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2.
Am J Nephrol ; 50(6): 411-421, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31630148

RESUMO

BACKGROUND: Residual kidney function (RKF) conveys a survival benefit among dialysis patients, but the mechanism remains unclear. Improved volume control, clearance of protein-bound and middle molecules, reduced inflammation and preserved erythropoietin and vitamin D production are among the proposed mechanisms. Preservation of RKF requires techniques to measure it accurately to be able to uncover factors that accelerate its loss and interventions that preserve it and ultimately to individualize therapy. The average of renal creatinine and urea clearance provides a superior estimate of RKF in dialysis patients, when compared with daily urine volume. However, both involve the difficult task of obtaining an accurate 24-h urine sample. SUMMARY: In this article, we first review the definition and measurement of RKF, including newly proposed markers such as serum levels of beta2-microglobulin, cystatin C and beta-trace protein. We then discuss the predictors of RKF loss in new dialysis patients. We review several strategies to preserve RKF such as renin-angiotensin-aldosterone system blockade, incremental dialysis, use of biocompatible membranes and ultrapure dialysate in hemodialysis (HD) patients, and use of biocompatible solutions in peritoneal dialysis (PD) patients. Despite their generally adverse effects on renal function, aminoglycoside antibiotics have not been shown to have adverse effects on RKF in well-hydrated patients with end-stage renal disease (ESRD). Presently, the roles of better blood pressure control, diuretic usage, diet, and dialysis modality on RKF remain to be clearly established. Key Messages: RKF is an important and favorable prognostic indicator of reduced morbidity, mortality, and higher quality of life in both PD an HD patients. Further investigation is warranted to uncover factors that protect or impair RKF. This should lead to improved quality of life and prolonged lifespan in patients with ESRD and cost-reduction through patient centeredness, individualized therapy, and precision medicine approaches.

3.
J Am Soc Nephrol ; 30(10): 2027-2036, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31383730

RESUMO

BACKGROUND: Two coding variants in the apo L1 gene (APOL1) are strongly associated with kidney disease in blacks. Kidney disease itself increases the risk of cardiovascular disease, but whether these variants have an independent direct effect on the risk of cardiovascular disease is unclear. Previous studies have had inconsistent results. METHODS: We conducted a two-stage individual participant data meta-analysis to assess the association of APOL1 kidney-risk variants with adjudicated cardiovascular disease events and death, independent of kidney measures. The analysis included 21,305 blacks from eight large cohorts. RESULTS: Over 8.9±5.0 years of follow-up, 2076 incident cardiovascular disease events occurred in the 16,216 participants who did not have cardiovascular disease at study enrollment. In fully-adjusted analyses, individuals possessing two APOL1 kidney-risk variants had similar risk of incident cardiovascular disease (coronary heart disease, myocardial infarction, stroke and heart failure; hazard ratio 1.11, 95% confidence interval, 0.96 to 1.28) compared to individuals with zero or one kidney-risk variant. The risk of coronary heart disease, myocardial infarction, stroke and heart failure considered individually was also comparable by APOL1 genotype. APOL1 genotype was also not associated with death. There was no difference in adjusted associations by level of kidney function, age, diabetes status, or body-mass index. CONCLUSIONS: In this large, two-stage individual participant data meta-analysis, APOL1 kidney-risk variants were not associated with incident cardiovascular disease or death independent of kidney measures.

4.
J Am Heart Assoc ; 8(9): e011013, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31014164

RESUMO

Background Obtaining 24-hour ambulatory blood pressure ( BP ) is recommended for the detection of masked or white-coat hypertension. Our objective was to determine whether the magnitude of the difference between ambulatory and clinic BP s has prognostic implications. Methods and Results We included 610 participants of the AASK (African American Study of Kidney Disease and Hypertension) Cohort Study who had clinic and ambulatory BPs performed in close proximity in time. We used Cox models to determine the association between the absolute systolic BP ( SBP ) difference between clinic and awake ambulatory BPs (primary predictor) and death and end-stage renal disease. Of 610 AASK Cohort Study participants, 200 (32.8%) died during a median follow-up of 9.9 years; 178 (29.2%) developed end-stage renal disease. There was a U-shaped association between the clinic and ambulatory SBP difference with risk of death, but not end-stage renal disease. A 5- to <10-mm Hg higher clinic versus awake SBP (white-coat effect) was associated with a trend toward higher (adjusted) mortality risk (adjusted hazard ratio, 1.84; 95% CI, 0.94-3.56) compared with a 0- to <5-mm Hg clinic-awake SBP difference (reference group). A ≥10-mm Hg clinic-awake SBP difference was associated with even higher mortality risk (adjusted hazard ratio, 2.31; 95% CI, 1.27-4.22). A ≥-5-mm Hg clinic-awake SBP difference was also associated with higher mortality (adjusted hazard ratio, 1.82; 95% CI, 1.05-3.15) compared with the reference group. Conclusions A U-shaped association exists between the magnitude of the difference between clinic and ambulatory SBP and mortality. Higher clinic versus ambulatory BPs (as in white-coat effect) may be associated with higher risk of death in black patients with chronic kidney disease.

5.
Sci Rep ; 9(1): 5055, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911067

RESUMO

The intra-renal dopamine (DA) system is highly expressed in the proximal tubule and contributes to Na+ and blood pressure homeostasis, as well as to the development of nephropathy. In the kidney, the enzyme DOPA Decarboxylase (DDC) originating from the circulation. We used a twin/family study design, followed by polymorphism association analysis at DDC locus to elucidate heritable influences on renal DA production. Dense single nucleotide polymorphism (SNP) genotyping across the DDC locus on chromosome 7p12 was analyzed by re-sequencing guided by trait-associated genetic markers to discover the responsible genetic variation. We also characterized kinetics of the expressed DDC mutant enzyme. Systematic polymorphism screening across the 15-Exon DDC locus revealed a single coding variant in Exon-14 that was associated with DA excretion and multiple other renal traits indicating pleiotropy. When expressed and characterized in eukaryotic cells, the 462Gln variant displayed lower Vmax (maximal rate of product formation by an enzyme) (21.3 versus 44.9 nmol/min/mg) and lower Km (substrate concentration at which half-maximal product formation is achieved by an enzyme.)(36.2 versus 46.8 µM) than the wild-type (Arg462) allele. The highly heritable DA excretion trait is substantially influenced by a previously uncharacterized common coding variant (Arg462Gln) at the DDC gene that affects multiple renal tubular and glomerular traits, and predicts accelerated functional decline in chronic kidney disease.

6.
Clin J Am Soc Nephrol ; 13(7): 1013-1021, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29903900

RESUMO

BACKGROUND AND OBJECTIVES: Black Americans with and without APOL1 kidney disease risk variants face high risk of ESKD. Soluble urokinase-type plasminogen activator receptor (suPAR), a circulating signaling protein and marker of immune activation, constitutes a promising biomarker of CKD-associated risks. We aimed to quantify the associations between serum suPAR concentration and adverse outcomes in Black Americans with and without APOL1 kidney disease risk variants, over and above iodine-125 iothalamate measured GFR and proteinuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from the African-American Study of Kidney Disease and Hypertension, a multicenter clinical trial followed by a cohort phase with a median total follow-up of 9.7 years (interquartile range, 6.5-10.9 years), we examined the associations of suPAR with CKD progression (defined as doubling of serum creatinine or ESKD), ESKD, worsening proteinuria (defined as pre-ESKD doubling of 24-hour urine protein-to-creatinine ratio to ≥220 mg/g), and all-cause death. RESULTS: At baseline, the median suPAR was 4462 pg/ml, mean measured GFR was 46 ml/min per 1.73 m2, and median 24-hour urine protein-to-creatinine ratio was 80 mg/g. After controlling for baseline demographics, randomization arm, GFR, proteinuria, APOL1 risk status, and clinical risk factors, there was a 1.26-times higher risk for CKD progression per SD higher baseline log-transformed suPAR (hazard ratio [HR], 1.26; 95% confidence interval [95% CI], 1.11 to 1.43; P<0.001). Higher suPAR was also independently associated with risk of ESKD (HR, 1.36; 95% CI, 1.17 to 1.58; P<0.001) and death (HR, 1.25; 95% CI, 1.08 to 1.45; P=0.003). suPAR was only associated with worsening proteinuria in patients with two APOLI risk alleles (HR, 1.46; 95% CI, 1.08 to 1.99; P=0.02). CONCLUSIONS: Higher suPAR was associated with various adverse outcomes in Black Americans with CKD, with and without APOL1 kidney disease risk variants, independently of proteinuria and GFR.


Assuntos
Afro-Americanos , Receptores de Ativador de Plasminogênio Tipo Uroquinase/sangue , Insuficiência Renal Crônica/sangue , Apolipoproteína L1/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
7.
J Am Soc Nephrol ; 29(7): 1939-1947, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29777021

RESUMO

Background Metabolite levels reflect physiologic homeostasis and may serve as biomarkers of disease progression. Identifying metabolites associated with APOL1 risk alleles-genetic variants associated with CKD risk commonly present in persons of African descent-may reveal novel markers of CKD progression relevant to other populations.Methods We evaluated associations between the number of APOL1 risk alleles and 760 serum metabolites identified via untargeted profiling in participants of the African American Study of Kidney Disease and Hypertension (AASK) (n=588; Bonferroni significance threshold P<6.5×10-5) and replicated findings in 678 black participants with CKD in BioMe, an electronic medical record-linked biobank. We tested the metabolite association with CKD progression in AASK, BioMe, and the Modification of Diet in Renal Disease (MDRD) Study.Results One metabolite, 6-bromotryptophan, was significant in AASK (P=4.7×10-5) and replicated in BioMe (P=5.7×10-3) participants, with lower levels associated with more APOL1 risk alleles. Lower levels of 6-bromotryptophan were associated with CKD progression in AASK and BioMe participants and in white participants in the MDRD Study, independent of demographics and clinical characteristics, including baseline GFR (adjusted hazard ratio per two-fold higher 6-bromotryptophan level, AASK, 0.76; 95% confidence interval [95% CI], 0.64 to 0.91; BioMe, 0.61; 95% CI, 0.43 to 0.85; MDRD, 0.52; 95% CI, 0.34 to 0.79). The interaction between the APOL1 risk alleles and 6-bromotryptophan was not significant. The identity of 6-bromotryptophan was confirmed in experiments comparing its molecular signature with that of authentic standards of other bromotryptophan isomers.Conclusions Serum 6-bromotryptophan is a consistent and novel risk factor for CKD progression.


Assuntos
Apolipoproteína L1/genética , Progressão da Doença , Insuficiência Renal Crônica/sangue , Triptofano/análogos & derivados , Adulto , Afro-Americanos/genética , Idoso , Alelos , Biomarcadores/sangue , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/genética , Fatores de Risco , Triptofano/sangue
8.
Clin Kidney J ; 11(1): 130-135, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29423212

RESUMO

Oxidative stress plays a key role in the pathophysiological process of uremia and its complications, particularly in cardiovascular disease. The level of oxidative stress markers is known to increase as chronic kidney disease progresses and correlates significantly with the level of renal function. Hemodialysis and peritoneal dialysis are major modes of renal replacement therapy for end-stage renal disease patients, but unfortunately they are also accompanied by increased oxidative stress. Successful kidney transplantation, however, results in near normalization of the antioxidant status and lipid metabolism by eliminating free radicals despite the surge of oxidative stress caused by the surgical procedure and ischemic injury to the organ during the operation. This success is associated with both improved renal function, reduced cardiovascular complications and overall improved morbidity and mortality. Measuring oxidative stress markers such as malondialdehyde is promising in predicting allograft survival and delayed graft function.

9.
Clin J Am Soc Nephrol ; 12(11): 1771-1777, 2017 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-29051146

RESUMO

BACKGROUND AND OBJECTIVES: The natural history of kidney disease among blacks who carry the APOL1 high-risk variants varies, with only a subgroup progressing to ESRD. We aimed to determine whether the APOL1 risk variants are associated with incident proteinuria in the context of hypertension-attributed CKD, and whether subsequent kidney function decline after the onset of proteinuria differs by APOL1 risk status. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using Cox models, we studied the association between APOL1 risk status and incident proteinuria (defined as a doubling of urine protein-to-creatinine ratio to a level ≥0.22 g/g creatinine) among African-American Study of Kidney Disease and Hypertension (AASK) trial participants with APOL1 genotyping and without proteinuria at baseline. RESULTS: Of the 480 participants in our study, 82 (17%) had the high-risk genotypes (2 alleles), and 254 (53%) developed proteinuria over a median follow-up of 6.8 years. At baseline, mean eGFR was lower in the APOL1 high-risk group compared with the low-risk group (0 or 1 allele; 49.6 versus 53.2 ml/min per 1.73 m2, respectively; P=0.02), but median proteinuria was similar (0.04 g/g creatinine for both groups; P=0.43). Individuals with the high-risk genotypes were 1.72-fold more likely to develop incident proteinuria compared with those with the low-risk genotypes (95% confidence interval, 1.27 to 2.32), independent of age, sex, ancestry, baseline eGFR, baseline systolic BP, and randomized treatment groups. Although eGFR declined faster after the onset of proteinuria, this rate did not differ significantly by APOL1 risk status. CONCLUSIONS: Among blacks with established moderate CKD, the APOL1 high-risk variants are associated with greater risk of incident proteinuria. After proteinuria onset, kidney function declines more rapidly but does not differ by APOL1 risk status. This suggests that factors that lead to proteinuria, beyond APOL1, may additionally drive CKD progression.


Assuntos
Afro-Americanos/genética , Apolipoproteína L1/genética , Proteinúria/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Idoso , Creatinina/urina , Feminino , Seguimentos , Genótipo , Taxa de Filtração Glomerular/genética , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Proteinúria/urina , Insuficiência Renal Crônica/etiologia , Fatores de Risco
10.
Front Med (Lausanne) ; 4: 97, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28770199

RESUMO

The African American Study of Kidney Disease and Hypertension (AASK), a randomized double-blinded treatment trial, was motivated by the high rate of hypertension-related renal disease in the African-American population and the scarcity of effective therapies. This study describes a pattern-based classification approach to predict the rate of decline of kidney function using surface-enhanced laser desorption ionization/time of flight proteomic data from rapid and slow progressors classified by rate of change in glomerular filtration rate. An accurate classification model consisting of 7 out of 5,751 serum proteomic features is constructed by applying the logical analysis of data (LAD) methodology. On cross-validation by 10-folding, the model was shown to have an accuracy of 80.6 ± 0.11%, sensitivity of 78.4 ± 0.17%, and specificity of 78.5 ± 0.16%. The LAD discriminant is used to identify the patients in different risk groups. The LAD risk scores assigned to 116 AASK patients generated a receiver operating curves curve with AUC 0.899 (CI 0.845-0.953) and outperforms the risk scores assigned by proteinuria, one of the best predictors of chronic kidney disease progression.

11.
Arterioscler Thromb Vasc Biol ; 37(9): 1765-1769, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28572159

RESUMO

OBJECTIVE: Among African Americans, the apolipoprotein L1 (APOL1) risk variants have been associated with various types of kidney disease and chronic kidney disease progression. We aimed to determine whether these same risk variants also confer an increased risk for cardiovascular disease. APPROACH AND RESULTS: In a cohort of African Americans with hypertension-attributed chronic kidney disease followed for up to 12 years, we used Cox proportional hazards models to estimate the relative hazard of a composite cardiovascular disease outcome (cardiovascular death or hospitalization for myocardial infarction, cardiac revascularization procedure, heart failure, or stroke) for the APOL1 high- (2 risk variants) versus low-risk (0-1 risk variant) genotypes. We adjusted for age, sex, ancestry, smoking, heart disease history, body mass index, cholesterol, randomized treatment groups, and baseline and longitudinal estimated glomerular filtration rate, systolic blood pressure, and proteinuria. Among 693 participants with APOL1 genotyping available (23% high risk), the high-risk group had lower mean estimated glomerular filtration rate (44.7 versus 50.1 mL/min per 1.73 m2) and greater proteinuria (median 0.19 versus 0.06) compared with the low-risk group at baseline. There was no significant association between APOL1 genotypes and the composite cardiovascular disease outcome in both unadjusted (hazard ratio=1.23; 95% confidence interval: 0.83-1.81) and fully adjusted (hazard ratio=1.16; 95% confidence interval: 0.77-1.76) models; however, in using an additive model, APOL1 high-risk variants were associated with increased cardiovascular mortality. CONCLUSIONS: Among African Americans with hypertension-attributed chronic kidney disease, APOL1 risk variants were not associated with an overall risk for cardiovascular disease although some signals for cardiovascular mortality were noted.


Assuntos
Afro-Americanos/genética , Apolipoproteínas/genética , Variação Genética , Insuficiência Cardíaca/genética , Hipertensão/genética , Lipoproteínas HDL/genética , Infarto do Miocárdio/genética , Insuficiência Renal Crônica/genética , Acidente Vascular Cerebral/genética , Adulto , Apolipoproteína L1 , Distribuição de Qui-Quadrado , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Insuficiência Cardíaca/etnologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Hospitalização , Humanos , Hipertensão/etnologia , Hipertensão/mortalidade , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/terapia , Revascularização Miocárdica , Fenótipo , Prognóstico , Modelos de Riscos Proporcionais , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/terapia , Fatores de Tempo , Estados Unidos/epidemiologia
12.
Nat Med ; 23(8): 945-953, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28650456

RESUMO

Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvß3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvß3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvß3 integrin activation is a mechanism for CKD.


Assuntos
Apolipoproteínas/genética , Integrina alfaVbeta3/metabolismo , Lipoproteínas HDL/genética , Podócitos/metabolismo , Proteinúria/genética , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Insuficiência Renal Crônica/genética , Adolescente , Adulto , Afro-Americanos , Idoso , Alelos , Animais , Apolipoproteína L1 , Apolipoproteínas/metabolismo , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lipoproteínas HDL/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Proteinúria/metabolismo , Insuficiência Renal Crônica/metabolismo , Ressonância de Plasmônio de Superfície , Adulto Jovem
13.
Am J Nephrol ; 45(3): 217-225, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28135709

RESUMO

BACKGROUND: Post-procedural acute kidney injury (AKI) is associated with significantly increased short- and long-term mortalities, and renal loss. Few studies have compared the incidence of post-procedural AKI and in-hospital mortality between 2 major modalities of revascularization - coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) - and results have been inconsistent. METHODS: We generated a propensity score-matched cohort that includes a total of 286,670 hospitalizations with multi-vessel coronary disease undergoing CABG or PCI (2004-2012) from the National Inpatient Sample database. We compared incidence of AKI, AKI requiring renal replacement therapy (RRT), in-hospital mortality, hospital stay, and charges between CABG and PCI groups. RESULTS: The incidence of AKI after CABG was higher than PCI (8.9 vs. 4.5%, OR 2.05, 95% CI 1.99-2.12, p < 0.001). The incidence of AKI requiring RRT was also higher after CABG (1.1 vs. 0.5%, OR 2.14, 95% CI 1.96-2.34, p < 0.001). Likewise, in-hospital mortality was higher after CABG than PCI (2.0 vs. 1.4%, OR 1.44, 95% CI 1.35-1.52, p < 0.001). Among patients with pre-existing chronic kidney disease (stages I-IV), those undergoing CABG was associated with 2.0-2.3-fold higher odds of developing AKI than those undergoing PCI. The patients treated with CABG had a significantly longer hospital stay and higher hospital charges. CONCLUSIONS: Patients undergoing CABG are associated with (1) increased risk of developing post-procedural AKI, (2) higher likelihood of receiving RRT, and (3) worse short-term survival. Long-term renal outcome remains to be studied.


Assuntos
Lesão Renal Aguda/mortalidade , Ponte de Artéria Coronária , Mortalidade Hospitalar , Intervenção Coronária Percutânea , Enxerto Vascular , Lesão Renal Aguda/cirurgia , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/complicações , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Razão de Chances , Pontuação de Propensão , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos , United States Agency for Healthcare Research and Quality
14.
J Am Soc Nephrol ; 28(2): 671-677, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27516235

RESUMO

We recently showed an association between strict BP control and lower mortality risk during two decades of follow-up of prior participants in the Modification of Diet in Renal Disease (MDRD) trial. Here, we determined the risk of ESRD and mortality during extended follow-up of the African American Study of Kidney Disease and Hypertension (AASK) trial. We linked 1067 former AASK participants with CKD previously randomized to strict or usual BP control (mean arterial pressure ≤92 mmHg or 102-107 mmHg, respectively) to the US Renal Data System and Social Security Death Index; 397 patients had ESRD and 475 deaths occurred during a median follow-up of 14.4 years from 1995 to 2012. Compared with the usual BP arm, the strict BP arm had unadjusted and adjusted relative risks of ESRD of 0.92 (95% confidence interval [95% CI], 0.75 to 1.12) and 0.95 (95% CI, 0.78 to 1.16; P=0.64), respectively, and unadjusted and adjusted relative risks of death of 0.92 (95% CI, 0.77 to 1.10) and 0.81 (95% CI, 0.68 to 0.98; P=0.03), respectively. In meta-analyses of individual-level data from the MDRD and the AASK trials, unadjusted relative risk of ESRD was 0.88 (95% CI, 0.78 to 1.00) and unadjusted relative risk of death was 0.87 (95% CI, 0.76 to 0.99) for strict versus usual BP arms. Our findings suggest that, during long-term follow-up, strict BP control does not delay the onset of ESRD but may reduce the relative risk of death in CKD.


Assuntos
Hipertensão/complicações , Hipertensão/prevenção & controle , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/etiologia , Feminino , Humanos , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de Tempo
15.
Kidney Int ; 91(2): 443-450, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27927600

RESUMO

Although APOL1 high-risk genotype partially accounts for the increased susceptibility of blacks to chronic kidney disease (CKD), whether APOL1 associates differentially with mortality risk remains controversial. Here we evaluate the association between APOL1 genotype and risk of death and determine whether APOL1 status modifies the association between strict versus usual blood pressure control and mortality risk. We performed a retrospective analysis of the African American Study of Kidney Disease and Hypertension trial that randomized black participants with CKD to strict versus usual blood pressure control from 1995 to 2001. This included 682 participants with known APOL1 genotype (157 with high-risk genotype) previously assigned to either strict (mean arterial pressure [MAP] 92 mm Hg or less) versus usual blood pressure control (MAP 102-107 mm Hg) during the trial. During a median follow-up of 14.5 years, risk of death did not differ between individuals with high- versus low-risk APOL1 genotypes (unadjusted hazard ratio 1.00 [95% confidence interval 0.76-1.33]). However, a significant interaction was detected between the APOL1 risk group and blood pressure control strategy. In the APOL1 high-risk group, the risk of death was 42% lower comparing strict versus usual blood pressure control (0.58 [0.35-0.97]). In the APOL1 low-risk group, the risk of death comparing strict versus usual blood pressure control was not significantly different (1.09 [0.84-1.43]). Thus, strict blood pressure control during CKD associates with a lower risk of death in blacks with the high-risk CKD APOL1 genotype. Knowledge of APOL1 status could inform selection of blood pressure treatment targets in black CKD patients.


Assuntos
Anti-Hipertensivos/uso terapêutico , Apolipoproteínas/genética , Pressão Arterial/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Lipoproteínas HDL/genética , Insuficiência Renal Crônica/genética , Adulto , Afro-Americanos/genética , Apolipoproteína L1 , Pressão Arterial/genética , Feminino , Genótipo , Humanos , Hipertensão/genética , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Rim/fisiopatologia , Falência Renal Crônica/genética , Falência Renal Crônica/mortalidade , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
16.
Infect Dis Clin Pract (Baltim Md) ; 24(5): 254-260, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27885316

RESUMO

Among culture-negative endocarditis in the United States, Bartonella species are the most common cause, with Bartonella henselae and Bartonella quintana comprising the majority of cases. Kidney manifestations, particularly glomerulonephritis, are common sequelae of infectious endocarditis, with nearly half of all Bartonella patients demonstrating renal involvement. Although a pauci-immune pattern is a frequent finding in infectious endocarditis-associated glomerulonephritis, it is rarely reported in Bartonella endocarditis. Anti-neutrophil cytoplasmic antibody (ANCA) positivity can be seen with many pathogens causing endocarditis and has been previously reported with Bartonella species. In addition, ANCA-associated vasculitis can also present with renal and cardiac involvement, including noninfectious valvular vegetations and pauci-immune glomerulonephritis. Given the overlap in their clinical presentation, it is difficult to differentiate between Bartonella endocarditis and ANCA-associated vasculitis but imperative to do so to guide management decisions. We present a case of ANCA-positive Bartonella endocarditis with associated pauci-immune glomerulonephritis that was successfully treated with medical management alone.

17.
Clin Kidney J ; 9(3): 444-53, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27274832

RESUMO

BACKGROUND: In the setting of chronic kidney disease (CKD), altered extra-renal urate handling may be necessary to regulate plasma uric acid. The Remote Sensing and Signaling Hypothesis (Nigam S. What do drug transporters really do? Nat Rev Drug Discov 2015; 14: 29-44) suggests that multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters in different tissues are part of an inter-organ communication system that maintains levels of urate and other metabolites after organ injury. METHODS: Data from the Chronic Renal Insufficiency Cohort (CRIC; n = 3598) were used to study associations between serum uric acid and single nucleotide polymorphisms (SNPs) on the following uric acid transporters: ABCG2 (BRCP), SLC22A6 (OAT1), SLC22A8 (OAT3), SLC22A10 (OAT5), SLC22A11 (OAT4), SLC22A12 (URAT1), SLC22A13 (OAT10), SLC17A1-A3 (NPTs), SLC2A9 (GLUT9), ABCC2 (MRP2) and ABCC4 (MRP4). Regression models, controlling for principal components age, gender and renal function, were run separately for those of European (EA) and African ancestry (AA), and P-values corrected for multiple comparisons. A twin cohort with participants of EA and normal renal function was used for comparison. RESULTS: Among those of EA in CRIC, statistically significant signals were observed for SNPs in ABCG2 (rs4148157; beta-coefficient = 0.68; P = 4.78E-13) and SNPs in SLC2A9 (rs13125646; beta-coefficient = -0.30; P = 1.06E-5). Among those of AA, the strongest (but not statistically significant) signals were observed for SNPs in SLC2A9, followed by SNPs in ABCG2. In the twin study (normal renal function), only SNPs in SLC2A9 were significant (rs4481233; beta-coefficient=-0.45; P = 7.0E-6). In CRIC, weaker associations were also found for SLC17A3 (NPT4) and gender-specific associations found for SLC22A8 (OAT3), SLC22A11 (OAT4), and ABCC4 (MRP4). CONCLUSIONS: In patients of EA with CKD (CRIC cohort), we found striking associations between uric acid and SNPs on ABCG2, a key transporter of uric acid by intestine. Compared with ABCG2, SLC2A9 played a much less significant role in this subset of patients with CKD. SNPs in other SLC (e.g. SLC22A8 or OAT3) and ABC (e.g. ABCC4 or MRP4) genes appear to make a weak gender-dependent contribution to uric acid homeostasis in CKD. As renal urate transport is affected in the setting of declining kidney function, extra-renal ABCG2 appears to play a compensatory role-a notion consistent with animal studies and the Remote Sensing and Signaling Hypothesis. Overall, the data indicate how different urate transporters become more or less important depending on renal function, ethnicity and gender. Therapies focused on enhancing ABCG2 urate handling may be helpful in the setting of CKD and hyperuricemia.

18.
J Am Soc Nephrol ; 27(10): 3140-3152, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26940095

RESUMO

Apolipoprotein L-1 (APOL1) high-risk alleles and the glutathione-S-transferase-µ1 (GSTM1) null allele have been shown separately to associate with CKD progression in the African American Study of Kidney Disease and Hypertension (AASK) trial participants. Here, we determined combined effects of GSTM1 null and APOL1 high-risk alleles on clinical outcomes in 682 AASK participants who were classified into four groups by GSTM1 null or active genotype and APOL1 high- or low-risk genotype. We assessed survival differences among these groups by log-rank test and Cox regression adjusted for important clinical variables for time to GFR event (change in GFR of 50% or 25-ml/min per 1.73 m2 decline), incident ESRD, death, or composite outcomes. The groups differed significantly in event-free survival for incident ESRD and composite outcomes (P≤0.001 by log-rank test). Compared with the reference GSTM1 active/APOL1 low-risk group, other groups had these hazard ratios for the composite outcome of incident ESRD and change in GFR: GSTM1 active/APOL1 high-risk hazard ratio, 2.13; 95% confidence interval, 0.76 to 5.90 (P=0.15); GSTM1 null/APOL1 low-risk hazard ratio, 2.05; 95% confidence interval, 1.08 to 3.88 (P=0.03); and GSTM1 null/APOL1 high-risk hazard ratio, 3.0; 95% confidence interval, 1.51 to 5.96 (P=0.002). In conclusion, GSTM1 null and APOL1 high-risk alleles deleteriously affect CKD progression among blacks with hypertension, and subjects with both GSTM1 null and APOL1 high-risk genotypes had highest risk of adverse renal outcomes. Larger cohorts are needed to fully explore interactions of GSTM1 and APOL1 genotypes in other subgroups.


Assuntos
Apolipoproteínas/genética , Glutationa Transferase/genética , Lipoproteínas HDL/genética , Insuficiência Renal Crônica/genética , Afro-Americanos , Alelos , Apolipoproteína L1 , Estudos de Coortes , Progressão da Doença , Feminino , Genótipo , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Medição de Risco
19.
Clin J Am Soc Nephrol ; 10(12): 2128-35, 2015 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-26430087

RESUMO

BACKGROUND AND OBJECTIVES: Common apolipoprotein L1 (APOL1) variants are associated with increased risk of progressive CKD; however, not all individuals with high-risk APOL1 variants experience CKD progression. Identification of factors contributing to heterogeneity has important scientific and clinical implications. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using multivariable Cox models, we analyzed data from 693 participants in the African American Study of Kidney Disease and Hypertension to identify factors that modify the association between APOL1 genotypes and CKD progression (doubling of serum creatinine or incident ESRD). RESULTS: Participant mean age was 54 years old, median GFR was 49 ml/min per 1.73 m(2), and 23% had the APOL1 high-risk genotype (two copies of the high-risk allele). Over a mean follow-up of 7.8 years, 288 (42%) participants experienced CKD progression. As previously reported, the high-risk genotype was associated with higher risk of CKD progression compared with the low-risk genotype (hazard ratio [HR], 1.88; 95% confidence interval [95% CI], 1.46 to 2.41). Although we found some suggestion that obesity (HR, 1.48; 95% CI, 1.05 to 2.08 and HR, 2.44; 95% CI, 1.66 to 3.57 for body mass index ≥ 30 versus <30 kg/m(2); P interaction =0.04) and increased urinary excretion of urea nitrogen (HR, 1.43; 95% CI, 0.98 to 2.09 versus HR, 2.33; 95% CI, 1.65 to 3.30 for urine urea nitrogen ≥ 8 versus <8 g/d; P interaction =0.04) were associated with lower APOL1-associated risk for CKD progression, these findings were not robust in sensitivity analyses with alternative cut points. No other sociodemographic (e.g., education and income), clinical (e.g., systolic BP and smoking), or laboratory (e.g., net endogenous acid production, urinary sodium and potassium excretions, 25-hydroxy vitamin D, intact parathyroid hormone, or fibroblast growth factor 23) variables modified the association between APOL1 and CKD progression (P interaction >0.05 for each). CONCLUSIONS: Sociodemographic factors and common risk factors for CKD progression do not seem to alter APOL1-related CKD progression. Additional investigation is needed to identify nontraditional factors that may affect the association between APOL1 and progressive CKD.


Assuntos
Apolipoproteínas/genética , Interação Gene-Ambiente , Falência Renal Crônica/genética , Lipoproteínas HDL/genética , Insuficiência Renal Crônica/genética , Adulto , Afro-Americanos/genética , Apolipoproteína L1 , Biomarcadores/sangue , Creatinina/sangue , Progressão da Doença , Feminino , Frequência do Gene , Estudos de Associação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/etnologia , Incidência , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/etnologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/etnologia , Fenótipo , Modelos de Riscos Proporcionais , Fatores de Proteção , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etnologia , Fatores de Risco , Fatores Socioeconômicos , Fatores de Tempo , Estados Unidos/epidemiologia , Regulação para Cima
20.
Pharmacogenet Genomics ; 25(9): 444-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26111150

RESUMO

AIM/OBJECTIVES/BACKGROUND: Hypertension is a risk factor for cardiovascular and kidney disease and is most prevalent in African-American adults. The renin-angiotensin-aldosterone system is integral in blood pressure regulation; angiotensin-converting enzyme inhibitors such as ramipril are first-line treatment options. As decreases in angiotensin result in catecholamine release, ß-adrenergic receptor (ADRB) polymorphisms may influence blood pressure response to ramipril. METHODS: Associations between ADRB polymorphisms and blood pressure response to ramipril were analyzed in the African American Study of Kidney Disease and Hypertension, a randomized clinical trial. A total of 336 participants were included in this analysis. Six polymorphisms were analyzed here: (a) ADRB1 rs1801252 (Ser49Gly) and rs1801253 (Gly389Arg); and (b) ADRB2 rs2053044, rs1042711, rs1042713 (Arg16Gly), and rs1042714 (Gln27Glu). Time to reach a mean arterial pressure (MAP) of 107 mmHg within the first 60 days after randomization was studied using Kaplan-Meier and Cox proportional hazards modeling for univariate and adjusted analyses. RESULTS: Genotypes at rs2053044, upstream from the ADRB2 5' untranslated region, were associated with time to reach target MAP among those randomized to the usual treatment group. Participants with the GG genotype achieved target MAP on average 12.2 days (38.1%) later than in comparison with those with the A allele (P=0.01). After adjusting for covariates, those with the AA/AG genotype had 2.09 greater odds of reaching MAP of 107 mmHg or less within 60 days of treatment in comparison with those with a GG genotype (hazard ratio=2.09, 95% confidence interval=1.21-3.60). CONCLUSION: Results suggest that ADRB2 rs2053044 genotypes may be a determinant of blood pressure response to ramipril. Additional studies are needed to clarify the effect of rs2053044 and other 5' untranslated region polymorphisms on gene expression and blood pressure response to angiotensin-converting enzyme inhibitors.


Assuntos
Afro-Americanos/genética , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/genética , Receptores Adrenérgicos beta 2/genética , Regiões 5' não Traduzidas , Anlodipino/administração & dosagem , Anlodipino/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Feminino , Humanos , Hipertensão/etnologia , Masculino , Metoprolol/administração & dosagem , Metoprolol/farmacologia , Ramipril/administração & dosagem , Ramipril/farmacologia , Receptores Adrenérgicos beta 1/genética
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