Henk E. Sluiter

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.

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.

Haemodynamic, Hormonal, and Diuretic Effects of Felodipine in Healthy Normotensive Volunteers

SummaryFelodipine 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 nor- adrenaline (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.

The Natriuretic Effect of the Dihydropyridine Calcium Antagonist Felodipine: A Placebo-Controlled Study Involving Intravenous Angiotensin II in Normotensive Volunteers

Changes in systemic and renal hemodynamics and in the renin-angiotensin system caused by infusion of the calcium antagonist felodipine were investigated in a placebo-controlled study with 12 normotensive volunteers before and during a graded infusion of angiotensin II (AII). In spite of a fall in blood pressure through vasodilatation, felodipine had a natriuretic effect. There was only a transient rise in effective renal plasma flow (ERPF), whereas glomerular filtration rate (GFR) did not change. Urinary sodium excretion remained elevated when ERPF had normalized. Urinary potassium excretion did not change. AII-induced reductions in ERPF, GFR, and sodium excretion were abolished by felodipine. Felodipine also partly antagonized the rise in plasma aldosterone levels caused by AII. We conclude that the natriuretic effect of dihydropyridine calcium antagonists is probably not caused by a single mechanism, but may be dependent on changes in renal hemodynamics together with a diminished sodium reabsorption at multiple tubular sites. Interference with AII-mediated renal mechanisms and an impairment of the action of aldosterone may contribute to this natriuretic effect as well.

Quality of care in patients with chronic kidney disease is determined by hospital specific factors

BACKGROUND Guidelines have set goals for risk factor management in chronic kidney disease (CKD) patients. These goals are often not met. In this analysis, we set out to assess the quality of risk factor management in CKD and to identify factors that determine the quality of care (QoC). For that purpose, baseline data of the MASTERPLAN (Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse practitioners) study have been used. MASTERPLAN is a multicentre study which evaluates the effect of a multifactorial intervention in prevalent CKD patients on cardiovascular (CV) events and progression of kidney failure. METHODS QoC was quantified using a score based on the number of 11 defined treatment goals on target. The maximum score per patient was 11. RESULTS The average (±SD) QoC score was 6.7 (±1.5). The average score per centre ranged from 5.9 to 6.9. In a multivariable analysis, centre proved to be a significant, independent determinant of QoC with a difference up to 0.7 between centres. This difference remained when adjustments were made for those risk factors primarily treated by pharmacotherapy. Other factors that were significantly related to the QoC were estimated glomerular filtration rate, Caucasian race, diabetes mellitus, diabetic nephropathy as cause of kidney disease and previous kidney transplantation. CONCLUSIONS In CKD patients, risk factors for progression of kidney failure and CV events were inadequately controlled. Treatment centre proved to be an important determinant of QoC. This data may point towards the physicians interest and preference as important determinants of QoC. This is a potentially modifiable determinant of the quality of patient care [Trial registration ISRCTN registry: 73187232 (http://isrctn.org)].

Haemodynamic Effects of Intravenous Felodipine in Normotensive and Hypertensive Subjects

SummaryThe 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 body weight 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.

Prednisone-Induced Fluctuations of Proteinuria in Patients with a Nephrotic Syndrome

We studied the effect of prednisone on urinary protein excretion in 19 patients with a nephrotic syndrome, who were treated with prednisone (125-150 mg) on alternate days. We found a typical, fluctuating pattern of proteinuria resulting from an increased protein excretion rate on prednisone days and a decreased protein excretion rate on nonprednisone days. The urinary protein excretion on prednisone days was 9.9 +/- 3.3 g/24 h, as compared to 5.7 +/- 3.8 g/24 h on nonprednisone days (mean +/- SD). In the whole group of patients the percentual change in proteinuria was significantly correlated with the endogenous creatinine clearance. However, systematic differences between creatinine excretion rates on prednisone and nonprednisone days were not found in individual patients. In 6 patients, renal hemodynamics were studied more precisely, using a single injection technique. Only a slight and nonsignificant decrease in glomerular filtration rate was found on nonprednisone days (delta = -9.6 +/- 16.3%; mean +/- SD). Filtration fraction remained unchanged. It is therefore suggested that the effects of prednisone on proteinuria are not simply mediated by overall changes in renal hemodynamics.

The influence of alpha1-adrenergic blockade on the acute antihypertensive effect of nifedipine

SummaryThe 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 alpha1-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.

Felodipine in Hypertensive Patients

SummaryIn a double-blind study, 128 patients with essential hypertension, refractory to β-blocker monotherapy, were randomised to 1 of 4 treatment groups. Felodipine 2.5mg twice daily, 5mg twice daily, 10mg twice daily or matched placebo twice daily were administered in addition to the β-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 β-blocker monotherapy. It may be necessary to increase this dose to 10mg twice daily in selected patients.

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.