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Biomedical subjects

J F Wetzels

Publications and source records attributed to J F Wetzels.

At least 55 records · Page 3Linked to original sources
PubMed1998

Antihypertensive treatment of patients with proteinuric renal diseases: risks or benefits of calcium channel blockers?

In patients with proteinuric renal diseases the rate of progression of renal insufficiency is determined by the level of blood pressure and proteinuria. It has been demonstrated that strict blood pressure control with angiotensin converting enzyme (ACE)-inhibitors or beta-blockers, aimed at reaching values below 130/80 mm Hg, attenuates the deterioration of renal function. In general, the beneficial effects of these drugs are reflected in a parallel lowering of proteinuria. Calcium channel blockers are effective antihypertensive drugs, however, their safety in patients with proteinuric renal diseases and renal insufficiency may be questioned because of reported untoward effects on urinary protein excretion. The present review discusses the potential benefits and risks of calcium channel blockers (CCBs) in the treatment of patients with renal diseases. To this end we have evaluated the effects of these drugs in animal models of progressive renal injury. In these animal models adverse effects of CCBs have been reported which are attributed to an impairment of autoregulation. In patients with proteinuria, the dihydropyridine CCBs do not lower proteinuria despite a reduction of blood pressure. Studies on the effects on the course of renal function are limited, however, the available data do suggest that this class of CCBs may be less advantageous than other antihypertensive drugs, thus arguing against the use of these agents as first-line drugs in patients with proteinuric renal diseases. Information on the effects of the non-dihydropyridine CCBs is limited to a small number of studies in patients with diabetic renal disease. Although the data suggest that these classes of CCBs might be more beneficial, more studies are needed, particularly in patients with non-diabetic renal diseases, before founded conclusions can be reached.

Animals↗
PubMed1998

Prognostic factors in idiopathic membranous nephropathy.

Membranous nephropathy is the most frequent cause of glomerulonephritis in adults with nephrotic syndrome. Approximately one quarter of the patients develop end-stage renal disease. Another quarter enters complete remission during follow-up. Treating all patients with membranous nephropathy with immunosuppressive drugs would unnecessarily expose at least one quarter of the patients to these toxic drugs. Identifying patients at highest risk would allow tailor-made treatment. Many risk factors have been found, such as male sex, HLA type DR3+/B8+, white race, advanced age, and tubulointerstitial changes or focal sclerosis found with renal biopsy. In addition, nephrotic syndrome, elevation of immunoglobulin G excretion or beta2-microglobulin excretion, low serum albumin, high serum cholesterol, an elevation of urinary excretion of complement activation products, impaired renal function at diagnosis, and, finally, hypertension are associated with a higher risk of renal function deterioration during follow-up. We have critically reviewed the literature and summarized the clinical significance of the above-mentioned risk factors in predicting subsequent renal function deterioration in patients with membranous nephropathy.

Adolescent↗
PubMed1998

Effects of low-dose nifedipine on urinary protein excretion rate in patients with renal disease.

BACKGROUND: The observation that proteinuria is an important determinant of the progression of renal disease has prompted numerous studies on the effects of antihypertensive agents on protein excretion. Reports on the proteinuric effects of calcium-channel blockers are quite controversial. It has been suggested that the short-acting dihydropyridine calcium-channel blocker nifedipine increases protein excretion by interference with tubular protein reabsorption. METHODS: In a randomized controlled trial 10 patients with renal disease and proteinuria were treated with a dose of 10 mg nifedipine o.d. (slow release formulation) for 1 week. The acute effects on renal and systemic haemodynamics and on urinary albumin, IgG, and beta2-microglobulin excretion were investigated during a clearance study in the supine position after the first dose. After 1 week of treatment urinary protein excretion rates were measured in 24-h urine samples collected in the ambulatory patient in consecutive fractions of 4-8 h during normal daily activities. RESULTS: After the first dose nifedipine lowered mean arterial blood pressure in the supine position by 7+/-1 mmHg (<0.01), attenuated proximal tubular sodium reabsorption (fractional excretion of sodium 3.48+/-0.49 vs 2.62+/-0.35% during control, P<0.02), but did not affect proximal tubular protein reabsorption (fractional urinary excretion of beta2-microglobulin 0.97+/-0.30 vs 0.98+/-0.32% during control, NS). The decrease in blood pressure was not accompanied by decreases in urinary albumin or IgG excretion rates. The selectivity index as well as GFR, RPF, and FF did not change. Continued treatment for 1 week with nifedipine did not influence 24-h protein excretion. However, we observed a rise of proteinuria during daily activities in the first 4 h after drug intake compared to the start of the study with the patients in supine position. During control measurements there was a slight increase in proteinuria. During nifedipine the increase in proteinuria was more marked and correlated with the selectivity index. CONCLUSIONS: (1) Nifedipine 10 mg orally did not impair tubular protein reabsorption. (2) Nifedipine had no immediate antiproteinuric effect despite the observed blood pressure reduction. (3) Nifedipine increased proteinuria in ambulatory urine collections. This latter observation might explain the seemingly different effects of dihydropyridine calcium-channel blockers as reported in previous studies.

Adult↗
PubMed1998

Oral cyclophosphamide versus chlorambucil in the treatment of patients with membranous nephropathy and renal insufficiency.

We treated patients with idiopathic membranous nephropathy (iMGN) and renal insufficiency, using: (i) (n = 15) monthly cycles of steroids (1 g methyl-prednisolone i.v. on three consecutive days, followed by oral prednisone 0.5 mg/kg/day months 1, 3 and 5) and chlorambucil (0.15 mg/kg/day months 2, 4 and 6); or (ii) (n = 17) oral cyclophosphamide (1.5-2.0 mg/kg/day for 1 year) and steroids in a comparable dose. The groups were comparable in age, renal function and levels of proteinuria. During the 6 months preceding treatment, serum creatinine levels increased from 148 +/- 50 to 219 +/- 73 mumol/l in the chlorambucil group and from 164 +/- 86 to 274 +/- 126 mumol/l in the cyclophosphamide group. Median (range) follow-ups were: chlorambucil 38 months (8-71); cyclophosphamide 26 months (5-68) (NS). Renal function improved in both groups, but the improvement was short-lived in the chlorambucil group; 12 months after starting treatment, mean serum creatinine was 6.3 mumol/l lower in the chlorambucil group and 121 mumol/l lower in the cyclophosphamide group (p < 0.01). Four chlorambucil-treated patients developed ESRD, and five needed a second course of therapy, whereas only one cyclophosphamide-treated patient developed ESRD (p < 0.05). Remissions of proteinuria occurred more frequently after cyclophosphamide treatment (15/17 vs. 5/15; p < 0.01). Side-effects necessitated interruption of treatment in six patients on cyclophosphamide and in 11 on chlorambucil (p < 0.05). In our patients, oral cyclophosphamide was better tolerated than oral chlorambucil. The suggested greater efficacy of the oral cyclophosphamide regimen needs to be ascertained by longer follow-up.

Adult↗
PubMed1998

Influence of angiotensin converting enzyme inhibition and angiotensin II type 1 receptor antagonism on renal sodium and water handling and albuminuria during infusion of atrial natriuretic factor into healthy volunteers.

BACKGROUND: Atrial natriuretic factor increases urinary sodium and water excretion. It also causes an increase in albuminuria. Angiotensin converting enzyme inhibition attenuates the effects of atrial natriuretic factor on renal sodium and water handling; however, it is not known whether this effect is mediated by the accompanied decrease in blood pressure or by suppression of the renin-angiotensin system. OBJECTIVE: To test the hypothesis that atrial natriuretic factor mediates natriuresis and diuresis by inhibiting angiotensin II, by studying the effects of the angiotensin converting enzyme inhibitor enalapril and the angiotensin II type 1 receptor antagonist losartan. In addition, the effects of these drugs on atrial natriuretic factor-induced albuminuria were examined. DESIGN AND METHODS: We investigated the effects of enalapril and losartan on atrial natriuretic factor-induced changes in urinary excretion of sodium, water and albumin from eight healthy volunteers. Measurements of systemic and renal haemodynamics in these subjects were performed before and during a 2 h infusion of atrial natriuretic factor [0.01 microg/kg per min (low dose) for the first 60 min and 0.02 microg/kg per min (high dose) for the second 60 min]. Measurements were performed after 5 days of pretreatment with placebo, 50 mg losartan or 20 mg enalapril daily. RESULTS: Mean arterial pressures during the clearance study were 84.6 +/- 1.7 mmHg after placebo, 84.0 +/- 2.2 mmHg after losartan treatment and 80.0 +/- 2.5 mmHg after enalapril treatment (P < 0.05). Plasma renin activity was significantly increased both by losartan and by enalapril treatments. Neither enalapril nor losartan treatment attenuated atrial natriuretic factor-induced changes in renal haemodynamics. After placebo pretreatment, fractional urinary excretion of sodium increased significantly during infusion of atrial natriuretic factor. Losartan treatment did not influence the increase in urinary excretion of sodium during infusion of atrial natriuretic factor, whereas enalapril treatment significantly attenuated this increase (P < 0.01). Atrial natriuretic factor significantly increased albuminuria. Neither losartan nor enalapril treatment reduced atrial natriuretic factor-induced albuminuria. CONCLUSIONS: Enalapril treatment lowered blood pressure and attenuated the atrial natriuretic factor-induced increase in urinary excretion of sodium. In contrast, the angiotensin II type 1 receptor antagonist losartan, at a dosage that did not lower blood pressure, did not attenuate the increase in urinary excretion of sodium. These data indicate that atrial natriuretic factor increases natriuresis and diuresis independently of angiotensin II. The increase in albuminuria during infusion of atrial natriuretic factor was not influenced by enalapril and losartan treatments.

Adult↗
PubMed1998

Glycosylation is not essential for vasopressin-dependent routing of aquaporin-2 in transfected Madin-Darby canine kidney cells.

Glycosylation has been shown to be important for proper routing and membrane insertion of a number of proteins. In the collecting duct, aquaporin-2 (AQP2) is inserted into the apical membrane after stimulation of vasopressin type-2 receptors and retrieved into an endosomal compartment after withdrawal of vasopressin. The extent of glycosylation of AQP2 in human kidney and urine and the effects of deglycoylation on routing of AQP2 in an AQP2-transfected Madin-Darby canine kidney cell line (clone WT10) were investigated. Semiquantitative immunoblotting of human kidney membranes and urine showed an AQP2 glycosylation of 35 to 45% for medulla, papilla, and urine, with low variation among individuals. The 1-desamino-8-D-arginine vasopressin-induced transcellular osmotic water permeability (Pf) of WT10 cells by a factor of 2.6 +/- 0.2 was reduced to 1.5 +/- 0.1 after pretreatment with the glycosylation inhibitor tunicamycin. However, when WT10 cells were incubated with 8-br-cAMP, the Pf increased by a factor 2.8 +/- 0.2 and by 2.9 +/- 0.2 after prior incubation with tunicamycin. Immunoblot analyses revealed that in WT10 cells, 34% of AQP2 is glycosylated, which was reduced to 2% after tunicamycin treatment. Surface biotinylation and subsequent semiquantitative immunoblotting revealed that stimulation by cAMP increased the level of AQP2 in the apical membrane of WT10 cells 1.5-fold. independent of the presence of tunicamycin. However, in tunicamycin-treated WT10 cells, all AQP2 in the apical membrane was unglycosylated, whereas in untreated cells 30% of AQP2 in the apical membrane was glycosylated. These results prove that glycosylation has no function in the routing of AQP2 in Madin-Darby canine kidney cells.

Animals↗
PubMed1997

[Glomerulonephritis caused by acute serum sickness].

A 51-year-old male patient was treated for a rejection episode after kidney transplantation with horse antithymocyte globulin (ATG). Twelve days after the start of the ATG treatment he developed fever, arthralgia, purpura and acute renal failure. This clinical picture is characteristic of serum sickness, resulting from formation of antibodies to a foreign protein and development of immune complexes. Kidney biopsy revealed an endocapillary glomerulonephritis. Immune complexes probably develop in the mesangium and along the glomerular basal membrane through local formation and precipitation from the circulation. Spontaneous recovery is the rule.

Acute Disease↗
PubMed1997

Recurrence of type I membranoproliferative glomerulonephritis after renal transplantation: analysis of the incidence, risk factors, and impact on graft survival.

BACKGROUND: The information in the medical literature on the incidence of recurrence of type I membranoproliferative glomerulonephritis (MPGN) after renal transplantation and its impact on graft survival is limited because most data are derived from case reports or from studies involving a small number of patients. METHODS: We analyzed the data from our transplant center. Among 1097 adult patients receiving their first allograft between 1977 and 1994, we identified 32 patients with type I MPGN. RESULTS: A recurrence was detected in 9 of the 27 recipients of a first cadaveric graft (33%). The cumulative incidence reached 48% at 4 years after transplantation when patients with graft failure from other causes were censored. All patients with recurrent MPGN had clinically significant proteinuria (>1 g/24 hr) that was first observed at a median time of 20 months (range, 1.5-42 months) after transplantation. Graft survival was significantly worse in patients with recurrence as compared with patients without recurrence. Mean duration of graft survival after the diagnosis of recurrence was 40 months. We could not detect any clinical characteristics of patients or donors that were associated with recurrent disease. However, an increased risk of recurrence was observed in patients with the HLA haplotype B8DR3. Four patients received an HLA-identical graft from a living related donor. Recurrence occurred in three patients (75%), with ensuing graft loss in two. The only patient with a haploidentical living related graft did not have a recurrence. Five patients with a recurrence in the first graft received a second transplant. Recurrence was observed in four of these patients (80%). CONCLUSIONS: Type I MPGN recurred after renal transplantation in half of the patients. The incidence may be even higher in recipients of an identical living related donor graft and in patients receiving a second transplant after having experienced a recurrence in their first graft. Recurrence of type I MPGN has a detrimental effect on graft survival.

Adult↗
PubMed1997

Glycine protection against hypoxic injury in isolated rat proximal tubules: the role of proteases.

BACKGROUND: Isolated rat proximal tubules are frequently used as a model to study hypoxic injury. Glycine is a very effective protective agent against hypoxia-induced cell injury in this model. The mechanisms involved in hypoxic renal injury and glycine protection are still debated. We have focused on the role of proteolytic enzymes. METHODS: Isolated rat proximal tubules in suspension were gassed with either 95%O2/5%CO2 or 95%N2/5%CO2 to create normoxic or hypoxic conditions. Cell injury was assessed by the release of LDH. Activity of proteolytic enzymes was measured by quantifying the release of fluorescent 7-amino-4-methylcoumarin from specific substrates, which were added to tubules in suspension or to cytosolic fractions of permeabilized tubules. RESULTS: Fifteen minutes of hypoxia caused cell injury, which was completely prevented by glycine. Activities of serine-, aspartate-, and the calcium-dependent cysteine protease calpain were increased in these hypoxic tubules in suspension, but only calpain activity was attenuated by glycine. Cytosolic fractions obtained by digitonin-permeabilization of hypoxic (15 min) tubules showed increased proteolytic activity of all measured classes of proteases and glycine prevented these increases. In measurements performed at an earlier time point (7.5 min) neither changes in calpain activity nor effects of glycine were detected. Calpain activity was not inhibited directly by glycine. CONCLUSIONS: Hypoxia increases the activity of several classes of proteases. The effects of glycine on protease activation are equivocal, and may merely reflect the potential of glycine to prevent hypoxia-induced lethal membrane injury.

Animals↗
PubMed1997

Mouse glomerular epithelial cells in culture with features of podocytes in vivo express aminopeptidase A and angiotensinogen but not other components of the renin-angiotensin system.

The binding of antibodies to podocytic antigens such as the Heymann antigen or aminopeptidase A may lead to the induction of a membranous glomerulonephritis in several species. To study the possible future interactions of antibodies with antigens on these podocytes, epithelial cells from isolated mouse glomeruli were cultured. By indirect immunofluorescence, the cells were positive for cytokeratin, vimentin, desmin, and the ZO-1 protein, a component of the tight junction complex. When rat monoclonal antibodies were used, the cells were also positive for the hydrolases aminopeptidase A and dipeptidyl peptidase IV, and they stained with ASD-33, a monoclonal antibody that recognized an epitope only present on the cell membranes of mouse podocytes. They were negative for the von Willebrand factor and did not stain with a monoclonal antibody (ASD-13) that binds to endothelial cells of glomeruli and peritubular capillaries. By electron microscopy, the cells showed tight junctions but lacked Weibel Palade bodies (endothelium), desmosomes, and cilia (parietal epithelium). The mRNA expression of several components of the renin-angiotensin system was also examined, and some factors indirectly coupled to the renin-angiotensin system component angiotensin II in this podocytic culture by RT-PCR analysis. mRNA Expression for the angiotensin II degrading hydrolase aminopeptidase A and angiotensinogen was found, but this was not found for any other component of this system, such as renin, angiotensin-converting enzyme, or the angiotensin II receptors AT1a, AT1b, and AT2. Low mRNA expression for dipeptidyl peptidase IV was observed. In addition, expression of the growth factors transforming growth factor-beta and interleukin-7, and the extracellular matrix components fibronectin, laminin B2, perlecan, and collagen IV alpha 1, was observed. Given these characteristics, a glomerular epithelial cell culture with features of podocytes in vivo that will allow future studies on the interaction of anti-aminopeptidase A monoclonal antibodies and angiotensin II with aminopeptidase A was established. This is of interest in light of the observation that injection of mice with anti-aminopeptidase A antibodies causes an acute albuminuria.

Aminopeptidases↗
PubMed1997

Urinary IgG excretion as a prognostic factor in idiopathic membranous nephropathy.

In membranous nephropathy it would be of great value to be able to identify in an early phase patients at highest risk for disease progression, since potentially toxic treatment could then be restricted to these patients only. We measured renal hemodynamics, serum proteins and urinary protein excretion in 22 patients with membranous nephropathy, nephrotic syndrome and normal renal function (endogenous creatinine clearance > 85 ml/min). These patients were followed for a mean of 56 months. Renal function deteriorated in nine patients. When using univariate analysis, deterioration of renal) function appeared to be associated with a low serum albumin and transferrin, high urinary transferrin, beta-microglobulin, and IgG excretion, but not with renal hemodynamics. A step-up procedure, used for selecting variables associated with survival, showed that IgG excretion was independently associated with renal function deterioration. In patients with membranous nephropathy and normal renal function, the urinary excretion rate of IgG predicts future renal function outcome.

Adult↗
PubMed1996

Inhibition of aminopeptidase A activity causes an acute albuminuria in mice: an angiotensin II-mediated effect?

The hydrolase aminopeptidase A is an important regulator of the renin-angiotensin system, since it inactivates its most vasoactive component angiotensin II (Ang II). A single i.v. injection of a monoclonal antibody against mouse aminopeptidase A (ASD-4) induces a membranous-like glomerulonephritis in mice, characterized by an acute albuminuria, that is not dependent on complement, the coagulation system, or inflammatory cells. We hypothesized that this albuminuria is the consequence of a reduction in aminopeptidase A enzyme activity, that might subsequently lead to an increase in Ang II levels. Aminopeptidase A enzyme activity was analysed in vitro by a fluorimetric enzyme assay and in vivo by enzyme histochemistry. The role of Ang II in the induction of albuminuria in this model was studied by measuring the renal aminopeptidase A mRNA expression in our model by a competitive PCR assay as an indirect measure of Ang II levels. In addition, the role of Ang II in this model was studied by preventing the formation of Ang II with the angiotensin-converting enzyme inhibitor enalapril or by blocking of the Ang II receptor with the AT1 receptor antagonist losartan. Only antibodies that were able to inhibit the aminopeptidase A enzyme activity in vitro and in vivo induced an acute albuminuria in mice. Renal aminopeptidase A mRNA expression was increased by injection of the anti-aminopeptidase A antibody. Both enalapril and losartan treatment reduced the acute albuminuria, measured 1 day after injection of a monoclonal antibody against aminopeptidase A, by 91% and 83%, respectively. It is concluded that the induction of acute albuminuria is correlated to the enzyme-inhibiting capacity of the anti-aminopeptidase A antibodies. This impaired enzymatic activity most likely leads to an increase in the levels of Ang II, the best known substrate of aminopeptidase A. The results of our additional experiments are in keeping with our hypothesis that Ang II mediates this acute albuminuria. Whether this occurs by an increase of blood pressure or by a growth factor-like effect remains to be defined by further studies in this model.

Acute Disease↗