin did not affect significantly the patients or the dialyzer.
Asunto(s)
Heparina/farmacología , Diálisis Renal , Animales , Bovinos , Heparina/sangre , Humanos , Espectroscopía de Resonancia Magnética , Preparaciones Farmacéuticas , PorcinosRESUMEN
The nuclear factor E2-related factor 2 (Nrf2) plays an important role in cellular protection against cancer, renal, pulmonary, cardiovascular and neurodegenerative diseases where oxidative stress and inflammation are common conditions. The Nrf2 regulates the expression of detoxifying enzymes by recognizing the human Antioxidant Response Element (ARE) binding site and it can regulate antioxidant and anti-inflammatory cellular responses, playing an important protective role on the development of the diseases. Studies designed to investigate how effective Nrf2 activators or modulators are need to be initiated. Several recent studies have shown that nutritional compounds can modulate the activation of Nrf2-Keap1 system. This review aims to discuss some of the key nutritional compounds that promote the activation of Nrf2, which may have impact on the human health.
Asunto(s)
Antioxidantes/farmacología , Dietoterapia , Inflamación/terapia , Factor 2 Relacionado con NF-E2/metabolismo , Catequina/farmacología , Disulfuros , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Resveratrol , Transducción de Señal , Estilbenos/farmacología , Ácidos Sulfínicos/farmacologíaRESUMEN
Inflammation and oxidative stress are two major components involved in the atherogenic process generated by the innate immune response to lipoprotein peroxidation, which is accelerated in patients with chronic kidney disease (CKD). Whereas the redox-sensitive transcription factor nuclear factor-κB (NF-κB) plays an important role in the coordinated expression of inflammatory genes, the nuclear factor E2-related factor 2 (Nrf2) is the transcription factor that is responsible for both constitutive and inducible expression of antioxidant response element (ARE)-regulated genes. Thus, Nrf2 can regulate antioxidant and anti-inflammatory cellular responses of this system, playing an important protective role on the development of the uremic phenotype. This review describes the Nrf2 system and its possible role in CKD patients.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Insuficiencia Renal Crónica/metabolismo , Animales , Elementos de Respuesta Antioxidante/genética , Regulación de la Expresión Génica , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2/genética , FN-kappa B/genética , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Zinc-α2-glycoprotein (ZAG) is a lipid mobilizing factor. Its anti-inflammatory action and expression pattern suggest that ZAG could act by protecting against the obesity-associated disorders. In hemodialysis (HD) patients, ZAG levels were described to be elevated but its effects on markers of inflammation and LDL oxidation are still unclear. We investigated the relationship between ZAG and markers of systemic inflammation and LDL atherogenic modification profile in HD patients. METHODS: Forty-three patients regularly on HD were studied and compared to 20 healthy subjects. Plasma ZAG, adiponectin, electronegative LDL [LDL(-)], an atherosclerotic negatively charged LDL subfraction, and anti-LDL(-) autoantibodies levels were measured by ELISA. Markers of inflammation and atherogenic cell recruitment (TNF-α, interleukin-6, VCAM-1, ICAM-1, MCP-1 and PAI-1) were also determined. RESULTS: Inflammatory markers and atherogenic cell recruitment were higher in HD patients when compared to healthy subjects. ZAG levels were also higher in HD patients (151.5 ± 50.1 mg/l vs 54.6 ± 23.0 mg/l; p<0.0001) and its levels were negatively correlated with TNF-α (r=-0.39; p=0.001) and VCAM-1 (r=-0.52; p<0.0001) and, positively correlated with anti-LDL(-) autoantibodies (r=0.38; p=0.016). On multivariate analyses, plasma ZAG levels were independently associated with VCAM-1 (p=0.01). CONCLUSION: ZAG is inversely associated with markers of pro-atherogenic factors linked to systemic inflammation and oxidative stress. Thus, this adipokine may constitute a novel marker of a favorable metabolic profile regarding cardiovascular risk factors in HD population.