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BACKGROUND: Detecting peripheral neuropathy (PNP) is crucial in preventing complications such as foot ulceration. Clinical examinations for PNP are infrequently provided to patients at high risk due to restrictions on facilities, care providers, or time. A gamified health assessment approach combining wearable sensors holds the potential to address these challenges and provide individuals with instantaneous feedback on their health status. OBJECTIVE: We aimed to develop and evaluate an application that assesses PNP through video games controlled by pressure sensor-equipped insoles. METHODS: In the proof-of-concept exploratory cohort study, a complete game-based framework that allowed the study participant to play 4 video games solely by modulating plantar pressure values was established in an outpatient clinic setting. Foot plantar pressures were measured by the sensor-equipped insole and transferred via Bluetooth to an Android tablet for game control in real time. Game results and sensor data were delivered to the study server for visualization and analysis. Each session lasted about 15 minutes. In total, 299 patients with diabetes mellitus and 30 with metabolic syndrome were tested using the game application. Patients' game performance was initially assessed by hypothesis-driven key capabilities that consisted of reaction time, sensation, skillfulness, balance, endurance, and muscle strength. Subsequently, specific game features were extracted from gaming data sets and compared with nerve conduction study findings, neuropathy symptoms, or disability scores. Multiple machine learning algorithms were applied to 70% (n=122) of acquired data to train predictive models for PNP, while the remaining data were held out for final model evaluation. RESULTS: Overall, clinically evident PNP was present in 247 of 329 (75.1%) participants, with 88 (26.7%) individuals showing asymmetric nerve deficits. In a subcohort (n=37) undergoing nerve conduction study as the gold standard, sensory and motor nerve conduction velocities and nerve amplitudes in lower extremities significantly correlated with 79 game features (|R|>0.4, highest R value +0.65; P<.001; adjusted R2=0.36). Within another subcohort (n=173) with normal cognition and matched covariates (age, sex, BMI, etc), hypothesis-driven key capabilities and specific game features were significantly correlated with the presence of PNP. Predictive models using selected game features achieved 76.1% (left) and 81.7% (right foot) accuracy for PNP detection. Multiclass models yielded an area under the receiver operating characteristic curve of 0.76 (left foot) and 0.72 (right foot) for assessing nerve damage patterns (small, large, or mixed nerve fiber damage). CONCLUSIONS: The game-based application presents a promising avenue for PNP screening and classification. Evaluation in expanded cohorts may iteratively optimize artificial intelligence model efficacy. The integration of engaging motivational elements and automated data interpretation will support acceptance as a telemedical application.
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Doenças do Sistema Nervoso Periférico , Jogos de Vídeo , Humanos , Doenças do Sistema Nervoso Periférico/diagnóstico , Masculino , Feminino , Estudo de Prova de Conceito , Pessoa de Meia-Idade , Adulto , Dispositivos Eletrônicos Vestíveis , Inteligência Artificial , Estudos de Coortes , IdosoRESUMO
BACKGROUND: Autoantibodies (Abs) against angiotensin-II type 1 (AT(1)R) and endothelin-1 type A receptors (ETAR) are investigated in the present study as B-cell originated humoral factors that may activate the respective receptors on endothelial cells. The prevalence of the Abs was determined in patients with peripheral arterial occlusive disease (PAD). PATIENTS AND METHODS: In a prospective observational study 200 patients undergoing angiography and proven advanced PAD were enrolled. Serum samples, clinical data and laboratory values for classical cardiovascular risk factors were collected. Autoantibody titers for AT(1)R and ETAR were determined by solid-phase ELISA and correlative analyses with laboratory parameters and clinical data for common cardiovascular risk factors were performed. RESULTS: Anti-ETAR antibody titers were detected in 57 % of the patients, elevated anti-AT(1)R titers in 61.5 %. About 50 % were positive for both Abs. A strong intercorrelation between ETAR and AT(1)R titers was present (r2 0.79). In patients with positive titers for both Abs females presented significantly higher titers for ETAR (p = 0.045) and AT(1)R (p = 0.02). Autoantibody titers directed against surface receptors ETA and AT(1) are highly correlated in PAD. Titers were independent from classical risk factors in any patient subgroup. CONCLUSIONS: This study opens a new perspective on the involvement of the immune system, hereby represented by functional autoantibodies, in the atherosclerotic pathophysiology, leaving behind the common background of classical risk factors.
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Autoanticorpos/sangue , Imunidade Humoral , Doença Arterial Periférica/imunologia , Receptor Tipo 1 de Angiotensina/imunologia , Receptor de Endotelina A/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico por imagem , Prognóstico , Estudos Prospectivos , Radiografia , Fatores de RiscoRESUMO
BACKGROUND: In males with end stage renal disease biochemical hypogonadism is a frequent finding. Testosterone and sex hormone binding globulin (SHBG) have been associated with insulin resistance, a well-known condition in uremia. The aim of the present study was to investigate in males on chronic hemodialysis the relationship of testosterone and SHBG serum levels with insulin resistance. METHODS: In a cross-sectional study we enrolled men treated with chronic hemodialysis who did not suffer from an acute illness or other endocrinopathy, as well as primary hypogonadism, and were not hospitalised. Diabetes mellitus, diabetic nephropathy or previous transplantation were not exclusion criteria. As controls we used a community-based group of healthy males matched for age and Body Mass Index (BMI). We assessed the BMI (kg/m2) from body weight and height, the body fat content (%) by bioelectrical impedance and serum testosterone (ng/ml), SHBG (nmol/L) and estradiol (pg/ml) by standard methods. Testosterone < 3.25 ng/ml defined biochemical hypogonadism. In non-diabetic males, we calculated the homeostasis model assessment index (HOMA-R), an estimate of insulin resistance, from serum fasting insulin and glucose. RESULTS: 27 men (age 54.4 ± 19 years) on chronic hemodialysis (treatment duration 29.1 ± 14.4 months) and 51 healthy men (age 47.1 ± 9.6 years) were included. In men on hemodialysis vs. healthy men there were increased serum levels of SHBG (40.9 ± 26.9 vs. 27.6 ± 11.9 nmol/L; p = 0.031) and a significantly enhanced frequency of biochemical hypogonadism (22.2 vs. 3.9%; p = 0.011). In cases without diabetes (n = 22) a significant correlation was observed between the HOMA-R (r = -0.586, p = 0.004) and the fasting insulin levels (r = -0.650, p = 0.001) on the one hand and the serum SHBG levels on the other. CONCLUSIONS: Our findings confirm enhanced prevalence of biochemical hypogonadism in males on chronic hemodialysis. In non-diabetic cases the serum levels of SHBG correlated with serum insulin and insulin resistance.
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Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapeutic options to prevent or reverse DKD progression are limited. Endothelial and glomerular filtration barrier (GFB) dysfunction and sterile inflammation are associated with DKD. Neutrophil extracellular traps (NETs), originally identified as an innate immune mechanism to combat infection, have been implicated in sterile inflammatory responses in non-communicable diseases. However, the contribution of NETs in DKD remains unknown. Here, we show that biomarkers of NETs are increased in diabetic mice and diabetic patients and that these changes correlate with DKD severity. Mechanistically, NETs promote NLRP3 inflammasome activation and glomerular endothelial dysfunction under high glucose stress in vitro and in vivo. Inhibition of NETs (PAD4 inhibitor) ameliorate endothelial dysfunction and renal injury in DKD. Taken together, NET-induced sterile inflammation promotes diabetes-associated endothelial dysfunction, identifying a new pathomechanism contributing to DKD. Inhibition of NETs may be a promising therapeutic strategy in DKD.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Armadilhas Extracelulares , Animais , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Armadilhas Extracelulares/metabolismo , Inflamassomos/metabolismo , Inflamação/complicações , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
A major obstacle in diabetes is the metabolic or hyperglycemic memory, which lacks specific therapies. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, human samples and in vitro models. Tubular and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans. Mechanistically, sustained tubular p21 expression in DKD is linked to demethylation of its promoter and reduced DNMT1 expression. Two disease resolving agents, protease activated protein C (3K3A-aPC) and parmodulin-2, reversed sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence is a pathway contributing to the hyperglycemic memory, which can be therapeutically targeted.
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Inibidor de Quinase Dependente de Ciclina p21 , Diabetes Mellitus , Nefropatias Diabéticas , Hiperglicemia , Animais , Senescência Celular , Inibidor de Quinase Dependente de Ciclina p21/genética , Diabetes Mellitus/patologia , Nefropatias Diabéticas/patologia , Humanos , Hiperglicemia/patologia , RimRESUMO
Chronic heart failure is associated with high morbidity and mortality and is the most common hospital diagnosis for elderly patients. Concomitant or superimposed acute or chronic kidney injury, as is the case with cardiorenal syndrome, has a dramatic impact on the outcome. The inhibition of the neurohumoral axis and the adequate treatment of hypervolemia are fundamental elements of modern cardiac insufficiency therapies. In addition to optimal conservative therapy, there are other options: VADâimplantation, hemodialysis and peritoneal dialysis. The PD offers biological and clinical benefits as an additive therapy for the treatment of patients with heart failure, refractory hypervolemia and non-urinary renal failure.
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Síndrome Cardiorrenal , Volume Sanguíneo , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/fisiopatologia , Síndrome Cardiorrenal/terapia , Humanos , Diálise PeritonealRESUMO
T helper (h) lymphocytes in pathogenic immune response at mucosal effector site play a key role in IgA nephropathy (IgAN). We evaluated the impact of some Th1/Th2/Th3/T(R)-type, and of monocyte/macrophage cytokines on IgAN susceptibility with a family-based association study including 53 patients, 45 complete trios, 4 incomplete trios and 36 discordant siblings. Cytokine gene polymorphisms with a potential regulatory role on their production were investigated using the family-based association test (FBAT): IFNgamma intron-1 CA repeat at position 1349-1373; IL-13 -1055C/T; TGFbeta +915G/C; IL-10 5'-proximal and distal microsatellites; TNFalpha -308G/A, -238G/A. The FBAT multi-allelic analysis showed an association between IFNgamma polymorphism and susceptibility to IgAN (P=0.03). The bi-allelic analysis evidenced that the 13-CA repeat allele was preferentially transmitted to the affected individuals (P=0.006; Bonferroni P-value=0.04). The direct sequencing of IFNgamma amplicons showed a strict association between the 13-CA repeat allele and the A variant of the +874T/A single nucleotide polymorphism (SNP rs2430561) directly adjacent to the 5' end of the microsatellite. The in vitro production of IFNgamma evaluated in peripheral blood mononuclear cells from 10 genotyped patients demonstrated a correlation between the +874A allele and a lower production of IFNgamma (P=0.028 Mann-Whitney test). This SNP affects IFNgamma production lying within a binding site for the transcription factor NF-kappaB. No significant difference was observed in the 15 years renal survival between IgAN patients carrying different IFNgamma gene polymorphisms. This first family-based association study demonstrates that the +874A allele, strictly associated with IFNgamma 13-CA repeat allele, confers susceptibility to IgAN, without influencing renal survival.
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Predisposição Genética para Doença , Glomerulonefrite por IGA/genética , Interferon gama/genética , Polimorfismo Genético , Alelos , Estudos de Casos e Controles , Repetições de Dinucleotídeos/genética , Humanos , Repetições de Microssatélites/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Recent findings of an impaired protein ratio of type I to type III procollagen showed a disturbed collagen metabolism in incisional hernia development. We analyzed the type I and type III procollagen messenger RNA to investigate whether these findings represent the altered extracellular matrix or a primary defect at the transcriptional level. METHODS: We examined cultured skin fibroblasts of patients with incisional or recurrent incisional hernia in comparison with those without any previous incision (control) and those with a skin scar without clinical appearance of a hernia (scar). Immunohistochemical detection of a lowered protein ratio of type I and type III collagen in the hernia skin tissue leads to mRNA expression analysis. The procollagen mRNA and the ratio of type I to type III procollagen mRNA are detected by reverse transcriptase-polymerase chain reaction and Northern blot analysis, the collagens type I and III by Western blot analysis. RESULTS: Reverse transcriptase-polymerase chain reaction revealed an increase of type I procollagen mRNA in the incisional and recurrent hernia (0.90 +/- 0.04 and 1.19 +/- 0.04, respectively) compared with stable scar (0.54 +/- 0.02) or healthy tissue (0.43 +/- 0.01). The obvious rise of type III procollagen mRNA to 4.13 +/- 0.04 for incisional, 6.02 +/- 0.03 for recurrent hernia, 2.29 +/- 0.04 for stable scar, and 1.72 +/- 0.03 for the healthy tissue showed a significantly decreased ratio of type I to type III procollagen mRNA in the hernia patients as compared with the controls (P <.01). By Western blot analysis, an increase of type I and type III collagen protein and a significant rise in the corresponding ratio in the recurrent hernia group were detected. CONCLUSIONS: The altered synthesis of type I and type III collagen in cultured skin fibroblasts suggests a disorder of collagen metabolism, at least in patients with recurrent hernia. Hence, a basically impaired wound healing process is likely to contribute to the unsatisfactory results of incisional hernia repair.
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Colágeno Tipo III/genética , Colágeno Tipo I/genética , Fibroblastos/metabolismo , Hérnia/metabolismo , Complicações Pós-Operatórias/metabolismo , RNA Mensageiro/metabolismo , Western Blotting , Células Cultivadas , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In patients on chronic hemodialysis hypotensive episodes are frequently encountered during the course of treatment and the prevalence of atherosclerosis is increased. Endothelin-1 (ET-1), an endothelium-derived peptide with vasoconstrictive and mitogenic effects on smooth muscles, is involved in vascular tone regulation and in the pathogenesis of atherosclerosis. The aim of the present study was to investigate plasma ET-1 during hemodialysis treatment and to explore the probable influence of pre-existing hypertension. Forty-seven hemodialysis patients (21 females, mean age 62 +/- 12 years) were evaluated and hypertensive patients (n = 33) were compared to normotensive patients (n = 14). Relative blood volume changes (hemoglobinometry) and blood pressure were measured. Samples were taken before, every hour during and after hemodialysis. Plasma ET-1 was measured by enzyme-linked immunosorbent assay and results were corrected according to hemoconcentration. Hemodialysis with an ultrafiltration rate of 2224 +/- 933 mL was performed. Total blood volume at the end of hemodialysis was 89.4 +/- 8.2% of the pretreatment volume. The fall in blood pressure (137/74 +/- 22/11 mmHg vs 127/73 +/- 30/14 mmHg) correlated with the decrease in blood volume (mean blood pressure: r = 0.33). Plasma ET-1 increased from 1.29 +/- 0.47 pg/mL before to 1.46 +/- 0.56 pg/mL (reference range 0.3-0.9) at the end of hemodialysis (P < 0.05). This rise was more pronounced in patients with hypertension than in normotensive individuals (P < 0.05). The change in blood volume (r = 0.41) and blood pressure (mean blood pressure: r = 0.34) correlated with plasma ET-1 at the end of hemodialysis (P < 0.05). Plasma ET-1 was enhanced in hemodialysis patients compared to normal subjects. During the hemodialysis session an increase in ET-1 was encountered, which was more pronounced in hypertensive than in normotensive patients and paralleled the hemodynamic changes. Apart from pre-existing hypertension, further factors potentially influencing ET-1 include local endothelial injury (arteriovenous fistula) and generalized bioincompatibility reactions (e.g. foreign surface contact) occurring during hemodialysis.
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Endotelina-1/sangue , Hipertensão/complicações , Falência Renal Crônica/terapia , Diálise Renal , Idoso , Pressão Sanguínea , Volume Sanguíneo , Feminino , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Variants of the interleukin-1ß gene (IL1B) are implicated in the development of diabetic nephropathy (DN). The present candidate-gene association study was conducted to investigate the association between the IL1B C-511T variant and the risk of DN in a Caucasian population. The study population consisted of 173 cases (patients with type 2 diabetes mellitus [DM] and DN) and 186 controls (patients with DM free of DN). Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The PCR product was a 304-bp long DNA fragment of the IL1B gene promoter region, extending from position -702 to -398 and including the polymorphic AvaI site (at position -511). The magnitude of the overall association was tested using the generalized odds ratio (ORG) metric, a genetic model-free approach. The ORs (adjusted for effect modifiers) of the additive and co-dominant models were also estimated. The mode of inheritance was assessed using the degree of dominance index (h). There was a significant difference in the genotype distribution between the group of cases with DN compared with diseased controls free of DN (p=0.014). Analysis produced a significant ORG (ORG=1.74, 95% confidence interval [CI]=1.20-2.52), indicating that the risk of DN is significantly associated with the mutational load. The risk of developing DN is significantly enhanced in IL1B T allele carriers (dominant model, p=0.005) and in homozygotes (additive model, p=0.018) respectively. However, the recessive model for T allele (p=0.097) and the co-dominant model (p=0.085) produced non-significant results. Considering that the additive model was significant (OR=2.53, 95% CI=1.20-5.36) and the co-dominant is non-significant (OR=1.53, 95% CI=0.97-2.40), the mode of inheritance is complete "additiveness," with the degree of dominance being h=0. The findings provided evidence that the IL1B C-511T variant might be associated with development of DN.
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Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Predisposição Genética para Doença , Interleucina-1beta/genética , Polimorfismo Genético , Idoso , Estudos de Casos e Controles , Humanos , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Hepcidin regulates iron absorption and recycling and is central to host defense, protection from reactive iron species, and a biomarker of iron-related pathophysiology. We assessed the value of hepcidin measured preoperatively for the prediction of in-hospital mortality and renal outcomes. METHODS: We studied 100 adult patients undergoing cardiac surgery in the control arm of a randomized, controlled trial. Plasma and urine were sampled before induction of anesthesia, and hepcidin-25 was quantified by competitive enzyme-linked immunoassay. Renal outcomes were acute kidney injury defined by risk, injury, failure, loss of function, end-stage renal disease (RIFLE) classification and need for renal replacement therapy. Variables with the potential to influence hepcidin expression were investigated. RESULTS: Low preoperative hepcidin concentration in urine (median, 15.3 ng/mL; 25-75 percentiles, 0-129.1) and plasma (median, 49.2 ng/mL; 25th-75th percentile, 0-52.2) predicted mortality (area under the curve-receiver operating characteristic [AUC-ROC] for urine hepcidin, 0.89; 95% confidence interval, 0.73-0.99; cutoff, 130 ng/mL; sensitivity, 73%; specificity, 100%; and AUC-ROC for plasma hepcidin, 0.90; 95% confidence interval, 0.80-0.99; cutoff, 55 ng/mL; sensitivity, 83%; specificity, 100%). Survivors had median preoperative hepcidin concentrations of 325.3 ng/mL (25th-75th percentile, 120-770.1 ng/mL) in urine and 113.1 ng/mL (25th-75th percentile, 77.7-203.1 ng/mL) in plasma. Preoperative serum creatinine did not predict mortality (AUC-ROC, 0.50; 95% confidence interval, 0.10-0.94). Furthermore, preoperative urine, plasma hepcidin, and serum creatinine did not distinguish patients requiring postoperative renal replacement therapy from those without (urine: AUC-ROC, 0.62; 95% confidence interval, 0.38-0.86; plasma: AUC-ROC, 0.63; 95% confidence interval, 0.34-0.91; serum creatinine: AUC-ROC, 0.61; 95% confidence interval, 0.22-0.99). Preoperative renal function and hemoglobin did not correlate with hepcidin indices whereas plasma markers of inflammation did. CONCLUSIONS: Low preoperative hepcidin concentration might be a risk factor for in-hospital mortality. Findings should be validated in larger patient cohorts with a greater number of events.
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Peptídeos Catiônicos Antimicrobianos/sangue , Peptídeos Catiônicos Antimicrobianos/urina , Procedimentos Cirúrgicos Cardíacos/mortalidade , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/terapia , Idoso , Área Sob a Curva , Biomarcadores/sangue , Biomarcadores/urina , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Creatinina/sangue , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Feminino , Alemanha , Hemoglobinas/metabolismo , Hepcidinas , Mortalidade Hospitalar , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Período Pré-Operatório , Curva ROC , Terapia de Substituição Renal , Fatores de Risco , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, but its etiologic mechanisms are still poorly understood. Different prevalences among ethnic groups and familial aggregation, together with an increased familial risk, suggest important genetic influences on its pathogenesis. A locus for familial IgAN, called "IGAN1," on chromosome 6q22-23 has been described, without the identification of any responsible gene. The partners of the European IgAN Consortium organized a second genomewide scan in 22 new informative Italian multiplex families. A total of 186 subjects (59 affected and 127 unaffected) were genotyped and were included in a two-stage genomewide linkage analysis. The regions 4q26-31 and 17q12-22 exhibited the strongest evidence of linkage by nonparametric analysis (best P=.0025 and .0045, respectively). These localizations were also supported by multipoint parametric analysis, in which peak LOD scores of 1.83 ( alpha =0.50) and 2.56 ( alpha =0.65) were obtained using the affected-only dominant model, and by allowance for the presence of genetic heterogeneity. Our results provide further evidence for genetic heterogeneity among families with IgAN. Evidence of linkage to multiple chromosomal regions is consistent with both an oligo/polygenic and a multiple-susceptibility-gene model for familial IgAN, with small or moderate effects in determining the pathological phenotype. Although we identified new candidate regions, replication studies are required to confirm the genetic contribution to familial IgAN.
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Heterogeneidade Genética , Ligação Genética , Glomerulonefrite por IGA/genética , Adolescente , Adulto , Cromossomos Humanos , Feminino , Predisposição Genética para Doença , Humanos , Escore Lod , Masculino , Modelos Genéticos , LinhagemRESUMO
BACKGROUND/AIMS: Insulin resistance is a well-known phenomenon in uremia. Resistin, a recently discovered insulin inhibitor secreted by adipocytes, is associated with obesity and insulin resistance in mice. Adiponectin, also secreted by adipocytes, is known to reduce insulin resistance in humans. The aim of the present study was to address the hypothesis that changes in resistin or adiponectin serum levels may relate to body composition and to insulin resistance in patients with end-stage renal disease. METHODS: In a cross-sectional study, 33 non-diabetic patients (24 males and 9 females, mean age 61.5+/-15.8 years) with end-stage renal disease on chronic hemodialysis (treatment duration 41+/-31 months) that lacked signs of infection were enrolled. The control group consisted of 33, matched for age, sex and body mass index (BMI), healthy volunteers (22 males, 11 females, mean age 62.6+/-12.1 years). BMI (kg/m(2)) was calculated from body weight and height. Body fat (%) was measured by means of bioelectrical impedance. Blood samples were taken always in the morning after a 12-hour fasting period before and after the hemodialysis session. Resistin and adiponectin serum concentrations were measured by enzyme immunoassays and insulin by an electrochemiluminescence immunoassay. The post-treatment values were corrected regarding the hemoconcentration. The homeostasis model assessment index (HOMA-R) was calculated as an estimate of insulin resistance from the fasting glucose and insulin serum levels. RESULTS: Pre-treatment resistin serum levels were significantly increased in hemodialysis patients compared to healthy controls (19.2+/-6.2 vs. 3.9+/-1.8 ng/ml; p<0.001). Hemodialysis did not alter resistin levels, as pre- and post-treatment levels were not different when corrected for hemoconcentration (19.2+/-6.2 vs. 18.7+/-5.0 ng/ml; p=0.54). Adiponectin levels were also increased in hemodialysis patients compared to healthy controls (25.4+/-21.5 vs. 10.5+/-5.9 microg/ml; p<0.001). A significant inverse correlation was observed between the serum adiponectin levels before the hemodialysis session on the one hand and the BMI (r=-0.527, p=0.002), the HOMA-R (r=-0.378, p<0.05) and the fasting insulin levels (r=-0.397, p<0.05) on the other. However, no significant correlation was observed between serum resistin levels on the one hand versus HOMA-R index (3.2+/-3.9 mmol.microIU/ml; r=-0.098, p=0.59), insulin levels (13.3+/-14.4 mU/l; r=-0.073, p=0.69), glucose levels (89+/-13 mg/dl; r=-0.049, p=0.78), BMI (25.6+/-3.7 kg/m(2); r=-0.041, p=0.82) and body fat content (26.4+/-8.4%; r=-0.018, p=0.94) on the other hand. CONCLUSION: Resistin serum levels are significantly elevated in non-diabetic patients with end-stage renal disease that are treated by hemodialysis. The hemodialysis procedure does not affect the resistin levels. Along with previous observations in patients with renal insufficiency in the pre-dialysis stage, our findings implicate an important role of the kidney in resistin elimination. However, increased resistin serum levels in hemodialysis patients are not related to reduced insulin sensitivity encountered in uremia.
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Resistência à Insulina , Falência Renal Crônica/sangue , Diálise Renal , Adiponectina/sangue , Índice de Massa Corporal , Feminino , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , ResistinaRESUMO
In patients on chronic hemodialysis the prevalence of atherosclerosis is increased and is by far the leading cause of morbidity and mortality. Endothelin-1, an endothelium-derived peptide with vasoconstrictive and mitogenic effects on vascular smooth muscles, is involved in the pathogenesis of atherosclerosis. The aim of the present study was to investigate the time course of plasma endothelin-1 levels during a hemodialysis session and to explore the influence of preexisting type 2 diabetes mellitus. Forty-five clinically stable hemodialysis patients (21 females, 24 males; mean age 62 +/- 12 years) were evaluated. Patients with type 2 diabetes (n= 11) were compared with the group of patients without diabetes (n=34). Relative blood volume (BV) changes (hemoglobinometry) and blood pressure (BP) was measured. Samples were taken before, every hour during, and after hemodialysis. Plasma endothelin-1 levels were measured by enzyme-linked immunoassay (ELISA) and results were corrected according to hemoconcentration. Hemodialysis with an ultrafiltration of 2215 +/- 952 mL was performed. Total BV at the end of hemodialysis was 89.3% +/- 8.3% of the pretreatment volume. Plasma endothelin-1 was enhanced in hemodialysis patients compared to normal subjects and increased from 1.28 +/- 0.47 before to 1.44 +/- 0.54 pg/mL (ref. 0.3-0.9) at the end of hemodialysis (p<0.05). The BV change (r=0.41) and the BP (mean BP: r=0.34) correlated with plasma endothelin-1 at the end of hemodialysis (p<0.05). The levels of endothelin-1 were significantly higher in the group of dialysis patients with type 2 diabetes compared to nondiabetics in all measurements (p<0.05). These findings suggest a potential role of endothelin-1 in the pathogenesis of vascular dysfunction in diabetes mellitus. The dialysis procedure per se, through vasoconstriction due to BV decrease, local endothelial injury (a.v. fistula), or bioincompatibility reactions (foreign surface contact) may additionally alter endothelial cell functions.