Variant-genetic and transcript-expression analysis showed a role for the chemokine-receptor CCR5 in COVID-19 severity.

The chemokine receptor CCR5 has been implicated in COVID-19. CCR5 and its ligands are overexpressed in patients. The pharmacological targeting of CCR5 would improve the COVID-19 severity. We sought to investigate the role of the CCR5-Δ32 variant (rs333) in COVID-19. The CCR5-Δ32 was genotyped in 801 patients (353 in the intensive care unit, ICU) and 660 healthy controls, and the deletion was significantly less frequent in hospitalysed COVID-19 than in healthy controls (p = 0.01, OR = 0.66, 95%CI = 0.49-0.88). Of note, we did not find homozygotes among the patients, compared to 1% of the controls. The CCR5 transcript was measured in leukocytes from 85 patients and 40 controls. We found a significantly higher expression of the CCR5 transcript among the patients, with significant difference when comparing the non-deletion carriers (controls = 35; patients = 81; p = 0.01). ICU-patients showed non-significantly higher expression than no-ICU cases. Our study points to CCR5 as a genetic marker for COVID-19. The pharmacological targeting of CCR5 should be a promising treatment for COVID-19.

The APOB polymorphism rs1801701 A/G (p.R3638Q) is an independent risk factor for early-onset coronary artery disease: Data from a Spanish cohort.

BACKGROUND AND AIMS: Apoliprotein B (ApoB) has been associated with hypercholesterolemia and ischemic coronary disease. This study was aimed to determine the effect of two APOB gene variants in the risk of developing early-onset coronary artery disease (EO-CAD) in a Spanish population. The association of these polymorphisms with hypercholesterolemia was also analysed. METHODS AND RESULTS: The study involved a total of 889 healthy population controls (397 male) and 790 EO-CAD cases (636 male; EO-CAD was defined as male <60 years and women <65 years). All the patients had at least one vessel with angiography documented atherosclerotic lesion. Patients and controls were genotyped for the APOB variants rs1801701 A/G (p.R3638Q) and rs1367117 C/T (p.T98I). Allele and genotype frequencies were compared between the groups (patients vs. controls, hyper-vs. normo-cholesterolemia) by logistic regression. The rs1801701 was significantly associated with EO-CAD in male (OR = 1.44, 95%CI = 1.05-1.99) and female (OR = 2.22, 95%CI = 1.58-3.14). This SNP was significantly associated with hypercholesterolemia in female, with a trend in male. The association with EO-CAD was independent of hypercholesterolemia (multiple logistic regression). CONCLUSION: A common APOB polymorphism (rs1801701) was an independent risk factor for EO-CAD in our population. The risk-effect was more significant in female than in male.

Los médicos de familia y el sobrediagnóstico: el reto de elegir sabiamente / Family doctors and overdiagnosis: The challenge of choosing wisely

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Genetic Variation in the H19-IGF2 Cluster Might Confer Risk of Developing Impaired Renal Function.

The H19-IGF2 imprinted gene region could be implicated in the risk of developing impaired renal function (IRF). Our aim was to determine the association of several common H19-IGF2 variants and IRF in a cohort of elderly healthy individuals. The study involved 675 individuals >65 years of age, 184 with type 2 diabetes mellitus (T2DM), and 105 with IRF (estimated glomerular filtration rate [eGFR] <60). They were genotyped for two common H19 single nucleotide polymorphisms (SNPs) (rs2839698 and rs10732516), one H19-IGF2 intergenic indel (rs201858505), and one indel in the 3'UTR of the IGF2. For the H19 SNPs, we also determined the allele present in the methylated chromosome through genotyping the DNA digested with a methylation-sensitive endonuclease. None of the four H19-IGF2 variants was associated with IRF in our cohort. We found a significantly higher frequency of the 3'UTR IGF2 deletion (D) in the eGFR <60 group (p = 0.01; odds ratio = 1.16, 95% confidence interval = 1.10-2.51). This association was independent of age and T2DM, two strong predictors of IRF. In conclusion, a common indel variant in the 3'UTR of the IGF2 gene was associated with the risk of IRF. This association could be explained by the role of IGF2 in podocyte survival, through regulation of IGF2 expression by differential binding of miRNAs to the indel sequences. Functional studies should be necessary to clarify this issue.

Gene variants in the NF-KB pathway (NFKB1, NFKBIA, NFKBIZ) and their association with type 2 diabetes and impaired renal function.

The NF-kappaB pathway might play a role in the pathogenesis of renal disease and type 2 diabetes (T2DM). Our aim was to determine whether common polymorphisms in NF-kappaB genes were associated with impaired renal function and T2DM in a cohort of healthy elderly individuals. We studied 487 individuals, all Caucasian and aged 65-85 years. A total of 104 (21%) had impaired renal function (estimated glomerular filtration rate, eGFR < 60) and 146 (30%) were classified as diabetics. The genotypes of 4 common variants were determined through PCR-RFLP or fluorescent capillary electrophoresis. The NFKB1 variants were significantly associated with T2DM: rs7667496 p = 0.01, OR = 1.68; and rs28362491 p = 0.02, OR = 1.67. They remained significantly associated in a multiple logistic regression with age, gender, hypertension, body mass index, and cholesterol. There was a trend toward the association of these variants with eGFR < 60. The two NFKB1 variants were in linkage disequilibrium (D' = -0.86), and homozygous for the two non-risk alleles (rs7667496 CC + rs28362491 II), were significantly more common in the non-diabetics (p = 0.02). In our cohort the NFKB1 variation was an independent risk factor for developing T2DM. Additional studies to confirm this association are of special interest, as well as studies to give a functional explanation to the genetic association.

Anemia en la enfermedad renal crónica: protocolo de estudio, manejo y derivación a Nefrología / Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology

El objetivo del protocolo es conocer qué estudios deben solicitarse ante una anemia en un paciente con enfermedad renal crónica, el diagnóstico diferencial de la anemia renal, conocer y corregir otras anemias carenciales y los criterios de remisión del paciente anémico con enfermedad renal crónica a Nefrología u otras especialidades (AU)

The objective of this protocol is to know which test are needed to study an anaemia in a patient with chronic kidney disease, the differential diagnosis of renal anaemia, to know and correct other deficiency anaemias, and the criteria for referral to Nephrology or other specialties of the anaemic patient with chronic kidney disease (AU)

Anemia en la enfermedad renal crónica: protocolo de estudio, manejo y derivación a Nefrología / Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology

El objetivo del protocolo es conocer qué estudios deben solicitarse ante una anemia en un paciente con enfermedad renal crónica, el diagnóstico diferencial de la anemia renal, conocer y corregir otras anemias carenciales y los criterios de remisión del paciente anémico con enfermedad renal crónica a Nefrología u otras especialidades (AU)

The objective of this protocol is to know which test are needed to study an anaemia in a patient with chronic kidney disease, the differential diagnosis of renal anaemia, to know and correct other deficiency anaemias, and the criteria for referral to Nephrology or other specialties of the anaemic patient with chronic kidney disease (AU)

Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology. / Anemia en la enfermedad renal crónica: protocolo de estudio, manejo y derivación a Nefrología.

The objective of this protocol is to know which test are needed to study an anaemia in a patient with chronic kidney disease, the differential diagnosis of renal anaemia, to know and correct other deficiency anaemias, and the criteria for referral to Nephrology or other specialties of the anaemic patient with chronic kidney disease.

[Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology]. / Anemia en la enfermedad renal crónica: protocolo de estudio, manejo y derivación a Nefrología.

The objective of this protocol is to know which test are needed to study an anaemia in a patient with chronic kidney disease, the differential diagnosis of renal anaemia, to know and correct other deficiency anaemias, and the criteria for referral to Nephrology or other specialties of the anaemic patient with chronic kidney disease.

Screening of the Filamin C Gene in a Large Cohort of Hypertrophic Cardiomyopathy Patients.

BACKGROUND: Recent exome sequencing studies identified filamin C (FLNC) as a candidate gene for hypertrophic cardiomyopathy (HCM). Our aim was to determine the rate of FLNC candidate variants in a large cohort of HCM patients who were also sequenced for the main sarcomere genes. METHODS AND RESULTS: A total of 448 HCM patients were next generation-sequenced (semiconductor chip technology) for the MYH7, MYBPC3, TNNT2, TNNI3, ACTC1, TNNC1, MYL2, MYL3, TPM1, and FLNC genes. We also sequenced 450 healthy controls from the same population. Based on the reported population frequencies, bioinformatic criteria, and familial segregation, we identified 20 FLNC candidate variants (13 new; 1 nonsense; and 19 missense) in 22 patients. Compared with the patients, only 1 of the control's missense variants was nonreported (P=0.007; Fisher exact probability test). Based on the familial segregation and the reported functional studies, 6 of the candidate variants (in 7 patients) were finally classified as likely pathogenic, 10 as variants of uncertain significance, and 4 as likely benign. CONCLUSIONS: We provide a compelling evidence of the involvement of FLNC in the development of HCM. Most of the FLNC variants were associated with mild forms of HCM and a reduced penetrance, with few affected in the families to confirm the segregation. Our work, together with others who found FLNC variants among patients with dilated and restrictive cardiomyopathies, pointed to this gene as an important cause of structural cardiomyopathies.

KCNQ1 gene variants in the risk for type 2 diabetes and impaired renal function in the Spanish Renastur cohort.

Several common KCNQ1 gene polymorphisms have been associated with the risk of type 2 diabetes (T2DM) and diabetic nephropathy. This effect is explained by the role of the kcnq1 protein as a potassium channel that in the pancreatic beta-cells drives an electrical signal that facilitates glucose-stimulated insulin secretion. The KCNQ1 gene is also expressed in the kidney, and could thus be implicated in the risk of developing impaired renal function. To test this hypothesis, we genotyped six common KCNQ1 gene variants (three single nucleotide polymorphisms, rs2237892, rs2237895, and rs231362, and three intronic indels) in 681 healthy elderly individuals (>65 years old) from the Spanish Renastur cohort. None of the six variants was associated with T2DM (180 diabetics vs. 581 non-diabetics). The intron 12 insertion allele was associated with a reduced estimated glomerular filtration rate (eGFR<60, n = 90 vs. eGFR≥60, n = 591; II vs ID + DD genotypes, p = 0.031, OR = 2.06, 95%CI = 1.12-4.14). We also performed a next generation sequencing search of variants in the coding regions of the KCNQ1 gene in 100 individuals with the extreme eGFR values. We found two rare amino acid changes (p.K393N and p.P408A) and the 393 Asn variant was found only among diabetics (n = 4; p = 0.05). The two rare alleles were present in the two eGFR groups. Our results suggest that a common KCNQ1 intron 12 indel polymorphism is a risk factor for impaired renal function independent of T2DM. If this association is confirmed by others, further research to determine the mechanism that drives this association would be warranted.

Impact of a soy drink on climacteric symptoms: an open-label, crossover, randomized clinical trial.

OBJECTIVES: The objective of this study is to evaluate the effects of a soy drink with a high concentration of isoflavones (ViveSoy®) on climacteric symptoms. METHODS: An open-label, controlled, crossover clinical trial was conducted in 147 peri- and postmenopausal women. Eligible women were recruited from 13 Spanish health centers and randomly assigned to one of the two sequence groups (control or ViveSoy®, 500 mL per day, 15 g of protein and 50 mg of isoflavones). Each intervention phase lasted for 12 weeks with a 6-week washout period. Changes on the Menopause Rating Scale and quality of life questionnaires, as well as lipid profile, cardiovascular risk and carbohydrate and bone metabolism were assessed. Statistical analysis was performed using a mixed-effects model. RESULTS: A sample of 147 female volunteers was recruited of which 90 were evaluable. In both sequence groups, adherence to the intervention was high. Regular consumption of ViveSoy® reduced climacteric symptoms by 20.4% (p = 0.001) and symptoms in the urogenital domain by 21.3% (p < 0.05). It also improved health-related quality life by 18.1%, as per the MRS questionnaire (p <0.05). CONCLUSION: Regular consumption of ViveSoy® improves both the somatic and urogenital domain symptoms of menopause, as well as health-related quality of life in peri- and postmenopausal women.

Next generation sequencing search for uromodulin gene variants related with impaired renal function.

Uromodulin gene (UMOD) mutations have been linked to rare forms of mendelian dominant medullary cystic kidney disease and familial hyperuricemia. In addition, common single nucleotide polymorphisms in the UMOD promoter have been associated with the risk for impaired renal function and chronic kidney disease. Our main purpose was to identify UMOD variants related with impaired renal function in an elderly population. The UMOD gene was next generation sequenced in a total of 100 healthy individuals with normal or reduced renal function [measured as the rate of estimated glomerular filtration (eGFR)]. The identified missense changes and the common promoter rs12917707 polymorphism were determined in individuals with reduced (n = 88) and normal (n = 442) eGFR values. Allele and genotype frequencies were compared between the groups. We only identified a rare UMOD misense change, p.V458L, and the rare leu allele was significantly more frequent in a cohort of individuals with reduced (eGFR < 60) compared to normal eGFR (P = 0.02). The common rs12917707 polymorphism previously linked to renal function and kidney disease was not associated with impaired filtration rate in our cohort. We found a significant effect of the rare p.V458L variant on the value of estimated glomerular filtration. This finding deserves further validation in larger cohorts.

Association between the IL17RA rs4819554 polymorphism and reduced renal filtration rate in the Spanish RENASTUR cohort.

DNA variants at the genes that encode components of the IL17-pathway may contribute to the risk of impaired renal function/chronic kidney disease. Our aim was to determine whether common IL17RA single nucleotide polymorphisms (SNPs) were associated with a reduced estimated glomerular filtration rate (eGFR) in a cohort of healthy elderly individuals (n=650). We found a significantly higher frequency of SNP rs4819554 AA homozygotes among individuals with eGFR<60 ml/min/1.73 m(2) (n=90) (p=0.005, OR=2.11; 1.26-3.54), an effect that was independent of the presence of type 2 diabetes. Allele rs4819554 A had been associated to the risk of developing end stage renal disease, and was also linked to an increased expression of the IL17RA protein and higher levels of Th17 cell subsets. A scenario in which the pro-inflammatory role of the IL17-pathway contributes to kidney damage might explain the association between Il17RA polymorphisms and an impaired renal function.

Documento de consenso para la detección y manejo de la enfermedad renal crónica / Consensus document for the detection and management of chronic kidney disease

La enfermedad renal crónica (ERC) es un importante problema de salud pública que puede afectar en sus diferentes estadios a cerca del 10% de la población española y que supone una elevada morbimortalidad, así como un importante consumo de recursos al Sistema Nacional de Salud. Diez sociedades científicas involucradas en el manejo del paciente renal nos hemos puesto de acuerdo para hacer una puesta al día del anterior documento de consenso sobre ERC de 2007. El presente es la edición abreviada del documento general extenso, que puede ser consultado en las páginas Web de cada una de las sociedades firmantes. Contiene los siguientes aspectos: definición, epidemiología y factores de riesgo de la ERC; criterios de diagnóstico, evaluación y estadificación de la ERC, albuminuria y estimación del filtrado glomerular; concepto y factores de progresión; criterios de derivación a nefrología; seguimiento del paciente, actitudes y objetivos por especialidad; prevención de la nefrotoxicidad; detección del daño cardiovascular; actitudes, estilo de vida y tratamiento: manejo de la hipertensión arterial, dislipidemia, hiperglucemia, tabaquismo, obesidad, hiperuricemia, anemia, alteraciones del metabolismo mineral y óseo; seguimiento coordinado por atención primaria-otras especialidades-nefrología; manejo del paciente en tratamiento renal sustitutivo, hemodiálisis, diálisis peritoneal y trasplante renal; tratamiento paliativo de la uremia terminal. Esperamos que sirva de gran ayuda en el manejo multidisciplinar del paciente con ERC, a la vista de las recomendaciones más actualizadas (AU)

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations (AU)

Documento de consenso para la detección y manejo de la enfermedad renal crónica / Consensus document for the detection and management of chronic kidney disease

La enfermedad renal crónica (ERC) es un importante problema de salud pública que puede afectar en sus diferentes estadios a cerca del 10% de la población española y que supone una elevada morbimortalidad, así como un importante consumo de recursos al Sistema Nacional de Salud. Diez sociedades científicas involucradas en el manejo del paciente renal nos hemos puesto de acuerdo para hacer una puesta al día del anterior documento de consenso sobre ERC de 2007. El presente es la edición abreviada del documento general extenso, que puede ser consultado en las páginas Web de cada una de las sociedades firmantes. Contiene los siguientes aspectos: definición, epidemiología y factores de riesgo de la ERC; criterios de diagnóstico, evaluación y estadificación de la ERC, albuminuria y estimación del filtrado glomerular; concepto y factores de progresión; criterios de derivación a nefrología; seguimiento del paciente, actitudes y objetivos por especialidad; prevención de la nefrotoxicidad; detección del daño cardiovascular; actitudes, estilo de vida y tratamiento: manejo de la hipertensión arterial, dislipidemia, hiperglucemia, tabaquismo, obesidad, hiperuricemia, anemia, alteraciones del metabolismo mineral y óseo; seguimiento coordinado por atención primaria-otras especialidades-nefrología; manejo del paciente en tratamiento renal sustitutivo, hemodiálisis, diálisis peritoneal y trasplante renal; tratamiento paliativo de la uremia terminal. Esperamos que sirva de gran ayuda en el manejo multidisciplinar del paciente con ERC, a la vista de las recomendaciones más actualizadas

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations

Documento de consenso para la detección y manejo de la enfermedad renal crónica / Consensus document for the detection and management of chronic kidney disease

La enfermedad renal crónica (ERC) es un importante problema de salud pública que puede afectar en sus diferentes estadios a cerca del 10% de la población española y que supone una elevada morbimortalidad, así como un importante consumo de recursos al Sistema Nacional de Salud. Diez sociedades científicas involucradas en el manejo del paciente renal nos hemos puesto de acuerdo para hacer una puesta al día del anterior documento de consenso sobre ERC de 2007. El presente es la edición abreviada del documento general extenso, que puede ser consultado en las páginas Web de cada una de las sociedades firmantes. Contiene los siguientes aspectos: definición, epidemiología y factores de riesgo de la ERC; criterios de diagnóstico, evaluación y estadificación de la ERC, albuminuria y estimación del filtrado glomerular; concepto y factores de progresión; criterios de derivación a nefrología; seguimiento del paciente, actitudes y objetivos por especialidad; prevención de la nefrotoxicidad; detección del daño cardiovascular; actitudes, estilo de vida y tratamiento: manejo de la hipertensión arterial, dislipidemia, hiperglucemia, tabaquismo, obesidad, hiperuricemia, anemia, alteraciones del metabolismo mineral y óseo; seguimiento coordinado por atención primaria-otras especialidades-nefrología; manejo del paciente en tratamiento renal sustitutivo, hemodiálisis, diálisis peritoneal y trasplante renal; tratamiento paliativo de la uremia terminal. Esperamos que sirva de gran ayuda en el manejo multidisciplinar del paciente con ERC, a la vista de las recomendaciones más actualizadas

Chronic kidney disease (CKD) is an important global health problem, involving to 10% of the Spanish population, promoting high morbidity and mortality for the patient and an elevate consumption of the total health resources for the National Health System. This is a summary of an executive consensus document of ten scientific societies involved in the care of the renal patient, that actualizes the consensus document published in 2007. The central extended document can be consulted in the web page of each society. The aspects included in the document are: Concept, epidemiology and risk factors for CKD. Diagnostic criteria, evaluation and stages of CKD, albuminuria and glomerular filtration rate estimation. Progression factors for renal damage. Patient remission criteria. Follow-up and objectives of each speciality control. Nephrotoxicity prevention. Cardio-vascular damage detection. Diet, life-style and treatment attitudes: hypertension, dyslipidaemia, hyperglycemia, smoking, obesity, hyperuricemia, anemia, mineral and bone disorders. Multidisciplinary management for Primary Care, other specialities and Nephrology. Integrated management of CKD patient in haemodialysis, peritoneal dialysis and renal transplant patients. Management of the uremic patient in palliative care. We hope that this document may be of help for the multidisciplinary management of CKD patients by summarizing the most updated recommendations