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1.
J Am Soc Nephrol ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511360

RESUMO

BACKGROUND: Patient-centered care for older adults with CKD requires communication about patient's values, goals of care, and treatment preferences. Eliciting this information requires tools that patients understand and that enable effective communication about their care preferences. METHODS: Nephrology clinic patients age ≥60 years with stage 4 or 5 nondialysis-dependent CKD selected one of four responses to the question, "If you had a serious illness, what would be important to you?" Condensed versions of the options were, "Live as long as possible;" "Try treatments, but do not suffer;" "Focus on comfort;" or "Unsure." Patients also completed a validated health outcome prioritization tool and an instrument determining the acceptability of end-of-life scenarios. Patient responses to the three tools were compared. RESULTS: Of the 382 participants, 35% (n=134) selected "Try treatments, but do not suffer;" 33% (n=126) chose "Focus on comfort;" 20% (n=75) opted for "Live as long as possible;" and 12% (n=47) selected "Unsure." Answers were associated with patients' first health outcome priority and acceptability of end-of-life scenarios. One third of patients with a preference to "Focus on comfort" reported that a life on dialysis would not be worth living compared with 5% of those who chose "Live as long as possible" (P<0.001). About 90% of patients agreed to share their preferences with their providers. CONCLUSIONS: Older adults with advanced CKD have diverse treatment preferences and want to share them. A single treatment preference question correlated well with longer, validated health preference tools and may provide a point of entry for discussions about patient's treatment goals.

2.
BMJ Open ; 9(8): e030661, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31471443

RESUMO

OBJECTIVE: To examine whether lifestyle factors, including sedentary time and physical activity, could independently contribute to risk of end-stage renal disease (ESRD). STUDY DESIGN: Case-cohort study. SETTING: South-eastern USA. PARTICIPANTS: The Southern Community Cohort Study recruited ~86 000 black and white participants from 2002 to 2009. We assembled a case cohort of 692 incident ESRD cases and a probability sample of 4113 participants. PREDICTORS: Sedentary time was calculated as hours/day from daily sitting activities. Physical activity was calculated as metabolic equivalent (MET)-hours/day from engagement in light, moderate and vigorous activities. OUTCOMES: Incident ESRD. RESULTS: At baseline, among the subcohort, mean (SD) age was 52 (8.6) years, and median (25th, 75th centile) estimated glomerular filtration rate (eGFR) was 102.8 (85.9-117.9) mL/min/1.73 m2. Medians (25th-75th centile) for sedentary time and physical activity were 8.0 (5.5-12.0) hours/day and 17.2 (8.7-31.9) MET-hours/day, respectively. Median follow-up was 9.4 years. We observed significant interactions between eGFR and both physical activity and sedentary behaviour (p<0.001). The partial effect plot of the association between physical activity and log relative hazard of ESRD suggests that ESRD risk decreases as physical activity increases when eGFR is 90 mL/min/1.73 m2. The inverse association is most pronounced at physical activity levels >27 MET-hours/day. High levels of sitting time were associated with increased ESRD risk only among those with reduced kidney function (eGFR ≤30 mL/min/1.73 m2); this association was attenuated after excluding the first 2 years of follow-up. CONCLUSIONS: In a population with a high prevalence of chronic kidney disease risk factors such as hypertension and diabetes, physical activity appears to be associated with reduced risk of ESRD among those with preserved kidney function. A positive association between sitting time and ESRD observed among those with advanced kidney disease is likely due to reverse causation.

3.
Am J Kidney Dis ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31537394

RESUMO

RATIONALE & OBJECTIVE: The extent of recovery of kidney function following acute kidney injury (AKI) is known to be associated with future chronic kidney disease. Less is known about how the timing of recovery affects the rate of future loss of kidney function. STUDY DESIGN: We performed a retrospective cohort study examining the independent association between the timing of recovery from moderate to severe AKI and future loss of kidney function. SETTING & PARTICIPANTS: 47,903 adult US veterans with stage 2 or 3 AKI who recovered to within 120% of baseline creatinine level within 90 days of peak injury. EXPOSURE: The timing of recovery of kidney function from peak inpatient serum creatinine level grouped into 1 to 4, 5 to 10, 11 to 30, and 31 to 90 days. OUTCOME: A sustained 40% decline in estimated glomerular filtration rate below that calculated from the last serum creatinine level available during the 90-day recovery period or kidney failure (2 outpatient estimated glomerular filtration rates<15mL/min/1.73m2, dialysis procedures > 90 days apart, kidney transplantation, or registry within the US Renal Data System). ANALYTICAL APPROACH: Time to the primary outcome was examined using multivariable Cox proportional hazards regression. RESULTS: Among 47,903 patients, 29,316 (61%), 10,360 (22%), 4,520 (9%), and 3,707 (8%) recovered within 1 to 4, 5 to 10, 11 to 30, and 31 to 90 days, respectively. With a median follow-up of 42 months, unadjusted incidence rates for the kidney outcome were 2.01, 3.55, 3.86, and 3.68 events/100 person-years, respectively. Compared with 1 to 4 days, recovery within 5 to 10, 11 to 30, and 31 to 90 days was associated with increased rates of the primary outcome: adjusted HRs were 1.33 (95% CI, 1.24-1.43), 1.41 (95% CI, 1.28-1.54), and 1.58 (95% CI, 1.43-1.75), respectively. LIMITATIONS: Predominately male population, residual confounding, and inability to make causal inferences because of the retrospective observational study design. CONCLUSIONS: The timing of recovery provides an added dimension to AKI phenotyping and prognostic information regarding the future occurrence of loss of kidney function. Studies to identify effective interventions on the timing of recovery from AKI are warranted.

4.
BMC Nephrol ; 20(1): 308, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31390993

RESUMO

INTRODUCTION: The Southern Community Cohort Study is a prospective study of low socioeconomic status (SES) blacks and whites from the southeastern US, where the burden of end-stage renal disease (ESRD) and its risk factors are high. We tested whether the 2.4-fold elevated risk of ESRD we previously observed in blacks compared to whites was explained by differences in baseline kidney function. METHODS: We conducted a case-cohort study of incident ESRD cases (n = 737) with stored blood and a probability sampled subcohort (n = 4238) and calculated estimated glomerular filtration rate (eGFR) from serum creatinine. 86% of participants were enrolled from community health centers in medically underserved areas and 14% from the general population in 12 states in the southeastern United States. Incident ESRD after entry into the cohort was ascertained by linkage of the cohort with the US Renal Data System (USRDS). RESULTS: Median (25th, 75th percentile) eGFR at baseline was 63.3 (36.0, 98.2) ml/min/1.73m2 for ESRD cases and 103.2 (86.0, 117.9) for subcohort. Black ESRD cases had higher median (25th, 75th) eGFR [63.3 (35.9, 95.9)] compared to whites [59.1 (39.4, 99.2)]. In multivariable Cox models accounting for sampling weights, baseline eGFR was a strong predictor of ESRD risk, and an interaction with race was detected (P = 0.029). The higher ESRD risk among blacks relative to whites persisted (hazard ratio: 2.58; 95% confidence interval: 1.65, 4.03) after adjustment for eGFR. CONCLUSION: In this predominantly lower SES cohort, the racial disparity in ESRD risk is not explained by differences in baseline kidney function.

5.
Nat Commun ; 10(1): 3842, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451708

RESUMO

Chronic kidney disease (CKD), defined by low estimated glomerular filtration rate (eGFR), contributes to global morbidity and mortality. Here we conduct a transethnic Genome-Wide Association Study of eGFR in 280,722 participants of the Million Veteran Program (MVP), with replication in 765,289 participants from the Chronic Kidney Disease Genetics (CKDGen) Consortium. We identify 82 previously unreported variants, confirm 54 loci, and report interesting findings including association of the sickle cell allele of betaglobin among non-Hispanic blacks. Our transcriptome-wide association study of kidney function in healthy kidney tissue identifies 36 previously unreported and nine known genes, and maps gene expression to renal cell types. In a Phenome-Wide Association Study in 192,868 MVP participants using a weighted genetic score we detect associations with CKD stages and complications and kidney stones. This investigation reinterprets the genetic architecture of kidney function to identify the gene, tissue, and anatomical context of renal homeostasis and the clinical consequences of dysregulation.

6.
Circulation ; 140(12): 1031-1040, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31337231

RESUMO

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

7.
J Palliat Med ; 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31259659

RESUMO

Background: Self-rated health (SRH) and the surprise question (SQ) capture perceptions of health and are independent risk factors for poor outcomes. Little is known about their association with physiologic and functional decline. Objective: Determine the association of SRH and SQ with frailty and functional status in older adults with chronic kidney disease (CKD) and their utility as screening tools. Design: Prospective cohort study. Setting/Subjects: Two hundred seventy-two adults, age ≥60 years, with advanced CKD seen in nephrology clinic. Measurements: Patients completed SRH and were evaluated for frailty (Fried criteria and Clinical Frailty Scale [CFS]) and functional status (Katz and Lawton indices of activities of daily living [ADLs] and instrumental ADLs [iADLs]). Providers completed the SQ. Correlations were evaluated using Spearman's rho. Results: Fifteen percent of patients were frail, 8% had ≥1 ADL deficit, and 29% had ≥1 iADL deficit. SRH and SQ were moderately correlated with frailty and iADLs. A SRH of excellent, very good, or good was predictive of nonfrail status (Fried negative predictive value [NPV]: 0.92; CFS NPV: 0.92) and preserved ADL function (NPV for ≥1 deficit: 0.96). A SQ response of 5, 4, or 3 (i.e., surprised) was predictive of nonfrail status and preserved ADL function (CFS NPV: 0.90; ADL ≥1 deficit NPV: 0.95). A SQ response of 1 or 2 had a positive predictive value of 0.64 for ≥1 iADL deficit. Conclusions: Subjective health measures may be useful screening tools for frailty and functional status.

8.
Eur J Vasc Endovasc Surg ; 57(5): 719-728, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31000459

RESUMO

BACKGROUND: The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation. METHODS: Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)2D, 24,25(OH)2D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall. RESULTS: Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)2D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups. CONCLUSIONS: Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.


Assuntos
Derivação Arteriovenosa Cirúrgica , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Minerais/sangue , Diálise Renal/métodos , Remodelação Vascular , Adulto , Idoso , Biomarcadores/sangue , Calcificação Fisiológica , Cálcio/sangue , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fosfatos/sangue , Veias/metabolismo , Veias/patologia , Vitamina D/sangue
9.
J Diabetes Complications ; 33(4): 296-301, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30795915

RESUMO

CONTEXT: Diabetic kidney disease (DKD) is the leading cause of end stage kidney disease (ESKD) and is associated with a considerably shortened lifespan. While glucose-lowering therapy targeting glycated hemoglobin (HbA1c) <7% is proven to reduce the risk of developing DKD, its effects on complications of DKD are unclear. OBJECTIVE: We examined the associations of HbA1c with risks of progression to ESKD and death within a clinic-based study of CKD. We hypothesized that higher HbA1c concentrations would be associated with increased risks of ESKD and death. DESIGN AND SETTING: We studied 618 participants from the Seattle Kidney Study (mean eGFR 42 ml/min), 308 of whom had diabetes, and tested associations of baseline HbA1c with time to a composite outcome of initiation of renal replacement therapy or death. RESULTS: During a median follow-up of 4.2 years, there were 343 instances of the composite outcome (11.5 per 100 person-years). Among participants with diabetes, in both crude and adjusted analyses, higher HbA1c levels (examined continuously or categorically) were not associated with the risk of the composite outcome (HR (95% CI): 0.99 (0.88, 1.10) per 1% additional HbA1c, p = 0.79). HbA1c was not associated with ESKD or mortality when the outcomes were examined separately, nor when stratified between insulin users and non-users. CONCLUSION: In a referred population of established DKD, higher HbA1c was not associated with higher risk of ESKD or death. These data support current recommendations to be conservative with glycemic control among patients with advanced diabetes complications, such as CKD.

10.
Nat Genet ; 51(1): 51-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578418

RESUMO

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.


Assuntos
Pressão Sanguínea/genética , Grupos Étnicos/genética , Adolescente , Animais , Feminino , Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Túbulos Renais/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Transcriptoma/genética , Regulação para Cima/genética
12.
J Am Soc Nephrol ; 29(12): 2870-2878, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30385652

RESUMO

BACKGROUND: Older adults with advanced CKD have significant pain, other symptoms, and disability. To help ensure that care is consistent with patients' values, nephrology providers should understand their patients' priorities when they make clinical recommendations. METHODS: Patients aged ≥60 years with advanced (stage 4 or 5) non-dialysis-dependent CKD receiving care at a CKD clinic completed a validated health outcome prioritization tool to ascertain their health outcome priorities. For each patient, the nephrology provider completed the same health outcome prioritization tool. Patients also answered questions to self-rate their health and completed an end-of-life scenarios instrument. We examined the associations between priorities and self-reported health status and between priorities and acceptance of common end-of-life scenarios, and also measured concordance between patients' priorities and providers' perceptions of priorities. RESULTS: Among 271 patients (median age 71 years), the top health outcome priority was maintaining independence (49%), followed by staying alive (35%), reducing pain (9%), and reducing other symptoms (6%). Nearly half of patients ranked staying alive as their third or fourth priority. There was no relationship between patients' self-rated health status and top priority, but acceptance of some end-of-life scenarios differed significantly between groups with different top priorities. Providers' perceptions about patients' top health outcome priorities were correct only 35% of the time. Patient-provider concordance for any individual health outcome ranking was similarly poor. CONCLUSIONS: Nearly half of older adults with advanced CKD ranked maintaining independence as their top heath outcome priority. Almost as many ranked being alive as their last or second-to-last priority. Nephrology providers demonstrated limited knowledge of their patients' priorities.

13.
Nat Commun ; 9(1): 4228, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315176

RESUMO

Elevated serum urate levels can cause gout, an excruciating disease with suboptimal treatment. Previous GWAS identified common variants with modest effects on serum urate. Here we report large-scale whole-exome sequencing association studies of serum urate and kidney function among ≤19,517 European ancestry and African-American individuals. We identify aggregate associations of low-frequency damaging variants in the urate transporters SLC22A12 (URAT1; p = 1.3 × 10-56) and SLC2A9 (p = 4.5 × 10-7). Gout risk in rare SLC22A12 variant carriers is halved (OR = 0.5, p = 4.9 × 10-3). Selected rare variants in SLC22A12 are validated in transport studies, confirming three as loss-of-function (R325W, R405C, and T467M) and illustrating the therapeutic potential of the new URAT1-blocker lesinurad. In SLC2A9, mapping of rare variants of large effects onto the predicted protein structure reveals new residues that may affect urate binding. These findings provide new insights into the genetic architecture of serum urate, and highlight molecular targets in SLC22A12 and SLC2A9 for lowering serum urate and preventing gout.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30334632

RESUMO

OBJECTIVE: The aim of this study was to identify and test whether AKI sub-phenotypes have prognostic and therapeutic implications. METHODS: First, latent class analysis methodology was applied independently in two critically ill populations (Discovery: n=794 and Replication: n=425) with AKI. Second, a parsimonious classification model was developed to identify AKI sub-phenotypes. Third, the classification model was applied to patients with AKI in the Vasopressin in Septic Shock (VASST: n=271) clinical trial and differences in treatment response were determined. In all three populations, AKI was defined using serum creatinine and urine output. RESULTS: A two-sub-phenotype LCA model had the best fit in both the Discovery (p = 0.004) and Replication (p= 0.004) AKI groups. The risk of 7-day renal non-recovery and 28-day mortality was greater with AKI sub-phenotype 2 (AKI-SP2) relative to AKI sub-phenotype 1 (AKI-SP1). The AKI sub-phenotypes discriminated risk for poor clinical outcomes better than the Kidney Disease Improving Global Outcomes (KDIGO) Stages of AKI. A three-variable model that included markers of endothelial dysfunction and inflammation accurately determined sub-phenotype membership (C-statistic 0.92). In VASST, vasopressin compared to norepinephrine was associated with improved 90-day mortality in AKI-SP1 (27% vs 46%, respectively; p=0.02), but no significant difference in AKI-SP2 (45% vs 49%, respectively; p=0.99) and the p-value for interaction was 0.05. CONCLUSION: This analysis identified two molecularly distinct AKI sub-phenotypes with different clinical outcomes and response to vasopressin therapy. Identification of AKI sub-phenotypes could improve risk prognostication and may be useful for predictive enrichment in clinical trials.

15.
J Am Soc Nephrol ; 29(10): 2583-2592, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30217807

RESUMO

BACKGROUND: Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences. METHODS: We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR. RESULTS: We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0×10-24), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level. CONCLUSIONS: Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

16.
Clin J Am Soc Nephrol ; 13(8): 1225-1233, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30045914

RESUMO

BACKGROUND AND OBJECTIVES: HDL particles obtained from patients on chronic hemodialysis exhibit lower cholesterol efflux capacity and are enriched in inflammatory proteins compared with those in healthy individuals. Observed alterations in HDL proteins could be due to effects of CKD, but also may be influenced by the hemodialysis procedure, which stimulates proinflammatory and prothrombotic pathways. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared HDL-associated proteins in 143 participants who initiated hemodialysis within the previous year with those of 110 participants with advanced CKD from the Hemodialysis Fistula Maturation Study. We quantified concentrations of 38 HDL-associated proteins relative to total HDL protein using targeted mass spectrometry assays that included a stable isotope-labeled internal standard. We used linear regression to compare the relative abundances of HDL-associated proteins after adjustment and required a false discovery rate q value ≤10% to control for multiple testing. We further assessed the association between hemodialysis initiation and cholesterol efflux capacity in a subset of 80 participants. RESULTS: After adjustment for demographics, comorbidities, and other clinical characteristics, eight HDL-associated proteins met the prespecified false discovery threshold for association. Recent hemodialysis initiation was associated with higher HDL-associated concentrations of serum amyloid A1, A2, and A4; hemoglobin-ß; haptoglobin-related protein; cholesterylester transfer protein; phospholipid transfer protein; and apo E. The trend for participants recently initiating hemodialysis for lower cholesterol efflux capacity compared with individuals with advanced CKD did not reach statistical significance. CONCLUSIONS: Compared with advanced CKD, hemodialysis initiation within the previous year is associated with higher concentrations of eight HDL proteins related to inflammation and lipid metabolism. Identified associations differ from those recently observed for nondialysis-requiring CKD. Hemodialysis initiation may further impair cholesterol efflux capacity. Further work is needed to clarify the clinical significance of the identified proteins with respect to cardiovascular risk. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_07_25_CJASNPodcast_18_8_W.mp3.

17.
Am J Kidney Dis ; 72(4): 519-528, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29866459

RESUMO

RATIONALE & OBJECTIVE: Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 (GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Individuals with CKD enrolled in either of 2 multicenter CKD cohort studies: the Seattle Kidney Study or C-PROBE (Clinical Phenotyping and Resource Biobank Study). EXPOSURES: Circulating GDF-15, Gal-3, and sST2 measured at baseline. OUTCOMES: Primary outcome was all-cause mortality. Secondary outcomes included hospitalization for physician-adjudicated heart failure and the atherosclerotic CVD events of myocardial infarction and cerebrovascular accident. ANALYTIC APPROACH: Cox proportional hazards models used to test the association of each biomarker with each outcome, adjusting for demographics, CVD risk factors, and kidney function. RESULTS: Among 883 participants, mean estimated glomerular filtration rate was 49±19mL/min/1.73m2. Higher GDF-15 (adjusted HR [aHR] per 1-SD higher, 1.87; 95% CI, 1.53-2.29), Gal-3 (aHR per 1-SD higher, 1.51; 95% CI, 1.36-1.78), and sST2 (aHR per 1-SD higher, 1.36; 95% CI, 1.17-1.58) concentrations were significantly associated with mortality. Only GDF-15 level was also associated with heart failure events (HR per 1-SD higher, 1.56; 95% CI, 1.12-2.16). There were no detectable associations between GDF-15, Gal-3, or sST2 concentrations and atherosclerotic CVD events. LIMITATIONS: Event rates for heart failure and atherosclerotic CVD were low. CONCLUSIONS: Adults with CKD and higher circulating GDF-15, Gal-3, and sST2 concentrations experienced greater mortality. Elevated GDF-15 concentration was also associated with an increased rate of heart failure. Further work is needed to elucidate the mechanisms linking these circulating biomarkers with CVD in patients with CKD.

18.
J Clin Endocrinol Metab ; 103(4): 1380-1392, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29325163

RESUMO

Context: Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. Objective: The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. Design: Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). Patients or Other Participants: In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. Main Outcome Measures: Blood concentrations of 25(OH)D were measured for all participants. Results: Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. Conclusions: Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.


Assuntos
Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/etnologia , Vitamina D/análogos & derivados , Adolescente , Adulto , Afro-Americanos/genética , Idoso , Índice de Massa Corporal , Criança , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia , Vitamina D/sangue , Vitamina D/genética , Deficiência de Vitamina D/genética , Adulto Jovem
19.
J Am Soc Nephrol ; 29(1): 250-259, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29038285

RESUMO

CKD is steadily increasing along with obesity worldwide. Furthermore, obesity is a proinflammatory risk factor for progression of CKD and cardiovascular disease. We tested the hypothesis that implementation of caloric restriction and aerobic exercise is feasible and can improve the proinflammatory metabolic milieu in patients with moderate to severe CKD through a pilot, randomized, 2×2 factorial design trial. Of 122 participants consented, 111 were randomized to receive caloric restriction and aerobic exercise, caloric restriction alone, aerobic exercise alone, or usual care. Of those randomized, 42% were women, 25% were diabetic, and 91% were hypertensive; 104 started intervention, and 92 completed the 4-month study. Primary outcomes were a change from baseline in absolute fat mass, body weight, plasma F2-isoprostane concentrations, and peak oxygen uptake (VO2 peak). Compared with usual care, the combined intervention led to statistically significant decreases in body weight and body fat percentage. Caloric restriction alone also led to significant decreases in these measures, but aerobic exercise alone did not. The combined intervention and each independent intervention also led to significant decreases in F2-isoprostane and IL-6 concentrations. No intervention produced significant changes in VO2 peak, kidney function, or urine albumin-to-creatinine ratio. In conclusion, 4-month dietary calorie restriction and aerobic exercise had significant, albeit clinically modest, benefits on body weight, fat mass, and markers of oxidative stress and inflammatory response in patients with moderate to severe CKD. These results suggest healthy lifestyle interventions as a nonpharmacologic strategy to improve markers of metabolic health in these patients.

20.
Ann Intern Med ; 167(9): 630-641, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29052707

RESUMO

Background: Primary aldosteronism is recognized as a severe form of renin-independent aldosteronism that results in excessive mineralocorticoid receptor (MR) activation. Objective: To investigate whether a spectrum of subclinical renin-independent aldosteronism that increases risk for hypertension exists among normotensive persons. Design: Cohort study. Setting: National community-based study. Participants: 850 untreated normotensive participants in MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity (PRA). Measurements: Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed, ≤0.50 µg/L per hour; indeterminate, 0.51 to 0.99 µg/L per hour; unsuppressed, ≥1.0 µg/L per hour), were associated with incident hypertension (defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of antihypertensive medications). Cross-sectional analyses investigated associations between aldosterone and MR activity, assessed via serum potassium and urinary fractional excretion of potassium. Results: A suppressed renin phenotype was associated with a higher rate of incident hypertension than other PRA phenotypes (incidence rates per 1000 person-years of follow-up: suppressed renin phenotype, 85.4 events [95% CI, 73.4 to 99.3 events]; indeterminate renin phenotype, 53.3 events [CI, 42.8 to 66.4 events]; unsuppressed renin phenotype, 54.5 events [CI, 41.8 to 71.0 events]). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension, whereas no association between aldosterone and hypertension was seen when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed. Limitation: Sodium and potassium were measured several years before renin and aldosterone. Conclusion: Suppression of renin and higher aldosterone concentrations in the context of this renin suppression are associated with an increased risk for hypertension and possibly also with increased MR activity. These findings suggest a clinically relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension. Primary Funding Source: National Institutes of Health.


Assuntos
Hiperaldosteronismo/complicações , Hipertensão/complicações , Idoso , Idoso de 80 Anos ou mais , Aldosterona/sangue , Estudos Transversais , Feminino , Humanos , Hiperaldosteronismo/sangue , Hipertensão/epidemiologia , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Potássio/sangue , Potássio/urina , Receptores de Mineralocorticoides/metabolismo , Renina/sangue , Fatores de Risco
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