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Purpose: Blood pressure (BP) reduction after renal sympathetic denervation (RDN) is highly variable. Renal nerve stimulation (RNS) can localize sympathetic nerves. The RNS trial aimed to investigate the medium-term BP-lowering effects of the use of RNS during RDN, and explore if RNS can check the completeness of the denervation., Material and Methods: Forty-four treatment-resistant hypertensive patients were included in the prospective, single-center RNS trial. The primary study endpoint was change in 24-h BP at 6- to 12-month follow-up after RDN. The secondary study endpoints were the acute procedural RNS-induced BP response before and after RDN; number of antihypertensive drugs at follow-up; and the correlation between the RNS-induced BP increase before versus after RDN (delta [Δ] RNS-induced BP)., Results: Before RDN, the RNS-induced systolic BP rise was 43(±21) mmHg, and decreased to 9(±12) mmHg after RDN ( p  < 0.001). Mean 24-h systolic/diastolic BP decreased from 147(±12)/82(±11) mmHg at baseline to 135(±11)/76(±10) mmHg ( p  < 0.001/<0.001) at follow-up (10 [6-12] months), with 1 antihypertensive drug less compared to baseline. The Δ RNS-induced BP and the 24-h BP decrease at follow-up were correlated for systolic ( R  = 0.44, p  = 0.004) and diastolic ( R  = 0.48, p  = 0.003) BP. Patients with ≤0 mmHg residual RNS-induced BP response after RDN had a significant lower mean 24-h systolic BP at follow-up compared to the patients with >0 mmHg residual RNS-induced BP response (126 ± 4 mmHg versus 135 ± 10 mmHg, p  = 0.04). 83% of the patients with ≤0 mmHg residual RNS-induced BP response had normal 24-h BP at follow-up, compared to 33% in the patients with >0 mmHg residual RNS-induced BP response ( p  = 0.023)., Conclusion: The use of RNS during RDN leads to clinically significant and sustained lowering of 24-h BP with fewer antihypertensive drugs at follow-up. RNS-induced BP changes were correlated with 24-h BP changes at follow-up. Moreover, patients with complete denervation had significant lower BP compared to the patients with incomplete denervation.

Background: Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Despite the impact of CVDs, risk factors are often insufficiently controlled in patients at high risk. Recently, integrated multidisciplinary cardiovascular risk management (CVRM) programmes have been introduced in primary care., Aim: To investigate the effects of a CVRM programme on systolic blood pressure (SBP) and low-density lipoprotein (LDL)-cholesterol., Design & Setting: A prospective observational study was undertaken in patients at high cardiovascular (CV) risk who were aged 40-80 years. Integrated CVRM care was compared with usual care in general practice in the Netherlands., Method: Intervention and usual care patients were matched at baseline on age, sex, and presence of CVD. During 1 year of follow-up, patients received integrated or usual CVRM care in general practice. Primary outcomes were SBP and LDL-cholesterol. Secondary outcomes included calculated 10-year CV risk, body mass index (BMI), lifestyle (smoking, physical activity, and dietary habits), medication use, patient satisfaction, healthcare consumption, morbidity, comorbidity, and mortality. Mixed-model analyses were used to assess the outcomes., Results: Totals of 372 and 317 patients were included in the intervention and usual care group, respectively. Mean age at baseline was 65.1 years and 66.2 years, respectively, and 42% were female in both groups. After 1 year, no differences were observed in: SBP (137.2 mmHg versus 139.0 mmHg in the intervention and usual care group, respectively); LDL-cholesterol (2.6 mmol/l in both groups); or in any of the secondary outcomes., Conclusion: Integrated CVRM care in general practice did not lead to a lower SBP or LDL-cholesterol in patients at high CV risk. Further research is needed to improve CVRM., (Copyright © 2021, The Authors.)

Background: Renal nerve stimulation (RNS) is used to localize sympathetic nerve tissue for selective renal nerve sympathetic denervation (RDN). Examination of heart rate variability (HRV) provides a way to assess the state of the autonomic nervous system. The current study aimed to examine the acute changes in HRV caused by RNS before and after RDN., Methods and Results: 30 patients with hypertension referred for RDN were included. RNS was performed under general anesthesia before and after RDN. Heart rate (HR) and blood pressure (BP) were continuously monitored. HRV characteristics were assessed 1 min before and after RNS and RDN. RNS before RDN elicited a maximum increase in systolic BP of 45 (± 22) mmHg which was attenuated to 13 (± 12) mmHg (p < 0.001) after RDN. RNS before RDN decreased the sinus cycle length from 1210 (± 201) ms to 1170 (± 203) ms (p = 0.03), after RDN this effect was blunted (p = 0.59). The LF/HF ratio in response to RNS changed from ∆ + 0.448 (± 0.550) before RDN to ∆ - 0.656 (± 0.252) after RDN (p = 0.02). Selecting patients off beta-blockade (n = 11), the RNS-induced changes in HRV components before versus after RDN were more pronounced (LF/HF ratio ∆ + 0.900 ± 1.171 versus ∆ - 0.828 ± 0.519, p = 0.01), whereas changes in HRV parameters in patients on beta-blockade (n = 19) were no longer significant. In patients with diabetes mellitus (n = 7), RNS induced no changes in HRV parameters (LF/HF ratio ∆ - 0.039 ± 0.103 versus ∆ - 0.460 ± 0.491, p = 0.92)., Conclusion: RNS induces changes in HRV suggesting increased sympathetic activity. Conversely, after RDN, the RNS-induced changes in HRV suggesting a lower sympathetic autonomic balance. These changes were most pronounced in beta-blocker naïve patients and not present in patients with diabetes mellitus. These findings could support RNS-guided RDN to optimize results.

Background: Renal nerve denervation (RDN) is developed as a potential treatment for hypertension. Recently, we reported the use of renal nerve stimulation (RNS) to localize sympathetic nerve tissue for subsequent selective RDN. The effects of RNS on arterial pressure dynamics remain unknown. The current study aimed to describe the acute changes in arterial pressure dynamics response to RNS before and after RDN., Methods and Results: Twenty six patients with drug-resistant hypertension referred for RDN were included. RNS was performed under general anesthesia before and after RDN. We continuously monitored heart rate (HR) and invasive femoral blood pressure (BP). Augmentation pressure (AP) and index (Aix), pulse pressure (PP), time to reflected wave, maximum systolic BP and dicrotic notch were calculated. Systolic and diastolic BP at site of maximum response significantly increased in response to RNS (120 ± 16/62 ± 9 to 150 ± 22/75 ± 15 mmHg) (p < 0.001/< 0.001), whereas after RDN no RNS-induced BP change was observed (p > 0.10). RNS increased Aix (29 ± 11 to 32 ± 13%, p = 0.005), PP (59 ± 14 to 75 ± 17 mmHg, p < 0.001), time to reflected wave (63 ± 18 to 71 ± 25 ms, p = 0.004) and time to maximum systolic pressure (167 ± 36 to 181 ± 46 ms, p = 0.004) before RDN, whereas no changes were observed after RDN (p > 0.18). All changes were BP dependent. RNS had no influence on HR or the time to dicrotic notch (p > 0.12).   CONCLUSION: RNS induces temporary rises in Aix, PP, time to maximum systolic pressure and time to reflected wave. These changes are BP dependent and were completely blunted after RDN.

Purpose: Recently we reported the use of renal nerve stimulation (RNS) during renal denervation (RDN) procedures. RNS induced changes in blood pressure (BP) and heart rate are not fully delineated yet. We hypothesized that electrical stimulation of the sympathetic nerve tissue in the renal artery would lead to an increase in BP and vagal stimulation would cause a decrease in BP. We report the different patterns of BP and heart rate responses elicited by RNS prior to RDN., Methods: 35 patients with drug-resistant hypertension were included. RNS was performed under general anesthesia at four sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP and heart rate changes were monitored., Results: A total of 289 RNS sites in 35 patients were analyzed. An increase in systolic BP of >10 mmHg was regarded as a positive BP response to RNS. This pattern of response was observed in 180 sites (62%). 86 RNS sites (30%) showed an indifferent response with BP changes ≤10 mmHg. At 13 sites (4.5%) RNS elicited a decrease in BP up to -8 mmHg. However, 10 RNS sites (3.5%) showed a pronounced vagal response with hypotension and sinus cycle lengths ranging between 4224-10272 milliseconds. These sites were distributed among two patients., Conclusion: RNS identified sympathetic and parasympathetic nerve tissue in the renal arteries. RNS can be potentially used to map nerve bundles and guide selective ablation of sympathetic nerve fibers and prevent inadvertent ablation of parasympathetic nerve tissue during RDN.

Background: Hypertension is an important, modifiable risk factor for the development of atrial fibrillation (AF). Even after pulmonary vein isolation (PVI), 20-40% experience recurrent AF. Animal studies have shown that renal denervation (RDN) reduces AF inducibility. One clinical study with important limitations suggested that RDN additional to PVI could reduce recurrent AF., Objective: The goal of this multicenter randomized controlled study is to investigate whether RDN added to PVI reduces AF recurrence., Methods: The main end point is the time until first AF recurrence according to EHRA guidelines after a blanking period of 3 months. Assuming a 12-month accrual period and 12 months of follow-up, a power of 0.80, a two-sided alpha of 0.05 and an expected drop-out of 10% per group, 69 patients per group are required. We plan to randomize a total of 138 hypertensive patients with AF and signs of sympathetic overdrive in a 1:1 fashion. Patients should use at least two antihypertensive drugs. Sympathetic overdrive includes obesity, exercise-induced excessive blood pressure (BP) increase, significant white coat hypertension, hospital admission or fever induced AF, tachycardia induced AF and diabetes mellitus. The interventional group will undergo PVI + RDN and the control group will undergo PVI., Results: Patients will have follow-up for 1 year, and continuous loop monitoring is advocated., Conclusion: This randomized, controlled study will elucidate if RDN on top of PVI reduces AF recurrence.

Renal sympathetic nerve denervation (RDN) is accepted as a treatment option for patients with resistant hypertension. However, results on decline in ambulatory blood pressure (BP) measurement (ABPM) are conflicting. The high rate of nonresponders may be related to increased systemic vascular stiffness rather than sympathetic overdrive. A single center, prospective registry including 26 patients with treatment resistant hypertension who underwent RDN at the Isala Hospital in the Netherlands. Renal perivascular calcium scores were obtained from noncontrast computed tomography scans. Patients were divided into 3 groups based on their calcium scores (group I: low 0-50, group II: intermediate 50-1000, and group III: high >1000). The primary end point was change in 24-hour ABPM at 6 months follow-up post-RDN compared to baseline. Seven patients had low calcium scores (group I), 13 patients intermediate (group II), and 6 patients had high calcium scores (group III). The groups differed significantly at baseline in age and baseline diastolic 24-hour ABPM. At 6-month follow-up, no difference in 24-hour systolic ABPM response was observed between the 3 groups; a systolic ABPM decline of respectively -9 ± 12, -6 ± 12, -12 ± 10 mm Hg was found. Also the decline in diastolic ambulatory and office systolic and diastolic BP was not significantly different between the 3 groups at follow-up. Our preliminary data showed that the extent of renal perivascular calcification is not associated with the ABPM response to RDN in patients with resistant hypertension.

Renal denervation may be more effective if performed distal in the renal artery because of smaller distances between the lumen and perivascular nerves. The authors reviewed the angiographic results of 97 patients and compared blood pressure reduction in relation to the location of the denervation. No significant differences in blood pressure reduction or complications were found between patient groups divided according to their spatial distribution of the ablations (proximal to the bifurcation in both arteries, distal to the bifurcation in one artery and distal in the other artery, or distal to the bifurcation in both arteries), but systolic ambulatory blood pressure reduction was significantly related to the number of distal ablations. No differences in adverse events were observed. In conclusion, we found no reason to believe that renal denervation distal to the bifurcation poses additional risks over the currently advised approach of proximal denervation, but improved efficacy remains to be conclusively established., (©2017 Wiley Periodicals, Inc.)

Blood pressure (BP) response to renal denervation (RDN) is highly variable and its effectiveness debated. A procedural end point for RDN may improve consistency of response. The objective of the current analysis was to look for the association between renal nerve stimulation (RNS)-induced BP increase before and after RDN and changes in ambulatory BP monitoring (ABPM) after RDN. Fourteen patients with drug-resistant hypertension referred for RDN were included. RNS was performed under general anesthesia at 4 sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP changes were monitored and correlated to changes in ambulatory BP at a follow-up of 3 to 6 months after RDN. RNS resulted in a systolic BP increase of 50±27 mm Hg before RDN and systolic BP increase of 13±16 mm Hg after RDN (P<0.001). Average systolic ABPM was 153±11 mm Hg before RDN and decreased to 137±10 mm Hg at 3- to 6-month follow-up (P=0.003). Changes in RNS-induced BP increase before versus immediately after RDN and changes in ABPM before versus 3 to 6 months after RDN were correlated, both for systolic BP (R=0.77, P=0.001) and diastolic BP (R=0.79, P=0.001). RNS-induced maximum BP increase before RDN had a correlation of R=0.61 (P=0.020) for systolic and R=0.71 (P=0.004) for diastolic ABPM changes. RNS-induced BP changes before versus after RDN were correlated with changes in 24-hour ABPM 3 to 6 months after RDN. RNS should be tested as an acute end point to assess the efficacy of RDN and predict BP response to RDN., (© 2016 American Heart Association, Inc.)

Blood pressure response to renal denervation is highly variable, and the proportion of responders is disappointing. This may be partly because of accessory renal arteries too small for denervation, causing incomplete ablation. Renal nerve stimulation before and after renal denervation is a promising approach to assess completeness of renal denervation and may predict blood pressure response to renal denervation. The objective of the current study was to assess renal nerve stimulation-induced blood pressure increase before and after renal sympathetic denervation in main and accessory renal arteries of anaesthetized patients with drug-resistant hypertension. The study included 21 patients. Nine patients had at least 1 accessory renal artery in which renal denervation was not feasible. Renal nerve stimulation was performed in the main arteries of all patients and in accessory renal arteries of 6 of 9 patients with accessory arteries, both before and after renal sympathetic denervation. Renal nerve stimulation before renal denervation elicited a substantial increase in systolic blood pressure, both in main (25.6±2.9 mm Hg; P<0.001) and accessory (24.3±7.4 mm Hg; P=0.047) renal arteries. After renal denervation, renal nerve stimulation-induced systolic blood pressure increase was blunted in the main renal arteries (Δ systolic blood pressure, 8.6±3.7 mm Hg; P=0.020), but not in the nondenervated renal accessory renal arteries (Δ systolic blood pressure, 27.1±7.6 mm Hg; P=0.917). This residual source of renal sympathetic tone may result in persistent hypertension after ablation and partly account for the large response variability., (© 2016 American Heart Association, Inc.)

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.

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.

Objective: Insulin detemir is a soluble long-acting basal insulin analog designed to overcome the limitations of conventional basal insulin formulations. Accordingly, insulin detemir has been compared with NPH insulin with respect to glycemic control (HbA1c, prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration., Research Design and Methods: People with type 1 diabetes (n = 408) were randomized in an open-label, parallel-group trial of 16-week treatment duration using either insulin detemir or NPH insulin. Insulin detemir was administered twice daily using two different regimens, either before breakfast and at bedtime (IDet(morn+bed)) or at a 12-h interval (IDet(12h)). NPH insulin was administered before breakfast and at bedtime. Mealtime insulin was given as the rapid-acting insulin analog insulin aspart., Results: With both insulin detemir groups, clinic fasting plasma glucose was lower than with NPH insulin (IDet(12h) vs. NPH, -1.5 mmol/l [95% CI -2.51 to -0.48], P = 0.004; IDet(morn+bed) vs. NPH, -2.3 mmol/l (-3.32 to -1.29), P < 0.001), as was self-measured prebreakfast plasma glucose (P = 0.006 and P = 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P = 0.046; 32%, P = 0.002; respectively) compared with NPH insulin in the last 12 weeks of treatment, this being mainly attributable to a 53% reduction in nocturnal hypoglycemia in the IDet(morn+bed) group (P < 0.001). Although HbA1c for each insulin detemir group was not different from the NPH group, HbA1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference -0.18% [-0.34 to -0.02], P = 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P < 0.001). The NPH group gained weight during the study, but there was no change in weight in either of the insulin detemir groups (IDet(12h) vs. NPH, -0.8 kg [-1.44 to -0.24], P = 0.006; IDet(morn+bed) vs. NPH, -0.6 kg [-1.23 to -0.03], P = 0.040)., Conclusions: Overall glycemic control with insulin detemir was improved compared with NPH insulin. The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person's needs.

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.

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)

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 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 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.

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)

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.

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.

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.

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.