No effect of the angiotensin receptor blocker candesartan on cerebrovascular autoregulation in rats during very high and low sodium intake.

Autoregulation of cerebral blood flow (CBF) denotes that CBF is constant despite fluctuation of blood pressure within wide limits. Inhibition of the renin-angiotensin system (RAS) is known to decrease the lower and upper limits of CBF autoregulation. We have previously shown that this includes inhibition by the angiotensin receptor blocker (ARB) candesartan. In the present study we investigated the influence of the ARB candesartan on the lower limit of CBF autoregulation in two groups of Sprague-Dawley rats, on high (4.0% Na+) and low (0.004% Na+) sodium diet, respectively. Control animals were given the same diet, but no ARB. CBF was studied with the laser Doppler method. Blood pressure was lowered by controlled bleeding. Results revealed that both high and low sodium diet with low and high renin levels respectively block the influence of candesartan on CBF autoregulation. This was expected in rats on a high salt diet with a low renin level, but unexpected in rats with a low salt intake with a high renin level.

Long-Term Effects of High-Protein Diets on Renal Function.

Chronic kidney disease (CKD) has a prevalence of approximately 13% and is most frequently caused by diabetes and hypertension. In population studies, CKD etiology is often uncertain. Some experimental and observational human studies have suggested that high-protein intake may increase CKD progression and even cause CKD in healthy people. The protein source may be important. Daily red meat consumption over years may increase CKD risk, whereas white meat and dairy proteins appear to have no such effect, and fruit and vegetable proteins may be renal protective. Few randomized trials exist with an observation time greater than 6 months, and most of these were conducted in patients with preexisting diseases that dispose to CKD. Results conflict and do not allow any conclusion about kidney-damaging effects of long-term, high-protein intake. Until additional data become available, present knowledge seems to substantiate a concern. Screening for CKD should be considered before and during long-term, high-protein intake.

Bradykinin antagonist counteracts the acute effect of both angiotensin-converting enzyme inhibition and of angiotensin receptor blockade on the lower limit of autoregulation of cerebral blood flow.

The lower limit of autoregulation of cerebral blood flow (CBF) can be modulated with both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB). The influence of bradykinin antagonism on ARB-induced changes was the subject of this study. CBF was measured in Sprague-Dawley rats with laser Doppler technique. The blood pressure was lowered by controlled bleeding. Six groups of rats were studied: a control group and five groups given drugs intravenously: an ACE inhibitor (enalaprilat), an ARB (candesartan), a bradykinin-2 receptor antagonist (Hoe 140), a combination of enalaprilat and Hoe 140, and a combination of candesartan and Hoe 140. In the control group, the lower limit of CBF autoregulation was 54±9 mm Hg (mean±s.d.), with enalaprilat it was 46±6, with candesartan 39±8, with Hoe 140 53±6, with enalaprilat/Hoe 140 52±6, and with candesartan/Hoe 140 50±7. Both enalaprilat and candesartan lowered the lower limit of autoregulation of CBF significantly. The bradykinin antagonist abolished not only the effect of the ACE inhibitor but surprisingly also the effect of the ARB on the lower limit of CBF autoregulation, the latter suggesting an effect on intravascular bradykinin.

Eplerenone attenuates pulse wave reflection in chronic kidney disease stage 3-4--a randomized controlled study.

BACKGROUND: Patients with chronic kidney disease (CKD) have high cardiovascular mortality and morbidity associated with increased arterial stiffness. Plasma aldosterone levels are increased in CKD, and aldosterone has been found to increase vascular inflammation and fibrosis. It was hypothesized that aldosterone receptor inhibition with eplerenone could reduce arterial stiffness in CKD stage 3-4. STUDY DESIGN: The design was randomized, open, parallel group. Measurements of arterial stiffness markers were undertaken at weeks 1 and 24. INTERVENTION: 24 weeks of add-on treatment with 25-50 mg eplerenone or standard medication. OUTCOMES: Primary outcome parameter was carotid-femoral pulse wave velocity (cfPWV). Secondary outcomes were augmentation index (AIx), ambulatory arterial stiffness index (AASI) and urinary albumin excretion. RESULTS: Fifty-four CKD patients (mean eGFR 36 mL/min/1.73 m(2), SD 11) were randomized. Forty-six patients completed the trial. The mean difference in cfPWV changes between groups was 0.1 m/s (95%CI: -1.0, 1.3), P = 0.8. The mean difference in AIx changes between groups was 4.4% (0.1, 8.6), P = 0.04. AASI was unchanged in both groups. The ratio of change in urinary albumin excretion in the eplerenone group compared to the control was 0.61 (0.37, 1.01), P = 0.05. Four patients were withdrawn from the eplerenone group including three because of possible side effects; one was withdrawn from the control group. Mild hyperkalemia was seen on three occasions and was easily managed. LIMITATIONS: The full planned number of patients was not attained. The duration of the trial may have been too short to obtain full effect of eplerenone on the arteries. CONCLUSIONS: Add-on treatment with eplerenone in CKD stage 3-4 did not significantly reduce cfPWV. There may be beneficial vascular effects leading to attenuated pulse wave reflection. Treatment was well-tolerated. TRIAL REGISTRATION: ClinicalTrials.govNCT01100203.

[Secondary prevention of stroke with effective antihypertensive treatment]. / Sekundær prævention af apopleksi med effektiv antihypertensiv behandling.

In this meta-analysis, four of five placebo-controlled studies showed that antihypertensive treatment prevented stroke recurrence, most markedly in a study with a combination of an angiotensin-converting enzyme inhibitor and a diuretic. Studies with beta-blockers were not included. Two head-to-head comparisons of a calcium antagonist and an angiotensin receptor antagonist showed no clear difference. Danish studies show that approximately 60% of patients with stroke are hypertensive one year after discharge from hospital. Antihypertensive treatment should be started or intensified in such patients.

Beneficial effects on arterial stiffness and pulse-wave reflection of combined enalapril and candesartan in chronic kidney disease--a randomized trial.

BACKGROUND: Cardiovascular disease (CVD) is highly prevalent in patients with chronic kidney disease (CKD). Inhibition of the renin-angiotensinsystem (RAS) in hypertension causes differential effects on central and brachial blood pressure (BP), which has been translated into improved outcome. The objective was to examine if a more complete inhibition of RAS by combining an angiotensin converting enzyme inhibitor (ACEI) and an angiotensin receptor antagonist (ARB) compared to monotherapy has an additive effect on central BP and pulse-wave velocity (PWV), which are known markers of CVD. METHODS: Sixty-seven CKD patients (mean GFR 30, range 13-59 ml/min/1.73 m(2)) participated in an open randomized study of 16 weeks of monotherapy with either enalapril or candesartan followed by 8 weeks of dual blockade aiming at a total dose of 16 mg candesartan and 20 mg enalapril o.d. Pulse-wave measurements were performed at week 0, 8, 16 and 24 by the SphygmoCor device. RESULTS: Significant additive BP independent reductions were found after dual blockade in aortic PWV (-0.3 m/s, P<0.05) and in augmentation index (-2%, P<0.01) compared to monotherapy. Furthermore pulse pressure amplification was improved (P<0.05) and central systolic BP reduced (-6 mmHg, P<0.01). CONCLUSIONS: Dual blockade of the RAS resulted in an additive BP independent reduction in pulse-wave reflection and arterial stiffness compared to monotherapy in CKD patients. TRIAL REGISTRATION: Clinical trial.gov NCT00235287.

Ambulatory arterial stiffness index in chronic kidney disease stage 2-5. Reproducibility and relationship with pulse wave parameters and kidney function.

BACKGROUND: Arterial stiffness contributes to the increased cardiovascular risk in patients with chronic kidney disease (CKD). Reproducible and easily obtainable indices of arterial stiffness are needed in order to monitor therapeutic strategies. The ambulatory arterial stiffness index (AASI) has been proposed as such a marker. The present study investigated the day-to-day reproducibility of AASI in CKD stage 2-5 and its relationship with other markers of arterial stiffness as well as with kidney function. METHODS: Eighty-three patients (29% female, median age 62 years) were studied by 24 h ambulatory blood pressure monitoring (ABPM), aortic pulse wave velocity (aPWV), augmentation index (AIx) and estimated glomerular filtration rate (eGFR) at a median interval of 7 days. Individual AASIs were calculated from 24 h ABPMs as 1 minus the regression slope of diastolic blood pressure over systolic blood pressure. RESULTS: Mean AASI, aPWV, AIx and 24 h pulse pressure (PP) were similar on repeated measurements. The intraclass correlation coefficients were between 72% and 78% for AASI calculated by three different methods, 87% for aPWV, 88% for AIx, and 96% for 24 h PP. The correlation coefficients between AASI and aPWV were from 0.48 to 0.53; with AIx it was between 0.19 and 0.34. After adjustment for covariates none of the arterial stiffness indices were significantly correlated to eGFR. CONCLUSIONS: In patients with CKD stage 2-5 AASI had a moderate, but acceptable reproducibility. The correlation between AASI and aPWV was good whilst the correlation between AASI and AIx was considerably lower. There was no significant correlation between AASI and eGFR.

Low birth weight is associated with earlier onset of end-stage renal disease in Danish patients with autosomal dominant polycystic kidney disease.

Low-birth-weight individuals have a higher risk of hypertension and end-stage renal disease (ESRD). Here we investigated whether low birth weight was associated with earlier onset of ESRD in patients with autosomal dominant polycystic kidney disease (ADPKD). In collaboration with all Danish departments of nephrology, 307 of 357 patients with ADPKD and ESRD born and living in Denmark were recruited. We were able to analyze complete data of 284 patients obtained from both hospital medical files and midwife protocols in the Danish State Archives. Multivariable linear regression adjusted for birth weight, adult height, mean arterial pressure, gender, birth decade, and type of antihypertensive treatment showed that for every kilogram increase in birth weight, the age at onset of ESRD significantly increased by 1.7 years. Male gender and increased mean arterial pressure were both associated with earlier onset of ESRD. Patients treated with renin-angiotensin system blockade or calcium channel blockers during follow-up had significantly later onset of ESRD by 4.3 years and 2.1 years, respectively. Treatment with beta-blockade or a diuretic was not associated with the age at onset of ESRD. Thus, low birth weight may contribute to considerable phenotypic variability in the progression of renal disease between individuals with ADPKD.

Changes in causes of death and risk of cancer in Danish patients with autosomal dominant polycystic kidney disease and end-stage renal disease.

BACKGROUND: With the improved prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD), causes of death and the risk of cancer might have changed. This was investigated in a Danish population with ADPKD and end-stage renal disease (ESRD) between 1 January 1993 and 31 December 2008. METHODS: Data were retrieved from three Danish national registries and a total of 823 patients were identified of which 431 had died during the study period. The 16 years were divided into two 8-year periods and the causes of death were divided into six categories: cancer, cardiovascular, cerebrovascular, infection, other and unknown. RESULTS: Cardiovascular disease was the major cause of death. A multivariate competing risk model comparing the two 8-year periods, adjusted for age at ESRD, gender and treatment modality, showed that deaths from cardiovascular disease decreased by 35% [hazard ratios (HR) 0.65, P=0.008] and deaths from cerebrovascular disease decreased by 69% (HR 0.31, P=0.0003) from the first to the second time period. There were no significant changes between the time periods in death from cancer, infection, other or unknown. From the first to the second 8-year interval, the prevalence of cancer increased by 35% (P=0.0002) while the cancer incidence was stable. CONCLUSIONS: In Danish patients with ADPKD and ESRD, there was a significant reduction in cardiovascular and cerebrovascular deaths from 1993 to 2008. The prevalence of cancer increased without significant change in cancer incidence or deaths from cancer.

Moderate antiproteinuric effect of add-on aldosterone blockade with eplerenone in non-diabetic chronic kidney disease. A randomized cross-over study.

BACKGROUND: Reduction of proteinuria and blood pressure (BP) with blockers of the renin-angiotensin system (RAS) impairs the progression of chronic kidney disease (CKD). The aldosterone antagonist spironolactone has an antiproteinuric effect, but its use is limited by side effects. The present study evaluated the short-term antiproteinuric effect and safety of the selective aldosterone antagonist eplerenone in non-diabetic CKD. STUDY DESIGN: Open randomized cross-over trial. SETTING AND PARTICIPANTS: Forty patients with non-diabetic CKD and urinary albumin excretion greater than 300 mg/24 hours. INTERVENTION: Eight weeks of once-daily administration of add-on 25-50 mg eplerenone to stable standard antihypertensive treatment including RAS-blockade. OUTCOMES & MEASUREMENTS: 24 hour urinary albumin excretion, BP, p-potassium, and creatinine clearance. RESULTS: The mean urinary albumin excretion was 22% [CI: 14,28], P < 0.001, lower during treatment with eplerenone. Mean systolic BP was 4 mmHg [CI: 2,6], P = 0.002, diastolic BP was 2 mmHg [CI: 0,4], P = 0.02, creatinine clearance was 5% [CI: 2,8], P = 0.005, lower during eplerenone treatment. After correction for BP and creatinine clearance differences between the study periods, the mean urinary albumin excretion was 14% [CI: 4,24], P = 0.008 lower during treatment. Mean p-potassium was 0.1 mEq/L [CI: 0.1,0.2] higher during eplerenone treatment, P<0.001. Eplerenone was thus well tolerated and no patients were withdrawn due to hyperkalaemia. LIMITATIONS: Open label, no wash-out period and a moderate sample size. CONCLUSIONS: In non-diabetic CKD patients, the addition of eplerenone to standard antihypertensive treatment including RAS-blockade caused a moderate BP independent fall in albuminuria, a minor fall in creatinine clearance and a 0.1 mEq/L increase in p-potassium. TRIAL REGISTRATION: Clinicaltrials.gov NCT00430924.

Improved prognosis in patients with autosomal dominant polycystic kidney disease in Denmark.

BACKGROUND AND OBJECTIVES: The introduction of new therapies, including agents that block the renin-angiotensin system, may have affected progression of autosomal dominant polycystic kidney disease (ADPKD). We investigated whether the age when reaching ESRD and survival during renal replacement therapy in Danish patients with ADPKD changed from January 1, 1990, through December 31, 2007. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: According to the Danish National Registry on Regular Dialysis and Transplantation, 693 patients with ADPKD reached ESRD in the study period. The 18 years were divided into three consecutive 6-year intervals. RESULTS: The incidence of reaching ESRD for patients with ADPKD increased from 6.45 per million people in 1990 through 1995 to 7.59 per million people in 2002 through 2007, and the mean age at onset of ESRD increased by 4.7 years. The age-adjusted male-to-female ratio for onset of ESRD changed from 1.6 to 1.1, indicating a trend toward similar progression in both genders. From onset of ESRD, a Cox regression analysis to compare the first and second 6-year intervals, adjusted for age, gender, and treatment modality, showed that patient survival improved by 38%. Although NS, a similar trend was found during the second and third time intervals. CONCLUSIONS: This study demonstrates that in Danish patients with ADPKD, the prognosis had significantly improved during the study period. Furthermore, the results indicate that male gender may be losing its importance as a risk factor for progression in ADPKD.

Feasibility of combined treatment with enalapril and candesartan in advanced chronic kidney disease.

BACKGROUND: Dual blockade of the renin-angiotensin system (RAS) has been claimed to have a specific renal protective effect in chronic kidney disease (CKD). The present short-term study reports on the feasibility of dual blockade in a consecutive group of patients with CKD stage 3-5. METHODS: Forty-seven CKD patients, mean age 59 years, with mean estimated glomerular filtration rate (GFR) 26 ml/min/1.73 m(2) (range 13-49) and blood pressure (BP) 133/78 mmHg, were block randomized in an open study to 16 weeks of monotherapy with increasing doses of RAS blockade aiming at enalapril 20 mg o.d. or candesartan 16 mg o.d. Thereafter, the complementary drug was added in incremental doses over a period of 5 weeks aiming at combined enalapril 20 mg and candesartan 16 mg for 3 weeks. Seventy-five percent of the patients were known to be RAS blockade tolerant. Blood samples and BP were measured every 2-3 weeks. Doses of study medication were reduced in case of hyperkalemia >5.5 mmol/l, a sustained rise in p-creatinine >30% or symptomatic hypotension. RESULTS: Twenty-one patients (45%) did not tolerate dual blockade in aimed dosages due to unacceptable p-creatinine increase (n = 12, including two study withdrawals), hypotension (n = 6), general discomfort (n = 2) or unmanageable hyperkalemia (n = 1). Hyperkalemia >5.5 mmol/l was seen in seven patients (15%). The reduced-dose group had baseline lower eGFR and diastolic BP. CONCLUSIONS: Forty-five percent of CKD stage 3-5 patients did not tolerate dual RAS blockade with 20 mg enalapril and 16 mg candesartan daily, primarily due to loss of renal function or hypotension. Hyperkalemia could be managed in most patients. Caution is recommended when giving this treatment to patients with advanced CKD.

Estimating glomerular filtration rate using the new CKD-EPI equation and other equations in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: No studies have compared the performance of equations for estimating glomerular filtration rate (GFR) in patients with autosomal dominant polycystic kidney disease (ADPKD), where the declining GFR typically is followed for many years or even decades. This was the purpose of the present investigation. METHODS: 101 ADPKD patients with chronic kidney disease stages 1-5 were recruited and GFR was measured with the (51)Cr-EDTA clearance method, and estimated with the Modification of Diet in Renal Disease Study (MDRD) equation with 4 variables, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault equation adjusted for body surface area and the MDRD equation with cystatin C. Performance was evaluated by mean bias, precision and accuracy. RESULTS: The MDRD equation with cystatin C had 97% of GFR estimates within 30% of measured GFR (accuracy). Both the CKD-EPI and Cockcroft-Gault equations had an accuracy of 90% whereas the MDRD equation had an accuracy of 83%. This difference of accuracy was especially marked with GFR >60 ml/min/1.73 m(2). CONCLUSION: For estimating GFR in ADPKD patients the MDRD equation with cystatin C incorporated had the best performance. The CKD-EPI or the Cockcroft-Gault equations showed better performance compared to the 4-variable MDRD equation.

Angiotensin AT1-receptor blockers and cerebrovascular protection: do they actually have a cutting edge over angiotensin-converting enzyme inhibitors?

First, an update of the vascular systemic and tissue renin-angiotensin-aldosterone system is provided to explain how it is regulated at the systemic and tissue levels, and how many angiotensin peptides and receptors can be modulated by the various antihypertensive drugs. Second, experimental data is presented to support the hypothesis that antihypertensive drugs that increase angiotensin II formation, such as diuretics, AT1-receptor blockers and dihydropyridines, may have greater brain anti-ischemic effects than antihypertensive drugs that decrease angiotensin II formation, such as beta-blockers and angiotensin-converting enzyme inhibitors, because they increase activation of angiotensin AT2 and AT4 receptors. Indeed, these trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia. Third, we review most of the large primary and secondary stroke prevention trials as well as the ACCESS acute stroke trial in which antihypertensive drugs were evaluated. With the exception of the secondary stroke prevention trial PRoFESS, most trials support the hypothesis that angiotensin II-increasing drugs confer specific blood pressure-independent brain ischemia protection when compared with angiotensin II-decreasing drugs or placebo. A careful analysis of the PRoFESS trial, however, reveals study design limitations, the main one being that diastolic BP (<80 mmHg) in the first month post-stroke may have been too low in at least one third of the population with baseline systolic blood pressure less than 130 mmHg, because a high dose of telmisartan was given after a very short post-stroke delay (median 15 days) without discontinuation of the baseline antihypertensive treatment.

[Hypertension and renal disease]. / Hypertension og nyresygdom.

Renal mechanisms, in particular the renin-angiotensin system and renal salt handling, are of major importance in blood pressure regulation. Co-existence of hypertension and decreased renal function may be due to nephrosclerosis secondary to hypertension, or primary renal disease with secondary hypertension. Mild degrees of chronic kidney disease (CKD) can be detected in around 10% of the population, and detection is important as CKD is an important risk factor for atherosclerotic cardiovascular disease. Conversely, heart failure may cause an impairment of renal function. In chronic progressive nephropathy, effective blood pressure lowering is of paramount importance, and angiotensin converting enzyme inhibitors and angiotensin receptor blockers are agents of choice.

[Hypertension and the brain]. / Hypertension og hjernen.

Hypertension is a major and modifiable risk factor of stroke and dementia. Hypertension causes remodelling of the cerebral resistance vessels, impairing their tolerance to very low blood pressure. In primary prevention of stroke, the effect of beta-blockers is inferior to other classes of antihypertensives. In secondary prevention of stroke, ACE-inhibitors and angiotensin blockers may be recommended as first choice drugs. Lowering of the blood pressure is, however, more important than the choice of drug.

Asymmetric dimethylarginine, oxidative stress, and vascular nitric oxide synthase in essential hypertension.

We reported impaired endothelium-derived relaxation factor/nitric oxide (EDRF/NO) responses and constitutive nitric oxide synthase (cNOS) activity in subcutaneous vessels dissected from patients with essential hypertension (n = 9) compared with normal controls (n = 10). We now test the hypothesis that the patients in this study have increased circulating levels of the cNOS inhibitor, asymmetric dimethylarginine (ADMA), or the lipid peroxidation product of linoleic acid, 13-hydroxyoctadecadienoic acid (HODE), which is a marker of reactive oxygen species. Patients had significantly (P < 0.001) elevated (means +/- SD) plasma levels of ADMA (P(ADMA), 766 +/- 217 vs. 393 +/- 57 nmol/l) and symmetric dimethylarginine (P(SDMA): 644 +/- 140 vs. 399 +/- 70 nmol/l) but similar levels of L-arginine accompanied by significantly (P < 0.015) increased rates of renal ADMA excretion (21 +/- 9 vs. 14 +/- 5 nmol/mumol creatinine) and decreased rates of renal ADMA clearance (18 +/- 3 vs. 28 +/- 5 ml/min). They had significantly increased plasma levels of HODE (P(HODE): 309 +/- 30 vs. 226 +/- 24 nmol/l) and renal HODE excretion (433 +/- 93 vs. 299 +/- 67 nmol/micromol creatinine). For the combined group of normal and hypertensive subjects, the individual values for plasma levels of ADMA and HODE were both significantly (P < 0.001) and inversely correlated with microvascular EDRF/NO and positively correlated with mean blood pressure. In conclusion, elevated levels of ADMA and oxidative stress in a group of hypertensive patients could contribute to the associated microvascular endothelial dysfunction and elevated blood pressure.

Longitudinal observations on circadian blood pressure variation in chronic kidney disease stages 3-5.

BACKGROUND: It has been suggested that status as a 'non-dipper' determined from 24-h blood pressure (BP) recordings is associated with increased risk of end-organ damage but little is known about the consistency of dipper status in renal patients. The present post hoc analysis evaluated dipper/non-dipper status prospectively in a study on dosage of enalapril in progressive chronic kidney disease (CKD) stages 3-5. METHODS: In 34 patients, 24-h ambulatory BP (A&D TM2421) was measured at baseline and every 4 months for 1 year or until the need for renal replacement therapy. For each BP recording patients were classified as dippers or non-dippers based on the presence or absence of a nighttime reduction in both systolic and diastolic BP > 10%. Antihypertensive treatment aimed at an office BP < 120/80 mmHg. GFR was measured by the plasma clearance of (51)Cr-EDTA and albuminuria was determined from 24-h collections. RESULTS: A total of 125 24-h BP recordings were made. Ten patients were constant dippers and five were constant non-dippers throughout the study whereas nineteen patients changed dipping status apparently at random. When analysing pairs of sequential recordings in the individual patient, non-dipper and dipper status remained unaltered in 25 (27%) and 32 (35%) of comparisons, respectively, whereas it was inconsistent in 34 (38%) of cases. No correlation between dipper status and GFR, decline in renal function, degree of albuminuria or BP level could be demonstrated. CONCLUSIONS: The consistency of circadian BP variation seems to be poor in CKD stages 3-5 and single measurements of 24-h ambulatory BP are therefore probably inadequate for the evaluation of dipping status.