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1.
Diabetes Care ; 42(8): 1454-1463, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31186299

RESUMO

OBJECTIVE: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS: Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope -3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.

2.
Hypertension ; 74(1): 83-94, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31079532

RESUMO

In patients with diabetic kidney disease (DKD), plasma renin activity is usually decreased, but there is limited information on urinary renin and its origin. Urinary renin was evaluated in samples from patients with longstanding type I diabetes mellitus and mice with streptozotocin-induced diabetes mellitus. Renin-reporter mouse model (Ren1d-Cre;mT/mG) was made diabetic with streptozotocin to examine whether the distribution of cells of the renin lineage was altered in a chronic diabetic environment. Active renin was increased in urine samples from patients with DKD (n=36), compared with those without DKD (n=38; 3.2 versus 1.3 pg/mg creatinine; P<0.001). In mice with streptozotocin-induced diabetes mellitus, urine renin was also increased compared with nondiabetic controls. By immunohistochemistry, in mice with streptozotocin-induced diabetes mellitus, juxtaglomerular apparatus and proximal tubular renin staining were reduced, whereas collecting tubule staining, by contrast, was increased. To examine the role of filtration and tubular reabsorption on urinary renin, mice were either infused with either mouse or human recombinant renin and lysine (a blocker of proximal tubular protein reabsorption). Infusion of either form of renin together with lysine markedly increased urinary renin such that it was no longer different between nondiabetic and diabetic mice. Megalin mRNA was reduced in the kidney cortex of streptozotocin-treated mice (0.70±0.09 versus 1.01±0.04 in controls, P=0.01) consistent with impaired tubular reabsorption. In Ren1d-Cre;mT/mG with streptozotocin-induced diabetes mellitus, the distribution of renin lineage cells within the kidney was similar to nondiabetic renin-reporter mice. No evidence for migration of cells of renin linage to the collecting duct in diabetic mice could be found. Renin mRNA in microdissected collecting ducts from streptozotocin-treated mice, moreover, was not significantly different than in controls, whereas in kidney cortex, largely reflecting juxtaglomerular apparatus renin, it was significantly reduced. In conclusion, in urine from patients with type 1 diabetes mellitus and DKD and from mice with streptozotocin-induced diabetes mellitus, renin is elevated. This cannot be attributed to production from cells of the renin lineage migrating to the collecting duct in a chronic hyperglycemic environment. Rather, the elevated levels of urinary renin found in DKD are best attributed to altered glomerular filteration and impaired proximal tubular reabsorption.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/urina , Túbulos Renais Coletores/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Renina/urina , Animais , Biópsia por Agulha , Estudos de Coortes , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Feminino , Taxa de Filtração Glomerular , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Distribuição Aleatória , Valores de Referência , Renina/sangue , Sensibilidade e Especificidade , Urinálise
4.
Science ; 364(6436)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30975860

RESUMO

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.


Assuntos
Adaptação Fisiológica , Astronautas , Voo Espacial , Imunidade Adaptativa , Peso Corporal , Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Dano ao DNA , Metilação de DNA , Microbioma Gastrointestinal , Instabilidade Genômica , Humanos , Masculino , Homeostase do Telômero , Fatores de Tempo , Estados Unidos , United States National Aeronautics and Space Administration
5.
J Diabetes Complications ; 32(12): 1160-1168, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30316542

RESUMO

AIMS: To determine among adolescents and young adults with youth-onset type 1 diabetes and type 2 diabetes the rates and risk factors for albuminuria regression and progression. METHODS: Data from SEARCH, a longitudinal observational study of youth-onset type 1 diabetes (N = 1316) and type 2 diabetes (N = 143) were analyzed. Urine albumin:creatinine ratio (UACR) was measured from random urine specimens at baseline and follow-up visits (mean 7 years later). Albuminuria regression was defined as halving of baseline UACR when baseline UACR was ≥30 µg/mg; progression was defined as doubling of baseline UACR when follow-up UACR was ≥30 µg/mg, respectively. Multivariable regression assessed risk factors associated with low-risk albuminuria category (combined persistently-low albuminuria and regression) versus moderate-risk albuminuria category (combined persistently-high albuminuria and progression). RESULTS: Albuminuria progression was more common in type 2 diabetes versus type 1 diabetes (15.4% versus 6.0%, p<0.001). Moderate-risk albuminuria was associated with increasing HbA1c (adjusted OR (aOR) = 1.3, 95% CI 1.1-1.6) and lack of private health insurance (aOR = 2.7, 95%CI 1.1-6.5) in type 1 diabetes; and African American race (OR = 4.6, 95% CI 1.2-14.2), lower estimated insulin sensitivity score (aOR = 2.1, 95% CI 1.4-3.3), baseline UACR (aOR = 3.2, 95% CI 1.7-5.8), and follow-up estimated glomerular filtration rate (eGFR) (10-unit increase aOR = 1.3, 95% CI 1.0, 1.5) in type 2 diabetes. CONCLUSIONS: In the first decade of diabetes duration, kidney complications in type 2 diabetes are significantly more aggressive than in type 1 diabetes and may be associated with less modifiable risk factors including race, insulin sensitivity, and eGFR. Early interventions may help reduce long-term kidney complications.


Assuntos
Albuminúria/epidemiologia , Albuminúria/patologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Adolescente , Adulto , Idade de Início , Albuminúria/complicações , Albuminúria/diagnóstico , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/patologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Prevalência , Sistema de Registros , Fatores de Risco , Estados Unidos/epidemiologia , Adulto Jovem
6.
Diabetes Care ; 41(11): 2361-2369, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30150236

RESUMO

OBJECTIVE: We examined the association of urine complement proteins with progression to end-stage renal disease (ESRD) or death in people with type 2 diabetes and proteinuric diabetic kidney disease (DKD). RESEARCH DESIGN AND METHODS: Using targeted mass spectrometry, we quantified urinary abundance of 12 complement proteins in a predominantly Mexican American cohort with type 2 diabetes and proteinuric DKD (n = 141). The association of urine complement proteins with progression to ESRD or death was evaluated using time-to-event analyses. RESULTS: At baseline, median estimated glomerular filtration rate (eGFR) was 54 mL/min/1.73 m2 and urine protein-to-creatinine ratio 2.6 g/g. Sixty-seven participants developed ESRD or died, of whom 39 progressed to ESRD over a median of 3.1 years and 40 died over a median 3.6 years. Higher urine CD59, an inhibitor of terminal complement complex formation, was associated with a lower risk of ESRD (hazard ratio [HR] [95% CI per doubling] 0.50 [0.29-0.87]) and death (HR [95% CI] 0.56 [0.34-0.93]), after adjustment for demographic and clinical covariates, including baseline eGFR and proteinuria. Higher urine complement components 4 and 8 were associated with lower risk of death (HR [95% CI] 0.57 [0.41-0.79] and 0.66 [0.44-0.97], respectively); higher urine factor H-related protein 2, a positive regulator of the alternative complement pathway, was associated with greater risk of death (HR [95% CI] 1.61 [1.05-2.48]) in fully adjusted models. CONCLUSIONS: In a largely Mexican American cohort with type 2 diabetes and proteinuric DKD, urine abundance of several complement and complement regulatory proteins was strongly associated with progression to ESRD and death.


Assuntos
Proteínas do Sistema Complemento/urina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/diagnóstico , Falência Renal Crônica/diagnóstico , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/etnologia , Nefropatias Diabéticas/etnologia , Nefropatias Diabéticas/mortalidade , Nefropatias Diabéticas/urina , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/etnologia , Falência Renal Crônica/mortalidade , Falência Renal Crônica/urina , Masculino , Espectrometria de Massas , Americanos Mexicanos , Pessoa de Meia-Idade , Prognóstico , Proteinúria/diagnóstico , Proteinúria/etnologia , Proteinúria/mortalidade , Proteinúria/patologia , Fatores de Risco , Análise de Sobrevida
7.
EBioMedicine ; 26: 68-77, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29128444

RESUMO

Chronic kidney disease (CKD) is a public health problem with very high prevalence and mortality. Yet, there is a paucity of effective treatment options, partly due to insufficient knowledge of underlying pathophysiology. We combined metabolomics (GCMS) with kidney gene expression studies to identify metabolic pathways that are altered in adults with non-diabetic stage 3-4 CKD versus healthy adults. Urinary excretion rate of 27 metabolites and plasma concentration of 33 metabolites differed significantly in CKD patients versus controls (estimate range-68% to +113%). Pathway analysis revealed that the citric acid cycle was the most significantly affected, with urinary excretion of citrate, cis-aconitate, isocitrate, 2-oxoglutarate and succinate reduced by 40-68%. Reduction of the citric acid cycle metabolites in urine was replicated in an independent cohort. Expression of genes regulating aconitate, isocitrate, 2-oxoglutarate and succinate were significantly reduced in kidney biopsies. We observed increased urine citrate excretion (+74%, p=0.00009) and plasma 2-oxoglutarate concentrations (+12%, p=0.002) in CKD patients during treatment with a vitamin-D receptor agonist in a randomized trial. In conclusion, urinary excretion of citric acid cycle metabolites and renal expression of genes regulating these metabolites were reduced in non-diabetic CKD. This supports the emerging view of CKD as a state of mitochondrial dysfunction.


Assuntos
Metabolômica , Mitocôndrias/metabolismo , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/genética , Ácido Aconítico/metabolismo , Idoso , Biópsia , Ciclo do Ácido Cítrico/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Isocitratos/metabolismo , Ácidos Cetoglutáricos/metabolismo , Rim/metabolismo , Rim/patologia , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Mitocôndrias/genética , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/urina , Ácido Succínico/metabolismo
8.
Clin Chem ; 63(9): 1515-1526, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28667184

RESUMO

BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing, leading to significant morbidity and mortality. Kidney biopsy remains the gold standard for diagnosing the underlying etiology of CKD, but the procedure carries complication risks. The aim of this study was to identify novel noninvasive biomarkers correlating with kidney function and histopathology in biopsy-proven CKD patients. METHODS: We profiled 2402 urinary microRNAs (miRNAs) to identify and confirm differentially expressed miRNAs associated with kidney function and histopathology in patients with diabetic nephropathy (n = 58) or lupus nephritis (n = 89), important etiologies of CKD, compared with healthy controls (n = 93 and 119, respectively). Top performing miRNAs were then measured in 2 independent multi-institutional cohorts of patients with diabetes mellitus with (n = 74) or without nephropathy (n = 71) and systemic lupus erythematosus with (n = 86) or without (n = 37) nephritis. RESULTS: In patients with diabetic nephropathy, miR-2861, miR-1915-3p, and miR-4532 were down-regulated (>10-fold, P < 0.0001) and were associated with estimated glomerular filtration rate (P < 0.01) and interstitial fibrosis/tubular atrophy (P < 0.05). The c-statistics for miR-2861, miR-1915-3p, and miR-4532 were 0.91, 0.86, and 0.85, respectively. In lupus nephritis patients, miR-3201 and miR-1273e were down-regulated (>3-fold, P < 0.0001) and associated with endocapillary glomerular inflammation (P < 0.01), with c-statistics of 0.97 and 0.91, respectively. CONCLUSIONS: We have identified novel miRNAs that correlate with histopathological lesions and functional markers of kidney damage to facilitate sensitive, specific, and noninvasive detection of diabetic nephropathy and lupus nephritis.


Assuntos
Biomarcadores/análise , Nefropatias Diabéticas/diagnóstico , Nefrite Lúpica/diagnóstico , MicroRNAs/genética , Adulto , Biomarcadores/urina , Período de Replicação do DNA , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/fisiopatologia , Feminino , Humanos , Nefrite Lúpica/genética , Nefrite Lúpica/fisiopatologia , Masculino , MicroRNAs/urina , Reprodutibilidade dos Testes , Transcriptoma
9.
Am J Physiol Renal Physiol ; 313(2): F487-F494, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28468961

RESUMO

The pathways implicated in diabetic kidney disease (DKD) are largely derived from animal models. To examine if alterations in renin-angiotensin system (RAS) in humans are concordant with those in rodent models, we measured concentration of angiotensinogen (AOG), cathepsin D (CTSD), angiotensin-converting enzyme (ACE), and ACE2 and enzymatic activities of ACE, ACE2, and aminopeptidase-A in FVB mice 13-20 wk after treatment with streptozotocin (n = 9) or vehicle (n = 15) and people with long-standing type 1 diabetes, with (n = 37) or without (n = 81) DKD. In streptozotocin-treated mice, urine AOG and CTSD were 10.4- and 3.0-fold higher than in controls, respectively (P < 0.001). Enzymatic activities of ACE, ACE2, and APA were 6.2-, 3.2-, and 18.8-fold higher, respectively, in diabetic animals (P < 0.001). Angiotensin II was 2.4-fold higher in diabetic animals (P = 0.017). Compared with people without DKD, those with DKD had higher urine AOG (170 vs. 15 µg/g) and CTSD (147 vs. 31 µg/g). In people with DKD, urine ACE concentration was 1.8-fold higher (1.4 vs. 0.8 µg/g in those without DKD), while its enzymatic activity was 0.6-fold lower (1.0 vs. 1.6 × 109 RFU/g in those without DKD). Lower ACE activity, but not ACE protein concentration, was associated with ACE inhibitor (ACEI) treatment. After adjustment for clinical covariates, AOG, CTSD, ACE concentration, and ACE activity remained associated with DKD. In conclusion, in mice with streptozotocin-induced diabetes and in humans with DKD, urine concentrations and enzymatic activities of several RAS components are concordantly increased, consistent with enhanced RAS activity and greater angiotensin II formation. ACEI use was associated with a specific reduction in urine ACE activity, not ACE protein concentration, suggesting that it may be a marker of exposure to this widely-used therapy.


Assuntos
Diabetes Mellitus Experimental/urina , Diabetes Mellitus Tipo 1/urina , Nefropatias Diabéticas/urina , Enzimas/urina , Insuficiência Renal Crônica/urina , Sistema Renina-Angiotensina , Adulto , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Biomarcadores/urina , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/diagnóstico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Regulação para Cima , Urinálise
10.
Horm Res Paediatr ; 87(6): 385-395, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28554178

RESUMO

BACKGROUND/AIMS: In adults, lower vitamin D has been associated with increased albuminuria. This association has not been extensively studied in youth with or without type 1 diabetes. METHODS: We examined the cross-sectional association between vitamin D and albuminuria (urine albumin to creatinine ratio ≥30 mg/g) in 8,789 participants of the National Health and Nutrition Survey 2001-2006 (NHANES), who were 6-19 years old. Further, we examined the association between vitamin D and albuminuria in 938 participants from the SEARCH Nutritional Ancillary Study (SNAS), a longitudinal cohort of youth with type 1 diabetes. RESULTS: Of the NHANES participants, 5.3, 19.5, and 53.7% had vitamin D levels <30, 50 and 80 nmol/L, respectively. Albuminuria was present in 12.8% and was more common in younger children, females, non-Hispanic whites, non-obese children, and children with hypertension. After adjustments, there was no association between vitamin D and albuminuria. Among the SNAS participants with type 1 diabetes, we also found no association between baseline vitamin D and subsequent albuminuria in unadjusted or adjusted analyses. CONCLUSION: We did not find an association between serum vitamin D and albuminuria in either non-diabetic youth or those with type 1 diabetes. Further research is needed to more fully understand this relationship.


Assuntos
Albuminúria , Complicações do Diabetes , Diabetes Mellitus Tipo 1 , Vitamina D/sangue , Adolescente , Adulto , Fatores Etários , Albuminúria/sangue , Albuminúria/epidemiologia , Albuminúria/urina , Criança , Complicações do Diabetes/sangue , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/urina , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/urina , Feminino , Humanos , Masculino , Fatores Sexuais
11.
JAMA Cardiol ; 2(3): 314-318, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28002548

RESUMO

Importance: Cardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Understanding the relative contributions of cardiovascular disease event types to the excess burden of cardiovascular disease is important for developing effective strategies to improve outcomes. Objective: To determine absolute rates and risk differences of incident heart failure (HF), coronary heart disease (CHD), and stroke in participants with vs without CKD. Design, Setting and Participants: We pooled participants without prevalent cardiovascular disease from 3 community-based cohort studies: the Jackson Heart Study, Cardiovascular Health Study, and Multi-Ethnic Study of Atherosclerosis. The Jackson Heart Study was conducted between 2000 and 2010, the Cardiovascular Health Study was conducted between 1989 and 2003, and the Multi-Ethnic Study of Atherosclerosis was conducted between 2000 and 2012. Exposures: Chronic kidney disease was defined as estimated glomerular filtration rate less than 60 mL/min/1.73 m2, calculated using the combined creatinine-cystatin C CKD-Epidemiology Collaboration Equation. Main Outcomes and Measures: Poisson regression was used to calculate incidence rates (IRs) and risk differences of adjudicated incident HF, CHD, and stroke, comparing participants with vs without CKD. Results: Among 14 462 participants, the mean (SD) age was 63 (12) years, 59% (n = 8533) were women, and 44% (n = 6363) were African American. Overall, 1461 (10%) had CKD (mean [SD] estimated glomerular filtration rate, 49 [10] mL/min/1.73 m2). Unadjusted IRs for participants with and without CKD, respectively, were 22.0 (95% CI, 19.3-24.8) and 6.2 (95% CI, 5.8-6.7) per 1000 person-years for HF; 24.5 (95% CI, 21.6-27.5) and 8.4 (95% CI, 7.9-9.0) per 1000 person-years for CHD; and 13.4 (95% CI, 11.3-15.5) and 4.8 (95% CI, 4.4-5.3) for stroke. Adjusting for demographics, cohort, hypertension, diabetes, hyperlipidemia, and tobacco use, risk differences comparing participants with vs without CKD (per 1000 person-years) were 2.3 (95% CI, 1.2-3.3) for HF, 2.3 (95% CI, 1.2-3.4) for CHD, and 0.8 (95% CI, 0.09-1.5) for stroke. Among African American and Hispanic participants, adjusted risk differences comparing participants with vs without CKD for HF were 3.5 (95% CI, 1.5-5.5) and 7.8 (95% CI, 2.2-13.3) per 1000 person-years, respectively. Conclusions and Relevance: Among 3 diverse community-based cohorts, CKD was associated with an increased risk of HF that was similar in magnitude to CHD and greater than stroke. The excess risk of HF associated with CKD was particularly large among African American and Hispanic individuals. Efforts to improve health outcomes for patients with CKD should prioritize HF in addition to CHD prevention.


Assuntos
Afro-Americanos , Doença das Coronárias/etnologia , Insuficiência Cardíaca/etnologia , Insuficiência Renal Crônica/complicações , Medição de Risco , Acidente Vascular Cerebral/etnologia , Doença das Coronárias/etiologia , Feminino , Seguimentos , Insuficiência Cardíaca/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Morbidade/tendências , Prognóstico , Insuficiência Renal Crônica/etnologia , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Taxa de Sobrevida/tendências , Fatores de Tempo , Estados Unidos/epidemiologia
12.
Am J Physiol Renal Physiol ; 312(4): F716-F731, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-27558558

RESUMO

Increasing incidences of obesity and diabetes have made diabetic kidney disease (DKD) the leading cause of chronic kidney disease and end-stage renal disease worldwide. Despite current pharmacological treatments, including strategies for optimizing glycemic control and inhibitors of the renin-angiotensin system, DKD still makes up almost one-half of all cases of end-stage renal disease in the United States. Compelling and mounting evidence has clearly demonstrated that immunity and inflammation play a paramount role in the pathogenesis of DKD. This article reviews the involvement of the immune system in DKD and identifies important roles of key immune and inflammatory mediators. One of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD. Novel and evolving treatment approaches target protein kinases, transcription factors, chemokines, adhesion molecules, growth factors, advanced glycation end-products, and other inflammatory molecules. This is the beginning of a new era in the understanding and treatment of DKD, and we may have finally reached a tipping point in our fight against the growing burden of DKD.


Assuntos
Anti-Inflamatórios/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Descoberta de Drogas/métodos , Mediadores da Inflamação/antagonistas & inibidores , Rim/efeitos dos fármacos , Nefrite/tratamento farmacológico , Receptores Imunológicos/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Nefropatias Diabéticas/imunologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Humanos , Mediadores da Inflamação/metabolismo , Rim/imunologia , Rim/metabolismo , Rim/patologia , Terapia de Alvo Molecular , Nefrite/imunologia , Nefrite/metabolismo , Nefrite/patologia , Valor Preditivo dos Testes , Receptores Imunológicos/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
J Diabetes Complications ; 30(8): 1467-1472, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27522272

RESUMO

AIMS: To determine if serum levels of serum amyloid A (SAA) predict death and end-stage renal disease in a cohort of people with diabetic kidney disease. METHODS: In a longitudinal cohort study of 135 participants with type 2 diabetes and diabetic kidney disease, serum samples were assayed for SAA. Censored time-to-event analyses in Cox-proportional hazard models were utilized to assess SAA as a predictor of the primary outcome of death and end-stage renal disease. RESULTS: Participants were 73% Mexican-American (99/135) and 55% men (75/135), with a mean±SD age of 57±7.5years. At baseline, participants had hemoglobin A1c of 8.6±2.3%, systolic blood pressure of 153±27mm Hg, body mass index of 31±9kg/m2, median urine-albumin-to-creatinine ratio of 1861mg/g (interquartile range 720-3912mg/g), and estimated glomerular filtration rate of 55.7±22.3ml/min/1.73m2. Over a median duration of follow-up of 3.5years, 44% (60/135) of participants experienced a primary outcome event. The hazards ratio for the primary outcome was 3.03 (95% CI 1.43-6.40, p=0.003) in the highest (>1.0 µg/ml) compared to the lowest (<0.55 µg/ml) SAA tertile in a model adjusted for urine-albumin-to-creatinine ratio, estimated glomerular filtration rate, age, sex, and race/ethnicity. Addition of SAA as a covariate improved the model C-statistic (Δ c=0.017). CONCLUSIONS: In a longitudinal cohort study of participants with type 2 diabetes and DKD, higher levels of serum SAA predicted higher risk of death and ESRD. SAA is a promising targetable biomarker for DKD.


Assuntos
Diabetes Mellitus Tipo 2/mortalidade , Nefropatias Diabéticas/mortalidade , Falência Renal Crônica/mortalidade , Proteína Amiloide A Sérica/análise , Idoso , California , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/sangue , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/sangue , Estudos Longitudinais , Masculino , Americanos Mexicanos , Pessoa de Meia-Idade , Fatores de Risco
14.
JAMA ; 316(6): 602-10, 2016 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-27532915

RESUMO

IMPORTANCE: Diabetic kidney disease is the leading cause of chronic and end-stage kidney disease in the United States and worldwide. Changes in demographics and treatments may affect the prevalence and clinical manifestations of diabetic kidney disease. OBJECTIVE: To characterize the clinical manifestations of kidney disease among US adults with diabetes over time. DESIGN, SETTING, AND PARTICIPANTS: Serial cross-sectional studies of adults aged 20 years or older with diabetes mellitus participating in National Health and Nutrition Examination Surveys from 1988 through 2014. EXPOSURES: Diabetes was defined as hemoglobin A1c greater than 6.5% or use of glucose-lowering medications. MAIN OUTCOMES AND MEASURES: Albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), macroalbuminuria (urine albumin-to-creatinine ratio ≥300 mg/g), reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m2), and severely reduced eGFR (<30 mL/min/1.73 m2), incorporating data on biological variability to estimate the prevalence of persistent abnormalities. RESULTS: There were 6251 adults with diabetes included (1431 from 1988-1994, 1443 from 1999-2004, 1280 from 2005-2008, and 2097 from 2009-2014). The prevalence of any diabetic kidney disease, defined as persistent albuminuria, persistent reduced eGFR, or both, did not significantly change over time from 28.4% (95% CI, 23.8%-32.9%) in 1988-1994 to 26.2% (95% CI, 22.6%-29.9%) in 2009-2014 (prevalence ratio, 0.95 [95% CI, 0.86-1.06] adjusting for age, sex, and race/ethnicity; P = .39 for trend). However, the prevalence of albuminuria decreased progressively over time from 20.8% (95% CI, 16.3%-25.3%) in 1988-1994 to 15.9% (95% CI, 12.7%-19.0%) in 2009-2014 (adjusted prevalence ratio, 0.76 [95% CI, 0.65-0.89]; P < .001 for trend). In contrast, the prevalence of reduced eGFR increased from 9.2% (95% CI, 6.2%-12.2%) in 1988-1994 to 14.1% (95% CI, 11.3%-17.0%) in 2009-2014 (adjusted prevalence ratio, 1.61 [95% CI, 1.33-1.95] comparing 2009-2014 with 1988-1994; P < .001 for trend), with a similar pattern for severely reduced eGFR (adjusted prevalence ratio, 2.86 [95% CI, 1.38-5.91]; P = .004 for trend). Significant heterogeneity in the temporal trend for albuminuria was noted by age (P = .049 for interaction) and race/ethnicity (P = .007 for interaction), with a decreasing prevalence of albuminuria observed only among adults younger than 65 years and non-Hispanic whites, whereas the prevalence of reduced GFR increased without significant differences by age or race/ethnicity. In 2009-2014, approximately 8.2 million adults with diabetes (95% CI, 6.5-9.9 million adults) had albuminuria, reduced eGFR, or both. CONCLUSIONS AND RELEVANCE: Among US adults with diabetes from 1988 to 2014, the overall prevalence of diabetic kidney disease did not change significantly, whereas the prevalence of albuminuria declined and the prevalence of reduced eGFR increased.


Assuntos
Albuminúria/epidemiologia , Nefropatias Diabéticas/epidemiologia , Falência Renal Crônica/epidemiologia , Adulto , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Idoso , Albuminúria/diagnóstico , Albuminúria/etnologia , Estudos Transversais , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Nefropatias Diabéticas/etnologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Taxa de Filtração Glomerular , Hemoglobina A Glicada/análise , Hispano-Americanos/estatística & dados numéricos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Falência Renal Crônica/etnologia , Masculino , México/etnologia , Pessoa de Meia-Idade , Inquéritos Nutricionais , Prevalência , Fatores de Tempo , Estados Unidos/epidemiologia
15.
Drug Metab Dispos ; 44(10): 1692-6, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27481856

RESUMO

The existing biobanks of remnant tissue from clinically indicated kidney biopsies are attractive potential reservoirs for quantification of clinically relevant human tissue proteins by quantitative proteomics. However, a significant caveat of this strategy is that the tissues are often preserved in optimal cutting temperature (OCT) medium. Although OCT is an effective method of preserving the morphologic and immunohistological characteristics of tissues for later study, it significantly impacts efforts to quantify protein expression by liquid chromatography-tandem mass spectrometry methods. We report here a simple, reproducible, and cost-effective procedure to extract proteins from OCT-embedded tissue samples. Briefly, the excess frozen OCT medium was scraped before thawing from the tissue specimens stored at -80°C for ∼3 months. The tissue samples were homogenized and diethyl ether/methanol extraction was performed to remove the remaining OCT medium. The recovered protein was denatured, reduced, and alkylated. The second step of protein extraction and desalting was performed by chloroform/methanol/water extraction of denatured proteins. The resultant protein pellet was trypsin-digested and the marker proteins of various kidney cellular compartments were quantified by targeted selective reaction monitoring proteomics. Upon comparison of peptide signals from OCT-embedded tissue and flash-frozen tissue from the same donors, both individual protein quantities, and their interindividual variabilities, were similar. Therefore, the approach reported here can be applied to clinical reservoirs of OCT-preserved kidney tissue to be used for quantitative proteomics studies of clinically relevant proteins expressed in different parts of the kidney (including drug transporters and metabolizing enzymes).


Assuntos
Rim/metabolismo , Proteínas/isolamento & purificação , Idoso , Cromatografia Líquida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espectrometria de Massas em Tandem , Temperatura Ambiente
16.
Nephrol Dial Transplant ; 31(12): 2057-2064, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27257276

RESUMO

BACKGROUND: African Americans and patients with chronic kidney disease (CKD) are at high risk for clinical heart failure (HF). In this study, we aimed to determine the association of markers of kidney disease with subclinical HF (by echocardiogram) and risk of clinical HF among a large, well-characterized community-based cohort of African American patients. We also examined whether the association of markers of kidney disease with HF was attenuated with adjustment for echocardiographic measures. METHODS: We studied participants in the Jackson Heart Study, a large community-based cohort of African Americans. Estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR) were measured at baseline. We tested the association of eGFR and urine ACR with left ventricular mass (LVM), left ventricular ejection fraction (LVEF) and physician-adjudicated incident HF. RESULTS: Among the 3332 participants in the study, 166 (5%) had eGFR <60 mL/min/1.73 m2 and 405 (12%) had urine ACR ≥30 mg/g. In models adjusted for demographics, comorbidity and the alternative measure of kidney disease, lower eGFR and higher urine ACR were associated with higher LVM {ß-coefficient 1.54 [95% confidence interval (CI) 0.78-2.31] per 10 mL/min/1.73 m2 decrease in eGFR and 2.87 (95% CI 1.85-3.88) per doubling of urine ACR}. There was no association of eGFR and urine ACR with LVEF [ß-coefficient -0.12 (95% CI -0.28-0.04) and -0.11 (95% CI -0.35-0.12), respectively]. There was no association of eGFR with the risk of incident HF [HR 1.02 (95% CI 0.91-1.14) per 10 mL/min/1.73 m2 decrease], while there was a significant association of urine ACR [HR 2.22 (95% CI 1.29-3.84) per doubling of urine ACR]. This association was only modestly attenuated with adjustment for LVM [HR 1.95 (95% CI 1.09-3.49)]. CONCLUSIONS: Among a community-based cohort of African Americans, lower eGFR and higher ACR were associated with higher LVM. Furthermore, higher urine ACR was associated with incident HF, which was not entirely explained by the presence of left ventricular disease.


Assuntos
Insuficiência Cardíaca/urina , Insuficiência Renal Crônica/urina , Afro-Americanos , Idoso , Albuminúria/epidemiologia , Albuminúria/etiologia , Albuminúria/urina , Doenças Assintomáticas , Biomarcadores/urina , Comorbidade , Feminino , Taxa de Filtração Glomerular , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Risco , Função Ventricular Esquerda
17.
Clin J Am Soc Nephrol ; 11(8): 1384-91, 2016 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-27340284

RESUMO

BACKGROUND AND OBJECTIVES: Blacks have high rates of cardiovascular disease and mortality. Diabetes and CKD, risk factors for cardiovascular mortality in the general population, are common among blacks. We sought to assess their contribution to cardiovascular disease and mortality in blacks. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational cohort study was of 3211 participants in the Jackson Heart Study (enrolled 2000-2004). Rates of incident stroke, incident coronary heart disease, and cardiovascular mortality were quantified in participants with diabetes, CKD (eGFR<60 ml/min per 1.73 m(2), urine albumin-to-creatinine ratio ≥30 mg/g, or both), or both through 2012, with a median follow-up of 6.99 years. RESULTS: Four hundred fifty-six (14.2%) participants had only diabetes, 257 (8.0%) had only CKD, 201 (6.3%) had both, and 2297 (71.5%) had neither. Diabetes without CKD was associated with excess risks of incident stroke, incident coronary heart disease, and cardiovascular mortality after adjustment for demographic and clinical covariates, including prevalent cardiovascular disease (excess incidence rates, 2.6; 95% confidence interval, 0.5 to 4.7; 2.6; 95% confidence interval, 0.3 to 4.8; and 2.4; 95% confidence interval, 0.4 to 4.3 per 1000 person-years, respectively). CKD without diabetes was associated with comparable nonsignificant excess risks for incident stroke and coronary heart disease (2.5; 95% confidence interval, -0.1 to 5.2 and 2.4; 95% confidence interval, -0.8 to 5.5 per 1000 person-years, respectively) but a larger excess risk for cardiovascular mortality (7.3; 95% confidence interval, 3.0 to 11.5 per 1000 person-years). Diabetes and CKD together were associated with greater excess risks for incident stroke (13.8; 95% confidence interval, 5.3 to 22.3 per 1000 person-years), coronary heart disease (12.8; 95% confidence interval, 4.9 to 20.8 per 1000 person-years), and cardiovascular mortality (14.8; 95% confidence interval, 7.2 to 22.3 per 1000 person-years). The excess risks associated with the combination of diabetes and CKD were larger than those associated with established risk factors, including prevalent cardiovascular disease. CONCLUSIONS: The combination of diabetes and kidney disease is associated with substantial excess risks of cardiovascular events and mortality among blacks.


Assuntos
Afro-Americanos/estatística & dados numéricos , Doença das Coronárias/etnologia , Diabetes Mellitus/etnologia , Insuficiência Renal Crônica/etnologia , Acidente Vascular Cerebral/etnologia , Adulto , Doenças Cardiovasculares/mortalidade , Comorbidade , Feminino , Inquéritos Epidemiológicos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mississippi/epidemiologia , Estudos Prospectivos , Fatores de Risco
19.
J Am Soc Nephrol ; 27(9): 2861-71, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26823551

RESUMO

Kidney disease leads to clinically relevant disturbances in glucose and insulin homeostasis, but the pathophysiology in moderate-severe CKD remains incompletely defined. In a cross-sectional study of 59 participants with nondiabetic CKD (mean eGFR =37.6 ml/min per 1.73 m(2)) and 39 healthy control subjects, we quantified insulin sensitivity, clearance, and secretion and glucose tolerance using hyperinsulinemic-euglycemic clamp and intravenous and oral glucose tolerance tests. Participants with CKD had lower insulin sensitivity than participants without CKD (mean[SD] 3.9[2.0] versus 5.0 [2.0] mg/min per µU/ml; P<0.01). Insulin clearance correlated with insulin sensitivity (r=0.72; P<0.001) and was also lower in participants with CKD than controls (876 [226] versus 998 [212] ml/min; P<0.01). Adjustment for physical activity, diet, fat mass, and fatfree mass in addition to demographics and smoking partially attenuated associations of CKD with insulin sensitivity (adjusted difference, -0.7; 95% confidence interval, -1.4 to 0.0 mg/min per µU/ml) and insulin clearance (adjusted difference, -85; 95% confidence interval, -160 to -10 ml/min). Among participants with CKD, eGFR did not significantly correlate with insulin sensitivity or clearance. Insulin secretion and glucose tolerance did not differ significantly between groups, but 65% of participants with CKD had impaired glucose tolerance. In conclusion, moderate-severe CKD associated with reductions in insulin sensitivity and clearance that are explained, in part, by differences in lifestyle and body composition. We did not observe a CKD-specific deficit in insulin secretion, but the combination of insulin resistance and inadequate augmentation of insulin secretion led to a high prevalence of impaired glucose tolerance.


Assuntos
Glucose/fisiologia , Homeostase , Resistência à Insulina/fisiologia , Insuficiência Renal Crônica/fisiopatologia , Estudos Transversais , Feminino , Humanos , Insulina , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
20.
J Diabetes Complications ; 29(8): 1024-31, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26412030

RESUMO

AIMS: The renin-angiotensin-aldosterone system (RAAS), bone morphogenetic protein (BMP) and WNT pathways are dysregulated in diabetic kidney disease (DKD). Urine excretion of angiotensinogen, gremlin-1 and matrix metalloproteinase-7 (MMP-7), components of the RAAS, BMP and WNT pathways, respectively, is increased in DKD. We asked if this increase is associated with subsequent progression to end-stage renal disease (ESRD) or death. METHODS: Using time-to-event analyses, we examined the association of baseline urine concentration of these proteins with progression to ESRD or death in a predominantly Mexican-American cohort with type 2 diabetes and proteinuric DKD (n=141). RESULTS: Progression to ESRD occurred for 38 participants over a median follow-up of 3.0years; 39 participants died over a median follow-up of 3.6years. Urine MMP-7 and gremlin-1 were associated with increased risk of ESRD after adjustment for demographic and clinical covariates. Angiotensinogen showed a U-shaped relationship with ESRD, with the middle tertile associated with lowest risk of ESRD. After additional adjustment for glomerular filtration rate and albuminuria, all associations with ESRD lost significance. Only urine MMP-7 was associated with mortality, and this association remained robust in the fully adjusted model with a Hazard ratio of 3.59 (95% confidence interval 1.31 to 9.85) for highest vs. lowest tertile. Serum MMP-7 was not associated with mortality and did not attenuate the association of urine MMP-7 with mortality (HR 4.03 for highest vs. lowest urine MMP-7 tertile). CONCLUSIONS: Among people with type 2 diabetes and proteinuric DKD, urine MMP-7 concentration was strongly associated with subsequent mortality.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Falência Renal Crônica/epidemiologia , Rim/fisiopatologia , Metaloproteinase 7 da Matriz/urina , Insuficiência Renal/epidemiologia , Regulação para Cima , Idoso , Estudos de Coortes , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/mortalidade , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Feminino , Seguimentos , Taxa de Filtração Glomerular , Hospitais Públicos , Hospitais Urbanos , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Falência Renal Crônica/fisiopatologia , Los Angeles/epidemiologia , Masculino , Americanos Mexicanos , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal/complicações , Insuficiência Renal/mortalidade , Insuficiência Renal/fisiopatologia , Risco
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