Retinal capillary and arteriolar changes in patients with chronic kidney disease.

RATIONALE: Premature cardiovascular disease is a leading cause of death in patients with chronic kidney disease (CKD). In animal models CKD has been shown to cause renal and extrarenal vascular remodeling and capillary rarefaction, but data in humans with CKD are sparse. Retinal arteriolar wall-to-lumen ratio (WLR) is an established marker of early end-organ damage and there is evidence that arteriolar and capillary changes in the retinal circulation mirror those in the general and in particular the cerebrovascular microcirculation. OBJECTIVE: The aim of this study was to compare retinal capillary density and arteriolar structure between patients with CKD and healthy individuals. METHODS: We compared 76 patients with CKD stage 3+ or proteinuria >500 mg/g creatinine in the presence of a normal GFR from the German Chronic Kidney Disease cohort to 53 healthy control subjects, who participated in clinical trials during 2007 and 2015 in our Clinical Research Center. Retinal vascular parameters were measured non-invasively in vivo by scanning laser Doppler Flowmetry (SLDF, Heidelberg Engineering, Germany). Capillary rarefaction was assessed by intercapillary distance. RESULTS: Patients with CKD showed greater WLR (0.403 ±â€¯0.11 vs 0.351 ±â€¯0.11, p = 0.010) and greater wall thickness (WT) (15.1 ±â€¯4.1 vs 13.5 ±â€¯3.8, p = 0.026) compared to healthy individuals. Intercapillary distance (ICD) (22.4 ±â€¯5.7 vs 20.2 ±â€¯4.1, p = 0.008) was greater in the CKD group compared to the healthy control group. After adjustment for differences in clinical characteristics of the groups (age, gender, BMI, serum cholesterol) WLR (p = 0.046), WT (p = 0.025) and ICD (p = 0.003) remained significantly different between the two groups. There was a correlation between serum phosphate level and WLR in the CKD group (r = 0.288, p = 0.013). CONCLUSION: Patients with moderately severe CKD show retinal signs of end-organ damage indicated by an increased wall-to-lumen ratio and capillary rarefaction.

Skin Sodium Concentration Correlates with Left Ventricular Hypertrophy in CKD.

The pathogenesis of left ventricular hypertrophy in patients with CKD is incompletely understood. Sodium intake, which is usually assessed by measuring urinary sodium excretion, has been inconsistently linked with left ventricular hypertrophy. However, tissues such as skin and muscle may store sodium. Using 23sodium-magnetic resonance imaging, a technique recently developed for the assessment of tissue sodium content in humans, we determined skin sodium content at the level of the calf in 99 patients with mild to moderate CKD (42 women; median [range] age, 65 [23-78] years). We also assessed total body overhydration (bioimpedance spectroscopy), 24-hour BP, and left ventricular mass (cardiac magnetic resonance imaging). Skin sodium content, but not total body overhydration, correlated with systolic BP (r=0.33, P=0.002). Moreover, skin sodium content correlated more strongly than total body overhydration did with left ventricular mass (r=0.56, P<0.001 versus r=0.35, P<0.001; P<0.01 between the two correlations). Linear regression analysis demonstrated that skin sodium content is a strong explanatory variable for left ventricular mass, unaffected by BP and total body overhydration. In conclusion, we found skin sodium content to be closely linked to left ventricular mass in patients with CKD. Interventions that reduce skin sodium content might improve cardiovascular outcomes in these patients.

Effects of saxagliptin on early microvascular changes in patients with type 2 diabetes.

BACKGROUND: Patients with diabetes mellitus are at increased risk for microvascular complications. Early changes in microcirculation are characterized by hyperperfusion (e.g. in the retina and kidney) and increased pulse wave reflection leading to increased aortic pressure. We investigated the effects of the DPP-4-inhibitor saxagliptin on early retinal microvascular changes. METHODS: In this double-blind, controlled, cross-over trial 50 patients (without clinical signs of microvascular alterations) with type-2 diabetes (mean duration of 4 years) were randomized to receive placebo or 5 mg saxagliptin for 6 weeks. Retinal arteriolar structure and retinal capillary flow (RCF) at baseline and during flicker-light exposure was assessed by scanning laser Doppler flowmetry. Central hemodynamics were assessed by pulse wave analysis. RESULTS: Postprandial blood glucose (9.27 ± 0.4 versus 10.1 ± 0.4 mmol/L; p = 0.001) and HbA1c (6.84 ± 0.15 (51 ± 1.6) versus 7.10 ± 0.17% (54 ± 1.9 mmol/mol); p < 0.001) were significantly reduced with saxagliptin treatment compared to placebo. RCF was significantly reduced after treatment with saxagliptin (288 ± 13.2 versus 314 ± 14.1 AU; p = 0.033). This was most pronounced in a subgroup of patients (n = 32) with a fall in postprandial blood glucose (280 ± 12.1 versus 314 ± 16.6 AU; p = 0.011). No significant changes in RCF were seen during flicker-light exposure between placebo and saxagliptin, but the vasodilatory capacity increased two-fold with saxagliptin treatment. Central augmentation pressure tended to be lower after treatment with saxagliptin (p = 0.094), and central systolic blood pressure was significantly reduced (119 ± 2.3 versus 124 ± 2.3 mmHg; p = 0.038). CONCLUSIONS: Our data suggest that treatment with saxagliptin for 6 weeks normalizes retinal capillary flow and improves central hemodynamics in type-2 diabetes. TRIAL REGISTRATION: The study was registered at (ID: NCT01319357).

Effects of manidipine vs. amlodipine on intrarenal haemodynamics in patients with arterial hypertension.

AIMS: Intraglomerular pressure is one of the main drivers of progression of renal failure. Experimental data suggest that there are important differences between calcium channel blockers (CCBs) in their renal haemodynamic effects: manidipine reduces, whereas amlodipine increases intraglomerular pressure. The aim of this study was to investigate the effects of manidipine and amlodipine treatment on intragomerular pressure (P(glom)) in patients with mild to moderate essential hypertension. METHODS: In this randomized, double-blind, parallel group study, hypertensive patients were randomly assigned to receive manidipine 20 mg (n = 54) or amlodipine 10 mg (n = 50) for 4 weeks. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined by constant-infusion input-clearance technique with p-aminohippurate (PAH) and inulin. P(glom) and resistances of the afferent (R(A)) and efferent (R(E)) arterioles were calculated according to the model established by Gomez. RESULTS: P(glom) did not change in the manidipine group (P = 0.951), whereas a significant increase occurred in the amlodipine group (P = 0.009). There was a significant difference in the change of P(glom) by 1.2 mmHg between the manidipine and amlodipine group (P = 0.042). In both treatment arms, R(A) was reduced (manidipine P = 0.018; amlodipine P < 0.001). The reduction of R(A) was significantly more pronounced with amlodipine compared with manidipine treatment (P < 0.001). R(E) increased in both treatment arms (manidipine P = 0.012; amlodipine P = 0.002), with no difference between the treatment arms. Both CCBs significantly reduced systolic and diastolic blood pressure (BP) (both P < 0.001). However, amlodipine treatment resulted in a significantly greater decrease of BP compared with manidipine (P < 0.001). CONCLUSIONS: In accordance with experimental data after antihypertensive treatment of 4 weeks, intraglomerular pressure was significantly lower with the CCB manidipine than with amlodipine, resulting and explaining their disparate effects on albuminuria.

Influence of blood flow on arteriolar wall-to-lumen ratio in the human retinal circulation in vivo.

OBJECTIVE: We hypothesized that blood flow impacts on arteriolar wall-to-lumen ratio and that vasodilatory capacity is negatively related to arteriolar wall-to-lumen ratio in the human retinal vascular bed. METHODS: The study cohort comprised 141 non-diabetic untreated male patients with (n=52) or without (n=89) arterial hypertension but without evidence for cardiovascular disease. Retinal capillary blood flow (RCF) before and after exposure to flicker light and to infusion of nitric oxide (NO) synthase inhibitor N-monomethyl-L-arginine (L-NMMA), and parameters of retinal arteriolar morphology, e.g. wall-to-lumen ratio, were assessed non-invasively and in vivo by scanning laser Doppler flowmetry. RESULTS: The study cohort was grouped according to the median RCF into two groups. Patients with RCF above the median revealed lower wall-to-lumen ratio (0.30 ± 0.1 vs 0.34 ± 0.1 (-), P adjusted=0.023) compared to patients with RCF equal or below the median. In addition, RCF was negatively related to wall-to-lumen ratio independently of cardiovascular risk factors (ß=-0.224, P=0.026). In parallel, the decrease of RCF to L-NMMA infusion was greater in patients with RCF above the median compared to the counter group (-8.95 ± 11 vs. 0.35 ± 15 (%), P adjusted <0.001). The increase in RCF to flicker light exposure was negatively related to wall-to-lumen ratio in hypertensive but not in normotensive or all patients (r=-0.292, P=0.047, r=-0.035, P=0.746 and r=-0.126, P=0.144, respectively). CONCLUSIONS: In the retinal circulation blood flow impacts on arteriolar wall-to-lumen ratio. Basal NO activity might modulate blood flow and arteriolar morphological changes. In hypertensive, but not in normotensive patients, the vasodilatory capacity is negatively related to arteriolar wall-to-lumen ratio in the human retinal vascular bed.

Lethal varicella-zoster virus reactivation without skin lesions following renal transplantation.

Patients after solid organ transplantation are at increased risk of developing herpes zoster and are more likely to develop major complications such as cutaneous dissemination, post-herpetic neuralgia and visceral organ involvement. We report on a 68-year-old woman being varicella-zoster virus (VZV)-seropositive prior to transplantation, who developed fatal VZV meningoencephalitis after renal transplantation presenting with non-specific neurologic symptoms. The case illustrates that VZV reactivation may occur in renal transplant recipients in the absence of skin lesions. Approaches towards risk assessment pre-transplantation and prophylactic regimens for the prevention of VZV recurrence are needed.

Renal resistive index--a valid tool to assess renal endothelial function in humans?

BACKGROUND: In humans, renal endothelial function is assessed by the vasoconstrictive response to L-NG-monomethyl arginine (L-NMMA). We hypothesized that Doppler sonographic measurements of the renal resistive index in response to inhibition of nitric oxide synthase offer a new methodological approach for testing renal endothelial function. METHODS: Forty-one patients without nephropathy were included. Para-aminohippurate and inulin clearance were performed under basal conditions and during L-NMMA infusion. In parallel, renal resistive index was assessed by Doppler sonography, and central blood pressure was determined. RESULTS: Following nitric oxide synthase inhibition, renal resistive index increased significantly, and 29% of our patients developed Doppler sonographic diastolic zero flow. Renal plasma flow decreased in response to L-NMMA, and conversely, renal vascular resistance increased. There was no correlation of renal vascular resistance and renal resistive index at baseline and during nitric oxide synthase inhibition. Changes in renal resistive index were not related to changes in renal perfusion or renal vascular resistance. Renal resistive index correlated with central pulse pressure at baseline and during L-NMMA infusion, whereas renal vascular resistance did not correlate with central pulse pressure. CONCLUSION: Our data do not support the hypothesis that renal resistive index is a tool to test renal endothelial function in humans and should not be used interchangeably with renal vascular resistance.

Dihydropyridine calcium antagonists are associated with increased albuminuria in treatment-resistant hypertensives.

ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) are superior to dihydropyridine calcium-antagonists (DHP) with regard to reduction of albuminuria in patients with diabetic nephropathy. It has been argued that with blood pressure outside the targets DHP may exaggerate albuminuria in hypertensive patients. We addressed the question in an observational study in patients with difficult-to-treat essential hypertension. We analyzed baseline data from patients (n=80) screened for a clinical trial in treatment-resistant hypertension. All patients were treated with an ACEI/ARB, a diuretic and at least a third drug in the highest tolerated dose. We compared 50 patients who were treated with DHPs with 30 who were not. Albuminuria was assessed as albumin excretion in 24-hour urine. Values are given as mean ± SD. All comparisons were made using unpaired t-test. There were no differences with regard to demographic parameters, blood pressure or duration of hypertension between both groups. Albumin excretion was 14.3 ± 16.9 mg/d in patients treated with DHPs and 8.5 ± 6.6 mg/d in patients treated without DHPs (p=0.036). Our data indicate that even in patients treated with ACEI/ARBs DHPs are associated with increased albuminuria. Since increases of albuminuria even in the low range are associated with increased cardiovascular risk, detection of albuminuria should influence the choice of antihypertensive drugs in hypertensive patients with albuminuria.

Renal vascular endothelial function in hypertensive patients with type 2 diabetes mellitus.

BACKGROUND: Basal nitric oxide (NO) activity has a pivotal role in the regulation of glomerular hemodynamics, and in animal experiments, its alteration has been associated with morphological changes characteristic of diabetic nephropathy. STUDY DESIGN: Prospective observational-study during a mean follow-up of 2.1 years. SETTING & PARTICIPANTS: 66 hypertensive patients (aged 30 to 80 years) with type 2 diabetes and estimated glomerular filtration rate (GFR) greater than 80 mL/min/1.73 m(2) with normoalbuminuria or microalbuminuria. PREDICTOR: Mean arterial pressure during follow-up during treatment with telmisartan or ramipril for 9 weeks, followed by treatment according to the discretion of the individual primary care physician. OUTCOMES & MEASUREMENTS: Renal vascular resistance, renal plasma flow, GFR, and change in renal plasma flow in response to infusion of the NO synthase inhibitor N-monomethyl-L-arginine as an indicator of basal NO activity in the renal vasculature. RESULTS: 50 of 66 patients could be reexamined. At follow-up, mean arterial pressure decreased from 106 +/- 9.1 to 100 +/- 11 mm Hg (P < 0.001). Body mass index and hemoglobin A(1c) levels were unaltered. Renal vascular resistance decreased (from 128 +/- 44 to 103 +/- 30 mm Hg/mL/min/1.73 m(2); P < 0.001), renal plasma flow increased (from 490 +/- 133 to 589 +/- 154 mL/min/1.73 m(2); P < 0.001), and GFR did not change (113 +/- 22 versus 116 +/- 26 mL/min/1.73 m(2); P = 0.4) during follow-up. The decrease in renal plasma flow in response to N-monomethyl-l-arginine infusion was more pronounced at follow-up (-56.7 +/- 39 versus -73.4 +/- 48 mL/min/1.73 m(2); P = 0.02), indicating improved basal NO activity. After adjustment for possible confounders, patients with a marked decrease in mean arterial pressure showed more improved basal NO activity during follow-up than those with a less pronounced decrease in mean arterial pressure (P = 0.04). LIMITATIONS: Patients were treated according to the discretion of the individual primary care physician. CONCLUSIONS: During follow-up, renal vascular resistance, renal plasma flow, and renal endothelial function (indicated by basal NO activity) improved. Better blood pressure control was associated with improved endothelial function of the renal vasculature, thereby potentially mediating the changes in renal hemodynamics.

Gender is related to alterations of renal endothelial function in type 2 diabetes.

BACKGROUND: Gender has been shown to affect endothelial function of the forearm circulation in patients with type 2 diabetes, but data on the renal circulation are lacking. We hypothesized that renal vascular nitric oxide (NO) availability is higher, and oxidative stress lower, in female compared to male patients with type 2 diabetes. METHODS: In 41 male and 39 female patients with type 2 diabetes, renal plasma flow (RPF) was determined by constant infusion input clearance at baseline and following infusion of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 4.25 mg/kg) to assess basal renal vascular NO availability. After a subsequent infusion of L-arginine (100 mg/kg) to restore baseline conditions, vitamin C (45 mg/kg) was co-infused to determine levels of oxidative stress in the renal circulation. RESULTS: Baseline renal haemodynamics were similar between genders. L-NMMA-induced renal vasoconstriction was more pronounced in females compared to males (-89 +/- 69 versus -60 +/- 52 ml/min/1.73 m(2), P = 0.03). After administration of L-arginine to restore baseline perfusion, the co-infusion of vitamin C led to a lesser increase of RPF in females than in males (+37 +/- 86 versus +60 +/- 52 ml/min/1.73 m(2), P = 0.05). CONCLUSIONS: Our data demonstrate that NO availability in the renal circulation is greater in female than in male patients with type 2 diabetes that is associated with reduced levels of oxidative stress in females. The role of this gender-related difference in renal endothelial function for the initiation and progression of diabetic nephropathy should be addressed in future studies.

Left Ventricular Structure in Patients With Mild-to-Moderate CKD-a Magnetic Resonance Imaging Study.

INTRODUCTION: The high burden of left ventricular (LV) abnormalities in patients with advanced chronic kidney disease (CKD) is well established. However, less is known about the prevalence, patterns, and determinants of LV abnormalities in patients with early CKD. METHODS: We examined LV structure in 290 patients with a median estimated glomerular filtration rate (eGFR) of 51 ml/min per 1.73 m2 by magnetic resonance imaging (MRI). We explored associations with clinical and hemodynamic parameters, hydration (bioimpedance), endothelial function, inflammation (including C-reactive protein and tumor necrosis factor-α and its soluble receptors) and mineral bone disease (MBD) markers (including vitamin D, parathyroid hormone, α-klotho and fibroblast growth factor-23). RESULTS: Normal geometry was found in 56% of patients, dilation in 4%, concentric remodeling in 10%, and LV hypertrophy in 29%. Linear regression analysis revealed that greater LV mass was independently associated with male sex, greater body mass index (BMI), and higher 24-hour systolic blood pressure (24-hour SBP). Concentric remodeling was independently associated with age, male sex, higher 24-hour SBP, and greater hemoglobin levels. Surprisingly, neither hydration status, nor endothelial function, nor any of the inflammatory or MBD parameters added significantly to these models. CONCLUSION: Abnormal LV structure was found in almost one-half of the patients. Reducing BMI and 24-hour SBP and avoiding high hemoglobin concentrations appear to be the key factors to prevent abnormal LV remodeling in patients with mild-to-moderate CKD.

Blood Pressure Pattern and Target Organ Damage in Patients With Chronic Kidney Disease.

In patients with chronic kidney disease, data on blood pressure (BP) pattern and its association with target organ damage, which indicates elevated cardiovascular risk, are sparse. In 305 treated hypertensive chronic kidney disease patients, we assessed BP pattern, left ventricular mass (magnetic resonance imaging), intima-media thickness (ultrasound), 24-hour-pulse wave velocity and 24-hour-central augmentation index (Mobil-O-Graph). Controlled hypertension (normal office and ambulatory BP) was found in 41% and sustained uncontrolled hypertension (elevated office and ambulatory BP) in 30% of patients. Misclassification of BP status occurred in 29%: white coat uncontrolled hypertension (elevated office but normal ambulatory BP) was detected in 11% and masked uncontrolled hypertension (normal office but elevated ambulatory BP) in 18% of patients. Left ventricular mass was increased in white coat uncontrolled hypertension (+11.2 g), masked uncontrolled hypertension (+9.4 g), and sustained uncontrolled hypertension (+16.6 g) compared with controlled hypertension. Intima-media thickness was similar across all 4 BP groups. Twenty-four hour-pulse wave velocity and 24-hour-central augmentation index were increased in masked uncontrolled hypertension (+0.5 m/sec and +2.5%) and sustained uncontrolled hypertension (+0.5 m/sec and +2.9%) compared with controlled hypertension. In conclusion, based on office BP measurements, misclassification of true BP status occurred in almost one-third of chronic kidney disease patients. Both types of misclassification (white coat uncontrolled hypertension and masked uncontrolled hypertension) were associated with parameters of target organ damage. Ambulatory BP monitoring should be used routinely to identify chronic kidney disease patients at high cardiovascular risk.

Increased Aldosterone Release During Head-Up Tilt in Early Primary Hypertension.

BACKGROUND: Hyperaldosteronism is well known cause of secondary hypertension. However, the importance of aldosterone for the much larger group of patients with primary hypertension is less clear. We hypothesized that in young subjects with primary hypertension, the rise of plasma aldosterone levels in response to head-up tilt testing as a stress stimulus is exaggerated. METHODS: Hemodynamics (blood pressure (BP), heart rate (HR), cardiac index (CI), and total peripheral vascular resistance index (TPRI), all by TaskForce monitor) and hormones (plasma renin activity (PRA), angiotensin II (Ang II), aldosterone) were measured before and during 30 minutes of head-up tilt in 45 young hypertensive and 45 normotensive subjects. RESULTS: BP, HR, CI, and TPRI all increased in response to head-up tilt, with no difference between groups. There was no difference in baseline PRA, Ang II, and aldosterone between groups. During head-up tilt, PRA, and Ang II levels increased similarly. However, aldosterone levels increased to a greater extent in the hypertensive vs. normotensive subjects (P = 0.0021). CONCLUSIONS: Our data suggest that an increased release of aldosterone in response to orthostatic stress is a feature of early primary hypertension. The similar increase in PRA and Ang II suggests a potential role for secretagogues of aldosterone other than Ang II in this response. In addition to its established role in secondary hypertension, dysregulation of aldosterone release might contribute to the development of primary arterial hypertension.

Low dose-eplerenone treatment decreases aortic stiffness in patients with resistant hypertension.

Vascular damage is aggravated in animal models of hypertension with mineralocorticoid (MR) excess and in hypertensive patients with primary hyperaldosteronism. MR antagonism has shown to provide effective blood pressure (BP)-control in patients with treatment resistant hypertension (TRH), but the concurrent effects on the vasculature have not been examined. In a randomized, double-blinded, placebo-controlled parallel-group study, 51 patients with TRH received either eplerenone 50 mg or placebo for 6 months together with additional antihypertensives titrated to achieve a BP target of <140/90 mm Hg. Pulse wave velocity (PWV), augmentation index (AIx), augmentation pressure (AP), AP normalized to a heart rate of 75/min (AP@HR75), renal resistive index (RRI), intima-media thickness (IMT) and urinary albumin excretion rate (UAER) were assessed before and after treatment. PWV was reduced only with eplerenone (from 11.3±3.6 to 9.8±2.6 m/s, P˂.001), but not with placebo (10.3±2.0 to 10.1±1.8 m/s, P=.60), despite similar reductions in BP (-35±20/-15±11 mm Hg vs -30±19/-13±7 mm Hg, n.s.). Further, reductions in AP and AP@HR75 were greater with eplerenone, while changes in AIx, RRI, IMT and UAER were similar. Our data show that eplerenone beneficially affects markers of arterial stiffness and wave reflection in patients with TRH, independently of BP lowering. These data add to the evidence that MR antagonism should be the preferred treatment option in TRH.

L-Arginine does not affect renal morphology and cell survival in ischemic acute renal failure in rats.

BACKGROUND: L-Arginine (L-Arg), a substrate of nitric oxide synthases, improves renal function in ischemic acute renal failure (iARF). We evaluated whether L-Arg improves renal morphology and cell survival in the course of iARF. METHODS AND RESULTS: iARF was induced in rats by bilateral clamping of renal arteries for 45 min. L-Arg was applied intraperitoneally during clamping, and orally during 14 days of follow-up. Morphology and cell survival of renal cortical and medullar tissue was analyzed on days 1, 3, 7, and 14 of follow-up, using toluidine blue staining and immunohistochemistry of perfusion-fixated tissue, and Western blot analysis of tissue homogenate. Renal tubular injury showed typical features of necrosis and was most severe on days 1 and 3 after clamping, predominantly in S3 segments, with almost complete recovery by day 14. Enhanced medullar monocyte infiltration, determined by ED-1 expression as well as by immunohistochemistry, and enhanced expression of proliferating cell nuclear antigen (PCNA), indicative of proliferation and regeneration, accompanied these morphological changes. Compared to controls, L-Arg had no impact on renal morphology, ED-1, and PCNA expression. Furthermore, expression of markers of apoptosis Bcl-2, Bax, and cleaved caspase-3 was only slightly increased in iARF rats, compared to sham-operated animals, and was also not influenced by L-Arg. CONCLUSION: Despite its repeatedly reported positive impact on renal function as also shown in our model, L-Arg does not alter cell death and proliferation in the course of iARF in our model. Thus, different mechanisms have to be considered, in particular improved intrarenal hemodynamics.

Olmesartan improves pulse wave velocity and lowers central systolic blood pressure and ambulatory blood pressure in patients with metabolic syndrome.

Ambulatory blood pressure (BP) and central systolic BP (cSBP) are superior to brachial office BP measurements in predicting cardiovascular end organ damage. The authors aimed to analyze the effect of olmesartan 80 mg (OLM 80) vs 20 mg (OLM 20) vs amlodipine 5 mg (AML 5) on central hemodymamics and ambulatory BP in patients with metabolic syndrome (MetS).In a double-blind, three-phase crossover study comprising 69 untreated patients with MetS defined by the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults guidelines, the effects of OLM 80 on central hemodynamics (cSBP), central pulse pressure), pulse wave velocity (PWV), and 24-hour ambulatory BP were compared with OLM 20 and AML 5, given for 6 weeks each. In 69 patients (47 men, 22 women) (51.5±9.75 years), reduction in cSBP was the highest with OLM 80 and significantly greater than the reduction with AML 5 (-14.1 mm Hg vs -9.7 mm Hg, P=.0117). All three substances significantly reduced 24-hour ambulatory systolic (OLM 80 and OLM 20 P<.0001; AML 5 P=.0105). BP and 24-hour diastolic BP (OLM 80 and OLM 20 P<.0001; AML 5 P=.0126). PWV was significantly reduced by OLM 80 (-0.58 m/s, P=.0088) and by OLM 20 (-0.48 m/s, P=.0362) but not by AML 5 (-0.28 m/s, P=.2065). For PWV, no significant differences were detected between the three groups. OLM significantly improves arterial stiffness as demonstrated by the reduction in PWV and in cSBP. In addition, 24-hour ambulatory BP was reduced to a greater extent with OLM 80 than with AML 5.

Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease.

BACKGROUND: Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25--the key hormone of iron-metabolism--on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels. METHODS: 249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003-2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models. RESULTS: Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05). CONCLUSIONS: We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define "high risk" populations in CKD.

Prevention of electrocardiographic left ventricular remodeling by the angiotensin receptor blocker olmesartan in patients with type 2 diabetes.

OBJECTIVE: To assess the ability of olmesartan (OLM) to prevent or delay left ventricular remodeling and hypertrophy in patients with type 2 diabetes. METHODS: This prespecified ECG substudy of Randomised OlmesArtan and Diabetes MicroAlbuminuria Prevention (ROADMAP), which compared OLM with placebo, assessed the signs of left ventricular remodeling in patients with a 12-lead ECG at baseline and after at least 2 years. Cornell voltage QRS duration product (primary objective), Cornell voltage index and Sokolow-Lyon index were assessed. RESULTS: In total, 9418 ECG recordings and 1513 patients from ROADMAP were analyzed (placebo, n = 736; OLM, n = 777). Quartiles defined by baseline Cornell voltage QRS duration product were assessed and the proportion of patients in the highest quartile (≥200 mVms) increased from 24.0 to 26.5% in the placebo group and decreased from 25.5 to 22.3% in the OLM group [odds ratio (OR) 0.598 (95% confidence interval [CI] 0.440-0.813); P = 0.0011]. The OR did not change after adjustment for baseline parameters. By the end of study, 38.7% of patients in the placebo group and 34.7% in the OLM group shifted from a lower to a higher quartile or remained in the highest quartile of Cornell voltage QRS duration product [OR 0.797 (95% CI 0.637-0.996); P = 0.0465]. This translated into a 20.3% risk reduction with OLM and suggested OLM attenuated the progression of left ventricular remodeling versus placebo. CONCLUSION: OLM substantially delayed the development of left ventricular remodeling in type 2 diabetes. This effect was not explained by the differences in blood pressure control. Thus, OLM delayed the onset of microalbuminuria, as well as the ECG signs of cardiac structural adaptation in type 2 diabetes.

First experience in analysing pulsatile retinal capillary flow and arteriolar structural parameters measured noninvasively in hypertensive patients.

OBJECTIVE: Increased pulsatile pressure induces as well as aggravates microvascular damage. Scanning laser Doppler flowmetry allows the noninvasive assessment of both retinal capillary flow (RCF) and arteriolar structural parameters of the retinal circulation. Moreover, pulsatile characteristics of the retinal arterioles can be assessed. METHODS: In study 1, reliability of pulsatile RCF and structural parameters were examined in randomly selected patients. In study 2, pulsatile RCF as well as the structural parameters of retinal arterioles were assessed in hypertension grade 1-2 (HT1-2; n = 20) and treatment-resistant hypertension (TRH; n = 19). RESULTS: In study 1, test-retest, interobserver and intraobserver reliability of all parameters showed coefficients of variation of less than 10%. In study 2, it was shown that patients with TRH had higher pulse pressure (P = 0.003) and pulsed RCF values (P < 0.001) as patients with HT1-2. Patients with HT1-2 had no change in the vessel diameter, but a significant difference in lumen diameter, resulting in an altered wall thickness (P = 0.001) between systole and diastole. In contrast, patients with TRH showed differences in vessel diameter (P = 0.005) as well as lumen diameter (P = 0.001), resulting in an unaltered wall thickness between systole and diastole. Hence, wall thickness change as a result of pulsed flow regulation observed in HT1-2 was missing in TRH. CONCLUSION: We suggest a new reliable tool for evaluating the pulsatility in the retinal circulation in humans, and found significant differences in pulsatile RCF and structural parameters between patients with HT1-2 and those with TRH.