Safety and long-term effects of renal denervation: Rationale and design of the Dutch registry.

BACKGROUND: Percutaneous renal denervation (RDN) has recently been introduced as a treatment for therapy-resistant hypertension. Also, it has been suggested that RDN may be beneficial for other conditions characterised by increased sympathetic nerve activity. There are still many uncertainties with regard to efficacy, safety, predictors for success and long-term effects. To answer these important questions, we initiated a Dutch RDN registry aiming to collect data from all RDN procedures performed in the Netherlands. METHODS: The Dutch RDN registry is an ongoing investigator-initiated, prospective, multicentre cohort study. Twenty-six Dutch hospitals agreed to participate in this registry. All patients who undergo RDN, regardless of the clinical indication or device that is used, will be included. Data are currently being collected on eligibility and screening, treatment and follow-up. RESULTS: Procedures have been performed since August 2010. At present, data from 306 patients have been entered into the database. The main indication for RDN was hypertension (n = 302, 99%). Patients had a mean office blood pressure of 177/100 (±29/16) mmHg with a median use of three (range 0-8) blood pressure lowering drugs. Mean 24-hour blood pressure before RDN was 157/93 (±18/13) mmHg. RDN was performed with different devices, with the Simplicity™ catheter currently used most frequently. CONCLUSION: Here we report on the rationale and design of the Dutch RDN registry. Enrolment in this investigator-initiated study is ongoing. We present baseline characteristics of the first 306 participants.

[Diagnosis of diabetes mellitus: limited use for portable blood-glucose measuring devices]. / Diagnostiek van diabetes mellitus: beperkte plaats voor draagbare glucosemeters.

In the Netherlands, guidelines for the diagnosis of diabetes mellitus are confusing and differ from the international guidelines. Capillary blood-glucose testing using a blood-glucose device is allowed used as a diagnostic tool, although this test is imprecise. The Dutch laboratories measure blood-glucose concentrations by a more precise accurate method, but sometimes measure glucose levels in capillary whole blood and sometimes in venous plasma. These results are not comparable, because the results of capillary measurements are lower than the plasma measurements. In daily practice, health-care professionals are using different methods and are often not aware of the differences in glucose values that may result. They do not realise that glucose devices and laboratory glucose measurements may differ and that capillary- and plasma-glucose values are not interchangeable. Uniformity within the Dutch laboratories with regard to the glucose measurements is urgently needed, as is revision of the Dutch guidelines concerning the diagnosis of diabetes mellitus. This should be based solely on venous plasma-glucose values determined in a laboratory. Portable blood-glucose devices should not be used as a diagnostic tool for diabetes mellitus. These should only be used for blood-glucose control monitoring during treatment or as a screening tool.

ACE polymorphism does not determine short-term renal response to ACE-inhibition in proteinuric patients.

BACKGROUND: The renal response to ACE inhibition is known to vary between individuals. The ACE genotype is a determinant of the ACE concentrations in plasma and tissue, and therefore might affect the renal response to ACE inhibition in renal patients. METHODS: To test this hypothesis we studied the short-term response to ACE inhibition (enalapril or lisinopril 10/20 mg/d) in 61 stable proteinuric patients (> 1.0 g/day) in relation to the ACE genotype (DD N = 16, ID N = 32, II N = 13). RESULTS: Baseline values were not significantly different for the three groups. ACE inhibition significantly reduced proteinuria, mean arterial pressure, GFR and FF in all genotype groups. The reduction in proteinuria, MAP, GFR and FF was not different between the genotype groups. ERPF increased significantly and to the same extent in all three groups. CONCLUSIONS: We conclude that in proteinuric patients the short-term responses to ACE inhibition of proteinuria, blood pressure, and renal haemodynamics are not determined by ACE genotype. Thus, ACE gene polymorphism does not account for the known interindividual variation in the short-term renal response to ACE inhibition.

Symptomatic antiproteinuric treatment decreases serum lipoprotein (a) concentration in patients with glomerular proteinuria.

Elevated serum levels of the atherogenic and thrombogenic lipoprotein (a) (Lp(a)) have been recognized as a feature of the nephrotic syndrome associated hyperlipidaemia. To examine a possible relationship between serum Lp(a) concentration and proteinuria, serum albumin, or blood pressure, we studied nine patients with nephrotic-range proteinuria both at baseline and after various forms of antihypertensive and antiproteinuric treatment. In fixed order, patients received conventional antihypertensive treatment (either alpha-methyldopa or clonidine), subsequently ACE-inhibition therapy (lisinopril), ACE inhibition combined with an NSAID (indomethacin), and finally NSAID plus conventional antihypertensive therapy. Measurements were performed at the end of each 2-month study period. When compared to controls (n = 29), proteinuric patients before treatment showed increased levels of total cholesterol, very-low and low-density lipoprotein (VLDL+LDL) cholesterol, triglycerides and apolipoprotein B (apoB), while high-density lipoprotein (HDL) HDL cholesterol was lower. Lp(a) was significantly higher in patients (107 (95% CI: 55-208) mg/l) as compared to controls (25 (13-49) mg/l, P < 0.01). Conventional antihypertensive treatment did not reduce proteinuria, while Lp(a) remained unaffected. ACE-inhibitor treatment lowered proteinuria, raised serum albumin, while La(a) tended to fall (-11 +/- 8%). Addition of an NSAID induced a further fall in proteinuria and a rise in serum albumin. Lp(a) now fell by 40 +/- 5% from baseline values (P < 0.01). Both serum total, HDL and VLDL+LDL cholesterol fell significantly. Finally, during subsequent single therapy with NSAID most parameters, including proteinuria and Lp(a), returned towards values obtained during single therapy with ACE inhibiton.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiproteinuric drugs in patients with idiopathic membranous glomerulopathy.

We studied the effects of symptomatic, antiproteinuric treatment with NSAID's (n = 28) and ACE-inhibitors (n = 14) in patients with proteinuria due to idiopathic membranous glomerulopathy (MGP). These two treatment groups were compared with a group of patients who did not receive antiproteinuric medication (n = 14). Urinary protein loss was effectively lowered by NSAID and ACE inhibitor therapy from 9.5 +/- 1.0 to 4.5 +/- 0.5 g/day (mean +/- SEM) and from 9.8 +/- 1.4 to 3.9 +/- 0.7 g/day respectively, whereas the control group showed a slight fall in proteinuria from 6.9 +/- 0.8 to 5.5 +/- 0.8 g/day. As a result of this treatment hypoalbuminaemia and hypercholesterolaemia improved significantly: serum albumin rose in the NSAID group from 25.4 +/- 1.2 to 29.0 +/- 1.0, and in the ACEi group from 29.9 +/- 1.8 to 32.7 +/- 1.2 g/l (control group from 27.4 +/- 1.6 to 27.8 +/- 1.6 g/l, while cholesterol was lowered in the NSAID group from 8.5 +/- 0.5 to 7.5 +/- 0.4 and in the ACEi group from 8.7 +/- 0.5 to 7.6 +/- 0.4 mmol/l (control group from 9.7 +/- 1.1 to 8.5 +/- 1.0 mmol/l). The antiproteinuric effect of both drugs was well maintained during an 18-month follow-up. Progression towards end-stage renal failure was observed especially in patients with impaired renal function at entry. Remission of proteinuria occurred particularly in patients with lower baseline values of proteinuria, irrespective of the treatment modality.(ABSTRACT TRUNCATED AT 250 WORDS)

The antiproteinuric effects of blood pressure-lowering agents: differences between nondiabetics and diabetics.

The mechanism of the antiproteinuric effect of angiotensin-converting enzyme (ACE) inhibitors in diabetic and nondiabetic renal disease is as yet unknown. A meta-analysis of studies on the effects of ACE inhibitors and other antihypertensive drugs on proteinuria, blood pressure, and renal hemodynamics in nondiabetic renal disease revealed that ACE inhibitors lower proteinuria more than other antihypertensives. Moreover, a close correlation (p less than 0.01) between changes in urinary protein loss and in filtration fraction was found, whereas such a correlation could not be detected between changes in proteinuria and in blood pressure. This suggests that, at least in nondiabetic renal disease, the fall in proteinuria during ACE inhibition is the consequence of the intrarenal effect of the drug more than the systemic effect. Data on the mechanism of action of ACE inhibitors in diabetic microalbuminuria and in diabetic overt proteinuria are less consistent. A fall in proteinuria on antihypertensive drugs in these patients can be observed also without a significant fall in blood pressure, and without any change in filtration fraction. We therefore conclude that one should be cautious in extrapolating the data from studies in diabetic renal disease to patients with nondiabetic nephropathies. Moreover, we argue also that nonhemodynamic effects of ACE inhibitors also could be involved in the antiproteinuric effect of these drugs.

Angiotensin II does not acutely reverse the reduction of proteinuria by long-term ACE inhibition.

Angiotensin converting enzyme (ACE) inhibitors are known to lower urinary protein excretion in human renal disease. This proteinuria lowering effect of ACE inhibition has been hypothesized to be a result of renal hemodynamic changes due to the inhibition of angiotensin II (Ang II) production. To test this hypothesis we studied the short-term effects of different doses of exogenous Ang II (5%, 10% and 20% of the pressor dose) on renal hemodynamics and urinary protein excretion in comparison with placebo infusion in six non-diabetic normotensive proteinuric patients, both before and after three months treatment with the ACE inhibitor, lisinopril. Lisinopril lowered proteinuria from 7.5 +/- 1.9 to 2.7 +/- 0.6 g/24 hr and induced a fall in blood pressure, renal vascular resistance and filtration fraction, whereas plasma Ang II levels were similar to the pre-treatment values. Ang II infusion induced typical effects which appeared to be similar before and during lisinopril treatment: a dose-related fall in renal plasma flow and rise in systemic blood pressure, renal vascular resistance and filtration fraction, while the glomerular filtration rate remained relatively stable. However, neither before nor during lisinopril therapy did any changes in urinary protein loss occur during the infusions of Ang II, despite the fact that Ang II reversed the long-term systemic and renal hemodynamic changes induced by the ACE inhibitor. We conclude that the long-term antiproteinuric effect of the ACE inhibitor, lisinopril, is neither mediated through changes in circulatory Ang II levels nor influenced by acute changes in systemic and renal hemodynamics, suggesting a non-hemodynamic mechanism of action.

Additive antiproteinuric effect of angiotensin-converting enzyme inhibition and non-steroidal anti-inflammatory drug therapy: a clue to the mechanism of action.

1. Both the angiotensin-converting enzyme inhibitor, lisinopril, and the non-steroidal anti-inflammatory drug, indomethacin, lower urinary protein excretion in renal disease and improve the selectivity of the residual proteinuria. Despite the clearly different renal haemodynamic profiles of the two drugs, we hypothesize that the antiproteinuric effect has a final common pathway that is a reduction in glomerular filtration pressure. 2. We studied the effects of lisinopril and indomethacin, separately and in combination, on urinary protein excretion, selectivity of proteinuria and renal haemodynamics in nine non-diabetic patients with overt proteinuria. 3. Urinary protein excretion was 5.4 +/- 2.5 g/24 h in the control period. Lisinopril monotherapy lowered urinary protein excretion by 53 +/- 26%. During indomethacin treatment urinary protein excretion was reduced by 63 +/- 24%. After adding indomethacin to lisinopril, urinary protein excretion fell by a further 58 +/- 23%, resulting in a 79 +/- 17% decrease during combined therapy. 4. Although both lisinopril and indomethacin monotherapy appeared to result in an improvement in glomerular protein permeselectivity, no further improvement was seen during the combination therapy. 5. The change in proteinuria were associated with changes in glomerular filtration rate, which showed a pronounced fall with combination therapy. The renal haemodynamic profiles during the different therapies suggest a post-glomerular vasodilatation by lisinopril and a pre-glomerular vasoconstriction by indomethacin, and the combination of both during the combined treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Additive antiproteinuric effect of the NSAID indomethacin and the ACE inhibitor lisinopril.

Both angiotensin-converting enzyme (ACE) inhibitors like lisinopril and nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin have been shown to lower urinary protein excretion in renal disease. If this effect is caused by different mechanisms of action, the combination of these agents could have an additive antiproteinuric effect. We studied the effects of lisinopril and indomethacin separately and in combination in 10 patients with the nephrotic syndrome. Proteinuria was lowered from 10.5 +/- 1.8 g/24 h in the control period to 4.5 +/- 1.1 g/24 h on indomethacin, 4.3 +/- 1.0 g/24 h on lisinopril and to 2.4 +/- 0.8 g/24 h on the combination. Glomerular filtration rate (GFR) fell on either monotherapy, but particularly on the combination of drugs. The renal hemodynamic changes suggested a preglomerular vasoconstriction by indomethacin and a postglomerular vasodilation by lisinopril. Severe hyperkalemia occurred in 3 patients on the combination therapy. We conclude that the combination of indomethacin and lisinopril has an additive antiproteinuric effect. This, as well as the more pronounced fall in GFR on the combination, may suggest that both drugs lower proteinuria by decreasing intraglomerular capillary pressure but via different mechanisms. Combining these drugs may be useful in the symptomatic treatment of nephrotic syndrome, but renal function and serum potassium should be monitored carefully.

Lisinopril in hypertensive patients with renal function impairment.

The antihypertensive and renal effects of the angiotensin-converting enzyme inhibitor lisinopril were studied in a group of patients with moderate-to-severe hypertension and impaired renal function. After 12 weeks of treatment, most patients had good blood pressure response to lisinopril monotherapy. During this period, correlations between antihypertensive effect, drug dose, and serum drug level were observed. These correlations were no longer evident after prolonged treatment. During a 1-year follow-up period, the drug dose was lowered gradually without losing antihypertensive effect. Hyperkalemia occurred in one third of the patients. During the 1-year follow-up, the glomerular filtration rate (GFR) decreased in two thirds of the patients and remained stable in the other third. In this latter group, the pretreatment GFR was higher, and the effective renal plasma flow had increased, whereas in the patients with a decreased GFR no renal vasodilation had occurred during lisinopril therapy. Thus, lisinopril is an effective antihypertensive drug for patients with impaired renal function. The dose should be adjusted to the pretreatment GFR, and a decrease in dosage should be considered with prolonged treatment.

Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril.

We studied the efficacy of the ACE inhibitor lisinopril in treating overt proteinuria in comparison with the NSAID indomethacin, and evaluated some of the conditions that could influence this antiproteinuric effect. In 12 patients with a proteinuria varying from 3.2 to 10.5 g/24 hr, a diastolic BP ranging from 64 to 105 mm Hg, and a GFR varying from 34 to 127 ml/min, the effect of different lisinopril doses and of changing dietary sodium intake was evaluated. Proteinuria fell by 27 +/- 20% from 6.1 +/- 2.1 to 4.5 +/- 1.9 g/24 hr on a low dose (median 5 mg/day) lisinopril and by 50 +/- 17% to 3.1 +/- 1.4 g/24 hr on a higher dose (median 10 mg/day), irrespective of initial proteinuria, BP, or GFR. This antiproteinuric effect was abolished by increasing salt intake from 50 to 200 mmol/day, and was recovered again by re-instituting the sodium restricted diet. The antiproteinuric effect of 10 mg/day lisinopril was comparable to the reduction in proteinuria (by 57 +/- 21% to 2.8 +/- 2.0 g/24 hr) on 150 mg/day indomethacin, while adverse effects were less and renal hemodynamic effects were more favorable during lisinopril. In some patients it took several weeks before the effect of the ACE inhibitor on proteinuria was stabilized. Thus, the antiproteinuric effect of the ACE inhibitor lisinopril appears to be dose and time related, and is strongly dependent on dietary sodium restriction, whereas it does not depend on initial proteinuria, BP, or GFR. The effect is comparable to that of indomethacin, while adverse effects are less.

Reduction of proteinuria by angiotensin converting enzyme inhibition.

The effects of the angiotensin converting enzyme (ACE) inhibitor lisinopril on blood pressure, proteinuria and renal hemodynamics were evaluated in 13 patients with renal disease of different origin. A comparison was made with the effects of conventional antihypertensive therapy. Both drug regimens significantly lowered blood pressure, while only after 12 weeks of treatment with lisinopril, blood pressure was significantly lower than during conventional therapy. Lisinopril reduced proteinuria (by 61 +/- 40%), whereas conventional therapy had no significant effect on protein excretion. During the first eight weeks of treatment with lisinopril, there was a comparable degree of blood pressure reduction with both treatment regimens, whereas urinary protein loss was significantly less during ACE inhibition. There was only a nearly-significant positive correlation between the fall in proteinuria during lisinopril and the concomitant decrease in mean arterial pressure. Glomerular filtration rate decreased from 26.3 +/- 11.6 to 20.6 +/- 9.4 ml/min during treatment with lisinopril. This decrease was not correlated with the fall in proteinuria. A significant positive correlation existed between the fall in urinary protein excretion and both the decrease in overall renal vascular resistance, and the fall in filtration fraction. Although blood pressure lowering by itself could contribute to the antiproteinuric effect of lisinopril, our results suggest that this effect of ACE inhibition is also due to efferent (postglomerular) vasodilation. We conclude that the ACE inhibitor lisinopril effectively reduces blood pressure and proteinuria in renal disease. The latter effect is not only the result of a lower blood pressure, but is probably also due to a fall in intraglomerular capillary pressure.