Background: Microalbuminuria is an early sign of kidney disease in diabetes and indicates cardiovascular risk. We tested if a prespecified urinary proteomic risk classifier (CKD273) was associated with development of microalbuminuria and if progression to microalbuminuria could be prevented with the mineralocorticoid receptor antagonist spironolactone. Methods: Prospective multicentre study in people with type 2 diabetes, normal urinary albumin excretion and preserved renal function in 15 European specialist centres. High-risk individuals determined by CKD273 were randomised 1:1 (interactive web response system) in a double-blind randomised controlled trial comparing spironolactone 25 mg o.d. to placebo. Primary endpoint was development of confirmed microalbuminuria in all individuals with available data. Secondary endpoints included reduction in incidence of microalbuminuria with spironolactone and association between CKD273 and impaired renal function defined as a glomerular filtration rate < 60 ml/min per 1•73 m 2. This study is registered with ClinicalTrials.gov: NCT02040441 and is completed. Findings: From March 25, 2014 to September 30, 2018 we followed 1775 participants, 12% (n=216) had high-risk urinary proteomic pattern of which 209 were included in the trial and assigned spironolactone (n=102) or placebo (n=107). Median follow-up time was 2•51 years (IQR 2•0-3•0). Progression to microalbuminuria was seen in 28•2% of high-risk and 8•9% of low-risk people (P< 0•001) (hazard ratio (HR), 2•48; 95% confidence interval [CI], 1•80 to 3•42 P<0•001, independent of baseline clinical characteristics). A 30% decline in eGFR from baseline was seen in 42 (19•4 %) high-risk participants compared to 62 (3•9 %) low-risk participants, HR 5•15; 95 % CI (3•41 to 7•76; p<0.0001). Development of microalbuminuria was seen in 35 (33%) randomised to placebo and 26 (25%) randomised to spironolactone treatment (HR 0•81, 95% CI, 0•49 to 1•34, P=0•41). Harms: hyperkalaemia was seen in 13 versus 4, and gynaecomastia in 3 versus 0 subjects on spironolactone and placebo, respectively. Interpretation: In people with type 2 diabetes and normoalbuminuria, the urinary proteomic classifier CKD273 was associated with a 2•5 times increased risk for progression to microalbuminuria over a median of 2•5 years, independent of clinical characteristics. Spironolactone did not prevent progression to microalbuminuria in high-risk subjects.

BackgroundWhether to treat octogenarians with colorectal cancer (CRC) in the same manner as younger patients remains a challenging issue. The purpose of this study was to analyse postoperative complications and long-term survival in a consecutive cohort of octogenarians who were surgically treated for CRC.MethodsOctogenarians with primary CRC suitable for curative surgery between January 2008 and December 2011 were included. Data about comorbidities, tumour stage, and complications were retrospectively collected from patient files. Data about survival were retrieved with use of the Dutch database for persons and addresses. To identify factors associated with severe postoperative complications and postoperative survival, logistic regression analyses, and Cox regression analyses were performed. Odds ratios and hazard ratios (HR) with 95% confidence intervals (CI) were estimated.ResultsIn a series of 108 octogenarians, median age was 83 years (range 80–94 years). Median follow-up was 47 (range 1–107) months. Major postoperative complications occurred in 25% of the patients. No risk factors for development of severe postoperative complications could be identified. The 30-day mortality was 7%; 1- and 5-year mortality was 19% and 56%, respectively. Overall median survival was 48 months: 66 months in patients without complications versus 13 months in patients with postoperative complications. Postoperative complications were most predictive of decreased survival (HR 3.16; 95% CI 1.79–5.59), even including tumour characteristics, comorbidity, and emergency surgery.ConclusionsLong-term survival in octogenarians deemed fit for surgery is reasonably good. Prevention of major postoperative complications could further improve clinical outcome.

Cardiovascular risk management is an integral part of treatment in Type 2 Diabetes Mellitus (T2DM), and requires pharmacological as well as nutritional management. We hypothesize that a systematic assessment of both pharmacological and nutritional management can identify targets for the improvement of treatment quality. Therefore, we analysed blood pressure (BP) management in the DIAbetes and LifEstyle Cohort Twente (DIALECT). DIALECT is an observational cohort from routine diabetes care, performed at the ZGT Hospital (Almelo and Hengelo, The Netherlands). BP was measured for 15 min with one minute intervals. Sodium and potassium intake was derived from 24-hour urinary excretion. We determined the adherence to pharmacological and non-pharmacological guidelines in patients with BP on target (BP-OT) and BP not on target (BP-NOT). In total, 450 patients were included from August 2009 until January 2016. The mean age was 63 ± 9 years, and the majority was male (58%). In total, 53% had BP-OT. In those with BP-NOT, pharmacological management was suboptimal (zero to two antihypertensive drugs) in 62% of patients, and nutritional guideline adherence was suboptimal in 100% of patients (only 8% had a sodium intake on target, 66% had a potassium intake on target, 3% had a sodium-to-potassium ratio on target, and body mass index was <30 kg/m2 in 35%). These data show pharmacological undertreatment and a low adherence to nutritional guidelines. Uncontrolled BP is common in T2DM, and our data show a window of opportunity for improving BP control, especially in nutritional management. To improve treatment quality, we advocate to incorporate the integrated monitoring of nutritional management in quality improvement cycles in routine care.

Introduction Dietary protein intake may influence development of renal function impairment in diabetes mellitus type 2 (T2DM). We assessed the association between sources of protein and prevalence of renal function impairment. Methods Cross-sectional analyses were performed in baseline data of 420 patients of the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1) study. Protein intake was assessed using a Food Frequency Questionnaire, modified for accurate assessment of protein intake, including types and sources of protein. Renal function impairment was defined as estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m 2 (Chronic Kidney Disease Epidemiology Collaboration formula). Results Among 420 patients with T2DM, 99 renal function impairment cases were identified. Multivariate Cox proportional hazard models were used and adjusted for the main lifestyle and dietary factors. The prevalence ratios in the fully adjusted model were 1 (reference), 0.74 (95% confidence interval [CI]: 0.44–1.27; P = 0.28) and 0.47 (95% CI: 0.23–0.98; P = 0.04) according to increasing tertiles of vegetable protein intake. For animal protein intake the prevalence ratios were 1 (reference), 1.10 (95% CI: 0.64–1.88; P = 0.74) and 1.06 (95% CI: 0.56–1.99; P = 0.87) according to increasing tertiles of intake. Theoretical replacement models showed that replacing 3 energy percent from animal protein by vegetable protein lowered the prevalence ratio for the association with renal function impairment to 0.20 (95% CI: 0.06–0.63; P = 0.01). Conclusion In conclusion, we found that higher intake of vegetable protein was associated with a lower prevalence of renal function impairment, and theoretical replacement of animal protein with vegetable protein was inversely associated with renal function impairment among patients with T2DM.

Several studies reported sex differences in aldosterone. It is unknown whether these differences are associated with differences in volume regulation. Therefore we studied both aldosterone and extracellular volume in men and women on different sodium intakes. In healthy normotensive men ( n = 18) and premenopausal women ( n = 18) we investigated plasma aldosterone, blood pressure, and extracellular volume (I-iothalamate), during both low (target intake 50 mmol Na/day) and high sodium intake (target intake 200 mmol Na/day) in a crossover setup. Furthermore, we studied the adrenal response to angiotensin II infusion (0.3, 1.0, and 3.0 ng·kg·min for 1 h) on both sodium intakes. Men had a significantly higher plasma aldosterone, extracellular volume, and systolic blood pressure than women during high sodium intake ( P < 0.05). During low sodium intake, extracellular volume and blood pressure were higher in men as well ( P < 0.05), whereas the difference in plasma aldosterone was no longer significant ( P = 0.252). The adrenal response to exogenous angiotensin II was significantly lower in men than in women on both sodium intakes. Constitutive sex differences in the regulation of aldosterone, characterized by a higher aldosterone and a lower adrenal response to exogenous angiotensin II infusion in men, are associated with a higher extracellular volume and blood pressure in men. These findings suggest that sex differences in the regulation of aldosterone contribute to differences in volume regulation between men and women.

To study whether fibroblast growth factor 23 (FGF23) is associated with adverse outcomes in patients with type 2 diabetes and normal or mildly impaired kidney function. RESEARCH DESIGN AND METHODS We analyzed C-terminal FGF23 levels in 310 patients with type 2 diabetes and estimated glomerular filtration rate ‡60 mL/min/1.73 m 2. Associations of FGF23 with all-cause mortality and major adverse cardiovascular events (MACE) were studied by Cox regression. RESULTS During a follow-up of 5.8 years (3.3-6.5), 47 patients developed MACE and 28 patients died. FGF23 was associated with an increased risk of all-cause mortality (age-and sex-adjusted hazard ratio 2.78 [95% CI 1.76-4.40]) and MACE (1.67 [1.12-2.49]). Results were similar after additional adjustment for other potential confounders and were consistent upon replication in an independent cohort. CONCLUSIONS In patients with type 2 diabetes and normal or mildly impaired kidney function, FGF23 is associated with an increased risk of cardiovascular events and mortality. In patients with chronic kidney disease (CKD), a higher plasma fibroblast growth factor 23 (FGF23) level has been consistently associated with an increased cardiovascular morbidity and mortality risk (1). Circulating levels of FGF23 increase early in the course of CKD (1), and kidney function is among the strongest determinants of FGF23 levels (2). Alternatively, type 2 diabetes, the most important cause of CKD, is accompanied by abnormalities in bone and mineral metabolism and elevated plasma FGF23 levels (3-5). Currently, it is unknown whether FGF23 is linked with adverse outcomes in patients with type 2 diabetes and normal or mildly impaired kidney function. Therefore, we aimed to investigate whether FGF23 levels are associated with mortality and cardiovascular events in patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) $60 mL/min/1.73 m 2. RESEARCH DESIGN AND METHODS The design of the DIAbetes and LifEstyle Cohort Twente (DIALECT) prospective cohort study has been described in detail previously (6). The study has been approved by the

In type 2 diabetes mellitus (T2D), the handling of magnesium is disturbed. Magnesium deficiency may be associated with a higher risk of coronary heart disease (CHD). We investigated the associations between (1) dietary magnesium intake; (2) 24 h urinary magnesium excretion; and (3) plasma magnesium concentration with prevalent CHD in T2D patients. This cross-sectional analysis was performed on baseline data from the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1, n = 450, age 63 ± 9 years, 57% men, and diabetes duration of 11 (7–18) years). Prevalence ratios (95% CI) of CHD by sex-specific quartiles of magnesium indicators, as well as by magnesium intake per dietary source, were determined using multivariable Cox proportional hazard models. CHD was present in 100 (22%) subjects. Adjusted CHD prevalence ratios for the highest compared to the lowest quartiles were 0.40 (0.20, 0.79) for magnesium intake, 0.63 (0.32, 1.26) for 24 h urinary magnesium excretion, and 0.62 (0.32, 1.20) for plasma magnesium concentration. For every 10 mg increase of magnesium intake from vegetables, the prevalence of CHD was, statistically non-significantly, lower (0.75 (0.52, 1.08)). In this T2D cohort, higher magnesium intake, higher 24 h urinary magnesium excretion, and higher plasma magnesium concentration are associated with a lower prevalence of CHD.

Background/ObjectivesLowering low-density lipoprotein cholesterol (LDLc) in type 2 diabetes mellitus is of paramount importance in preventing cardiovascular disease. However, treatment targets for LDLc are often not reached. We studied the prevalence of LDLc target achievement in a real-life population of type 2 diabetes mellitus patients in secondary care, and investigated whether in those not on target, there is room for intensifying pharmacological and lifestyle management according to current treatment guidelines.Subjects/MethodsWe performed a cross-sectional analysis in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1; n = 450, age 63 ± 9 years, 58% men, diabetes duration 11 (7–18) years). At baseline, we determined plasma LDLc concentration, pharmacological treatment (i.e., statin use), and lifestyle (physical activity and dietary intake). Patients were divided according to LDLc < 1.8, LDLc 1.8–2.5, and LDLc > 2.5 mmol/l. Dietary intake was collected from a validated Food Frequency Questionnaire (177 items) and we determined guideline adherence for different food groups. Physical activity was assessed with the Short Questionnaire to ASsess Health enhancing behavior.ResultsLDLc data were available in 428 type 2 diabetes mellitus patients. LDLc ≤ 2.5 mmol/l was achieved in 317 patients (76%). In total, 76% of patients used statins, in those with LDLc > 2.5 mmol/l, this was 44%. Adherence to lifestyle guidelines was not different between the LDLc groups and was as follows: body mass index 6%, physical activity 59%, vegetables 7%, fruit 28%, legumes 59%, nuts 14%, dairy 19%, fish 36%, tea 8%, fats 66%, red meat 12%, processed meat 2%, alcohol 71%, sweetened beverages 34%, and sodium 12%.ConclusionsIn type 2 diabetes mellitus patients in secondary health care, the target LDLc is achieved by three quarters of patients. Increasing statin treatment could be a first step to improve LDLc. In addition, there are ample opportunities for lifestyle management through increasing adherence to lifestyle guidelines.