Circadian rhythm and day to day variability of serum potassium concentration: a pilot study.

BACKGROUND: Hyperkalemia is a common and life-threatening complication frequently seen in patients with acute kidney injury, end-stage renal disease and chronic heart failure. Cardiac arrest and ventricular fibrillation are possible consequences. Biosensors are currently being developed to measure serum potassium under ambulatory conditions and trigger an alarm if the potassium concentration exceeds normal limits. Only few studies exist on the circadian rhythm of potassium; and its dependence on age and kidney function is less clear. METHODS: Our observational monocentric exploratory study included 30 subjects of which 15 had impaired renal function (RF) (GFR <60 ml/min/1.73 m(2)). Subjects were further categorized into three age groups: 18-39 years (N normal RF = 5, N impaired RF = 4), 40-59 years (N normal RF = 5, N impaired RF = 6), 60-80 years (N normal RF = 5, N impaired RF = 5). Serum potassium levels were measured every 2 h during a 24 h period and repeated once after 2, 4, or 6 days. RESULTS: In the 15 subjects with normal RF, the lowest mean potassium level (3.96 ± 0.14 mmol/l) was observed at 9 p.m. and the greatest (4.23 ± 0.23 mmol/l) at 1 p.m. In patients with impaired RF the lowest mean potassium level (4.20 ± 0.32 mmol/l) was observed at 9 p.m. and the highest (4.57 ± 0.46 mmol/l) at 3 p.m. The range between the mean of minimum and maximum was greater in patients with impaired RF (0.71 ± 0.45 mmol/l) than in subjects with normal RF (0.53 ± 0.14 mmol/l) [p < 0.001]. No difference in the circadian rhythm was found between the first and second examination. CONCLUSION: Our results indicate that patients with normal and impaired RF have comparable circadian patterns of serum potassium concentrations, but higher fluctuations in patients with impaired RF. These results have clinical relevance for developing an automatic biosensor to measure the potassium concentration in blood under ambulatory conditions in patients at high risk for potassium fluctuations.

Sympathetic blockade prevents the decrease in cardiac VEGF expression and capillary supply in experimental renal failure.

Uremic cardiomyopathy of men and rodents is characterized by lower myocardial capillary supply that in rats could be prevented by central and peripheral blockade of the sympathetic nervous system. The underlying pathomechanisms remain largely unknown. We investigated whether alterations of cardiac vascular endothelial growth factor (VEGF) gene and protein expression were involved. In our long-term experiment, we analyzed whether VEGF gene and protein expression was altered in the heart of male Sprague-Dawley rats with either sham operation (sham, n=10) or subtotal nephrectomy (SNX, n=10). In our short-term experiment (17 sham, 24 SNX), the effect of a putative downregulation of sympathetic nervous activity by surgical renal denervation (interruption of renal afferent pathways) on cardiac gene expression of VEGF, flt-1, and flk-1 and on myocardial capillary supply was analyzed. In the long-term study, cardiac capillary supply and vascular endothelial growth factor gene and protein expression were significantly lower in SNX than in sham. In the short-term experiment, cardiac VEGF mRNA expression was significantly lower in untreated SNX (4,258±2,078 units) than in both sham groups (11,709±4,169 and 8,998±4,823 units); this decrease was significantly prevented by renal denervation (8,190±3,889, P<0.05). We conclude that cardiac VEGF gene and protein expression is reduced in experimental renal failure, and this may be considered as one potential reason for impaired myocardial adaptation under the situation of cardiac hypertrophy. The beneficial effect of sympathetic downregulation on cardiac structure and function in renal failure may be at least in part explained by increased cardiac VEGF gene expression.

[Chronic kidney disease and the cardiovascular system]. / Chronische Nierenerkrankungen und kardiovaskuläres System.

Depending on the reduction in glomerular filtration rate (GFR) as a measure of renal insufficiency and depending on their age, patients with chronic kidney disease have a 1.5 to 1,000-fold higher cardiovascular risk. Renal insufficiency is inherently an independent risk factor for cardiovascular events, which is likewise the case for patients also presenting with hypertension or diabetes mellitus. When cardiac insufficiency or coronary heart disease is already manifest, the GFR is the most important predictive factor for the patients' further survival. Proteinuria or albuminuria as signs of kidney disease are also important markers and correlate with the cardiovascular risk in the range of both macro- and microalbuminuria. Endothelial dysfunction, oxidative stress, dyslipidemia, and increased atherosclerosis are being discussed as pathophysiological mechanisms of elevated cardiovascular risk.

[Shared decision-making with hypertensive patients. Results of an implementation in Germany]. / "Shared Decision-Making" mit Bluthochdruckpatienten. Ergebnisse einer Implementierung in Deutschland.

BACKGROUND AND OBJECTIVE: Lack of compliance is a common problem in the treatment of hypertension. Ineffective physician-patient-communication and a lack of patients involvement can play a crucial role. We tested the hypothesis that shared decision-making (SDM) results in higher involvement of patients in their blood pressure lowering therapy and evaluated the effects of SDM on the control of blood pressure. PATIENTS AND METHODS: Two groups of 84 hypertensives were compared: an intervention group (26 women and 13 men, age 61 +/- 10 years) treated by 15 specially SDM-trained primary care physicians, and a control group of 45 hypertensives. All 84 patients were enrolled in a patient education programme. Changes of blood pressure were assessed after one year by self-measurements. Questionnaires about their attitude to patient autonomy, the SDM process, quality of life, physician-patient-relationship and life-style changes were analysed as well. RESULTS: After one year the blood pressure had decreased in both the intervention group (-9.26 +/- 10.2/-5.3 +/- 9.5 mmHg, p < 0.001) and in the control group (-6.0 +/- 11.8/-3.0 +/- 8.3 mmHg, p < 0.05), without a significant difference between the two groups. Among a subgroup of patients with a marked preference for SDM there was a close correlation between an increase of SDM and a decrease in systolic blood pressure (p = 0.016). Also, the numbers of antihypertensive drugs increased more in the intervention group (p = 0.022) than in control patients. Furthermore, increase in knowledge about hypertension and its treatment was greater in the intervention group (P=0.006). CONCLUSION: Implementation of SDM had a significant effect on systolic blood pressure control only in the subgroup of patients with marked preference for SDM. Thus, the identification of patients with a preference for SDM may improve blood pressure control and their adherence to the prescribed drug therapy.

Influence of short-term versus prolonged cardiopulmonary receptor stimulation on renal and preganglionic adrenal sympathetic nerve activity in rats.

Renal and preganglionic adrenal sympathetic nerve activities (RSNA, ASNA) are regulated differentially. Various cardiopulmonary receptor (CPR) stimulation procedures were performed to distinguish short-term and prolonged as well as mechanical and chemical stimulatory effects on RSNA and ASNA. In anesthetized male Sprague-Dawley rats blood pressure, heart rate, left ventricular end-diastolic pressure (LVEDP), RSNA and ASNA were recorded. CPRs were stimulated as follows: Short-term mechanical: LVEDP changes (+/-4, +/-6, +/-8 mmHg) via aortic and caval vein occlusion; Short-term chemical: phenylbiguanide (PBG-bolus, 0.1, 1, 10 microg IV); Prolonged mechanical (15 min): volume expansion (0.9% NaCl, 5% body weight) and hemorrhage, to modulate LVEDP; Prolonged chemical: PBG infusion (32 microg/min IV, for 15 min); Stimulations were done with 1) all afferents intact, 2) bilateral cervical vagotomy (VX), 3) VX + SAD (sino-aortic denervation; short-term protocols and hemorrhage).1) Short-term mechanical stimuli decreased RSNA (-52 +/- 12%) and ASNA (-37 +/- 13%). 2) PBG-bolus decreased RSNA (-54 +/- 12%) but increased ASNA (+40 +/- 13%). 3) Volume expansion decreased RSNA (-55 +/- 7%), ASNA was unaffected. 4) PBG infusion persistently decreased RSNA (-60 +/- 6%) but just shortly increased ASNA (+120 +/- 15%); VX abolished all responses. 5) Hypotensive hemorrhage decreased RSNA (-39 +/- 9%) but increased ASNA (+42 +/- 9%). VX abolished RSNA response; ASNA response only disappeared with VX + SAD.Short-term mechanical CPR stimulation uniformly decreased sympathetic activities, whereas chemical stimulation had opposing effects on renal and adrenal sympathetic responses. All prolonged stimuli decreased RSNA, whereas ASNA was virtually unaffected: Sympathetic out.ow is differentially controlled not only with regard to target organs or afferent receptors but also stimulus time pattern.

Mechanisms and consequences of sympathetic hyperactivity in renal disease.

Kidney impairment of different origins can lead within a short time to structural and functional maladaptations of the kidney, which may culminate in end-stage renal failure. The most common causes of chronic renal failure are due to hypertensive and diabetic renal impairment [Moore et al. 1999, Ritz et al. 1999]. Moreover, an inadequate blood pressure control in primary renal diseases further accelerates the decline of renal function. In spite of improved therapeutic measures the number of patients with chronic renal failure continues to increase dramatically [Mailloux and Haley 1998]. Cardiovascular morbidity and mortality in patients with chronic renal failure are extraordinarily high and are more frequent than that observed in the general population [Vita et al. 1999]. Measures, which can reduce the high incidence of cardiovascular complications, have priority in the treatment of chronic renal failure patients. ACE-inhibitors have been shown to be the best choice in this case. Until now a possible role for sympathetic hyperactivity has not been seriously considered although there is very good clinical and experimental evidence for such a role. This overview will give a summary of the currently known experimental and clinical findings about the role of the sympathetic nervous system in hypertension and renal disease and to expound possible therapeutic strategies.

Angiotensinogen gene core promoter variants and non-modulating hypertension.

Non-modulation has been suggested as a possible intermediate phenotype defining a subgroup of genetic hypertension. The trait is characterized by an attenuated response of renal blood flow and/or aldosterone to angiotensin (Ang) II. We tested the hypothesis that functional polymorphisms of the core promoter of the angiotensinogen gene are associated with non-modulation. Fifty-six young, white, male, untreated hypertensive patients and 65 age-matched normotensive volunteers were genotyped for 3 known functional variants of the angiotensinogen core promoter. All subjects were infused with 2 doses (0.5 and 3 ng/kg per minute) of Ang II while they were on a high sodium diet (250 mmol/d). The blood pressure, renal plasma flow, and aldosterone responses to Ang II were not affected by the -6 G/A polymorphism. The -20 A/C variant had no significant effects on the blood pressure or renal hemodynamic response to Ang II. However, the aldosterone response to both doses of Ang II was significantly decreased in -20 C allele carriers compared with -20 AA homozygotes in a multivariate analysis. The -18 T allele was not detected in our population, and there was a linkage dysequilibrium between -20 C and -6 A: -20 C almost exclusively occurred on the -6 A allele. Haplotype analysis indicated that the -20 C/-6 A haplotype but not the -20 A/-6 A haplotype was associated with a decreased aldosterone response to Ang II. We conclude that the -20 C variant or the -20 C/-6 A haplotype of the angiotensinogen core promoter is associated with a blunted aldosterone response to Ang II and may thus contribute to the non-modulating phenotype.

Angiotensin II type 1 receptor blockade prevents lethal malignant hypertension: relation to kidney inflammation.

BACKGROUND: Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect. METHODS AND RESULTS: Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (n=14) or 3 (n=12) mg. kg(-1). d(-1) or solvent (n=27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects. CONCLUSIONS: Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsartan.

Renin uptake by the endothelium mediates vascular angiotensin formation.

We investigated the role of the vascular endothelium in the local production of angiotensin. Angiotensin release from isolated rat hindquarters perfused with an artificial medium was measured by high-performance liquid chromatography and radioimmunoassay. Perfused hindquarters with endothelium released angiotensin I spontaneously, indicating ongoing renin-angiotensinogen reaction. Endothelium denudation (by a detergent, validated by electron microscopy and by the absence of a vasodilator response to acetylcholine) reduced angiotensin I release by >90%, whereas bilateral nephrectomy 24 hours before perfusion abolished the release completely. Infusion of renin into perfused hindquarters induced sustained local angiotensin I release in the presence of an intact endothelium but not after endothelium denudation. The conversion of angiotensin I to angiotensin II was abrogated by endothelium denudation, whereas the disappearance of angiotensin II was unchanged. Endothelium denudation diminished the pressor response to angiotensin II but abolished the response to renin and angiotensin I. Expression of renin messenger RNA, investigated by reverse-transcription polymerase chain reaction using 4 different primer combinations, was not detected in up to 5 microg vascular RNA, whereas a renin signal was readily detected with 5 ng kidney RNA. The effects of endothelium destruction on Ang I formation support the notion that the endothelium mediates vascular angiotensin formation by taking up renin.

Outcome survey in unselected hypertensive patients with type 2 diabetes mellitus: effects of ACE inhibition.

Although the benefit of angiotensin converting enzyme (ACE) inhibitors in diabetic nephropathy is well documented in double-blind randomized, controlled clinical trials, it is uncertain whether the benefit extends to unselected patients with diabetes mellitus and arterial hypertension in general practice. In 2504 unselected patients with type 2 diabetes mellitus (mean age 63+/-10 years) blood pressure, cardiovascular, renal, and metabolic parameters were assessed at baseline and during a treatment period of 1 year with the ACE inhibitor cilazapril by primary care physicians. The average dose of cilazapril was 2.5 mg/day. Outcome measures were blood pressure, serum creatinine, proteinuria (dip stick), HbA1c levels, evaluation of edema, and exertional dyspnea. In the study cohort, systolic blood pressure decreased by 24+/-17 mm Hg and diastolic blood pressure by 12+/-11 mm Hg. An increase in serum creatinine (> 0.2 mg/dL) occurred more frequently in patients with than in those without renal involvement (19% v 7%; P < .05). Serum creatinine decreased more frequently in patients with renal involvement than in those without (26%+/-4% v 12%+/-3.8%; P < .05). Overall renal function in patients with diabetic nephropathy (n = 318) improved (2.1+/-1.6 mg/dL v 1.7+/-1.4 mg/dL; P < .05). The frequency of proteinuria was lower after 1 year than at baseline (62%+/-9% v 82%+/-8%; P < .05). Metabolic control of diabetes mellitus improved in parallel (median HbA1c 8.0% v 7.0%; P < .01). Scores for edema formation and exertional dyspnea improved as well (P < .01). In this outcome survey of unselected patients with type 2 diabetes mellitus and arterial hypertension, the ACE inhibitor cilazapril effectively lowered blood pressure, which was associated with an improvement in glucose metabolism, cardiac function, and renal function.

Inducible nitric oxide synthase and glomerular hemodynamics in rats with liver cirrhosis.

This study was designed to test the hypothesis that glomerular de novo expression of inducible nitric oxide synthase (iNOS) contributes to renal hemodynamic abnormalities in liver cirrhosis developed 3 wk after common bile duct ligature (CBDL). De novo expression of iNOS mRNA was detected by RT-PCR in RNA extracts from isolated CBDL rat glomeruli whereas no iNOS mRNA was found in control rat glomerular RNA. Immunohistochemical staining for iNOS was negative in control animals whereas, in CBDL rats, positive iNOS staining was detected in an apparently mesangial pattern in all glomeruli. Western blots of protein extracts from isolated glomeruli of CBDL rats, but not control animals, showed a prominent iNOS band of 130 kDa. Mean arterial pressure (MAP), renal plasma flow (RPF; p-aminohippurate clearance), and glomerular filtration rate (GFR; inulin clearance) were unaltered in CBDL rats, but the application of 4 mg/kg L-N(6)-(1-iminoethyl)lysine, a specific inhibitor of iNOS, reduced GFR and RPF significantly in CBDL rats, whereas control animals were not affected. Similar results were obtained with lipopolysaccharide (LPS)-pretreated animals, which were studied as a positive control for iNOS expression and as a model for recent iNOS induction. We conclude that de novo expression of iNOS occurs in glomeruli of rats with liver cirrhosis and that nitric oxide, generated by iNOS, contributes to the maintenance of glomerular filtration in the early state of this disease.

Glomerular osteopontin expression and macrophage infiltration in glomerulosclerosis of DOCA-salt rats.

Expression of the chemoattractant osteopontin (OPN) may contribute to macrophage infiltration in many types of tubulointerstitial kidney disease, but the role of OPN in chronic glomerulosclerosis is unknown. We hypothesized that glomerular OPN expression and macrophage infiltration occur in deoxycorticosterone acetate (DOCA)-salt glomerulosclerosis in rats. Uninephrectomized rats receiving DOCA pellets and 1% saline were compared with control rats. OPN mRNA was determined by Northern blot, and OPN protein was determined by Western blot. The localization of OPN was studied by in situ hybridization and double immunohistochemistry with glomerular cell markers. Macrophage infiltration was quantified by counting ED-1-positive cells, and semiquantitative glomerulosclerosis scores were obtained. In DOCA-salt rats, OPN mRNA in the kidney was increased 2-fold over control after 9 days and 3 weeks and 20-fold after 6 weeks. Tubulointerstitial OPN staining was apparent after 21 days of DOCA treatment. Glomerular OPN mRNA and protein was detected after 42 days in parietal and visceral epithelial cells, activated myofibroblasts, and occasionally mesangial cells. Progressive glomerular macrophage infiltration occurred during the development of DOCA hypertension, paralleling the degree of glomerulosclerosis. Glomeruli staining positive for osteopontin contained more macrophages (18.4 +/- 3.4 per cross-section) than osteopontin-negative glomeruli (3.6 +/- 0.5; P < 0.05). Glomerular OPN expression occurs in chronic hypertensive glomerulosclerosis and is associated with macrophage infiltration. The data suggest a role for OPN as a chemoattractant in hypertensive glomerulosclerosis.

Impaired sodium excretion during mental stress in mild essential hypertension.

In hypertensive rats, environmental stress causes sodium retention by an exaggerated increase in renal sympathetic nerve activity, which is modulated by angiotensin II. We tested whether similar effects can be observed in humans. In 66 normotensive subjects (half of them with a family history of hypertension) and 36 subjects with mild essential hypertension, urinary sodium excretion and renal hemodynamics were examined at rest and during mental stress treated either with placebo or ACE inhibition in a double-blind, randomized, cross-over design. Despite a marked increase in glomerular filtration rate in response to mental stress (Deltaglomerular filtration rate, 4.3+/-7.7 mL/min in normotensives without versus 5.6+/-8.4 mL/min in normotensives with a family history versus 10.1+/-5.7 mL/min in patients with mild essential hypertension; P:<0.002), the increase in urinary sodium excretion was blunted in patients with mild essential hypertension (Deltaurinary sodium excretion, 0.12+/-0.17 mmol/min versus 0.10+/-0.14 mmol/min versus 0.05+/-0.14 mmol/min; P:<0.05). ACE inhibition corrected the natriuretic response to mental stress in subjects with mild essential hypertension (Deltaurinary sodium excretion, 0.05+/-0.14 mmol/min with placebo versus 0.13+/-0.19 mmol/min with ACE inhibition; P:<0.01); thus, after ACE inhibition, urinary sodium excretion increased similarly in all 3 groups. In conclusion, impaired sodium excretion occurs during mental stress in human essential hypertension but not in subjects with positive family history of hypertension. This abnormality in sodium handling during activation of the sympathetic nervous system appears to be mediated by angiotensin II.

Efficacy and drug interactions of the new HMG-CoA reductase inhibitors cerivastatin and atorvastatin in CsA-treated renal transplant recipients.

BACKGROUND: Hyperlipidaemia is an important risk factor for cardiovascular disease in renal transplant recipients. The aim of this study was to test the efficacy and possible drug-drug interactions of the new HMG-CoA reductase inhibitors (statins) atorvastatin and cerivastatin in cyclosporin A (CsA)-treated renal transplant patients. Subjects and methods. Thirty patients with stable graft function and LDL cholesterol of 130 mg/dl were randomly assigned to active treatment groups (10 mg atorvastatin or 0.2 mg cerivastatin), or a control group. CsA blood trough levels were controlled on a weekly basis and adapted if they changed more than 25% from baseline values (100-150 ng/ml). Lipid levels and routine laboratory parameters before and after a treatment period of 3 months were compared. RESULTS: In the group treated with cerivastatin no significant changes in CsA blood trough levels occurred (CsA 116+/-21 ng/ml vs 110+/-20 ng/ml). In contrast, in the group treated with atorvastatin, four of 10 patients had a rise in CsA blood trough levels of more than 25% within 7-14 days of starting therapy. In the remaining patients no significant changes in CsA drug levels occurred. After therapy with atorvastatin or cerivastatin, total cholesterol, LDL cholesterol, and triglycerides were significantly lower compared with baseline conditions. No changes of CsA or lipoprotein levels were present in the control group. CONCLUSION: In our study population both statins were very effective in lowering elevated LDL cholesterol levels. Cerivastatin did not influence CsA blood trough levels, whereas atorvastatin increased CsA levels in four of 10 patients. Further research in a larger study is necessary in order to confirm these results and to investigate the possible reasons for this drug interaction.

Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury.

BACKGROUND: We investigated whether monocyte chemoattractant protein-1 (MCP-1) is expressed in hypertensive nephrosclerosis, and tested the effect of angiotensin II type 1 receptor blockade on MCP-1 expression and macrophage (MPhi) infiltration. METHODS: Rats with two-kidney, one-clip (2K1C) hypertension with and without treatment with the angiotensin II type 1 receptor antagonist valsartan (3 mg/kg/day) were studied. In these animals as well as in spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP), hypertensive mRen-2 transgenic rats (TGR), and respective control strains, MCP-1 expression in the kidney was investigated by Northern and Western blots and by immunohistochemistry. Glomerular and interstitial MPhis were counted. RESULTS: In the nonclipped kidney of 2K1C rats, MCP-1 expression was elevated at 14 and 28 days when significant MPhi infiltration was present. MCP-1 was localized to glomerular endothelial and epithelial cells, interstitial and tubular cells, MPhis, and vascular smooth muscle cells. A similar pattern of MCP-1 staining was present in TGR kidneys, whereas MCP-1 expression was not increased in SHR and SHR-SP. Valsartan reduced but did not normalize blood pressure, blocked the induction of MCP-1 protein in 2K1C kidneys, and decreased interstitial MPhi infiltration significantly. CONCLUSION: MCP-1 expression is increased in angiotensin II-dependent models of hypertensive nephrosclerosis and is temporally and spatially related to MPhi infiltration. The angiotensin II type 1 receptor mediates the induction of MCP-1.