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1.
Ren Fail ; 41(1): 427-433, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31162987

RESUMO

Objectives: Diabetic kidney disease (DKD) is an independent predictor of cardiovascular morbidity and mortality in type 1 diabetes (T1D). We aimed to explore clinical and biochemical factors, including the achievement of American Diabetes Association (ADA) recommended targets associated with DKD in people living with T1D for ≥50 years. Methods: This was a post hoc analysis of a cross-sectional study of 75 participants enrolled in the Canadian Study of Longevity in T1D. We explored diabetes-related complications, including neuropathy, retinopathy, cardiovascular disease, and DKD. Study participants were dichotomized based on the achievement of ADA recommended targets as the low-target group (achieving ≤4 targets, n = 31) and high-target group (achieving >4 targets, n = 44). The outcome of interest was DKD defined by estimated glomerular filtration rate (eGFR) values <60/mL/min/1.73 m2 and/or 24-h albumin excretion >30 mg. Multivariable logistic regression models were employed to estimate odds ratios (ORs) for DKD with 95% confidence intervals (CIs). Results: Of the 75 participants with prolonged T1D duration (45% male, mean age 66 years), 25 participants had DKD and 50 did not. There was no statistical difference between the high- and low-target groups in terms of age and body mass index. eGFR was significantly higher and the prevalence of diabetic retinopathy was significantly lower in the high-target group. Older age at diagnosis of T1D and lower frequency component to high-frequency component ratio increased the odds of having DKD. Conclusions: In adults with prolonged T1D duration, older age at diagnosis and lower heart rate variability may be associated with DKD.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/epidemiologia , Frequência Cardíaca/fisiologia , Fatores Etários , Idoso , Canadá/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Feminino , Humanos , Longevidade/fisiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco
2.
Diabetes Obes Metab ; 21(6): 1388-1398, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30761725

RESUMO

AIMS: To examine the relationship between normal plasma uric acid (PUA) levels, renal haemodynamic function, arterial stiffness and plasma renin and aldosterone over a wide range of type 1 diabetes (T1D) durations in adolescents, young adults and older adults. MATERIALS AND METHODS: PUA, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), vascular stiffness parameters (aortic augmentation index [AIx], carotid AIx, carotid femoral pulse wave velocity [cfPWV]), and plasma renin and aldosterone were measured during a euglycaemic clamp in people with T1D: 27 adolescents (mean ± SD age 16.8 ± 1.9 years), 52 young adults (mean ± SD age 25.6 ± 5.5 years) and 66 older adults (mean ± SD age 65.7 ± 7.5 years). RESULTS: PUA was highest in patients with the longest T1D duration: 197 ± 44 µmol/L in adolescents versus 264 ± 82 µmol/L in older adults (P < 0.001). Higher PUA correlated with lower GFR only in older adults, even after correcting for age, glycated haemoglobin and sex (ß = -2.12 ± 0.56; P = 0.0003), but not in adolescents or young adults. Higher PUA correlated with lower carotid AIx (ß = -1.90, P = 0.02) in adolescents. In contrast, PUA correlated with higher cfPWV (P = 0.02) and higher plasma renin (P = 0.01) in older adults with T1D. CONCLUSIONS: The relationship between higher PUA with lower GFR, increased arterial stiffness and renin angiotensin aldosterone system (RAAS) activation was observed only in older adults with longstanding T1D. T1D duration may modify the association between PUA, renal haemodynamic function and RAAS activation, leading to renal vasoconstriction and ischaemia. Further work must determine whether pharmacological PUA-lowering prevents or reverses injurious haemodynamic and neurohormonal sequelae of longstanding T1D, thereby improving clinical outcomes.

3.
Am J Kidney Dis ; 73(6): 786-796, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30799029

RESUMO

RATIONALE & OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) is associated with renal and cardiovascular disease in diabetes. Unfortunately, early RAAS blockade in patients with type 1 diabetes mellitus (T1DM) does not prevent the development of complications. We sought to examine the role of hyperfiltration and RAAS activation across a wide range of T1DM duration to better understand renal hemodynamic status in patients with T1DM. STUDY DESIGN: Post hoc analysis of blood samples. SETTING & PARTICIPANTS: 148 Canadian patients with T1DM: 28 adolescents (aged 16.2±2.0 years), 54 young adults (25.4±5.6 years), and 66 older adults (65.7±7.5 years) studied in a clinical investigation unit. EXPOSURE: Angiotensin II infusion (1ng/kg/min; a measure of RAAS activation) during a euglycemic clamp. OUTCOMES: Glomerular filtration rate measured using inulin clearance, effective renal plasma flow measured using para-aminohippurate, afferent (RA) and efferent (RE) arteriolar resistances, and glomerular hydrostatic pressure estimated using the Gomez equations. RESULTS: In a stepwise fashion, glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure were higher, while renal vascular resistance and RA were lower in adolescents versus young adults versus older adults. RE was similar in adolescents versus young adults but was higher in older adults. Angiotensin II resulted in blunted renal hemodynamic responses in older adults (renal vascular resistance increase of 3.3% ± 1.6% vs 4.9% ± 1.9% in adolescents; P<0.001), suggesting a state of enhanced RAAS activation. LIMITATIONS: Homogeneous study participants limit the generalizability of findings to other populations. Studying older adult participants with T1DM may be associated with a survivorship bias. CONCLUSIONS: A state of relatively low RAAS activity and predominant afferent dilation rather than efferent constriction characterize early adolescents and young adults with T1DM. This state of endogenous RAAS inactivity in early T1DM may explain why pharmacologic blockade of this neurohormonal system is often ineffective in reducing kidney disease progression in this setting. Older adults with long-standing T1DM who have predominant afferent constriction and RAAS activation may experience renoprotection from therapies that target the afferent arteriole. Further work is required to understand the potential role of non-RAAS pharmacologic agents that target RA in patients with early and long-standing T1DM.

4.
Diabetes Obes Metab ; 21(3): 575-583, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30311395

RESUMO

OBJECTIVE: Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). METHODS: The study sample comprised patients with longstanding T1D (duration ≥50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m2 and <30 mg/d urine albumin excretion) and 22 had DKD, in addition to 73 control participants. GFRINULIN and ERPFPAH were measured, RVR was calculated, and afferent (RA )/efferent (RE ) areteriolar resistances were derived from Gomez equations. Plasma neutrophil gelatinase-associated lipocalin (NGAL), ß2 microglobulin (B2M), osteopontin (OPN) and uromodulin (UMOD) were measured using immunoassay kits from Meso Scale Discovery. RESULTS: Plasma NGAL, B2M and OPN were higher and UMOD was lower in DKD patients vs DKD resistors and non-diabetic controls. In participants with T1D, plasma NGAL inversely correlated with GFR (r = -0.33; P = 0.006) and ERPF (r = -0.34; P = 0.006), and correlated positively with RA (r = 0.26; P = 0.03) and RVR (r = 0.31; P = 0.01). In participants without T1D, NGAL and B2M inversely correlated with GFR (NGAL r = -0.18; P = 0.13 and B2M r = -0.49; P < 0.0001) and with ERPF (NGAL r = -0.19; P = 0.1 and B2M r = -0.42; P = 0.0003), and correlated positively with RA (NGAL r = 0.19; P = 0.10 and B2M r = 0.3; P = 0.01) and with RVR (NGAL r = 0.20; P = 0.09 and B2M r = 0.34; P = 0.003). Differences were significant after adjusting for age, sex, HbA1c, SBP and LDL. There were statistical interactions between T1D status, B2M and intrarenal haemodynamic function (P < 0.05). CONCLUSIONS: Elevated NGAL relates to intrarenal haemodynamic dysfunction in T1D, whereas elevated NGAL and B2M relate to intrarenal haemodynamic dysfunction in adults without T1D. These data may define a diabetes-specific interplay between tubular injury and intrarenal haemodynamic dysfunction.


Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Nefropatias Diabéticas/diagnóstico , Hemodinâmica/fisiologia , Rim/irrigação sanguínea , Rim/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Canadá , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Lipocalina-2/análise , Lipocalina-2/sangue , Longevidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fluxo Sanguíneo Regional/fisiologia , Resistência Vascular/fisiologia , Microglobulina beta-2/análise , Microglobulina beta-2/sangue
5.
Diabetes Care ; 42(2): 273-280, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30523033

RESUMO

OBJECTIVE: The importance of renin-angiotensin-aldosterone system (RAAS) activation in retinopathy for long-standing diabetes is not well understood. We determined retinopathy stage and evaluated associations with other vascular complications before and after physiological RAAS activation in adults with long-standing (≥50 years duration) type 1 diabetes. RESEARCH DESIGN AND METHODS: Participants underwent retinal examination by digital funduscopic photography and optical coherence tomography and were classified as having nonproliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), or no diabetic retinopathy (NDR) with or without diabetic macular edema (DME). Neuropathy was measured by clinical neuropathy examination scores, electrophysiologically, and by corneal confocal microscopy. Renal function was measured by inulin and para-aminohippurate clearance methods. Arterial stiffness was measured by applanation tonometry. Renal function, blood pressure, and arterial stiffness were measured before and after RAAS activation with angiotensin II (ANGII). Associations were determined using linear regression. RESULTS: Twelve (16%) of the 75 participants had NDR, 24 (32%) had NPDR, and 39 (52%) had PDR. A low overall prevalence of DME (4%) was observed. Those with PDR had worse nerve function and reduced corneal nerve density, were more likely to have macrovascular disease, and had increased arterial stiffness in response to ANGII compared with those with NPDR or NDR. Prevalence of kidney disease or renal hemodynamic function did not differ by retinopathy status. CONCLUSIONS: PDR was associated with neuropathy severity and cardiovascular and peripheral vascular disease. In those with PDR, RAAS activation may be linked to vascular stiffening, an effect that persists in long-standing type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/epidemiologia , Retinopatia Diabética , Longevidade/fisiologia , Sistema Renina-Angiotensina/fisiologia , Adulto , Idoso , Pressão Sanguínea/fisiologia , Canadá/epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/fisiopatologia , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/fisiopatologia , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/fisiopatologia , Feminino , Humanos , Edema Macular/diagnóstico , Edema Macular/epidemiologia , Edema Macular/etiologia , Edema Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fotografação , Prevalência , Tomografia de Coerência Óptica , Rigidez Vascular/fisiologia
6.
Diabetes Care ; 41(4): 831-839, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29437821

RESUMO

OBJECTIVE: Central adiposity is considered to be an important cardiorenal risk factor in the general population and in type 1 diabetes. We sought to determine the relationship between central adiposity and intrarenal hemodynamic function in adults with long-standing type 1 diabetes with and without diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS: Patients with type 1 diabetes (n = 66, duration ≥50 years) and age-/sex-matched control subjects (n = 73) were studied. The cohort was stratified into 44 DN Resistors (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2 and <30 mg/day urine albumin) and 22 patients with DN (eGFR ≤60 mL/min/1.73 m2 or ≥30 mg/day urine albumin). Intrarenal hemodynamic function (glomerular filtration rate for inulin [GFRINULIN], effective renal plasma flow for p-aminohippuric acid [ERPFPAH]) was measured. Afferent arteriolar resistance, efferent arteriolar resistance, renal blood flow, renal vascular resistance [RVR], filtration fraction, and glomerular pressure were derived from the Gomez equations. Fat and lean mass were quantified by DXA. RESULTS: Whereas measures of adiposity did not associate with GFRINULIN or ERPFPAH in healthy control subjects, trunk fat mass inversely correlated with GFRINULIN (r = -0.46, P < 0.0001) and ERPFPAH (r = -0.31, P = 0.01) and positively correlated with RVR (r = 0.53, P = 0.0003) in type 1 diabetes. In analyses stratified by DN status, greater central adiposity related to lower GFRINULIN values in DN and DN Resistors, but the relationships between central adiposity and ERPFPAH and RVR were attenuated and/or reversed in patients with DN compared with DN Resistors. CONCLUSIONS: The adiposity-intrarenal hemodynamic function relationship may be modified by the presence of type 1 diabetes and DN, requiring further study of the mechanisms by which adiposity influences renal hemodynamic function.


Assuntos
Adiposidade , Diabetes Mellitus Tipo 1/sangue , Nefropatias Diabéticas/sangue , Obesidade/sangue , Idoso , Canadá , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/complicações , Feminino , Taxa de Filtração Glomerular , Hemodinâmica , Humanos , Longevidade , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Circulação Renal , Resistência Vascular
7.
JCI Insight ; 3(1)2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29321380

RESUMO

BACKGROUND: In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation. METHODS: Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation. RESULTS: Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity. CONCLUSION: In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction. FUNDING: JDRF operating grant 17-2013-312.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Sistema Renina-Angiotensina/fisiologia , Vasoconstrição/fisiologia , Idoso , Angiotensina II/farmacologia , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/fisiopatologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Infusões Intravenosas , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos
8.
Am J Physiol Renal Physiol ; 314(3): F412-F422, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29141939

RESUMO

Focal segmental glomerulosclerosis (FSGS) is an important cause of nondiabetic chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibition (SGLT2i) therapy attenuates the progression of diabetic nephropathy, but it remains unclear whether SGLT2i provides renoprotection in nondiabetic CKD such as FSGS. The primary aim of this pilot study was to determine the effect of 8 wk of dapagliflozin on glomerular filtration rate (GFR) in humans and in experimental FSGS. Secondary end points were related to changes in renal hemodynamic function, proteinuria, and blood pressure (BP). GFR (inulin) and renal plasma flow (para-aminohippurate), proteinuria, and BP were measured in patients with FSGS ( n = 10), and similar parameters were measured in subtotally nephrectomized (SNx) rats. In response to dapagliflozin, changes in GFR, renal plasma flow, and 24-h urine protein excretion were not statistically significant in humans or rats. Systolic BP (SBP) decreased in SNx rats (196 ± 26 vs. 165 ± 33 mmHg; P < 0.001), whereas changes were not statistically significant in humans (SBP 112.7 ± 8.5 to 112.8 ± 11.2 mmHg, diastolic BP 71.8 ± 6.5 to 69.6 ± 8.4 mmHg; P = not significant), although hematocrit increased (0.40 ± 0.05 to 0.42 ± 0.05%; P = 0.03). In archival kidney tissue from a separate patient cohort, renal parenchymal SGLT2 mRNA expression was decreased in individuals with FSGS compared with controls. Short-term treatment with the SGLT2i dapagliflozin did not modify renal hemodynamic function or attenuate proteinuria in humans or in experimental FSGS. This may be related to downregulation of renal SGLT2 expression. Studies examining the impact of SGLT2i on markers of kidney disease in patients with other causes of nondiabetic CKD are needed.


Assuntos
Arteríolas/efeitos dos fármacos , Compostos Benzidrílicos/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glucosídeos/uso terapêutico , Rim/irrigação sanguínea , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Vasoconstrição/efeitos dos fármacos , Adulto , Animais , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Modelos Animais de Doenças , Feminino , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudo de Prova de Conceito , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Fatores de Tempo , Resultado do Tratamento
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