Cryoglobulinemic Vasculitis in Disguise: Cryofibrinogenemia as Variant of Monoclonal Gammopathy of Renal Significance.

Monoclonal gammopathy with cryoactivity (ie, cryoglobulins) that causes glomerulonephritis is considered within the spectrum of monoclonal gammopathy of renal significance. Cryofibrinogenemia (cryoactivity of coagulation factors) is very rarely associated with glomerulonephritis. We present a 39-year-old woman with a relapsing nephrotic syndrome. Laboratory investigation detected cryofibrinogen; the precipitate consisted of fibrinogen and a monoclonal immunoglobulin (M-protein; IgG-λ), and the latter was also detected in serum (4g/L). Initial conventional immunosuppressive therapy resulted in temporary renal remission. In view of the M-protein, subsequent therapy consisted of bortezomib/dexamethasone and high-dose melphalan followed by autologous hematopoietic stem cell transplantation, and resulted in a very good partial hematological response and temporary renal remission. However, after hematological and renal relapse, we performed unique experiments to clarify the role of the M-protein. Mixing patient serum with donor plasma resulted in cryoactivity, composed of M-protein+fibrinogen. Patient plasma deprived of M-protein did not have cryoactivity. Therefore, cryoactivity was dependent on the M-protein. We started lenalidomide, which resulted in very good partial hematological and renal remission. Thus, cryofibrinogenemia can be the consequence of an M-protein, which we suggest should be defined as monoclonal gammopathy of renal significance.

Low Urinary Potassium Excretion Is Associated with Higher Risk of All-Cause Mortality in Patients with Type 2 Diabetes: Results of the Dutch Diabetes and Lifestyle Cohort Twente (DIALECT).

BACKGROUND: Low 24-h urinary potassium excretion, reflecting low potassium intake, is associated with premature mortality in the general population. OBJECTIVES: To determine whether urinary potassium excretion is associated with all-cause mortality in patients with type 2 diabetes. METHODS: We performed a prospective cohort study in 654 patients with type 2 diabetes in the Diabetes and Lifestyle Cohort Twente (DIALECT). Sex-specific tertiles of 24-h urinary potassium excretion were analyzed in a multivariable Cox regression model with all-cause mortality. The outpatient program of the hospital uses a continuous surveillance system by the municipal registry of death to ensure up-to-date information on the patient's status (alive or deceased). FFQs were used to study associations between urinary potassium excretion and food products. RESULTS: Urinary potassium excretion at baseline was 84 ± 25 mmol/d in males and 65 ± 22 mmol/d in females, corresponding to estimated potassium intakes of 4250 ± 1270 mg/d and 3300 ± 875 mg/d. During a median follow-up of 5.2 (IQR: 2.7-7.9] y, 96 participants died. In a fully adjusted model, patients in the lowest sex-specific tertile had a higher risk of all-cause mortality, compared with patients in the highest sex-specific tertile (HR: 2.09; 95% CI: 1.06, 4.10; P = 0.03). Patients in the lowest sex-specific tertile consumed fewer fruits and vegetables, dairy, coffee, and potato products compared with patients in the highest sex-specific tertile (all P < 0.05). CONCLUSIONS: Low potassium intake is associated with a higher risk of all-cause mortality in Dutch patients with type 2 diabetes. Intervention studies are needed to determine whether potassium supplementation improves longevity in patients with type 2 diabetes. This trial was registered in the Dutch Trial Register as NTR trial code 5855.

Adherence to Statin Therapy and Attainment of LDL Cholesterol Targets in an Outpatient Population of Type 2 Diabetes Patients: Analysis in the DIAbetes and LifEstyle Cohort Twente (DIALECT).

Objective: To assess adherence to statin therapy and its association with sociodemographic data, medical characteristics, LDLc levels, and LDLc target attainment in real-world T2D patients treated in secondary care. Research Design and Methods: Cross-sectional analyses were performed on baseline data of 393 patients in the DIAbetes and LifEstyle Cohort Twente (DIALECT). The medication possession ratio (MPR), calculated with pharmacy dispensing data, was used to determine adherence to statins for an intended period of 24 months. Statins were included in the analyses if they were used for at least six consecutive months with at least three dispenses. Adherence was defined as an MPR ≥80%. Associations with adherence were assessed using descriptive statistics and binary logistic regression. Results: Overall, 80% of the patients had a statin prescription and of those, 89% were adherent. The proportion of patients who reached LDLc targets of ≤2.5 mmol/L and <1.8 mmol/L differed significantly between the adherent, nonadherent and non-statin group (90% vs. 74% vs. 46%; p < 0.01 and 56% vs. 26% vs. 6%; p < 0.01, respectively). Serum LDLc levels were lower in the adherent versus the nonadherent and non-statin group (1.76 ± 0.60 vs. 2.23 ± 0.90 vs. 2.71 ± 0.67 mmol/L; p < 0.01). Higher HbA1c levels were independently associated with nonadherence (OR: 1.05, 95% CI 1.01-1.08; p < 0.01). Mediation adherence (OR: 2.88, 95% CI 1.04-7.97; p = 0.041) and lower BMI (OR: 0.88, 95% CI 0.81-0.96; p < 0.01) were independently associated with attaining the LDLc target of ≤2.5 mmol/L. Conclusion: In patients with T2D treated in secondary care, statin adherence was relatively high and was associated with significantly lower LDLc levels. It is important to identify nonadherence as it appeared an important determinant of failure to reach LDLc targets. The finding that many patients who failed to attain LDLc targets did not receive statin treatment offers an opportunity to improve diabetes care.

[An asymptomatic patient with lactate acidosis and hypercapnia]. / Een asymptomatische patiënt met lactaatacidose en hypercapnie.

BACKGROUND: Blood gas analyses are used to identify acid-base and respiratory disturbances. Blood gas abnormalities can be first signs of serious underlying disease. CASE DESCRIPTION: An 82-year old women with chronic kidney disease (eGFR 35 ml/min/1.73m2) and rheumatoid arthritis was admitted to the geriatric ward due to a urinary tract infection and bloody diarrhea. She repeatedly had a low oxygen saturation, although without symptoms. Capillary blood gas analysis was evidently disturbed (pH 6.96, pCO2 9.3 kPa, lactate 8.4 mmol/l), and led to consultation of the intensivist. Careful physical examination demonstrated that the patients' hands had blue discoloration, typical for Raynaud's phenomenon. Arterial blood gas demonstrated normal results. CONCLUSION: Capillary blood gas analysis is less reliable when peripheral circulation is disturbed. When the results are aberrant, it is important to distinguish between peripheral vascular disease and diminished systemic circulation. Arterial blood gas analysis can be used to support the diagnosis.

Low Physical Activity in Patients with Complicated Type 2 Diabetes Mellitus Is Associated with Low Muscle Mass and Low Protein Intake.

OBJECTIVE: In order to promote physical activity (PA) in patients with complicated type 2 diabetes, a better understanding of daily movement is required. We (1) objectively assessed PA in patients with type 2 diabetes, and (2) studied the association between muscle mass, dietary protein intake, and PA. Methods: We performed cross-sectional analyses in all patients included in the Diabetes and Lifestyle Cohort Twente (DIALECT) between November 2016 and November 2018. Patients were divided into four groups: <5000, 5000-6999, 7000-9999, ≥ 10,000 steps/day. We studied the association between muscle mass (24 h urinary creatinine excretion rate, CER) and protein intake (by Maroni formula), and the main outcome variable PA (steps/day, Fitbit Flex device) using multivariate linear regression analyses. RESULTS: In the 217 included patients, the median steps/day were 6118 (4115-8638). Of these patients, 48 patients (22%) took 7000-9999 steps/day, 37 patients (17%) took ≥ 10,000 steps/day, and 78 patients (36%) took <5000 steps/day. Patients with <5000 steps/day had, in comparison to patients who took ≥10,000 steps/day, a higher body mass index (BMI) (33 ± 6 vs. 30 ± 5 kg/m2, p = 0.009), lower CER (11.7 ± 4.8 vs. 14.8 ± 3.8 mmol/24 h, p = 0.001), and lower protein intake (0.84 ± 0.29 vs. 1.08 ± 0.22 g/kg/day, p < 0.001). Both creatinine excretion (ß = 0.26, p < 0.001) and dietary protein intake (ß = 0.31, p < 0.001) were strongly associated with PA, which remained unchanged after adjustment for potential confounders. CONCLUSIONS: Prevalent insufficient protein intake and low muscle mass co-exist in obese patients with low physical activity. Dedicated intervention studies are needed to study the role of sufficient protein intake and physical activity in increasing or maintaining muscle mass in patients with type 2 diabetes.

Lifestyle-Related Exposure to Cadmium and Lead is Associated with Diabetic Kidney Disease.

BACKGROUND: Environmental factors contributing to diabetic kidney disease are incompletely understood. We investigated whether blood cadmium and lead concentrations were associated with the prevalence of diabetic kidney disease, and to what extent lifestyle-related exposures (diet and smoking) contribute to blood cadmium and lead concentrations. MATERIAL AND METHODS: In a cross-sectional analysis in 231 patients with type 2 diabetes included in the DIAbetes and LifEstyle Cohort Twente (DIALECT-1), blood cadmium and lead concentrations were determined using inductively coupled plasma mass spectrometry. The associations between diet (derived from food frequency questionnaire), smoking and cadmium and lead were determined using multivariate linear regression. The associations between cadmium and lead and diabetic kidney disease (albumin excretion >30 mg/24 h and/or creatinine clearance <60 mL/min/1.73 m2) were determined using multivariate logistic regression. RESULTS: Median blood concentrations were 2.94 nmol/L (interquartile range (IQR): 1.78-4.98 nmol/L) for cadmium and 0.07 µmol/L (IQR: 0.04-0.09 µmol/L) for lead, i.e., below acute toxicity values. Every doubling of lead concentration was associated with a 1.75 (95% confidence interval (CI): 1.11-2.74) times higher risk for albuminuria. In addition, both cadmium (odds ratio (OR) 1.50 95% CI: 1.02-2.21) and lead (OR 1.83 95% CI: 1.07-3.15) were associated with an increased risk for reduced creatinine clearance. Both passive smoking and active smoking were positively associated with cadmium concentration. Alcohol intake was positively associated with lead concentration. No positive associations were found between dietary intake and cadmium or lead. CONCLUSIONS: The association between cadmium and lead and the prevalence of diabetic kidney disease suggests cadmium and lead might contribute to the development of diabetic kidney disease. Exposure to cadmium and lead could be a so far underappreciated nephrotoxic mechanism of smoking and alcohol consumption.

Fibroblast Growth Factor 23 and Mortality in Patients With Type 2 Diabetes and Normal or Mildly Impaired Kidney Function.

OBJECTIVE: 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 m2. 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.

Body weight course in the DIAbetes and LifEstyle Cohort Twente (DIALECT-1)-A 20-year observational study.

BACKGROUND: Although weight gain increases risk of type 2 diabetes, real-life data on the weight course in patients with established type 2 diabetes are scarce. We assessed weight course in a real-life diabetes secondary care setting and analyzed its association with patient characteristics, lifestyle habits and initiation of insulin, glucagon like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i). METHODS: Data on weight, insulin, GLP-1 RA and SGLT-2i use were collected retrospectively (12 years) and prospectively (8 years) from patients included in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1, n = 450, age 63 ± 9 years, 58% men, diabetes duration [7-18] years). Lifestyle habits were assessed using validated questionnaires. The association of clinical parameters with body mass index (BMI) course was determined using linear mixed models. Patients who underwent bariatric surgery (n = 19) had a distinct BMI course and were excluded from the study. RESULTS: Baseline BMI was 31.3 (0.3) and was higher in women, patients aged <60 years and patients with unfavorable lifestyle habits. BMI increased to 32.5 (0.3) after 12 years (P<0.001), and thereafter decreased to 31.5 (0.3) after 20 years, resulting in a similar BMI as the baseline BMI (P = 0.96, compared to baseline). Clinical parameters or initiation of insulin or SGLT-2i were not associated with BMI course. Patients who initiated GLP-1 RA declined in BMI compared to non-users (Pinteraction = 0.003). CONCLUSIONS: High BMI that real-life patients with type 2 diabetes gained earlier in life, remained stable in the following decades. Weight loss interventions should remain a priority, and GLP-1 RA might be considered to support weight loss.

High Dietary Intake of Vegetable Protein Is Associated With Lower Prevalence of Renal Function Impairment: Results of the Dutch DIALECT-1 Cohort.

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 m2 (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.

Requirements of an Application to Monitor Diet, Physical Activity and Glucose Values in Patients with Type 2 Diabetes: The Diameter.

Adherence to a healthy diet and regular physical activity are two important factors in sufficient type 2 diabetes mellitus management. It is recognized that the traditional treatment of outpatients does not meet the requirements for sufficient lifestyle management. It is hypothesised that a personalized diabetes management mHealth application can help. Such an application ideally measures food intake, physical activity, glucose values, and medication use, and then integrates this to provide patients and healthcare professionals insight in these factors, as well as the effect of lifestyle on glucose values in daily life. The lifestyle data can be used to give tailored coaching to improve adherence to lifestyle recommendations and medication use. This study describes the requirements for such an application: the Diameter. An iterative mixed method design approach is used that consists of a cohort study, pilot studies, literature search, and expert meetings. The requirements are defined according to the Function and events, Interactions and usability, Content and structure and Style and aesthetics (FICS) framework. This resulted in 81 requirements for the dietary (n = 37), activity and sedentary (n = 15), glycaemic (n = 12), and general (n = 17) parts. Although many applications are currently available, many of these requirements are not implemented. This stresses the need for the Diameter as a new personalized diabetes application.

Detection of carnosinase-1 in urine of healthy individuals and patients with type 2 diabetes: correlation with albuminuria and renal function.

Low serum carnosinase (CN-1) concentrations are associated with low risk for development of diabetic nephropathy (DN) in patients with type 2 diabetes (T2D). Although CN-1 is expressed in the kidney, urinary CN-1 (CNU) excretion and its pathological relevance in patients with T2D have not been investigated to date. The present study therefore assessed the extent of CNU excretion in healthy subjects (n = 243) and in patients with T2D (n = 361) enrolled in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1) in relation to functional renal parameters. CNU was detected in a high proportion of healthy individuals, 180 (74%); median CNU excretion was 0.25 mg/24 h [(IQR 0-0.65 mg/24 h]. In patients with T2D the prevalence and extent of CNU increased in parallel with albuminuria (r = 0.59, p < 0.0001; median CNU 0.1 vs 0.2 vs 1.5 mg/24 h, p < 0.0001; prevalence of CNU 61 vs. 81 vs. 97% p < 0.05 in normo- (n = 241), micro- (n = 80) and macroalbuminuria (n = 40), respectively). Patients with estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 displayed higher median CNU excretion rates in comparison to patients with preserved eGFR (> 90 ml/min/1.73 m2) (1.36 vs 0.13 mg/24 h, p < 0.05). Backward stepwise multivariate linear regression analysis revealed albuminuria, eGFR and glycosuria to be independent factors of CNU excretion rates, all together explaining 37% of variation of CNU excretion rates (R2 = 0.37, p < 0.0001). These results show for the first time that CN-1 can be detected in urine and warrants prospective studies to assess the relevance of CNU for renal function deterioration in diabetes patients.

Long-Term Survival in Octogenarians After Surgical Treatment for Colorectal Cancer: Prevention of Postoperative Complications is Key.

BACKGROUND: Whether 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. METHODS: Octogenarians 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. RESULTS: In 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. CONCLUSIONS: Long-term survival in octogenarians deemed fit for surgery is reasonably good. Prevention of major postoperative complications could further improve clinical outcome.

Glycaemic control in the diabetes and Lifestyle Cohort Twente: A cross-sectional assessment of lifestyle and pharmacological management on Hba1c target achievement.

The majority of patients with type 2 diabetes do not reach target levels of glycated haemoglobin (HbA1c < 7%). We investigated the prevalence of HbA1c-target achievement and opportunities afforded by lifestyle and pharmacological treatment to increase target achievement. We performed cross-sectional analyses of baseline data from the Diabetes and Lifestyle Cohort Twente-1 (DIALECT-1). Patients were divided according to (1) HbA1c <53 and ≥53 mmol/mol (<7%) and (2) non-insulin treatment and tertiles of daily insulin use. We found that 161 (36%) patients achieved the target HbA1c level. Patients with HbA1c ≥53 mmol/mol had a longer duration of diabetes (13 [8-20] vs 9 [4-14] years; P < .001) and more frequently were insulin-users (76% vs 41%, P < .001). Patients in the highest tertile of insulin use had a higher body mass index than those in the lowest tertile (35.8 ± 5.5 vs 29.8 ± 5.5 kg/m2 ; P < .001). Achievement of target HbA1c is low in this type 2 diabetes population. High resistance to pharmacological treatment, paralleled with high body mass index, illustrates that increasing insulin sensitivity through lifestyle intervention is the best opportunity to improve HbA1c target achievement in this real-life population.

Real-life achievement of lipid-lowering treatment targets in the DIAbetes and LifEstyle Cohort Twente: systemic assessment of pharmacological and nutritional factors.

BACKGROUND/OBJECTIVES: Lowering 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/METHODS: We 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. RESULTS: LDLc 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%. CONCLUSIONS: In 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.

Higher Dietary Magnesium Intake and Higher Magnesium Status Are Associated with Lower Prevalence of Coronary Heart Disease in Patients with Type 2 Diabetes.

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.

Sex differences in renin-angiotensin-aldosterone system affect extracellular volume in healthy subjects.

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 (125I-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-1·min-1 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.

Renoprotective RAAS inhibition does not affect the association between worse renal function and higher plasma aldosterone levels.

BACKGROUND: Aldosterone is elevated in chronic kidney disease (CKD) and may be involved in hypertension. Surprisingly, the determinants of the plasma aldosterone concentration (PAC) and its role in hypertension are not well studied in CKD. Therefore, we studied the determinants of aldosterone and its association with blood pressure in CKD patients. We also studied this during renin-angiotensin-aldosterone system inhibition (RAASi) to establish clinical relevance, as RAASi is the treatment of choice in CKD with albuminuria. METHODS: We performed a post-hoc analysis on data from a randomized controlled double blind cross-over trial in non-diabetic CKD patients (n = 33, creatinine clearance (CrCl) 85 (75-95) ml/min, proteinuria 3.2 (2.5-4.0) g/day). Patients were treated with losartan 100 mg (ARB), and ARB + hydrochlorothiazide 25 mg (HCT), during both a regular (200 ± 10 mmol Na+/day) and low (89 ± 8 mmol Na+/day) dietary sodium intake, in 6-week study periods. PAC data at the end of each study period were analyzed. The association between PAC and blood pressure was analyzed continuously, and according to PAC above or below the median. RESULTS: Lower CrCl was correlated with higher PAC during placebo as well as during ARB (ß = -1.213, P = 0.008 and ß = -1.090, P = 0.010). Higher PAC was not explained by high renin, illustrated by a comparable association between CrCl and the aldosterone-to-renin ratio. The association between lower CrCl and higher PAC was also found in a second study with single RAASi with ACE inhibition (ACEi; lisinopril 40 mg/day), and dual RAASi (lisinopril 40 mg/day + valsartan 320 mg/day). Higher PAC was associated with a higher systolic blood pressure (P = 0.010) during different study periods. Only during maximal treatment with ARB + HCT + dietary sodium restriction, blood pressure was no longer different in subjects with a PAC above and below the median. CONCLUSIONS: In CKD patients with a standardized regular sodium intake, worse renal function is associated with a higher aldosterone, untreated and during RAASi with either ARB, ACEi, or both. Furthermore, higher aldosterone is associated with higher blood pressure, which can be treated with the combination of RAASi, HCT and dietary sodium restriction. The first study was performed before it was standard to register trials and the study was not retrospectively registered. The second study was registered in the Netherlands Trial Register on the 5th of May 2006 (NTR675).

Integrated Assessment of Pharmacological and Nutritional Cardiovascular Risk Management: Blood Pressure Control in the DIAbetes and LifEstyle Cohort Twente (DIALECT).

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 minutes 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.