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2.
PLoS One ; 14(3): e0213157, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30897159

RESUMO

INTRODUCTION: Patients with diabetes mellitus type 2 (DM2) are at high risk for micro- and macrovascular disease. Here, we explore the degree of traditional risk factor control in the baseline visit of a cohort of DM2 outpatients. METHODS: DIACORE (DIAbetes COhoRtE) is a prospective cohort study of 3000 adult DM2 outpatients. Here, we present results from the baseline visit. Sociodemographic and anthropometric variables, cardiovascular risk factors, comorbidities and medication were assessed by interview and medical exams. Serum-creatinine based estimated glomerular filtration rate (eGFRcrea) and urinary albumin-creatinine ratio (UACR) were determined for classification of chronic kidney disease (CKD). The proportion of patients with adequate control of traditional risk factors (blood pressure<140/90mmHg, HbA1c<7.5%, LDL<100mg/dl) was calculated in 2892 patients with non-missing data in 9 relevant variables within each KDIGO 2012 CKD class. RESULTS: In the analyzed baseline data (n = 2892, 60.2% men), mean (standard deviation) values for age, DM2 duration and HbA1c were 65.3 (9.3) years, 10.3 (8.4) years and 6.9% (1.1) respectively. Of these 2892 patients, 18.7% had CKD stage 3 or higher, 25.7% had UACR≥30mg/g. Adequate blood pressure, HbA1c and LDL control was achieved in 55.7%, 78.5% and 34.4%, respectively. In 16.4% of patients (473), all three risk factors were below recommended targets. The proportion of adequate risk factor control was similar across KDIGO eGFRcrea classes. Adequate blood pressure and HbA1c control were significantly associated with lower UACR category without and with controlling for other risk factors (p<0.0001, p = 0.0002, respectively). CONCLUSION: In our study of patients with diabetes mellitus type 2, we observed a low level of risk factor control indicating potential for risk reduction.

3.
Nat Genet ; 51(3): 452-469, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30778226

RESUMO

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.


Assuntos
Predisposição Genética para Doença/genética , Variação Genética/genética , Homeostase/genética , Lipídeos/genética , Proteínas/genética , Animais , Distribuição da Gordura Corporal/métodos , Índice de Massa Corporal , Estudos de Casos e Controles , Drosophila/genética , Exoma/genética , Feminino , Frequência do Gene/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Fatores de Risco , Relação Cintura-Quadril/métodos
4.
Sleep Med ; 54: 205-212, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30583274

RESUMO

BACKGROUND: Diabetes-associated Kidney Disease (DKD) is a common comorbidity in patients with type 2 diabetes. The present study investigates whether daytime sleeping duration in patients, ill with type 2 diabetes, is associated with DKD. METHODS: A total of 733 outpatients of the cross-sectional baseline survey of the DIACORE study were analyzed with respect to their self-reported daytime sleeping duration, assessed by a standardized questionnaire. DKD was defined as eGFR <60 ml/min/1.73 m2 and/or urinary albumin-to-creatinine-ratio (UACR) > 30 mg/g. RESULTS: Mean daytime sleeping duration was 17 ± 27 min. With increasing daytime sleeping duration a statistically significant decrease in eGFR (p = 0.002) and increase in UACR (p < 0.001) were found, respectively. Prevalence of DKD was significantly higher in patients with longer daytime sleeping duration (31% in patients not napping, 40% in patients napping less than 30 min, 47% in patients napping 30-60 min, 56% in patients napping 60 min or more; p = 0.001). After accounting for known modulators (Age, sex, BMI, waist-hip-ratio, systolic and diastolic blood pressure, physical activity, diabetes duration, HbA1c, homeostasis model assessment (HOMA-Index), nighttime sleeping duration, apnea-hypopnea-index (AHI), Epworth Sleepiness Scale (ESS)), longer daytime sleeping duration was significantly associated with impaired eGFR [B (95% CI) = -0.05 (-0.09; 0.00), p = 0.044] and increased UACR [B (95% CI) = 0.01 (0.01; 0.02), p < 0.001], respectively. CONCLUSION: Increased daytime sleeping duration is significantly associated with reduced eGFR and higher UACR, independent of known modulators of DKD. The direction of this relationship remains unclear.

5.
Sleep Med ; 48: 53-60, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29859478

RESUMO

BACKGROUND: Severe chronic vascular disease (CVD) is a major cause of co-morbidity and mortality in patients with type 2 diabetes (DM2). Sleep-disordered breathing (SDB) has been linked to CVD in the general population due to enhanced sympathetic activation, oxidative stress, endothelial dysfunction, and hypertension; however data for DM2 patients is scarce. Therefore, the aim of the present analysis to assess whether SDB is associated with CVD in patients with DM2, independent of other known associated factors. METHODS: We analyzed cross-sectional data of 679 patients with DM2 from the DIACORE-SDB sub-study for association of SDB with CVD. SDB was assessed with a validated 2-channel ambulatory monitoring device. CVD was ascertained as a previous diagnosis of peripheral artery disease (PAD), coronary artery disease (CAD), or stroke via medical records and general practitioners. RESULTS: Of the analyzed 679 patients, 228 (34%) had SDB (respiratory event index [REI] ≥15/hour); and were significantly more often affected by CVD than patients without SDB (38% vs. 23%, p < 0.01; PAD 7% vs. 2%, p = 0.01; CAD 27% vs. 18%, p = 0.01; stroke 11% vs. 6%, p = 0.07). Regression analysis accounting for known modulators of CVD, such as age, body-mass index, systolic blood pressure, duration of DM2, HbA1c, smoking status, and low-density lipoprotein showed that the REI was independently associated with CVD (OR 1.099 per 5 REI points; 95%CI = [1.024, 1.179]). CONCLUSIONS: In patients with DM2, SDB is significantly associated with CVD, independent of other known modulators of atherosclerosis.

7.
Nat Genet ; 50(5): 766-767, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29549330

RESUMO

In the version of this article originally published, one of the two authors with the name Wei Zhao was omitted from the author list and the affiliations for both authors were assigned to the single Wei Zhao in the author list. In addition, the ORCID for Wei Zhao (Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA) was incorrectly assigned to author Wei Zhou. The errors have been corrected in the HTML and PDF versions of the article.

8.
Transplantation ; 102(6): 969-977, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29470350

RESUMO

BACKGROUND: HLA-specific antibodies detected by solid phase assays are increasingly used to define unacceptable HLA antigen mismatches (UAM) before renal transplantation. The accuracy of this approach is unclear. METHODS: Day of transplant sera from 211 complement-dependent cytotoxicity crossmatch-negative patients were retrospectively analyzed for donor-specific anti-HLA antibodies (DSA) using Luminex technology. HLA were defined as UAM if DSA had mean fluorescence intensity above (I) 3000 (patients retransplanted and those with DSA against HLA class I and II) or 5000 (all other patients), (II) 5000 for HLA-A, -B, and -DR and 10 000 for HLA DQ or (III) 10 000 (all HLA). We then studied the accuracy of these algorithms to identify patients with antibody-mediated rejection (AMR) and graft loss. UAM were also determined in 256 transplant candidates and vPRA levels calculated. RESULTS: At transplantation, 67 of 211 patients had DSA. Of these, 31 (algorithm I), 24 (II) and 17 (III) had UAM. Nine (I and II) and 8 (III) of 11 early AMR episodes and 7 (I), 6 (II) and 5 (III) of 9 graft losses occurred in UAM-positive patients during 4.9 years of follow-up. Algorithms I and II identified patients with persistently lower glomerular filtration rate even in the absence of overt AMR. Of the waiting list patients, 22-33% had UAM with median virtual panel reactive antibody of 69.2% to 79.1%. CONCLUSIONS: Algorithms I and II had comparable efficacy but were superior to Algorithm III in identifying at-risk patients at an acceptable false-positive rate. However, Luminex-defined UAM significantly restrict the donor pool of affected patients, which might prolong waiting time.

9.
Nat Genet ; 50(1): 26-41, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29273807

RESUMO

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

10.
J Am Soc Nephrol ; 28(8): 2311-2321, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28360221

RESUMO

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.


Assuntos
Loci Gênicos , Plasma/química , Simportadores de Sódio-Bicarbonato/genética , Sódio/análise , Fatores de Transcrição/genética , Desequilíbrio Hidroeletrolítico/sangue , Desequilíbrio Hidroeletrolítico/genética , Idoso , Grupos de Populações Continentais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar
11.
Nephrol Dial Transplant ; 32(4): 730-737, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28339671

RESUMO

Background: Pre-transplant donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) have been associated with antibody-mediated rejection (AMR) and early kidney allograft loss. Uncertainties remain regarding the general applicability of these findings and the optimal induction therapy in DSA-positive patients. Methods: Pre-transplant sera from 174 patients receiving a crossmatch-negative kidney transplant were retrospectively analysed for DSA using Luminex technology. DSA with mean-fluorescence intensity (MFI) values above 500 were considered positive. All recipients received basiliximab induction and tacrolimus-based maintenance immunosuppression. DSA were monitored post-transplantation in patients with pre-transplant DSA. Antibody results were correlated with the incidence of rejection and graft loss. Results: In total, 61/174 patients had pre-transplant DSA. We found a strong correlation between the presence of DSA against class I and II HLA and DSA MFI greater than 10 000. Both DSA patterns independently predicted an increased risk of early AMR (odds ratio 4.24 and 4.75, respectively, P < 0.05). The risk for AMR in patients with intermediate MFI (3000-10 000) gradually increased with increasing MFI but group sizes were too small to allow for final conclusions. The risk for AMR was comparable to nonsensitized patients in patients with only class I or II HLA-DSA or MFI below 3000. 5-year allograft survival was lowest in patients with simultaneous presence of class I and II HLA-DSA and MFI above 10 000 (45%) but was comparable between patients with only HLA class I or II or no DSA (90.0, 90.0 and 88.1%, respectively). AMR was the only independent predictor of graft loss. Undetectable DSA 14 days post-transplant predicted excellent long-term outcome. Conclusion: . The favourable outcome in the majority of DSA-positive patients despite non-depleting antibody induction and the poor outcome in patients with class I and II HLA-DSA and high DSA strength call for a differentiated therapeutic approach in this patient population.


Assuntos
Rejeição de Enxerto/diagnóstico , Sobrevivência de Enxerto/imunologia , Antígenos HLA/imunologia , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Doadores de Tecidos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Teste de Histocompatibilidade , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
12.
BMC Immunol ; 18(1): 15, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28270092

RESUMO

BACKGROUND: Uncontrolled cytomegalovirus (CMV) replication in immunocompromised solid-organ transplant recipients is a clinically relevant issue and an indication of impaired CMV-specific cell-mediated immunity (CMI). Primary aim of this study was to assess the suitability of the immune monitoring tool T-Track® CMV to determine CMV-reactive CMI in a cohort of hemodialysis patients representative of patients eligible for renal transplantation. Positive and negative agreement of T-Track® CMV with CMV serology was examined in 124 hemodialysis patients, of whom 67 (54%) revealed a positive CMV serostatus. Secondary aim of the study was to evaluate T-Track® CMV performance against two unrelated CMV-specific CMI monitoring assays, QuantiFERON®-CMV and a cocktail of six class I iTAg™ MHC Tetramers. RESULTS: Positive T-Track® CMV results were obtained in 90% (60/67) of CMV-seropositive hemodialysis patients. In comparison, 73% (45/62) and 77% (40/52) positive agreement with CMV serology was achieved using QuantiFERON®-CMV and iTAg™ MHC Tetramer. Positive T-Track® CMV responses in CMV-seropositive patients were dominated by pp65-reactive cells (58/67 [87%]), while IE-1-responsive cells contributed to an improved (87% to 90%) positive agreement of T-Track® CMV with CMV serology. Interestingly, T-Track® CMV, QuantiFERON®-CMV and iTAg™ MHC Tetramers showed 79% (45/57), 87% (48/55) and 93% (42/45) negative agreement with serology, respectively, and a strong inter-assay variability. Notably, T-Track® CMV was able to detect IE-1-reactive cells in blood samples of patients with a negative CMV serology, suggesting either a previous exposure to CMV that yielded a cellular but no humoral immune response, or TCR cross-reactivity with foreign antigens, both suggesting a possible protective immunity against CMV in these patients. CONCLUSION: T-Track® CMV is a highly sensitive assay, enabling the functional assessment of CMV-responsive cells in hemodialysis patients prior to renal transplantation. T-Track® CMV thus represents a valuable immune monitoring tool to identify candidate transplant recipients potentially at increased risk for CMV-related clinical complications.


Assuntos
Infecções por Citomegalovirus/diagnóstico , Citomegalovirus/imunologia , Hospedeiro Imunocomprometido , Falência Renal Crônica/diagnóstico , Diálise Renal , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , Células Cultivadas , Estudos de Coortes , Infecções por Citomegalovirus/imunologia , Feminino , Humanos , Proteínas Imediatamente Precoces/imunologia , Imunidade Celular , Imunoensaio , Falência Renal Crônica/imunologia , Falência Renal Crônica/terapia , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Monitorização Imunológica/métodos , Variações Dependentes do Observador , Fosfoproteínas/imunologia , Sensibilidade e Especificidade , Proteínas da Matriz Viral/imunologia , Listas de Espera
13.
Ann Med ; 49(6): 487-495, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28281834

RESUMO

INTRODUCTION: Diabetes-associated kidney disease is characterized by impairment of renal function and albuminuria. The aim of the present study was to assess whether sleep-disordered breathing is associated with decreased estimated glomerular filtration rate or increased urine-albumin-to-creatinine-ratio independently from known modulators of diabetes-associated kidney disease. MATERIAL AND METHODS: Estimated glomerular filtration rate and urine-albumin-to-creatinine-ratio were determined in the baseline survey of the DIACORE-SDB substudy, a prospectively planned study of Diabetes mellitus 2 patients. As a measure of the severity of sleep-disordered breathing, the apnea-hypopnea-index was assessed using a 2-channel ambulatory SDB-monitoring device. RESULTS: A total of 679 patients (mean age 66 years, men 61%, mean body-mass-index 31.2 kg/m2) were analyzed. In multivariable linear regression models adjusting for known modulators of diabetes-associated kidney disease, such as sex, age, body-mass-index, systolic blood pressure, duration of diabetes and HbA1c, apnea-hypopnea-index [beta-estimate -0.2 ml/min/1.73 m2, 95% CI (-0.3; -0.1), p = .004], duration of diabetes and age were associated with estimated glomerular filtration rate. Apnea-hypopnea-index [beta-estimate 0.01 mg/g, 95% CI (0.00; 0.02), p = .009], duration of diabetes, HbA1c and systolic blood pressure were associated with ln(urine-albumin-to-creatinine-ratio). CONCLUSION: In patients with diabetes mellitus type 2, more severe sleep-disordered breathing is significantly associated with lower estimated glomerular filtration rate and increased albuminuria, independent of known modulators of diabetes-associated kidney disease.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/complicações , Síndromes da Apneia do Sono/etiologia , Idoso , Albuminúria/etiologia , Albuminúria/urina , Índice de Massa Corporal , Creatinina/urina , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/urina , Feminino , Taxa de Filtração Glomerular , Hemoglobina A Glicada/análise , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polissonografia , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Sono/fisiologia
14.
Nature ; 542(7640): 186-190, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28146470

RESUMO

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.


Assuntos
Estatura/genética , Frequência do Gene/genética , Variação Genética/genética , Proteínas ADAMTS/genética , Adulto , Alelos , Moléculas de Adesão Celular/genética , Feminino , Genoma Humano/genética , Glicoproteínas/genética , Glicoproteínas/metabolismo , Glicosaminoglicanos/biossíntese , Proteínas Hedgehog/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fatores Reguladores de Interferon/genética , Subunidade alfa de Receptor de Interleucina-11/genética , Masculino , Herança Multifatorial/genética , NADPH Oxidase 4 , NADPH Oxidases/genética , Fenótipo , Proteína Plasmática A Associada à Gravidez/metabolismo , Pró-Colágeno N-Endopeptidase/genética , Proteoglicanas/biossíntese , Proteólise , Receptores Androgênicos/genética , Somatomedinas/metabolismo
15.
Hypertension ; 69(2): 297-303, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28049698

RESUMO

Living kidney donation is associated with a small but significant increase in cardiovascular mortality. In addition, mildly decreased kidney function is associated with an increase of left ventricular mass and with cardiovascular disease in patients with chronic kidney disease. To investigate this association, we evaluated the impact of mildly decreased kidney function after living kidney donation on subclinical cardiac structural and functional changes. In this prospective cohort study, cardiac and renal magnetic resonance imaging and laboratory analyses were performed in 23 living kidney donors (mean age 54±10 years, 52% male) before donation and at 4 and 12 months after nephrectomy. Mean estimated glomerular filtration rate was 102±15 mL min-1 1.73 m-2 before donation and 70±13 mL min-1 1.73 m-2 at 12 months (P<0.001). Left ventricular mass increased from 112±22 to 115±23 g (P<0.001). In addition, heart rate was significantly increased (65±7 to 74±14; P=0.04). Concurrently, kidney and adrenal gland volume increased from 163±33 to 195±34 mL (P<0.001) and from 7.6±2.2 to 8.4±2.4 mL (P=0.032), respectively, as did procollagen type III (Δ0.11 ng/mL, P<0.001) and not N-terminal probrain natriuretic peptide (Δ14 pg/mL, P=0.25). The mild decrease in kidney function after living kidney donation leads to a significant but clinically negligible increase in left ventricular mass 12 months after living kidney donation. This study of a longitudinal analysis of living kidney donors provides direct evidence of a kidney-heart link.


Assuntos
Doenças Cardiovasculares/etiologia , Taxa de Filtração Glomerular/fisiologia , Ventrículos do Coração/diagnóstico por imagem , Transplante de Rim , Doadores Vivos , Insuficiência Renal Crônica/complicações , Obtenção de Tecidos e Órgãos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Feminino , Seguimentos , Alemanha/epidemiologia , Ventrículos do Coração/fisiopatologia , Humanos , Incidência , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/cirurgia , Fatores de Risco , Fatores de Tempo
16.
J Am Soc Nephrol ; 28(3): 981-994, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27920155

RESUMO

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10-7), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10-8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.


Assuntos
Exoma/genética , Taxa de Filtração Glomerular/genética , Rim/embriologia , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Son Of Sevenless/genética , Animais , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Peixe-Zebra
17.
J Am Soc Nephrol ; 28(3): 923-934, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27729571

RESUMO

The rate of decline of renal function varies significantly among individuals with CKD. To understand better the contribution of genetics to CKD progression, we performed a genome-wide association study among participants in the Chronic Renal Insufficiency Cohort Study. Our outcome of interest was CKD progression measured as change in eGFR over time among 1331 blacks and 1476 whites with CKD. We stratified all analyses by race and subsequently, diabetes status. Single-nucleotide polymorphisms (SNPs) that surpassed a significance threshold of P<1×10-6 for association with eGFR slope were selected as candidates for follow-up and secondarily tested for association with proteinuria and time to ESRD. We identified 12 such SNPs among black patients and six such SNPs among white patients. We were able to conduct follow-up analyses of three candidate SNPs in similar (replication) cohorts and eight candidate SNPs in phenotype-related (validation) cohorts. Among blacks without diabetes, rs653747 in LINC00923 replicated in the African American Study of Kidney Disease and Hypertension cohort (discovery P=5.42×10-7; replication P=0.039; combined P=7.42×10-9). This SNP also associated with ESRD (hazard ratio, 2.0 (95% confidence interval, 1.5 to 2.7); P=4.90×10-6). Similarly, rs931891 in LINC00923 associated with eGFR decline (P=1.44×10-4) in white patients without diabetes. In summary, SNPs in LINC00923, an RNA gene expressed in the kidney, significantly associated with CKD progression in individuals with nondiabetic CKD. However, the lack of equivalent cohorts hampered replication for most discovery loci. Further replication of our findings in comparable study populations is warranted.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Progressão da Doença , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla , Insuficiência Renal Crônica/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
Lancet ; 388(10048): 940-1, 2016 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-27452609
19.
Dtsch Med Wochenschr ; 141(3): 186-9, 2016 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-26841180

RESUMO

The reduction of micro- and macrovascular end points in patients with diabetes mellitus type 2 is achieved by control of traditional risk factors such as hyperglycemia, hyperlipidemia, obesity and hypertension. However, most of the glucose lowering medication available is excreted by the kidney. Thus, in patients with diabetes-associated chronic kidney disease, the glucose lowering therapy has to account for renal function to avoid hypoglycemic episodes and other side effects such as lactic acidosis due to metformin.


Assuntos
Nefropatias Diabéticas , Acidose Láctica , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/prevenção & controle , Humanos , Hiperglicemia , Hipertensão , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Obesidade , Fatores de Risco
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