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Introduction: Advances in the field of genetic testing have spurred its use in transplantation. Potential benefits of genetic testing in transplant nephrology include diagnosis, treatment, risk stratification of recurrent disease, and risk stratification in potential donors. However, it is unclear how to best apply genetic testing in this population to maximize its yield. We describe our transplant center's approach to selective genetic testing as part of kidney transplant candidate and donor evaluation. Methods: Transplant recipient candidates were tested if they had a history of ESRD at age <50, primary FSGS, complement-mediated or unknown etiology of kidney disease, or had a family history of kidney disease. Donors were tested if age <35, were related to their potential recipients with known genetic susceptibility or had a first-degree relative with a history of kidney disease of unknown etiology. A targeted NGS gene panel of 385 genes was used. Clinical implications and downstream effects were monitored. Results: Over 30% of recipients tested within the established criteria were positive for a pathogenic variant. The most common pathogenic variants were APOL1 high-risk genotypes as well as collagen 4-alpha-3, -4 and -5. Donor testing done according to our inclusion criteria resulted in about 12% yield. Positive test results in recipients helped with stratification of the risk of recurrent disease. Positive test results in potential donors guided informed decisions on when not to move forward with a donation. Discussion: Integrating targeted panel genetic testing into a kidney transplant clinic in conjunction with a selective criteria for testing donors and recipients ensured a reasonable diagnostic yield. The results had implications on clinical management, risk stratification and in some cases were instrumental in directing downstream changes including when to stop the evaluation process. Given the impact on management and transplant decisions, we advocate for the widespread use of genetic testing in selected individuals undergoing transplant evaluation and donation who meet pre-defined criteria.
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INTRODUCTION: Older patients with advanced chronic kidney disease (CKD) often are inadequately prepared to make informed decisions about treatments including dialysis and cardiopulmonary resuscitation. Further, evidence shows that patients with advanced CKD do not commonly engage in advance care planning (ACP), may suffer from poor quality of life, and may be exposed to end-of-life care that is not concordant with their goals. We aim to study the effectiveness of a video intervention on ACP, treatment preferences and other patient-reported outcomes. METHODS AND ANALYSIS: The Video Images about Decisions for Ethical Outcomes in Kidney Disease trial is a multi-centre randomised controlled trial that will test the effectiveness of an intervention that includes a CKD-related video decision aid followed by recording personal video declarations about goals of care and treatment preferences in older adults with advancing CKD. We aim to enrol 600 patients over 5 years at 10 sites. ETHICS AND DISSEMINATION: Regulatory and ethical aspects of this trial include a single Institutional Review Board mechanism for approval, data use agreements among sites, and a Data Safety and Monitoring Board. We intend to disseminate findings at national meetings and publish our results. TRIAL REGISTRATION NUMBER: NCT04347629.
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Planificación Anticipada de Atención , Insuficiencia Renal Crónica , Cuidado Terminal , Anciano , Humanos , Estudios Multicéntricos como Asunto , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Diálisis Renal , Insuficiencia Renal Crónica/terapiaRESUMEN
Coronavirus disease 2019 (COVID-19) appears to be associated with increased arterial and venous thromboembolic disease. These presumed abnormalities in hemostasis have been associated with filter clotting during continuous renal replacement therapy (CRRT). We aimed to characterize the burden of CRRT filter clotting in COVID-19 infection and to describe a CRRT anticoagulation protocol that used anti-factor Xa levels for systemic heparin dosing. Multi-center study of consecutive patients with COVID-19 receiving CRRT. Primary outcome was CRRT filter loss. Sixty-five patients were analyzed, including 17 using an anti-factor Xa protocol to guide systemic heparin dosing. Fifty-four out of 65 patients (83%) lost at least one filter. Median first filter survival time was 6.5 [2.5, 33.5] h. There was no difference in first or second filter loss between the anti-Xa protocol and standard of care anticoagulation groups, however fewer patients lost their third filter in the protocolized group (55% vs. 93%) resulting in a longer median third filter survival time (24 [15.1, 54.2] vs. 17.3 [9.5, 35.1] h, p = 0.04). The rate of CRRT filter loss is high in COVID-19 infection. An anticoagulation protocol using systemic unfractionated heparin, dosed by anti-factor Xa levels is reasonable approach to anticoagulation in this population.
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Biomarcadores Farmacológicos/análisis , COVID-19 , Terapia de Reemplazo Renal Continuo , Enfermedad Crítica/terapia , Monitoreo de Drogas/métodos , Heparina , Filtros Microporos/efectos adversos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Coagulación Sanguínea/efectos de los fármacos , COVID-19/sangre , COVID-19/fisiopatología , COVID-19/terapia , Protocolos Clínicos , Terapia de Reemplazo Renal Continuo/efectos adversos , Terapia de Reemplazo Renal Continuo/métodos , Relación Dosis-Respuesta a Droga , Análisis de Falla de Equipo , Factor Xa/análisis , Femenino , Heparina/administración & dosificación , Heparina/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , SARS-CoV-2Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo I/diagnóstico , Hipoxia/etiología , Metahemoglobinemia/diagnóstico , Mieloma Múltiple/diagnóstico , Urato Oxidasa/efectos adversos , Diagnóstico Diferencial , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Humanos , Hipercalcemia/etiología , Pruebas de Función Renal , Pulmón/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Metahemoglobinemia/inducido químicamente , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Oxígeno/sangre , Radiografía TorácicaAsunto(s)
Muerte Súbita Cardíaca/etiología , Ácido Glicirretínico/efectos adversos , Glycyrrhiza/efectos adversos , Hiperaldosteronismo/diagnóstico , Mineralocorticoides/sangre , Aldosterona/sangre , Análisis Químico de la Sangre , Cateterismo Cardíaco , Reanimación Cardiopulmonar , Diagnóstico Diferencial , Electroencefalografía , Resultado Fatal , Ácido Glicirretínico/farmacología , Humanos , Hidrocortisona/orina , Hiperaldosteronismo/inducido químicamente , Hipopotasemia/diagnóstico , Hipopotasemia/etiología , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Fibrilación Ventricular/complicacionesRESUMEN
Importance: Urine sediment microscopy is commonly performed during the evaluation of kidney disease. Interobserver reliability of nephrologists' urine sediment examination has not been well studied. Objective: Assess interobserver reliability of the urine sediment examination. Design, Setting, and Participants: In this diagnostic test study, urine samples were prospectively collected from a convenience sample of adult patients from an academic hospital in the United States undergoing kidney biopsy from July 11, 2018, to March 20, 2019. Digital images and videos of urine sediment findings were captured using a bright-field microscope. These images and videos along with urine dipstick results were incorporated in online surveys and sent to expert nephrologists at 15 US teaching hospitals. They were asked to identify individual sediment findings and the most likely underlying disease process. Exposures: Urine dipstick results and urine sediment images from patients undergoing native kidney biopsy. Main Outcomes and Measures: Interobserver reliability of urine sediment microscopy findings estimated by overall percent agreement and Fleiss κ coefficients. Secondary outcomes included concordance of diagnoses suspected by nephrologists with corresponding kidney biopsy results. Results: In total, 10 surveys from 10 patients containing 76 study questions on individual features were sent to 21 nephrologists, 14 (67%) of whom completed them all. Their combined 1064 responses were analyzed. Overall percent agreement for casts was an estimated 59% (95% CI, 50%-69%), κ = 0.52 (95% CI, 0.42-0.62). For other sediment findings, overall percent agreement was an estimated 69% (95% CI, 61%-77%), κ = 0.65 (95% CI, 0.56-0.73). The κ estimates ranged from 0.13 (95% CI, 0.10-0.17) for mixed cellular casts to 0.90 (95% CI, 0.87-0.94) for squamous epithelial cells. Conclusions and Relevance: In this study, substantial variability occurred in the interpretation of urine sediment findings, even among expert nephrologists. Educational or technological innovations may help improve the urine sediment as a diagnostic tool.
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Urinálisis/métodos , Urinálisis/normas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nefrólogos , Variaciones Dependientes del Observador , Estudios Prospectivos , Reproducibilidad de los ResultadosAsunto(s)
Glomerulonefritis por IGA/diagnóstico , Riñón/patología , Adulto , Biopsia , Creatinina/sangre , Diagnóstico Diferencial , Glomerulonefritis/diagnóstico , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/cirugía , Hematuria/etiología , Humanos , Hipertensión/etiología , Riñón/diagnóstico por imagen , Trasplante de Riñón , Masculino , Insuficiencia Renal/etiología , UltrasonografíaRESUMEN
Background: Genetic testing in nephrology is increasingly described in the literature and several groups have suggested significant clinical benefit. However, studies to date have described experience from established genetic testing centers or from externally funded research programs. Methods: We established a de novo kidney genetics clinic within an academic adult general nephrology practice. Key features of this effort included a pipeline for internal referrals, flexible scheduling, close coordination between the nephrologist and a genetic counselor, and utilization of commercial panel-based testing. Over the first year, we examined the outcomes of genetic testing, the time to return of genetic testing, and out-of-pocket cost to patients. Results: Thirty patients were referred and 23 were evaluated over the course of five clinic sessions. Nineteen patients underwent genetic testing with new diagnoses in nine patients (47%), inconclusive results in three patients (16%), and clearance for kidney donation in two patients (11%). On average, return of genetic results occurred 55 days (range 9-174 days) from the day of sample submission and the average out-of-pocket cost to patients was $155 (range $0-$1623). Conclusions: We established a kidney genetics clinic, without a pre-existing genetics infrastructure or dedicated research funding, that identified a new diagnosis in approximately 50% of patients tested. This study provides a clinical practice model for successfully incorporating genetic testing into ambulatory nephrology care with minimal capital investment and limited financial effect on patients.
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Nefrología , Pacientes Ambulatorios , Adulto , Instituciones de Atención Ambulatoria , Pruebas Genéticas , Humanos , RiñónRESUMEN
BACKGROUND: This study reports the clinical and pathological features of 12 cases of primary Sjogren syndrome (pSS) with renal involvement presenting with proximal tubular dysfunction in a single center, and investigates the possible correlation of ectopic germinal center formation and megalin/cubilin down-expression. METHOD: Clinical and pathological records were reviewed. Immunohistochemistry was carried out to detect megalin, cubilin, CD21 and IL-17 expression. RESULTS: Patients presented with different degrees of proximal renal tubule lesion and decreased estimated glomerular filtration rate (eGFR). Renal biopsy revealed tubulointerstitial nephritis, with tubular epithelial cell degeneration, tubular atrophy, interstitial inflammation and focal fibrosis. Immunohistochemistry revealed decreased expression of megalin and cubilin, two important multiligand protein receptors on the brush border of proximal tubular epithelial cells. IL-17 secreted by Th17 subtype effector T cells was diffusely detected in the renal proximal tubule, with a negative correlation of IL-17 and megalin expression. In addition, ectopic germinal centers characterized by CD21+ follicular dendritic cells were present in the renal interstitium. In patients with a decreased eGFR, treatment with 4 weeks of glucocorticoid therapy resulted in an improved eGFR in 75% of patients. CONCLUSION: We report 12 cases of pSS characterized by Fanconi syndrome. The decreased megalin and cubilin expression may contribute to the proximal tubular reabsorption defect, possibly secondary to Th17 infiltration and formation of ectopic germinal centers.
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Coristoma/patología , Síndrome de Fanconi/etiología , Centro Germinal , Enfermedades Renales/patología , Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad/biosíntesis , Síndrome de Sjögren/complicaciones , Adolescente , Niño , Síndrome de Fanconi/patología , Femenino , Humanos , Masculino , Síndrome de Sjögren/patologíaRESUMEN
Novel, all-oral interferon-free direct-acting antiviral agents have revolutionized the management of hepatitis C virus (HCV) infection by producing exceptional cure rates with minimal adverse events. While provocation or exacerbation of autoimmunity has been reported in HCV-infected patients receiving interferon, this phenomenon has not been reported in patients receiving interferon-free HCV therapy. We report the occurrence of three cases of lupus-like immune complex-mediated glomerulonephritis occurring shortly after exposure to sofosbuvir-based direct-acting antiviral therapies. In all three cases, renal function quickly improved with immunosuppression. However, two of the three patients developed infectious complications of immunosuppression and died. This is the first report of a lupus-like immune complex mediated glomerulonephritis occurring in the context of HCV eradication with all-oral direct-acting antiviral therapies.
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PURPOSE OF REVIEW: The review summarizes recent studies on chronic kidney disease-mineral bone disorders, with a focus on new developments in disease management. RECENT FINDINGS: The term chronic kidney disease-mineral bone disorder has come to describe an increasingly complex network of alterations in minerals and skeletal disorders that contribute to the significant cardiovascular morbidity and mortality seen in patients with chronic kidney disease and end stage renal disease. Clinical studies continue to suggest associations with clinical outcomes, yet current clinical trials have failed to support causality. Variability in practice exists as current guidelines for management of mineral bone disorders are often based on weak evidence. Recent studies implicate novel pathways for therapeutic intervention in clinical trials. SUMMARY: Mineral bone disorders in chronic kidney disease arise from alterations in a number of molecules in an increasingly complex physiological network interconnecting bone and the cardiovascular system. Despite extensive associations with improved outcomes in a number of molecules, clinical trials have yet to prove causality and there is an absence of new therapies available to improve patient outcomes. Additional clinical trials that can incorporate the complexity of mineral bone disorders, and with the ability to intervene on more than one pathway, are needed to advance patient care.
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Enfermedades Óseas Metabólicas/tratamiento farmacológico , Hiperparatiroidismo Secundario/terapia , Hiperfosfatemia/terapia , Insuficiencia Renal Crónica/complicaciones , Enfermedades Óseas Metabólicas/etiología , Calcifilaxia/etiología , Calcifilaxia/terapia , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/sangre , Fracturas Óseas/etiología , Fracturas Óseas/prevención & control , Humanos , Hiperparatiroidismo Secundario/etiología , Hiperfosfatemia/etiología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/fisiopatología , Insuficiencia Renal Crónica/fisiopatología , Vitamina D/sangre , Vitamina D/uso terapéuticoRESUMEN
UNLABELLED: Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral direct-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. The authors studied case series of patients with HCV-MCS who were treated with sofosbuvir-based regimens and historical controls treated with pegylated interferon and ribavirin in a single health care network. HCV-MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (n = 7) was established by kidney biopsy (n = 5) or by two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7-2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events. CONCLUSION: SVR12 rates for sofosbuvir-based DAA regimens in HCV-MCS were 83%, significantly higher than historical controls treated with pegylated interferon and ribavirin; patients with glomerulonephritis experienced improvement in renal function, including those not concomitantly treated with immunosuppression.
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Antivirales/uso terapéutico , Crioglobulinemia/tratamiento farmacológico , Crioglobulinemia/virología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Ribavirina/uso terapéutico , Sofosbuvir/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
We investigated on the mechanism responsible for the reduced ATP-sensitive K(+)(K(ATP)) channel activity recorded from skeletal muscle of K(+)-depleted rats. Patch-clamp and gene expression measurements of K(ATP) channel subunits were performed. A down-regulation of the K(ATP) channel subunits Kir6.2(-70%) and SUR2A(-46%) in skeletal muscles of K(+)-depleted rats but no changes in the expression of Kir6.1, SUR1 and SUR2B subunits were observed. A reduced K(ATP) channel currents of -69.5% in K(+)-depleted rats was observed. The Kir6.2/SUR2A-B agonist cromakalim showed similar potency in activating the K(ATP) channels of normokalaemic and K(+)-depleted rats but reduced efficacy in K(+)-depleted rats. The Kir6.2/SUR1-2B agonist diazoxide activated K(ATP) channels in normokalaemic and K(+)-depleted rats with equal potency and efficacy. The down-regulation of the Kir6.2 explains the reduced K(ATP) channel activity in K(+)-depleted rats. The lower expression of SUR2A explains the reduced efficacy of cromakalim; preserved SUR1 expression accounts for the efficacy of diazoxide. Kir6.2/SUR2A deficiency is associated with impaired muscle function in K(+)-depleted rats and in hypoPP.
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Canales KATP/deficiencia , Músculo Esquelético/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Deficiencia de Potasio/metabolismo , Animales , Cromakalim/farmacología , Diazóxido/farmacología , Parálisis Periódica Hipopotasémica/genética , Parálisis Periódica Hipopotasémica/metabolismo , Parálisis Periódica Hipopotasémica/fisiopatología , Canales KATP/efectos de los fármacos , Canales KATP/genética , Masculino , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Músculo Esquelético/fisiopatología , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna/efectos de los fármacos , Canales de Potasio de Rectificación Interna/genética , Deficiencia de Potasio/genética , Deficiencia de Potasio/fisiopatología , Ratas , Ratas Wistar , Sarcolema/efectos de los fármacos , Sarcolema/genética , Sarcolema/metabolismo , Vasodilatadores/farmacologíaRESUMEN
Thymoglobulin (Genzyme, Cambridge, MA) is an antithymocyte globulin preparation used for induction immunosuppression therapy in solid organ transplantation. It is being utilized with increasing frequency in orthotopic liver transplantation (OLT) in an effort to minimize or delay the use of calcineurin inhibitors due to their inherent nephrotoxicity. Experience with thymoglobulin in OLT remains limited. We report a case of serum sickness in a patient who received thymoglobulin following OLT. The patient experienced intermittent fevers, polyarthralgia, and acute renal failure 9 days after completion of thymoglobulin administration. The patient's symptoms resolved rapidly and completely with a course of intravenous steroids. We review a set of diagnostic criteria for serum sickness and emphasize the importance of early recognition of the process. Early treatment of serum sickness with steroids or plasmapheresis is highly effective and can reduce unnecessary morbidity from this unusual sequela of induction immunosuppression with antithymocyte globulin.
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Anticuerpos Monoclonales/efectos adversos , Trasplante de Hígado , Enfermedad del Suero/etiología , Lesión Renal Aguda/etiología , Animales , Anticuerpos Monoclonales/uso terapéutico , Suero Antilinfocítico , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Inyecciones Intravenosas , Metilprednisolona/administración & dosificación , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Conejos , Resultado del TratamientoRESUMEN
ATP-sensitive K(+) channels (K(ATP)) are an octameric complex of inwardly rectifying K(+) channels (Kir6.1 and Kir6.2) and sulfonylurea receptors (SUR1 and SUR2A/B), which are involved in several diseases. The tissue-selective expression of the subunits leads to different channels; however, the composition and role of the functional channel in native muscle fibers is not known. In this article, the properties of K(ATP) channels of fast-twitch and slow-twitch muscles were compared by combining patch-clamp experiments with measurements of gene expression. We found that the density of K(ATP) currents/area was muscle-type specific, being higher in fast-twitch muscles compared with the slow-twitch muscle. The density of K(ATP) currents/area was correlated with the level of Kir6.2 expression. SUR2A was the most abundant subunit expressed in all muscles, whereas the vascular SUR2B subunit was expressed but at lower levels. A significant expression of the pancreatic SUR1 was also found in fast-twitch muscles. Pharmacological experiments showed that the channel response to the SUR1 agonist diazoxide, SUR2A/B agonist cromakalim, SUR1 antagonist tolbutamide, and the SUR1/SUR2A/B-antagonist glibenclamide matched the SURs expression pattern. Muscle-specific K(ATP) subunit compositions contribute to the physiological performance of different muscle fiber types and determine the pharmacological actions of drugs modulating K(ATP) activity in muscle diseases.
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Adenosina Trifosfato/química , Biofisica/métodos , Canales de Potasio/química , Proteínas Recombinantes de Fusión/química , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Antiarrítmicos/farmacología , Antihipertensivos/farmacología , Cromakalim/metabolismo , Cromakalim/farmacología , Cartilla de ADN/química , Diazóxido/farmacología , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica , Gliburida/farmacología , Hipoglucemiantes/farmacología , Canales KATP , Cinética , Masculino , Modelos Estadísticos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Músculos/metabolismo , Técnicas de Placa-Clamp , Fenotipo , Potasio/química , Potasio/metabolismo , Canales de Potasio/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Ratas , Ratas Wistar , Receptores de Droga/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptores de Sulfonilureas , Tolbutamida/farmacologíaRESUMEN
Potassium channels are essential for a variety of cellular processes ranging from membrane excitability to cellular proliferation. The KCNE genes (KCNE1-5) encode a family of single-transmembrane-domain proteins that modulate the properties of several potassium channels, suggesting a physiologic role for these accessory subunits in many human tissues. To investigate the expression and transcriptional control of KCNE genes we mapped transcription start sites, delineated 5' genomic structure, and characterized functional promoter elements for each gene. We identified alternatively spliced transcripts for both KCNE1 and KCNE3, including a cardiac-specific KCNE1 transcript. Analysis of relative expression levels of KCNE1-5 in a panel of human tissues revealed distinct, but overlapping, expression patterns. The coexpression of multiple functionally distinct KCNE genes in some tissues infers complex accessory subunit modification of potassium channels. Identification of the core promoter elements necessary for transcriptional control of the KCNE genes facilitates future work investigating factors responsible for tissue-specific expression as well as the discovery of promoter variants associated with disease.
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Regulación de la Expresión Génica/fisiología , Canales de Potasio con Entrada de Voltaje/biosíntesis , Regiones Promotoras Genéticas/genética , Transcripción Genética/genética , Humanos , Especificidad de Órganos/genética , Canales de Potasio con Entrada de Voltaje/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately ad 1700 and segregating the same KCNQ1 mutation (A341V). METHODS AND RESULTS: The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking beta-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (< or =440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7+/-4 versus 13+/-9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. CONCLUSIONS: KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.
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Variación Genética , Canal de Potasio KCNQ1/genética , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/fisiopatología , Estudios de Cohortes , Efecto Fundador , Tamización de Portadores Genéticos , Humanos , Síndrome de QT Prolongado/congénito , Mutación , Fenotipo , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Clinical heterogeneity among patients with long-QT syndrome (LQTS) sharing the same disease-causing mutation is usually attributed to variable penetrance. One potential explanation for this phenomenon is the coexistence of modifier gene alleles, possibly common single nucleotide polymorphisms, altering arrhythmia susceptibility. We demonstrate this concept in a family segregating a novel, low-penetrant KCNH2 mutation along with a common single nucleotide polymorphism in the same gene. METHODS AND RESULTS: The proband is a 44-year-old white woman with palpitations associated with presyncope since age 20, who presented with ventricular fibrillation and cardiac arrest. Intermittent QT prolongation was subsequently observed (max QTc, 530 ms), and LQT2 was diagnosed after the identification of a missense KCNH2 mutation (A1116V) altering a conserved residue in the distal carboxyl-terminus of the encoded HERG protein. The proband also carried the common KCNH2 polymorphism K897T on the nonmutant allele. Relatives who carried A1116V without K897T were asymptomatic, but some exhibited transient mild QTc prolongation, suggesting latent disease. Heterologous expression studies performed in cultured mammalian cells and using bicistronic vectors linked to different fluorescent proteins demonstrated that coexpression of A1116V with K897T together resulted in significantly reduced current amplitude as compared with coexpression of either allele with WT-HERG. Thus, the presence of KCNH2-K897T is predicted to exaggerate the IKr reduction caused by the A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband carrying both alleles. CONCLUSIONS: We have provided evidence that a common KCNH2 polymorphism may modify the clinical expression of a latent LQT2 mutation. A similar mechanism may contribute to the risk for sudden death in more prevalent cardiac diseases.
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Canales de Potasio Éter-A-Go-Go/genética , Síndrome de QT Prolongado/genética , Mutación , Polimorfismo de Nucleótido Simple , Adulto , Muerte Súbita Cardíaca/etiología , Canal de Potasio ERG1 , Electrocardiografía , Femenino , Humanos , Síndrome de QT Prolongado/fisiopatología , FenotipoRESUMEN
Voltage-gated potassium (K(V)) channels are modulated by at least three distinct classes of proteins including the KCNE family of single transmembrane accessory subunits. In the human genome, KCNE proteins are encoded by five genes designated KCNE1 through KCNE5. KCNE1 associates with KCNQ1 in vitro to generate a potassium current closely resembling the slowly activating delayed rectifier (I(Ks)). Other KCNE proteins also affect the activity of heterologously expressed KCNQ1. To investigate the potential physiological relevance of this gene family in human heart, we examined the relative expression of KCNQ1 and all five KCNE genes in samples derived from normal tissues representing major regions of human heart by real-time, quantitative RT-PCR. KCNE genes are expressed in human heart with a relative abundance ranking of KCNE1 > KCNE4 > KCNE5 approximately KCNE3 >> KCNE2. In situ hybridization revealed prominent expression of KCNE1 and KCNE3-5 in human atrial myocytes. In cardiomyopathic hearts, expression of KCNE1, KCNE3, KCNE4, and KCNQ1 was significantly increased, while KCNE2 and KCNE5 exhibited reduced expression. In a cell line stably expressing KCNQ1 and KCNE1, transient expression of KCNE3, KCNE4, or KCNE5 significantly altered I(Ks) current profiles. Even in the presence of additional KCNE1, KCNE4 and KCNE5 exert dominant effects on I(Ks). Although KCNE1 is the predominant KCNE family member expressed in human heart, the abundance of other KCNE transcripts including potential KCNQ1 suppressors (KCNE4 and KCNE5) and their altered expression patterns in disease lead us to speculate that a balance of KCNE accessory subunits may be important for cardiac K(V) channel function.