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1.
Nat Immunol ; 18(8): 826-831, 2017 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-28722720

RESUMEN

Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.


Asunto(s)
Enfermedades Transmisibles/inmunología , Inmunidad Celular/inmunología , Inmunidad Humoral/inmunología , Inflamación/inmunología , Enfermedad Aguda , Enfermedad Crónica , Humanos
3.
Am J Kidney Dis ; 84(3): 275-285.e1, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38608748

RESUMEN

RATIONALE & OBJECTIVE: Body mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. We hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan. STUDY DESIGN: A retrospective cohort study. SETTING & PARTICIPANTS: 1,053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and at high risk of rapid disease progression. PREDICTOR: Estimates of visceral adiposity extracted from coronal plane magnetic resonance imaging (MRI) scans using deep learning. OUTCOME: Annual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. ANALYTICAL APPROACH: Multinomial logistic regression and linear mixed models. RESULTS: In fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of≥7% versus<5% (odds ratio [OR], 4.78 [95% CI, 3.03-7.47]). The association was stronger in women than men (interaction P<0.01). In linear mixed models with an outcome of percent change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (3-way interaction of treatment ∗ time ∗ visceral adiposity, P=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual percent change in TKV for individuals with a normal BMI (DeLong's test z score: -2.03; P=0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in women (fully adjusted OR, 1.06 [95% CI, 1.01-1.11] per 10 unit increase in visceral adiposity) but not men (OR, 0.98 [95% CI, 0.95-1.02]). LIMITATIONS: Retrospective; rapid progressors; computational demand of deep learning. CONCLUSIONS: Visceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model independently associates with more rapid kidney growth and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity. PLAIN-LANGUAGE SUMMARY: We analyzed images from a previous study with the drug tolvaptan conducted in patients with autosomal dominant polycystic kidney disease (ADPKD) to measure the amount of fat tissue surrounding the kidneys (visceral fat). We had previously shown body mass index can predict kidney growth in this population; now we determined whether visceral fat was an important factor associated with kidney growth. Using a machine learning tool to automate measurement of fat in images, we observed that visceral fat was independently associated with kidney growth, that it was a better predictor of faster kidney growth in lean patients than body mass index, and that having more visceral fat made treatment of ADPKD with tolvaptan less effective.


Asunto(s)
Progresión de la Enfermedad , Grasa Intraabdominal , Riñón Poliquístico Autosómico Dominante , Tolvaptán , Humanos , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Masculino , Femenino , Estudios Retrospectivos , Tolvaptán/uso terapéutico , Tolvaptán/farmacología , Adulto , Grasa Intraabdominal/diagnóstico por imagen , Persona de Mediana Edad , Estudios de Cohortes , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Obesidad Abdominal , Índice de Masa Corporal , Imagen por Resonancia Magnética , Adiposidad
4.
Am J Kidney Dis ; 84(3): 286-297.e1, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38621633

RESUMEN

RATIONALE & OBJECTIVE: In this pilot study, we hypothesized that autosomal dominant polycystic kidney disease (ADPKD) is characterized by impaired kidney oxidative metabolism that associates with kidney size and cyst burden. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Twenty adults with ADPKD (age, 31±6 years; 65% women; body mass index [BMI], 26.8 [22.7-30.4] kg/m2; estimated glomerular filtration rate [eGFR, 2021 CKD-EPI creatinine], 103±18mL/min/1.73m2; height-adjusted total kidney volume [HTKV], 731±370mL/m; Mayo classifications 1B [5%], 1C [42%], 1D [21%], and 1E [32%]) and 11 controls in normal weight category (NWC) (age, 25±3 years; 45% women; BMI, 22.5 [21.7-24.2] kg/m2; eGFR, 113±15mL/min/1.73m2; HTKV, 159±31mL/m) at the University of Colorado Anschutz Medical Campus. PREDICTORS: ADPKD status (yes/no) and severity (Mayo classifications). OUTCOME: HTKV and cyst burden by magnetic resonance imaging, kidney oxidative metabolism, and perfusion by 11C-acetate positron emission tomography/computed tomography, insulin sensitivity by hyperinsulinemic-euglycemic clamps (presented as ratio of M-value of steady state insulin concentration [M/I]). ANALYTICAL APPROACH: For categorical variables, χ2/Fisher's exact tests, and for continuous variables t tests/Mann-Whitney U tests. Pearson correlation was used to estimate the relationships between variables. RESULTS: Compared with NWC individuals, the participants with ADPKD exhibited lower mean±SD M/I ratio (0.586±0.205 vs 0.424±0.171 [mg/kg lean/min]/(µIU/mL), P=0.04), lower median cortical perfusion (1.93 [IQR, 1.80-2.09] vs 0.68 [IQR, 0.47-1.04] mL/min/g, P<0.001) and lower median total kidney oxidative metabolism (0.17 [IQR, 0.16-0.19] vs. 0.14 [IQR, 0.12-0.15] min-1, P=0.001) in voxel-wise models excluding cysts. HTKV correlated inversely with cortical perfusion (r: -0.83, P < 0.001), total kidney oxidative metabolism (r: -0.61, P<0.001) and M/I (r: -0.41, P = 0.03). LIMITATIONS: Small sample size and cross-sectional design. CONCLUSIONS: Adults with ADPKD and preserved kidney function exhibited impaired renal perfusion and kidney oxidative metabolism across a wide range of cysts and kidney enlargements. FUNDING: Grants from government (National Institutes of Health, Centers for Disease Control and Prevention) and not-for-profit (JDRF) entities. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study numbers NCT04407481 and NCT04074668. PLAIN-LANGUAGE SUMMARY: In our study, we explored how a common genetic kidney condition, autosomal dominant polycystic kidney disease (ADPKD), relates to kidney metabolism. ADPKD leads to the growth of numerous cysts in the kidneys, which can impact their ability to work properly. We wanted to understand the kidneys' ability to process oxygen and blood flow in ADPKD. Our approach involved using advanced imaging techniques to observe kidney metabolism and blood flow in people with ADPKD compared with healthy individuals. We discovered that those with ADPKD had significant changes in kidney oxygen metabolism even when their kidney function was still normal. These findings are crucial as they provide deeper insights into ADPKD, potentially guiding future treatments to target these changes.


Asunto(s)
Tasa de Filtración Glomerular , Riñón , Riñón Poliquístico Autosómico Dominante , Humanos , Riñón Poliquístico Autosómico Dominante/metabolismo , Riñón Poliquístico Autosómico Dominante/patología , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Femenino , Proyectos Piloto , Masculino , Adulto , Estudios Transversales , Riñón/patología , Riñón/diagnóstico por imagen , Riñón/metabolismo , Adulto Joven , Metabolismo Energético/fisiología , Quistes/metabolismo , Quistes/patología , Quistes/diagnóstico por imagen
5.
BMC Nephrol ; 25(1): 206, 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38918734

RESUMEN

BACKGROUND: Tubular biomarkers, which reflect tubular dysfunction or injury, are associated with incident chronic kidney disease and kidney function decline. Several tubular biomarkers have also been implicated in the progression of autosomal dominant polycystic kidney disease (ADPKD). We evaluated changes in multiple tubular biomarkers in four groups of patients with ADPKD who participated in one of two clinical trials (metformin therapy and diet-induced weight loss), based on evidence suggesting that such interventions could reduce tubule injury. METHODS: 66 participants (26 M/40 F) with ADPKD and an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m2 who participated in either a metformin clinical trial (n = 22 metformin; n = 23 placebo) or dietary weight loss study (n = 10 daily caloric restriction [DCR]; n = 11 intermittent fasting [IMF]) were included in assessments of urinary tubular biomarkers (kidney injury molecule-1 [KIM-1], fatty-acid binding protein [FABP], interleukin-18 [IL-18], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin [NGAL], clusterin, and human cartilage glycoprotein-40 [YKL-40]; normalized to urine creatinine), at baseline and 12 months. The association of baseline tubular biomarkers with both baseline and change in height-adjusted total kidney volume (HtTKV; percent change from baseline to 12 months) and estimated glomerular filtration rate (eGFR; absolute change at 12 months vs. baseline), with covariate adjustment, was also assessed using multiple linear regression. RESULTS: Mean ± s.d. age was 48 ± 8 years, eGFR was 71 ± 16 ml/min/1.73m2, and baseline BMI was 30.5 ± 5.9 kg/m2. None of the tubular biomarkers changed with any intervention as compared to placebo. Additionally, baseline tubular biomarkers were not associated with either baseline or change in eGFR or HtTKV over 12 months, after adjustments for demographics, group assignment, and clinical characteristics. CONCLUSIONS: Tubular biomarkers did not change with dietary-induced weight loss or metformin, nor did they associate with kidney disease progression, in this cohort of patients with ADPKD.


Asunto(s)
Biomarcadores , Restricción Calórica , Tasa de Filtración Glomerular , Túbulos Renales , Metformina , Riñón Poliquístico Autosómico Dominante , Humanos , Metformina/uso terapéutico , Riñón Poliquístico Autosómico Dominante/orina , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Riñón Poliquístico Autosómico Dominante/dietoterapia , Masculino , Femenino , Biomarcadores/orina , Persona de Mediana Edad , Túbulos Renales/patología , Túbulos Renales/efectos de los fármacos , Adulto , Lipocalina 2/orina , Quimiocina CCL2/orina , Proteínas de Unión a Ácidos Grasos/orina , Receptor Celular 1 del Virus de la Hepatitis A/metabolismo , Receptor Celular 1 del Virus de la Hepatitis A/análisis , Proteína 1 Similar a Quitinasa-3/orina , Hipoglucemiantes/uso terapéutico
6.
J Am Soc Nephrol ; 34(8): 1433-1444, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37228030

RESUMEN

SIGNIFICANCE STATEMENT: Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. In this randomized, controlled trial, treatment with sodium bicarbonate (NaHCO 3 ) did not improve vascular endothelial function or reduce arterial stiffness in participants with CKD stage 3b-4 with normal serum bicarbonate levels. In addition, NaHCO 3 treatment did not reduce left ventricular mass index. NaHCO 3 did increase plasma bicarbonate levels and urinary citrate excretion and reduce urinary ammonium excretion, indicating that the intervention was indeed effective. NaHCO 3 therapy was safe with no significant changes in BP, weight, or edema. These results do not support the use of NaHCO 3 for vascular dysfunction in participants with CKD. BACKGROUND: Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. Prospective interventional trials with sodium bicarbonate (NaHCO 3 ) are lacking. METHODS: We conducted a randomized, double-blind, placebo-controlled trial examining the effect of NaHCO 3 on vascular function in 109 patients with CKD stage 3b-4 (eGFR 15-44 ml/min per 1.73 m 2 ) with normal serum bicarbonate levels (22-27 mEq/L). Participants were randomized 1:1 to NaHCO 3 or placebo at a dose of 0.5 mEq/lean body weight-kg per day for 12 months. The coprimary end points were change in brachial artery flow-mediated dilation (FMD) and change in aortic pulse wave velocity over 12 months. RESULTS: Ninety patients completed this study. After 12 months, plasma bicarbonate levels increased significantly in the NaHCO 3 group compared with placebo (mean [SD] difference between groups 1.35±2.1, P = 0.003). NaHCO 3 treatment did not result in a significant improvement in aortic pulse wave velocity from baseline. NaHCO 3 did result in a significant increase in flow-mediated dilation after 1 month; however, this effect disappeared at 6 and 12 months. NaHCO 3 resulted in a significant increase in 24-hour urine citrate and pH and a significant decrease in 24-hour urine ammonia. There was no significant change in left ventricular mass index, ejection fraction, or eGFR with NaHCO 3 . NaHCO 3 treatment was safe and well-tolerated with no significant changes in BP, antihypertensive medication, weight, plasma calcium, or potassium levels. CONCLUSION: Our results do not support the use of NaHCO 3 for vascular dysfunction in participants with CKD and normal serum bicarbonate levels.


Asunto(s)
Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Humanos , Bicarbonato de Sodio/uso terapéutico , Bicarbonatos , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Análisis de la Onda del Pulso , Estudios Prospectivos , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Método Doble Ciego
7.
Am J Nephrol ; 54(5-6): 165-174, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37231790

RESUMEN

INTRODUCTION: Cerebrovascular dysfunction, characterized by increased brain pulsatile flow, reduced cerebrovascular reactivity, and cerebral hypoperfusion precedes the onset of dementia and is linked to cognitive dysfunction. Autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of dementia, and intracranial aneurysms are more prevalent in ADPKD patients. However, cerebrovascular function has not been previously characterized in patients with ADPKD. METHODS: Using transcranial Doppler, we compared middle cerebral artery (MCA) pulsatility index (PI, cerebrovascular stiffness) and MCA blood velocity response to hypercapnia (normalized for blood pressure and end-tidal CO2, cerebrovascular reactivity) in patients with early-stage ADPKD versus age-matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function) and measured carotid-femoral pulse-wave velocity (PWV, aortic stiffness). RESULTS: Fifteen participants with ADPKD (9F, 27 ± 4 yrs, eGFR: 106 ± 22 mL/min/1.73 m2) were compared to 15 healthy controls (8F, 29 ± 4 yrs, eGFR: 109 ± 14 mL/min/1.73 m2). MCA PI was unexpectedly lower in ADPKD (0.71 ± 0.07) versus controls (0.82 ± 0.09 AU; p < 0.001); however, normalized MCA blood velocity in response to hypercapnia did not differ between groups (2.0 ± 1.2 vs. 2.1 ± 0.8 %Δ/mm Hg; p = 0.85). Lower MCA PI was associated with a lower crystalized composite score (cognition), which persisted after adjustment for age, sex, eGFR, and education (ß = 0.58, p = 0.007). There was no association of MCA PI with carotid-femoral PWV (r = 0.01, p = 0.96), despite greater carotid-femoral PWV in ADPKD, suggesting MCA PI reflects vascular properties other than arterial stiffness (such as low wall shear stress) in ADPKD. DISCUSSION/CONCLUSION: MCA PI is lower in patients with ADPKD. Follow-up research on this observation is merited as low PI has been associated with intracranial aneurysm in other populations.


Asunto(s)
Demencia , Riñón Poliquístico Autosómico Dominante , Rigidez Vascular , Humanos , Riñón Poliquístico Autosómico Dominante/complicaciones , Hipercapnia , Presión Sanguínea/fisiología , Cognición/fisiología , Velocidad del Flujo Sanguíneo/fisiología
8.
J Med Genet ; 59(11): 1069-1074, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35393337

RESUMEN

BACKGROUND: Biallelic pathogenic variants in FXR1 have recently been associated with two congenital myopathy phenotypes: a severe form associated with hypotonia, long bone fractures, respiratory insufficiency and infantile death, and a milder form characterised by proximal muscle weakness with survival into adulthood. OBJECTIVE: We report eight patients from four unrelated families with biallelic pathogenic variants in exon 15 of FXR1. METHODS: Whole exome sequencing was used to detect variants in FXR1. RESULTS: Common clinical features were noted for all patients, which included proximal myopathy, normal serum creatine kinase levels and diffuse muscle atrophy with relative preservation of the quadriceps femoris muscle on muscle imaging. Additionally, some patients with FXR1-related myopathy had respiratory involvement and required bilevel positive airway pressure support. Muscle biopsy showed multi-minicores and type I fibre predominance with internalised nuclei. CONCLUSION: FXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants in FXR1 can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype-phenotype correlations difficult. Our work broadens the phenotypic spectrum of FXR1-related congenital myopathy.


Asunto(s)
Enfermedades Musculares , Humanos , Linaje , Mutación , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Homocigoto , Creatina Quinasa/genética , Proteínas de Unión al ARN/genética
9.
Hum Mol Genet ; 29(1): 20-30, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31511858

RESUMEN

McArdle disease is a disorder of carbohydrate metabolism that causes painful skeletal muscle cramps and skeletal muscle damage leading to transient myoglobinuria and increased risk of kidney failure. McArdle disease is caused by recessive mutations in the muscle glycogen phosphorylase (PYGM) gene leading to absence of PYGM enzyme in skeletal muscle and preventing access to energy from muscle glycogen stores. There is currently no cure for McArdle disease. Using a preclinical animal model, we aimed to identify a clinically translatable and relevant therapy for McArdle disease. We evaluated the safety and efficacy of recombinant adeno-associated virus serotype 8 (rAAV8) to treat a murine model of McArdle disease via delivery of a functional copy of the disease-causing gene, Pygm. Intraperitoneal injection of rAAV8-Pygm at post-natal day 1-3 resulted in Pygm expression at 8 weeks of age, accompanied by improved skeletal muscle architecture, reduced accumulation of glycogen and restoration of voluntary running wheel activity to wild-type levels. We did not observe any adverse reaction to the treatment at 8 weeks post-injection. Thus, we have investigated a highly promising gene therapy for McArdle disease with a clear path to the ovine large animal model endemic to Western Australia and subsequently to patients.


Asunto(s)
Glucógeno Fosforilasa de Forma Muscular/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo V/metabolismo , Glucógeno/metabolismo , Músculo Esquelético/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Glucógeno Fosforilasa de Forma Muscular/genética , Enfermedad del Almacenamiento de Glucógeno Tipo V/genética , Inflamación/genética , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL
10.
Am J Kidney Dis ; 79(4): 518-526, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34391872

RESUMEN

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure and has few treatment options. Metformin is well tolerated and safe in other patient populations. The primary objective of this clinical trial was to determine the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus. STUDY DESIGN: Prospective randomized controlled double-blind clinical trial. SETTING & PARTICIPANTS: 51 adults aged 30-60 years with ADPKD, without diabetes, and an estimated glomerular filtration rate (eGFR) 50-80 mL/min/1.73 m2. EXPOSURE: Metformin (maximum dose 2,000 mg/d) or placebo for 12 months. OUTCOME: Coprimary end points were the percentage of participants in each group prescribed at the end of the 12-month period: (1) the full randomized dose or (2) at least 50% of the randomized dose. Secondary and exploratory outcomes were the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in eGFR over a 12-month period. RESULTS: The participants' mean age was 48 ± 8 (SD) years, and eGFR was 70 ± 14 mL/min/1.73 m2. The metformin group had no cases of lactic acidosis, and there was 1 episode of mild hypoglycemia in each group. Participants in the metformin group reported more adverse symptoms, mostly related to the gastrointestinal tract. Eleven of 22 metformin-treated participants (50%) completed the treatment phase on the full dose compared with 23 of 23 in the placebo group (100%). In the metformin group, 82% of participants tolerated at least 50% of the dose, compared with 100% in the placebo group. In exploratory analyses, changes in htTKV or eGFR were not significantly different between the groups. LIMITATIONS: Short study duration. CONCLUSIONS: We found that 50% or more of the maximal metformin dose was safe and well tolerated over 12 months in patients with ADPKD. Safety of other preparations of metformin as well as its efficacy should be tested in future clinical trials. FUNDING: Government and philanthropic grants (NIDDK and the Zell Foundation). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02903511.


Asunto(s)
Metformina , Riñón Poliquístico Autosómico Dominante , Adulto , Progresión de la Enfermedad , Estudios de Factibilidad , Tasa de Filtración Glomerular , Humanos , Riñón , Metformina/uso terapéutico , Persona de Mediana Edad , Riñón Poliquístico Autosómico Dominante/complicaciones , Riñón Poliquístico Autosómico Dominante/tratamiento farmacológico , Estudios Prospectivos
11.
J Paediatr Child Health ; 58(2): 281-287, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34387892

RESUMEN

AIM: Familial hypercholesterolaemia (FH) is a common and treatable cause of premature coronary artery disease. However, the majority of individuals with FH remain undiagnosed. This study investigated the feasibility, acceptability and cost-effectiveness of screening children aged 1-2 years for FH at the time of an immunisation. METHODS: Children 1-2 years of age were offered screening for FH with a point-of-care total cholesterol (TC) test by capillary-collected blood sample at the time of an immunisation. An additional blood sample was taken to allow genetic testing if the TC level was above the 95th percentile (>5.3 mmol/L). Parents of children diagnosed with FH were offered testing. Following detection of the affected parent, cascade testing of their first-degree blood relatives was performed. RESULTS: We screened 448 children with 32 (7.1%) having a TC ≥ 5.3 mmol/L. The FH diagnosis was confirmed in three children (1:150 screened). Reverse cascade testing of other family members identified a further five individuals with FH; hence, eight new cases of FH were diagnosed from screening 448 children (1:56 screened). Ninety-six percent of parents would screen future children for FH. The approach was cost-effective, at $3979 per quality-adjusted life year gained. CONCLUSION: In Western Australia, universal screening of children aged 1-2 years for FH, undertaken at the time of an immunisation, was a feasible and effective approach to detect children, parents and other blood relatives with FH. The approach was acceptable to parents and is potentially a highly cost-effective detection strategy for families at risk of FH.


Asunto(s)
Hiperlipoproteinemia Tipo II , Australia , Preescolar , Pruebas Genéticas , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/genética , Lactante , Tamizaje Masivo , Padres , Proyectos Piloto
12.
BMC Cancer ; 21(1): 779, 2021 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-34233636

RESUMEN

BACKGROUND: There are no epidemiological studies describing rare cancers in Western Australia (WA). We aimed to fill this gap by estimating the incidence and five-year survival of rare, less common and common cancers in WA, based on definitions for rarity used by the Australian Institute of Health and Welfare and cancer groupings from the project on Surveillance of Rare Cancers in Europe (RARECARE). This research will enable policy- and decision-makers to better understand the size and nature of the public health problem presented by rare cancers in WA. It is anticipated that this study will inform improved health service design and delivery for all WA cancer patients, but particularly those with rare and less common cancers. METHODS: We estimated incidence and five-year survival rates of rare, less common and common cancers in WA using data sourced from the WA Cancer Registry for the 2013-2017 period. Cancers were defined as rare (< 6), less common (6-12), or common (> 12) based on their crude incidence rate per 100,000 people per year. RESULTS: Rare cancers make up 21.5% of all cancer diagnoses in WA, with a significantly poorer five-year survival of 58.2% (95% confidence interval (CI) 57.3-59.1%), compared to patients diagnosed with a common cancer, whose five-year survival was 87.8% (95% CI 87.3-88.3%). Survival for less common cancers was significantly poorer than both rare and common cancers, at 48.1% (95% CI 47.3-49.0%). Together, rare and less common cancers represent 48.4% of all cancer diagnoses in WA. CONCLUSIONS: While rare cancers are individually scarce, collectively over one in five cancer patients in WA are diagnosed with a rare cancer. These patients experience significantly worse prognoses compared to patients with common cancers.


Asunto(s)
Neoplasias/epidemiología , Enfermedades Raras/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Análisis de Supervivencia , Australia Occidental , Adulto Joven
13.
Hum Mol Genet ; 27(4): 638-648, 2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29293963

RESUMEN

Nemaline myopathy (NM) is a heterogeneous congenital skeletal muscle disease with cytoplasmic rod-like structures (nemaline bodies) in muscle tissue. While weakness in NM is related to contractile abnormalities, myofiber smallness is an additional abnormality in NM that may be treatable. We evaluated the effects of mRK35 (a myostatin inhibitor developed by Pfizer) treatment in the TgACTA1D286G mouse model of NM. mRK35 induced skeletal muscle growth that led to significant increases in animal bodyweight, forelimb grip strength and muscle fiber force, although it should be noted that animal weight and forelimb grip strength in untreated TgACTA1D286G mice was not different from controls. Treatment was also associated with an increase in the number of tubular aggregates found in skeletal muscle. These findings suggest that myostatin inhibition may be useful in promoting muscle growth and strength in Acta1-mutant muscle, while also further establishing the relationship between low levels of myostatin and tubular aggregate formation.


Asunto(s)
Actinas/metabolismo , Músculo Esquelético/metabolismo , Miopatías Nemalínicas/metabolismo , Actinas/genética , Animales , Miembro Anterior/metabolismo , Miembro Anterior/fisiología , Fuerza de la Mano/fisiología , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/fisiología , Miopatías Nemalínicas/fisiopatología , Miostatina/metabolismo
14.
Clin Nephrol ; 94(1): 26-35, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32449678

RESUMEN

AIMS: Arterial stiffness increases with both advancing age and chronic kidney disease (CKD) and may contribute to kidney function decline, but evidence is inconsistent. We hypothesized that greater baseline arterial stiffness (assessed as pulse pressure (PP) and carotid-femoral pulse-wave velocity CFPWV)) was independently associated with kidney disease progression over the follow-up period (3.8 years) in the Systolic Blood Pressure Intervention Trial (SPRINT). MATERIALS AND METHODS: 8,815 SPRINT participants were included in the analysis of PP. 592 adults who participated in a SPRINT ancillary study that measured CFPWV were included in subgroup analyses. Cox proportional hazards analysis was used to examine the association between PP and time to kidney disease progression endpoints: (A) incident estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 in non-CKD participants at baseline; (B) 50% decline in eGFR, initiation of dialysis, or transplant in those with baseline CKD. Mixed model analyses examined the association of baseline PP/CFPWV with follow-up eGFR. RESULTS AND CONCLUSION: Mean ± SD age was 68 ± 10 years, baseline PP was 62 ± 14 mmHg, and CFPWV was 10.8 ± 2.7 m/s. In the fully adjusted model, PP ≥ median was associated with an increased hazard of kidney disease progression endpoints (HR: 1.93 (1.43 - 2.61)). The association remained significant in individuals without (2.05 (1.47 - 2.87)) but not with baseline CKD (1.28 (0.55 - 2.65)). In fully adjusted models, higher baseline PP associated with eGFR decline (p < 0.0001 (all, CKD, non-CKD)), but baseline CFPWV did not. Among older adults at high risk for cardiovascular events, baseline PP was associated with kidney disease progression.


Asunto(s)
Presión Sanguínea/fisiología , Insuficiencia Renal Crónica , Rigidez Vascular/fisiología , Anciano , Progresión de la Enfermedad , Humanos , Persona de Mediana Edad , Análisis de la Onda del Pulso , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/fisiopatología
15.
Am J Hum Genet ; 99(5): 1086-1105, 2016 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-27745833

RESUMEN

This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase. Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands. PYROXD1 is a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins (FAD-binding) and catalyze pyridine-nucleotide-dependent (NAD/NADH) reduction of thiol residues in other proteins. Complementation experiments in yeast lacking glutathione reductase glr1 show that human PYROXD1 has reductase activity that is strongly impaired by the disease-associated missense mutations. Immunolocalization studies in human muscle and zebrafish myofibers demonstrate that PYROXD1 localizes to the nucleus and to striated sarcomeric compartments. Zebrafish with ryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease.


Asunto(s)
Núcleo Celular/genética , Miopatías Distales/genética , Variación Genética , Miopatías Estructurales Congénitas/genética , Oxidorreductasas/genética , Secuencia de Aminoácidos , Animales , Células COS , Núcleo Celular/metabolismo , Chlorocebus aethiops , Estudios de Cohortes , Creatina Quinasa/genética , Creatina Quinasa/metabolismo , Citoplasma/metabolismo , Miopatías Distales/patología , Proteína 4 Similar a ELAV/genética , Proteína 4 Similar a ELAV/metabolismo , Femenino , Flavoproteínas/metabolismo , Eliminación de Gen , Estudio de Asociación del Genoma Completo , Glutatión Reductasa/genética , Glutatión Reductasa/metabolismo , Células HEK293 , Humanos , Masculino , Músculo Esquelético/patología , Mutación Missense , Miopatías Estructurales Congénitas/patología , Oxidorreductasas/metabolismo , Linaje , Conformación Proteica , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Pez Cebra/genética
16.
Am J Kidney Dis ; 74(2): 213-223, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30803706

RESUMEN

RATIONALE & OBJECTIVE: Vascular dysfunction, characterized by impaired vascular endothelial function and increased large-elastic artery stiffness, is evident early in autosomal dominant polycystic kidney disease (ADPKD) and is an important predictor of cardiovascular events and mortality. Aldosterone excess has been implicated in the development of endothelial dysfunction and arterial stiffness, in part by causing increased oxidative stress and inflammation. We hypothesized that aldosterone antagonism would reduce vascular dysfunction in patients with early-stage ADPKD. STUDY DESIGN: Prospective, randomized, controlled, double-blind, clinical trial. SETTING & PARTICIPANTS: 61 adults aged 20 to 55 years with ADPKD, estimated glomerular filtration rate ≥ 60mL/min/1.73m2, and receiving a renin-angiotensin-aldosterone system inhibitor. INTERVENTION: Spironolactone (maximum dose, 50mg/d) or placebo for 24 weeks. OUTCOMES: Change in brachial artery flow-mediated dilation (FMDBA) was the primary end point and change in carotid-femoral pulse-wave velocity (CFPWV) was the secondary end point. RESULTS: 60 participants completed the trial. Participants had a mean age of 34±10 (SD) years, 54% were women, and 84% were non-Hispanic white. Spironolactone did not change FMDBA (8.0% ± 5.5% and 7.8% ± 4.3% at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 8.4% ± 6.2% and 8.0% ± 4.6%; P=0.9for comparison of change between groups) or CFPWV (640±127 and 603±101cm/s at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 659±138 and 658±131cm/s; P=0.1). Brachial systolic blood pressure was reduced with spironolactone (median change, -6 [IQR, -15, 1] vs -2 [IQR, -7, 10] mm Hg in the placebo group; P=0.04). Spironolactone did not change the majority of circulating and/or endothelial cell markers of oxidative stress/inflammation and did not change vascular oxidative stress. LIMITATIONS: Low level of baseline vascular dysfunction; lack of aldosterone measurements. CONCLUSIONS: 24 weeks of aldosterone antagonism reduced systolic blood pressure without changing vascular function in patients with early-stage ADPKD. FUNDING: NIDDK, NIH National Center for Advancing Translational Sciences, and the Zell Family Foundation. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01853553.


Asunto(s)
Vasos Sanguíneos/efectos de los fármacos , Vasos Sanguíneos/fisiopatología , Antagonistas de Receptores de Mineralocorticoides/farmacología , Riñón Poliquístico Autosómico Dominante/fisiopatología , Espironolactona/farmacología , Adulto , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Femenino , Humanos , Masculino , Estudios Prospectivos , Adulto Joven
17.
Am J Nephrol ; 49(4): 263-270, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30820005

RESUMEN

BACKGROUND: Long-term patterns of fibroblast growth factor 23 (FGF23) are poorly characterized among dialysis patients. OBJECTIVES: To identify different FGF23 trajectories and determine clinical factors that predict distinct FGF23 trajectories and whether FGF23 trajectories differ in regard to their associations with all-cause mortality among prevalent hemodialysis patients. METHODS: The HEMO study was a randomized multicenter study evaluating the effects of high-dose vs. standard-dose and high-flux vs. low-flux hemodialysis on mortality. We measured intact FGF23 levels in stored serum samples at baseline and annually among 919 HEMO participants and identified FGF23 trajectories using group-based modeling. Logistic regression determined predictors of trajectories. Cox regression models evaluated the association between trajectory and all-cause mortality. RESULTS: We identified 5 distinct FGF23 trajectory groups during the initial 24 months: low stable, low increasing, elevated increasing, elevated decreasing, and elevated stable. In multivariable models, diabetes, high dose dialysis, no venous catheter, low serum calcium, phosphorus, and interleukin-6, no vitamin D analog use, and greater residual kidney function were associated with the low stable trajectory group compared to the elevated stable group. High flux dialysis, no venous catheter, and low serum phosphorus and 25-hydroxyvitamin D were associated with the elevated decreasing trajectory group compared to the elevated stable group. After full adjustment, the low stable trajectory group was associated with reduced mortality (hazard ratio [HR] 0.61; 95% CI -0.41-0.91) compared to the elevated stable trajectory group. CONCLUSIONS: We identified 5 distinct FGF23 trajectories over 24 months among HEMO study participants including a decreasing trajectory. The low stable FGF23 trajectory was associated with a reduced HR of all-cause mortality.


Asunto(s)
Enfermedades Cardiovasculares/mortalidad , Factores de Crecimiento de Fibroblastos/sangre , Fallo Renal Crónico/terapia , Diálisis Renal/métodos , Adulto , Anciano , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Femenino , Factor-23 de Crecimiento de Fibroblastos , Estudios de Seguimiento , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Medición de Riesgo
18.
J Am Soc Nephrol ; 29(2): 571-578, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29118087

RESUMEN

The association of overweight/obesity with disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) remains untested. We hypothesized that overweight/obesity associates with faster progression in early-stage ADPKD. Overall, 441 nondiabetic participants with ADPKD and an eGFR>60 ml/min per 1.73 m2 who participated in the Halt Progression of Polycystic Kidney Disease Study A were categorized on the basis of body mass index (BMI; calculated using nonkidney and nonliver weight) as normal weight (18.5-24.9 kg/m2; reference; n=192), overweight (25.0-29.9 kg/m2; n=168), or obese (≥30 kg/m2; n=81). We evaluated the longitudinal (5-year) association of overweight/obesity with change in total kidney volume (TKV) by magnetic resonance imaging using linear regression and multinomial logistic regression models. Among participants, mean±SD age was 37±8 years, annual percent change in TKV was 7.4%±5.1%, and BMI was 26.3±4.9 kg/m2 The annual percent change in TKV increased with increasing BMI category (normal weight: 6.1%±4.7%, overweight: 7.9%±4.8%, obese: 9.4%±6.2%; P<0.001). In the fully adjusted model, higher BMI associated with greater annual percent change in TKV (ß=0.79; 95% confidence interval [95% CI], 0.18 to 1.39, per 5-unit increase in BMI). Overweight and obesity associated with increased odds of annual percent change in TKV ≥7% compared with <5% (overweight: odds ratio, 2.02; 95% CI, 1.15 to 3.56; obese: odds ratio, 3.76; 95% CI, 1.81 to 7.80). Obesity also independently associated with greater eGFR decline (slope) versus normal weight (fully adjusted ß =-0.08; 95% CI, -0.15 to -0.02). In conclusion, overweight and, particularly, obesity are strongly and independently associated with rate of progression in early-stage ADPKD.


Asunto(s)
Riñón/patología , Obesidad/epidemiología , Riñón Poliquístico Autosómico Dominante/fisiopatología , Adulto , Índice de Masa Corporal , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Riñón/diagnóstico por imagen , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Sobrepeso/epidemiología , Factores de Tiempo
20.
Am J Nephrol ; 47(1): 57-65, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29393090

RESUMEN

BACKGROUND: Dietary sodium may influence cognitive function through its effects on cerebrovascular function and cerebral blood flow. METHODS: The aim of this study was to evaluate the association of dietary sodium intake with cognitive decline in community-dwelling older adults. We also evaluated the associations of dietary potassium and sodium:potassium intake with cognitive decline, and associations of these nutrients with micro- and macro-structural brain magnetic resonance imaging (MRI) indices. In all, 1,194 participants in the Health Aging and Body Composition study with measurements of dietary sodium intake (food frequency questionnaire [FFQ]) and change in the modified Mini Mental State Exam (3MS) were included. RESULTS: The age of participants was 74 ± 3 years with a mean dietary sodium intake of 2,677 ± 1,060 mg/day. During follow-up (6.9 ± 0.1 years), 340 (28%) had a clinically significant decline in 3MS score (≥1.5 SD of mean decline). After adjustment, dietary sodium intake was not associated with odds of cognitive decline (OR 0.96, 95% CI 0.50-1.84 per doubling of sodium). Similarly, potassium was not associated with cognitive decline; however, higher sodium:potassium intake was associated with increased odds of cognitive decline (OR 2.02 [95% CI 1.01-4.03] per unit increase). Neither sodium or potassium alone nor sodium:potassium were associated with micro- or macro-structural brain MRI indices. These results are limited by the use of FFQ. CONCLUSIONS: In community-dwelling older adults, higher sodium:potassium, but not sodium or potassium intake alone, was associated with decline in cognitive function, with no associations observed with micro- and macro-structural brain MRI indices. These findings do not support reduction dietary sodium/increased potassium intake to prevent cognitive decline with aging.


Asunto(s)
Encéfalo/diagnóstico por imagen , Cognición/efectos de los fármacos , Disfunción Cognitiva/diagnóstico por imagen , Potasio en la Dieta/administración & dosificación , Sodio en la Dieta/administración & dosificación , Anciano , Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Cognición/fisiología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Femenino , Estudios de Seguimiento , Envejecimiento Saludable/fisiología , Humanos , Vida Independiente , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Estado Nutricional/fisiología , Factores de Riesgo
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