F.J. van Ittersum

Aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril as initial choice in hypertensive type II diabetic individuals: effects on albumin excretion, endothelial function and inflammation in a double-blind, randomized clinical trial.

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals. A total of 70 hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mmHg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mmHg. After titration, patients were treated for 12 months. Mean blood pressures changed from 157/93, 151/94 and 149/93 at baseline to 135/80, 135/82 and 131/80 mmHg after titration in the hydrochlorothiazide (n=24), candesartan (n=24) and lisinopril (n=22) groups. About 70% reached target blood pressures. However, only 45% had blood pressures <130/85 mmHg. Urinary albumin excretion and levels of soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 decreased (GEE regression coefficients, −2.40 mg/24 h (P<0.001), −85 ng/ml (P=0.01) and −50 ng/ml (P=0.02)), but brachial artery endothelium-dependent and -independent vasodilation and levels of von Willebrand factor and C-reactive protein did not change (GEE regression coefficients, 0.21 mm (P=0.07), 0.04 mm (P=0.43), 0.04 IU/ml (P=0.33) and −1.15 mg/l (P=0.64)). No differences in outcome variables between treatment groups were observed. These data show that achievement of target blood pressures below 130/85 mmHg in hypertensive type II diabetes is difficult. Aggressive antihypertensive therapy can improve urinary albumin excretion, endothelial function and inflammatory activity in hypertensive type II diabetic individuals, regardless of the type of antihypertensive therapy used.

Autonomic nervous function, arterial stiffness and blood pressure in patients with Type I diabetes mellitus and normal urinary albumin excretion

Type I diabetic patients (DM-1) with an elevated urinary albumin excretion (UAE>30 mg/24 h) have a high cardiovascular risk. However, DM-1 patients with normal UAE have incipient abnormalities of the cardiovascular and nervous systems, such as elevations of blood pressures, increases in arterial stiffness and deterioration of autonomic nervous function. We studied the interrelationships of these abnormalities in normoalbuminuric DM-1 patients. In 76 patients, we performed two cardiovascular reflex tests (deep in- and expiration test (IE test) and lying-to-standing test (LS test)), and determined aortic pulse wave velocity (PWV), local arterial compliances of the common carotid, femoral and brachial arteries, and 24-h blood pressures. The ΔRRmax value of the LS test was associated with aortic PWV (negatively) and the compliance coefficients of the carotid, femoral and brachial arteries. Per 100-ms increase in ΔRRmax, pulse wave velocity decreased by 0.39 m/s, compliance coefficients of the carotid, femoral and brachial arteries increased by 0.06, 0.08 and 0.05 mm2/kPa, respectively. These associations were independent of age, 24-h mean arterial pressure and 24-h heart rate. Increases in arterial stiffness were associated with increases in 24-h systolic and pulse pressure (per 1 m/s increase in PWV, systolic and pulse pressure increased by 2.1 and 1.7 mmHg, respectively). In normoalbuminuric DM-1 patients, deterioration of autonomic nervous function is associated with an increase in arterial stiffness, which, in turn, was associated with, and may cause, increased systolic and pulse pressure. These findings suggest that preventive strategies targeting autonomic dysfunction may reduce cardiovascular morbidity in diabetes.

Aggressive antihypertensive strategies based on hydrochlorothiazide, candesartan or lisinopril decrease left ventricular mass and improve arterial compliance in patients with type II diabetes mellitus and hypertension

We investigated the effects of aggressive antihypertensive therapy based on hydrochlorothiazide, candesartan or lisinopril on left ventricular mass (LVM) index and arterial stiffness in hypertensive type II diabetic individuals. Seventy hypertensive type II diabetic individuals were treated with three antihypertensive strategies in a randomized, double-blind, double-dummy design. Blood pressure was titrated to levels below 130/85 mm Hg or a decrease in systolic pressure of 10% with a diastolic pressure below 85 mm Hg. After titration, patients were treated for 12 months. Mean blood pressures were 157/93, 151/94 and 149/93 mm Hg at baseline in the hydrochlorothiazide (n=24), candesartan (n=24) and lisinopril (n=22) groups, and 135/80, 135/82 and 131/80 mm Hg after titration. About 70% reached target blood pressures, with the median use of three antihypertensive drugs. Left ventricular mass index and all estimates of arterial stiffness showed significant improvement after 12 months: that is, LVM index (−11 g/m2; −8%); carotid distensibility coefficient (DC; +2.8 × 10−3 kPa−1; +27%), compliance coefficient (CC; +0.13 mm2/kPa; +21%) and elastic modulus (−0.19 kPa; −16%); femoral DC (+1.6 × 10−3 kPa−1; +50%) and CC (+0.08 mm2/kPa; +26%); brachial DC (+2.1 × 10−3 kPa−1; +39%) and CC (+0.03 mm2/kPa; +27%) and total systemic arterial compliance (+0.29 ml/mm Hg; +16%). No differences in outcome variables between treatment groups were observed. Aggressive antihypertensive treatment, although difficult to achieve, resulted in substantial reductions of LVM index and arterial stiffness in relatively uncomplicated hypertensive type II diabetic individuals. Strategies based on renin–angiotensin system inhibitors were not clearly superior to conventional (i.e. diuretic-based) strategies.

The PROCARE consortium: Toward an improved allocation strategy for kidney allografts

Kidney transplantation is the best treatment option for patients with end-stage renal failure. At present, approximately 800 Dutch patients are registered on the active waiting list of Eurotransplant. The waiting time in the Netherlands for a kidney from a deceased donor is on average between 3 and 4 years. During this period, patients are fully dependent on dialysis, which replaces only partly the renal function, whereas the quality of life is limited. Mortality among patients on the waiting list is high. In order to increase the number of kidney donors, several initiatives have been undertaken by the Dutch Kidney Foundation including national calls for donor registration and providing information on organ donation and kidney transplantation. The aim of the national PROCARE consortium is to develop improved matching algorithms that will lead to a prolonged survival of transplanted donor kidneys and a reduced HLA immunization. The latter will positively affect the waiting time for a retransplantation. The present algorithm for allocation is among others based on matching for HLA antigens, which were originally defined by antibodies using serological typing techniques. However, several studies suggest that this algorithm needs adaptation and that other immune parameters which are currently not included may assist in improving graft survival rates. We will employ a multicenter-based evaluation on 5429 patients transplanted between 1995 and 2005 in the Netherlands. The association between key clinical endpoints and selected laboratory defined parameters will be examined, including Luminex-defined HLA antibody specificities, T and B cell epitopes recognized on the mismatched HLA antigens, non-HLA antibodies, and also polymorphisms in complement and Fc receptors functionally associated with effector functions of anti-graft antibodies. From these data, key parameters determining the success of kidney transplantation will be identified which will lead to the identification of additional parameters to be included in future matching algorithms aiming to extend survival of transplanted kidneys and to diminish HLA immunization. Computer simulation studies will reveal the number of patients having a direct benefit from improved matching, the effect on shortening of the waiting list, and the decrease in waiting time.

Differential effects of donor-specific HLA antibodies in living- versus deceased-donor transplantation.

The presence of donor‐specific anti‐HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long‐term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement‐dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10‐year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10‐year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10‐year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.

Zeven jaar klinisch lijnonderwijs aan de Vrije Universiteit: de problemen, de docententraining en het onderwijsmateriaal

De Faculteit Geneeskunde van de Vrije Universiteit kent sinds 1990 het klinisch lijnonderwijs (KLO). Hierin wordt op probleemgestuurde wijze klinisch redeneren geoefend met behulp van casuistiek. Onlangs is het KLO geevalueerd en is aan de hand van de gesignaleerde problemen een docententraining georganiseerd met als belangrijkste doel het oefenen in het schrijven van onderwijsmateriaal (casuistiek) voor het KLO. Na deze training zijn docenten zelf het onderwijsmateriaal gaan (her)schrijven met begeleiding van een projectgroep. Inmiddels zijn de meeste casus voor het KLO aangepast en is er een permanente redactiecommissie KLO ingesteld, die de kwaliteit van het onderwijsmateriaal bewaakt. In dit artikel wordt de docententraining beschreven, evenals de uitkomsten daarvan met betrekking tot het vernieuwde onderwijsmateriaal.

Routine hemodialysis induces a decline in plasma magnesium concentration in most patients: a prospective observational cohort study

In hemodialysis patients, lower plasma magnesium (Mg) concentrations are associated with a higher overall and cardiovascular mortality. The optimal concentration appears to be above the reference range for the healthy population. Plasma Mg is not routinely measured after hemodialysis. Aim of this study was to determine the effect of routine hemodialysis on plasma Mg. Plasma Mg was measured in duplicate before (Mgpre) and after (Mgpost) dialysis in 6 consecutive hemodialysis sessions of 34 patients using a fixed 0.50 mmol/L dialysate Mg concentration. Mean Mgpre was 0.88 mmol/L (±0.14) and mean Mgpost was statistically significantly lower: mean intra-dialytic decline 0.10 mmol/L (95%-CI 0.06–0.13). A 0.10 mmol/L higher Mgpre was associated with a 0.03 mmol/L higher Mgpost (95%-CI 0.024–0.037). At a Mgpre of 0.74 mmol/L, Mgpost equalled Mgpre. There was an intra-dialytic decline of plasma Mg at higher Mgpre values and an increase at lower Mgpre values. In conclusion, in the majority of the hemodialysis patients, Mgpre concentrations are in the reference range of the healthy population, which may be too low for hemodialysis patients. Routine hemodialysis with the widely used 0.50 mmol/L dialysate Mg concentration, further declines magnesium in the majority of patients. Current dialysate Mg concentrations may be too low.

Differences in peritoneal response after exposure to low-GDP bicarbonate/lactate-buffered dialysis solution compared to conventional dialysis solution in a uremic mouse model

BackgroundLong-term exposure of conventional peritoneal dialysis (PD) fluid is associated with structural membrane alterations and technique failure. Previously, it has been shown that infiltrating IL-17-secreting CD4+T cells and pro-fibrotic M2 macrophages play a critical role in the PD-induced pathogenesis. Although more biocompatible PD solutions are recognized to better preserve the peritoneal membrane integrity, the impact of these fluids on the composition of the peritoneal cell infiltrate is unknown.Materials and methodsIn a uremic PD mouse model, we compared the effects of daily instillation of standard lactate (LS) or bicarbonate/lactate-buffered solutions (BLS) and respective controls on peritoneal fibrosis, vascularisation, and inflammation.ResultsDaily exposure of LS fluid during a period of 8 weeks resulted in a peritoneal increase of αSMA and collagen accompanied with new vessel formation compared to the BLS group. Effluent from LS-treated mouse showed a higher percentage of CD4+ IL-17+ cell population while BLS exposure resulted in an increased macrophage population. Significantly enhanced inflammatory cytokines such as TGFβ1, TNFα, INFγ, and MIP-1β were detected in the effluent of BLS-exposed mice when compared to other groups. Further, immunohistochemistry of macrophage subset infiltrates in the BLS group confirmed a higher ratio of pro-inflammatory M1 macrophages over the pro-fibrotic M2 subset compared to LS.ConclusionDevelopment of the peritoneal fibrosis and angiogenesis was prevented in the BLS-exposed mice, which may underlie its improved biocompatibility. Peritoneal recruitment of M1 macrophages and lower number of CD4+ IL-17+ cells might explain the peritoneal integrity preservation observed in BLS-exposed mouse.