Geriatric Assessments Can Predict Functional Outcome and Mortality after Urological Tumor Surgery.

INTRODUCTION: Older patients undergoing major urological tumor surgery are at severe risk of functional deterioration, complications, and mortality. We prospectively evaluated geriatric assessment tools and developed a novel easy-to-use assessment tool for clinical use. METHODS: In 159 patients, geriatric assessment tools were used prior to cystectomy, prostatectomy, and renal tumor surgery, and their peri- and postoperative courses were recorded. Using all the tests, a short and easy-to-use assessment tool was developed, and nomograms were generated to predict functional outcomes and mortality. RESULTS: Of all the patients, 13.8% underwent radical cystectomy, 37.7% underwent radical prostatectomy, and 48.4% underwent tumor surgery of the kidney at the age of 70 years or older. The average age was 75.6 years. Incomplete functional recovery at day 30 and day 180 was observed in 37.7% and 36.1% of the patients, respectively, and incomplete functional recovery was associated with impaired mobility, previous care dependency, frailty, comorbidities, and a high ASA score. The only predictor for high-grade complications was comorbidities, whereas mortality was associated with the geriatric screening tool scores, impaired mobility, preoperative care dependency, and comorbidities. The Erlangen Index (EI), a combination of the selected assessment tools, showed a good prediction of early (p = 0.002) and medium-term (p = 0.002) functional outcomes and mortality (p = 0.001). CONCLUSION: Our prospective evaluation confirms the high risk of incomplete functional recovery, high-grade complications, and mortality in older patients undergoing major urological tumor surgery. The EI is an easy-to-use preoperative assessment tool and therefore should be used in preoperative patient counseling.

Frail Older Individuals Maintaining a Steady Standing Position: Associations Between Sway Measurements with Frailty Status Across Four Different Frailty Instruments.

OBJECTIVE: An analysis of the relationships between static equilibrium parameters and frailty status and/or severity across four different frailty measures. DESIGN: Cross-sectional analysis. SETTING: Geriatric wards of a general hospital. PARTICIPANTS: One hundred twenty-three geriatric inpatients comprising 70 women (56.5%) and 53 men (42.7%) with an age range of 68-95 years. METHODS: The variation in the center of pressure (CoP), ie, the length of sway, the area of sway, and the mean speed, was assessed for different positions/tasks: 1) wide standing with eyes open (WSEO); 2) wide standing with eyes closed (WSEC); 3) narrow standing with eyes open (NSEO) and 4) narrow standing with eyes closed (NSEC), using a force plate. Frailty status and/or frailty severity were evaluated using the frailty phenotype (FP), the clinical frailty scale (CFS), the 14-item frailty index based on a comprehensive geriatric assessment (FI-CGA), and a 47-item frailty index (FI). RESULTS: WSEO length of sway (FP, CFS, FI-CGA, FI), WSEO area of sway (FP, CFS, FI-CGA, FI), and WSEO mean speed (FP, CFS, FI-CGA, FI), WSEC length of sway (FP, FI-CGA, FI), WSEC area of sway (FP, FI-CGA, FI) and WSEC mean speed (FI-CGA, FI), NSEO length of sway (FP, FI-CGA, FI), NSEO area of sway (FP, CFS, FI-CGA, FI), and NSEO mean speed (FP, CFS, FI-CGA, FI), NSEC length of sway (FI-CGA, FI), NSEC area of sway (FI-CGA, FI) and NSEC mean speed (FI-CGA, FI) were associated with the frailty status and/or severity across the four different frailty instruments (all p < 0.05, respectively). CONCLUSION: Greater fluctuations in CoP with increasing frailty status and/or severity were a uniform finding across various major frailty instruments.

Predictability of a modified Mini- Nutritional- Assessment version on six-month and one-year mortality in hospitalized geriatric patients: a comparative analysis.

Recently we introduced a modified Mini Nutritional Assessment (MNA) Short Form (MNA-SF) and Long Form (MNA-SF) with operationalization of the 'mobility' and 'neuropsychological problems' items of the MNA using scores on Barthel Index mobility item and Mini Mental State Examination and Geriatric Depression Scale scores. We have now evaluated the abilities of this modified MNA-SF and MNA-LF to predict mortality in comparison with the standard MNA-SF and MNA-LF and the Nutritional Risk Screening 2002 (NRS 2002) and the Malnutrition Universal Screening Tool (MUST). A prospective analysis was performed in 240 hospitalised geriatric patients aged ≥ 65 years. Malnutrition and/or malnutrition risk were assessed using the modified MNA-SF and MNA-LF, the standard MNA-SF and MNA-LF, and the NRS 2002 and MUST. The modified MNA-SF and MNA-LF and the standard MNA-SF and MNA-LF assessments (all p < 0.05), but not NRS 2002 or MUST (all p ≥ 0.05), predicted six-month and/or one-year mortality. Prediction of six-month and/or one-year mortality by the modified MNA-SF was comparable with predictions by the standard MNA-SF and MNA-LF (all p ≥ 0.05). The modified MNA-LF showed better prediction of six-month and one-year mortality than the standard MNA-SF and MNA-LF (all p < 0.05). The modified MNA-LF (all adjusted p < 0.05), but none of the other instruments (all adjusted p ≥ 0.05), predicted six-month and one-year mortality independently of age, sex, frailty, comorbidity and ADL disability burden. The modified MNA-SF and MNA-LF emerged as potentially valuable tools for predicting mortality in patients hospitalised on geriatric wards.

Changes of a frailty index based on common blood and urine tests during a hospital stay on geriatric wards predict 6-month and 1-year mortality in older people.

BACKGROUND: We aimed to evaluate the abilities of a 21-item frailty index based on laboratory blood and urine tests (FI-Lab21) assessed at different points in time, ie, at admission to hospital (FI-Lab21admission) and before discharge from hospital (FI-Lab21discharge), and the change of the FI-Lab21 during the hospital stay to predict 6-month and 1-year mortality in hospitalized geriatric patients. METHODS: Five hundred hospitalized geriatric patients aged ≥65 years were included in this analysis. Follow-up data were acquired after a period of 6 months and 1 year. RESULTS: The FI-Lab21admission and FI-Lab21discharge scores were 0.33±0.15 and 0.31±0.14, respectively (P<0.001). The FI-Lab21admission and FI-Lab21discharge both predicted 6-month and 1-year mortality (areas under the receiver operating characteristic curves: 0.72, 0.72, 0.77, and 0.75, respectively, all P<0.001). The predictive abilities for 6-month and 1-year mortality of the FI-Lab21admission were inferior compared with those of the FI-Lab21discharge (all P<0.05). Patients with a reduction in or stable FI-Lab21 score during the hospital stay revealed lower 6-month and 1-year mortality rates compared with the persons whose FI-Lab21 score increased during the hospital stay (all P<0.05). After adjustment for age, sex, and FI-Lab21admission, each 1% decrease in the FI-Lab21 during the hospital stay was associated with a decrease in 6-month and 1-year mortality of 5.9% and 5.3% (both P<0.001), respectively. CONCLUSION: The FI-Lab21 assessed at admission or discharge and the changes of the FI-Lab21 during the hospital stay emerged as interesting and feasible approaches to stratify mortality risk in hospitalized geriatric patients.

Operationalizing a frailty index using routine blood and urine tests.

BACKGROUND: Uncomplicated frailty instruments are desirable for use in a busy clinical setting. The aim of this study was to operationalize a frailty index (FI) from routine blood and urine tests, and to evaluate the properties of this FI compared to other frailty instruments. MATERIALS AND METHODS: We conducted a secondary analysis of a prospective cohort study on 306 patients aged ≥65 years hospitalized on geriatric wards. An FI comprising 22 routine blood parameters and one standard urine parameter (FI-Lab), a 50-item FI based on a comprehensive geriatric assessment (FI-CGA), a combined FI (FI-combined [items from the FI-Lab + others from the FI-CGA]), the Clinical Frailty Scale, rule-based frailty definition, and frailty phenotype were operationalized from data obtained during patients' hospital stays (ie, before discharge [baseline examination]). Follow-up data were obtained up to 1 year after the baseline examination. RESULTS: The mean FI-Lab score was 0.34±15, with an upper limit of 0.74. The FI-Lab was correlated with all the other frailty instruments (all P<0.001). The FI-Lab revealed an area under the receiver-operating characteristic curve (AUC) for 6-month and 1-year mortality of 0.765 (0.694-0.836) and 0.769 (0.706-0.833), respectively (all P<0.001). Each 0.01 increment in FI-Lab increased the risk (adjusted for age and sex) for 6-month and 1-year mortality by 7.2% and 7.1%, respectively (all adjusted P<0.001). When any of the other FIs (except the FI-combined) were also included in the models, each 0.01 increment in FI-Lab score was associated with an increase in the risk of 6-month and 1-year mortality by 4.1%-5.4% (all adjusted P<0.001). CONCLUSION: The FI-Lab showed key characteristics of an FI. The FI-Lab can be applied as a single frailty measure or in combination with/in addition to other frailty instruments.

Comparing the predictive accuracy of frailty, comorbidity, and disability for mortality: a 1-year follow-up in patients hospitalized in geriatric wards.

BACKGROUND: Studies evaluating and comparing the power of frailty, comorbidity, and disability instruments, together and in parallel, for predicting mortality are limited. OBJECTIVE: This study aimed to evaluate and compare the measures of frailty, comorbidity, and disability in predicting 1-year mortality in geriatric inpatients. DESIGN: Prospective cohort study. PATIENTS AND SETTING: A total of 307 inpatients aged ≥65 years in geriatric wards of a general hospital participated in the study. MEASUREMENTS: The patients were evaluated in relation to different frailty, comorbidity, and disability instruments during their hospital stays. These included three frailty (the seven-category Clinical Frailty Scale [CFS-7], a 41-item frailty index [FI], and the FRAIL scale), two comorbidity (the Cumulative Illness Rating Scale for Geriatrics [CIRS-G] and the comorbidity domain of the FI [Comorbidity-D-FI]), and two disability instruments (disability in basic activities of daily living [ADL-Katz] and the instrumental and basic activities of daily living domains of the FI [IADL/ADL-D-FI]). The patients were followed-up over 1 year. RESULTS: Using FI, CIRS-G, Comorbidity-D-FI, and ADL-Katz, this study identified a patient group with a high (≥50%) 1-year mortality rate in all of the patients and the two patient subgroups (ie, patients aged 65-82 years and ≥83 years). The CFS-7, FI, FRAIL scale, CIRS-G, Comorbidity-D-FI, and IADL/ADL-D-FI (analyzed as full scales) revealed useful discriminative accuracy for 1-year mortality (ie, an area under the curve >0.7) in all the patients and the two patient subgroups (all P<0.001). Thereby, CFS-7 (in all patients and the two patient subgroups) and FI (in the subgroup of patients aged ≥83 years) showed greater discriminative accuracy for 1-year mortality compared to other instruments (all P<0.05). CONCLUSION: All the different instruments emerged as suitable tools for risk stratification in geriatric inpatients. Among them, CFS-7, and in those patients aged ≥83 years, also the FI, might most accurately predict 1-year mortality in the aforementioned group of individuals.

Significance of frailty for predicting adverse clinical outcomes in different patient groups with specific medical conditions.

Frailty is a major health burden in an aging society. It constitutes a clinical state of reduced physiological reserves that is associated with a diminished ability to withstand internal and external stressors. Frail patients have an increased risk for adverse clinical outcomes, such as mortality, readmission to hospital, institutionalization and falls. Of further clinical interest, frailty might be at least in part reversible in some patients and subject to preventive strategies. In daily clinical practice older patients with a complex health status, who are mostly frail or at least at risk of developing frailty, are frequently cared for by geriatricians. Recently, clinicians and scientists from other medical disciplines, such as cardiology, pulmonology, gastroenterology, nephrology, endocrinology, rheumatology, surgery and critical care medicine also discovered frailty to be an interesting instrument for risk stratification of patients, including younger patients. In this review we highlight the results of recent studies that demonstrated the significance of frailty to predict adverse clinical outcomes in patients with specific medical conditions, such as cardiac, lung, liver and kidney diseases as well as diabetes mellitus, osteoarthritis, trauma patients, patients undergoing surgery and critically ill patients. Multiple studies in patients with the aforementioned specific medical conditions could be identified demonstrating a predictive role of frailty for several adverse clinical outcomes. The association between frailty and adverse clinical outcomes reported in these studies was in part independent of several major potential confounder factors, such as age, sex, race, comorbidities and disabilities and were also detected in younger patients.

Haemoglobin and vascular function in the human retinal vascular bed.

OBJECTIVE: Haemoglobin is a potential nitric oxide (NO) scavenger. Haemoglobin is associated with blood viscosity and the red blood cell free layer width of microvessels that impact on shear stress in the microcirculation. We hypothesized that haemoglobin modulates retinal vascular function. METHODS: In 139 nondiabetic male patients with haemoglobin levels within the normal range, the vasodilatatory response of retinal capillary blood flow (RCF) to flicker light exposure and the vasoconstrictor response of RCF to infusion of NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) were assessed. The latter, because of the selective nature of L-NMMA, reflects a parameter of basal NO activity of retinal vasculature. Examinations of retinal parameters were performed noninvasively and in vivo using scanning laser Doppler flowmetry. RESULTS: Patients with haemoglobin greater or equal the median revealed reduced increase of RCF to flicker light exposure (2.83 ± 12 vs. 9.52 ± 14 (%), P adjusted = 0.002), and greater decrease of RCF to L-NMMA infusion (-7.35 ± 13 vs. -0.92 ± 14 (%), P adjusted = 0.008), compared with patients with haemoglobin below the median. Haemoglobin was negatively related to the percentage change of RCF to flicker light exposure (r = -0.249, P = 0.004) and to L-NMMA infusion (r = -0.201, P = 0.018). In multiple linear regression analysis haemoglobin was an independent determinant of the percentage change of RCF to flicker light exposure (model 1: ß = -0.278, P = 0.003 and model 2: ß = -0.283, P = 0.002) and to L-NMMA infusion (model 1: ß = -0.256, P = 0.005 and model 2: ß = -0.269, P = 0.004). CONCLUSION: Haemoglobin emerged as an independent determinant of vascular function in the human retinal vascular bed.

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.

Impaired increase of retinal capillary blood flow to flicker light exposure in arterial hypertension.

We hypothesized that the increase of retinal capillary blood flow (RCF) to flicker light exposure is impaired in subjects with arterial hypertension. In 146 nondiabetic untreated male subjects with (n=50) or without (n=96) arterial hypertension, RCF was measured before and after flicker light exposure noninvasively and in vivo using scanning laser Doppler flowmetry. In addition, in a subgroup of 28 subjects, the change of RCF to flicker light exposure was again assessed during parallel infusion of nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA). The increase of RCF to flicker light exposure was lower in patients with untreated hypertension compared with normotensive subjects when expressed in absolute terms (7.69±54 versus 27.2±44 AU; P adjusted=0.013) or percent changes (2.95±14 versus 8.33±12%; P adjusted=0.023). Systolic (ß=-0.216; P=0.023) but not diastolic blood pressure (ß=-0.117; P=0.243) or mean arterial pressure (ß=-0.178; P=0.073) was negatively related to the percent change of RCF to flicker light exposure, independently of other cardiovascular risk factors. In the subgroup of 28 subjects, the increase of RCF to flicker light exposure was similar at baseline and during parallel infusion of L-NMMA when expressed in absolute terms (20.0±51 versus 22.6±56 AU; P=0.731) or percent changes (7.12±16 versus 8.29±18%; P=0.607). The increase of RCF to flicker light exposure is impaired in arterial hypertension. In the subgroup of the total study cohort, nitric oxide was not a major determinant of the increase of RCF to flicker light exposure.

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.

Postchallenge hyperglycemia is closely related with early vascular damage in overweight and obese patients.

OBJECTIVE: There is ongoing discussion on how best to screen for diabetes mellitus. Previous studies suggest that an abnormal oral glucose tolerance test (OGTT) is better than fasting glucose levels in predicting cardiovascular mortality, which is largely determined by macrovascular complications in type 2 diabetes. We examined the relationship between screening methods for diabetes and indices of vascular damage in young individuals at high risk of type 2 diabetes. METHODS: Overweight and obese individuals (n = 76, average age 38 ± 6 years) were screened for diabetes by measuring fasting glucose levels, HbA1c and by performing the OGTT. Indices of early vascular damage, including the central augmentation index (cAIx) and pulse pressure amplification (PPA), were assessed by pulse wave analysis (Sphygmocor). Linear regression analyses were performed to identify independent predictors of vascular damage. RESULTS: Central SBP and DBP (BPs) were best predicted by age and by peripheral BP levels. cAIx was independently predicted by age (r = +0.324, P = 0.008), DBP (r = +0.294, P = 0.011) and 2-h glucose values of the OGTT (r = +0.390, P = 0.001). PPA was independently predicted by age (r = -0.445, P < 0.001) and 2-h glucose value of the OGTT (r = -0.353, P = 0.003). CONCLUSIONS: The 2-h value of the OGTT was superior to fasting glucose levels and HbA1c in predicting cAIx and PPA in young individuals at high risk of type 2 diabetes. Cardiovascular mortality is largely determined by macrovascular complications in type 2 diabetes, and these data suggest that diabetes screening by OGTT may help to identify those individuals with the greatest risk of future vascular complications.

Reversibility of the effects of aliskiren in the renal versus systemic circulation.

BACKGROUND AND OBJECTIVES: Renal hemodynamic effects of inhibitors of the renin-angiotensin system can increase the risk of acute kidney injury under certain conditions. The BP-lowering effects of the renin inhibitor aliskiren are sustained 3-4 weeks after withdrawal. In this study, the reversibility of the renal hemodynamic effects of aliskiren was tested. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this open-label study, renal perfusion was measured by 1.5-T magnetic resonance imaging-arterial spin labeling in 34 subjects with arterial hypertension before aliskiren (pre-aliskiren), after 4 weeks of aliskiren treatment (300 mg), and 4-5 days (∼2.5-3.0× plasma half-life) after withdrawal (post-aliskiren). RESULTS: Aliskiren reduced systolic BP from 152 ± 14 to 139 ± 16 mmHg (P<0.0001), which was sustained post-aliskiren (136 ± 13 mmHg, P=1.00 versus aliskiren). Aliskiren significantly altered renal perfusion (P=0.005), increasing from 272 ± 25 pre-aliskiren to 287 ± 29 ml/min per 100 g during aliskiren (P=0.03). This increase in renal perfusion was completely reversed post-aliskiren (272 ± 26 ml/min per 100 g, P=0.03 versus aliskiren, P=0.63 versus pre-aliskiren). No changes were noted in urinary angiotensinogen levels. Plasma renin activity was reduced by aliskiren, which was sustained post-aliskiren. Angiotensin II and aldosterone were reduced by aliskiren but recovered post-aliskiren to pre-aliskiren levels. CONCLUSIONS: After withdrawal of aliskiren, the effects on BP were sustained, whereas increase in renal perfusion was reversed, which was associated with recovery of angiotensin II and aldosterone to pretreatment levels. Renal hemodynamic effects are more readily reversible than systemic effects of aliskiren.

New software analyses increase the reliability of measurements of retinal arterioles morphology by scanning laser Doppler flowmetry in humans.

OBJECTIVE: The investigation of the retinal arterioles offers the unique opportunity to analyze in vivo arteriolar remodeling in arterial hypertension in humans. We analyzed the reliability of assessing retinal arteriolar morphology with our new version of the software analyses for scanning laser Doppler flowmetry. METHOD: In the test-retest reliability study, 10 eyes of 10 healthy persons were measured during 5 days under routine laboratory conditions with the Heidelberg Retinal Flowmetry. In a second study, interobserver and intraobserver reliability was analyzed from retinal images of 18 patients with three types of arterial hypertension by three readers and the most experienced reader analyzed all images twice on two different days. Images were analyzed by the old and the newly developed software versions. To characterize the reliability, the coefficients of variation were calculated. RESULTS: The test-retest study analyzed with the new program showed that the variation coefficients of vessel and lumen diameter, wall thickness, wall/lumen ratio and new calculated parameter: lumen/vessel diameter ratio of retinal arterioles were significantly less than 10%, with the exception of the wall cross-sectional area (12.5%). The interobserver and intraobserver reliability showed in nearly all circumstances coefficients of variations of less than 10% and did not differ across various readers and patient groups. CONCLUSION: The new software 'SLDF version 4.0' clearly improved the reliability of assessing the structural parameters of the retinal arterioles. The application delivers reliable measurements of the retinal arteriolar structure in vivo in humans.

Folic acid treatment normalizes NOS-dependence of vascular tone in the metabolic syndrome.

Obese subjects with the metabolic syndrome (MS+) are more prone to microvascular complications than obese subjects without the metabolic syndrome (MS-). Excessive vascular nitric oxide (NO) production has been demonstrated in MS+ compared to MS-, perhaps driven by increased inflammation or oxidative stress. We tested whether in MS+, folic acid (FA) treatment could normalize NO synthase (NOS)-dependence of vascular tone in the retina and kidney. MS+ (n = 49) and MS- (n = 26) subjects were included in a randomized, double-blind, crossover trial. After 4-weeks' treatment with placebo or FA (5 mg/day), several cytokines (C-reactive protein (CRP), interleukin-1ß, adiponectin), and markers of oxidative stress (glutathione/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (TAC)) were determined. NOS-dependence of retinal and renal vascular tone was assessed by retinal scanning laser Doppler flowmetry and renal clearance technique, respectively. FA had no effect on cytokine levels, but increased GSH/GSSG ratio overall (36 ± 76 vs. 102 ± 200, P = 0.04), indicative of a reduction in oxidative stress. In MS+, treatment with FA reduced NOS-dependence of retinal and renal vascular tone compared to placebo (P = 0.03 and P = 0.04, respectively). FA had no effect in MS-. After treatment with FA, NOS-dependence of retinal and renal vascular tone was similar between MS+ and MS-. Retinal and renal vascular tone in MS+ subjects is characterized by increased dependence on NOS. NOS-dependence in MS+ could be corrected by FA treatment to levels not dissimilar in MS-, and this was associated with a reduction in oxidative stress. Future trials should test whether these effects translate into a reduction of microvascular complications.

Basal nitric oxide activity is an independent determinant of arteriolar structure in the human retinal circulation.

OBJECTIVE: Experimental data indicate that nitric oxide might play a role in structure and remodeling of peripheral small arteries and arterioles. We hypothesized that retinal arteriolar structure is modulated by basal nitric oxide activity. METHODS: The study cohort comprised 97 male untreated patients with normal and elevated blood pressure but without clinical evidence for cardiovascular disease. The changes of retinal capillary blood flow (RCF) to nitric oxide synthase inhibitor N-monomethyl-L-arginine (L-NMMA), that reflects basal nitric oxide activity of retinal vasculature, and to flicker light, that in part nitric oxide dependently provokes retinal vasodilatation, and parameters of retinal arteriolar structure, for example wall-to-lumen ratio (WLR), were assessed noninvasively and in vivo by scanning laser Doppler flowmetry. RESULTS: Participants were stratified according to the median WLR of retinal arterioles into two groups. In the group with WLR above the median RCF in response to infusion of L-NMMA decreased to a smaller extent (-3.82 ± 26 vs. -26.0 ± 45 arbitrary units and -0.83 ± 8.4 vs. -5.88 ± 11%, P = 0.004 and P = 0.015; respectively), whereas RCF in response to flicker light did not differ significantly compared to the counter group (22.2 ± 56 vs. 39.8 ± 51 arbitrary units and 7.42 ± 15 vs. 11.9 ± 14%, P = 0.112 and P = 0.149). In the whole study cohort WLR of retinal arterioles was related with the decrease of RCF to L-NMMA infusion [when expressed in absolute terms (r = 0.252, P = 0.013) and in percentage change (r = 0.213, P = 0.036)] and inversely related with the change of RCF to flicker light [when expressed in absolute terms (r = -0.203, P = 0.048) but not clearly when expressed in percentage change (r = -0.161, P = 0.120)]. Adjustment for major cardiovascular risk factors and changes of systemic hemodynamics in response to L-NMMA infusion revealed an independent relationship between WLR of retinal arterioles and percentage change of RCF to L-NMMA infusion (ß = 0.300, P = 0.007). CONCLUSION: Basal nitric oxide activity emerged as an independent determinant of arteriolar remodeling in the human retinal circulation in vivo.

Measurement of kidney perfusion by magnetic resonance imaging: comparison of MRI with arterial spin labeling to para-aminohippuric acid plasma clearance in male subjects with metabolic syndrome.

BACKGROUND: Magnetic resonance imaging with arterial spin labeling (MRI-ASL) is a non-invasive approach to measure organ perfusion. We aimed to examine whether MRI-ASL kidney perfusion measurements are related to measurements of renal plasma flow (RPF) by para-aminohippuric acid (PAH) plasma clearance and whether changes of kidney perfusion in response to treatment with telmisartan can be detected by MRI-ASL. METHODS: Twenty-four patients with metabolic syndrome and an estimated creatinine clearance according to Cockroft and Gault of > or =60 ml/min were included in the study. Kidney perfusion was assessed by MRI-ASL measurements of a single coronal kidney slice (with flow-sensitive alternating inversion recovery and true fast imaging with steady-state processing sequence) and by measurements of RPF using PAH plasma clearance before and after 2 weeks of treatment with the angiotensin receptor blocker telmisartan. All MRI-ASL examinations were performed on a 1.5 T scanner. RESULTS: Two weeks of therapy with telmisartan led to a significant increase of RPF (from 313 +/- 47 to 348 +/- 69 ml/min/m, P = 0.007) and MRI-ASL kidney perfusion measurements (from 253 +/- 20 to 268 +/- 25 ml/min/100 g, P = 0.020). RPF measurements were related with MRI-ASL kidney perfusion measurements (r = 0.575, P < 0.001). Changes of RPF measurements and changes of MRI-ASL kidney perfusion measurements in response to treatment with telmisartan revealed a close relationship when expressed in absolute terms (r = 0.548, P = 0.015) and in percentage changes (r = 0.514, P = 0.025). CONCLUSIONS: Perfusion measurement of a single coronal kidney slice by MRI-ASL is able to approximate kidney perfusion and to approximate changes in kidney perfusion due to pharmacological intervention.

Rosuvastatin does not affect intrarenal hemodynamics in patients with hypercholesterolemia.

BACKGROUND: It has been proposed that hyperlipidemia contributes to the progression of renal diseases, and conversely, that treatment with statins decreases the progressive decline of renal function. Increased glomerular pressure has been found to cause endothelial dysfunction of glomerular capillaries. However, the potential renoprotective effects of statin treatment have not been fully elucidated and so far no study has analyzed the effects of statin treatment on intrarenal hemodynamics. METHODS: Forty hypercholesterolemic patients were randomly assigned to receive rosuvastatin or placebo in a double-blind crossover study. Renal plasma flow(RPF) and glomerular filtration rate (GFR) were determined by constant input clearance technique with p-aminohippurate (PAH) and inulin. Glomerular hydrostatic pressure (Pglom) and resistances of the afferent(RA) and efferent arterioles (RE) were calculated according to the model originally established by Gomez. RESULTS: RPF and GFR were similar after treatment with rosuvastatin and placebo. Neither Pglom (66.2 +/- 3.9vs. 66.4 +/- 5.1 mm Hg, p=0.861) nor RA (3,200 +/- 1,780 vs.3,188 +/- 1,870 dyn-s-cm-5, p=0.957) or RE (3,620 +/- 1,174vs. 3,490 +/- 1,272 dyn-s-cm-5, p=0.378) were affected by treatment with rosuvastatin, compared with placebo. CONCLUSIONS: The beneficial effects on renal function by statin treatment seem not to be mediated by changes in intrarenal hemodynamics in patients with hypercholesterolemia.