Medicine (Austin & Northern Health) - Research Publications
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ItemEffects of Salt Supplementation on the Albuminuric Response to Telmisartan With or Without Hydrochlorothiazide Therapy in Hypertensive Patients With Type 2 Diabetes Are Modulated by Habitual Dietary Salt Intake(AMER DIABETES ASSOC, 2009-08)OBJECTIVE This prospective randomized double-blind placebo-controlled crossover study examined the effects of sodium chloride (NaCl) supplementation on the antialbuminuric action of telmisartan with or without hydrochlorothiazide (HCT) in hypertensive patients with type 2 diabetes, increased albumin excretion rate (AER), and habitual low dietary salt intake (LDS; <100 mmol sodium/24 h on two of three consecutive occasions) or high dietary salt intake (HDS; >200 mmol sodium/24 h on two of three consecutive occasions). RESEARCH DESIGN AND METHODS Following a washout period, subjects (n = 32) received 40 mg/day telmisartan for 4 weeks followed by 40 mg telmisartan plus 12.5 mg/day HCT for 4 weeks. For the last 2 weeks of each treatment period, patients received either 100 mmol/day NaCl or placebo capsules. After a second washout, the regimen was repeated with supplements in reverse order. AER and ambulatory blood pressure were measured at weeks 0, 4, 8, 14, 18, and 22. RESULTS In LDS, NaCl supplementation reduced the anti-albuminuric effect of telmisartan with or without HCT from 42.3% (placebo) to 9.5% (P = 0.004). By contrast, in HDS, NaCl supplementation did not reduce the AER response to telmisartan with or without HCT (placebo 30.9%, NaCl 28.1%, P = 0.7). Changes in AER were independent of changes in blood pressure. CONCLUSIONS The AER response to telmisartan with or without HCT under habitual low salt intake can be blunted by NaCl supplementation. By contrast, when there is already a suppressed renin angiotensin aldosterone system under habitual high dietary salt intake, the additional NaCl does not alter the AER response.
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ItemRelationship between urinary sodium-to-potassium ratio and ambulatory blood pressure in patients with diabetes mellitus(WILEY, 2018-01)Previous studies investigating the relationship between sodium intake and blood pressure have mostly relied on dietary recall and clinic blood pressure measurement. In this cross-sectional study, we aimed to investigate the relationship between 24 hour urinary sodium and potassium excretion, and their ratio, with 24 hour ambulatory blood pressure parameters including nocturnal blood pressure dipping in patients with type 1 and 2 diabetes. We report that in 116 patients with diabetes, systolic blood pressure was significantly predicted by the time of day, age, the interaction between dipping status with time, and 24 hour urinary sodium-to-potassium ratio (R2 = 0.83) with a relative contribution of 53%, 21%, 20% and 6%, respectively. However, there was no interaction between urinary sodium-to-potassium ratio and dipping status.
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ItemContribution of cardiometabolic risk factors to estimated glomerular filtration rate decline in Indigenous Australians with and without albuminuria - the eGFR Follow-up Study(WILEY, 2018-07)AIM: We assessed associations between cardiometabolic risk factors and estimated glomerular filtration rate (eGFR) decline according to baseline albuminuria to identify potential treatment targets in Indigenous Australians. METHODS: The eGFR Follow-up Study is a longitudinal cohort of 520 Indigenous Australians. Linear regression was used to estimate associations between baseline cardiometabolic risk factors and annual Chronic Kidney Disease Epidemiology Collaboration eGFR change (mL/min per 1.73m2 /year), among those classified with baseline normoalbuminuria (urine albumin-to-creatinine ratio (uACR) <3 mg/mmol; n = 297), microalbuminuria (uACR 3-30 mg/mmol; n = 114) and macroalbuminuria (uACR ≥30 mg/mmol; n = 109). RESULTS: After a median of 3 years follow-up, progressive declines of the age- and sex-adjusted mean eGFR were observed across albuminuria categories (-2.0 [-2.6 to -1.4], -2.5 [-3.7 to -1.3] and -6.3 [-7.8 to -4.9] mL/min per 1.72m2 /year). Although a borderline association was observed between greater baseline haemoglobin A1c and eGFR decline in those with macroalbuminuria (P = 0.059), relationships were not significant in those with microalbuminuria (P = 0.187) or normoalbuminuria (P = 0.23). Greater baseline blood pressure, C-reactive protein, waist-to-hip ratio and lower high-density lipoprotein cholesterol showed non-significant trends with greater eGFR decline in the presence of albuminuria. CONCLUSION: Over a 3 year period, marked eGFR decline was observed with greater baseline albuminuria. Cardiometabolic risk factors were not strong predictors for eGFR decline in Indigenous Australians without albuminuria. Longer follow-up may elucidate the role of these predictors and other mechanisms in chronic kidney disease progression in this population.
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ItemDietary Salt Intake and Mortality in Patients With Type 2 Diabetes(AMER DIABETES ASSOC, 2011-03)OBJECTIVE: Many guidelines recommend that patients with type 2 diabetes should aim to reduce their intake of salt. However, the precise relationship between dietary salt intake and mortality in patients with type 2 diabetes has not been previously explored. RESEARCH DESIGN AND METHODS: Six hundred and thirty-eight patients attending a single diabetes clinic were followed in a prospective cohort study. Baseline sodium excretion was estimated from 24-h urinary collections (24hU(Na)). The predictors of all-cause and cardiovascular mortality were determined by Cox regression and competing risk modeling, respectively. RESULTS: The mean baseline 24hU(Na) was 184 ± 73 mmol/24 h, which remained consistent throughout the follow-up (intraindividual coefficient of variation [CV] 23 ± 11%). Over a median of 9.9 years, there were 175 deaths, 75 (43%) of which were secondary to cardiovascular events. All-cause mortality was inversely associated with 24hU(Na), after adjusting for other baseline risk factors (P < 0.001). For every 100 mmol rise in 24hU(Na), all-cause mortality was 28% lower (95% CI 6-45%, P = 0.02). After adjusting for the competing risk of noncardiovascular death and other predictors, 24hU(Na) was also significantly associated with cardiovascular mortality (sub-hazard ratio 0.65 [95% CI 0.44-0.95]; P = 0.03). CONCLUSIONS: In patients with type 2 diabetes, lower 24-h urinary sodium excretion was paradoxically associated with increased all-cause and cardiovascular mortality. Interventional studies are necessary to determine if dietary salt has a causative role in determining adverse outcomes in patients with type 2 diabetes and the appropriateness of guidelines advocating salt restriction in this setting.
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ItemChanges in soluble tumor necrosis factor receptor type 1 levels and early renal function decline in patients with diabetes(WILEY, 2019-11)The relationship between serial changes in soluble tumor necrosis factor receptor type 1 (TNFR1) levels and an early decline in estimated glomerular filtration rate (eGFR) decline remains to be defined. We found that in patients with an early decline in renal function (n = 30), soluble TNFR1 values increased (2,595 ± 683 vs 3,596 ± 1,203 pg/mL, P < 0.001) as eGFR decreased (89 ± 1 vs 51 ± 2 mL/min/1.73m2 , P < 0.001) over an 8-year period. In contrast, there were no significant changes in soluble TNFR1 levels in patients with stable renal function (n = 17). In a multilevel mixed effects regression model, changes in soluble TNFR1 levels were found to be independently associated with eGFR decline (Z = -4.31, P < 0.001). An early decline in eGFR is associated with an increase in soluble TNFR levels; however, the factors driving this increase and the possible pathological role that soluble TNFR1 plays in progressive diabetic kidney disease remain to be determined.
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ItemComparison of endothelial function and sympathetic nervous system activity along the glucose continuum in individuals with differing metabolic risk profiles and low dietary sodium intake(BMJ PUBLISHING GROUP, 2019-06)OBJECTIVE: Low sodium intake may trigger sympathetic nervous system (SNS) activation and endothelial dysfunction. Studies have not explored these associations along the glucose continuum. Accordingly, we compared endothelial function and SNS activity in individuals with low sodium intake and differing categories of metabolic risk along the glucose continuum. We hypothesized that low sodium intake is associated with (1) impairment of endothelial function and (2) higher SNS activity in individuals with higher metabolic risk. RESEARCH DESIGN AND METHODS: In this prospective observational study, participants (n=54) with low sodium intake (single 24 hours urine sodium excretion <150 mmol/24 hours) were categorized based on oral glucose tolerance testing as: normal glucose tolerance (NGT, n=10), impaired glucose tolerance (IGT, n=15), treatment naive type 2 diabetes (T2D-) (n=12) or treated type 2 diabetes (T2D+) (n=17). We assessed endothelial function using pulse amplitude tonometry (PAT) derived reactive hyperemic index and PAT ratio; arterial stiffness via augmentation index; muscle sympathetic nerve activity (MSNA) using microneurography; cardiac baroreflex; heart rate; blood pressure; glycosylated hemoglobin A1c (HbA1c) and lipid profile. RESULTS: Mean (SD) sodium excretion was 110.6 (26) mmol/24 hours. Compared with NGT, IGT and T2D-, the T2D+ group had lower MSNA (p=0.005), PAT ratio (p=0.04) and baroreflex sensitivity (p=0.0002) and an augmented heart rate (p=0.02). The T2D+ group had appropriate mean (SD) glycemic (HbA1c 7.2 (1.72)%), total cholesterol (4.2 (1.0) mmol/L), low-density lipoprotein (2.2 (1.0) mmol/L) and blood pressure (systolic 136 (13), diastolic 78 (12)) (mm Hg) control. CONCLUSIONS: Individuals with T2D+ have impaired endothelial and baroreflex function, despite low sodium intake, appropriately managed cardiometabolic risk factors and lower SNS activity, compared with others along the glucose continuum. Whether low sodium intake is associated with modulation of the sympathovascular profile in T2D requires further investigation.
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ItemThree Dimensional Glomerular Reconstruction: A Novel Approach to Evaluate Renal Microanatomy in Diabetic Kidney Disease(NATURE PORTFOLIO, 2019-02-12)Mesangial metrics reflect glomerular filtration surface area in diabetes. The point-sampled intercept (PSI) method is the conventional method to calculate these parameters. However, this is time consuming and subject to underestimation. We introduce a novel three-dimensional (3D) reconstruction method applicable to light microscopy to measure mesangial metrics. Transmission electron microscopy (TEM), PSI and our new 3D imaging methods were used to quantify mesangial metrics from 22 patients with type 2 diabetes, normo-, micro- and macroalbuminuria and an estimated glomerular filtration rate of <60 mL/min/1.73 m2. Repeated-measures ANOVA test was used to test the equality of the measurement means from the three methods and the degree of inter method variability. Repeated-measures and post-estimation ANOVA tests together with correlation coefficient measurements were used to compare the methods with TEM as reference. There was a statistically significant difference in mesangial volume measurements (F(2, 16) = 15.53, p = 0.0002). The PSI method underestimated measurements compared to TEM and 3D methods by 30% (p = 0.001) and 15%, respectively (p < 0.001). 3D and TEM measurements did not differ significantly. 3D reconstruction is a reliable and time efficient method for calculating mesangial metrics. It may prove to be a useful tool in clinical and experimental diabetic kidney disease.
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ItemDietary sodium and potassium intake in people with diabetes: are guidelines being met?(SPRINGERNATURE, 2020-06-17)OBJECTIVE: Despite public health bodies advocating for lowering dietary sodium and increasing potassium intake to improve cardiovascular outcomes, people with diabetes are not meeting these targets. We hypothesize that (i) both at an individual level and within the cohort, there will be a low adherence to the guidelines and (ii) sodium and potassium intake will remain stable over time. METHODS: We conducted this prospective study in a cohort of 904 participants with diabetes who provided 24-h urine collections from 2009 to 2015. Dietary sodium and potassium intake were estimated from 24-h urinary sodium (uNa) and potassium (uK) measurements. Additional data were collected for: 24-h urinary volume (uVol), creatinine (uCr),; serum creatinine, urea, estimated glomerular filtration rate (eGFR), glycated haemoglobin (HbA1c), fasting glucose, lipids); clinical characteristics (age, blood pressure (BP), body mass index (BMI) and duration of diabetes). Adherence to recommended dietary sodium (uNa < 2300 mg/24 h (100mmol/24 h)) and potassium (uK > 4680 mg/24 h(120 mmol/24)) intake were the main outcome measures. RESULTS: Participants (n = 904) completed 3689 urine collections (average four collections/participant). The mean ± SD (mmol/24 h) for uNa was 181 ± 73 and uK was 76 ± 25. After correcting uNa for uCr, 7% and 5% of participants met dietary sodium and potassium guidelines respectively. Males were less likely to meet sodium guidelines (OR 0.40, p < 0.001) but were more likely to meet potassium guidelines (OR 6.13, p < 0.001). Longer duration of diabetes was associated with higher adherence to sodium and potassium guidelines (OR 1.04, p < 0.001 and OR 0.96, p = 0.006 respectively). Increasing age was significantly associated with adherence to potassium guidelines (OR 0.97, p = 0.007). CONCLUSIONS: People with diabetes do not follow current dietary sodium and potassium guidelines and are less likely to change their dietary intake of sodium and potassium over time.
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ItemEffects of glycaemic management on diabetic kidney disease(BAISHIDENG PUBLISHING GROUP INC, 2017-05-15)Hyperglycaemia contributes to the onset and progression of diabetic kidney disease (DKD). Observational studies have not consistently demonstrated a glucose threshold, in terms of HbA1c levels, for the onset of DKD. Tight glucose control has clearly been shown to reduce the incidence of micro- or macroalbuminuria. However, evidence is now also emerging to suggest that intensive glucose control can slow glomerular filtration rate loss and possibly progression to end stage kidney disease. Achieving tight glucose control needs to be balanced against the increasing appreciation that glucose targets for the prevention of diabetes related complications need be individualised for each patient. Recently, empagliflozin which is an oral glucose lowering agent of the sodium glucose cotransporter-2 inhibitor class has been shown to have renal protective effects. However, the magnitude of empagliflozin's reno-protective properties are over and above that expected from its glucose lowering effects and most likely largely result from mechanisms involving alterations in intra-renal haemodynamics. Liraglutide and semaglutide, both injectable glucose lowering agents which are analogues of human glucagon like peptide-1 have also been shown to reduce progression to macroalbuminuria through mechanisms that remain to be fully elucidated. Here we review the evidence from observational and interventional studies that link good glucose control with improved renal outcomes. We also briefly review the potential reno-protective effects of newer glucose lowering agents.
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ItemSodium and Its Role in Cardiovascular Disease - The Debate Continues(FRONTIERS MEDIA SA, 2016-12-23)Guidelines have recommended significant reductions in dietary sodium intake to improve cardiovascular health. However, these dietary sodium intake recommendations have been questioned as emerging evidence has shown that there is a higher risk of cardiovascular disease with a low sodium diet, including in individuals with type 2 diabetes. This may be related to the other pleotropic effects of dietary sodium intake. Therefore, despite recent review of dietary sodium intake guidelines by multiple organizations, including the dietary guidelines for Americans, American Diabetes Association, and American Heart Association, concerns about the impact of the degree of sodium restriction on cardiovascular health continue to be raised. This literature review examines the effects of dietary sodium intake on factors contributing to cardiovascular health, including left ventricular hypertrophy, heart rate, albuminuria, rennin-angiotensin-aldosterone system activation, serum lipids, insulin sensitivity, sympathetic nervous system activation, endothelial function, and immune function. In the last part of this review, the association between dietary sodium intake and cardiovascular outcomes, especially in individuals with diabetes, is explored. Given the increased risk of cardiovascular disease in individuals with diabetes and the increasing incidence of diabetes worldwide, this review is important in summarizing the recent evidence regarding the effects of dietary sodium intake on cardiovascular health, especially in this population.