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RATIONALE & OBJECTIVE: Genetic etiologies have been identified among approximately 10% of adults with chronic kidney disease (CKD). However, data are lacking regarding the prevalence of monogenic etiologies especially among members of minority groups. This study characterized the genetic markers among members of an Israeli minority group with end-stage kidney disease (ESKD). STUDY DESIGN: A national-multicenter cross-sectional study of Israeli Druze patients (an Arabic-speaking Near-Eastern transnational population isolate) who are receiving maintenance dialysis for ESKD. All study participants underwent exome sequencing. SETTING & PARTICIPANTS: We recruited 94 adults with ESKD, comprising 97% of the total 97 Druze individuals throughout Israel being treated with dialysis during the study period. PREDICTORS: Demographics and clinical characteristics of kidney disease. OUTCOME: Genetic markers. ANALYTICAL APPROACH: Whole-exome sequencing and the relationship of markers to clinical phenotypes. RESULTS: We identified genetic etiologies in 17 of 94 participants (18%). None had a previous molecular diagnosis. A novel, population-specific, WDR19 homozygous pathogenic variant (p.Cys293Tyr) was the most common genetic finding. Other monogenic etiologies included PKD1, PKD2, type IV collagen mutations, and monogenic forms of noncommunicable diseases. The pre-exome clinical diagnosis corresponded to the final molecular diagnosis in fewer than half of the participants. LIMITATIONS: This study was limited to Druze individuals, so its generalizability may be limited. CONCLUSIONS: Exome sequencing identified a genetic diagnosis in approximately 18% of Druze individuals with ESKD. These results support conducting genetic analyses in minority populations with high rates of CKD and for whom phenotypic disease specificity may be low. PLAIN-LANGUAGE SUMMARY: Chronic kidney disease (CKD) affects many people worldwide and has multiple genetic causes. However, there is limited information on the prevalence of genetic etiologies, especially among minority populations. Our national-multicenter study focused on Israeli Druze patients. Using exome-sequencing, we identified previously undetected genetic causes in nearly 20% of patients, including a new and population-specific WDR19 homozygous pathogenic variant. This mutation has not been previously described; it is extremely rare globally but is common among the Druze, which highlights the importance of studying minority populations with high rates of CKD. Our findings provide insights into the genetic basis of end-stage kidney disease in the Israeli Druze, expand the WDR19 phenotypic spectrum, and emphasize the potential value of genetic testing in such populations.
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Fallo Renal Crónico , Insuficiencia Renal Crónica , Adulto , Humanos , Grupos Minoritarios , Israel/epidemiología , Marcadores Genéticos , Estudios Transversales , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/genética , Fallo Renal Crónico/terapia , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/diagnóstico , Poblaciones Minoritarias, Vulnerables y Desiguales en SaludRESUMEN
Background: Type 2 diabetes mellitus (T2DM), especially hyperglycemia, is associated with increased glucose cell toxicity and oxidative stress that can lead to irreversible damage in the kidney such as diabetic nephropathy (DN). Autophagy plays a key role in the degradation of damaged intracellular proteins in order to maintain intracellular homeostasis and cell integrity. The disturbance of autophagy is involved in the pathogenesis of diabetic nephropathy. We aim to investigate the molecular effect of sodium-glucose transporter 2 inhibitor (SGLT2i) on the expression of ATG5 and its downstream collaborator LC3-II in diabetic nice model. Material and Methods. We used eight weeks old male mice: twenty C57BL/6 wild type (C57BL/6), twenty BTBR ob/ob (DM), and twenty BTBR ob/ob that were treated with empagliflozin (DM+EMPA), FDA approved SGLT2i. Lysate from murine renal cortex was analyzed by Western blot and immunohistochemistry. ATG5, LC3B, and fibronectin expression were analyzed in murine kidney tissues. All mice were sacrificed 13 weeks after the beginning of the experiment. Results: Histological and Western blot analyses reveal decrease ATG5, LC3-II, and fibronectin levels at renal specimens taken from DM mice. EMPA treatment reduced T2DM mice body weight and blood glucose and increased urine glucose. Further, it upregulated all of the abovementioned proteins. Conclusions: Hyperglycemia reduces LC3-II and ATG5 protein levels which contribute to deficiencies in the autophagy process, with development and progression of DN. SGLT2i significantly reduces progression of DN and onset of end-stage renal disease in T2DM patients, probably through its effect on autophagy.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Hiperglucemia , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Masculino , Ratones , Animales , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Fibronectinas , Ratones Endogámicos C57BL , Glucemia/metabolismo , Autofagia , Hiperglucemia/metabolismoRESUMEN
BACKGROUND: Autophagy is a catabolic mechanism that involves lysosomal-dependent degradation of unnecessary intracellular components and responsible for normal cellular homeostasis. Autophagy pathway and its key participant ATG5/LC3 are associated with several pathologies such as diabetes mellitus and its complications. METHODS: Levels and expression of autophagy key components ATG5 and LC3B were analyzed in both human model and murine tissues. One hundred and twenty human subjects were divided into four groups: Healthy (control), diabetes mellitus without complications, diabetic nephropathy, and diabetic retinopathy. Additionally, we used kidneys from WT healthy and diabetic nephropathy mice. Lysate derived from human peripheral blood mononuclear cells and murine renal cortex lysates were subjected to western blot and immunohistochemical analysis. RESULTS: Western blot and immunohistochemical analysis demonstrate that ATG5 protein levels were significantly decreased in diabetes mellitus, diabetic nephropathy (DN), and diabetic retinopathy patients versus healthy controls and in DN mice compared to healthy mice (0.65 ± 0.04; 1.15 ± 0.13 A.U. units, respectively). Quantification of staining area (%) of ATG5 mice tissue expression also decreased in DN versus healthy mice (4.42 ± 1.08%; 10.87 ± 1.01%, respectively). LC3B LEVELS AND EXPRESSION: Significant reduction in peripheral blood mononuclear cells in diabetic patients (with or without complications) vs. healthy controls. Renal LC3B levels were lower in DN versus healthy mice (0.36 ± 0.03; 0.68 ± 0.07 A.U. units). Renal LC3B staining quantification revealed significant reduction in DN versus healthy mice (1.7 ± 0.23%; 8.56 ± 1.7%). CONCLUSION: We conclude that ATG5, as well as LC3B, are down regulated in diabetic patients with or without complications. This diminution contributes to deficiencies in the autophagy process.
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Diabetes Mellitus , Nefropatías Diabéticas , Animales , Autofagia , Proteína 5 Relacionada con la Autofagia/genética , Nefropatías Diabéticas/genética , Expresión Génica , Humanos , Leucocitos Mononucleares , RatonesRESUMEN
INTRODUCTION: Diabetes mellitus (DM) is the leading cause of end stage renal disease; 40% of the patients worldwide will require replacement therapy after 20 years of DM. Early-stage diabetic nephropathy is characterized by hyper filtration with micro-and macro albuminuria. Later on end-stage renal disease (ESRD) can appear; 40% of diabetic patients develop micro-and macrovascular complications, with increased risk among patients with genetic predisposition, such as Haptoglobin 2-2 phenotype. The most frequent complications are diabetic kidney disease, diabetic retinopathy and coronary artery disease. Chronic systemic inflammation and the inflammatory response, such as increased circulating cytokines have been recognized as main players in the development and progression of diabetic nephropathy. DM is also associated with increased oxidative stress, and alterations in carbohydrate, lipid and protein metabolism. Blocking the renin- angiotensin- aldosterone system (RAAS) is not sufficient to delay the progression of DM. Autophagy may be involved in the pathogenesis of diabetic nephropathy. Under normal blood glucose level, autophagy is an important protective mechanism in renal epithelial cells, including podocytes, proximal tubular, mesangial and endothelial cells. Down regulation of the autophagy mechanism, as in hyperglycemic condition, can contribute to the development and progression of DM. The recently used new family of drugs SGL2Tis (sodium-glucose cotransporter-2 inhibitors) reduces the typical glomerular hyper-filtration. Preclinical and clinical studies focusing on SGLT2I treatment have consistently demonstrated a reduction in albuminuria and maintenance of renal function. SGLT2 inhibition may lead to positive molecular changes in podocyte cells and proximal tubule cells by directly affect basal autophagy.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Autofagia , Nefropatías Diabéticas/etiología , Células Endoteliales , HumanosRESUMEN
BACKGROUND: Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes and is the leading cause of end-stage renal disease (ESRD) and replacement therapy worldwide. Vitamin D levels in DN patients are very low due to the decrease in the synthesis and activity of 1-α hydroxylase in the proximal tubule cells and decrease in the vitamin D receptor abundance. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The selective activator of the vitamin D receptor, paricalcitol, reduces proteinuria and slows the progression of kidney injury. The precise mechanism through which vitamin D affects diabetic status and provides kidney protection remains to be determined. METHODS: Diabetes mellitus (DM) was induced in 94 8-week-old DBA/2J mice by intraperitoneal injection of streptozotocin (STZ). DM mice were randomly divided into receiving vehicle or treatment with paricalcitol, the active vitamin D analog, 1 week after DM induction or paricalcitol treatment 3 weeks after DM induction. An additional control group of healthy wild-type mice was not treated. Urine albumin, blood urea nitrogen, and creatinine levels were measured before and at the end of the paricalcitol treatment. Periodic acid-Schiff, immunohistochemistry staining, and western blot of the renal tissues of vitamin D receptor, villin, nephrin, and podocin expressions, were analyzed. RESULTS: Paricalcitol treatment restored villin, nephrin, and podocin protein levels that were downregulated upon DM induction, and reduced fibronectin protein level. Vitamin D receptor activation by paricalcitol may reduce proteinuria of DN in mice and alleviate high-glucose-induced injury of kidney podocytes by regulating the key molecules such nephrin-podocin. CONCLUSIONS: Paricalcitol treatment was associated with improved structural changes in type 1 diabetic mice including upregulation of vitamin D receptor expression, and decreased fibrosis markers such as fibronectin. These effects may contribute to the consistent benefit of vitamin D analog to slow the deterioration in glomerular function and reduce the risk of ESRD in patients with type 1 and 2 diabetes mellitus. Our results suggest that additional use of paricalcitol may be beneficial in treating patients with diabetes under standard therapeutic strategies.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Nefropatías Diabéticas/prevención & control , Ergocalciferoles/farmacología , Riñón/efectos de los fármacos , Proteinuria/prevención & control , Receptores de Calcitriol/agonistas , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Fibronectinas/metabolismo , Fibrosis , Riñón/metabolismo , Riñón/patología , Ratones Endogámicos DBA , Proteinuria/etiología , Proteinuria/metabolismo , Proteinuria/patología , Receptores de Calcitriol/metabolismo , EstreptozocinaRESUMEN
Diabetes mellitus (DM) is the leading cause of end stage renal disease. 40% of the patients worldwide will require replacement therapy after 20 years of DM worldwide. Early-stage diabetic nephropathy is characterized by hyperfiltration related to hypeglycemia-induced afferent artery vasodilatation with micro-and macroalbuminuria. Later on, proteinuria with arterial hypertension may appear, culminating in glomerular filtration rate (GFR) decline and end stage renal disease. Forty percent of diabetic patients develop microvascular and macrovascular complications, with increased risk among patients with genetic predisposition, such as Haptoglobin 2-2 phenotype. The most frequent complications in the daily clinical practice are diabetic kidney disease, diabetic retinopathy and vascular disease, such as coronary artery disease and stroke. Various pathways are involved in the pathogenesis of diabetic kidney disease. Chronic systemic inflammation and the inflammatory response, such as increased circulating cytokines (Interleukins), have been recognized as main players in the development and progression of diabetic kidney disease. DM is also associated with increased oxidative stress, and alterations in carbohydrate, lipid and protein metabolism. Overexpression of the renin-angiotensin-aldosterone system (RAAS) in the kidney, the vitamin D-Vitamin D receptor-klotho axis, and autophagy. Differences in the ATG5 protein levels or ATG5 gene expression involved in the autophagy process have been associated with diabetic complications such as diabetic kidney disease. Under normal blood glucose level, autophagy is an important protective mechanism in renal epithelial cells, including podocytes, proximal tubular, mesangial and endothelial cells. Down regulation of the autophagic mechanism, as in hyperglycemic condition, can contribute to the development and progression of diabetic kidney disease.
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Autofagia , Nefropatías Diabéticas/fisiopatología , Autofagia/fisiología , Nefropatías Diabéticas/complicaciones , HumanosRESUMEN
OBJECTIVE: Inflammation plays a major role in albuminuria in type 2 diabetes mellitus (T2DM). Our previous studies have shown that the expression of vitamin D receptor (VDR) is downregulated in T2DM which is closely associated with the severity of albuminuria. In this study, we investigated the expression of anti-inflammatory cytokine protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in T2DM and explored its relationship to albuminuria and VDR. METHODS: 101 T2DM patients were divided into three groups based on urinary albumin-to-creatinine ratio (uACR): normal albuminuria (uACR < 30 mg/g, n = 29), microalbuminuria (30 mg/g ≤ uACR < 300 mg/g, n = 34), and macroalbuminuria (uACR ≥ 300 mg/g, n = 38). Thirty healthy individuals were included as controls. Serum was analyzed for PTPN2 and IL-6 expression, and peripheral blood mononuclear cells (PBMCs) were analyzed for PTPN2 and VDR expression. THP-1 cells were incubated with high glucose and further treated with or without paricalcitol, a vitamin D analog. The levels of PTPN2, VDR, IL-6, TNFα, and MCP-1 were analyzed. In addition, anti-inflammatory activities of PTPN2 were further explored in THP-1 cells stimulated with high glucose after PTPN2 silencing or overexpression. RESULTS: PTPN2 expression was downregulated in T2DM with the lowest level observed in macroalbuminuria patients. PTPN2 level positively correlated with VDR but negatively correlated with uACR and IL-6. When stimulated with high glucose, there was an increase in inflammatory factors and a decrease in PTPN2 expression. Treatment with paricalcitol reversed these effects. However, paricalcitol failed to exert anti-inflammatory effects in the setting of PTPN2 knockdown. Thus, low levels of PTPN2 aggravated glucose-stimulated inflammation, while high levels of PTPN2 reduced it. CONCLUSION: PTPN2, an anti-inflammatory factor regulated by VDR, was reduced in T2DM CKD stages 1-2. Taken together, our results suggest that therapeutic strategies that enhance PTPN2 may be beneficial for controlling inflammation in T2DM.
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Albuminuria/etiología , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/etiología , Inflamación/etiología , Proteína Tirosina Fosfatasa no Receptora Tipo 2/sangre , Receptores de Calcitriol/deficiencia , Insuficiencia Renal Crónica/etiología , Adulto , Anciano , Albuminuria/sangre , Albuminuria/diagnóstico , Albuminuria/orina , Biomarcadores/sangre , Biomarcadores/orina , Estudios de Casos y Controles , Quimiocina CCL2/metabolismo , Creatinina/orina , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/orina , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/orina , Regulación hacia Abajo , Femenino , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Inflamación/orina , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Receptores de Calcitriol/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/orina , Células THP-1 , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The haptoglobin (Hp) genotype (1-1 and 2-2) is a major determinant of nephropathy progression in diabetes mellitus patients. Hp 2-2 diabetic mice have impaired Hb clearance and increased iron deposits and oxidative stress in the proximal tubules (PCT), leading to increased renal injury. However, the precise mechanism of the PCT injury in diabetic nephropathy (DN) remains elusive. In the kidney, 1,25(OH)2D3 suppresses the inflammatory response to renal tubular injury and requires normal renal expression of the α-klotho protein. In this study, we set out to test the hypothesis that the increased renal iron deposits in the PCT of Hp 2-2 DN affect the α-klotho-vitamin D receptor (VDR) axis and thereby exacerbates the PCT injury generated by the iron deposits. Immunohistochemical analysis of human and mouse kidney biopsies along with western blot analysis showed that the increased iron deposits in the PCT of the Hp 2-2 genotype were accompanied with significantly decreased α-klotho and VDR renal expression but significantly increased 1-α-hydroxylase renal expression. In conclusion, the iron-klotho-VDR axis is a major player in the mechanism contributing to iron-mediated PCT injury in diabetic Hp 2-2 mice and patients. Targeting this axis may open the way for new ideas regarding the pathogenesis and treatment of DN.
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Nefropatías Diabéticas/metabolismo , Glucuronidasa/metabolismo , Haptoglobinas/genética , Hierro/metabolismo , Túbulos Renales Proximales/metabolismo , Receptores de Calcitriol/metabolismo , Insuficiencia Renal Crónica/metabolismo , Adulto , Anciano , Animales , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/patología , Modelos Animales de Enfermedad , Femenino , Genotipo , Haptoglobinas/metabolismo , Humanos , Túbulos Renales Proximales/patología , Proteínas Klotho , Masculino , Ratones , Persona de Mediana Edad , Estrés Oxidativo , Insuficiencia Renal Crónica/patología , Adulto JovenRESUMEN
We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.
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Pruebas Respiratorias , Enfermedad/clasificación , Nanopartículas del Metal/química , Nanotubos de Carbono/química , Reconocimiento de Normas Patrones Automatizadas , Compuestos Orgánicos Volátiles/análisis , Adulto , Inteligencia Artificial , Técnicas Biosensibles , Estudios de Casos y Controles , Femenino , Oro/química , Humanos , Masculino , Persona de Mediana EdadRESUMEN
INTRODUCTION: The antioxidant protein haptoglobin (Hp) plays a major role in the development of diabetic complications such as diabetic nephropathy and retinopathy. In humans, two alleles of Hp were identified: 1 and 2 with three possible genotypes: 1-1, 2-1, and 2-2. The Hp protein products differ in their biochemical and biophysical properties, such as their antioxidant capacity. The Hp1 protein is superior to the Hp2 protein in binding to free hemoglobin and neutralizing its oxidative potential and the accompanying renal and retinal injury. Hence, diabetic patients with different Hp phenotypes have variable susceptibility to developing diabetic nephropathy and retinopathy. In diabetes, the kidney and the retinal injury progress gradually over time. Thus, understanding the factors that mediate the aggravation and progression of these complications is of critical importance. One of the latest hypotheses regarding the involvement of haptoglobin in the development of diabetic complications is its contribution to impaired vitamin D activation in the kidney. Over the last few years, great efforts were made in the field to explore this notion and decrypt the mechanism behind it. The goal in this area is that the research findings will be translated into clinical practice and lead to the development of a pharmacogenomics clinical approach that will deal with diabetic complications by selective administration of vitamin D according to the Hp genotype.
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Nefropatías Diabéticas/genética , Retinopatía Diabética/genética , Haptoglobinas/genética , Haptoglobinas/fisiología , Antioxidantes , Nefropatías Diabéticas/metabolismo , Retinopatía Diabética/metabolismo , Genotipo , Humanos , Polimorfismo GenéticoRESUMEN
Elevated systolic pulmonary artery pressure (s-PAP, ≥35 mmHg) serves as an independent predictor of mortality in hemodialysis (HD) and diabetic (DM) patients. A polymorphism in the antioxidant Haptoglobin (Hp) gene has been shown to regulate the bioavailability of nitric oxide (NO), a major mediator of pulmonary vascular tone. We therefore set out to test the hypothesis that the Hp polymorphism may be a determinant of developing elevated s-PAP specifically in the DM state due to a decreased bioavailability of NO. To test our hypothesis we Hp typed and performed transthoracic echocardiography on a series of HD patients and stratified them into elevated and normal s-PAP groups and then evaluated whether there was a significant association between the Hp type, elevated s-PAP, and decreased NO bioavailability as defined by low plasma nitrite. We found a statistically significant interaction between the Hp type and DM on the prevalence of elevated s-PAP and lower mean nitrite levels with the combination of elevated s-PAP and low nitrite levels being significantly more prevalent in Hp 2-2 DM individuals. We conclude that the Hp 2 type is associated with elevated s-PAP levels and low plasma nitrite levels in HD patients specifically in the DM state.
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Presión Arterial , Diabetes Mellitus/metabolismo , Haptoglobinas/genética , Hipertensión Pulmonar/metabolismo , Fallo Renal Crónico/metabolismo , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Arteria Pulmonar/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Estudios Transversales , Complicaciones de la Diabetes , Ecocardiografía , Femenino , Humanos , Hipertensión Pulmonar/genética , Fallo Renal Crónico/terapia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo Genético , Presión Esfenoidal Pulmonar , Diálisis RenalRESUMEN
PATIENT: Female, 77. FINAL DIAGNOSIS: Bacteremia. SYMPTOMS: Chills ⢠diarrhea ⢠fever ⢠nausea. MEDICATION: - CLINICAL PROCEDURE: X-Ray ⢠CBC ⢠urine and blood cultur. SPECIALTY: Infectious diseases. OBJECTIVE: Rare disease. BACKGROUND: Cedecea davisae is a gram negative, oxidase negative bacilli that include 5 species. In the medical literature there are very few reports that describe infections caused by different species of the Cedecea genus. CASE REPORT: In this paper we report a fourth case of bacteremia in a 77 year-old patient with a chronic renal disease that was successfully treated with ceftazidim and ciprofloxacin. Additionally, we present a review of all the reported infections that were caused by C. davisae. CONCLUSIONS: Five cases (not including our report) of Cedecea bacteremia were reported so far. Cedecea infections and particularly C. davisae infections can be difficult to treat due to the antibiotic resistance of the bacterium. Therefore we propose to consider treating C. davisae bacteremia with a combined antibiotic treatment until getting laboratory results for antibiotic-sensitivity tests.
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Diabetic nephropathy (DN) is the leading cause of end stage renal disease and dialysis worldwide. Despite aggressive treatment, the number of patients on hemodialysis due to type 1 and type 2 diabetes mellitus is increasing annually. The lack of reliable animal models that mimic human disease has delayed the identification of specific factors that cause or predict DN. Different investigators around the world are testing different murine models. Validation criteria for early and advanced DN, phenotypic methods, background strain have recently been developed. Establishment of an authentic mouse model of DN will undoubtedly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN and to study new treatments. Here we describe the characteristics of our new mouse model with type 1 diabetes mellitus and different haptoglobin genotypes that can mimic human DN.
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Nefropatías Diabéticas/patología , Albuminuria/patología , Animales , Diabetes Mellitus Tipo 1/patología , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Tasa de Filtración Glomerular/fisiología , RatonesRESUMEN
BACKGROUND: Staphylococcus aureus infective endocarditis (IE) is a characteristic community-acquired infection, however most cases are presently occurring in the health care setting. This study investigated the incidence and risk factors for S. aureus IE in patients with nosocomial and health care-associated S. aureus bacteraemia (SAB). METHODS: Consecutive patients with health care-associated and hospital-acquired SAB were prospectively recruited over a 30-month period. Patients were followed up for at least 12 weeks after the initial positive blood culture result. The primary endpoint was the diagnosis of IE. RESULTS: IE occurred in 11 of 303 patients (3.6%). Patient characteristics at diagnosis and that were associated with IE included the number of positive blood cultures obtained during hospitalization (p = 0.003), the duration of bacteraemia (p < 0.001), bacteraemia persisting for > 3 days (odds ratio (OR) 14.5, 95% confidence interval (CI) 4.0-52.8; p < 0.001), performance of echocardiography (OR 1.88, 95% CI 1.69-2.1; p = 0.001), presence of a well known predisposing risk for IE (OR 57.2, 95% CI 13.6-240.5; p < 0.001), a non-fatal McCabe score (OR 2.10, 95% CI 1.4-3.1; p = 0.02), and the duration of fever related to the infection (p = 0.026). On multivariable analysis, the presence of a predisposing risk for IE, prolonged bacteraemia, and non-fatal McCabe score remained significantly associated with IE. CONCLUSIONS: In this study the incidence of IE was lower than previously reported. Three clinical characteristics were identified as risk factors for IE among patients with SAB acquired in a health care setting.
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Bacteriemia/complicaciones , Infección Hospitalaria/epidemiología , Endocarditis/epidemiología , Infecciones Estafilocócicas/epidemiología , Staphylococcus aureus/aislamiento & purificación , Anciano , Bacteriemia/microbiología , Infección Hospitalaria/microbiología , Endocarditis/microbiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Infecciones Estafilocócicas/microbiologíaRESUMEN
The haptoglobin (Hp) genotype is a major determinant of progression of nephropathy in individuals with diabetes mellitus (DM). The major function of the Hp protein is to bind and modulate the fate of extracorpuscular hemoglobin and its iron cargo. We have previously demonstrated an interaction between the Hp genotype and the DM on the accumulation of iron in renal proximal tubule cells. The primary objective of this study was to determine the intracellular localization of this iron in the proximal tubule cell and to assess its potential toxicity. Transmission electron microscopy demonstrated a marked accumulation of electron-dense deposits in the lysosomes of proximal tubules cells in Hp 2-2 DM mice. Energy-dispersive X-ray spectroscopy and electron energy loss spectroscopy were used to perform elemental analysis of these deposits and demonstrated that these deposits were iron rich. These deposits were associated with lysosomal membrane lipid peroxidation and loss of lysosomal membrane integrity. Vitamin E administration to Hp 2-2 DM mice resulted in a significant decrease in both intralysosomal iron-induced oxidation and lysosomal destabilization. Iron-induced renal tubular injury may play a major role in the development of diabetic nephropathy and may be a target for slowing the progression of renal disease.
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Diabetes Mellitus Experimental/complicaciones , Nefropatías Diabéticas/genética , Haptoglobinas/genética , Túbulos Renales Proximales/patología , Lisosomas/patología , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/metabolismo , Genotipo , Membranas Intracelulares , Hierro/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción , Estrés Oxidativo , Vitamina E/farmacología , Vitamina E/uso terapéutico , beta-N-Acetilhexosaminidasas/metabolismoRESUMEN
AIM: To study the feasibility of a novel nanomedical method that utilizes breath testing for identifying chronic kidney disease (CKD) and disease progression. MATERIALS & METHODS: Exhaled breath samples were collected from 62 volunteers. The breath samples were analyzed using sensors based on organically functionalized gold nanoparticles, combined with support vector machine analysis. Sensitivity and specificity with reference to CKD patient classification according to estimated glomerular filtration rate were determined using cross-validation. The chemical composition of the breath samples was studied using gas chromatography linked with mass spectrometry. RESULTS: A combination of two to three gold nanoparticles sensors provided good distinction between early-stage CKD and healthy states (accuracy of 79%) and between stage 4 and 5 CKD states (accuracy of 85%). A single sensor provided a distinction between early and advanced CKD (accuracy of 76%). Several substances in the breath were identified and could be associated with CKD-related biochemical processes or with the accumulation of toxins through kidney function loss. CONCLUSION: Breath testing using gold nanoparticle sensors holds future potential as a cost-effective, fast and reliable diagnostic test for early detection of CKD and monitoring of disease progression.
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Pruebas Respiratorias , Fallo Renal Crónico/diagnóstico , Nanopartículas/química , Adulto , Anciano , Anciano de 80 o más Años , Técnicas Biosensibles/métodos , Pruebas Respiratorias/métodos , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Oro/química , Humanos , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/fisiopatología , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Máquina de Vectores de SoporteRESUMEN
Gitelman's syndrome (GS), also known as familial hypokalemic hypomagnesemia, is a rare autosomal recessive hereditary salt-losing tubulopathy, characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria, which is usually caused by mutations in the SLC12A3 gene encoding the thiazide-sensitive sodium chloride contrasporter. Because 18-40% of suspected GS patients carry only one SLC12A3 mutant allele, large genomic rearrangements must account for unidentified mutations. The clinical manifestations of GS are highly variable in terms of age at presentation, severity of symptoms, and biochemical abnormalities. Molecular analysis in our sibling's patients revealed compound heterozygous mutations in the coding region of SLC12A3 as underlying their disease. Such compound heterozygosity can result in disease phenotype for such loss of function mutations in the absence of homozygosis through consanguineous inheritance of mutant alleles, identical by descent. Missense mutations account for approximately 70% of the mutations in GS, and there is a predisposition to large rearrangements caused by the presence of repeated sequences within the SLC12A3. We report two adult male siblings of Jewish origin with late onset GS, who presented in their fifth decade of life with muscle weakness, hypokalemia, hypomagnesaemia, and metabolic alkalosis. Rapid clinical and biochemical improvement was achieved by replacement therapy with potassium and magnesium.
Asunto(s)
Síndrome de Gitelman/genética , Síndrome de Gitelman/fisiopatología , Mutación/genética , Receptores de Droga/genética , Simportadores/genética , Adulto , Secuencia de Aminoácidos , Animales , Síndrome de Gitelman/tratamiento farmacológico , Humanos , Magnesio/uso terapéutico , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Potasio/uso terapéutico , Miembro 3 de la Familia de Transportadores de Soluto 12 , Resultado del TratamientoRESUMEN
Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains of heparan sulfate proteoglycans. Utilizing an ELISA method capable of detection and quantification of heparanase, we examined heparanase levels in the plasma and urine of a cohort of 29 patients diagnosed with type 2 diabetes mellitus (T2DM), 14 T2DM patients who underwent kidney transplantation, and 47 healthy volunteers. We provide evidence that heparanase levels in the urine of T2DM patients are markedly elevated compared to healthy controls (1162 ± 181 vs. 156 ± 29.6 pg/ml for T2DM and healthy controls, respectively), increase that is statistically highly significant (P<0.0001). Notably, heparanase levels were appreciably decreased in the urine of T2DM patients who underwent kidney transplantation, albeit remained still higher than healthy individuals (P<0.0001). Increased heparanase levels were also found in the plasma of T2DM patients. Importantly, urine heparanase was associated with elevated blood glucose levels, implying that glucose mediates heparanase upregulation and secretion into the urine and blood. Utilizing an in vitro system, we show that insulin stimulates heparanase secretion by kidney 293 cells, and even higher secretion is observed when insulin is added to cells maintained under high glucose conditions. These results provide evidence for a significant involvement of heparanase in diabetic complications.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/orina , Glucuronidasa/sangre , Glucuronidasa/orina , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Glucemia/análisis , Glucemia/fisiología , Estudios de Casos y Controles , Células Cultivadas , Diabetes Mellitus Tipo 2/terapia , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/terapia , Nefropatías Diabéticas/orina , Femenino , Glucuronidasa/genética , Humanos , Insulina/sangre , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Regulación hacia ArribaRESUMEN
In pre-eclampsia, poor placentation causes both oxidative and endoplasmic reticulum stress of the placenta. The anti-oxidative protein Haptoglobin has three phenotypes: 1-1, 1-2, and 2-2. Haptoglobin 1-1 is a more potent antioxidant. Our objective was to determine whether haptoglobin 1-1 was less common in women with preeclampsia which is a disease with an oxidatives-stress component, compared to the healthy population. Haptoglobin phenotype was compared in 240 healthy and 120 preeclamptic gravida in a case-control study. Statistical analysis was performed using Chi square test. The prevalence of haptoglobin 1-1 was 13% among healthy women and 6% among preeclamptic women (P=0.049). Secondary analysis was also performed. The prevalence of haptoglobin 1-1 is higher in healthy compared to preeclamptic subjects, a finding compatible with a protective role. Haptoglobin 1-1 might have a protective role in preeclampsia. Further work is needed with more Hp 1-1 subjects before we can conclude on the possible use of Haptoglobin phenotype to assess the risk of preeclampsia.