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1.
Artigo em Inglês | MEDLINE | ID: mdl-32421350

RESUMO

Vascular dysfunction plays an important role in the etiology of chronic kidney disease (CKD), and is associated with cardiovascular diseases (CVD). Sex differences in vascular function are common in clinical and non-clinical populations. However, no data exist in individuals with CKD. The following study tested the hypothesis that sex and/or aging differences exist on vascular function in patients with CKD. Endothelium dependent dilation (EDD) [measured via brachial artery flow-mediated dilation] and endothelium independent dilation (EID) [via nitroglycerin-mediated dilation] were assessed. Analyses were adjusted for several variables that could influence vascular function (diabetes, CVD, blood pressure). Women in general, had higher EDD values than men (6.5±4.9 vs. 4.4±3.4%); however, EID did not differ among these groups. In younger men and women (<55yrs), EDD and EID were higher (P<0.05) than their older (≥55yrs) counterparts (EDD: 7.0±4.1 vs. 4.4±3.8%; EID: 24.0±9.6 vs. 18.3±9.2%). Additionally, younger women exhibited a higher (P<0.05) EDD and EID compared with the younger males (EDD: 9.5±6.4 vs. 5.1±3.8%; P=0.01; EID: 24.0±9.6 vs. 18.3±9.2%). No differences in EDD and EID were present between older men and women with CKD. Diabetes independently predicted lower EID, but not EDD in men and women. Blood pressure and CVD did not predict EDD or EID. This is the first study to show significant sex differences in vascular function. Moreover, these differences are evident between younger men and women with CKD, but are abolished with age. Additional studies are needed to better understand the mechanisms that may underlie sex differences in vascular dysfunction with CKD.

2.
J Nephrol ; 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32436182

RESUMO

BACKGROUND: Lower serum bicarbonate levels are associated with an increased risk of kidney disease progression. Whether lower serum bicarbonate levels are associated with an increased risk of developing acute kidney injury (AKI) is unclear. METHODS: We included 8393 patients from the Systolic Blood Pressure Intervention Trial (SPRINT) that had baseline serum bicarbonate levels and complete data available. AKI was a predetermined adjudicated adverse event that was determined by hospital admission and discharge records with AKI as a recorded diagnosis. Serum bicarbonate was examined in clinically significant cutoffs ≤ 24, 25-28 and > 28 mEq/L, with 25-28 mEq/L as the reference group. Cox proportional hazard models were used to examine the association between serum bicarbonate and development of AKI. RESULTS: The mean (SD) age, estimated glomerular filtration rate (eGFR), and serum bicarbonate level at baseline were 68 (9) years, 77 (23) ml/min/1.73m2 and 26.3 (2.6) mEq/L, respectively. Participants with serum bicarbonate levels ≤ 24 mEq/L were more likely to be male and to have lower baseline eGFR. After a median follow-up time of 3.3 years, 293 participants developed AKI. More patients in the lower bicarbonate group developed AKI (6.1% vs 2.8% in the 25-28 mEq/L and 2.1% in the > 28 mEq/L). A bicarbonate level ≤ 24 mEq/L was associated with a significantly increased risk of AKI compared to those with a bicarbonate level of 25-28 mEq/L after full adjustment (HR 1.42, 95% CI 1.1-1.8). CONCLUSION: Lower serum bicarbonate levels are an independent risk factor for the development of AKI.

3.
Kidney Int ; 97(5): 966-979, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32081304

RESUMO

Neutrophil gelatinase associated lipocalin (NGAL, Lcn2) is the most widely studied biomarker of acute kidney injury (AKI). Previous studies have demonstrated that NGAL is produced by the kidney and released into the urine and plasma. Consequently, NGAL is currently considered a tubule specific injury marker of AKI. However, the utility of NGAL to predict AKI has been variable suggesting that other mechanisms of production are present. IL-6 is a proinflammatory cytokine increased in plasma by two hours of AKI and mediates distant organ effects. Herein, we investigated the role of IL-6 in renal and extra-renal NGAL production. Wild type mice with ischemic AKI had increased plasma IL-6, increased hepatic NGAL mRNA, increased plasma NGAL, and increased urine NGAL; all reduced in IL-6 knockout mice. Intravenous IL-6 in normal mice increased hepatic NGAL mRNA, plasma NGAL and urine NGAL. In mice with hepatocyte specific NGAL deletion (Lcn2hep-/-) and ischemic AKI, hepatic NGAL mRNA was absent, and plasma and urine NGAL were reduced. Since urine NGAL levels appear to be dependent on plasma levels, the renal handling of circulating NGAL was examined using recombinant human NGAL. After intravenous recombinant human NGAL administration to mice, human NGAL in mouse urine was detected by ELISA during proximal tubular dysfunction, but not in pre-renal azotemia. Thus, during AKI, IL-6 mediates hepatic NGAL production, hepatocytes are the primary source of plasma and urine NGAL, and plasma NGAL appears in the urine during proximal tubule dysfunction. Hence, our data change the paradigm by which NGAL should be interpreted as a biomarker of AKI.

4.
Mol Immunol ; 118: 142-152, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31884386

RESUMO

Antibody-mediated rejection (AbMR) adversely affects long-term graft survival in kidney transplantation. Currently, the diagnosis of AbMR requires a kidney biopsy, and detection of complement C4d deposition in the allograft is one of the diagnostic criteria. Complement activation also generates several soluble fragments which could potentially provide non-invasive biomarkers of the process. Furthermore, microvesicles released into the plasma from injured cells can serve as biomarkers of vascular injury. To explore whether soluble complement fragments or complement fragments bound to endothelial microvesicles can be used to non-invasively detect AbMR, we developed an in vitro model in which human endothelial cells were exposed to anti-HLA antibodies and complement sufficient serum. We found that complement fragments C4a and sC5b-9 were increased in the supernatants of cells exposed to complement-sufficient serum compared to cells treated complement-deficient serum. Furthermore, complement activation on the cell surface was associated with the release of microvesicles bearing C4 and C3 fragments. We next measured these analytes in plasma from kidney transplant recipients with biopsy-proven acute AbMR (n = 9) and compared the results with those from transplant recipients who also had impaired allograft function but who did not have AbMR (n = 30). Consistent with the in vitro results, complement fragments C4a and Ba were increased in plasma from patients with AbMR compared to control subjects (P < 0.001 and P < 0.01, respectively). Endothelial microvesicle counts were not increased in patients with AbMR, however, and the number of microvesicles with C4 and C3 bound to the surface was actually lower compared to control subjects (both P < 0.05). Our results suggest that plasma complement activation fragments may be useful as non-invasive biomarkers of antibody-mediated complement activation within the allograft. Complement-opsonized endothelial microvesicles are decreased in patients with AbMR, possibly due to enhanced clearance of microvesicles opsonized with C3 and C4 fragments.


Assuntos
Anticorpos/imunologia , Proteínas do Sistema Complemento/imunologia , Células Endoteliais/imunologia , Lesões do Sistema Vascular/imunologia , Adulto , Aloenxertos/imunologia , Biomarcadores/sangue , Biópsia , Células Cultivadas , Ativação do Complemento/imunologia , Feminino , Rejeição de Enxerto/imunologia , Humanos , Rim/imunologia , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo/métodos
5.
Kidney Blood Press Res ; 45(1): 131-141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31865342

RESUMO

BACKGROUND: Hyperuricemia may cause acute kidney injury by activating inflammatory, pro-oxidative and vasoconstrictive pathways. In addition, radiocontrast causes an acute uricosuria, potentially leading to crystal formation. We therefore aimed to investigate the effect of urine acidity and urine uric acid level on the development of contrast-induced nephropathy (CIN) in patients undergoing elective coronary angiography. METHODS: We enrolled 175 patients who underwent elective coronary angiography. CIN was defined as a >25% increase in the serum creatinine levels relative to basal values 48-72 h after contrast use. Prior to coronary angiography and 48-72 h later, serum uric acid, urea, creatinine, bicarbonate levels, and spot uric acid to creatinine ratio (UACR) were measured. RESULTS: Of the 175 subjects included, 29 (16.6%) developed CIN. Those who developed CIN had a higher prevalence of diabetes, higher UACR (0.60 vs. 0.44, p = 0.014), higher contrast volume, and lower serum sodium level. With univariate analysis of a logistic regression model, the risk of CIN was found to be associated with diabetes (p = 0.0016, OR = 3.8 [95% CI: 1.7-8.7]), urine UACR (p = 0.0027, OR = 9.6 [95% CI: 2.2-42.2]), serum sodium (p = 0.0079, OR = 0.8 [95% CI: 0.77-0.96]), and contrast volume (p = 0.0385, OR = 1.8 [95% CI: 1.03-3.09]). In a multiple logistic regression model with stepwise method of selection, diabetes (p = 0.0120, OR = 3.2 [95% CI: 1.3-8.1]) and UACR (p = 0.0163, OR = 6.9 [95% CI: 1.4-33.4]) were the 2 risk factors finally identified. CONCLUSIONS: We have demonstrated that higher urine UACR is associated with the development of CIN in patients undergoing elective coronary angiography.

6.
J Immunol ; 203(12): 3136-3147, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732528

RESUMO

Humoral autoimmunity is central to the development of systemic lupus erythematosus (SLE). Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment-derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling. C3d and CR2 also mediate immune complex binding to follicular dendritic cells. As the development of SLE involves subversion of normal B cell tolerance checkpoints, one might expect that CR2 ligation by C3d-bound immune complexes would promote development of SLE. However, prior studies in murine models of SLE using gene-targeted Cr2-/- mice, which lack both CR2 and complement receptor 1 (CR1), have demonstrated contradictory results. As a new approach, we developed a highly specific mouse anti-mouse C3d mAb that blocks its interaction with CR2. With this novel tool, we show that disruption of the critical C3d-CR2 ligand-receptor binding step alone substantially ameliorates autoimmunity and renal disease in the MRL/lpr model of SLE.

8.
PLoS One ; 14(6): e0217935, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31233518

RESUMO

BACKGROUND: Severe acute kidney injury (AKI) is associated with subsequent infection. Whether AKI followed by a return to baseline creatinine is associated with incident infection is unknown. OBJECTIVE: We hypothesized that risk of both short and long term infection would be higher among patients with AKI and return to baseline creatinine than in propensity score matched peers without AKI in the year following a non-infectious hospital admission. DESIGN: Retrospective, propensity score matched cohort study. PARTICIPANTS: We identified 494 patients who were hospitalized between January 1, 1999 and December 31, 2009 and had AKI followed by return to baseline creatinine. These were propensity score matched to controls without AKI. MAIN MEASURES: The predictor variable was AKI defined by International Classification of Diseases, Ninth Revision (ICD-9) codes and by the Kidney Disease Improving Global Outcomes definition, with return to baseline creatinine defined as a decrease in serum creatinine level to within 10% of the baseline value within 7 days of hospital discharge. The outcome variable was incident infection defined by ICD-9 code within 1 year of hospital discharge. RESULTS: AKI followed by return to baseline creatinine was associated with a 4.5-fold increased odds ratio for infection (odds ratio 4.53 [95% CI, 2.43-8.45]; p<0.0001) within 30 days following discharge. The association between AKI and subsequent infection remained significant at 31-60 days and 91 to 365 days but not during 61-90 days following discharge. CONCLUSION: Among patients from an integrated health care delivery system, non-infectious AKI followed by return to baseline creatinine was associated with an increased odds ratio for infection in the year following discharge.


Assuntos
Lesão Renal Aguda/sangue , Lesão Renal Aguda/complicações , Creatinina/sangue , /complicações , Pontuação de Propensão , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Análise de Sobrevida
9.
Am J Hypertens ; 32(7): 649-656, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-30977767

RESUMO

BACKGROUND: High dietary sodium intake may induce a small, yet physiologically relevant rise in serum sodium concentration, which associates with increased systolic blood pressure. Cellular data suggest that this association is mediated by increased endothelial cell stiffness. We hypothesized that higher serum sodium levels were associated with greater arterial stiffness in participants in the Systolic Blood Pressure Intervention Trial (SPRINT). METHODS: Multivariable linear regression was used to examine the association between baseline serum sodium level and (i) pulse pressure (PP; n = 8,813; a surrogate measure of arterial stiffness) and (ii) carotid-femoral pulse wave velocity (CFPWV; n = 591 in an ancillary study to SPRINT). RESULTS: Baseline mean ± SD age was 68 ± 9 years and serum sodium level was 140 ± 2 mmol/L. In the PP analysis, higher serum sodium was associated with increased baseline PP in the fully adjusted model (tertile 3 [≥141 mmol] vs. tertile 2 [139-140 mmol]; ß = 0.87, 95% CI = 0.32 to 1.43). Results were similar in those with and without chronic kidney disease. In the ancillary study, higher baseline serum sodium was not associated with increased baseline CFPWV in the fully adjusted model (ß = 0.35, 95% CI = -0.14 to 0.84). CONCLUSIONS: Among adults at high risk for cardiovascular events but free from diabetes, higher serum sodium was independently associated with baseline arterial stiffness in SPRINT, as measured by PP, but not by CFPWV. These results suggest that high serum sodium may be a marker of risk for increased PP, a surrogate index of arterial stiffness.

10.
Am J Nephrol ; 49(4): 263-270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820005

RESUMO

BACKGROUND: Long-term patterns of fibroblast growth factor 23 (FGF23) are poorly characterized among dialysis patients. OBJECTIVES: To identify different FGF23 trajectories and determine clinical factors that predict distinct FGF23 trajectories and whether FGF23 trajectories differ in regard to their associations with all-cause mortality among prevalent hemodialysis patients. METHODS: The HEMO study was a randomized multicenter study evaluating the effects of high-dose vs. standard-dose and high-flux vs. low-flux hemodialysis on mortality. We measured intact FGF23 levels in stored serum samples at baseline and annually among 919 HEMO participants and identified FGF23 trajectories using group-based modeling. Logistic regression determined predictors of trajectories. Cox regression models evaluated the association between trajectory and all-cause mortality. RESULTS: We identified 5 distinct FGF23 trajectory groups during the initial 24 months: low stable, low increasing, elevated increasing, elevated decreasing, and elevated stable. In multivariable models, diabetes, high dose dialysis, no venous catheter, low serum calcium, phosphorus, and interleukin-6, no vitamin D analog use, and greater residual kidney function were associated with the low stable trajectory group compared to the elevated stable group. High flux dialysis, no venous catheter, and low serum phosphorus and 25-hydroxyvitamin D were associated with the elevated decreasing trajectory group compared to the elevated stable group. After full adjustment, the low stable trajectory group was associated with reduced mortality (hazard ratio [HR] 0.61; 95% CI -0.41-0.91) compared to the elevated stable trajectory group. CONCLUSIONS: We identified 5 distinct FGF23 trajectories over 24 months among HEMO study participants including a decreasing trajectory. The low stable FGF23 trajectory was associated with a reduced HR of all-cause mortality.

11.
Am J Kidney Dis ; 74(2): 213-223, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30803706

RESUMO

RATIONALE & OBJECTIVE: Vascular dysfunction, characterized by impaired vascular endothelial function and increased large-elastic artery stiffness, is evident early in autosomal dominant polycystic kidney disease (ADPKD) and is an important predictor of cardiovascular events and mortality. Aldosterone excess has been implicated in the development of endothelial dysfunction and arterial stiffness, in part by causing increased oxidative stress and inflammation. We hypothesized that aldosterone antagonism would reduce vascular dysfunction in patients with early-stage ADPKD. STUDY DESIGN: Prospective, randomized, controlled, double-blind, clinical trial. SETTING & PARTICIPANTS: 61 adults aged 20 to 55 years with ADPKD, estimated glomerular filtration rate ≥ 60mL/min/1.73m2, and receiving a renin-angiotensin-aldosterone system inhibitor. INTERVENTION: Spironolactone (maximum dose, 50mg/d) or placebo for 24 weeks. OUTCOMES: Change in brachial artery flow-mediated dilation (FMDBA) was the primary end point and change in carotid-femoral pulse-wave velocity (CFPWV) was the secondary end point. RESULTS: 60 participants completed the trial. Participants had a mean age of 34±10 (SD) years, 54% were women, and 84% were non-Hispanic white. Spironolactone did not change FMDBA (8.0% ± 5.5% and 7.8% ± 4.3% at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 8.4% ± 6.2% and 8.0% ± 4.6%; P=0.9for comparison of change between groups) or CFPWV (640±127 and 603±101cm/s at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 659±138 and 658±131cm/s; P=0.1). Brachial systolic blood pressure was reduced with spironolactone (median change, -6 [IQR, -15, 1] vs -2 [IQR, -7, 10] mm Hg in the placebo group; P=0.04). Spironolactone did not change the majority of circulating and/or endothelial cell markers of oxidative stress/inflammation and did not change vascular oxidative stress. LIMITATIONS: Low level of baseline vascular dysfunction; lack of aldosterone measurements. CONCLUSIONS: 24 weeks of aldosterone antagonism reduced systolic blood pressure without changing vascular function in patients with early-stage ADPKD. FUNDING: NIDDK, NIH National Center for Advancing Translational Sciences, and the Zell Family Foundation. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01853553.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30805198

RESUMO

Background: Self-titration of blood pressure (BP) medications and lifestyle modifications are effective and safe strategies to lower BP. We assessed the feasibility of implementing a pharmacist-guided, patient-driven self-titration protocol and standardized dietary counseling to improve BP in the chronic kidney disease (CKD) clinic. Methods: Adult patients seen in the CKD clinic were identified via registry screening. Inclusion criteria were as follows: a diagnosis of hypertension, average of the last 3 office BP > 150/90 mmHg, and prescribed 3 or fewer BP medications. Patients with severe hypertension were excluded. BP goals were established and patients were referred to the clinical pharmacist who provided them a BP cuff, a BP medication titration plan (based on home BP monitoring), and dietary education. The following outcomes were evaluated: appeal of the program to patients identified by the registry, patient adherence to the protocol and 6-month office BP, and provider attitudes and acceptance of the protocol. Results: Seventeen patients enrolled in the pilot, the majority recruited via clinic schedule screening. Eleven of the 17 patients completed a 6-month office follow-up visit. Three of the 11 patients met their pre-specified office BP goal. There was, however, significant improvement in 6-month office systolic and diastolic BP. Twelve of 17 patients were adherent to entering home BP in EMR. Provider satisfaction with the protocol was high. Conclusion: Our preliminary data suggest that patient-driven self-titration of BP medications is feasible and well received by providers. Future studies are needed to validate these findings and to evaluate the safety and efficacy of this approach.

13.
Clin Transplant ; 33(1): e13453, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30472740

RESUMO

BACKGROUND: We examined the risk of adverse pregnancy outcomes in primiparous kidney donors compared to matched controls. METHODS: Fifty-nine women with a history of kidney donation prior to their first pregnancy with normal renal function and no history of kidney disease, diabetes or chronic hypertension were matched 1:4 by age (within 2 years) and race to women with two kidneys using data from an integrated healthcare delivery system. Adverse pregnancy outcomes were defined as preterm delivery (delivery <37 weeks), delivery via cesarean section, gestational hypertension, preeclampsia/eclampsia, gestational diabetes, length of stay in the hospital >3 days, infant death/transfer to acute facility and low birthweight (<2500 g). RESULTS: Living kidney donors did not have a higher risk of adverse outcomes compared to matched controls. There was a trend toward an increased risk of preeclampsia/eclampsia in kidney donors but it did not reach statistical significance (Odds ratio [OR]: 2.96, 95% CI: 0.98-8.94, P = 0.06). However, in kidney donors ≤30 years of age, there was a fourfold increased risk of preeclampsia/eclampsia (OR: 4.09, 95% CI: 1.07-15.59, P = 0.04). CONCLUSION: Overall, the risk of pregnancy-associated complications following kidney donation is small but potential female kidney donors should be counseled on the possible increased risk of preeclampsia.


Assuntos
Mortalidade Infantil/tendências , Recém-Nascido de Baixo Peso , Transplante de Rim , Doadores Vivos/provisão & distribução , Pré-Eclâmpsia/epidemiologia , Complicações na Gravidez/epidemiologia , Adulto , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Gravidez , Resultado da Gravidez , Prognóstico , Fatores de Risco , Estados Unidos/epidemiologia
14.
J Neurooncol ; 141(2): 289-301, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30460631

RESUMO

INTRODUCTION: IDH1 mutation has been identified as an early genetic event driving low grade gliomas (LGGs) and it has been proven to exerts a powerful epigenetic effect. Cells containing IDH1 mutation are refractory to epigenetical reprogramming to iPSC induced by expression of Yamanaka transcription factors, a feature that we employed to study early genetic amplifications or deletions in gliomagenesis. METHODS: We made iPSC clones from freshly surgically resected IDH1 mutant LGGs by forced expression of Yamanaka transcription factors. We sequenced the IDH locus and analyzed the genetic composition of multiple iPSC clones by array-based comparative genomic hybridization (aCGH). RESULTS: We hypothesize that the primary cell pool isolated from LGG tumor contains a heterogeneous population consisting tumor cells at various stages of tumor progression including cells with early genetic lesions if any prior to acquisition of IDH1 mutation. Because cells containing IDH1 mutation are refractory to reprogramming, we predict that iPSC clones should originate only from LGG cells without IDH1 mutation, i.e. cells prior to acquisition of IDH1 mutation. As expected, we found that none of the iPSC clones contains IDH1 mutation. Further analysis by aCGH of the iPSC clones reveals that they contain regional chromosomal amplifications which are also present in the primary LGG cells. CONCLUSIONS: These results indicate that there exists a subpopulation of cells harboring gene amplification but without IDH1 mutation in the LGG primary cell pool. Further analysis of TCGA LGG database demonstrates that these regional chromosomal amplifications are also present in some cases of low grade gliomas indicating they are reoccurring lesions in glioma albeit at a low frequency. Taken together, these data suggest that regional chromosomal alterations may exist prior to the acquisition of IDH mutations in at least some cases of LGGs.


Assuntos
Neoplasias Encefálicas/genética , Amplificação de Genes , Glioma/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Isocitrato Desidrogenase/genética , Adulto , Neoplasias Encefálicas/metabolismo , Aberrações Cromossômicas , Células Clonais/fisiologia , Glioma/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Isocitrato Desidrogenase/metabolismo , Masculino
15.
Crit Care Med ; 47(4): e325-e331, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30585829

RESUMO

OBJECTIVES: Thrombocytopenia is common in critically ill patients with severe acute kidney injury and may be worsened by the use of renal replacement therapy. In this study, we evaluate the effects of renal replacement therapy on subsequent platelet values, the prognostic significance of a decrease in platelets, and potential risk factors for platelet decreases. DESIGN: Post hoc analysis of the Acute Renal Failure Trial Network Study. SETTING: The Acute Renal Failure Trial Network study was a multicenter, prospective, randomized, parallel-group trial of two strategies for renal replacement therapy in critically ill patients with acute kidney injury conducted between November 2003 and July 2007 at 27 Veterans Affairs and university-affiliated medical centers. SUBJECTS: The Acute Renal Failure Trial Network study evaluated 1,124 patients with severe acute kidney injury requiring renal replacement therapy. INTERVENTIONS: Predictor variables were thrombocytopenia at initiation of renal replacement therapy and platelet decrease following renal replacement therapy initiation. MEASUREMENTS AND MAIN RESULTS: Outcomes were mortality at 28 days, 60 days, and 1 year, renal recovery, renal replacement therapy free days, ICU-free days, and hospital-free days. Baseline thrombocytopenia in patients requiring renal replacement therapy was associated with increased mortality and was also associated with lower rates of renal recovery. A decrease in platelet values following renal replacement therapy initiation was associated with increased mortality. Continuous renal replacement therapy was not an independent predictor of worsening thrombocytopenia compared with those treated with intermittent hemodialysis. CONCLUSIONS: Baseline thrombocytopenia and platelet decrease following renal replacement therapy initiation were associated with increased mortality, and baseline thrombocytopenia was associated with decreased rates of renal recovery. Continuous renal replacement therapy did not decrease platelets compared with hemodialysis.


Assuntos
Lesão Renal Aguda/mortalidade , Estado Terminal/mortalidade , Terapia de Substituição Renal/mortalidade , Trombocitopenia/mortalidade , Lesão Renal Aguda/terapia , Estado Terminal/terapia , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Terapia de Substituição Renal/efeitos adversos , Fatores de Risco
16.
PLoS One ; 13(11): e0207024, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30408104

RESUMO

OBJECTIVE: Fructose is commonplace in Western diets and is consumed primarily through added sugars as sucrose or high fructose corn syrup. High consumption of fructose has been linked to the development of metabolic disorders, such as cardiovascular diseases. The majority of the harmful effects of fructose can be traced to its uncontrolled and rapid metabolism, primarily within the liver. It has been speculated that the formulation of fructose-containing sweeteners can have varying impacts on its adverse effects. Unfortunately, there is limited data supporting this hypothesis. The objective of this study was to examine the impact of different fructose-containing sweeteners on the intestinal, hepatic, and oral bioavailability of fructose. METHODS: Portal and femoral vein catheters were surgically implanted in male Wistar rats. Animals were gavaged with a 1 g/kg carbohydrate solution consisting of fructose, 45% glucose/55% fructose, sucrose, glucose, or water. Blood samples were then collected from the portal and systemic circulation. Fructose levels were measured and pharmacokinetic parameters were calculated. RESULTS: Compared to animals that were gavaged with 45% glucose/55% fructose or sucrose, fructose-gavaged animals had a 40% greater fructose area under the curve and a 15% greater change in maximum fructose concentration in the portal circulation. In the systemic circulation of fructose-gavaged animals, the fructose area under the curve was 17% and 24% higher and the change in the maximum fructose concentration was 15% and 30% higher than the animals that received 45% glucose/55% fructose or sucrose, respectively. After the oral administration of fructose, 45% glucose/55% fructose, and sucrose, the bioavailability of fructose was as follows: intestinal availability was 0.62, 0.53 and 0.57; hepatic availability was 0.33, 0.45 and 0.45; and oral bioavailability was 0.19, 0.23 and 0.24, respectively. CONCLUSIONS: Our studies show that the co-ingestion of glucose did not enhance fructose absorption, rather, it decreased fructose metabolism in the liver. The intestinal, hepatic, and oral bioavailability of fructose was similar between 45% glucose/55% fructose and sucrose.


Assuntos
Frutose/farmacocinética , Fígado/metabolismo , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Glicemia/análise , Frutose/sangue , Glucose/metabolismo , Meia-Vida , Mucosa Intestinal/metabolismo , Masculino , Curva ROC , Ratos , Ratos Wistar
17.
PLoS One ; 13(10): e0205831, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30356327

RESUMO

BACKGROUND: Chronic kidney disease (CKD)-mineral and bone disorder (MBD) is a systemic disorder that leads to vascular calcification and accelerated atherosclerosis. Uric acid has been shown to associate with vascular calcification and with carotid intima-media thickness (CIMT) and to suppress the 1 α-hydroxylase enzyme leading to lower 1,25-dihydroxyvitamin D (1,25(OH)2D) and higher intact parathyroid hormone (iPTH) levels. We hypothesized that lowering serum uric acid would reduce CIMT, calcification propensity, and circulating markers of CKD-MBD in CKD. METHODS: This is a post-hoc analysis of a randomized, double-blind study of 80 patients with stage 3 CKD and hyperuricemia who received allopurinol or placebo for 12 weeks. CIMT and T50 were measured as markers of vascular disease and serum calcification propensity, respectively. The following markers of CKD-MBD were measured: serum calcium, phosphorus, vitamin D metabolites, iPTH, and fibroblast growth factor-23 (FGF-23). Expression of extra-renal 1α-hydroxylase was evaluated in endothelial cells of study participants. FINDINGS: Allopurinol successfully lowered serum uric acid levels compared to placebo with an estimate of -3.3 mg/dL (95% C.I. -4.1,-2.5; p < 0.0001). After 12 weeks, however, we found no significant change in CIMT or serum T50. There was not a significant change in vitamin D metabolites, iPTH, FGF-23, or the expression of endothelial 1α-hydroxylase. CONCLUSION: These data suggest that factors other than uric acid may play a more important role in the regulation of CKD- MBD including vascular calcification and vitamin D metabolism in patients with CKD.


Assuntos
Espessura Intima-Media Carotídea , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Ácido Úrico/sangue , Calcificação Vascular/patologia , Adolescente , Adulto , Idoso , Alopurinol/uso terapêutico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/patologia , Método Duplo-Cego , Feminino , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia , Vitamina D/metabolismo , Adulto Jovem
18.
Clin J Am Soc Nephrol ; 13(10): 1463-1470, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30237219

RESUMO

BACKGROUND AND OBJECTIVES: We examined the effect of alkali replacement for metabolic acidosis on vascular endothelial function in patients with CKD. METHODS: We performed a pilot, prospective, open-label 14-week crossover study examining the effect of oral sodium bicarbonate treatment on vascular function in 20 patients with an eGFR of 15-44 ml/min per 1.73 m2 with low serum bicarbonate levels (16-21 mEq/L). Each period was 6 weeks in duration with a 2-week washout period in between. Patients were treated to goal serum bicarbonate of ≥23 mEq/L. The primary end point was change in brachial artery flow-mediated dilation (FMD) between treatment and control conditions. Secondary end points included changes in markers of inflammation, bone turnover, mineral metabolism, and calcification. RESULTS: Eighteen patients completed the study and were included in the primary efficacy analysis. The mean (SD) age and eGFR were 59 (12) years and 26 (8) ml/min per 1.73 m2, respectively. Serum bicarbonate increased significantly with sodium bicarbonate treatment (+2.7±2.9 mEq/L, P≤0.001), whereas there was no change in bicarbonate levels in the control group. FMD significantly improved after sodium bicarbonate therapy (mean±SD, FMD baseline: 4.1%±4.1%; 6 weeks: 5.2%±2.9%; P=0.04) There was no significant change in FMD in the control group (mean±SD, FMD baseline: 4.6%±3.1%; 6 weeks: 4.1%±3.4%; P=0.20). Compared with control, sodium bicarbonate treatment resulted in a significant increase in FMD (mean, 1.8%; 95% confidence interval, 0.3 to 3.3; P=0.02). There was no significant change in bone markers or serum calcification propensity with treatment. Serum phosphorus and intact fibroblast growth factor 23 increased significantly during treatment. CONCLUSIONS: Treatment of metabolic acidosis with sodium bicarbonate significantly improved vascular endothelial function in patients with stages 3b and 4 CKD.


Assuntos
Acidose/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Bicarbonato de Sódio/farmacologia , Bicarbonato de Sódio/uso terapêutico , Acidose/etiologia , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Insuficiência Renal Crônica/complicações
19.
J Am Heart Assoc ; 7(14)2018 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-30006493

RESUMO

BACKGROUND: Endothelial microparticles are associated with chronic kidney disease (CKD) and complement activation. We hypothesized that the complement pathway is activated in patients with CKD via endothelial microparticles and that complement activation correlates with endothelial dysfunction in CKD. METHODS AND RESULTS: We analyzed complement data of 30 healthy subjects, 30 patients with stage III/IV CKD, and 30 renal transplant recipients with stage III/IV CKD, evaluating the potential correlation of complement fragments with brachial artery flow-mediated dilation, Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and urinary albumin/creatinine ratio. Endothelial microparticles were characterized via proteomic analysis and compared between study groups. Complement fragment Ba was significantly increased in CKD and post-kidney transplant CKD. Plasma Ba levels correlated significantly with lower brachial artery flow-mediated dilation, lower Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and higher urinary albumin/creatinine ratio. Factor D levels were significantly higher in the plasma microparticles of patients with CKD versus healthy controls. Plasma microparticles isolated from patients with CKD and containing factor D activated the alternative pathway in vitro. CONCLUSION: The alternative complement pathway is activated in CKD and correlates with endothelial dysfunction and markers of CKD. Future studies are needed to evaluate whether endothelial microparticles with increased factor D play a pathologic role in CKD-associated vascular disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02230202.


Assuntos
Micropartículas Derivadas de Células/metabolismo , Fator B do Complemento/metabolismo , Fator D do Complemento/metabolismo , Via Alternativa do Complemento , Endotélio Vascular/fisiopatologia , Insuficiência Renal Crônica/metabolismo , Adulto , Idoso , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/fisiopatologia , Estudos de Casos e Controles , Ativação do Complemento , Complemento C4a/metabolismo , Complemento C5a/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Proteínas do Sistema Complemento/metabolismo , Células Endoteliais , Feminino , Taxa de Filtração Glomerular , Humanos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Proteômica , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/cirurgia , Índice de Gravidade de Doença , Vasodilatação
20.
Clin J Am Soc Nephrol ; 13(3): 366-374, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29439092

RESUMO

BACKGROUND AND OBJECTIVES: Mild hyponatremia is a common finding in older adults; however, the association of lower serum sodium with cognition in older adults is currently unknown. We determined whether lower normal serum sodium is associated with cognitive impairment and risk of cognitive decline in community-dwelling older men. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Five thousand four hundred thirty-five community-dwelling men aged ≥65 years who participated in Osteoporotic Fractures in Men, a cohort study with a median follow-up for cognitive function of 4.6 years, were included in this analysis. Multivariable logistic regression was used to examine the association between baseline fasting serum sodium levels and the odds of prevalent cognitive impairment (cross-sectional analysis; modified Mini-Mental Status [3MS] score <1.5 SD [<84] below or Trail Making Test Part B time >1.5 SD above the mean [>223 seconds]) and cognitive decline (prospective analysis [n=3611]; decrease in follow-up 3MS score or increase in Trails B time >1.5 SD of the mean score/time change [>9 or >67 seconds]). RESULTS: Participants were aged 74±6 years with a fasting mean serum sodium level of 141±3 mmol/L. Fifteen percent (n=274), 12% (n=225), and 13% (n=242) had prevalent cognitive impairment in tertiles 1, 2, and 3, respectively. After adjustment, lower serum sodium was associated with prevalent cognitive impairment (tertile 1 [126-140 mmol/L] versus tertile 2 [141-142 mmol/L], odds ratio [OR], 1.30; 95% confidence interval [95% CI], 1.06 to 1.61). Fourteen percent (n=159), 10% (n=125), and 13% (n=159) had cognitive decline in tertiles 1, 2, and 3, respectively. Lower serum sodium was also associated with cognitive decline (tertile 1 versus tertile 2, OR, 1.37; 95% CI, 1.06 to 1.77). Tertile 3 (143-153 mmol/L) was additionally associated with cognitive decline. Results were similar in sensitivity analyses according to clinical cut-offs and by quartiles. CONCLUSIONS: In community-dwelling older men, serum sodium between 126-140, and 126-140 or 143-153 mmol/L, are independently associated with prevalent cognitive impairment and cognitive decline, respectively.


Assuntos
Cognição , Disfunção Cognitiva/epidemiologia , Hiponatremia/sangue , Hiponatremia/psicologia , Sódio/sangue , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Vida Independente , Masculino , Testes Neuropsicológicos , Prevalência , Estados Unidos/epidemiologia
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