Dietary sodium and potassium intake in people with diabetes: are guidelines being met?

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.

Effect of angiotensin II receptor blocker and salt supplementation on short-term blood pressure variability in type 2 diabetes.

High blood pressure variability (BPV) has been associated with increased cardiovascular (CV) risk. The effect of dietary salt and renin-angiotensin-aldosterone system (RAAS) activity on short-term BPV in type 2 diabetes mellitus (T2DM) is not well characterised. We aimed to determine the effect of dietary salt (sodium chloride, NaCl) supplementation on 24-h mean arterial BPV (24hBPV) during angiotensin II receptor blocker (telmisartan) use and to evaluate the effects of age, sex, plasma renin activity (PRA) and serum aldosterone on 24hBPV. In a randomised, double-blind, crossover study, patients with T2DM (n = 28), treated with telmisartan received NaCl (100 mmol/24 h) or placebo capsules during 2 weeks of telmisartan. Following a 6-week washout, the protocol was repeated in reverse. 24hBPV was evaluated as a co-efficient of variation [CV (%) = mean/standard deviation] × 100). Twenty-four hour urinary sodium excretion, ambulatory BP and biochemical tests were performed at each phase. Results were analysed using a linear mixed model to generate predicted values for 24hBPV. Predicted 24hBPV was higher with telmisartan vs baseline (p = 0.01), with a trend towards reduced 24hBPV with salt (p = 0.052). Predicted 24hBPV was lower in females (p = 0.017), increasing age (p = 0.001) and increasing PRA (p = 0.011). In patients with T2DM, predicted 24hBPV increased from baseline with telmisartan, but there was no additional increase in predicted 24hBPV with salt supplementation. This suggests that in the short-term, salt supplementation has no apparent deleterious effects on 24hBPV. Long-term studies are required to evaluate the effect of 24hBPV on CV outcomes in patients with T2DM.

Effect of Salt Supplementation on Sympathetic Activity and Endothelial Function in Salt-Sensitive Type 2 Diabetes.

CONTEXT: Lower sodium intake is paradoxically associated with higher mortality in type 2 diabetes (T2D). OBJECTIVE: To determine whether sympathetic nervous system (SNS) activation and endothelial dysfunction contribute to these observations, we examined the effect of salt supplementation on these systems in people with T2D with habitual low sodium. We hypothesized that salt supplementation would lower SNS activity and improve endothelial function compared to placebo. DESIGN: We conducted a randomized, double-blinded, placebo-controlled crossover trial. SETTING: The study took place in a tertiary referral diabetes outpatient clinic. PARTICIPANTS: Twenty-two people with T2D with habitual low sodium intake (24-hour urine sodium <150 mmol/24h) were included. INTERVENTION: Salt supplementation (100 mmol NaCl/24h) or placebo for 3 weeks was administered. MAIN OUTCOME MEASURES: The primary outcome of SNS activity and endothelial function was assessed as follows: Microneurography assessed muscle sympathetic nerve activity (MSNA), pulse amplitude tonometry assessed endothelial function via reactive hyperemic index (RHI), and arterial stiffness was assessed via augmentation index (AI). Secondary outcomes included cardiac baroreflex, serum aldosterone, ambulatory blood pressure monitoring (ABPM), heart rate variability (HRV), and salt sensitivity. RESULTS: Compared to placebo, salt supplementation increased MSNA (burst frequency P = .047, burst incidence P = .016); however, RHI (P = .24), AI (P = .201), ABPM (systolic P = .09, diastolic P = .14), and HRV were unaffected. Salt supplementation improved baroreflex (slope P = .026) and lowered aldosterone (P = .004), and in salt-resistant individuals there was a trend toward improved RHI (P = .07). CONCLUSIONS: In people with T2D and low habitual sodium intake, salt supplementation increased SNS activity without altering endothelial function or blood pressure but improved baroreflex function, a predictor of cardiac mortality. Salt-resistant individuals trended toward improved endothelial function with salt supplementation.

Comparison of endothelial function and sympathetic nervous system activity along the glucose continuum in individuals with differing metabolic risk profiles and low dietary sodium intake.

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.

Changes in soluble tumor necrosis factor receptor type 1 levels and early renal function decline in patients with diabetes.

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.

Is hyperfiltration associated with higher urine albumin-to-creatinine ratio at follow up among Indigenous Australians? The eGFR follow-up study.

BACKGROUND: Glomerular hyperfiltration is not able to be detected in clinical practice. We assessed whether hyperfiltration is associated with albuminuria progression among Indigenous Australians at high risk of diabetes and kidney disease to determine its role in kidney disease progression. METHODS: Longitudinal observational study of Indigenous Australians aged ≥18 years recruited from >20 sites, across diabetes and/or kidney function strata. At baseline, iohexol clearance was used to measure glomerular filtration rate (mGFR) and hyperfiltration was defined as (i) a mGFR of ≥125 mL/min/1.73 m2, and (ii) an age-adjusted definition, with the top 10% of the mGFR for each 10 year age group at baseline. Baseline and follow-up urine albumin-to-creatinine ratio (uACR) was collected, and linear regression was used to assess the associations of hyperfiltration and uACR at follow up. RESULTS: 407 individuals (33% men, mean age 47 years) were followed-up for a median of 3 years. At baseline, 234 had normoalbuminuria and 173 had albuminuria. Among participants with normoalbuminuria, those with mGFR ≥125 mL/min/1.73 m2 had 32% higher uACR at follow-up (p = 0.08), and those with age-adjusted hyperfiltration had 60% higher uACR (p = 0.037) compared to those who had normofiltration. These associations were independent of uACR at baseline, but attenuated by HbA1c. Associations were stronger among those without than those with albuminuria at baseline. CONCLUSIONS: Although not available for assessment in current clinical practice, hyperfiltration may represent a marker of subsequent albuminuria progression among individuals who have not yet developed albuminuria.

Three Dimensional Glomerular Reconstruction: A Novel Approach to Evaluate Renal Microanatomy in Diabetic Kidney Disease.

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.

The relationship between habitual dietary sodium intake and RAAS blockade on circulating microparticle levels in type two diabetes.

OBJECTIVE: Low sodium intake is paradoxically associated with adverse cardiovascular outcomes in individuals with type 2 diabetes mellitus (T2D), possibly from renin-angiotensin-aldosterone system (RAAS) activation, leading to endothelial dysfunction. In the present study, we investigated the associations between habitual sodium intake and RAAS blockade on endothelial function by measuring circulating microparticles (MPs) in individuals with T2D. METHODS: We conducted a prospective, cross-sectional study in 74 individuals with T2D. Habitual dietary sodium intake was estimated by using the mean of three corrected 24-h urine sodium excretion measurements (24hUNa). MP subtypes in platelet-free plasma were quantitated using flow cytometry. RESULTS: No associations between 24hUNa with levels of endothelial MPs were observed. Instead, a trend toward higher diabetes related CD36+/CD235a+ MP levels was associated with lower 24hUNa (rho = -0.23, P=0.05). When stratified according to tertiles of 24hUNa, platelet-derived CD42b+/CD41+ and CD42+/CD41+/Annexin V+ MPs were higher in the lowest tertile (24hUNa < 157 mmol/24 h) (P=0.02 respectively). Despite RAAS blockade being associated with lower levels of most MP subsets, it was not associated with lower MPs, in the setting of low sodium intake. CONCLUSION: Lower sodium intake is associated with higher circulating procoagulant MPs, but not with evidence of endothelial dysfunction in individuals with T2D.

Use of Readily Accessible Inflammatory Markers to Predict Diabetic Kidney Disease.

Diabetic kidney disease is a common complication of type 1 and type 2 diabetes and is the primary cause of end-stage renal disease in developed countries. Early detection of diabetic kidney disease will facilitate early intervention aimed at reducing the rate of progression to end-stage renal disease. Diabetic kidney disease has been traditionally classified based on the presence of albuminuria. More recently estimated glomerular filtration rate has also been incorporated into the staging of diabetic kidney disease. While albuminuric diabetic kidney disease is well described, the phenotype of non-albuminuric diabetic kidney disease is now widely accepted. An association between markers of inflammation and diabetic kidney disease has previously been demonstrated. Effector molecules of the innate immune system including C-reactive protein, interleukin-6, and tumor necrosis factor-α are increased in patients with diabetic kidney disease. Furthermore, renal infiltration of neutrophils, macrophages, and lymphocytes are observed in renal biopsies of patients with diabetic kidney disease. Similarly high serum neutrophil and low serum lymphocyte counts have been shown to be associated with diabetic kidney disease. The neutrophil-lymphocyte ratio is considered a robust measure of systemic inflammation and is associated with the presence of inflammatory conditions including the metabolic syndrome and insulin resistance. Cross-sectional studies have demonstrated a link between high levels of the above inflammatory biomarkers and diabetic kidney disease. Further longitudinal studies will be required to determine if these readily available inflammatory biomarkers can accurately predict the presence and prognosis of diabetic kidney disease, above and beyond albuminuria, and estimated glomerular filtration rate.

Glycemic Control as Primary Prevention for Diabetic Kidney Disease.

Improving strategies to prevent the development and progression of CKD is a highly desirable outcome for all involved in the care of patients with diabetes. This is because CKD is a major factor contributing to morbidly and mortality in patients with diabetes. Furthermore, diabetes is the leading cause of ESRD in most developed countries. Although tight glucose control is now an established modality for preventing the development and progression of albuminuria, evidence is now accumulating to suggest that it can also ameliorate glomerular filtration rate loss and possibly progression to ESRD. These benefits of intensive glucose control appear to be most pronounced when applied to patients with the early stages of CKD. Recently, medications that belong to the sodium glucose cotransporter-type 2 inhibitor and the glucagon-like peptide-1 receptor analogue classes have been shown to reduce progression of CKD in patients with type 2 diabetes and relatively well-preserved kidney function. Here, we review the evidence from observational and interventional clinical studies that link good glucose control with the primary prevention of diabetic kidney disease with a focus on preventing early glomerular filtration rate loss.

High Baseline Levels of Tumor Necrosis Factor Receptor 1 Are Associated With Progression of Kidney Disease in Indigenous Australians With Diabetes: The eGFR Follow-up Study.

OBJECTIVE: To examine the association between soluble tumor necrosis factor receptor 1 (sTNFR1) levels and kidney disease progression in Indigenous Australians at high risk of kidney disease. RESEARCH DESIGN AND METHODS: This longitudinal observational study examined participants aged ≥18 years recruited from >20 sites across diabetes and/or kidney function strata. Baseline measures included sTNFR1, serum creatinine, urine albumin-to-creatinine ratio (uACR), HbA1c, C-reactive protein (CRP), waist-to-hip ratio, systolic blood pressure, and medical history. Linear regression was used to estimate annual change in estimated glomerular filtration rate (eGFR) for increasing sTNFR1, and Cox proportional hazards were used to estimate the hazard ratio (HR) and 95% CI for developing a combined renal outcome (first of a ≥30% decline in eGFR with a follow-up eGFR <60 mL/min/1.73 m2, progression to renal replacement therapy, or renal death) for increasing sTNFR1. RESULTS: Over a median of 3 years, participants with diabetes (n = 194) in the highest compared with the lowest quartile of sTNFR1 experienced significantly greater eGFR decline (-4.22 mL/min/1.73 m2/year [95% CI -7.06 to -1.38]; P = 0.004), independent of baseline age, sex, eGFR, and uACR. The adjusted HR (95% CI) for participants with diabetes per doubling of sTNFR1 for the combined renal outcome (n = 32) was 3.8 (1.1-12.8; P = 0.03). No association between sTNFR1 and either renal outcome was observed for those without diabetes (n = 259). CONCLUSIONS: sTNFR1 is associated with greater kidney disease progression independent of albuminuria and eGFR in Indigenous Australians with diabetes. Further research is required to assess whether TNFR1 operates independently of other metabolic factors associated with kidney disease progression.

Trajectories of eGFR decline over a four year period in an Indigenous Australian population at high risk of CKD-the eGFR follow up study.

Being able to estimate kidney decline accurately is particularly important in Indigenous Australians, a population at increased risk of developing chronic kidney disease and end stage kidney disease. The aim of this analysis was to explore the trend of decline in estimated glomerular filtration rate (eGFR) over a four year period using multiple local creatinine measures, compared with estimates derived using centrally-measured enzymatic creatinine and with estimates derived using only two local measures. METHOD: The eGFR study comprised a cohort of over 600 Aboriginal Australian participants recruited from over twenty sites in urban, regional and remote Australia across five strata of health, diabetes and kidney function. Trajectories of eGFR were explored on 385 participants with at least three local creatinine records using graphical methods that compared the linear trends fitted using linear mixed models with non-linear trends fitted using fractional polynomial equations. Temporal changes of local creatinine were also characterized using group-based modelling. Analyses were stratified by eGFR (<60; 60-89; 90-119 and ≥120ml/min/1.73m2) and albuminuria categories (<3mg/mmol; 3-30mg/mmol; >30mg/mmol). RESULTS: Mean age of the participants was 48years, 64% were female and the median follow-up was 3years. Decline of eGFR was accurately estimated using simple linear regression models and locally measured creatinine was as good as centrally measured creatinine at predicting kidney decline in people with an eGFR<60 and an eGFR 60-90ml/min/1.73m2 with albuminuria. Analyses showed that one baseline and one follow-up locally measured creatinine may be sufficient to estimate short term (up to four years) kidney function decline. The greatest yearly decline was estimated in those with eGFR 60-90 and macro-albuminuria: -6.21 (-8.20, -4.23) ml/min/1.73m2. CONCLUSION: Short term estimates of kidney function decline can be reliably derived using an easy to implement and simple to interpret linear mixed effect model. Locally measured creatinine did not differ to centrally measured creatinine, thus is an accurate cost-efficient and timely means to monitoring kidney function progression.

Relationship between urinary sodium-to-potassium ratio and ambulatory blood pressure in patients with diabetes mellitus.

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.

Contribution of cardiometabolic risk factors to estimated glomerular filtration rate decline in Indigenous Australians with and without albuminuria - the eGFR Follow-up Study.

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.

Long-term intra-individual variability of albuminuria in type 2 diabetes mellitus: implications for categorization of albumin excretion rate.

BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease in the Western world. Early and accurate identification of DKD offers the best chance of slowing the progression of kidney disease. An important method for evaluating risk of progressive DKD is abnormal albumin excretion rate (AER). Due to the high variability in AER, most guidelines recommend the use of more than or equal to two out of three AER measurements within a 3- to 6-month period to categorise AER. There are recognised limitations of using AER as a marker of DKD because one quarter of patients with type 2 diabetes may develop kidney disease without an increase in albuminuria and spontaneous regression of albuminuria occurs frequently. Nevertheless, it is important to investigate the long-term intra-individual variability of AER in participants with type 2 diabetes. METHODS: Consecutive AER measurements (median 19 per subject) were performed in 497 participants with type 2 diabetes from 1999 to 2012 (mean follow-up 7.9 ± 3 years). Baseline clinical characteristics were collected to determine associations with AER variability. Participants were categorised as having normo-, micro- or macroalbuminuria according to their initial three AER measurements. Participants were then categorised into four patterns of AER trajectories: persistent, intermittent, progressing and regressing. Coefficients of variation were used to measure intra-individual AER variability. RESULTS: The median coefficient of variation of AER was 53.3%, 76.0% and 67.0% for subjects with normo-, micro- or macroalbuminuria at baseline. The coefficient of variation of AER was 37.7%, 66% and 94.8% for subjects with persistent, intermittent and progressing normoalbuminuria; 43%, 70.6%, 86.1% and 82.3% for subjects with persistent, intermittent, progressing and regressing microalbuminuria; and 55.2%, 67% and 82.4% for subjects with persistent, intermittent and regressing macroalbuminuria, respectively. CONCLUSION: High long-term variability of AER suggests that two out of three AER measurements may not always be adequate for the optimal categorisation and prediction of AER.

Effects of glycaemic management on diabetic kidney disease.

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.

Clinical predictive factors in diabetic kidney disease progression.

Diabetic kidney disease (DKD) represents a major component of the health burden associated with type 1 and type 2 diabetes. Recent advances have produced an explosion of 'novel' assay-based risk markers for DKD, though clinical use remains restricted. Although many patients with progressive DKD follow a classical albuminuria-based pathway, non-albuminuric DKD progression is now well recognized. In general, the following clinical and biochemical characteristics have been associated with progressive DKD in both type 1 and type 2 diabetes: increased hemoglobin A1c, systolic blood pressure, albuminuria grade, early glomerular filtration rate decline, duration of diabetes, age (including pubertal onset) and serum uric acid; the presence of concomitant microvascular complications; and positive family history. The same is true in type 2 diabetes for male sex category, in patients following an albuminuric pathway to DKD, and also true for the presence of increased pulse wave velocity. The following baseline clinical characteristics have been proposed as risk factors for DKD progression, but with further research required to assess the nature of any relationship: dyslipidemia (including low-density lipoprotein, total and high-density lipoprotein cholesterol); elevated body mass index; smoking status; hyperfiltration; decreases in vitamin D, hemoglobin and uric acid excretion (all known consequences of advanced DKD); and patient test result visit-to-visit variability (hemoglobin A1c, blood pressure and high-density lipoprotein cholesterol). The development of multifactorial 'renal risk equations' for type 2 diabetes has the potential to simplify the task of DKD prognostication; however, there are currently none for type 1 diabetes-specific populations. Significant progress has been made in the prediction of DKD progression using readily available clinical data, though further work is required to elicit the role of several variables, and to consolidate data to facilitate clinical implementation.

Comparison of creatinine and cystatin C based eGFR in the estimation of glomerular filtration rate in Indigenous Australians: The eGFR Study.

BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation that combines creatinine and cystatin C is superior to equations that include either measure alone in estimating glomerular filtration rate (GFR). However, whether cystatin C can provide any additional benefits in estimating GFR for Indigenous Australians, a population at high risk of end-stage kidney disease (ESKD) is unknown. METHODS: Using a cross-sectional analysis from the eGFR Study of 654 Indigenous Australians at high risk of ESKD, eGFR was calculated using the CKD-EPI equations for serum creatinine (eGFRcr), cystatin C (eGFRcysC) and combined creatinine and cystatin C (eGFRcysC+cr). Reference GFR (mGFR) was determined using a non-isotopic iohexol plasma disappearance technique over 4h. Performance of each equation to mGFR was assessed by calculating bias, % bias, precision and accuracy for the total population, and according to age, sex, kidney disease, diabetes, obesity and c-reactive protein. RESULTS: Data were available for 542 participants (38% men, mean [sd] age 45 [14] years). Bias was significantly greater for eGFRcysC (15.0mL/min/1.73m2; 95% CI 13.3-16.4, p<0.001) and eGFRcysC+cr (10.3; 8.8-11.5, p<0.001) compared to eGFRcr (5.4; 3.0-7.2). Accuracy was lower for eGFRcysC (80.3%; 76.7-83.5, p<0.001) but not for eGFRcysC+cr (91.9; 89.3-94.0, p=0.29) compared to eGFRcr (90.0; 87.2-92.4). Precision was comparable for all equations. The performance of eGFRcysC deteriorated across increasing levels of c-reactive protein. CONCLUSION: Cystatin C based eGFR equations may not perform well in populations with high levels of chronic inflammation. CKD-EPI eGFR based on serum creatinine remains the preferred equation in Indigenous Australians.

Cardio-renal protection with empagliflozin.

Cardiovascular (CV) and kidney disease are common and significant complications in people with type 2 diabetes (T2DM). CV disease is the leading cause of death, morbidly and hospitalisations for people with T2DM. Furthermore, diabetic kidney disease is a major risk factor for CV disease and is the main reason why patients need renal replacement therapy. In this perspective, we highlight the results of the recent landmark EMPA-REG OUTCOME trial which has shown that empagliflozin, a member of the sodium-glucose co-transporter 2 (SGLT-2) inhibitor class of glucose lowering medications, reduces death from CV causes, hospitalisation for heart failure and progression to end stage kidney disease in patients with T2DM and established CV disease. The SGLT2 receptor mediates high-capacity glucose uptake in the early proximal tubule, and SGLT2 inhibitors, via their ability to promote glycosuria, have been developed as glucose lowering medications. As well as having a glucose lowering effect, SGLT-2 inhibitors also reduce blood pressure, promote weight loss and reduce uric acid levels. Potential side-effects or concerns related to the use of SGLT-2 inhibitors include increased rates of urinary tract infections, genital tract infections, postural hypotension, diabetic ketoacidosis, acute kidney injury and possible increased rates of fractures. The exact mechanisms that result in empagliflozin's dramatic CV and renal protective effects, with a very favourable safety/tolerability profile, in the EMPA-REG study remain to be fully defined. However, they are most likely distinct from the glucose lowering effects of empagliflozin. CV safety trials involving dapagliflozin and canagliflozin, members of the SGLT-2 class, are under way and the results from these studies will help to answer the question as to whether the cardio-renal benefits of empagliflozin are a class-effect or not. Without doubt, trials to investigate whether SGLT-2 inhibitors have cardio-renal protective effects in patients without diabetes will start soon.

A Single Dose of Prednisolone as a Modulator of Undercarboxylated Osteocalcin and Insulin Sensitivity Post-Exercise in Healthy Young Men: A Study Protocol.

BACKGROUND: Undercarboxylated osteocalcin (ucOC) increases insulin sensitivity in mice. In humans, data are supportive, but the studies are mostly cross-sectional. Exercise increases whole-body insulin sensitivity, in part via ucOC, while acute glucocorticoid treatment suppresses ucOC in humans and mice. OBJECTIVES: A single dose of prednisolone reduces the rise in ucOC produced by exercise, which partly accounts for the failed increase in insulin sensitivity following exercise. METHODS: Healthy young men (n=12) aged 18 to 40 years will be recruited. Initial assessments will include analysis of fasting blood, body composition, aerobic power (VO2peak), and peak heart rate. Participants will then be randomly allocated, double-blind, to a single dose of 20 mg of prednisolone or placebo. The two experimental trials will involve 30 minutes of interval exercise (90%-95% peak heart rate), followed by 3 hours of recovery and 2 hours of euglycaemic- hyperinsulinaemic clamp (insulin clamp). Seven muscle biopsies and blood samples will be obtained at rest, following exercise and post-insulin clamps. RESULTS: The study is funded by the National Heart Foundation of Australia and Victoria University. Enrollment has already commenced and data collection will be completed in 2016. CONCLUSION: If the hypothesis is confirmed, the study will provide novel insights into the potential role of ucOC in insulin sensitivity in human subjects and will elucidate pathways involved in exercise-induced insulin sensitivity.