Gerald Vervoort

The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide

Rationale The endothelial nitric oxide synthase Glu298Asp polymorphism has been suggested to play a role in the development of hypertension, atherosclerosis and coronary artery disease. Objective To investigate functional differences between the various genotypes with respect to basal nitric oxide (NO) production, we estimated the response to endothelial NO synthase (ecNOS) inhibition by infusion of increasing doses of NG–monomethyl-l-arginine (l-NMMA) into the brachial artery during venous occlusion plethysmography. Methods In 41 healthy subjects forearm blood flow responses to intra-arterial infusion of increasing doses of l-NMMA (0.05, 0.1 and 0.2 mg/min per dl) and norepinephrine (10, 20 and 40 ng/min per dl) were measured. The genotype of the ecNOS Glu298Asp polymorphism was assessed. Results Nineteen subjects had the Glu/Glu genotype, 19 subjects had the Glu/Asp genotype and three subjects had the Asp/Asp genotype. Groups were comparable concerning demographic, hemodynamic and possible confounding factors. Subjects with the Asp allele showed a reduced response to infusion of l-NMMA as compared to subjects with the Glu/Glu genotype (ANOVA, P = 0.01). There was no significant difference in the response to infusion of the NO-independent vasoconstrictor, norepinephrine, between both groups. Conclusions The ecNOS Glu298Asp polymorphism is associated with reduced basal NO production and might therefore have functional implications in the development of atherosclerosis or hypertension.

Activation of the Sodium-Potassium Pump Contributes to Insulin-Induced Vasodilation in Humans

Systemic hyperinsulinemia induces vasodilation in human skeletal muscle. This vasodilation contributes to insulin-stimulated glucose uptake and has been found to be reduced in various insulin-resistant states. The mechanism of the effect of insulin on vascular tone is not completely understood. We hypothesized that activation of the sodium-potassium pump (Na+, K(+)-ATPase) located in endothelial or smooth muscle cells would be involved in the insulin-mediated vasodilation. Therefore, in 24 healthy, nonsmoking, nonobese, normotensive volunteers, we infused ouabain, a specific inhibitor of Na+, K(+)-ATPase, into the brachial artery before and during euglycemic hyperinsulinemia. As expected, insulin (systemic concentrations, approximately 700 [low] and 1400 [high] pmol.L-1) induced vasodilation in the control arm (forearm blood flow [FBF, plethysmography] from 1.6 +/- 0.2 to 2.1 +/- 0.4 mL.dL-1.min-1 [low insulin] and from 1.6 +/- 0.2 to 2.1 +/- 0.2 [high insulin], P < .05 for both), but the increase in FBF was abolished in the ouabain-infused forearm (from 1.3 +/- 0.1 to 1.4 +/- 0.2 mL.dL-1.min-1 [low] and from 1.3 +/- 0.1 to 1.3 +/- 0.1 [high], P = NS). Ouabain-induced increases in forearm potassium release were partly reversed by insulin. To investigate whether the mechanism of action could be at the endothelial level, we infused NG-monomethyl-I-arginine (L-NMMA), an inhibitor of endothelial nitric oxide synthase (0.05, 0.1, and 0.2 mg.dL-1.min-1) intra-arterially in 12 subjects and induced a clear dose-dependent decrease of FBF from 1.7 +/- 0.2 to 1.2 +/- 0.1 mL.dL-1.min-1 (P < .01). In contrast, after ouabain (and continued insulin) infusion, L-NMMA had no effect on FBF (from 1.6 +/- 0.4 to 1.5 +/- 0.3 mL.dL-1.min-1, n = 6, P = .66). These results demonstrate that insulin induces vasodilation by stimulation of Na+, K(+)-ATPase. This activation of Na+, K(+)-ATPase could occur at the level of the endothelium rather than that of vascular smooth muscle and contributes to the endothelium-dependent vasodilator response to insulin.

Multifactorial intervention with nurse practitioners does not change cardiovascular outcomes in patients with chronic kidney disease

Strict implementation of guidelines directed at multiple targets reduces vascular risk in diabetic patients. Whether this also applies to patients with chronic kidney disease (CKD) is uncertain. To evaluate this, the MASTERPLAN Study randomized 788 patients with CKD (estimated GFR 20-70 ml/min) to receive additional intensive nurse practitioner support (the intervention group) or nephrologist care (the control group). The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death. During a mean follow-up of 4.62 years, modest but significant decreases were found for blood pressure, LDL cholesterol, anemia, proteinuria along with the increased use of active vitamin D or analogs, aspirin and statins in the intervention group compared to the controls. No differences were found in the rate of smoking cessation, weight reduction, sodium excretion, physical activity, or glycemic control. Intensive control did not reduce the rate of the composite end point (21.3/1000 person-years in the intervention group compared to 23.8/1000 person-years in the controls (hazard ratio 0.90)). No differences were found in the secondary outcomes of vascular interventions, all-cause mortality or end-stage renal disease. Thus, the addition of intensive support by nurse practitioner care in patients with CKD improved some risk factor levels, but did not significantly reduce the rate of the primary or secondary end points.

Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion

Background  Glomerular hyperfiltration plays a role in the pathophysiology of diabetic nephropathy. An increase in the glomerular filtration rate (GFR) could result from primary actions at the glomerular/vascular level or could be the consequence of a primary increase in proximal tubular sodium reabsorption resulting in systemic volume expansion. Recently it was hypothesized that an increase in sodium reabsorption may lead to glomerular hyperfiltration through the tubulo‐glomerular feedback mechanism (tubular‐hypothesis) without volume expansion.

Nurse Practitioner Care Improves Renal Outcome in Patients with CKD

Treatment goals for patients with CKD are often unrealized for many reasons, but support by nurse practitioners may improve risk factor levels in these patients. Here, we analyzed renal endpoints of the Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse Practitioners (MASTERPLAN) study after extended follow-up to determine whether strict implementation of current CKD guidelines through the aid of nurse practitioners improves renal outcome. In total, 788 patients with moderate to severe CKD were randomized to receive nurse practitioner support added to physician care (intervention group) or physician care alone (control group). Median follow-up was 5.7 years. Renal outcome was a secondary endpoint of the MASTERPLAN study. We used a composite renal endpoint of death, ESRD, and 50% increase in serum creatinine. Event rates were compared with adjustment for baseline serum creatinine concentration and changes in estimated GFR were determined. During the randomized phase, there were small but significant differences between the groups in BP, proteinuria, LDL cholesterol, and use of aspirin, statins, active vitamin D, and antihypertensive medications, in favor of the intervention group. The intervention reduced the incidence of the composite renal endpoint by 20% (hazard ratio, 0.80; 95% confidence interval, 0.66 to 0.98; P=0.03). In the intervention group, the decrease in estimated GFR was 0.45 ml/min per 1.73 m(2) per year less than in the control group (P=0.01). In conclusion, additional support by nurse practitioners attenuated the decline of kidney function and improved renal outcome in patients with CKD.

Elevated skeletal muscle blood flow in noncomplicated type 1 diabetes mellitus: role of nitric oxide and sympathetic tone.

Capillary hyperperfusion precedes and contributes to the occurrence of diabetic microangiopathy. Vascular tone is regulated by the balance of vasodilating and vasoconstricting factors, of which nitric oxide (NO; an endothelium dependent vasodilator) and norepinephrine (NE; a potent vasoconstrictor), respectively, are of primary importance. To investigate the role of these factors in hyperperfusion, we measured forearm blood flow (FBF) in 50 patients with noncomplicated type 1 diabetes (DP) and 50 healthy control subjects (CS) under baseline conditions and during intrabrachial infusion of N(G)-monomethyl-L-arginine (L-NMMA), an endothelium-dependent vasoconstrictor, and acetylcholine (ACh), an endothelium-dependent vasodilator. Furthermore, we determined arterial plasma NE concentration at baseline and then determined alpha-adrenergic receptor sensitivity by measuring FBF response to intra-arterially infused NE. We found that basal FBF was increased in DP (2.9+/-0.1 versus 2.0+/-0.1 mL. min(-1). dL(-1) in CS; P<0.01). L-NMMA caused a similar vasoconstriction in both groups (28.5+/-1. 7% in DP versus 31.2+/-2.2% in CS; P=NS). Maximum blood flow during infusion of ACh was not different (23.3+/-1.9 mL. min(-1). dL(-1) in DP versus 20.1+/-1.6 in CS). Arterial plasma NE concentrations were significantly decreased in DP (0.57+/-0.03 versus 0.81+/-0.05 nmol/L in CS; P<0.01). The vasoconstrictive effect of NE was increased in DP (slope log dose-response curve, 31.3+/-1.5 versus 24.3+/-1.8 in CS; P<0.01). We conclude that basal FBF is increased in noncomplicated type 1 diabetes. We found no evidence of a disturbance of basal or stimulated NO production. Arterial plasma NE concentrations are decreased in noncomplicated type 1 diabetes. This may explain the vasodilatation at baseline and the increased vascular response to intra-arterially NE.

Atrial natriuretic peptide increases albuminuria in type 1 diabetic patients: evidence for blockade of tubular protein reabsorption.

It has been suggested that atrial natriuretic peptide (ANP) contributes to the glomerular hyperfiltration of diabetes mellitus. Infusion of ANP increases the urinary excretion of albumin in patients with type 1 diabetes mellitus (IDDM). Although the increased albuminuria is attributed to a rise in glomerular pressure, alterations in tubular protein handling might be involved.

Initial Implementation of a Web-Based Consultation Process for Patients With Chronic Kidney Disease

PURPOSE A Web-based consultation system (telenephrology) enables family physicians to consult a nephrologist about a patient with chronic kidney disease. Relevant data are exported from the patient’s electronic file to a protected digital environment from which advice can be formulated by the nephrologist. The primary purpose of this study was to assess the potential of telenephrology to reduce in-person referrals. METHODS In an observational, prospective study, we analyzed telenephrology consultations by 28 family practices and 5 nephrology departments in the Netherlands between May 2009 and August 2011. The primary outcome was the potential reduction of in-person referrals, measured as the difference between the number of intended referrals as stated by the family physician and the number of referrals requested by the nephrologist. The secondary outcome was the usability of the system, expressed as time invested, the implementation in daily work hours, and the response time. Furthermore, we evaluated the questions asked. RESULTS One hundred twenty-two new consultations were included in the study. In the absence of telenephrology, 43 patients (35.3%) would have been referred by their family physicians, whereas the nephrologist considered referral necessary in only 17 patients (13.9%) (P <.001). The family physician would have treated 79 patients in primary care. The nephrologist deemed referral necessary for 10 of these patients. Time investment per consultation amounted to less than 10 minutes. Consultations were mainly performed during office hours. Response time was 1.6 days (95% CI, 1.2–1.9 days). Most questions concerned estimated glomerular filtration rate, proteinuria, and blood pressure. CONCLUSION A Web-based consultation system might reduce the number of referrals and is usable. Telenephrology may contribute to an effective use of health facilities by allowing patients to be treated in primary care with remote support by a nephrologist.

Nocturnal blood glucose profiles in patients with type 1 diabetes mellitus on multiple (>4) daily insulin injection regimens

The aim of the study was to examine nocturnal blood glucose profiles in Type 1 diabetic patients on multiple (⩾4) daily insulin injections. Nocturnal blood glucose profiles were evaluated in 31 patients collecting blood samples half‐hourly from 23.00 till 07.30 h, while they were asleep. Nocturnal episodes of hypoglycaemia (blood glucose <3.0 mmol l−1) occurred in 29 % of these nights; 67 % of episodes were asymptomatic. In the early night (23.00–01.00 h), five episodes occurred with a median duration of 1 h. In the early morning (04.00–07.30 h) seven episodes occurred with a median duration of 3 h. No hypoglycaemia was noted from 01.00 to 04.00 h. Bedtime glucose levels appeared to predict ‘early night’ hypoglycaemia but not ‘early morning’ hypoglycaemia. Fasting glucose levels <5.5 mmol l−1 were indicative of preceding ‘early morning’ hypoglycaemia. There was a large intra‐individual variation in nocturnal blood glucose profiles. It is concluded that daily monitoring of bedtime and fasting blood glucose levels may be both more reliable and convenient for the prevention of nocturnal hypoglycaemia than periodic testing of blood glucose at 03.00h as is often advised. Setting a target of >5.5 mmol l−1 for fasting blood glucose may decrease the frequency of nocturnal hypoglycaemia.

Multifactorial approach and superior treatment efficacy in renal patients with the aid of nurse practitioners. Design of The MASTERPLAN Study [ISRCTN73187232]

BackgroundPatients with chronic kidney disease (CKD) are at a greatly increased risk of developing cardiovascular disease. Recently developed guidelines address multiple risk factors and life-style interventions. However, in current practice few patients reach their targets.A multifactorial approach with the aid of nurse practitioners was effective in achieving treatment goals and reducing vascular events in patients with diabetes mellitus and in patients with heart failure. We propose that this also holds for the CKD population.DesignMASTERPLAN is a multicenter randomized controlled clinical trial designed to evaluate whether a multifactorial approach with the aid of nurse-practicioners reduces cardiovascular risk in patients with CKD. Approximately 800 patients with a creatinine clearance (estimated by Cockcroft-Gault) between 20 to 70 ml/min, will be included. To all patients the same set of guidelines will be applied and specific cardioprotective medication will be prescribed. In the intervention group the nurse practitioner will provide lifestyle advice and actively address treatment goals. Follow-up will be five years. Primary endpoint is the composite of myocardial infarction, stroke and cardiovascular mortality. Secondary endpoints are cardiovascular morbidity, overall mortality, decline of renal function, change in markers of vascular damage and change in quality of life. Enrollment has started in April 2004 and the study is on track with 700 patients included on October 15th, 2005. This article describes the design of the MASTERPLAN study.