Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients With Uncomplicated Type 1 Diabetes.

Higher plasma uric acid (PUA) levels are associated with lower glomerular filtration rate (GFR) and higher blood pressure (BP) in patients with type 1 diabetes (T1D). Our aim was to determine the impact of PUA lowering on renal and vascular function in patients with uncomplicated T1D. T1D patients (n = 49) were studied under euglycemic and hyperglycemic conditions at baseline and after PUA lowering with febuxostat (FBX) for 8 weeks. Healthy control subjects were studied under normoglycemic conditions (n = 24). PUA, GFR (inulin), effective renal plasma flow (para-aminohippurate), BP, and hemodynamic responses to an infusion of angiotensin II (assessment of intrarenal renin-angiotensin-aldosterone system [RAAS]) were measured before and after FBX treatment. Arterial stiffness, flow-mediated dilation (FMD), nitroglycerin-mediated dilation (GMD), urinary nitric oxide (NO), and inflammatory markers were measured before and after FBX treatment. Gomez equations were used to estimate arteriolar afferent resistance, efferent resistance (RE), and glomerular hydrostatic pressure (PGLO). FBX had a modest systolic BP-lowering effect in T1D patients (112 ± 10 to 109 ± 9 mmHg, P = 0.049) without impacting arterial stiffness, FMD, GMD, or NO. FBX enhanced the filtration fraction response to hyperglycemia in T1D patients through larger increases in RE, PGLO, and interleukin-18 but without impacting the RAAS. FBX lowered systolic BP and modulated the renal RE responses to hyperglycemia but without impacting the RAAS or NO levels, suggesting that PUA may augment other hemodynamic or inflammatory mechanisms that control the renal response to hyperglycemia at the efferent arteriole. Ongoing outcome trials will determine cardiorenal outcomes of PUA lowering in patients with T1D.

The relationship between urinary renin-angiotensin system markers, renal function, and blood pressure in adolescents with type 1 diabetes.

The relationship between the renal renin-angiotensin aldosterone system (RAAS) and cardiorenal pathophysiology is unclear. Our aims were to assess 1) levels of urinary RAAS components and 2) the association between RAAS components and HbA1c, the urine albumin/creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and blood pressure (BP) in otherwise healthy adolescents with type 1 diabetes mellitus (TID) vs. healthy controls (HC). Urinary angiotensinogen and angtionsin-converting enzyme (ACE) 2 levels, activity of ACE and ACE2, BP, HbA1c, ACR, and eGFR were measured in 65 HC and 194 T1D from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT). Urinary levels of all RAAS components were higher in T1D vs. HC (P < 0.0001). Higher HbA1c was associated with higher urinary angiotensinogen, ACE2, and higher activity of ACE and ACE2 (P < 0.0001, P = 0.0003, P = 0.003, and P = 0.007 respectively) in T1D. Higher ACR (within the normal range) was associated with higher urinary angiotensinogen (P < 0.0001) and ACE activity (P = 0.007), but not with urinary ACE2 activity or ACE2 levels. These observations were absent in HC. Urinary RAAS components were not associated with BP or eGFR in T1D or HC. Otherwise healthy adolescents with T1D exhibit higher levels of urinary RAAS components compared with HC. While levels of all urinary RAAS components correlate with HbA1c in T1D, only urinary angiotensinogen and ACE activity correlate with ACR, suggesting that these factors reflect an intermediary pathogenic link between hyperglycemia and albuminuria within the normal range.

Early changes in cardiovascular structure and function in adolescents with type 1 diabetes.

BACKGROUND: Children with type 1 diabetes (T1D) are at higher risk of early adult-onset cardiovascular disease. We assessed cardiovascular structure and function in adolescents with T1D compared with healthy controls and the relationships between peripheral vascular function and myocardial parameters. METHODS AND RESULTS: 199 T1D [14.4 ± 1.6 years, diabetes duration 6.2 (2.0-12.8) years] and 178 controls (14.4 ± 2.1 years) completed endothelial function by flow mediated vasodilatation (FMD), arterial stiffness using pulse wave velocity (PWV) along with M-mode, pulse wave and tissue Doppler, and myocardial deformation echocardiographic imaging. Systolic (113 ± 10 vs. 110 ± 9 mmHg; p = 0.0005) and diastolic (62 ± 7 vs. 58 ± 7 mmHg; p < 0.0001) blood pressures, carotid femoral PWV and endothelial dysfunction measurements were increased in T1D compared with controls. Systolic and diastolic left ventricular dimensions and function by M-mode and pulse wave Doppler assessment were not significantly different. Mitral valve lateral e' (17.6 ± 2.6 vs. 18.6 ± 2.6 cm/s; p < 0.001) and a' (5.4 ± 1.1 vs. 5.9 ± 1.1 cm/s; p < 0.001) myocardial velocities were decreased and E/e' (7.3 ± 1.2 vs. 6.7 ± 1.3; p = 0.0003) increased in T1D. Left ventricular mid circumferential strain (-20.4 ± 2.3 vs. -19.5 ± 1.7 %; p < 0.001) was higher, whereas global longitudinal strain was lower (-19.0 ± 1.9 vs. -19.8 ± 1.5 % p < 0.001) in T1D. CONCLUSIONS: Adolescents with T1D exhibit early changes in blood pressure, peripheral vascular function and left ventricular myocardial deformation indices with a shift from longitudinal to circumferential shortening. Longitudinal follow-up of these changes in ongoing prospective trials may allow detection of those most at risk for cardiovascular abnormalities including hypertension that could preferentially benefit from early therapeutic interventions.

Association Between Plasma Uric Acid Levels and Cardiorenal Function in Adolescents With Type 1 Diabetes.

OBJECTIVE: The relationship between plasma uric acid (PUA) and renal and cardiovascular parameters in adolescents with type 1 diabetes (T1D) is not well understood. Our aims in this exploratory analysis were to study the association between PUA and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR), blood pressure, endothelial function, and arterial stiffness in T1D adolescents. These associations were also studied in healthy control (HC) subjects. RESEARCH DESIGN AND METHODS: We studied 188 T1D subjects recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and 65 HC subjects. Baseline PUA, eGFRcystatin C, ACR, blood pressure, flow-mediated dilation (FMD), and carotid-femoral pulse wave velocity (PWV) were measured. RESULTS: PUA was lower in T1D vs. HC subjects (242 ± 55 vs. 306 ± 74 µmol/L, respectively; P < 0.0001). Higher PUA was inversely associated with eGFR in T1D subjects (r = -0.48, P < 0.0001) even after correction for baseline clinical demographic characteristics. PUA was not associated with ACR in T1D after adjustment for potential confounders such as eGFR. For cardiovascular parameters, PUA levels did not associate with systolic blood pressure, FMD, or PWV in T1D or HC subjects. CONCLUSIONS: Even within the physiological range, PUA levels were significantly lower in T1D adolescent patients compared with HC subjects. There was an inverse relationship between PUA and eGFR in T1D, likely reflecting an increase in clearance. There were no associations observed with ACR, blood pressure, arterial stiffness, or endothelial function. Thus, in contrast with adults, PUA may not yet be associated with cardiorenal abnormalities in adolescents with T1D.

The urinary inflammatory profile in gluten free diet-adherent adolescents with type 1 diabetes and celiac disease.

AIMS: Our objective was to characterize urinary cytokine/chemokine excretion in adolescents with type 1 diabetes (T1D) and celiac disease (CD) adhering to gluten free diet (GFD) compared to matched T1D patients and healthy control (HC) group from an existing cohort. METHODS: Eighteen T1D+CD+GFD patients aged 10-16years were identified and matched 2:1 for age, sex, diabetes duration and glycated hemoglobin to 36 T1D subjects and 36 HC. T1D+CD+GFD patients were adherent with a GFD. Urine and serum levels of cytokines/chemokines as well as baseline clinical and laboratory variables were assessed. RESULTS: T1D+CD+GFD patients exhibited lower levels of urinary IL-1B, IL-4, IL-5 (p<0.05) and IFN-γ, IL-8 and G-CSF levels (p<0.07) compared with T1D patients. Urinary biomarker levels between T1D+CD+GFD and HC were mostly similar. In contrast, urinary FGF-2, Flt-3, IL-1B, IL-1RA, IL-4, IL-5, IL-9, IL-10, IL-12p40, IL-15, MIP-1ß, and TNF-ß (p<0.05) were higher in T1D patients compared to HC. Similar levels of inflammatory markers were seen in the serum for all 3 groups. CONCLUSIONS: T1D+CD+GFD patients demonstrated decreased urinary inflammatory cytokine/chemokines compared to T1D and some similar to HC, which is suggestive of a potential modulatory role of treated CD on urinary markers.

Reference values for pulse wave Doppler and tissue Doppler imaging in pediatric echocardiography.

BACKGROUND: In pediatric echocardiography, pulse wave Doppler, and tissue Doppler imaging velocities are widely used to assess cardiac function. Current reference values and Z scores, allowing adjustment for growth are limited by inconsistent methodologies and small sample size. Using a standardized approach for parametric modeling and Z score quality assessment, we propose new pediatric reference values and Z score equations for most left ventricular pulse wave Doppler and tissue Doppler imaging measurements. METHODS AND RESULTS: Two hundred thirty-three healthy pediatric subjects 1 to 18 years of age were prospectively recruited. Thirteen pulse wave Doppler and 14 tissue Doppler imaging measurements were recorded. Normalization for growth was done via a complete and standardized approach for parametric nonlinear regression modeling. Several analyses were performed to ensure adequate Z score distribution and to detect potential residual associations with growth or residual heteroscedasticity. Most measurements adopted a nonlinear relationship with growth and displayed significant heteroscedasticity. Compared with age, height, and weight, normalization for body surface area was most efficient in removing the effect of growth. Generally, polynomial and allometric models yielded adequate goodness-of-fit. Residual values for several measurements had significant departure from the normal distribution, which could be corrected using logarithmic or reciprocal transformation. Overall, weighted parametric nonlinear models allowed us to compute Z score equations with adequate normal distribution and without residual association with growth. CONCLUSIONS: We present Z scores for normalized pulse wave Doppler and tissue Doppler imaging in pediatric echocardiography. Further studies are needed to define the threshold beyond which health becomes a disease by integrating other important factors such as ventricular morphology, loading conditions, and heart rate.

Renal hyperfiltration is associated with glucose-dependent changes in fractional excretion of sodium in patients with uncomplicated type 1 diabetes.

OBJECTIVE: Renal hyperfiltration is a common abnormality associated with diabetic nephropathy in patients with type 1 diabetes (T1D). In animal models, increased proximal tubular sodium reabsorption results in decreased distal sodium delivery, tubuloglomerular feedback activation, afferent vasodilatation, and hyperfiltration. The role of tubular factors is less well understood in humans. The aim of the current study was therefore to compare the fractional sodium excretion (FENa) in hyperfiltering (T1D-H) versus normofiltering (T1D-N) patients and healthy control (HC) subjects, as well as the role of ambient hyperglycemia on FENa. RESEARCH DESIGN AND METHODS: Blood pressure, renal function (inulin for glomerular filtration rate [GFR], and paraaminohippurate for effective renal plasma flow), FENa, and circulating neurohormones were measured in T1D-H (n = 28, GFR ≥135 mL/min/1.73 m(2)), T1D-N (n = 30), and HC (n = 35) subjects during clamped euglycemia. Studies were repeated in a subset of patients during clamped hyperglycemia. RESULTS: During clamped euglycemia, T1D-H exhibited lower FENa than T1D-N and HC subjects (0.64 ± 0.06% vs. 0.91 ± 0.12% and 0.90 ± 0.10%, P < 0.05). During clamped hyperglycemia, FENa increased (Δ + 0.88 ± 0.22% vs. Δ + 0.02 ± 0.21%; between-group effect, P = 0.01) significantly in T1D-H, whereas FENa did not change in T1D-N. When treated as continuous variables, elevated GFR values were associated with hyperglycemia-induced increases in FENa (R(2) = 0.20, P = 0.007). CONCLUSIONS: Patients with uncomplicated T1D-H exhibit lower FENa under euglycemic conditions, which may help to identify patients with hyperfiltration outside of a controlled laboratory setting. Increased FENa in T1D-H but not T1D-N under clamped hyperglycemic conditions suggests that the mechanisms responsible for increased sodium reabsorption leading to hyperfiltration can be saturated.

Urinary ACE2 in healthy adults and patients with uncomplicated type 1 diabetes.

Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be renoprotective. We determined whether urinary ACE2 enzyme activity and protein levels (ELISA), as well as angiotensinogen and ACE, are elevated during clamped euglycemia (4-6 mmol·L(-1)) in patients with uncomplicated type 1 diabetes (T1D, n = 58) compared with normoglycemic controls (n = 21). We also measured the effect of clamped hyperglycemia (9-11 mmol·L(-1)) on each urinary factor in T1D patients. Urinary ACE2 activity and protein levels were higher during clamped euglycemia in T1D compared with the controls (p < 0.0001). In contrast, urinary angiotensinogen levels (p = 0.27) and ACE excretion (p = 0.68) did not differ. In response to clamped hyperglycemia in T1D, urinary ACE2 protein decreased (p < 0.0001), whereas urinary ACE2 activity as well as angiotensinogen and ACE levels remained unchanged. Urinary ACE2 activity and protein expression are increased in T1D patients prior to the onset of clinical complications. Further work is required to determine the functional role of urinary ACE2 in early T1D.

The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus.

BACKGROUND: Individuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity. METHODS: Blood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4-6 mmol/L) and hyperglycaemia (blood glucose 9-11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily). RESULTS: In response to empagliflozin during clamped euglycaemia, systolic blood pressure (111 ± 9 to 109 ± 9 mmHg, p = 0.02) and augmentation indices at the radial (-52% ± 16 to -57% ± 17, p = 0.0001), carotid (+1.3 ± 1 7.0 to -5.7 ± 17.0%, p < 0.0001) and aortic positions (+0.1 ± 13.4 to -6.2 ± 14.3%, p < 0.0001) declined. Similar effects on arterial stiffness were observed during clamped hyperglycaemia without changing blood pressure under this condition. Carotid-radial pulse wave velocity decreased significantly under both glycemic conditions (p ≤ 0.0001), while declines in carotid-femoral pulse wave velocity were only significant during clamped hyperglycaemia (5.7 ± 1.1 to 5.2 ± 0.9 m/s, p = 0.0017). HRV, plasma noradrenalin and adrenaline remained unchanged under both clamped euglycemic and hyperglycemic conditions. CONCLUSIONS: Empagliflozin is associated with a decline in arterial stiffness in young type 1 diabetes mellitus subjects. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose lowering, antihypertensive and weight reduction effects. CLINICAL TRIAL REGISTRATION: NCT01392560.

The effect of sex on endothelial function responses to clamped hyperglycemia in type 1 diabetes.

Although the female sex is associated with renal protection in non-diabetic nephropathy, men and women with type 1 diabetes mellitus (T1D) have a similar risk of developing nephropathy. As hyperglycemia is associated with exaggerated effects on blood pressure and renal hyperfiltration in women versus men with T1D, we examined the influence of clamped hyperglycemia on flow mediated vasodilatation (FMD) to determine if this parameter contributes to sex-related differences in the vascular function. After a controlled diet for seven days, blood pressure, ultrasound derived FMD and circulating renin angiotensin system mediators were measured in men (n=30) and women (n=28) with T1D during clamped euglycemia and hyperglycemia. Men and women were similar in pre-study dietary parameters, age, diabetes duration, body mass index, HbA1c, renal function and proteinuria. The systolic blood pressure (SBP) was higher in men during clamped euglycemia (121±2 vs. 108±2 mm Hg, P<0.0001) and hyperglycemia (121±2 vs. 111±2 mm Hg, P<0.0001), as were the circulating levels of angiotensin II (P<0.05). SBP increased in response to hyperglycemia in women but not in men. Consistently with differences in blood pressure during clamped euglycemia, FMD was higher in women than in men (8.06±0.55 vs. 4.15±0.52%, P<0.0001). In contrast, between-group differences in FMD during clamped hyperglycemia did not reach significance owing to a decline in FMD in women, versus men, in response to clamped hyperglycemia (P=0.040 for between-group change in FMD). Clamped hyperglycemia suppresses FMD in women, but not in men, with uncomplicated T1D, which may contribute to the relative loss of protection against renal disease progression in women with T1D.

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes.

AIMS/HYPOTHESIS: Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy. METHODS: Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days. RESULTS: Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005). CONCLUSIONS/INTERPRETATION: The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

Hyperfiltration and effect of nitric oxide inhibition on renal and endothelial function in humans with uncomplicated type 1 diabetes mellitus.

Studies of experimental diabetes mellitus (DM) suggest that increased nitric oxide (NO) bioactivity contributes to renal hyperfiltration. However, the role of NO in mediating hyperfiltration has not been fully elucidated in humans. Our aim was to examine the effect of NO synthase inhibition on renal and peripheral vascular function in normotensive subjects with uncomplicated type 1 DM. Renal function and brachial artery flow-mediated vasodilatation (FMD) were measured before and after an intravenous infusion of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NMMA) in 21 healthy control and 37 type 1 DM patients. Measurements in DM participants were made under clamped euglycemic conditions. The effect of l-NMMA on circulating and urinary NO metabolites (NO(x)) and cGMP and on urinary prostanoids was also determined. Baseline characteristics were similar in the two groups. For analysis, the DM patients were divided into those with hyperfiltration (DM-H, n = 18) and normal glomerular filtration rate (GFR) levels (DM-N, n = 19). Baseline urine NO(x) and cGMP were highest in DM-H. l-NMMA led to a decline in GFR in DM-H (152 ± 16 to 140 ± 11 ml·min(-1)·1.73 m(-2)) but not DM-N or healthy control participants. The decline in effective renal plasma flow in response to l-NMMA (806 ± 112 to 539 ± 80 ml·min(-1)·1.73 m(-2)) in DM-H was also exaggerated compared with the other groups (repeated measures ANOVA, P < 0.05), along with declines in urinary NO(x) metabolites and cGMP. Baseline FMD was lowest in DM-H compared with the other groups and did not change in response to l-NMMA. l-NMMA reduced FMD and plasma markers of NO bioactivity in the healthy control and DM-N groups. In patients with uncomplicated type 1 DM, renal hyperfiltration is associated with increased NO bioactivity in the kidney and reduced NO bioactivity in the systemic circulation, suggesting a paradoxical state of high renal and low systemic vascular NO bioactivity.

The effect of direct renin inhibition alone and in combination with ACE inhibition on endothelial function, arterial stiffness, and renal function in type 1 diabetes.

OBJECTIVE: Diabetes is associated with renin-angiotensin system (RAS) activation, leading to renal and systemic vascular dysfunction that contribute to end-organ injury and significant morbidity. RAS blockade with ACE inhibitors reduces, but does not abolish, RAS effects. Accordingly, our aim was to determine if direct renin inhibition alone, and in combination with an ACE inhibitor, corrects early hemodynamic abnormalities associated with type 1 diabetes. RESEARCH DESIGN AND METHODS: Arterial stiffness (augmentation index), flow-mediated vasodilatation (FMD), and renal hemodynamic function (inulin and paraaminohippurate clearance) were measured at baseline under clamped euglycemic and hyperglycemic conditions (n = 21). Measures were repeated after 4 weeks of aliskiren therapy and again after aliskiren plus ramipril. RESULTS: Blood pressure-lowering effects of aliskiren were similar during clamped euglycemia and hyperglycemia. Combination therapy augmented this effect under both glycemic conditions (P = 0.0005). Aliskiren reduced arterial stiffness under clamped euglycemic and hyperglycemic conditions, and the effects were augmented by dual RAS blockade (-3.4 ± 11.2 to -8.0 ± 11.5 to -14.3 ± 8.4%, respectively, during euglycemia, P = 0.0001). During clamped euglycemia, aliskiren increased FMD; dual therapy exaggerated this effect (5.1 ± 3.3 to 7.5 ± 3.0 to 10.8 ± 3.5%, repeated-measures ANOVA, P = 0.0001). Aliskiren monotherapy caused renal vasodilatation during clamped hyperglycemia only. In contrast, dual therapy augmented renal vasodilatory effects during clamped euglycemia and hyperglycemia. CONCLUSIONS: In patients with uncomplicated type 1 diabetes, aliskiren-based dual RAS blockade is associated with greater arterial compliance, FMD, and renal vasodilatation.