Clinical and genetic basis of hypertensive nephrosclerosis

array:21 ["pii" => "X2013251410050771" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2010.Jul.10372" "estado" => "S300" "fechaPublicacion" => "2010-11-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2010;30:687-97" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5797 "formatos" => array:3 [ "EPUB" => 275 "HTML" => 4887 "PDF" => 635 ] ] "Traduccion" => array:1 [ "es" => array:17 [ "pii" => "X0211699510050774" "issn" => "02116995" "doi" => "10.3265/Nefrologia.pre2010.Jul.10372" "estado" => "S300" "fechaPublicacion" => "2010-11-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia. 2010;30:687-97" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 25043 "formatos" => array:3 [ "EPUB" => 314 "HTML" => 23273 "PDF" => 1456 ] ] "es" => array:12 [ "idiomaDefecto" => true "titulo" => "Bases clínicas y genéticas de la nefroesclerosis hipertensiva. Estudio NEFROSEN" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "687" "paginaFinal" => "697" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Clinical and genetic basis of hypertensive nephrosclerosis" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10372_108_2737_es_10372_t1_copy1.jpg" "Alto" => 458 "Ancho" => 601 "Tamanyo" => 56671 ] ] "descripcion" => array:1 [ "es" => "Principales estudios sobre los polimorfismos del gen MYH9 y la presencia de nefropatía" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "B. Diez Ojea, R. Marín, E. Coto, F. Fernández Vega, R. Álvarez Navascués, G. Fernández Fresnedo, A. Pobes Martínez de Salinas, A. Suárez Laurés, C. García Monteavaro, M. Gorostidi, E. Sánchez, M. Arias, F. Ortega" "autores" => array:14 [ 0 => null 1 => array:2 [ "Iniciales" => "B." "apellidos" => "Diez Ojea" ] 2 => array:2 [ "Iniciales" => "R." "apellidos" => "Marín" ] 3 => array:2 [ "Iniciales" => "E." "apellidos" => "Coto" ] 4 => array:2 [ "Iniciales" => "F." "apellidos" => "Fernández Vega" ] 5 => array:2 [ "Iniciales" => "R." "apellidos" => "Álvarez Navascués" ] 6 => array:2 [ "Iniciales" => "G." "apellidos" => "Fernández Fresnedo" ] 7 => array:2 [ "Iniciales" => "A." "apellidos" => "Pobes Martínez de Salinas" ] 8 => array:2 [ "Iniciales" => "A." "apellidos" => "Suárez Laurés" ] 9 => array:2 [ "Iniciales" => "C." "apellidos" => "García Monteavaro" ] 10 => array:2 [ "Iniciales" => "M." "apellidos" => "Gorostidi" ] 11 => array:2 [ "Iniciales" => "E." "apellidos" => "Sánchez" ] 12 => array:2 [ "Iniciales" => "M." "apellidos" => "Arias" ] 13 => array:2 [ "Iniciales" => "F." "apellidos" => "Ortega" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "X2013251410050771" "doi" => "10.3265/Nefrologia.pre2010.Jul.10372" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251410050771?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699510050774?idApp=UINPBA000064" "url" => "/02116995/0000003000000006/v0_201502091423/X0211699510050774/v0_201502091424/es/main.assets" ] ] "itemSiguiente" => array:17 [ "pii" => "X2013251410050888" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2010.Sep.10590" "estado" => "S300" "fechaPublicacion" => "2010-11-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2010;30:698-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3672 "formatos" => array:3 [ "EPUB" => 293 "HTML" => 3016 "PDF" => 363 ] ] "en" => array:7 [ "idiomaDefecto" => true "titulo" => "Cadaveric donor procurement units faced with living donation" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "698" "paginaFinal" => "699" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Las unidades generadoras de donantes de órganos de cadáver ante la donación de vivo" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => " PROYECTO COLABORATIVO INTERNACIONAL DONANTE, A. Ríos, A.I. López-Navas, P. Ramírez, P. Parrilla" "autores" => array:5 [ 0 => array:1 [ "apellidos" => "PROYECTO COLABORATIVO INTERNACIONAL DONANTE" ] 1 => array:2 [ "Iniciales" => "A." "apellidos" => "Ríos" ] 2 => array:2 [ "Iniciales" => "A.I." "apellidos" => "López-Navas" ] 3 => array:2 [ "Iniciales" => "P." "apellidos" => "Ramírez" ] 4 => array:2 [ "Iniciales" => "P." "apellidos" => "Parrilla" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699510050880" "doi" => "10.3265/Nefrologia.pre2010.Sep.10590" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699510050880?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251410050888?idApp=UINPBA000064" "url" => "/20132514/0000003000000006/v0_201502091649/X2013251410050888/v0_201502091649/en/main.assets" ] "itemAnterior" => array:17 [ "pii" => "X2013251410050896" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2010.Jun.10428" "estado" => "S300" "fechaPublicacion" => "2010-11-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2010;30:681-6" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 6329 "formatos" => array:3 [ "EPUB" => 297 "HTML" => 5289 "PDF" => 743 ] ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "B-cell lymphoma of MALT involving the kidney and monoclonal gammopathy: a case report with revision of the literature" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "681" "paginaFinal" => "686" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Linfoma de células B tipo MALT con afectación renal y gammapatía monoclonal: presentación de un caso y revisión de la literatura" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10428_18107_6545_en_10428_18107_1935_es_10309_332_1935_en_figure11.jpg" "Alto" => 504 "Ancho" => 617 "Tamanyo" => 201659 ] ] "descripcion" => array:1 [ "en" => "CT showing tumoral growth through the renal cortex of the left kidney." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. Peces, C. Vega-Cabrera, C. Peces, A. Pobes, M.F. Fresno" "autores" => array:6 [ 0 => null 1 => array:2 [ "Iniciales" => "R." "apellidos" => "Peces" ] 2 => array:2 [ "Iniciales" => "C." "apellidos" => "Vega-Cabrera" ] 3 => array:2 [ "Iniciales" => "C." "apellidos" => "Peces" ] 4 => array:2 [ "Iniciales" => "A." "apellidos" => "Pobes" ] 5 => array:2 [ "Iniciales" => "M.F." "apellidos" => "Fresno" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699510050899" "doi" => "10.3265/Nefrologia.pre2010.Jun.10428" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699510050899?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251410050896?idApp=UINPBA000064" "url" => "/20132514/0000003000000006/v0_201502091649/X2013251410050896/v0_201502091649/en/main.assets" ] "en" => array:14 [ "idiomaDefecto" => true "titulo" => "Clinical and genetic basis of hypertensive nephrosclerosis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "687" "paginaFinal" => "697" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "B. Diez Ojea, R. Marín, E. Coto, F. Fernández Vega, R. Álvarez Navascués, G. Fernández Fresnedo, A. Pobes Martínez de Salinas, A. Suárez Laurés, C. García Monteavaro, M. Gorostidi, E. Sánchez, M. Arias, F. Ortega" "autores" => array:14 [ 0 => null 1 => array:4 [ "Iniciales" => "B." "apellidos" => "Diez Ojea" "email" => array:1 [ 0 => "beaojea@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "affb" ] ] ] 2 => array:3 [ "Iniciales" => "R." "apellidos" => "Marín" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "affc" ] ] ] 3 => array:3 [ "Iniciales" => "E." "apellidos" => "Coto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "d" "identificador" => "affd" ] ] ] 4 => array:3 [ "Iniciales" => "F." "apellidos" => "Fernández Vega" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "affe" ] ] ] 5 => array:3 [ "Iniciales" => "R." "apellidos" => "Álvarez Navascués" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "affe" ] ] ] 6 => array:3 [ "Iniciales" => "G." "apellidos" => "Fernández Fresnedo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "f" "identificador" => "afff" ] ] ] 7 => array:3 [ "Iniciales" => "A." "apellidos" => "Pobes Martínez de Salinas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "g" "identificador" => "affg" ] ] ] 8 => array:3 [ "Iniciales" => "A." "apellidos" => "Suárez Laurés" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "h" "identificador" => "affh" ] ] ] 9 => array:3 [ "Iniciales" => "C." "apellidos" => "García Monteavaro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "i" "identificador" => "affi" ] ] ] 10 => array:3 [ "Iniciales" => "M." "apellidos" => "Gorostidi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "affe" ] ] ] 11 => array:3 [ "Iniciales" => "E." "apellidos" => "Sánchez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "j" "identificador" => "affj" ] ] ] 12 => array:3 [ "Iniciales" => "M." "apellidos" => "Arias" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "k" "identificador" => "affk" ] ] ] 13 => array:3 [ "Iniciales" => "F." "apellidos" => "Ortega" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "affe" ] ] ] ] "afiliaciones" => array:10 [ 0 => array:3 [ "entidad" => "Sección de Nefrología, Hospital Valle del Nalón, Langreo, Asturias, " "etiqueta" => "b" "identificador" => "affb" ] 1 => array:3 [ "entidad" => "Unidad de Nefrología e Hipertensión, Centro Médico de Asturias, Oviedo, Asturias, " "etiqueta" => "c" "identificador" => "affc" ] 2 => array:3 [ "entidad" => "Laboratorio de Genética Molecular, Hospital Universitario Central de Asturias, Oviedo, Asturias, " "etiqueta" => "d" "identificador" => "affd" ] 3 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Central de Asturias, Oviedo, Asturias, " "etiqueta" => "e" "identificador" => "affe" ] 4 => array:3 [ "entidad" => "Sección de Nefrología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, " "etiqueta" => "f" "identificador" => "afff" ] 5 => array:3 [ "entidad" => "Sección de Nefrología, Hospital San Agustín, Avilés, Asturias, " "etiqueta" => "g" "identificador" => "affg" ] 6 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital de Cabueñes, Gijón, Asturias, " "etiqueta" => "h" "identificador" => "affh" ] 7 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital San Agustín, Avilés, Asturias, " "etiqueta" => "i" "identificador" => "affi" ] 8 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Central de Asturias Oviedo, Asturias, " "etiqueta" => "j" "identificador" => "affj" ] 9 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, " "etiqueta" => "k" "identificador" => "affk" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Bases clínicas y genéticas de la nefroesclerosis hipertensiva. Estudio NEFROSEN" ] ] "textoCompleto" => "INTRODUCTION The term nephrosclerosis is usually used for kidney disease which complicates arterial hypertension (AHT) and that primarily affects the preglomerular microvasculature.1,2 In practice, it is an entity with vague clinical profiles that groups hypertensive patients with chronic kidney disease (CKD) without other identifiable causes of disease.3,4  In nephrosclerosis, also known as benign nephroangiosclerosis or hypertensive nephropathy, the most characteristic microscopic lesion is hyalinosis of the afferent arterioles. Vascular changes produce vasoconstriction, glomerular ischaemia (retraction of glomerular tuft, focal or global sclerosis) and in some areas, interstitial fibrosis and tubular atrophy. Other authors point out that the hyalinisation of afferent arterioles would initially cause vasodilatation, glomerular hypertrophy and, in the long-term, segmental glomerulosclerosis lesions that overall favour the appearance of proteinuria and progression of the disease. These alterations are more frequent and severe in black patients, unrelated to the control of blood pressure or the degree of proteinuria. In fact, nephrosclerosis is a form of intrarenal renovascular disease, and in some cases may represent a magnification of the changes of kidney aging, from both a histological and clinical standpoint.5-7 Its causal relation with essential hypertension is still a subject of debate. It is not clear that treated AHT can lead to end-stage CKD.8-11 Therefore, some authors have postulated that renal structural alterations may precede hypertension, and that it would be an intrinsic process of the renal microvasculature with loss of self-regulation that would mainly result in excessive preglomerular vasoconstriction4 or persistent vasodilation of the afferent arteriole.6,7 A chronically impaired renal plasma flow, in the long run, leads to hypertension and CKD. Nephroangiosclerosis could have the same clinical significance as atherosclerosis in coronary or cerebral vessels.2,3 In the US, Europe and Spain, vascular kidney disease is the second most common cause of terminal CKD. However, the diagnosis of nephrosclerosis is usually made by exclusion, when no data for another type of kidney disease is found, and in very few cases is based on histological findings. There are no specific signs or symptoms, but there are some suggestive clinical findings (men aged 55-60 years, long-standing hypertension, left ventricular hypertrophy [LVH], mild CKD and proteinuria less than 0.5-1g/24 hours). As with diabetic kidney disease, a kidney biopsy is almost never performed. This attitude may be reasonable in many cases, but is a source of misdiagnoses.12 Some studies with small samples suggest that the degree of proteinuria may be variable, and may even reach the nephrotic range. However, there is general consensus that subnephrotic proteinuria values are typical of hypertensive nephrosclerosis. Clinical inclusion criteria for the African American Study of Kidney Disease and Hypertension (AASK) required a proteinuria level lower than 2.5 (UP/Cr).4,13,14 End-stage CKD onset age for African-Americans varied between 45 and 64 years, while for Caucasian Americans it is over 65 years.4 Compared with early glomerular or diabetic kidney diseases, the progression of kidney failure is slow in most cases, especially in whites. Renal function can remain stable for years if hypertension is well controlled. However, in a few cases the disease progresses to end-stage CKD.5,12,15 Vascular kidney disease is the most common cause of hospital visits for CKD in nephrology departments in Spain. Up to 39% of cases have this aetiology, higher than diabetic or glomerular kidney disease (20%).16 Despite the small percentage of patients with progression, its high prevalence makes it the second leading cause of end-stage CKD. The factors for progression of nephrosclerosis are not well recognised, which hampers the implementation of preventive measures. Usually, firstly the black race is cited, and later age, the degree of kidney failure at diagnosis, the level of systolic blood pressure (SBP) and the degree of proteinuria.1,13-20 In the AASK study, patients with proteinuria below 0.3g/24 hours, who had received ramipril, an angiotensin-converting enzyme inhibitor (ACEI) from the start had slower progression after an 11 year follow-up. This same study showed that old age (over 70 years) was inversely correlated with kidney failure.20,21 Only some cases of whites, perhaps those who are genetically predisposed, have an unfavourable clinical evolution. The progression of the disease has been associated with the concomitant presence of atherosclerotic lesions in the aorta and main renal arteries, and with processes such as Type 2 diabetes mellitus, hyperuricaemia and dyslipidaemia.3,5,10,19 In the Norwegian HUNT 2 population study, progression to end-stage CKD was associated with the estimated glomerular filtration rate (eGFR) and basal microalbuminuria in the multivariate analysis after 10 years of follow-up.22 In the last decade, the disease is being diagnosed mainly in patients older than 65-70 years of age and with vascular disease in other parts of the body. In these cases, nephrosclerosis is observed as a diffuse atherosclerosis of the renal arterioles.19,23,24 Recently, a lesser-known fact has been pointed out: the presence of concomitant cardiovascular disease is a factor for progression to kidney failure.25-29 Levin et al studied a group of 313 patients with kidney failure (eGFR of 10-75ml/min) and a mean follow-up of 23 months. They found that patients with cardiovascular diseases (ischaemic heart disease, cerebrovascular disease, peripheral artery disease or heart failure) increased the risk of progression to end-stage CKD (relative risk [RR] 1.58, P=.047).25 Hillegas et al’s study of 298 patients who had an acute myocardial infarction (AMI), found that the eGFR had declined 5.4ml/min after the first year, much higher than the usual 1ml/min/year reported for the general population.28 Elsayed et al studied 13,826 subjects, of which 18.5% were African American, enrolled in the Atherosclerosis Risk in Communities Study and Cardiovascular Health Study trials. They found that after 9 years of follow-up, patients with cardiovascular disease at baseline were significantly more likely to develop CKD (odds ratio [OR] 1.75, P<.001).29 In Spain there is an ongoing prospective study supported by the Spanish Society of Nephrology (SEN), the “ESTUDIO PRONEFROS”, which aims to determine the proportion of patients with nephrosclerosis showing progression to kidney failure. "Historical" nephrosclerosis cases have been excluded and only incident cases (n=430) over one year have been included. After 2 years of follow-up, preliminary data show that there is impaired renal function in only 3.9% of cases. Progression markers include the presence of higher baseline SBP and a higher rate of associated cardiovascular events.30 The explanation is complex and probably multifactorial: the deterioration of myocardial function implies a reduction of renal blood flow that would be added to the presence of microvascular and macrovascular renal injury. Furthermore, until just a few years ago, the presence of renal failure has led to underuse of cardioprotective drugs or more conservative application of coronary revascularisation or valvular prostheses.31 For years, the relationship between hyperuricaemia and CKD in patients with essential hypertension has been widely debated. While it is true that up to 40% of individuals with gout develop CKD, the fact remains that almost all have hypertension and arteriolosclerosis and glomerulosclerosis lesions similar to those seen in patients with nephrosclerosis. There is no evidence that hyperuricaemia is a risk factor for CKD. However, two recent studies have offered new perspectives: Iseki et al have shown that hyperuricaemia is an independent marker of renal failure for subjects at baseline who had normal renal function, especially women.32 Furthermore, Siu et al studied 54 patients and found that when uric acid is decreased with allopurinol progression to CKD is postponed.33 It seems necessary to promote studies specifically designed to clarify whether hyperuricaemia may be an independent risk factor for vascular and renal risk.34 The lack of correlation between the degree of hypertension control and the prevention of disease progression, from the clinical and histological standpoint suggests that this process may be an intrinsic and early renal disease. In some cases the clinical context maintains some similarity with focal segmental glomerulonephritis (FSGP). For many years, genetic markers have been sought that could explain the onset and progression of the disease. AHT, hyperuricaemia, dyslipidaemia and metabolic syndrome were frequently associated phenotypic factors, but not the cause of the process.2,3 Some studies carried out a decade ago verified a direct relationship between nephrosclerosis and ACE DD genotype. The D allele appears to be predominant in hypertensive patients with nephrosclerosis and could be a progression marker. Although the proportion of patients was small, studies were conducted on Caucasians, and included histological support and control groups of hypertensives without kidney disease and subjects from the general population.35,36 American nephrosclerosis genetic studies have been conducted primarily in African-Americans because the disease is more frequent and aggressive in this race.37-42 Two independent studies published recently have led to a new approach to the pathogenesis of nephrosclerosis. The study by Kao et al, which included 1372 patients, revealed a close relationship between the presence of end-stage CKD secondary to hypertensive nephrosclerosis in non-diabetics, and some polymorphisms of the MYH9 gene, located on chromosome 22, which encodes the non-muscle myosin heavy chain IIA.37 The study by Kopp et al compared 190 black individuals with 222 healthy controls. It found the same association with the presence of FSGP of idiopathic origin or secondary to infection with human immunodeficiency virus (HIV), but no relationship was found with progression.38 Furthermore, a study by Freedman et al confirmed the presence of the MYH9 gene polymorphisms in 696 African-American subjects with hypertensive kidney disease and end-stage CKD, compared with 948 control subjects without kidney disease, of whom 34% were hypertensive. However, not all individuals who were homozygous dominant for MYH9 risk alleles developed the disease, which suggests that other factors, such as environment or interaction with other genes, add to individual genetic susceptibility.39 Meanwhile, the same group recently reported an association between the MYH9 E1 haplotype and the presence of microalbuminuria in 1458 African-American patients with essential hypertension but no kidney disease. Increased risk has been observed for MYH9 E1 haplotype, which consists of the polymorphisms rs4821480, rs2032487, rs4821481 and rs3752462. However, the strength of the association is weaker than in subjects with FSGP and terminal CKD of hypertensive origin.40 Further complicating the issue, an association of that gene has been found in 751 diabetic black end-stage CKD patients compared with 227 diabetic controls without kidney disease and 925 healthy controls, but there is no clear correlation with the development of diabetic kidney disease because there is no histological confirmation. It has even been suggested that it may coincide with kidney disease related to baseline MYH9 polymorphisms.41 It appears that during the early stages, myosin IIA is primarily situated at the podocyte level and induces structural alterations. Recently, the role of podocyte loss and dysfunction has been reported as part of disease development. Wang et al conducted a study on 41 patients with biopsy diagnosis of hypertensive nephrosclerosis, finding less podocytes and a reduced intrarenal expression of protein genes such as nephrin, podocin and synaptopodin, which is also related to the decrease in eGFR, and inversely proportional with the degree of renal fibrosis.43 A bold new hypothesis on this issue states that polymorphisms of this gene would be markers of various kidney diseases that fall into one histological group, GSFP, and any of its variants, such as nephrosclerosis, which would be a disease akin to primary kidney disease with idiopathic GSFP and with the collapse observed in HIV.44 A renal disease associated with macrothrombocytopaenia has even been reported. Lastly, there are some rare entities associated with mutations of that gene, which are transmitted by autosomal dominant inheritance, known as MYH9-related disorders. These include the May-Hegglin anomaly and the Sebastian, Epstein and Fechtner syndromes, which are in many cases present with kidney disease, although its mechanism and that of MYH9-related hypertensive nephrosclerosis polymorphisms in blacks is currently unknown.45 However, not all cases of nephrosclerosis are associated with MYH9 haplotypes.46 For all these reasons, further studies are needed to provide a better understanding of its pathogenesis, and the potential role of detections of MYH9 polymorphisms in the diagnosis and evolution of CKD secondary to nephrosclerosis (Table 1). HYPOTHESIS Hypertensive nephrosclerosis is a CKD that rarely progresses. 1. Clinical progression markers would be related to: a) The presence of associated cardiovascular disease, especially cardiovascular events appearing on a recurring basis. b) The degree of proteinuria. c) Initial renal function. d) The patient being less than 70 years old. 2. Histological progression markers would be related to: a) The degree of global and segmental glomerulosclerosis. b) The degree of interstitial fibrosis. 3. Genetic markers would be related to: a) MYH9 gene polymorphisms. b) I/D polymorphisms of the ACE gene.  OBJECTIVES Primary Objective To determine if any MYH9 gene polymorphism is associated in Caucasians: a) With the association of essential hypertension and nephrosclerosis. b) With progression of the disease. Secondary Objectives 1. To compare the clinical characteristics of nephrosclerosis patients with essential hypertension and hypertensives with no kidney disease, and to determine clinical progression markers. 2. To recognise the importance of proteinuria, associated cardiovascular disease, sex, age (over and under 70 years), the presence of hyperuricaemia or gout, and concomitant treatments (antihypertensives, statins and antiplatelet agents). METHOD Study Design Multicentre retrospective study, which involves four hospitals in Asturias (Central Asturias University Hospital, Valle del Nalón Hospital, Cabueñes Hospital, and San Agustín Hospital), and the Marques de Valdecilla University Hospital in Cantabria. A basic study comparing patients with essential hypertension with nephrosclerosis patients versus hypertensive patients without kidney disease (control group). Furthermore, patients with nephrosclerosis and impaired kidney function are compared with those who are stable. For the genetic study, healthy controls from the general population with similar age and sex as the cases are also included. PATIENTS Cases The cases were selected between October 2009 and October 2010 from nephrology, kidney transplantation, haemodialysis and peritoneal dialysis units of the participating hospitals. Patients recruited have eGFR <60ml/min/1.73m2 (measured by the MDRD formula) in stages 3-5, attributed to nephrosclerosis according to standard clinical criteria (Table 2), with or without histological documentation. Diagnosis of CKD of unknown origin will not be valid, and patients with secondary, renovascular or accelerated hypertension will be excluded. Patients with stage 5, on dialysis or to undergo kidney transplant, may be admitted, provided that developmental data are available from their first contact with the hospital. The start of replacement therapy marks the end of follow-up. Cases younger than 80 years will be valid for the study. However, the selection will be made mainly of patients younger than 60 years, to minimise the effect of age-related gene denaturation. Controls The control group is from Central Asturias University Hospital and Nalón Valley Hospital, to simplify data collection, given that there are few differences between the subjects as they are from the same geographic area. Patients with essential hypertension are included with eGFR>60ml/min/1.73 m2 and microalbuminuria <300mg/g. Data for Each Patient There will be two sections of the study, one for the first hospital visit and one for the last ("current visit"). Clinical data are to be collected from all patients including socio-demographic variables, comorbidity and cardiovascular risk, medical treatment and physical examination, weight in kilograms, height in centimetres, systolic (SBP) and diastolic (DBP) blood pressure in millimetres of mercury, and heart rate. Analytical data will be recorded including renal function by serum creatinine, eGFR, creatinine clearance, microalbuminuria in urine alone (mg/g creatinine) and proteinuria in urine for 24 hours and also glucose, uric acid, cholesterol and calcium-phosphorus metabolism. Furthermore, the performance of imaging techniques (ultrasound, CT angiography, MR angiography or arteriography), and renal biopsy diagnosis (Table 3) are also included. Laboratory Analysis Routine laboratory tests shall be performed by the usual methods in the laboratory of each hospital. Blood samples for genetic studies will be submitted to the Laboratory of Molecular Genetics, Central Asturias University Hospital. DNA was obtained from leukocytes from 10ml of EDTA anticoagulated peripheral blood. The samples will be stored for 5 years. Major MYH9 gene polymorphisms to be identified are those which showed an association with hypertensive nephrosclerosis in non-diabetics (rs4821480 and rs3752462, belonging to E-1 haplotype), and with the ACE gene, by the polymerase chain reaction (PCR) test.   DEFINITIONS Progression of Kidney Disease Doubling of baseline creatinine, eGFR decline >50% above baseline or a reduction of 25ml/min/1.73m2 or onset at end-stage CKD (defined by the need for renal replacement therapy). Arterial Hypertension SBP>140mm Hg and/or DBP>90mm Hg, or treatment with diet or antihypertensive agents. The percentage of patients with SBP>130mm Hg and/or DBP>80mm Hg will also be analysed. Diabetes Mellitus Fasting glucose>126mg/dl or >200mg/dl 2 hours after oral glucose or antidiabetic treatment (diet, oral antidiabetic agents or insulin). Hypercholesterolaemia LDL cholesterol>100mg/dl, or treatment with lipid lowering agents. Smoker Tobacco consumption (cigarettes, cigars, pipe) during the last month. Former smoker: absence of tobacco use for a consecutive year. Obesity BMI>30kg/m2. Cardiovascular Comorbidity Must be properly documented. Presence of one or more of the following: ischaemic heart disease by acute myocardial infarction (AMI), unstable angina or stable angina, atrial fibrillation, heart failure, degenerative mitral or aortic valve disease, ischaemic, hemorrhagic, or transient stroke, or peripheral arterial disease. Left Ventricular Hypertrophy Diagnosis made by echocardiography, which is a more specific method than the electrocardiogram. ETHICAL ASPECTS The investigator must inform the patient about his or her participation in the study, which is voluntary and will not cause any change in the treatment or medical care to be received. Subsequently, the investigator must obtain the patient’s informed and voluntary consent. The highest levels of confidentiality must always be maintained, as well as compliance with national legislation on data protection. The study protocol was approved by the Research Ethics Committee of the Regional Clinical Research of Asturias. SAMPLE SIZE It is estimated that the size of the sample needed to observe the effects of MYH9 gene polymorphisms according to their allele frequencies for an alpha error of 0.05 and a beta error of 0.2, will be 500 cases with CKD and 500 controls. The subjects will be distributed as such: 500 cases, 300 hypertensive controls with no kidney disease and 200 general population subjects (healthy controls). We will attempt to control the sample for sex and age (Figure 1).   STATISTICAL ANALYSIS There will be a descriptive analysis of continuous variables, giving the mean, median, standard deviation and range, and in case of discrete variables, the frequency distribution and percentages. When necessary, 95% confidence intervals are calculated. The description of the main variables are based on age, sex, level of baseline renal failure and proteinuria, degree of hypertension control and dyslipidaemia and associated cardiovascular risk factors. The association between qualitative variables will be assessed with the chi-square or Fisher's exact test and quantitative variables using parametric tests (t-test, Pearson correlation coefficient and ANOVA). If a normal distribution cannot be assumed, non-parametric tests will be used such as Mann-Whitney U or Kruskal-Wallis. Comparison tests will be bilateral and considered significant when P<.05. A logistic regression model will be used to evaluate the association of those variables in which the result of the P comparison in the "raw" analysis is less than 0.15. Statistical analysis of the study will be conducted with SPSS for Windows, version 15.0 (SPSS, Chicago, IL). FINANCIAL SUPPORT The NEFROSEN Study is a typical clinical practice study that does not involve extra costs. It is being carried out with the sponsorship of the Spanish Society of Nephrology (SEN) through its "Kidney and Hypertension" Work Group. The cost for each case analysed in the genetic substudy of the MYH9 gene polymorphisms is about 10 euros. It is being financed with funds from the Fundación Renal Iñigo Álvarez de Toledo (Iñigo Alvarez de Toledo Kidney Foundation) in the Molecular Genetics Group. DISCUSSION Following the publication of genetic studies on nephrosclerosis, some documents have indicated that it should no longer be regarded as a disease that is secondary to essential hypertension. At least in the black race, it seems to be a genetically based disease closely related to GSFP, and it is estimated that there may be an association with MYH9 gene polymorphisms in 43% of African-American individuals who progress to end-stage CKD.47 Of these, control of hypertension does not stop progression, while in the white race it seems more effective, so it is speculated that the treatment of hypertensive nephrosclerosis should be approached from a different perspective that not only includes blocking RAS and strict control of blood pressure.48 However, much is still unknown about these findings. The referred studies have been conducted on patients with nephrosclerosis not supported by renal biopsies. This indicates the opportunity to reassess the cases of the AASK study (n=1094 patients), which is the only one that has been conducted with histological confirmation.13,14 In the white race there are no studies on whether these or other MYH9 polymorphisms might be involved in the disease. Only the Pattero et al group found an association of this gene with serum creatinine values in 2859 European individuals without kidney disease, coming from three different populations, while the genes related to renal function showed great heterogeneity.49 The proposed study is both clinical and genetic. Their relationship seems logical and complementary. The limitations are those related to a retrospective study design, together with the lack of a centralised laboratory for routine analysis, because the data are historic. Nephrosclerosis cases that maintain periodic visits over a variable time period, and patients that have progressed to end-stage CKD are included. In this respect, we have significant selection bias when calculating the percentage of patients whose disease has progressed, since many will be obtained from dialysis and transplant units. We will probably not be able to draw clear conclusions about disease progression but, despite these limitations, we believe a study such as this will be interesting because there are very few publications to date on this topic. It seems necessary to design prospective genetic studies to determine the relationship with this gene, both in terms of diagnosis and the possibility that it could be a progression marker.<a href="10372_108_10773_en_w4777105862010372_18107_2737_es_10372_465_2737_es_tabla_1_en.doc" class="elsevierStyleCrossRefs">10372_108_10773_en_w4777105862010372_18107_2737_es_10372_465_2737_es_tabla_1_en.doc</a>Table 1. Main studies on the polymorphisms of the MYH9 gene and the presence of kidney disease <a href="10372_108_10774_en_w4777105861010372_18107_2738_es_10372_465_2738_es_tabla_2_en.doc" class="elsevierStyleCrossRefs">10372_108_10774_en_w4777105861010372_18107_2738_es_10372_465_2738_es_tabla_2_en.doc</a>Table 2. Inclusion-exclusion criteria<a href="10372_108_10775_en_w4777105862210372_18107_2739_es_10372_465_2739_es_tabla_3_en.doc" class="elsevierStyleCrossRefs">10372_108_10775_en_w4777105862210372_18107_2739_es_10372_465_2739_es_tabla_3_en.doc</a>Table 3. Clinical and analytical data sheet<a href="10372_108_10776_en_w4777105862310372_18107_2740_es_10372_465_2740_es_figura_1_en_copy1.doc" class="elsevierStyleCrossRefs">10372_108_10776_en_w4777105862310372_18107_2740_es_10372_465_2740_es_figura_1_en_copy1.doc</a>Figure 1. Case and control recruitment." "pdfFichero" => "P1-E506-S2882-A10372-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441579" "palabras" => array:1 [ 0 => "Enfermedad renal crónica" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441581" "palabras" => array:1 [ 0 => "Gen MYH9" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441583" "palabras" => array:1 [ 0 => "Nefroesclerosis" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441585" "palabras" => array:1 [ 0 => "Hipertensión arterial esencial" ] ] ] "en" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441580" "palabras" => array:1 [ 0 => "Chronic kidney disease" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441582" "palabras" => array:1 [ 0 => "MYH9 gene" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441584" "palabras" => array:1 [ 0 => "Hypertensive nephrosclerosis" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441586" "palabras" => array:1 [ 0 => "Essential hypertension" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "Background: Hypertensive nephrosclerosis is a chronic kidney disease (CKD) associated with essential hypertension. The lack of correlation between hypertension control and progression to end-stage CKD suggests an intrinsic and primitive disease. New evidence suggests that MYH9 gene alterations are associated with polymorphisms in African Americans. The aim of this study is to investigate whether a polymorphism of MYH9 in Caucasians is linked to essential hypertension and nephrosclerosis. The secondary objective is to identify the clinical risk factors of progression to end-stage CKD. This is a retrospective study that will compare patients with nephrosclerosis and essential hypertensives without renal disease, and also patients with nephrosclerosis and impaired renal function with those that are stable. Method: Between October 2009 and October 2010, 500 patients with stages 3-5 CKD attributed to nephrosclerosis according to usual clinical criteria, and 300 essential hypertensives (eGFR>60mL/min/1.73m2; microalbuminuria <300mg/g) are to be recruited. A total of 200 healthy controls from the general population are also to be included for the genetic study. There are two study sections, being the first and final visits to the clinic (for stage 5 cases, the start of replacement therapy will be the end of follow-up). Clinical and laboratory data will be recorded, and blood samples will be collected. Discussion: Our study will aim to determine if there is a relationship between the diagnosis of nephrosclerosis and the MYH9 gene in Caucasians, and to study possible risk factors for progression to end-stage CKD, on both clinical and genetic bases. " ] "es" => array:1 [ "resumen" => " Justificación: Se conoce como nefroesclerosis la enfermedad renal crónica (ERC) que complica la hipertensión arterial (HTA) esencial. La ausencia de correlación entre el control de la HTA y la progresión a ERC terminal sugiere la existencia de una enfermedad intrínseca y primitiva. Recientemente se ha asociado con polimorfismos del gen MYH9 en individuos afroamericanos. El objetivo del trabajo que presentamos es determinar si algún polimorfismo de dicho gen se relaciona en raza caucásica con la asociación de HTA esencial y nefroesclerosis y, además, conocer los marcadores de progresión a ERC terminal. Será un estudio retrospectivo que comparará a pacientes con nefroesclerosisfrente a pacientes con HTa esencial sin enfermedad renal y, además, se incluirán pacientes con nefroesclerosis y progresión de la enfermedad renal frente a los que se mantienen estables. Métodos: Entre octubre de 2009 y octubre de 2010 se incluirán 500 pacientes con ERC (estadios 3-5) atribuida a nefroesclerosis según criterios clínicos habituales, y 300 pacientes afectados de HTA esencial (FGe >60 ml/min/1,73 m2; microalbuminuria <300 mg/g). Para el estudio genético también se incluirán 200 controles sanos de población general. Habrá dos cortes del estudio, la primera visita en el hospital y la visita final (en estadio 5 el inicio del tratamiento sustitutivo constituirá el final del seguimiento). Se registrarán datos clínicos y analíticos, y se recogerán muestras de sangre para el estudio genético. Discusión: Nuestro estudio, con la doble vertiente genética y clínica, tratará de determinar si en la raza caucásica existe relación entre el diagnóstico de nefroesclerosis y el gen MYH9, y estudiará, además, los posibles marcadores de progresión." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "mmc1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10372_108_10773_en_w4777105862010372_18107_2737_es_10372_465_2737_es_tabla_1_en.doc" "ficheroTamanyo" => 66048 ] "descripcion" => array:1 [ "en" => "Main studies on the polymorphisms of the MYH9 gene and the presence of kidney disease " ] ] 1 => array:8 [ "identificador" => "mmc2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10372_108_10774_en_w4777105861010372_18107_2738_es_10372_465_2738_es_tabla_2_en.doc" "ficheroTamanyo" => 60416 ] "descripcion" => array:1 [ "en" => "Inclusion-exclusion criteria" ] ] 2 => array:8 [ "identificador" => "mmc3" "etiqueta" => "Tab. 3" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10372_108_10775_en_w4777105862210372_18107_2739_es_10372_465_2739_es_tabla_3_en.doc" "ficheroTamanyo" => 102400 ] "descripcion" => array:1 [ "en" => "Clinical and analytical data sheet" ] ] 3 => array:8 [ "identificador" => "mmc4" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10372_108_10776_en_w4777105862310372_18107_2740_es_10372_465_2740_es_figura_1_en_copy1.doc" "ficheroTamanyo" => 60928 ] "descripcion" => array:1 [ "en" => "Case and control recruitment." ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:50 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "\u{A0}" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Luft FC. Hypertensive nephrosclerosis: update. Curr Opin Nephrol Hypertens 2004;13:147-54. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15202608" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "2.\u{A0}Freedman BI, Iskandar SS, Appel RG. The link between hypertension and nephrosclerosis.\u{A0} Am J Kidney Dis 1995;25:207-21. <a href="http://www.ncbi.nlm.nih.gov/pubmed/7847347" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "3.\u{A0}Marín R, Gorostidi M, Fernández-Vega F, Álvarez-Navascués R. \u{A0}Systemic and glomerular hypertension and progression of chronic renal disease: the dilemma of nephrosclerosis. Kidney Int Suppl 2005;(99):S52-S56." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "4.\u{A0}Luke RG. Hypertensive nephrosclerosis: pathogenesis and prevalence. Essential hypertension is an important cause of end-stage renal disease.\u{A0} Nephrol Dial Transplant 1999;14:2271-78." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "5.\u{A0}Marcantoni C, Ma LJ, Federspiel C, Fogo AB. Hypertensive nephrosclerosis in African Americans versus Caucasians. Kidney Int 2002;62:172-80. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12081576" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "6.\u{A0}Hill GS, Heudes D, Jacquot C, Gauthier E, Bariéty J. Morphometric evidence for impairment of renal autoregulation in advanced essential hypertension. Kidney Int 2006;69:823-31. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16518341" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "7.\u{A0}Keller G, Zimmer G, Mall G, Ritz E. Amann K. Nephron number in patients with primary hypertension. N Engl J Med 2003;348:101-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12519920" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "8.\u{A0}Hsu CY. Does non-malignant hypertension cause renal insufficiency? Evidence-based perspective. Curr Opin Nephrol Hypertens 2002;11:267-72. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11981255" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "9.\u{A0}Sarnak JA, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, et al.\u{A0}The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann Intern Med 2005;142:342-51. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15738453" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Siewert-Delle A, Ljungman S, Andersson OK, Wilhelmsen L. Does treated primary hypertension lead to end-stage renal disease? A 20-year follow-up of the Primary Prevention Study in Göteborg, Sweden. Nephrol Dial Transplant 1998;13:3084-90. <a href="http://www.ncbi.nlm.nih.gov/pubmed/9870470" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med 2005;165:923-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15851645" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Zarif L, Covic A, Iyengar S, Sehgal AR, Sedor JR, Schelling JR. Inaccuracy of clinical phenotyping parameters for hypertensive nephrosclerosis. Nephrol Dial Transplant 2000;15:1801-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11071968" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, et al, for the African American Study of Kidney Disease and Hypertension Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis. A randomised controlled trial. JAMA 2001;285:2719-28. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11386927" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Wright JT, Bakris G, Greene T, Agodoa LY, Appel LJ, et al, for the African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease. JAMA 2002;288:2421-31. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12435255" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Toto RB. Hypertensive nephrosclerosis in African Americans. Kidney Int 2003;64:2331-41. <a href="http://www.ncbi.nlm.nih.gov/pubmed/14633170" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Marin R, Fernández-Vega F, Gorostidi M, Ruilope LM, Díez M, et al. Blood pressure control in patients with chronic renal insufficiency in Spain: a cross-sectional study. J Hypertens 2006;24:395-402. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16508589" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Vikse BE, Aasarød K, Bostad L, Iversen BM. Clinical prognostic factors in biopsy-proven benign nephrosclerosis. Nephrol Dial Transplant 2003;18:517-23. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12584273" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Verhave JC, Hillege HL, Burgerhof JG, Gansevoort RT, De Zeeuw D, De Jong PE; PREVEND study group. The association between atherosclerotic risk factors and renal function in the general population. Kidney Int 2005;67:1967-73. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15840045" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Tracy ER, Strong JP, Newman WP III, Malcom GT, Oalmann MC, Guzman MA. Renovasculopathies of nephrosclerosis in relation to atherosclerosis at ages 25 to 54 years. Kidney Int 1996;49:564-70. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8821845" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Appel LJ, Wright JT Jr, Greene T, Kusek JW, Lewis JB, et al. Long-term effects of renin-angiotensin system-blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans. Arch Intern Med 2008;168:832-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18443258" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Norris KC, Greene T, Kopple J, Lea J, Lewis J, et al. Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease. J Am Soc Nephrol 2006;17:2928-36. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16959828" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hallan SI, Ritz E, Lydersen S, Romundstad S, Kvenild K, Orth SR. Combining GFR and albuminuria to classify CKD improves prediction of ESRD. J Am Soc Nephrol 2009;20:1069-77. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19357254" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Segura J, Campo C, Gil P, Roldán C, Vigil L, Rodicio JL, et al.\u{A0}Development of chronic kidney disease and cardiovascular prognosis in essential hypertensive patients. J Am Soc Nephrol 2004;15:1616-22. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15153573" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Wright JR, Duggal A, Thomas R, Reeve R, Roberts IS, Kalra PA. Clinicopathological correlation in biopsy-proven atherosclerotic nephropathy: implications for renal functional outcome in atherosclerotic renovascular disease. Nephrol Dial Transplant 2001;16:765-70. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11274271" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Levin A, Djurdjev O, Barrett B, Burgess E, Carlisle E, et al. Cardiovascular disease in patients with chronic kidney disease: getting to the heart of the matter. Am J Kidney Dis 2001;38:1398-407. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11728982" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "McClellan WM, Langston RD, Presley R. Medicare patients with cardiovascular disease has a high prevalence of chronic kidney disease and a high rate of progression to end-stage renal disease. J Am Soc Nephrol 2004;15:1912-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15213281" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Menon V, Sarnak MJ. The epidemiology of chronic kidney disease stages 1 to 4 and cardiovascular disease: a high-risk combination. Am J Kidney Dis 2005;45:223-32. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15696466" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hillege HL, Van Gilst WH, Van Veldhuisen DJ, Navis G, Grobbee DE, et al. Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: the CATS randomized trial. Eur Heart J 2003;24:412-20. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12633543" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Elsayed EF, Tighiouart H, Griffith J, Kurth T, Levey AS, et al. Cardiovascular disease and subsequent kidney disease. Arch Intern Med 2007;167:1130-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17563020" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Marín R, Fernández-Vega F, Díez Ojea B, Alcoy E, Palencia A, et al. Marcadores de progresión de enfermedad renal crónica en pacientes con con nefroesclerosis. Datos evolutivos. Estudio PRONEFROS. Nefrología 2008;28(Supl 4):48." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hostetter TH. Chronic kidney disease predicts cardiovascular disease. N Engl J Med 2004;351:1344-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15385664" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 2004;44:642-50. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15384015" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47:51-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16377385" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Feig DI, Kang DH, Johnson J. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-21. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18946066" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Fernández-Llama P, Poch E, Oriola J, Botey A, Coll E, et al. Angiotensin converting enzyme gene I/D polymorphism in essential hypertension and nephroangiosclerosis. Kidney Int 1998;53:1743-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/9607207" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Mallamaci F, Zuccalà A, Zoccali C, Testa A, Gaggi R, et al. The deletion polymorphism of the angiotensin-converting enzyme is associated with nephroangioesclerosis. Am J Hypertens 2000;13:433-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10821348" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008;40:1185-92. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18794854" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 2008;40:1175-84. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18794856" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Freedman BI, Hicks PJ, Bostrom MA, Cunningham ME, Liu Y, et al. Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are strongly associated with end-stage renal disease historically attributed to hypertension in African Americans. Kidney Int 2009;75:736-45. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19177153" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Freedman BI, Kopp JB, Winkler CA, Nelson GW, Rao DC, et al. Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with albuminuria in hypertensive African Americans: the HyperGEN study. Am J Nephrol 2009;29:626-32. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19153477" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Freedman BI, Hicks PJ, Bostrom MA, Comeau ME, Divers J, et al. Non-muscle myosin heavy chain 9 gene MYH9 associations in African Americans with clinically diagnosed type 2 diabetes mellitus-associated ESRD. Nephrol Dial Transplant 2009;24:3366-71. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19567477" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Behar DM, Rosset S, Tzur S, Selig S, Yudkovsky G, et al. African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans. Hum Mol Genet 2010;19:1816-27. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20144966" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Wang G, Lai FM, Kwan BC, Lai KB, Chow KM, Li PK, Szeto CC. Podocyte Loss in Human Hypertensive Nephrosclerosis. Am J Hypertens 2009;22:300-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19131934" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Murea M, Freedman BI. Essential hypertension and risk of nephropathy: a reappraisal. Curr Opin Nephrol Hypertens 2010;19:235-41. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20051853" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Singh N, Nainani N, Arora P, Venuto RC. CKD in MYH9-Related Disorders. Am J Kidney Dis 2009;54:732-40. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19726116" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Rao M, Balakrishnan VS. The genetic basis of kidney disease risk in African Americans: MYH9 as a new candidate gene. Am J Kidney Dis 2009;53:579-83. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19324247" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Divers J, Freedman BI. Susceptibility genes in common complex kidney disease. Curr Opin Nephrol Hypertens 2010;19:79-84. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19838113" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Freedman BI, Sedor JR. Hypertension-associated kidney disease: perhaps no more. J Am Soc Nephrol 2008;19:2047-51. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18923054" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Pattaro C, Aulchenko YS, Isaacs A, Vitart V, Hayward C, Franklin CS, et al. Genome-wide linkage analysis of serum creatinine in three isolated European populations. Kidney Int 2009;76:297-306. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19387472" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003000000006/v0_201502091649/X2013251410050771/v0_201502091649/en/main.assets" "Apartado" => array:4 [ "identificador" => "35442" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Research Protocols" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003000000006/v0_201502091649/X2013251410050771/v0_201502091649/en/P1-E506-S2882-A10372-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251410050771?idApp=UINPBA000064"]

Statistics

Bases clínicas y genéticas de la nefroesclerosis hipertensiva. Estudio NEFROSEN

, B.. Diez Ojeab, R.. Marínc, E.. Cotod, F.. Fernández Vegae, R.. Álvarez Navascuése, G.. Fernández Fresnedof, A.. Pobes Martínez de Salinasg, A.. Suárez Laurésh, C.. García Monteavaroi, M.. Gorostidie, E.. Sánchezj, M.. Ariask, F.. Ortegae

b Sección de Nefrología, Hospital Valle del Nalón, Langreo, Asturias,

c Unidad de Nefrología e Hipertensión, Centro Médico de Asturias, Oviedo, Asturias,

d Laboratorio de Genética Molecular, Hospital Universitario Central de Asturias, Oviedo, Asturias,

e Servicio de Nefrología, Hospital Universitario Central de Asturias, Oviedo, Asturias,

f Sección de Nefrología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria,

g Sección de Nefrología, Hospital San Agustín, Avilés, Asturias,

h Servicio de Nefrología, Hospital de Cabueñes, Gijón, Asturias,

i Servicio de Nefrología, Hospital San Agustín, Avilés, Asturias,

j Servicio de Nefrología, Hospital Universitario Central de Asturias Oviedo, Asturias,

k Servicio de Nefrología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria,

Read

11201

Times
was read the article

2932

Total PDF

8269

Total HTML

Share statistics

 array:21 [
  "pii" => "X2013251410050771"
  "issn" => "20132514"
  "doi" => "10.3265/Nefrologia.pre2010.Jul.10372"
  "estado" => "S300"
  "fechaPublicacion" => "2010-11-01"
  "documento" => "article"
  "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
  "subdocumento" => "fla"
  "cita" => "Nefrologia &#40;English Version&#41;. 2010;30:687-97"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 5797
    "formatos" => array:3 [
      "EPUB" => 275
      "HTML" => 4887
      "PDF" => 635
    ]
  ]
  "Traduccion" => array:1 [
    "es" => array:17 [
      "pii" => "X0211699510050774"
      "issn" => "02116995"
      "doi" => "10.3265/Nefrologia.pre2010.Jul.10372"
      "estado" => "S300"
      "fechaPublicacion" => "2010-11-01"
      "documento" => "article"
      "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
      "subdocumento" => "fla"
      "cita" => "Nefrologia. 2010;30:687-97"
      "abierto" => array:3 [
        "ES" => true
        "ES2" => true
        "LATM" => true
      ]
      "gratuito" => true
      "lecturas" => array:2 [
        "total" => 25043
        "formatos" => array:3 [
          "EPUB" => 314
          "HTML" => 23273
          "PDF" => 1456
        ]
      ]
      "es" => array:12 [
        "idiomaDefecto" => true
        "titulo" => "Bases cl&#237;nicas y gen&#233;ticas de la nefroesclerosis hipertensiva&#46; Estudio NEFROSEN"
        "tienePdf" => "es"
        "tieneTextoCompleto" => "es"
        "tieneResumen" => array:2 [
          0 => "es"
          1 => "en"
        ]
        "paginas" => array:1 [
          0 => array:2 [
            "paginaInicial" => "687"
            "paginaFinal" => "697"
          ]
        ]
        "titulosAlternativos" => array:1 [
          "en" => array:1 [
            "titulo" => "Clinical and genetic basis of hypertensive nephrosclerosis"
          ]
        ]
        "contieneResumen" => array:2 [
          "es" => true
          "en" => true
        ]
        "contieneTextoCompleto" => array:1 [
          "es" => true
        ]
        "contienePdf" => array:1 [
          "es" => true
        ]
        "resumenGrafico" => array:2 [
          "original" => 0
          "multimedia" => array:8 [
            "identificador" => "fig1"
            "etiqueta" => "Tab.  1"
            "tipo" => "MULTIMEDIAFIGURA"
            "mostrarFloat" => true
            "mostrarDisplay" => false
            "copyright" => "Elsevier Espa&#241;a"
            "figura" => array:1 [
              0 => array:4 [
                "imagen" => "10372_108_2737_es_10372_t1_copy1.jpg"
                "Alto" => 458
                "Ancho" => 601
                "Tamanyo" => 56671
              ]
            ]
            "descripcion" => array:1 [
              "es" => "Principales estudios sobre los polimorfismos del gen MYH9 y la presencia de nefropat&#237;a"
            ]
          ]
        ]
        "autores" => array:1 [
          0 => array:2 [
            "autoresLista" => "B. Diez Ojea, R. Mar&#237;n, E. Coto, F. Fern&#225;ndez Vega, R. &#193;lvarez Navascu&#233;s, G. Fern&#225;ndez Fresnedo, A. Pobes Mart&#237;nez de Salinas, A. Su&#225;rez Laur&#233;s, C. Garc&#237;a Monteavaro, M. Gorostidi, E. S&#225;nchez, M. Arias, F. Ortega"
            "autores" => array:14 [
              0 => null
              1 => array:2 [
                "Iniciales" => "B."
                "apellidos" => "Diez Ojea"
              ]
              2 => array:2 [
                "Iniciales" => "R."
                "apellidos" => "Mar&#237;n"
              ]
              3 => array:2 [
                "Iniciales" => "E."
                "apellidos" => "Coto"
              ]
              4 => array:2 [
                "Iniciales" => "F."
                "apellidos" => "Fern&#225;ndez Vega"
              ]
              5 => array:2 [
                "Iniciales" => "R."
                "apellidos" => "&#193;lvarez Navascu&#233;s"
              ]
              6 => array:2 [
                "Iniciales" => "G."
                "apellidos" => "Fern&#225;ndez Fresnedo"
              ]
              7 => array:2 [
                "Iniciales" => "A."
                "apellidos" => "Pobes Mart&#237;nez de Salinas"
              ]
              8 => array:2 [
                "Iniciales" => "A."
                "apellidos" => "Su&#225;rez Laur&#233;s"
              ]
              9 => array:2 [
                "Iniciales" => "C."
                "apellidos" => "Garc&#237;a Monteavaro"
              ]
              10 => array:2 [
                "Iniciales" => "M."
                "apellidos" => "Gorostidi"
              ]
              11 => array:2 [
                "Iniciales" => "E."
                "apellidos" => "S&#225;nchez"
              ]
              12 => array:2 [
                "Iniciales" => "M."
                "apellidos" => "Arias"
              ]
              13 => array:2 [
                "Iniciales" => "F."
                "apellidos" => "Ortega"
              ]
            ]
          ]
        ]
      ]
      "idiomaDefecto" => "es"
      "Traduccion" => array:1 [
        "en" => array:9 [
          "pii" => "X2013251410050771"
          "doi" => "10.3265/Nefrologia.pre2010.Jul.10372"
          "estado" => "S300"
          "subdocumento" => ""
          "abierto" => array:3 [
            "ES" => true
            "ES2" => true
            "LATM" => true
          ]
          "gratuito" => true
          "lecturas" => array:1 [
            "total" => 0
          ]
          "idiomaDefecto" => "en"
          "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251410050771?idApp=UINPBA000064"
        ]
      ]
      "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699510050774?idApp=UINPBA000064"
      "url" => "/02116995/0000003000000006/v0_201502091423/X0211699510050774/v0_201502091424/es/main.assets"
    ]
  ]
  "itemSiguiente" => array:17 [
    "pii" => "X2013251410050888"
    "issn" => "20132514"
    "doi" => "10.3265/Nefrologia.pre2010.Sep.10590"
    "estado" => "S300"
    "fechaPublicacion" => "2010-11-01"
    "documento" => "article"
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "fla"
    "cita" => "Nefrologia &#40;English Version&#41;. 2010;30:698-9"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 3672
      "formatos" => array:3 [
        "EPUB" => 293
        "HTML" => 3016
        "PDF" => 363
      ]
    ]
    "en" => array:7 [
      "idiomaDefecto" => true
      "titulo" => "Cadaveric donor procurement units faced with living donation"
      "tieneTextoCompleto" => "en"
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "698"
          "paginaFinal" => "699"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Las unidades generadoras de donantes de &#243;rganos de cad&#225;ver ante la donaci&#243;n de vivo"
        ]
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => " PROYECTO COLABORATIVO INTERNACIONAL DONANTE, A. R&#237;os, A.I. L&#243;pez-Navas, P. Ram&#237;rez, P. Parrilla"
          "autores" => array:5 [
            0 => array:1 [
              "apellidos" => "PROYECTO COLABORATIVO INTERNACIONAL DONANTE"
            ]
            1 => array:2 [
              "Iniciales" => "A."
              "apellidos" => "R&#237;os"
            ]
            2 => array:2 [
              "Iniciales" => "A.I."
              "apellidos" => "L&#243;pez-Navas"
            ]
            3 => array:2 [
              "Iniciales" => "P."
              "apellidos" => "Ram&#237;rez"
            ]
            4 => array:2 [
              "Iniciales" => "P."
              "apellidos" => "Parrilla"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "X0211699510050880"
        "doi" => "10.3265/Nefrologia.pre2010.Sep.10590"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699510050880?idApp=UINPBA000064"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251410050888?idApp=UINPBA000064"
    "url" => "/20132514/0000003000000006/v0_201502091649/X2013251410050888/v0_201502091649/en/main.assets"
  ]
  "itemAnterior" => array:17 [
    "pii" => "X2013251410050896"
    "issn" => "20132514"
    "doi" => "10.3265/Nefrologia.pre2010.Jun.10428"
    "estado" => "S300"
    "fechaPublicacion" => "2010-11-01"
    "documento" => "article"
    "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/"
    "subdocumento" => "fla"
    "cita" => "Nefrologia &#40;English Version&#41;. 2010;30:681-6"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 6329
      "formatos" => array:3 [
        "EPUB" => 297
        "HTML" => 5289
        "PDF" => 743
      ]
    ]
    "en" => array:12 [
      "idiomaDefecto" => true
      "titulo" => "B-cell lymphoma of MALT involving the kidney and monoclonal gammopathy&#58; a case report with revision of the literature"
      "tienePdf" => "en"
      "tieneTextoCompleto" => "en"
      "tieneResumen" => array:2 [
        0 => "en"
        1 => "es"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "681"
          "paginaFinal" => "686"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "es" => array:1 [
          "titulo" => "Linfoma de c&#233;lulas B tipo MALT con afectaci&#243;n renal y gammapat&#237;a monoclonal&#58; presentaci&#243;n de un caso y revisi&#243;n de la literatura"
        ]
      ]
      "contieneResumen" => array:2 [
        "en" => true
        "es" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "en" => true
      ]
      "contienePdf" => array:1 [
        "en" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:8 [
          "identificador" => "fig1"
          "etiqueta" => "Fig. 1"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "copyright" => "Elsevier Espa&#241;a"
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "10428_18107_6545_en_10428_18107_1935_es_10309_332_1935_en_figure11.jpg"
              "Alto" => 504
              "Ancho" => 617
              "Tamanyo" => 201659
            ]
          ]
          "descripcion" => array:1 [
            "en" => "CT showing tumoral growth through the renal cortex of the left kidney&#46;"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "R. Peces, C. Vega-Cabrera, C. Peces, A. Pobes, M.F. Fresno"
          "autores" => array:6 [
            0 => null
            1 => array:2 [
              "Iniciales" => "R."
              "apellidos" => "Peces"
            ]
            2 => array:2 [
              "Iniciales" => "C."
              "apellidos" => "Vega-Cabrera"
            ]
            3 => array:2 [
              "Iniciales" => "C."
              "apellidos" => "Peces"
            ]
            4 => array:2 [
              "Iniciales" => "A."
              "apellidos" => "Pobes"
            ]
            5 => array:2 [
              "Iniciales" => "M.F."
              "apellidos" => "Fresno"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "en"
    "Traduccion" => array:1 [
      "es" => array:9 [
        "pii" => "X0211699510050899"
        "doi" => "10.3265/Nefrologia.pre2010.Jun.10428"
        "estado" => "S300"
        "subdocumento" => ""
        "abierto" => array:3 [
          "ES" => true
          "ES2" => true
          "LATM" => true
        ]
        "gratuito" => true
        "lecturas" => array:1 [
          "total" => 0
        ]
        "idiomaDefecto" => "es"
        "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699510050899?idApp=UINPBA000064"
      ]
    ]
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251410050896?idApp=UINPBA000064"
    "url" => "/20132514/0000003000000006/v0_201502091649/X2013251410050896/v0_201502091649/en/main.assets"
  ]
  "en" => array:14 [
    "idiomaDefecto" => true
    "titulo" => "Clinical and genetic basis of hypertensive nephrosclerosis"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "687"
        "paginaFinal" => "697"
      ]
    ]
    "autores" => array:1 [
      0 => array:3 [
        "autoresLista" => "B. Diez Ojea, R. Mar&#237;n, E. Coto, F. Fern&#225;ndez Vega, R. &#193;lvarez Navascu&#233;s, G. Fern&#225;ndez Fresnedo, A. Pobes Mart&#237;nez de Salinas, A. Su&#225;rez Laur&#233;s, C. Garc&#237;a Monteavaro, M. Gorostidi, E. S&#225;nchez, M. Arias, F. Ortega"
        "autores" => array:14 [
          0 => null
          1 => array:4 [
            "Iniciales" => "B."
            "apellidos" => "Diez Ojea"
            "email" => array:1 [
              0 => "beaojea&#64;hotmail&#46;com"
            ]
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "affb"
              ]
            ]
          ]
          2 => array:3 [
            "Iniciales" => "R."
            "apellidos" => "Mar&#237;n"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "affc"
              ]
            ]
          ]
          3 => array:3 [
            "Iniciales" => "E."
            "apellidos" => "Coto"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "affd"
              ]
            ]
          ]
          4 => array:3 [
            "Iniciales" => "F."
            "apellidos" => "Fern&#225;ndez Vega"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">e</span>"
                "identificador" => "affe"
              ]
            ]
          ]
          5 => array:3 [
            "Iniciales" => "R."
            "apellidos" => "&#193;lvarez Navascu&#233;s"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">e</span>"
                "identificador" => "affe"
              ]
            ]
          ]
          6 => array:3 [
            "Iniciales" => "G."
            "apellidos" => "Fern&#225;ndez Fresnedo"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">f</span>"
                "identificador" => "afff"
              ]
            ]
          ]
          7 => array:3 [
            "Iniciales" => "A."
            "apellidos" => "Pobes Mart&#237;nez de Salinas"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">g</span>"
                "identificador" => "affg"
              ]
            ]
          ]
          8 => array:3 [
            "Iniciales" => "A."
            "apellidos" => "Su&#225;rez Laur&#233;s"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">h</span>"
                "identificador" => "affh"
              ]
            ]
          ]
          9 => array:3 [
            "Iniciales" => "C."
            "apellidos" => "Garc&#237;a Monteavaro"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">i</span>"
                "identificador" => "affi"
              ]
            ]
          ]
          10 => array:3 [
            "Iniciales" => "M."
            "apellidos" => "Gorostidi"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">e</span>"
                "identificador" => "affe"
              ]
            ]
          ]
          11 => array:3 [
            "Iniciales" => "E."
            "apellidos" => "S&#225;nchez"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">j</span>"
                "identificador" => "affj"
              ]
            ]
          ]
          12 => array:3 [
            "Iniciales" => "M."
            "apellidos" => "Arias"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">k</span>"
                "identificador" => "affk"
              ]
            ]
          ]
          13 => array:3 [
            "Iniciales" => "F."
            "apellidos" => "Ortega"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">e</span>"
                "identificador" => "affe"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:10 [
          0 => array:3 [
            "entidad" => "Sección de Nefrología, Hospital Valle del Nalón, Langreo, Asturias,  "
            "etiqueta" => "<span class="elsevierStyleSup">b</span>"
            "identificador" => "affb"
          ]
          1 => array:3 [
            "entidad" => "Unidad de Nefrología e Hipertensión, Centro Médico de Asturias, Oviedo, Asturias,  "
            "etiqueta" => "<span class="elsevierStyleSup">c</span>"
            "identificador" => "affc"
          ]
          2 => array:3 [
            "entidad" => "Laboratorio de Genética Molecular, Hospital Universitario Central de Asturias, Oviedo, Asturias,  "
            "etiqueta" => "<span class="elsevierStyleSup">d</span>"
            "identificador" => "affd"
          ]
          3 => array:3 [
            "entidad" => "Servicio de Nefrología, Hospital Universitario Central de Asturias, Oviedo, Asturias,  "
            "etiqueta" => "<span class="elsevierStyleSup">e</span>"
            "identificador" => "affe"
          ]
          4 => array:3 [
            "entidad" => "Sección de Nefrología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria,  "
            "etiqueta" => "<span class="elsevierStyleSup">f</span>"
            "identificador" => "afff"
          ]
          5 => array:3 [
            "entidad" => "Sección de Nefrología, Hospital San Agustín, Avilés, Asturias,  "
            "etiqueta" => "<span class="elsevierStyleSup">g</span>"
            "identificador" => "affg"
          ]
          6 => array:3 [
            "entidad" => "Servicio de Nefrología, Hospital de Cabueñes, Gijón, Asturias,  "
            "etiqueta" => "<span class="elsevierStyleSup">h</span>"
            "identificador" => "affh"
          ]
          7 => array:3 [
            "entidad" => "Servicio de Nefrología, Hospital San Agustín, Avilés, Asturias,  "
            "etiqueta" => "<span class="elsevierStyleSup">i</span>"
            "identificador" => "affi"
          ]
          8 => array:3 [
            "entidad" => "Servicio de Nefrología, Hospital Universitario Central de Asturias Oviedo, Asturias,  "
            "etiqueta" => "<span class="elsevierStyleSup">j</span>"
            "identificador" => "affj"
          ]
          9 => array:3 [
            "entidad" => "Servicio de Nefrología, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria,  "
            "etiqueta" => "<span class="elsevierStyleSup">k</span>"
            "identificador" => "affk"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Bases cl&#237;nicas y gen&#233;ticas de la nefroesclerosis hipertensiva&#46; Estudio NEFROSEN"
      ]
    ]
    "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The term nephrosclerosis is usually used for kidney disease which complicates arterial hypertension &#40;AHT&#41; and that primarily affects the preglomerular microvasculature&#46;<span class="elsevierStyleSup">1&#44;2</span> In practice&#44; it is an entity with vague clinical profiles that groups hypertensive patients with chronic kidney disease &#40;CKD&#41; without other identifiable causes of disease&#46;<span class="elsevierStyleSup">3&#44;4</span>&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In nephrosclerosis&#44; also known as benign nephroangiosclerosis or hypertensive nephropathy&#44; the most characteristic microscopic lesion is hyalinosis of the afferent arterioles&#46; Vascular changes produce vasoconstriction&#44; glomerular ischaemia &#40;retraction of glomerular tuft&#44; focal or global sclerosis&#41; and in some areas&#44; interstitial fibrosis and tubular atrophy&#46; Other authors point out that the hyalinisation of afferent arterioles would initially cause vasodilatation&#44; glomerular hypertrophy and&#44; in the long-term&#44; segmental glomerulosclerosis lesions that overall favour the appearance of proteinuria and progression of the disease&#46; These alterations are more frequent and severe in black patients&#44; unrelated to the control of blood pressure or the degree of proteinuria&#46; In fact&#44; nephrosclerosis is a form of intrarenal renovascular disease&#44; and in some cases may represent a magnification of the changes of kidney aging&#44; from both a histological and clinical standpoint&#46;<span class="elsevierStyleSup">5-7</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Its causal relation with essential hypertension is still a subject of debate&#46; It is not clear that treated AHT can lead to end-stage CKD&#46;<span class="elsevierStyleSup">8-11</span> Therefore&#44; some authors have postulated that renal structural alterations may precede hypertension&#44; and that it would be an intrinsic process of the renal microvasculature with loss of self-regulation that would mainly result in excessive preglomerular vasoconstriction<span class="elsevierStyleSup">4</span> or persistent vasodilation of the afferent arteriole&#46;<span class="elsevierStyleSup">6&#44;7</span> A chronically impaired renal plasma flow&#44; in the long run&#44; leads to hypertension and CKD&#46; Nephroangiosclerosis could have the same clinical significance as atherosclerosis in coronary or cerebral vessels&#46;<span class="elsevierStyleSup">2&#44;3</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In the US&#44; Europe and Spain&#44; vascular kidney disease is the second most common cause of terminal CKD&#46; However&#44; the diagnosis of nephrosclerosis is usually made by exclusion&#44; when no data for another type of kidney disease is found&#44; and in very few cases is based on histological findings&#46; There are no specific signs or symptoms&#44; but there are some suggestive clinical findings &#40;men aged 55-60 years&#44; long-standing hypertension&#44; left ventricular hypertrophy &#91;LVH&#93;&#44; mild CKD and proteinuria less than 0&#46;5-1g&#47;24 hours&#41;&#46; As with diabetic kidney disease&#44; a kidney biopsy is almost never performed&#46; This attitude may be reasonable in many cases&#44; but is a source of misdiagnoses&#46;<span class="elsevierStyleSup">12</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Some studies with small samples suggest that the degree of proteinuria may be variable&#44; and may even reach the nephrotic range&#46; However&#44; there is general consensus that subnephrotic proteinuria values are typical of hypertensive nephrosclerosis&#46; Clinical inclusion criteria for the African American Study of Kidney Disease and Hypertension &#40;AASK&#41; required a proteinuria level lower than 2&#46;5 &#40;UP&#47;Cr&#41;&#46;<span class="elsevierStyleSup">4&#44;13&#44;14 </span>End-stage CKD onset age for African-Americans varied between 45 and 64 years&#44; while for Caucasian Americans it is over 65 years&#46;<span class="elsevierStyleSup">4</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Compared with early glomerular or diabetic kidney diseases&#44; the progression of kidney failure is slow in most cases&#44; especially in whites&#46; Renal function can remain stable for years if hypertension is well controlled&#46; However&#44; in a few cases the disease progresses to end-stage CKD&#46;<span class="elsevierStyleSup">5&#44;12&#44;15</span> Vascular kidney disease is the most common cause of hospital visits for CKD in nephrology departments in Spain&#46; Up to 39&#37; of cases have this aetiology&#44; higher than diabetic or glomerular kidney disease &#40;20&#37;&#41;&#46;<span class="elsevierStyleSup">16</span> Despite the small percentage of patients with progression&#44; its high prevalence makes it the second leading cause of end-stage CKD&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The factors for progression of nephrosclerosis are not well recognised&#44; which hampers the implementation of preventive measures&#46; Usually&#44; firstly the black race is cited&#44; and later age&#44; the degree of kidney failure at diagnosis&#44; the level of systolic blood pressure &#40;SBP&#41; and the degree of proteinuria&#46;<span class="elsevierStyleSup">1&#44;13-20</span> In the AASK study&#44; patients with proteinuria below 0&#46;3g&#47;24 hours&#44; who had received ramipril&#44; an angiotensin-converting enzyme inhibitor &#40;ACEI&#41; from the start had slower progression after an 11 year follow-up&#46; This same study showed that old age &#40;over 70 years&#41; was inversely correlated with kidney failure&#46;<span class="elsevierStyleSup">20&#44;21</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Only some cases of whites&#44; perhaps those who are genetically predisposed&#44; have an unfavourable clinical evolution&#46; The progression of the disease has been associated with the concomitant presence of atherosclerotic lesions in the aorta and main renal arteries&#44; and with processes such as Type 2 diabetes mellitus&#44; hyperuricaemia and dyslipidaemia&#46;<span class="elsevierStyleSup">3&#44;5&#44;10&#44;19</span> In the Norwegian HUNT 2 population study&#44; progression to end-stage CKD was associated with the estimated glomerular filtration rate &#40;eGFR&#41; and basal microalbuminuria in the multivariate analysis after 10 years of follow-up&#46;<span class="elsevierStyleSup">22</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In the last decade&#44; the disease is being diagnosed mainly in patients older than 65-70 years of age and with vascular disease in other parts of the body&#46; In these cases&#44; nephrosclerosis is observed as a diffuse atherosclerosis of the renal arterioles&#46;<span class="elsevierStyleSup">19&#44;23&#44;24</span> Recently&#44; a lesser-known fact has been pointed out&#58; the presence of concomitant cardiovascular disease is a factor for progression to kidney failure&#46;<span class="elsevierStyleSup">25-29 </span>Levin et al studied a group of 313 patients with kidney failure &#40;eGFR of 10-75ml&#47;min&#41; and a mean follow-up of 23 months&#46; They found that patients with cardiovascular diseases &#40;ischaemic heart disease&#44; cerebrovascular disease&#44; peripheral artery disease or heart failure&#41; increased the risk of progression to end-stage CKD &#40;relative risk &#91;RR&#93; 1&#46;58&#44; <span class="elsevierStyleItalic">P</span>&#61;&#46;047&#41;&#46;<span class="elsevierStyleSup">25</span> Hillegas et al&#8217;s study of 298 patients who had an acute myocardial infarction &#40;AMI&#41;&#44; found that the eGFR had declined 5&#46;4ml&#47;min after the first year&#44; much higher than the usual 1ml&#47;min&#47;year reported for the general population&#46;<span class="elsevierStyleSup">28</span> Elsayed et al studied 13&#44;826 subjects&#44; of which 18&#46;5&#37; were African American&#44; enrolled in the Atherosclerosis Risk in Communities Study and Cardiovascular Health Study trials&#46; They found that after 9 years of follow-up&#44; patients with cardiovascular disease at baseline were significantly more likely to develop CKD &#40;odds ratio &#91;OR&#93; 1&#46;75&#44; <span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41;&#46;<span class="elsevierStyleSup">29</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In Spain there is an ongoing prospective study supported by the Spanish Society of Nephrology &#40;SEN&#41;&#44; the &#8220;<span class="elsevierStyleItalic">ESTUDIO PRONEFROS</span>&#8221;&#44; which aims to determine the proportion of patients with nephrosclerosis showing progression to kidney failure&#46; &#34;Historical&#34; nephrosclerosis cases have been excluded and only incident cases &#40;n&#61;430&#41; over one year have been included&#46; After 2 years of follow-up&#44; preliminary data show that there is impaired renal function in only 3&#46;9&#37; of cases&#46; Progression markers include the presence of higher baseline SBP and a higher rate of associated cardiovascular events&#46;<span class="elsevierStyleSup">30</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The explanation is complex and probably multifactorial&#58; the deterioration of myocardial function implies a reduction of renal blood flow that would be added to the presence of microvascular and macrovascular renal injury&#46; Furthermore&#44; until just a few years ago&#44; the presence of renal failure has led to underuse of cardioprotective drugs or more conservative application of coronary revascularisation or valvular prostheses&#46;<span class="elsevierStyleSup">31</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">For years&#44; the relationship between hyperuricaemia and CKD in patients with essential hypertension has been widely debated&#46; While it is true that up to 40&#37; of individuals with gout develop CKD&#44; the fact remains that almost all have hypertension and arteriolosclerosis and glomerulosclerosis lesions similar to those seen in patients with nephrosclerosis&#46; There is no evidence that hyperuricaemia is a risk factor for CKD&#46; However&#44; two recent studies have offered new perspectives&#58; Iseki et al have shown that hyperuricaemia is an independent marker of renal failure for subjects at baseline who had normal renal function&#44; especially women&#46;<span class="elsevierStyleSup">32</span> Furthermore&#44; Siu et al studied 54 patients and found that when uric acid is decreased with allopurinol progression to CKD is postponed&#46;<span class="elsevierStyleSup">33</span> It seems necessary to promote studies specifically designed to clarify whether hyperuricaemia may be an independent risk factor for vascular and renal risk&#46;<span class="elsevierStyleSup">34</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The lack of correlation between the degree of hypertension control and the prevention of disease progression&#44; from the clinical and histological standpoint suggests that this process may be an intrinsic and early renal disease&#46; In some cases the clinical context maintains some similarity with focal segmental glomerulonephritis &#40;FSGP&#41;&#46; For many years&#44; genetic markers have been sought that could explain the onset and progression of the disease&#46; AHT&#44; hyperuricaemia&#44; dyslipidaemia and metabolic syndrome were frequently associated phenotypic factors&#44; but not the cause of the process&#46;<span class="elsevierStyleSup">2&#44;3</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Some studies carried out a decade ago verified a direct relationship between nephrosclerosis and ACE DD genotype&#46; The D allele appears to be predominant in hypertensive patients with nephrosclerosis and could be a progression marker&#46; Although the proportion of patients was small&#44; studies were conducted on Caucasians&#44; and included histological support and control groups of hypertensives without kidney disease and subjects from the general population&#46;<span class="elsevierStyleSup">35&#44;36</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">American nephrosclerosis genetic studies have been conducted primarily in African-Americans because the disease is more frequent and aggressive in this race&#46;<span class="elsevierStyleSup">37-42</span><span class="elsevierStyleSup"> </span>Two independent studies published recently have led to a new approach to the pathogenesis of nephrosclerosis&#46; The study by Kao et al&#44; which included 1372 patients&#44; revealed a close relationship between the presence of end-stage CKD secondary to hypertensive nephrosclerosis in non-diabetics&#44; and some polymorphisms of the <span class="elsevierStyleItalic">MYH9</span> gene&#44; located on chromosome 22&#44; which encodes the non-muscle myosin heavy chain IIA&#46;<span class="elsevierStyleSup">37</span> The study by Kopp et al compared 190 black individuals with 222 healthy controls&#46; It found the same association with the presence of FSGP of idiopathic origin or secondary to infection with human immunodeficiency virus &#40;HIV&#41;&#44; but no relationship was found with progression&#46;<span class="elsevierStyleSup">38</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Furthermore&#44; a study by Freedman et al confirmed the presence of the <span class="elsevierStyleItalic">MYH9</span> gene polymorphisms in 696 African-American subjects with hypertensive kidney disease and end-stage CKD&#44; compared with 948 control subjects without kidney disease&#44; of whom 34&#37; were hypertensive&#46; However&#44; not all individuals who were homozygous dominant for <span class="elsevierStyleItalic">MYH9</span> risk alleles developed the disease&#44; which suggests that other factors&#44; such as environment or interaction with other genes&#44; add to individual genetic susceptibility&#46;<span class="elsevierStyleSup">39</span> Meanwhile&#44; the same group recently reported an association between the <span class="elsevierStyleItalic">MYH9</span> E1 haplotype and the presence of microalbuminuria in 1458 African-American patients with essential hypertension but no kidney disease&#46; Increased risk has been observed for <span class="elsevierStyleItalic">MYH9</span> E1 haplotype&#44; which consists of the polymorphisms rs4821480&#44; rs2032487&#44; rs4821481 and rs3752462&#46; However&#44; the strength of the association is weaker than in subjects with FSGP and terminal CKD of hypertensive origin&#46;<span class="elsevierStyleSup">40</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Further complicating the issue&#44; an association of that gene has been found in 751 diabetic black end-stage CKD patients compared with 227 diabetic controls without kidney disease and 925 healthy controls&#44; but there is no clear correlation with the development of diabetic kidney disease because there is no histological confirmation&#46; It has even been suggested that it may coincide with kidney disease related to baseline <span class="elsevierStyleItalic">MYH9</span> polymorphisms&#46;<span class="elsevierStyleSup">41</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">It appears that during the early stages&#44; myosin IIA is primarily situated at the podocyte level and induces structural alterations&#46; Recently&#44; the role of podocyte loss and dysfunction has been reported as part of disease development&#46; Wang et al conducted a study on 41 patients with biopsy diagnosis of hypertensive nephrosclerosis&#44; finding less podocytes and a reduced intrarenal expression of protein genes such as nephrin&#44; podocin and synaptopodin&#44; which is also related to the decrease in eGFR&#44; and inversely proportional with the degree of renal fibrosis&#46;<span class="elsevierStyleSup">43</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A bold new hypothesis on this issue states that polymorphisms of this gene would be markers of various kidney diseases that fall into one histological group&#44; GSFP&#44; and any of its variants&#44; such as nephrosclerosis&#44; which would be a disease akin to primary kidney disease with idiopathic GSFP and with the collapse observed in HIV&#46;<span class="elsevierStyleSup">44</span> A renal disease associated with macrothrombocytopaenia has even been reported&#46; Lastly&#44; there are some rare entities associated with mutations of that gene&#44; which are transmitted by autosomal dominant inheritance&#44; known as <span class="elsevierStyleItalic">MYH9</span>-related disorders&#46; These include the May-Hegglin anomaly and the Sebastian&#44; Epstein and Fechtner syndromes&#44; which are in many cases present with kidney disease&#44; although its mechanism and that of <span class="elsevierStyleItalic">MYH9</span>-related hypertensive nephrosclerosis polymorphisms in blacks is currently unknown&#46;<span class="elsevierStyleSup">45</span> However&#44; not all cases of nephrosclerosis are associated with <span class="elsevierStyleItalic">MYH9</span> haplotypes&#46;<span class="elsevierStyleSup">46</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">For all these reasons&#44; further studies are needed to provide a better understanding of its pathogenesis&#44; and the potential role of detections of <span class="elsevierStyleItalic">MYH9</span> polymorphisms in the diagnosis and evolution of CKD secondary to nephrosclerosis &#40;Table 1&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">HYPOTHESIS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Hypertensive nephrosclerosis is a CKD that rarely progresses&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">1&#46; Clinical progression markers would be related to&#58;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">a&#41; The presence of associated cardiovascular disease&#44; especially cardiovascular events appearing on a recurring basis&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">b&#41; The degree of proteinuria&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">c&#41; Initial renal function&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">d&#41; The patient being less than 70 years old&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">2&#46; Histological progression markers would be related to&#58;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">a&#41; The degree of global and segmental glomerulosclerosis&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">b&#41; The degree of interstitial fibrosis&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">3&#46; Genetic markers would be related to&#58;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">a&#41; <span class="elsevierStyleItalic">MYH9</span> gene polymorphisms&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">b&#41; I&#47;D polymorphisms of the ACE gene&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">OBJECTIVES</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Primary Objective</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">To determine if any <span class="elsevierStyleItalic">MYH9</span> gene polymorphism is associated in Caucasians&#58;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">a&#41; With the association of essential hypertension and nephrosclerosis&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">b&#41; With progression of the disease&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Secondary Objectives</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">1&#46; To compare the clinical characteristics of nephrosclerosis patients with essential hypertension and hypertensives with no kidney disease&#44; and to determine clinical progression markers&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">2&#46; To recognise the importance of proteinuria&#44; associated cardiovascular disease&#44; sex&#44; age &#40;over and under 70 years&#41;&#44; the presence of hyperuricaemia or gout&#44; and concomitant treatments &#40;antihypertensives&#44; statins and antiplatelet agents&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">METHOD</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Study Design</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">Multicentre retrospective study&#44; which involves four hospitals in Asturias &#40;Central Asturias University Hospital&#44; Valle del Nal&#243;n Hospital&#44; Cabue&#241;es Hospital&#44; and San Agust&#237;n Hospital&#41;&#44; and the Marques de Valdecilla University Hospital in Cantabria&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A basic study comparing patients with essential hypertension with nephrosclerosis patients versus hypertensive patients without kidney disease &#40;control group&#41;&#46; Furthermore&#44; patients with nephrosclerosis and impaired kidney function are compared with those who are stable&#46; For the genetic study&#44; healthy controls from the general population with similar age and sex as the cases are also included&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">PATIENTS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Cases</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The cases were selected between October 2009 and October 2010 from nephrology&#44; kidney transplantation&#44; haemodialysis and peritoneal dialysis units of the participating hospitals&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Patients recruited have eGFR &#60;60ml&#47;min&#47;1&#46;73m2 &#40;measured by the MDRD formula&#41; in stages 3-5&#44; attributed to nephrosclerosis according to standard clinical criteria &#40;Table 2&#41;&#44; with or without histological documentation&#46; Diagnosis of CKD of unknown origin will not be valid&#44; and patients with secondary&#44; renovascular or accelerated hypertension will be excluded&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Patients with stage 5&#44; on dialysis or to undergo kidney transplant&#44; may be admitted&#44; provided that developmental data are available from their first contact with the hospital&#46; The start of replacement therapy marks the end of follow-up&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Cases younger than 80 years will be valid for the study&#46; However&#44; the selection will be made mainly of patients younger than 60 years&#44; to minimise the effect of age-related gene denaturation&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Controls</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The control group is from Central Asturias University Hospital and Nal&#243;n Valley Hospital&#44; to simplify data collection&#44; given that there are few differences between the subjects as they are from the same geographic area&#46; Patients with essential hypertension are included with eGFR&#62;60ml&#47;min&#47;1&#46;73 m2 and microalbuminuria &#60;300mg&#47;g&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Data for Each Patient</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">There will be two sections of the study&#44; one for the first hospital visit and one for the last &#40;&#34;current visit&#34;&#41;&#46; Clinical data are to be collected from all patients including socio-demographic variables&#44; comorbidity and cardiovascular risk&#44; medical treatment and physical examination&#44; weight in kilograms&#44; height in centimetres&#44; systolic &#40;SBP&#41; and diastolic &#40;DBP&#41; blood pressure in millimetres of mercury&#44; and heart rate&#46; Analytical data will be recorded including renal function by serum creatinine&#44; eGFR&#44; creatinine clearance&#44; microalbuminuria in urine alone &#40;mg&#47;g creatinine&#41; and proteinuria in urine for 24 hours and also glucose&#44; uric acid&#44; cholesterol and calcium-phosphorus metabolism&#46; Furthermore&#44; the performance of imaging techniques &#40;ultrasound&#44; CT angiography&#44; MR angiography or arteriography&#41;&#44; and renal biopsy diagnosis &#40;Table 3&#41; are also included&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Laboratory Analysis</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">Routine laboratory tests shall be performed by the usual methods in the laboratory of each hospital&#46; Blood samples for genetic studies will be submitted to the Laboratory of Molecular Genetics&#44; Central Asturias University Hospital&#46; DNA was obtained from leukocytes from 10ml of EDTA anticoagulated peripheral blood&#46; The samples will be stored for 5 years&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Major <span class="elsevierStyleItalic">MYH9</span> gene polymorphisms to be identified are those which showed an association with hypertensive nephrosclerosis in non-diabetics &#40;rs4821480 and rs3752462&#44; belonging to E-1 haplotype&#41;&#44; and with the ACE gene&#44; by the polymerase chain reaction &#40;PCR&#41; test&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">DEFINITIONS</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Progression of Kidney Disease</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Doubling of baseline creatinine&#44; eGFR decline &#62;50&#37; above baseline or a reduction of 25ml&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span> or onset at end-stage CKD &#40;defined by the need for renal replacement therapy&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Arterial Hypertension</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">SBP&#62;140mm Hg and&#47;or DBP&#62;90mm Hg&#44; or treatment with diet or antihypertensive agents&#46; The percentage of patients with SBP&#62;130mm Hg and&#47;or DBP&#62;80mm Hg will also be analysed&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Diabetes Mellitus</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Fasting glucose&#62;126mg&#47;dl or &#62;200mg&#47;dl 2 hours after oral glucose or antidiabetic treatment &#40;diet&#44; oral antidiabetic agents or insulin&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Hypercholesterolaemia</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">LDL cholesterol&#62;100mg&#47;dl&#44; or treatment with lipid lowering agents&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Smoker</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Tobacco consumption &#40;cigarettes&#44; cigars&#44; pipe&#41; during the last month&#46; Former smoker&#58; absence of tobacco use for a consecutive year&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Obesity</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">BMI&#62;30kg&#47;m2&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Cardiovascular Comorbidity</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Must be properly documented&#46; Presence of one or more of the following&#58; ischaemic heart disease by acute myocardial infarction &#40;AMI&#41;&#44; unstable angina or stable angina&#44; atrial fibrillation&#44; heart failure&#44; degenerative mitral or aortic valve disease&#44; ischaemic&#44; hemorrhagic&#44; or transient stroke&#44; or peripheral arterial disease&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Left Ventricular Hypertrophy</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Diagnosis made by echocardiography&#44; which is a more specific method than the electrocardiogram&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">ETHICAL ASPECTS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The investigator must inform the patient about his or her participation in the study&#44; which is voluntary and will not cause any change in the treatment or medical care to be received&#46; Subsequently&#44; the investigator must obtain the patient&#8217;s informed and voluntary consent&#46; The highest levels of confidentiality must always be maintained&#44; as well as compliance with national legislation on data protection&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The study protocol was approved by the Research Ethics Committee of the Regional Clinical Research of Asturias&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">SAMPLE SIZE</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">It is estimated that the size of the sample needed to observe the effects of <span class="elsevierStyleItalic">MYH9</span> gene polymorphisms according to their allele frequencies for an alpha error of 0&#46;05 and a beta error of 0&#46;2&#44; will be 500 cases with CKD and 500 controls&#46; The subjects will be distributed as such&#58; 500 cases&#44; 300 hypertensive controls with no kidney disease and 200 general population subjects &#40;healthy controls&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">We will attempt to control the sample for sex and age &#40;Figure 1&#41;&#46; &#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">STATISTICAL ANALYSIS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">There will be a descriptive analysis of continuous variables&#44; giving the mean&#44; median&#44; standard deviation and range&#44; and in case of discrete variables&#44; the frequency distribution and percentages&#46; When necessary&#44; 95&#37; confidence intervals are calculated&#46; The description of the main variables are based on age&#44; sex&#44; level of baseline renal failure and proteinuria&#44; degree of hypertension control and dyslipidaemia and associated cardiovascular risk factors&#46; The association between qualitative variables will be assessed with the chi-square or Fisher&#39;s exact test and quantitative variables using parametric tests &#40;t-test&#44; Pearson correlation coefficient and ANOVA&#41;&#46; If a normal distribution cannot be assumed&#44; non-parametric tests will be used such as Mann-Whitney U or Kruskal-Wallis&#46; Comparison tests will be bilateral and considered significant when <span class="elsevierStyleItalic">P</span>&#60;&#46;05&#46; A logistic regression model will be used to evaluate the association of those variables in which the result of the <span class="elsevierStyleItalic">P</span> comparison in the &#34;raw&#34; analysis is less than 0&#46;15&#46; Statistical analysis of the study will be conducted with SPSS for Windows&#44; version 15&#46;0 &#40;SPSS&#44; Chicago&#44; IL&#41;&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">FINANCIAL SUPPORT</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The NEFROSEN Study is a typical clinical practice study that does not involve extra costs&#46; It is being carried out with the sponsorship of the Spanish Society of Nephrology &#40;SEN&#41; through its &#34;Kidney and Hypertension&#34; Work Group&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The cost for each case analysed in the genetic substudy of the <span class="elsevierStyleItalic">MYH9</span> gene polymorphisms is about 10 euros&#46; It is being financed with funds from the <span class="elsevierStyleItalic">Fundaci&#243;n Renal I&#241;igo &#193;lvarez de Toledo </span>&#40;I&#241;igo Alvarez de Toledo Kidney Foundation&#41; in the Molecular Genetics Group&#46;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Following the publication of genetic studies on nephrosclerosis&#44; some documents have indicated that it should no longer be regarded as a disease that is secondary to essential hypertension&#46; At least in the black race&#44; it seems to be a genetically based disease closely related to GSFP&#44; and it is estimated that there may be an association with <span class="elsevierStyleItalic">MYH9</span> gene polymorphisms in 43&#37; of African-American individuals who progress to end-stage CKD&#46;<span class="elsevierStyleSup">47</span> Of these&#44; control of hypertension does not stop progression&#44; while in the white race it seems more effective&#44; so it is speculated that the treatment of hypertensive nephrosclerosis should be approached from a different perspective that not only includes blocking RAS and strict control of blood pressure&#46;<span class="elsevierStyleSup">48</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">However&#44; much is still unknown about these findings&#46; The referred studies have been conducted on patients with nephrosclerosis not supported by renal biopsies&#46; This indicates the opportunity to reassess the cases of the AASK study &#40;n&#61;1094 patients&#41;&#44; which is the only one that has been conducted with histological confirmation&#46;<span class="elsevierStyleSup">13&#44;14</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In the white race there are no studies on whether these or other <span class="elsevierStyleItalic">MYH9</span> polymorphisms might be involved in the disease&#46; Only the Pattero et al group found an association of this gene with serum creatinine values in 2859 European individuals without kidney disease&#44; coming from three different populations&#44; while the genes related to renal function showed great heterogeneity&#46;<span class="elsevierStyleSup">49</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The proposed study is both clinical and genetic&#46; Their relationship seems logical and complementary&#46; The limitations are those related to a retrospective study design&#44; together with the lack of a centralised laboratory for routine analysis&#44; because the data are historic&#46; Nephrosclerosis cases that maintain periodic visits over a variable time period&#44; and patients that have progressed to end-stage CKD are included&#46; In this respect&#44; we have significant selection bias when calculating the percentage of patients whose disease has progressed&#44; since many will be obtained from dialysis and transplant units&#46; We will probably not be able to draw clear conclusions about disease progression but&#44; despite these limitations&#44; we believe a study such as this will be interesting because there are very few publications to date on this topic&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">It seems necessary to design prospective genetic studies to determine the relationship with this gene&#44; both in terms of diagnosis and the possibility that it could be a progression marker&#46;</p><p class="elsevierStylePara"><a href="10372&#95;108&#95;10773&#95;en&#95;w4777105862010372&#95;18107&#95;2737&#95;es&#95;10372&#95;465&#95;2737&#95;es&#95;tabla&#95;1&#95;en&#46;doc" class="elsevierStyleCrossRefs">10372&#95;108&#95;10773&#95;en&#95;w4777105862010372&#95;18107&#95;2737&#95;es&#95;10372&#95;465&#95;2737&#95;es&#95;tabla&#95;1&#95;en&#46;doc</a></p><p class="elsevierStylePara">Table 1&#46; Main studies on the polymorphisms of the MYH9 gene and the presence of kidney disease </p><p class="elsevierStylePara"><a href="10372&#95;108&#95;10774&#95;en&#95;w4777105861010372&#95;18107&#95;2738&#95;es&#95;10372&#95;465&#95;2738&#95;es&#95;tabla&#95;2&#95;en&#46;doc" class="elsevierStyleCrossRefs">10372&#95;108&#95;10774&#95;en&#95;w4777105861010372&#95;18107&#95;2738&#95;es&#95;10372&#95;465&#95;2738&#95;es&#95;tabla&#95;2&#95;en&#46;doc</a></p><p class="elsevierStylePara">Table 2&#46; Inclusion-exclusion criteria</p><p class="elsevierStylePara"><a href="10372&#95;108&#95;10775&#95;en&#95;w4777105862210372&#95;18107&#95;2739&#95;es&#95;10372&#95;465&#95;2739&#95;es&#95;tabla&#95;3&#95;en&#46;doc" class="elsevierStyleCrossRefs">10372&#95;108&#95;10775&#95;en&#95;w4777105862210372&#95;18107&#95;2739&#95;es&#95;10372&#95;465&#95;2739&#95;es&#95;tabla&#95;3&#95;en&#46;doc</a></p><p class="elsevierStylePara">Table 3&#46; Clinical and analytical data sheet</p><p class="elsevierStylePara"><a href="10372&#95;108&#95;10776&#95;en&#95;w4777105862310372&#95;18107&#95;2740&#95;es&#95;10372&#95;465&#95;2740&#95;es&#95;figura&#95;1&#95;en&#95;copy1&#46;doc" class="elsevierStyleCrossRefs">10372&#95;108&#95;10776&#95;en&#95;w4777105862310372&#95;18107&#95;2740&#95;es&#95;10372&#95;465&#95;2740&#95;es&#95;figura&#95;1&#95;en&#95;copy1&#46;doc</a></p><p class="elsevierStylePara">Figure 1&#46; Case and control recruitment&#46;</p>"
    "pdfFichero" => "P1-E506-S2882-A10372-EN.pdf"
    "tienePdf" => true
    "PalabrasClave" => array:2 [
      "es" => array:4 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec441579"
          "palabras" => array:1 [
            0 => "Enfermedad renal cr&#243;nica"
          ]
        ]
        1 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec441581"
          "palabras" => array:1 [
            0 => "Gen MYH9"
          ]
        ]
        2 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec441583"
          "palabras" => array:1 [
            0 => "Nefroesclerosis"
          ]
        ]
        3 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec441585"
          "palabras" => array:1 [
            0 => "Hipertensi&#243;n arterial esencial"
          ]
        ]
      ]
      "en" => array:4 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec441580"
          "palabras" => array:1 [
            0 => "Chronic kidney disease"
          ]
        ]
        1 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec441582"
          "palabras" => array:1 [
            0 => "MYH9 gene"
          ]
        ]
        2 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec441584"
          "palabras" => array:1 [
            0 => "Hypertensive nephrosclerosis"
          ]
        ]
        3 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec441586"
          "palabras" => array:1 [
            0 => "Essential hypertension"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:1 [
        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Background&#58; </span>Hypertensive nephrosclerosis is a chronic kidney disease &#40;CKD&#41; associated with essential hypertension&#46; The lack of correlation between hypertension control and progression to end-stage CKD suggests an intrinsic and primitive disease&#46; New evidence suggests that <span class="elsevierStyleItalic">MYH9</span><span class="elsevierStyleItalic"> </span>gene alterations are associated with polymorphisms in African Americans&#46; The aim of this study is to investigate whether a polymorphism of <span class="elsevierStyleItalic">MYH9</span><span class="elsevierStyleItalic"> </span>in Caucasians is linked to essential hypertension and nephrosclerosis&#46; The secondary objective is to identify the clinical risk factors of progression to end-stage CKD&#46; This is a retrospective study that will compare patients with nephrosclerosis and essential hypertensives without renal disease&#44; and also patients with nephrosclerosis and impaired renal function with those that are stable&#46; <span class="elsevierStyleBold">Method&#58; </span>Between October 2009 and October 2010&#44; 500 patients with stages 3-5 CKD attributed to nephrosclerosis according to usual clinical criteria&#44; and 300 essential hypertensives &#40;eGFR&#62;60mL&#47;min&#47;1&#46;73m<span class="elsevierStyleSup">2</span>&#59; microalbuminuria &#60;300mg&#47;g&#41; are to be recruited&#46; A total of 200 healthy controls from the general population are also to be included for the genetic study&#46; There are two study sections&#44; being the first and final visits to the clinic &#40;for stage 5 cases&#44; the start of replacement therapy will be the end of follow-up&#41;&#46; Clinical and laboratory data will be recorded&#44; and blood samples will be collected&#46; <span class="elsevierStyleBold">Discussio</span><span class="elsevierStyleBold">n&#58;</span> Our study will aim to determine if there is a relationship between the diagnosis of nephrosclerosis and the <span class="elsevierStyleItalic">MYH9</span> gene in Caucasians&#44; and to study possible risk factors for progression to end-stage CKD&#44; on both clinical and genetic bases&#46;&#160;</p>"
      ]
      "es" => array:1 [
        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">&#160;<span class="elsevierStyleBold">Justificaci&#243;n&#58;</span> Se conoce como&#160;nefroesclerosis&#160;la enfermedad renal cr&#243;nica &#40;ERC&#41; que complica la hipertensi&#243;n arterial &#40;HTA&#41; esencial&#46; La ausencia de correlaci&#243;n entre el control de la HTA y la progresi&#243;n a ERC terminal sugiere la existencia de una enfermedad intr&#237;nseca y primitiva&#46; Recientemente se ha asociado con polimorfismos del gen <span class="elsevierStyleItalic">MYH9 </span>en individuos afroamericanos&#46; El objetivo del trabajo que presentamos es determinar si alg&#250;n polimorfismo de dicho gen se relaciona en raza cauc&#225;sica con la asociaci&#243;n de HTA esencial y&#160;nefroesclerosis&#160;y&#44; adem&#225;s&#44; conocer los marcadores de progresi&#243;n a ERC terminal&#46; Ser&#225; un estudio retrospectivo que comparar&#225; a pacientes con&#160;nefroesclerosisfrente a pacientes con HTa esencial sin enfermedad renal y&#44; adem&#225;s&#44; se incluir&#225;n&#160;pacientes con&#160;nefroesclerosis&#160;y progresi&#243;n de la enfermedad renal frente a&#160;los que se mantienen estables&#46; <span class="elsevierStyleBold">M&#233;todos&#58;</span> Entre octubre de 2009 y octubre de 2010 se incluir&#225;n 500 pacientes con ERC &#40;estadios 3-5&#41; atribuida a&#160;nefroesclerosis&#160;seg&#250;n criterios cl&#237;nicos habituales&#44; y 300 pacientes afectados de HTA esencial &#40;FGe &#62;60 ml&#47;min&#47;1&#44;73 m<span class="elsevierStyleSup">2</span>&#59; microalbuminuria &#60;300 mg&#47;g&#41;&#46; Para el estudio gen&#233;tico tambi&#233;n se incluir&#225;n 200 controles sanos de poblaci&#243;n general&#46; Habr&#225; dos cortes del estudio&#44; la primera visita en el hospital y la visita final &#40;en estadio 5 el inicio del tratamiento sustitutivo constituir&#225; el final del seguimiento&#41;&#46; Se registrar&#225;n datos cl&#237;nicos&#160;y anal&#237;ticos&#44; y se recoger&#225;n muestras de sangre para el estudio gen&#233;tico&#46; <span class="elsevierStyleBold">Discusi&#243;n&#58; </span>Nuestro estudio&#44; con la doble vertiente gen&#233;tica y cl&#237;nica&#44; tratar&#225; de determinar si en la raza cauc&#225;sica existe relaci&#243;n entre el diagn&#243;stico de&#160;nefroesclerosis&#160;y el gen <span class="elsevierStyleItalic">MYH9</span>&#44; y estudiar&#225;&#44; adem&#225;s&#44; los posibles marcadores de progresi&#243;n&#46;</span></p>"
      ]
    ]
    "multimedia" => array:4 [
      0 => array:8 [
        "identificador" => "mmc1"
        "etiqueta" => "Tab. 1"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "Ecomponente" => array:2 [
          "fichero" => "10372_108_10773_en_w4777105862010372_18107_2737_es_10372_465_2737_es_tabla_1_en.doc"
          "ficheroTamanyo" => 66048
        ]
        "descripcion" => array:1 [
          "en" => "Main studies on the polymorphisms of the MYH9 gene and the presence of kidney disease "
        ]
      ]
      1 => array:8 [
        "identificador" => "mmc2"
        "etiqueta" => "Tab. 2"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "Ecomponente" => array:2 [
          "fichero" => "10372_108_10774_en_w4777105861010372_18107_2738_es_10372_465_2738_es_tabla_2_en.doc"
          "ficheroTamanyo" => 60416
        ]
        "descripcion" => array:1 [
          "en" => "Inclusion-exclusion criteria"
        ]
      ]
      2 => array:8 [
        "identificador" => "mmc3"
        "etiqueta" => "Tab. 3"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "Ecomponente" => array:2 [
          "fichero" => "10372_108_10775_en_w4777105862210372_18107_2739_es_10372_465_2739_es_tabla_3_en.doc"
          "ficheroTamanyo" => 102400
        ]
        "descripcion" => array:1 [
          "en" => "Clinical and analytical data sheet"
        ]
      ]
      3 => array:8 [
        "identificador" => "mmc4"
        "etiqueta" => "Fig. 1"
        "tipo" => "MULTIMEDIAECOMPONENTE"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "copyright" => "Elsevier Espa&#241;a"
        "Ecomponente" => array:2 [
          "fichero" => "10372_108_10776_en_w4777105862310372_18107_2740_es_10372_465_2740_es_figura_1_en_copy1.doc"
          "ficheroTamanyo" => 60928
        ]
        "descripcion" => array:1 [
          "en" => "Case and control recruitment."
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "Bibliography"
      "seccion" => array:1 [
        0 => array:1 [
          "bibliografiaReferencia" => array:50 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "\u{A0}"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Luft FC. Hypertensive nephrosclerosis: update. Curr Opin Nephrol Hypertens 2004;13:147-54. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15202608" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib3"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "2.\u{A0}Freedman BI, Iskandar SS, Appel RG. The link between hypertension and nephrosclerosis.\u{A0} Am J Kidney Dis 1995;25:207-21. <a href="http://www.ncbi.nlm.nih.gov/pubmed/7847347" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib4"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "3.\u{A0}Marín R, Gorostidi M, Fernández-Vega F, Álvarez-Navascués R. \u{A0}Systemic and glomerular hypertension and progression of chronic renal disease: the dilemma of nephrosclerosis. Kidney Int Suppl 2005;(99):S52-S56."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib5"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "4.\u{A0}Luke RG. Hypertensive nephrosclerosis: pathogenesis and prevalence. Essential hypertension is an important cause of end-stage renal disease.\u{A0} Nephrol Dial Transplant 1999;14:2271-78."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib6"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "5.\u{A0}Marcantoni C, Ma LJ, Federspiel C, Fogo AB. Hypertensive nephrosclerosis in African Americans versus Caucasians. Kidney Int 2002;62:172-80. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12081576" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "6.\u{A0}Hill GS, Heudes D, Jacquot C, Gauthier E, Bariéty J. Morphometric evidence for impairment of renal autoregulation in advanced essential hypertension. Kidney Int 2006;69:823-31. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16518341" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "7.\u{A0}Keller G, Zimmer G, Mall G, Ritz E. Amann K. Nephron number in patients with primary hypertension. N Engl J Med 2003;348:101-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12519920" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "8.\u{A0}Hsu CY. Does non-malignant hypertension cause renal insufficiency? Evidence-based perspective. Curr Opin Nephrol Hypertens 2002;11:267-72. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11981255" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib10"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "9.\u{A0}Sarnak JA, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, et al.\u{A0}The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann Intern Med 2005;142:342-51. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15738453" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib11"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Siewert-Delle A, Ljungman S, Andersson OK, Wilhelmsen L. Does treated primary hypertension lead to end-stage renal disease? A 20-year follow-up of the Primary Prevention Study in Göteborg, Sweden. Nephrol Dial Transplant 1998;13:3084-90. <a href="http://www.ncbi.nlm.nih.gov/pubmed/9870470" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib12"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Hsu CY, McCulloch CE, Darbinian J, Go AS, Iribarren C. Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease. Arch Intern Med 2005;165:923-8. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15851645" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib13"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Zarif L, Covic A, Iyengar S, Sehgal AR, Sedor JR, Schelling JR. Inaccuracy of clinical phenotyping parameters for hypertensive nephrosclerosis. Nephrol Dial Transplant 2000;15:1801-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11071968" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib14"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, et al, for the African American Study of Kidney Disease and Hypertension Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis. A randomised controlled trial. JAMA 2001;285:2719-28. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11386927" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib15"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Wright JT, Bakris G, Greene T, Agodoa LY, Appel LJ, et al, for the African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease. JAMA 2002;288:2421-31. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12435255" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib16"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Toto RB. Hypertensive nephrosclerosis in African Americans. Kidney Int 2003;64:2331-41. <a href="http://www.ncbi.nlm.nih.gov/pubmed/14633170" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib17"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Marin R, Fernández-Vega F, Gorostidi M, Ruilope LM, Díez M, et al. Blood pressure control in patients with chronic renal insufficiency in Spain: a cross-sectional study. J Hypertens 2006;24:395-402. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16508589" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib18"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Vikse BE, Aasarød K, Bostad L, Iversen BM. Clinical prognostic factors in biopsy-proven benign nephrosclerosis. Nephrol Dial Transplant 2003;18:517-23. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12584273" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib19"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Verhave JC, Hillege HL, Burgerhof JG, Gansevoort RT, De Zeeuw D, De Jong PE; PREVEND study group. The association between atherosclerotic risk factors and renal function in the general population. Kidney Int 2005;67:1967-73. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15840045" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib20"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Tracy ER, Strong JP, Newman WP III, Malcom GT, Oalmann MC, Guzman MA. Renovasculopathies of nephrosclerosis in relation to atherosclerosis at ages 25 to 54 years. Kidney Int 1996;49:564-70. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8821845" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib21"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Appel LJ, Wright JT Jr, Greene T, Kusek JW, Lewis JB, et al. Long-term effects of renin-angiotensin system-blocking therapy and a low blood pressure goal on progression of hypertensive chronic kidney disease in African Americans. Arch Intern Med 2008;168:832-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18443258" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib22"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Norris KC, Greene T, Kopple J, Lea J, Lewis J, et al. Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease. J Am Soc Nephrol 2006;17:2928-36. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16959828" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib23"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Hallan SI, Ritz E, Lydersen S, Romundstad S, Kvenild K, Orth SR. Combining GFR and albuminuria to classify CKD improves prediction of ESRD. J Am Soc Nephrol 2009;20:1069-77. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19357254" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib24"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Segura J, Campo C, Gil P, Roldán C, Vigil L, Rodicio JL, et al.\u{A0}Development of chronic kidney disease and cardiovascular prognosis in essential hypertensive patients. J Am Soc Nephrol 2004;15:1616-22. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15153573" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib25"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Wright JR, Duggal A, Thomas R, Reeve R, Roberts IS, Kalra PA. Clinicopathological correlation in biopsy-proven atherosclerotic nephropathy: implications for renal functional outcome in atherosclerotic renovascular disease. Nephrol Dial Transplant 2001;16:765-70. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11274271" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib26"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Levin A, Djurdjev O, Barrett B, Burgess E, Carlisle E, et al. Cardiovascular disease in patients with chronic kidney disease: getting to the heart of the matter. Am J Kidney Dis 2001;38:1398-407. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11728982" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib27"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "McClellan WM, Langston RD, Presley R. Medicare patients with cardiovascular disease has a high prevalence of chronic kidney disease and a high rate of progression to end-stage renal disease. J Am Soc Nephrol 2004;15:1912-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15213281" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib28"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Menon V, Sarnak MJ. The epidemiology of chronic kidney disease stages 1 to 4 and cardiovascular disease: a high-risk combination. Am J Kidney Dis 2005;45:223-32. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15696466" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib29"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Hillege HL, Van Gilst WH, Van Veldhuisen DJ, Navis G, Grobbee DE, et al. Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: the CATS randomized trial. Eur Heart J 2003;24:412-20. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12633543" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib30"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Elsayed EF, Tighiouart H, Griffith J, Kurth T, Levey AS, et al. Cardiovascular disease and subsequent kidney disease. Arch Intern Med 2007;167:1130-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17563020" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib31"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Marín R, Fernández-Vega F, Díez Ojea B, Alcoy E, Palencia A, et al. Marcadores de progresión de enfermedad renal crónica en pacientes con con nefroesclerosis. Datos evolutivos. Estudio PRONEFROS. Nefrología 2008;28(Supl 4):48."
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib32"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Hostetter TH. Chronic kidney disease predicts cardiovascular disease. N Engl J Med 2004;351:1344-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15385664" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib33"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Iseki K, Ikemiya Y, Inoue T, Iseki C, Kinjo K, Takishita S. Significance of hyperuricemia as a risk factor for developing ESRD in a screened cohort. Am J Kidney Dis 2004;44:642-50. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15384015" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib34"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006;47:51-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16377385" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib35"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Feig DI, Kang DH, Johnson J. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-21. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18946066" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib36"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Fernández-Llama P, Poch E, Oriola J, Botey A, Coll E, et al. Angiotensin converting enzyme gene I/D polymorphism in essential hypertension and nephroangiosclerosis. Kidney Int 1998;53:1743-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/9607207" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib37"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Mallamaci F, Zuccalà A, Zoccali C, Testa A, Gaggi R, et al. The deletion polymorphism of the angiotensin-converting enzyme is associated with nephroangioesclerosis. Am J Hypertens 2000;13:433-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10821348" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib38"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, et al. MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008;40:1185-92. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18794854" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib39"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 2008;40:1175-84. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18794856" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib40"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Freedman BI, Hicks PJ, Bostrom MA, Cunningham ME, Liu Y, et al. Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are strongly associated with end-stage renal disease historically attributed to hypertension in African Americans. Kidney Int 2009;75:736-45. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19177153" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib41"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Freedman BI, Kopp JB, Winkler CA, Nelson GW, Rao DC, et al. Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with albuminuria in hypertensive African Americans: the HyperGEN study. Am J Nephrol 2009;29:626-32. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19153477" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib42"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Freedman BI, Hicks PJ, Bostrom MA, Comeau ME, Divers J, et al. Non-muscle myosin heavy chain 9 gene MYH9 associations in African Americans with clinically diagnosed type 2 diabetes mellitus-associated ESRD. Nephrol Dial Transplant 2009;24:3366-71. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19567477" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib43"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Behar DM, Rosset S, Tzur S, Selig S, Yudkovsky G, et al. African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans. Hum Mol Genet 2010;19:1816-27. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20144966" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib44"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Wang G, Lai FM, Kwan BC, Lai KB, Chow KM, Li PK, Szeto CC. Podocyte Loss in Human Hypertensive Nephrosclerosis. Am J Hypertens 2009;22:300-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19131934" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib45"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Murea M, Freedman BI. Essential hypertension and risk of nephropathy: a reappraisal. Curr Opin Nephrol Hypertens 2010;19:235-41. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20051853" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib46"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Singh N, Nainani N, Arora P, Venuto RC. CKD in MYH9-Related Disorders. Am J Kidney Dis 2009;54:732-40. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19726116" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib47"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Rao M, Balakrishnan VS. The genetic basis of kidney disease risk in African Americans: MYH9 as a new candidate gene. Am J Kidney Dis 2009;53:579-83. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19324247" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib48"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Divers J, Freedman BI. Susceptibility genes in common complex kidney disease. Curr Opin Nephrol Hypertens 2010;19:79-84. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19838113" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib49"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Freedman BI, Sedor JR. Hypertension-associated kidney disease: perhaps no more. J Am Soc Nephrol 2008;19:2047-51. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18923054" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib50"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:3 [
                  "referenciaCompleta" => "Pattaro C, Aulchenko YS, Isaacs A, Vitart V, Hayward C, Franklin CS, et al. Genome-wide linkage analysis of serum creatinine in three isolated European populations. Kidney Int 2009;76:297-306. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19387472" target="_blank">[Pubmed]</a>"
                  "contribucion" => array:1 [
                    0 => null
                  ]
                  "host" => array:1 [
                    0 => null
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/20132514/0000003000000006/v0_201502091649/X2013251410050771/v0_201502091649/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "35442"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Research Protocols"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003000000006/v0_201502091649/X2013251410050771/v0_201502091649/en/P1-E506-S2882-A10372-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251410050771?idApp=UINPBA000064"
]

Article information

ISSN: 20132514
Original language: English

DOI:10.3265/Nefrologia.pre2010.Jul.10372

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 November	9	10	19
2024 October	73	68	141
2024 September	96	53	149
2024 August	94	68	162
2024 July	63	45	108
2024 June	114	58	172
2024 May	101	56	157
2024 April	59	116	175
2024 March	66	60	126
2024 February	37	69	106
2024 January	38	43	81
2023 December	50	41	91
2023 November	45	42	87
2023 October	50	47	97
2023 September	51	42	93
2023 August	50	35	85
2023 July	56	39	95
2023 June	68	44	112
2023 May	80	34	114
2023 April	52	37	89
2023 March	64	31	95
2023 February	65	24	89
2023 January	49	32	81
2022 December	47	42	89
2022 November	71	40	111
2022 October	54	64	118
2022 September	68	54	122
2022 August	67	52	119
2022 July	50	48	98
2022 June	55	46	101
2022 May	63	48	111
2022 April	93	63	156
2022 March	88	54	142
2022 February	67	54	121
2022 January	66	37	103
2021 December	51	46	97
2021 November	45	41	86
2021 October	55	54	109
2021 September	37	27	64
2021 August	31	46	77
2021 July	32	44	76
2021 June	26	26	52
2021 May	33	38	71
2021 April	105	32	137
2021 March	67	36	103
2021 February	91	18	109
2021 January	65	17	82
2020 December	55	13	68
2020 November	61	26	87
2020 October	44	21	65
2020 September	38	10	48
2020 August	51	18	69
2020 July	71	10	81
2020 June	50	18	68
2020 May	51	16	67
2020 April	49	26	75
2020 March	35	11	46
2020 February	51	21	72
2020 January	59	16	75
2019 December	58	22	80
2019 November	47	16	63
2019 October	51	21	72
2019 September	44	21	65
2019 August	41	9	50
2019 July	57	28	85
2019 June	40	23	63
2019 May	46	19	65
2019 April	84	32	116
2019 March	59	19	78
2019 February	31	14	45
2019 January	49	28	77
2018 December	87	29	116
2018 November	111	15	126
2018 October	67	14	81
2018 September	63	10	73
2018 August	57	25	82
2018 July	50	25	75
2018 June	31	13	44
2018 May	47	11	58
2018 April	44	9	53
2018 March	30	8	38
2018 February	39	3	42
2018 January	29	6	35
2017 December	45	11	56
2017 November	33	7	40
2017 October	46	13	59
2017 September	31	10	41
2017 August	41	9	50
2017 July	68	10	78
2017 June	78	11	89
2017 May	99	14	113
2017 April	68	9	77
2017 March	66	10	76
2017 February	47	7	54
2017 January	35	9	44
2016 December	98	8	106
2016 November	109	10	119
2016 October	122	20	142
2016 September	168	11	179
2016 August	312	7	319
2016 July	257	9	266
2016 June	182	0	182
2016 May	177	0	177
2016 April	161	0	161
2016 March	132	0	132
2016 February	160	0	160
2016 January	148	0	148
2015 December	168	0	168
2015 November	144	0	144
2015 October	139	0	139
2015 September	127	0	127
2015 August	96	0	96
2015 July	76	0	76
2015 June	32	0	32
2015 May	58	0	58
2015 April	12	0	12

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter