[The portfolio will increase the quality of specialist education]. / Het portfolio zal de kwaliteit van de speciajistenopleiding vergroten.

The portfolio gives the doctor who is undergoing training to become a specialist (Dutch abbreviation aios) a tool to help describe his or her own progress and the future targets in the training programme, and assists the trainer to obtain a more detailed insight into the educational goals that should receive more emphasis. The self-critical attitude of the aios that this helps to develop is a good guarantee for society of the thoroughness of medical specialist training.

Felodipine in hypertensive patients. A dose finding study in patients refractory to beta-blocker monotherapy.

In a double-blind study, 128 patients with essential hypertension, refractory to beta-blocker monotherapy, were randomised to 1 of 4 treatment groups. Felodipine 2.5 mg twice daily, 5mg twice daily, 10mg twice daily or matched placebo twice daily were administered in addition to the beta-blocker for 4 weeks. Mean supine blood pressure before randomisation to treatment was 167/104 +/- 20/7mm Hg. After 4 weeks of treatment, supine blood pressures 2 hours after dose were 161/98 +/- 20/10mm Hg (P), 152/92 +/- 23/8mm Hg (felodipine 2.5mg), 142/87 +/- 18/7mm Hg (felodipine 5mg) and 142/86 +/- 17/7mm Hg (felodipine 10mg). The falls in systolic and diastolic blood pressures were significantly greater for all 3 felodipine groups than for placebo. Blood pressure reductions were less marked 14 hours after dosage: 161/100 +/- 20/9mm Hg (P), 160/97 +/- 24/9mm Hg (felodipine 2.5mg), 153/97 +/- 21/11mm Hg (felodipine 5mg), and 157/94 +/- 19/9mm Hg (felodipine 10mg); but the two higher doses of felodipine produced a significantly greater sustained fall in blood pressure than placebo. There was a correlation between the dose of felodipine and its antihypertensive effect. Standing blood pressures were reduced to the same extent as supine measurements. Heart rate was not significantly affected. Bodyweight did not increase during the study. Side effects of felodipine therapy were minor, and mostly attributable to the vasodilatory properties of the drug. Only 4 patients withdrew because of side effects. It is concluded that felodipine is an effective and well tolerated antihypertensive drug, and that 5mg twice daily is a suitable starting dose in hypertensive patients refractory to beta-blocker monotherapy. It may be necessary to increase this dose to 10mg twice daily in selected patients.

Haemodynamic, hormonal, and diuretic effects of felodipine in healthy normotensive volunteers.

Felodipine and placebo were infused in a double-blind, crossover study in 10 healthy normotensive volunteers. Compared with placebo, felodipine caused a significant decrease in diastolic blood pressure and forearm vascular resistance, while there was no change in systolic blood pressure. The rises in heart rate, plasma renin activity and plasma noradrenaline (norepinephrine) concentration further demonstrated the vasodilating activity of felodipine. Plasma aldosterone, adrenaline (epinephrine) and antidiuretic hormone concentrations were similar after a 90-minute infusion of felodipine or placebo. The response of plasma aldosterone levels to exogenous adenocorticotrophic hormone showed evidence of a slight blunting during felodipine infusion. Felodipine had a marked diuretic effect, probably secondary to an increase in natriuresis, which might be due to a direct tubular effect of the drug.

Haemodynamic effects of intravenous felodipine in normotensive and hypertensive subjects.

The effects of intravenous administration of a new calcium antagonist, felodipine, were studied in healthy subjects and hypertensive patients. Felodipine infused at a rate of 0.01 mg/min in 10 normotensive volunteers caused gradual haemodynamic and hormonal changes compatible with a direct vasodilatory mechanism of action; it also had a diuretic and natriuretic effect. When infused at a mean dose of 0.02 mg/kg bodyweight over 20 to 120 minutes in 7 patients with a hypertensive emergency, felodipine caused a rapid reduction in blood pressure with a maximal fall in mean arterial pressure of 30.4 +/- 7.3% (mean +/- 1 SD) in 30 minutes. No serious side effects were observed. The haemodynamic effectiveness of an infusion rate of 0.01 mg/min was confirmed in a pilot study of 5 patients with refractory hypertension. On the basis of these findings, a schedule for the treatment of acute hypertension with intravenous felodipine is proposed.

Acute renal effects of felodipine in hypertensive patients with kidney disease.

In contrast to other types of directly acting vasodilators, calcium antagonists promote sodium excretion. It is not well established, however, whether these drugs also induce natriuresis in hypertensive patients with renal disease. Therefore, we studied the acute effects of the dihydropyridine calcium antagonist felodipine in nine such patients (CCr 68 +/- 19 ml/min) and 12 healthy normotensive subjects. In both the hypertensive patients and the normotensive subjects total and fractional sodium excretion rose during the first 40 minutes of intravenous felodipine infusion; in the hypertensive patients this rise of sodium excretion was positively correlated to the initial glomerular filtration rate (GFR) (r = 0.87, P less than 0.01). In the patients, during ongoing felodipine infusion, natriuresis was attenuated in the setting of a large continuing decrease of blood pressure. In contrast, in the normotensive subjects, in whom blood pressure did not fall any further, a steady rise of sodium excretion was observed. In both the hypertensive patients and the normotensive subjects GFR remained unchanged and renal vascular resistance decreased, whereas renal plasma flow increased only in the latter group. Changes in sodium excretion were not correlated to changes in renal hemodynamic parameters. It is concluded, that also in hypertensive patients with diminished renal function felodipine exerts a potentially advantageous natriuretic effect. However, this natriuretic effect is possibly less at lower GFR and seems to be attenuated by blood pressure reduction. The mechanism of this natriuretic effect as well as its contribution to the antihypertensive effect of felodipine still has to be clarified.

Is natriuresis on felodipine due to reversal of the renal effects of angiotensin II?

Felodipine induces natriuresis, possibly by renal hemodynamic and/or tubular effects. Theoretically, reversal of the sodium-retaining effect of angiotensin II (Ang II) could be involved. Therefore, we administered felodipine during Ang II infusion and during suppression of endogenous Ang II production in two double-blind studies in healthy volunteers. First, a gradually increasing dose of Ang II was infused during felodipine or solvent infusion. Before starting Ang II, felodipine had lowered renal vascular resistance (RVR) and filtration fraction (FF), and simultaneously increased CNa. The Ang II induced rise of mean arterial pressure (MAP) and renal vasoconstriction was partly antagonized and the falls in glomerular filtration rate (GFR) and CNa completely abolished by felodipine. The combination of felodipine and 3.0 ng/kg/min Ang II even enhanced natriuresis. Second, felodipine or solvent was infused after one week of pretreatment with placebo or the angiotensin converting enzyme (ACE) inhibitor ramipril, which reduced MAP and induced renal vasodilatation. Ramipril pretreatment did not influence significantly the blood pressure reduction, renal vasodilatation, and natriuresis caused by felodipine. In conclusion, it seems unlikely that the natriuretic effect of felodipine is due to interference with renal effects of endogenous Ang II. The fact that felodipine reverses sodium retention on exogenous Ang II may be explained by interference with systemic and renal hemodynamic effects of exogenous Ang II.

Effects of dihydropyridine calcium antagonists on rabbit renal Na,K-ATPase activity in vitro.

Dihydropyridines are reported to have a stimulatory effect on vascular smooth muscle Na,K-ATPase activity in vitro. We studied the effects of the dihydropyridine calcium antagonists nimodipine, nitrendipine, nisoldipine, niludipine, nifedipine and felodipine (10(-5) M) on purified Na,K-ATPase isolated from rabbit kidney outer medulla. We were unable to detect an effect of the drugs on the enzyme activity, either under optimal or suboptimal substrate conditions. Likewise, Na,K-ATPase activity, partly inhibited by the addition of ouabain (10(-6) M), Ca2+ (10(-3) M) or arachidonic acid (4 x 10(-5) M), was not influenced by the dihydropyridines. The absence of a stimulatory effect of dihydropyridines on renal Na,K-ATPase is in agreement with the known diuretic and natriuretic effects of the drugs in normotensive and hypertensive men.

A pheochromocytoma of the urinary bladder.

This case report describes a patient with a pheochromocytoma of the urinary bladder. The patient demonstrated an excessive increase of blood pressure and plasma catecholamines immediately after micturition. Ultrasound and CT-scanning confirmed the localisation of the tumour in the urinary bladder.

Differential effects of enalapril and atenolol on proteinuria and renal haemodynamics in non-diabetic renal disease.

OBJECTIVE: To compare the antihypertensive, renal haemodynamic and antiproteinuric effect of enalapril and atenolol in patients with proteinuria of non-diabetic origin. DESIGN: Prospective, double blind, randomised 16 week study after a pretreatment period of at least three weeks. SETTING: Outpatient nephrology and hypertension unit. PATIENTS: 27 patients with proteinuria (greater than 300 mg protein/day) of non-diabetic origin, moderately impaired renal function (creatinine clearance 30-90 ml/min), and a pretreatment diastolic blood pressure of greater than 80 mm Hg. INTERVENTIONS: Treatment with enalapril (10 mg/day, adjusted between 5 and 40 mg, if necessary) or atenolol (50 mg/day, adjusted between 25 and 100 mg if necessary) titrated against a target fall in diastolic blood pressure to less than 95 mm Hg or of greater than 10 mm Hg, or both. MAIN OUTCOME MEASURES: Blood pressure, renal haemodynamics, and urinary protein excretion. RESULTS: No differences were detected between the two groups before treatment. The falls in systolic and diastolic blood pressures during treatment were not significantly different between both groups. Proteinuria fell slightly with atenolol but significantly more with enalapril (mean change -0.38 (95% confidence interval -0.78 to 0.03) v -1.2 (-1.70 to -0.69) g/day respectively, p less than 0.02) as did filtration fraction (mean change -1.8 (-2.9 to -0.7) v -3.8 (-4.9 to -2.8)% respectively. Serum potassium concentration increased with enalapril (mean change 0.63 (SD 0.51) v 0.19 (0.47) mmol/l, p less than 0.05). CONCLUSIONS: Enalapril lowers proteinuria more than atenolol in patients with non-diabetic renal disease despite a similar blood pressure lowering effect of both drugs, and its antiproteinuric effect seems to be associated with the characteristic renal haemodynamic effect of angiotensin converting enzyme inhibitors.

Orthostatic proteinuria: a harmless variant of protein loss?

A 28-year-old young woman was referred to our department of Internal Medicine for analysis of unintentional weight loss. At initial analysis, a persistent proteinuria was found with no evident relation to her weight loss. Anamnestic as well as additional studies showed no evidence of a primary kidney disease. After this exclusion, orthostatic proteinuria was confirmed by simple urine analysis. Since the weight loss had not yet been explained, an analysis followed at the Department of Gastointestinal and Liver Diseases where inflammatory bowel disease (IBD) was found. Literature study shows that proteinuria may be associated with IBD. This concerns mainly selective tubular protein loss, without a distinctive change in protein loss with a change in position. Orthostatic proteinuria, therefore, remained the most likely diagnosis. In this case, the patient was advised to check both urine and kidney function annually.

Nurse practitioners improve quality of care in chronic kidney disease: two-year results of a randomised study.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular risk. Here we evaluate whether strict implementation of guidelines aimed at multiple targets with the aid of nurse practitioners (NP) improves management in patients with CKD. METHODS: MASTER PLAN is a randomised controlled clinical trial, performed in nine Dutch hospitals. Patients with CKD (estimated glomerular filtration rate (eGFR) 20-70 ml÷min) were randomised to receive NP support (intervention group (IG)) or physician care (control group (CG)). Patients were followed for a median of five years. Presented data are an interim analysis on risk factor control at two-year follow-up. RESULTS: We included 788 patients (532 M, 256 F), (393 CG, 395 IG), mean (±SD ) age 59 (±13) years, eGFR 38 (±15) ml÷min÷1.73m(2), blood pressure (BP) 138 (±21)÷80 (±11) mmHg. At two years 698 patients (352 IG, 346 CG) could be analysed. IG as compared with CG had lower systolic (133 vs 135 mmHg; p= 0.04) and diastolic BP (77 vs 80 mmHg; p=0.007), LDL cholesterol (2.30 vs 2.45 mmol(-l); p= 0.03), and increased use of ACE inhibitors, statins, aspirin and vitamin D. The intervention had no effect on smoking cessation, body weight, physical activity or sodium excretion. CONCLUSION: In both groups, risk factor management improved. However, changes in BP control, lipid management and medication use were more pronounced in IG than in CG. Lifestyle interventions were not effective. Coaching by NPs thus benefits everyday care of CKD patients. Whether these changes translate into improvement in clinical endpoints remains to be established.

Hospital specific factors affect quality of blood pressure treatment in chronic kidney disease.

BACKGROUND: Blood pressure (BP) is the most important modifiable risk factor for cardiovascular (CV) disease and progression of kidney dysfunction in patients with chronic kidney disease. Despite extensive antihypertensive treatment possibilities, adequate control is notoriously hard to achieve. Several determinants have been identified which affect BP control. In the current analysis we evaluated differences in achieved BP and achievement of the BP goal between hospitals and explored possible explanations. METHODS: At baseline, BP was measured in a supine position with an oscillometric device in 788 patients participating in the MASTER PLAN study. We also retrieved the last measured office BP from the patient records. Additional baseline characteristics were derived from the study database. Univariate and multivariate analyses were performed with general linear modelling using hospital as a random factor. RESULTS: In univariate analysis, hospital was a determinant of the level of systolic and diastolic BP at baseline. Adjustment for patient, kidney disease, treatment or hospital characteristics affected the relation. Yet, in a fully adjusted model, differences between centres persisted with a range of 15 mmHg for systolic BP and 11 mmHg for diastolic BP. CONCLUSION: Despite extensive adjustments, a clinically relevant, statistically significant difference between hospitals was found in standardised BP measurements at baseline of a randomised controlled study. We hypothesise that differences in the approach towards BP control exist at the physician level and that these explain the differences between hospitals.

The influence of alpha 1-adrenergic blockade on the acute antihypertensive effect of nifedipine.

The hypotensive effect of vasodilator monotherapy in hypertension is attenuated by a baroreceptor-mediated increase in the sympathetic release of noradrenaline. Nifedipine induces a rise in noradrenaline release, but it is not known to affect noradrenaline-induced vascular contraction of smooth muscle to a clinically significant degree. The haemodynamic and hormonal effects of a single sublingual dose of nifedipine 20 mg in 8 moderately hypertensive patients have been studied before and during postsynaptic alpha 1-blockade with prazosin. The antihypertensive effect of nifedipine was significantly increased by prazosin pretreatment (fall in mean arterial pressure 60 min after nifedipine: -16.7% with and -8.5% without prazosin), despite similar increases in plasma noradrenaline. Prazosin alone caused no change in supine blood pressure for 2 h after an oral dose of 2 mg. The findings are in keeping with the hypothesis that prazosin blocks a compensatory reaction to vasodilatation caused by nifedipine.

Evidence for renal vasodilation in pre-dialysis patients during correction of anemia by erythropoietin.

Results from animal experiments have suggested that treatment with recombinant human erythropoietin (rHuEPO) causes changes in renal hemodynamics which are detrimental to renal function. Therefore, the effects of correction of the anemia by rHuEPO on glomerular filtration rate (GFR; inulin clearance) and effective renal plasma flow (ERPF; PAH clearance) were studied in eight pre-dialysis patients. The studies were done before (Hct 0.24 +/- 0.05 liter/liter) and at 89 +/- 19 days after the start of rHuEPO therapy (Hct 0.39 +/- 0.03 liter/liter). To further evaluate the effects of ACE inhibition, 25 mg of captopril was given orally after baseline values had been obtained. Baseline GFR, renal blood flow (RBF) and filtration fraction (FF) did not change during rHuEPO therapy. At low hematocrit (Hct) captopril induced a significant increase in ERPF and RBF, and a decrease in MAP. After correction of the hematocrit the blood pressure lowering effect of captopril remained unchanged. However, captopril no longer induced changes in ERPF and RBF. We conclude that the increase in hematocrit had no adverse effects on GFR. The results suggest that changes in hematocrit may influence the effects of ACE inhibition on efferent vascular resistance. Therefore, the hematocrit should be taken into account when evaluating studies on the effects of ACE inhibition in the progression of chronic renal failure.