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Background/Aims: Arterial wave reflection, measured as augmentation index (AIx), and central pulse pressure (PP) closely predict cardiovascular events. We hypothesized that basal nitric oxide (NO) production would be a determinant of AIx and central PP. Methods: AIx and central PP were assessed at baseline by pulse wave analysis in 86 male subjects across a wide range of age, blood pressure and lipid values. The basal NO production in the cardiovascular system was then determined as change in AIx during NO synthase blockade with NG-monomethyl-L-arginine (L-NMMA, 3.25 mg/kg). Results: AIx increased from 17.5 ± 14.6 to 23.1 ± 14.2 during L-NMMA infusion (p < 0.001). The increase in AIx during NO synthase blockade, an index of basal NO production, was inversely related to baseline central AIx and PP, and positively to PP amplification. Multiple linear regression analyses disclosed that in addition to age and mean blood pressure, change of AIx to L-NMMA is a strong and independent determinant of baseline central AIx, central PP and PP amplification. Conclusion: Greater change of AIx to L-NMMA, an index of basal NO production, is associated with better large-artery function. Therefore, therapeutic interventions which increase the basal NO production might be particularly effective in reducing cardiovascular risk. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: The prognosis of patients on renal replacement therapy is critically determined by comorbidity. The purpose of the study was to evaluate the effect of nephrological care in the predialysis period on comorbidity parameters at time of initiation of hemodialysis: Methods: A prospective multicentric study evaluated 551 patients from 5 different regions (each more than 100 patients) in Germany consecutively at dialysis initiation. A questionnaire asked for intensity of predialytic nephrology care, clinical and biochemical parameters related to comorbidity. Results: Patients (n = 551) demographical data and diagnosis of renal failure are: diabetes mellitus (31%), hypertension/ nephrosclerosis (22%), glomerulonephritis (17%), others (30%). Cause of renal failure Age (y) Gender (M%) Nephr. Care (%) Diabetes mellitus 67 49 30 Hypertension/Sclerosis 70 62 33 Glomerulonephritis 57 66 55 Nephrological pretreatment vs. standard care had the following effects on biochemistry parameters: serum creatinine 7.0 vs 7.9 mg/dl, serum urea 206 vs 228 mg/dl, hemoglobin concentration 10.1 vs 9.5 g/dl; the frequencies of comorbidity parameters or cotreatment were: timely and electively dialysis initiation 84 vs 38%, hospitalisation during dialysis initiation 11 vs 18 days, hypertension 93 vs 83%, left ventricular hypertrophy 51 vs 67%, cardiovascular disease 24 vs 33%, malnutrition 24 vs 60%, erythropoietin treatment 58 vs 8%, iron supplementation 58 vs 5%, vitamin D therapy 78 vs 11%, acidosis therapy 60 vs 24%. Conclusions: The study shows that frequent and intensive nephrological care in the predialysis period minimizes the extent of comorbidity factors at dialysis initiation. Patients with glomerulonephritis are younger and receive more intensive nephrological care than diabetic or hypertensive patients. Therefore, prognosis of kidney patients should be significantly improved by providing routinely nephrological care already in the predialysis period. [ABSTRACT FROM AUTHOR]

Objective: Subcutaneous application of erythropoietin (epo) has been recently associated with the development of epo antibody induced pure red cell aplasia. Patients on peritoneal dialysis (PD) usually use s.c. application at home, where control of proper storage of Epo, another risk factor for development of epo-antibodies, may not be not tight. A switch to i.v. application of epo might be of advantage. In this study we explored the practicability of a monthly application of the long acting epo darbepoetin in 20 patients on PD. Methods: Twenty patients on maintenance therapy with s.c. epo were switched to i.v application of cumulative monthly dose of darbepoetin. The dose was calculated as (darbepoetin dose = maintanence dose/200 x 4). According to the monthly controls of hemoglobin the darbepoetin dose was adjusted. Ferritin and transferring saturation were measured every 4 month, and iron was substituted p.o. or i.v. as needed. The patients were followed for 7.2 ± 1.9 months. Results: Characteristics of the patients at start: age 45.7 ± 3.1, male 66%, CAPD 76%, CCPD 24%, vintage 3.1 ± 2.0, creatinin 13.3 ± 7.6 mg/dl, urea 137 ± 67 mg/dl, Kt/V 2.07 ± 0.44, Ferritin 180 ± 145 mg/dl, TSAT 31 ± 12%, folic acid 141 ± 162 nmol/l, vitamin B12 708 ± 1,455 pmol/l. No significant change in hemoglobin levels over 6 months was found. However, a non-significant increase in mean epo doses was observed. No serious side effects were reported. Conclusions: In peritoneal dialysis patients monthly i.v. application of darbepoetin is safe and effective, but an increase of the dose of darbepoetin can be expected in certain patients. [ABSTRACT FROM AUTHOR]

Objective: Arterial hypertension is a major side effect of erythropoietin. Because this side effect is known to be more frequent in persons with hypertension, we examined nitric oxide activity of the forearm artery after administrating erythropoiesis stimulating factor in normotensive and hypertensive patients. Methods: In a randomized, double blind, placebo-controlled crossover study darbepoetin alfa (33 µg/kg body weight Aranesp®) or placebo was administered i.v. to normotensive subjects (n = 17) and patients with mild essential hypertension (n = 17). All participants were young males, non-smokers, had no diabetes, hypercholesterolemia or any antihypertensive medication. After 24 hours we evaluated the response of forearm blood flow (FBF) to intra-arterially given acetycholine, to nitroprussid and to NG-monomethyl-L-arginine. Forearm blood flow was measured at baseline and during pharmacologic tests by strain-gauge plethysmography. Results: After a single injection of darbepoetin no changes of blood pressure were observed in normotensive and mildly hypertensive patients evaluated by 24 hour ambulatory blood pressure monitoring. The forearm blood flow in response to acetylcholine (12 µg/min) increased more marked after darbepoetin in the normotensive group (ΔFBF 6.70 ± 6.12 mL/min vs. placebo 4.09 ± 2.82 mL/min p = 0.05), but not in the hypertensive group (Δ FBF . 4.41 ± 3.07 mL/min vs. placebo 4.94 ± 4.10 mL/min n.s.). In response to nitroprussid (12.8 µ g/min) the forearm blood flow increased more marked after erythropoietin in normotensive subjects (ΔFBF 17.88 ± 5.87 mL/min vs. placebo 12.48 ± 4.44 mL/min p = 0.012), but not in hypertensive patients (Δ FBF 16.33 ± 5.26 mL/min vs. placebo 14.33 ± 5.27 mL/min n.s.). There were no significant differences in blood flow changes due to NG-monomethyl-L-arginine for both groups. Conclusions: A single injection of darbepoetin alfa leads to an enhanced response to endothelium-dependent and endotheliumindependent vasodilators in normotensive but not in hypertensive subjects. These findings suggest that darbepoetin leads to compensatory increased vasodilation in normotensive subjects thereby keeping the vascular tone an blood pressure in balance. No such counter-regulation to darbepoetin was found in young mildly hypertensive subjects. [ABSTRACT FROM AUTHOR]

Objective: Chronic allograft nephropathy and cardiovascular complications limit the long-term success of renal transplantation. Animal experiments have shown that Angiotensin-R-Blockers (AR-B) can lower the rate of graft failure. Moreover it has been suggested that AR-B might lower cardiovascular mortality as well. Methods: We designed a controlled trial (SECRET-study) in pts. following renal transplantation to evaluate whether the AR-B candesartan cilexetil (CC) (4 - 16 mg/day) vs. placebo (PL) can reduce the amount of graft failure (expected 5%/y) and cardiovascular morbidity (expected 3%/y). 700 pts. were to be included who were to be followed up for three years. During that time we expected to observe the primary endpoints graft failure and cardiovascular morbidity in more than 150 pts. Results: Following an interim analysis after 18 month, the study was discontinued since the observed event rate (26 primary endpoints) was only 25% of what had been expected. At the premature end of the study data of 502 pts. with a median follow-up of 23 month (11-39m) were available (11.500 pts.month). Cardiovascular morbidity and mortality (CC 9 pts., PL 8 pts.), graft failure (CC 1 pts., PL 6 pts.). creatinine doubling (CC 7 pts., PL 4 pts.) did not differ sign. between both groups. Median proteinuria was significantly (p < 0.001) decreased by CC (-27.4%) compared to PL (+15.4%). Although all possible concomitant antihypertensive drugs (except ACE-inhibitors) were allowed in order to lower blood pressure (BP) below 135/80 mmHg (controlled by an automatic device), BP was lowered more markedly (p < 0.001) in the CC group 139.9/84.4 to 130.0/80.3 compared to PL (139.8/84.6 to 133.3/80.8). Early treatment discontinuation was more often observed (p < 0.001) in the PL group esp. due to lack of antihypertensive efficacy (CC 2 pts., PL 17 pts.) and due to consent withdrawal (CC 9 pts., PL 19 pts.). Conclusions: The study failed to show the superiority of the AR-B CC in lowering graft failure and cardiovascular morbidity in renal transplant pts. This may be due to the excellent BP control achieved in both groups: no other intervention trial so far demonstrated mean BP levels of 130/80mmHg at the end of the study. However, treatment with CC was more effective in lowering BP in these pts., and in reducing proteinuria, which can be an early sign of chronic allograft nephropathy. [ABSTRACT FROM AUTHOR]

Objective: Both ACE inhibitors (ACE-I) and ATI receptor blockers (ARB) effectively reduce proteinuria given in standard dose. Since ARB's exhibit sid effect profile, we analyzed the antiproteinuric effect of candesartan (cand) at high and ultra high doses in a randomized, double-blind trial with parallel group design. Methods: Hypertensive and normotensive patiens with normal or middly impaired renal function (creatinine clearance 30 ml/min) and a protein excretion rate of 1-10 g/day and atreatment with ACE-I or ARB were eligible. If renal function and protein excretion rate were stable for 3 month, the trial started with a 4 week treatment of cand 16 mg. Thereafter, patiens were randomly assigned to double-blind therapy with cand 32 mg (15 patients) or cand 64 mg (17 patients) for 12 weeks, followed again a 4 week treatment of cand 16 mg. Measurement of blood pressure, proteon excretion, sodium excretion, creatinine clearance and (in a subset) of renal hemodynamics was performed at the end of each phase. Results: Protein excretion before the first treatment phase was indentical in both groups (cand 32 mg: 2.4 g/day, n.s.). At the end of the double-blind treatment phase protein excretion was significantly reduced to 1.9 + 1.2 g/day in the 64 mg group (p < 0.019), whereas no change was noticed in the 32 mg group (2.8 + 2.6 g/day), with a difference in the change of proteinuria between the group (p < 0.05). After down titrating to cand 16 mg protein ecretion increased to 3.0 g/day in the 64 mg group (p < 0.022), but remained unchanged in the 32 mg group (3.1 + 3.0 g/day n.s.). No change in blood pressure and creatinine clearance was noticed in response to the different doses of candesartan in and between the two groups. Conclusions: The data indicate a blood pressure independent antiproteinurie effect of ultra high dose treatment with the AT1 receptor blocker candesartan 64 mg compared to a standard or even doubled standard dose. [ABSTRACT FROM AUTHOR]

Objective: Increased renal nitric oxide production and/or activity has been associated with glomerular hyperfiltration, vascular permeability and modulation of glomerulosclerosis and tubulointerstitial fibrosis. Several studies demonstrated regulated expression of nitric oxide synthases (NOSes) in experimental diabetic nephropathy. However, the regulation of NOSes and its clinical relationship in diabetic nephropathy in man is still not yet specified. Methods: We investigated renal biopsies and clinical data of 36 patients with diabetic nephropathy, 10 renal biopsies without evidence of renal disease served as controls. Glomerular and cortical eNOS and iNOS expression were assessed by immunhistochemical staining and correlated with clinical data such as the duration of diabetes, creatinine clearance, duration of arterial hypertension, albuminuria/ proteinuria, HbA1c, duration of insulin therapy, presence of vascular complications or diabetic retinopathy and smoking. Results: Mean age of patients at biopsy was 59 years, mean duration of diabetes 13.6 years. Compared to normal biopsies, expression of cortical (14.2 ± 8 vs. 10.7 ± 5.5; P = 0.05) and glomerular (16.4 ± 8 vs. 4.6 ± 3.3; P < 0.001) eNOS was increased in type 2 diabetics, whereas no significant differences could be detected for iNOS. Expression of cortical eNOS related with duration of arterial hypertension (r = 0.55) and that of glomerular eNOS with the degree of microvascular complications (r = 0.43). Interestingly expression of glomerular iNOS was linked to the duration of insulin therapy (r = 0.65). In addition, patients treated with insulin for less than 1 year had significantly lower iNOS levels (same levels as healthy controls) compared to patients with insulin therapy for more than one year (1.4 ± 0.8 vs 3.3 ± 2.1; P < 0.05). No correlations could be detected for all other clinical parameters as mentioned above. Conclusions: This study demonstrates significantly increased eNOS expression in kidney biopsies from patients with histologically proven diabetic nephropathy. Expression of eNOS as well as iNOS were in addition related to clinical risk factors of disease progression. [ABSTRACT FROM AUTHOR]

Objective: We have shown a vasoconstricitve response to intravenous aldosterone infusion in healthy male volunteers, which occurred within 30 minutes. Recently, we described that in the human forearm aldosterone increases the vasoconstrictive response to phenylephrine and L-NMMA within 20 minutes after start of an intraarterial aldosterone infusion. Based on these data we hypothesized that aldosterone might be a stronger vasoconstrictor in hypertensives than in normotensives. Methods: To address this issue we examined 12 normotensive and 12 mildly hypertensive young males. In hypertensives secondary hypertension was excluded by clinical and laboratory measures. All hypertensives were previously and currently untreated and showed no hypertensive target organ damage. We infused aldosterone (Clinalfa, Läufelingen, Switzerland) for 60 minutes (0.1 mg as bolus and 3±g/min as continuous infusion). Cardiovascular parameters were measured using the Task Force Monitor device (CNSystems, Graz, Austria). Primary endpoint of our study was the change in total peripheral resistance index (TPRI) during the aldosterone infusion. Furthermore we evaluated stroke volume index (SVI), cardiac index (CI) and mean arterial blood pressure (MAP). For statistical comparison t-test and multifactorial (timepoint, group) ANOVA were used were applicable. Results: Hypertensives showed higher blood pressure (144 ± 11/89 ± 11 vs. 128 ± 8/79 ± 8 mmHg, p ≤ 0.05) and higher heart rate (71 ± 12 vs. 66 ± 12, p ≤ 0.01). There were no differences between both groups regarding age (29.3 ± 6.5 vs. 28.4 ± 5.9 years) and BMI (25.4 ± 3.2 vs. 24.0 ± 3.9 kg/m²). At baseline TPRI was slightly higher in hypertensives (44.2 ± 9.8 vs. 38.3 ± 7.6 ΔmmHg x min x L-1m-2), SVI was lower (35 ± 7 vs. 44 ± 10 ml/m², p ≤ 0.05), and CI was identical (2.3 ± 0.4 vs. 2.3 ± 0.5 L/min x m²). During aldosterone infusion TPRI increased in both groups. The increase was more pronounced in hypertensives reaching 2.4 ± 2.6 vs. 0.5 ± 1.2 after 15 minutes (p ≤ 0.05). Looking at the mean change over the whole time period of 60 minutes the difference was also statistically significant (2.1 ± 4.8 vs. 0.3 ± 2.4, p ≤ 0.01). This resulted in a more pronounced increase in MAP (mean change 1.7 ± 2.7 vs. 0.6 ± 2.8, p ≤ 0.05), whereas the changes in SVI and CI were identical. Conclusions: These data suggest that hypertensives are more susceptible to the vasoconstrictive effect of aldosterone. As this effect occurs as early as 15 minutes after the start of the aldosterone infusion it is a nongenomic effect, i.e. it is not mediated by the classical mineralocorticoid receptor. The importance of these effects in the pathogenesis of arterial hypertension remains to be established. [ABSTRACT FROM AUTHOR]