Roland Veelken

Additional Antiproteinuric Effect of Ultrahigh Dose Candesartan: A Double-Blind, Randomized, Prospective Study

Proteinuria indicates future renal and cardiovascular morbidity, and, conversely, its reduction is associated with improved outcome. In a randomized, double-blind trial with parallel group design, the antiproteinuric effect of candesartan at high doses was analyzed. Patients with normal or mildly impaired renal function, protein excretion rate of 1 to 10 g/d, and treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for 3 mo were eligible. After a 4-wk treatment with 16 mg/d candesartan, patients (n = 32) were allocated to double-blind therapy with either 32 or 64 mg/d candesartan for 12 wk (including 4 wk of uptitration), followed again by 4 wk of candesartan 16 mg/d. Proteinuria at study entry was similar in both groups (geometric mean [95% confidence interval (CI)]; 32 mg/d candesartan 2.14 g/d [95% CI, 1.45 to 3.17]; 64 mg/d candesartan 2.54 g/d [95% CI, 1.91 to 3.40]; NS). After the double-blind treatment phase, proteinuria was reduced to 1.42 g/d (0.85 to 2.37) in the 64-mg/d group (P = 0.017), without any change in the 32-mg/d group (2.02 g/d [95% CI, 1.26 to 3.26]). The change in proteinuria differed between the two groups in absolute (P = 0.025) and relative terms (-29 +/- 50 versus -0 +/- 26%; P = 0.012). After downtitration to 16 mg/d candesartan, proteinuria increased again to 2.38 g/d (1.57 to 3.62) in the 64-mg/d group (P = 0.001) but remained unchanged in the 32-mg/d group (2.04 g/d [95% CI, 1.17 to 3.57]; NS). No change in BP was noticed in response to the different doses of candesartan. These data indicate an additive antiproteinuric effect of ultrahigh dose of the angiotensin receptor blocker candesartan compared with standard dose.

Early interstitial changes in hypertension-induced renal injury.

To elucidate the mechanisms of hypertensive renal injury, we investigated the time course and extent of changes in matrix composition, as well as cell proliferation and infiltration in two-kidney, one clip rats. The nonclipped kidneys from hypertensive and sham-operated control rats (n = 5 to 10 in each group) were studied at 7, 14, 21, and 28 days after clipping. Systolic blood pressure was elevated by day 7 (154 +/- 3 versus 111 +/- 4 mm Hg in sham group, P < .001, n = 10 each). Hypertension resulted in an early expansion of the interstitial volume by 37%, whereas hypertensive vascular changes and glomerular injury did not become evident until day 21. Immunofluorescence studies revealed an early interstitial accumulation of collagens I, III, IV, V, VI, and fibronectin by day 7. In contrast, the glomeruli showed a mild to moderate increase in collagens I, III, IV, V, laminin, and fibronectin but not collagen VI later in the established phase of hypertension. Staining for proliferating cell nuclear antigen as a marker of cell replication was increased in tubular epithelial but not interstitial or glomerular cells. A progressive infiltration of macrophages (16 +/- 2 versus 9 +/- 1 ED1+ cells/mm2, P < .05, n = 6) and T lymphocytes (93 +/- 15 versus 74 +/- 7 CD4+ cells/mm2, n = 8) in the cortical interstitium had already occurred by day 7. On the other hand, only macrophages increased in number within the glomeruli. Thus, renovascular hypertension leads to an early tubular cell proliferation, mononuclear cell recruitment, and deposition of matrix proteins primarily within the interstitium. We conclude that the injury producing nephrosclerosis in this model extends far beyond the glomeruli. Both the tubules and the interstitium are actively involved and may be the more important initial sites of injury.

Renal Denervation in Moderate Treatment-Resistant Hypertension

OBJECTIVES This study sought to investigate the effect of renal denervation (RDN) in patients with treatment-resistant hypertension according to the established definition (Joint National Committee VII and European Society of Hypertension/European Society of Cardiology guidelines), that is, office blood pressure (BP) ≥140/90 mm Hg (with at least three antihypertensive drugs, including a diuretic, in adequate doses) and confirmed by 24-h ambulatory BP monitoring (ABPM). BACKGROUND RDN emerged as an innovative interventional antihypertensive therapy. However, so far, only patients with severe hypertension (systolic BP ≥160 mm Hg or ≥150 mm Hg for patients with type 2 diabetes) have been investigated. METHODS In this study, there were 54 patients with moderate treatment-resistant hypertension (office BP ≥140/90 mm Hg and <160/100 mm Hg and diagnosis confirmed by 24-h ABPM of ≥130/80 mm Hg) who underwent catheter-based RDN using the Symplicity catheter (Medtronic Inc., Mountain View, California). RESULTS Patients were treated with 5.1 ± 1.4 antihypertensive drugs on average. Office BP was significantly reduced by 13/7 mm Hg 6 months after RDN (systolic: 151 ± 6 mm Hg vs. 138 ± 21 mm Hg, p < 0.001; diastolic: 83 ± 11 mm Hg vs. 75 ± 11 mm Hg, p < 0.001). In patients (n = 36) who underwent ABPM 6 months after treatment, there was a reduction in average 24-h ABPM by 14/7 mm Hg (systolic: 150 ± 16 mm Hg vs. 136 ± 16 mm Hg, p < 0.001; diastolic: 83 ± 10 mm Hg vs. 76 ± 10 mm Hg, p < 0.001). In 51% of patients, office BP was controlled below 140/90 mm Hg after RDN. In addition, heart rate decreased from 67 ± 11 to 63 ± 10 beats/min (p = 0.006). CONCLUSIONS Our data indicate that RDN may reduce office and 24-h ambulatory BP substantially in patients with moderate treatment-resistant hypertension. (Renal Denervation in Treatment Resistant Hypertension; NCT01687725).

Increased vascular angiotensin formation in female rats harboring the mouse Ren-2 gene

Rats harboring the mouse Ren-2 transgene develop hypertension despite low levels of plasma renin activity. We tested the hypothesis that these rats exhibit an increase in vascular angiotensin formation caused by the presence of the transgene. We measured the release of angiotensins I and II from isolated perfused hindquarters by high-performance liquid chromatography and radioimmunoassay. Female rats heterozygous for the transgene had significantly elevated mean arterial pressure compared with control rats (189.3±9.5 versus 110.0±5.4 mm Hg, p < 0.05). Plasma angiotensin II was significantly decreased in transgenic rats. Transgenic rat hindquarters released more angiotensin I (121±37 versus 39±12 fmol/30 min, n = 7 each) and more angiotensin II (210±21 versus 62±12 fmol/30 min, p < 0.05, n = 7 each) than control rat hindquarters. Captopril increased angiotensin I release and decreased angiotensin II values in both transgenic and control rat hindquarters. Bilateral nephrectomy 24 hours before hindquarter perfusion greatly reduced angiotensin release from control rat hindquarters but not from transgenic rat hind limbs. We also tested for the presence of Ren-2 messenger RNA in mesenteric and aortic tissue by RNase protection assay and Northern blot analysis. We found that Ren-2 messenger RNA was present in mesenteric and aortic tissue of transgenic but not of control rats. We conclude that the Ren-2 transgene is expressed in vascular tissue of transgenic rats and may be responsible for substantial increases in vascular angiotensin formation.

Substance P induces a cardiovascular defense reaction in the rat: pharmacological characterization.

In this study in conscious rats, we tested the hypothesis that substance P, a central pressor peptide and a potential transmitter substance of pain pathways, could be involved in the cardiovascular defense reaction that is typically associated with unpleasant sensory stimuli. The hemodynamic responses to centrally administered substance P were pharmacologically characterized. The increases in blood pressure and heart rate after intracerebroventricular injections of substance P were accompanied by mesenteric and renal vasoconstriction and hind limb vasodilation (pulsed-Doppler flow probes). The pressor and vasoconstrictor responses were attenuated by peripheral α1-adrenoceptor blockade with prazosin but were not influenced by blockade of vascular vasopressin receptors with d(CH2)5Tyr(Me) arginine vasopressin (AVP). Cardiac β1-adrenoceptor blockade with metoprolol abolished the tachycardic and reduced the pressor responses. Substance P-induced hind limb vasodilation was not sensitive to intravenous atropine but was largely prevented by peripheral β2-adrenoceptor blockade with ICI 118,551. Thus, the substance P-indnced pressor effects are mediated by α1-adrenergic sympathetic vasoconstriction and β1-adrenergic cardiac stimulation, whereas the hind limb vasodilation is mainly due to β2-adrenergic stimulation. Substance P dose-dependently (0.01–10 4mUg i.c.v.) released oxytocin but not vasopressin or adrenocorticotropic hormone (ACTH) from the pituitary gland. High doses reduced basal ACTH levels. Together with the hemodynamic responses, a behavioral arousal reaction was observed, which included increased locomotion, grooming, scratching, and skin biting. Our results demonstrate that a neuropeptide can induce a classic cardiovascular defense reaction. The endocrine component of the substance P-induced response (oxytocin release) is compatible with stress reactions, and the behavioral component is compatible with the reaction to nodceptive stimuli in rodents. We conclude that in the central nervous system, substance P may be important for the generation of an integrated cardiovascular and behavioral response pattern within the efferent pathways of the reaction to nociceptive stimuli.

1166 A/C Polymorphism of the Angiotensin II Type 1 Receptor Gene and the Response to Short-Term Infusion of Angiotensin II

BACKGROUND Previous studies reported an association of the 1166 A/C polymorphism of the angiotensin II (Ang II) type 1 receptor gene with high blood pressure and cardiovascular disease. We tested the hypothesis that this polymorphism affects the blood-pressure, renal hemodynamic, and aldosterone response to infused Ang II. METHODS AND RESULTS Young, male, white volunteers (n = 116) with normal (n = 65) or mildly elevated (n = 51) blood pressure on a high salt intake were genotyped for the 1166 A/C polymorphism. Two doses of Ang II (0.5 and 3 ng x kg(-1) x min(-1) over 30 minutes each) increased blood pressure, plasma aldosterone, glomerular filtration rate, and filtration fraction and decreased renal blood flow. The blood-pressure, renal hemodynamic, and aldosterone responses were not significantly different between subjects homozygous for the A allele (n = 56) and heterozygous subjects (n = 47) or subjects homozygous for the C allele (n = 13). Comparison of A allele homozygotes with all C allele carriers pooled (n = 60) or restriction of the analysis to normotensive volunteers also revealed no significant differences between genotypes. CONCLUSIONS The 1166 C variant of the Ang II type 1 receptor does not lead to a greater blood-pressure, aldosterone, or renal vascular response to infused Ang II in young, male, white subjects. We conclude that the 1166 A/C polymorphism does not have a major effect on these actions of Ang II.

Autonomic Renal Denervation Ameliorates Experimental Glomerulonephritis

Increasing evidence indicates that inflammation of visceral organs is significantly affected by the autonomic nervous system. Such neuroimmune interactions have not been studied in the kidney. Here, we show that the rat kidney is innervated by both tyrosine hydroxylase-positive sympathetic efferent nerve fibers and calcitonin gene-related peptide-positive primary afferent nerve fibers, both of which are found in proximity to macrophages and dendritic cells. Complete surgical bilateral renal denervation was performed 2 d before glomerulonephritis was induced by injecting the monoclonal anti-Thy-1.1 antibody OX-7. Denervation significantly reduced albuminuria, mesangiolysis, formation of microaneurysms, deposition of glomerular collagen IV, and expression of TGF-beta compared with sham-operated controls. Accordingly, inflammation, identified by accumulation of interstitial macrophages and renal expression of TNF-alpha, and mesangial cell proliferation were significantly reduced. These findings indicate that autonomic renal denervation ameliorates and, by inference, innervation exacerbates acute inflammation in the kidney; therefore, neurotransmitters or neuropeptides and their receptors might represent novel targets for the treatment of acute glomerulonephritis.

How does minor renal dysfunction influence cardiovascular risk and the management of cardiovascular disease

This review focuses on the association between mild renal insufficiency (stage 2 and 3 of chronic kidney disease) and cardiovascular disease and discusses therapeutic options. Although the association of chronic renal insufficiency and cardiovascular risk was first shown in patients with end-stage renal disease, even minor renal dysfunction is now established as an independent risk for atherosclerotic cardiovascular disease. The association has been established in patients with a high cardiovascular risk but also in the general population. Treatment with angiotensin-converting enzyme inhibitors and statins can reduce cardiovascular morbidity and mortality in patients with renal insufficiency. Coronary revascularization improves the prognosis in patients with minor renal dysfunction, but there is still an underutilization of coronary revascularization procedures in people with renal insufficiency. The use of coronary stenting has now reduced the incidence of restenosis in these patients, and there is hope that the development of new devices will improve the prognosis in patients with renal insufficiency as well. Nevertheless, people with cardiovascular disease and renal insufficiency die significantly more often than people without renal insufficiency independent of prior successful treatment. Further investigations should focus on the causes of and possible preventive interventions for the staggering cardiovascular risk in the ever-increasing number of people with minor renal dysfunction.

Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension.

Objectives: Arterial hypertension and increased sympathetic activity are underlying pathogenetic mechanisms of the progressive loss of renal function in patients with chronic kidney disease (CKD). Meta-analyses have shown that impaired renal function is an independent cardiovascular risk factor. We hypothesized that renal denervation (RDN) decreases the decline of renal function in patients with CKD stages 3 and 4 and treatment-resistant hypertension. Methods: We performed an observational study of 27 patients with CKD stages 3 and 4, office blood pressure (BP) ≥ 140/90 mmHg, while on at least three antihypertensive drug classes including diuretic, and diagnosis confirmed by 24-h ambulatory BP measurement ≥ 130/80 mmHg. All patients underwent catheter-based RDN using the Symplicity Flex RDN System (Medtronic Inc., Santa Rosa, California, USA). Renal function was evaluated for up to 3 years prior and 1 year after RDN. The change in estimated glomerular filtration rate (eGFR) was calculated by regression slope individually for each patient before and after RDN. The study was registered at www.clinicaltrials.gov (ID: NCT01442883). Results: Mean baseline BP was 156 ± 12/82 ± 13 mmHg, despite treatment with 6.2 ± 1.1 antihypertensive drugs. One year after RDN, office BP was reduced by 20 ± 20 (P < 0.001)/8 ± 14 mmHg (P = 0.005) and average 24-h ambulatory BP by 9 ± 14 (P = 0.009)/4 ± 7 mmHg (P = 0.019). Before RDN, eGFR declined by –4.8 ± 3.8 ml/min per 1.73 m2 per year, and after RDN eGFR improved by +1.5 ± 10 ml/min per 1.73 m2 at 12 months (P = 0.009). Conclusions: Our observational pilot study in patients with CKD stages 3 and 4 indicates that treatment of hypertension with RDN decreases BP and slows or even halts the decline of renal function.

Extrarenal Na+ Balance, Volume, and Blood Pressure Homeostasis in Intact and Ovariectomized Deoxycorticosterone-Acetate Salt Rats

Water-free Na+ storage may buffer extracellular volume and mean arterial pressure (MAP) in spite of Na+ retention. We studied the relationship among internal Na+, K+, water balance, and MAP in Sprague-Dawley rats, with or without deoxycorticosterone-acetate (DOCA) salt, with or without ovariectomy (OVX). The rats were fed a low-salt (0.1% NaCl) or high-salt (8% NaCl) diet for 5 weeks. DOCA salt increased MAP (161±14 versus 123±4 mm Hg; P<0.05), and DOCA-OVX salt increased MAP further (181±22 mm Hg; P<0.05). DOCA salt increased the total body Na+ by ≈40% to 45%; however, water-free Na+ retention by osmotically inactive Na+ storage and by osmotically neutral Na+/K+ exchange allowed the rats to maintain the extracellular volume close to normal. DOCA-OVX salt rats showed similar Na+ retention. However, their osmotically inactive Na+ storage capacity was greatly reduced and only partially compensated by neutral Na+/K+ exchange, resulting in greater volume retention despite similar Na+ retention. For every 1% wet weight total body water gain, MAP increased by 2.3±0.2 mm Hg in DOCA salt rats and 2.5±0.3 mm Hg in DOCA-OVX salt rats. Because water-free Na+ retention buffered total body water content by 8% to 11% wet weight, we conclude that this internal Na+ escape buffered MAP. Extrarenal Na+ and volume balance seem to play an important role in long-term volume and MAP control.