A novel index for measuring the impact of devices on hypertension.

A key limitation in assessing the therapeutic impact of non-pharmacological approaches to treating hypertension is the method of reporting outcomes. Reducing the medications required to achieve the same blood pressure may be reported separately to a reduction in the blood pressure without change in medication, and thus lessen the reported beneficial impact of treatment. This study aims to derive a novel scoring system to gauge the therapeutic impact of non-drug treatment of hypertension by utilising a combination of excessive blood pressure and the number of anti-hypertensives into a combined score-the hypertensive index (HTi). The hypertensive index was empirically derived based on the systolic blood pressure and number of antihypertensive drugs, and applied retrospectively to a cohort undergoing intervention for renovascular hypertension. Subgroup and receiver operating characteristic analyses were used to compare the HTi to traditional methods of reporting outcomes. Following intervention (99 patients), 46% had improvement in both medication load and blood pressure, 29% had benefit in blood pressure without reduction in medication load, 15% had reduction in medication load without significant change in blood pressure and 9% showed no benefit in either parameter. The HTi was superior in detecting benefit from intervention compared with measuring blood pressure or medication load alone (AUC 0.94 vs 0.85;0.84). The hypertensive index may be a more sensitive marker of treatment effect than assessing blood pressure measurements alone. The use of such scoring systems in future trial design may allow more accurate reporting of the effects of interventions for hypertension.

Cardiovascular risk and kidney function profiling using conventional and novel biomarkers in young adults: the African-PREDICT study.

BACKGROUND: Low- and middle-income countries experience an increasing burden of chronic kidney disease. Cardiovascular risk factors, including advancing age, may contribute to this phenomenon. We (i) profiled cardiovascular risk factors and different biomarkers of subclinical kidney function and (ii) investigated the relationship between these variables. METHODS: We cross-sectionally analysed 956 apparently healthy adults between 20 and 30 years of age. Cardiovascular risk factors such as high adiposity, blood pressure, glucose levels, adverse lipid profiles and lifestyle factors were measured. Various biomarkers were used to assess subclinical kidney function, including estimated glomerular filtration rate (eGFR), urinary albumin, uromodulin and the CKD273 urinary proteomics classifier. These biomarkers were used to divide the total population into quartiles to compare extremes (25th percentiles) on the normal kidney function continuum. The lower 25th percentiles of eGFR and uromodulin and the upper 25th percentiles of urinary albumin and the CKD273 classifier represented the more unfavourable kidney function groups. RESULTS: In the lower 25th percentiles of eGFR and uromodulin and the upper 25th percentile of the CKD273 classifier, more adverse cardiovascular profiles were observed. In multi-variable adjusted regression analyses performed in the total group, eGFR associated negatively with HDL-C (ß= -0.44; p < 0.001) and GGT (ß= -0.24; p < 0.001), while the CKD273 classifier associated positively with age and these same risk factors (age: ß = 0.10; p = 0.021, HDL-C: ß = 0.23; p < 0.001, GGT: ß = 0.14; p = 0.002). CONCLUSION: Age, lifestyle and health measures impact kidney health even in the third decade.

Adjudicated myocarditis and multisystem illness trajectory in healthcare workers post-COVID-19.

BACKGROUND: We investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals. METHODS AND RESULTS: One hundred and sixty-eight patients were evaluated 28-60 days after the last episode of hospital care. Thirty-six (21%) were healthcare workers. Compared with non-healthcare workers, healthcare workers were of similar age (51.3 (8.7) years vs 55.0 (12.4) years; p=0.09) more often women (26 (72%) vs 48 (38%); p<0.01) and had lower 10-year cardiovascular risk (%) (8.1 (7.9) vs 15.0 (11.5); p<0.01) and Coronavirus Clinical Characterisation Consortium in-hospital mortality risk (7.3 (10.2) vs 12.7 (9.8); p<0.01). Healthcare worker status associated with less acute inflammation (peak C reactive protein 48 mg/L (IQR: 14-165) vs 112 mg/L (52-181)), milder illness reflected by WHO clinical severity score distribution (p=0.04) and shorter duration of admission (4 days (IQR: 2-6) vs 6 days (3-12)).In adjusted multivariate logistic regression analysis, healthcare worker status associated with a binary classification (probable/very likely vs not present/unlikely) of adjudicated myocarditis (OR: 2.99; 95% CI (1.01 to 8.89) by 28-60 days postdischarge).After a mean (SD, range) duration of follow-up after hospital discharge of 450 (88) days (range 290, 627 days), fewer healthcare workers died or were rehospitalised (1 (3%) vs 22 (17%); p=0.038) and secondary care referrals for post-COVID-19 syndrome were common (42%) and similar to non-healthcare workers (38%; p=0.934). CONCLUSION: Healthcare worker status was independently associated with the likelihood of adjudicated myocarditis, despite better antecedent health. Two in five healthcare workers had a secondary care referral for post-COVID-19 syndrome. TRIAL REGISTRATION NUMBER: NCT04403607.

Brain imaging factors associated with progression of subcortical hyperintensities in CADASIL over 2-year follow-up.

BACKGROUND AND PURPOSE: Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a cerebral small vessel disease manifesting with stroke, migraine and dementia in adults. The disease displays significant phenotypic variability that is incompletely explained. Early abnormalities in vascular function have been shown in animal models. We postulated that studying changes in vascular function may offer insights into disease progression. METHODS: Twenty-two subjects with CADASIL [50% female, 50 (±11) years] from 19 pedigrees were included in a longitudinal multimodality study using brain magnetic resonance imaging (MRI), clinical measures, neuropsychology and measures of peripheral vascular function. MRI studies included measurement of structural brain changes, cerebral blood flow (CBF) and cerebrovascular reactivity by arterial spin labelling and a CO2 respiratory challenge. RESULTS: Over 2 years, new stroke or transient ischaemic attack (TIA) occurred in five (23%) subjects and new significant disability in one (5%). There were significant increases in number of lacunes, subcortical hyperintensity volume and microbleeds, and a decrease in brain volume. CBF declined by 3.2 (±4.5) ml/100 g/min over 2 years. CBF and carotid-femoral pulse wave velocity at baseline predicted change in subcortical hyperintensity volume at follow-up. Carotid intima-media thickness and age predicted brain atrophy. Baseline CBF was lower in subjects who showed a decline in attention and working memory. CONCLUSIONS: Cerebral blood flow predicts radiological progression of hyperintensities and thus is a potential biomarker of disease progression in CADASIL. Over 2 years, there were changes in several relevant imaging biomarkers (CBF, brain volume, lacunes, microbleeds and hyperintensity volume). Future studies in CADASIL should consider assessment of CBF as prognostic factor.

Association of Thyroid Function Test Abnormalities and Thyroid Autoimmunity With Preterm Birth: A Systematic Review and Meta-analysis.

Importance: Maternal hypothyroidism and hyperthyroidism are risk factors for preterm birth. Milder thyroid function test abnormalities and thyroid autoimmunity are more prevalent, but it remains controversial if these are associated with preterm birth. Objective: To study if maternal thyroid function test abnormalities and thyroid autoimmunity are risk factors for preterm birth. Data Sources and Study Selection: Studies were identified through a search of the Ovid MEDLINE, EMBASE, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar databases from inception to March 18, 2018, and by publishing open invitations in relevant journals. Data sets from published and unpublished prospective cohort studies with data on thyroid function tests (thyrotropin [often referred to as thyroid-stimulating hormone or TSH] and free thyroxine [FT4] concentrations) or thyroid peroxidase (TPO) antibody measurements and gestational age at birth were screened for eligibility by 2 independent reviewers. Studies in which participants received treatment based on abnormal thyroid function tests were excluded. Data Extraction and Synthesis: The primary authors provided individual participant data that were analyzed using mixed-effects models. Main Outcomes and Measures: The primary outcome was preterm birth (<37 weeks' gestational age). Results: From 2526 published reports, 35 cohorts were invited to participate. After the addition of 5 unpublished data sets, a total of 19 cohorts were included. The study population included 47 045 pregnant women (mean age, 29 years; median gestational age at blood sampling, 12.9 weeks), of whom 1234 (3.1%) had subclinical hypothyroidism (increased thyrotropin concentration with normal FT4 concentration), 904 (2.2%) had isolated hypothyroxinemia (decreased FT4 concentration with normal thyrotropin concentration), and 3043 (7.5%) were TPO antibody positive; 2357 (5.0%) had a preterm birth. The risk of preterm birth was higher for women with subclinical hypothyroidism than euthyroid women (6.1% vs 5.0%, respectively; absolute risk difference, 1.4% [95% CI, 0%-3.2%]; odds ratio [OR], 1.29 [95% CI, 1.01-1.64]). Among women with isolated hypothyroxinemia, the risk of preterm birth was 7.1% vs 5.0% in euthyroid women (absolute risk difference, 2.3% [95% CI, 0.6%-4.5%]; OR, 1.46 [95% CI, 1.12-1.90]). In continuous analyses, each 1-SD higher maternal thyrotropin concentration was associated with a higher risk of preterm birth (absolute risk difference, 0.2% [95% CI, 0%-0.4%] per 1 SD; OR, 1.04 [95% CI, 1.00-1.09] per 1 SD). Thyroid peroxidase antibody-positive women had a higher risk of preterm birth vs TPO antibody-negative women (6.6% vs 4.9%, respectively; absolute risk difference, 1.6% [95% CI, 0.7%-2.8%]; OR, 1.33 [95% CI, 1.15-1.56]). Conclusions and Relevance: Among pregnant women without overt thyroid disease, subclinical hypothyroidism, isolated hypothyroxinemia, and TPO antibody positivity were significantly associated with higher risk of preterm birth. These results provide insights toward optimizing clinical decision-making strategies that should consider the potential harms and benefits of screening programs and levothyroxine treatment during pregnancy.

Characteristics of high- and low-risk individuals in the PRIORITY study: urinary proteomics and mineralocorticoid receptor antagonism for prevention of diabetic nephropathy in Type 2 diabetes.

AIM: To compare clinical baseline data in individuals with Type 2 diabetes and normoalbuminuria, who are at high or low risk of diabetic kidney disease based on the urinary proteomics classifier CKD273. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled international multicentre clinical trial and observational study in participants with Type 2 diabetes and normoalbuminuria, stratified into high- or low-risk groups based on CKD273 score. Clinical baseline data for the whole cohort and stratified by risk groups are reported. The associations between CKD273 and traditional risk factors for diabetic kidney disease were evaluated using univariate and logistic regression analysis. RESULTS: A total of 1777 participants from 15 centres were included, with 12.3% of these having a high-risk proteomic pattern. Participants in the high-risk group (n=218), were more likely to be men, were older, had longer diabetes duration, a lower estimated GFR and a higher urinary albumin:creatinine ratio than those in the low-risk group (n=1559, P<0.02). Numerical differences were small and univariate regression analyses showed weak associations (R2 < 0.04) of CKD273 with each baseline variable. In a logistic regression model including clinical variables known to be associated with diabetic kidney disease, estimated GFR, gender, log urinary albumin:creatinine ratio and use of renin-angiotensin system-blocking agents remained significant determinants of the CKD273 high-risk group: area under the curve 0.72 (95% CI 0.68-0.75; P<0.01). CONCLUSIONS: In this population of individuals with Type 2 diabetes and normoalbuminuria, traditional diabetic kidney disease risk factors differed slightly between participants at high risk and those at low risk of diabetic kidney disease, based on CKD273. These data suggest that CKD273 may provide additional prognostic information over and above the variables routinely available in the clinic. Testing the added value will be subject to our ongoing study. (European Union Clinical Trials Register: EudraCT 2012-000452-34 and Clinicaltrials.gov: NCT02040441).

Urinary Proteomics for Diagnosis and Monitoring of Diabetic Nephropathy.

The last decade has seen a surge in publications describing novel biomarkers for early detection of diabetic nephropathy (DN), but as yet none have outperformed albuminuria in well-designed prospective studies. This is partially attributable to our incomplete understanding of the many complex interrelated mechanisms underlying DN development, a heterogeneous process unlikely to be captured by a single biomarker. Proteomics offers the advantage of simultaneously analysing the entire protein content of a biological sample, and the technique has gained attention as a potential tool for a more accurate diagnosis of disease at an earlier stage as well as a means by which to unravel the pathogenesis of complex diseases such as DN using an untargeted approach. This review will discuss the potential of proteomics as both a clinical and research tool, evaluating exploratory work in animal models as well as diagnostic potential in human subjects.

Alterations in vascular function in primary aldosteronism: a cardiovascular magnetic resonance imaging study.

Excess aldosterone is associated with increased cardiovascular risk. Aldosterone has a permissive effect on vascular fibrosis. Cardiovascular magnetic resonance imaging (CMR) allows study of vascular function by measuring aortic distensibility. We compared aortic distensibility in primary aldosteronism (PA), essential hypertension (EH) and normal controls and explored the relationship between aortic distensibility and pulse wave velocity (PWV). We studied PA (n=14) and EH (n=33) subjects and age-matched healthy controls (n=17) with CMR, including measurement of aortic distensibility, and measured PWV using applanation tonometry. At recruitment, PA and EH patients had similar blood pressure and left ventricular mass. Subjects with PA had significantly lower aortic distensibility and higher PWV compared with EH and healthy controls. These changes were independent of other factors associated with reduced aortic distensibility, including ageing. There was a significant relationship between increasing aortic stiffness and age in keeping with physical and vascular ageing. As expected, aortic distensibility and PWV were closely correlated. These results demonstrate that PA patients display increased arterial stiffness compared with EH, independent of vascular ageing. The implication is that aldosterone invokes functional impairment of arterial function. The long-term implications of arterial stiffening in aldosterone excess require further study.

Pulse wave analysis for the prediction of preeclampsia.

Preeclampsia is associated with a number of changes to maternal vascular function. Assessment of arterial stiffness using pulse wave analysis (PWA) has been proposed as a means of predicting preeclampsia before the onset of clinically detectable disease. One hundred and eighty women with 2 risk factors for preeclampsia were examined at gestational weeks 16 and 28, of whom 17 (9.4%) developed preeclampsia. To study the effects of pregnancy itself women were also examined at 6-9 months post-natally; an additional 30 healthy non-pregnant women were also examined. PWA was performed using SphygmoCor; augmentation index (AIx), a marker of arterial wave reflection, was also measured using EndoPAT-2000. Women who developed preeclampsia were more likely to be overweight and had a higher brachial and central diastolic BP at gestational week 16 than those who remained normotensive. There was no difference in any parameter of arterial wave reflection between non-pregnant and pregnant women, nor between those who developed preeclampsia and those who remained normotensive, when examined at weeks 16 and 28 or post-natally. In this cohort of women with risk factors for preeclampsia, PWA did not provide additional information beyond brachial blood pressure and maternal risk factor profile about the risk of future development of preeclampsia.

Proteomics in hypertension.

Proteomics, the study of the proteins making up the proteome, has emerged in recent years as an important tool in several different fields of medical research for early disease detection, for assessment of response to treatment and for unravelling underlying pathophysiological mechanisms. Although the majority of patients with hypertension are treated in a similar manner, the causes underlying the condition are diverse, and often poorly understood. Genetic studies have implicated several different candidate genes, but it may be that examination of the 'downstream' products of genes, the proteins, will help to improve understanding of the link between the environmental and genetic effects that contribute towards development of hypertension. Proteomic studies can be performed quickly and reliably on several different sample types including plasma and urine, requiring minimal pre-test preparation. In this review, we will compare the different analytical platforms and technical issues involved in proteomic analysis. We will discuss existing studies of proteomics in hypertension, as well as related conditions such as renal disease, pre-eclampsia and coronary artery disease. We will also explore potential future applications of proteomics-based research, which may ultimately lead to improved population screening, monitoring of therapy and early detection of target organ damage.

Endothelial FOS expression and pre-eclampsia.

OBJECTIVE: To study gene expression profiles in human endothelial cells incubated with plasma from women who developed pre-eclampsia and women with normotensive pregnancies. DESIGN: A case-control study. SETTING: A longitudinal nested case-control study within three maternity units. POPULATION: A mixed obstetric population attending maternity hospitals in Glasgow. METHODS: Plasma was obtained at both 16 and 28 weeks of gestation from 12 women: six women subsequently developed pre-eclampsia (cases) and six women, matched for age, body mass index (BMI) and parity, remained normotensive (controls). Human umbilical vein endothelial cells (HUVECs) were incubated with plasma for 24 hour before RNA isolation. MAIN OUTCOME MEASURES: Gene expression profiles were compared between the two gestational time points using Illumina(®) HumanHT-12 v4 Expression BeadChips. Differential mRNA expression observed in microarray experiments were validated using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), and gene networks were analysed using Ingenuity(®) pathway analysis. RESULTS: There was a significant difference in the expression of 25 genes following incubation with plasma from controls, and an increase in the expression of 11 genes following incubation with plasma from cases, with no overlap between the two groups (false discovery rate, FDR < 0.05). There was a 3.74-fold (FDR < 0.001) increase in the expression of the c-Fos gene (FOS) when HUVECs were incubated with control plasma from 16 and 28 weeks of gestation, with no significant difference between the two time points with plasma from cases. Similar findings for FOS were obtained by qRT-PCR. CONCLUSIONS: Plasma from women who subsequently develop pre-eclampsia appears to contain factors that lead to the dysregulation of FOS in endothelial cells during pregnancy. Reduced expression of c-Fos may lead to impaired vasculogenesis, and thereby contribute to the development of pre-eclampsia.

Risk stratification scores in elective open abdominal aortic aneurysm repair: are they suitable for preoperative decision making?

OBJECTIVES: Risk indices help quantify the risk of cardiovascular events and death prior to making decisions about prophylactic AAA repair. This paper aims to study the predictive capabilities of 5 validated indices. DESIGN AND METHODS: A prospective observational multi-centre cohort study from August 2005 to September 2007 in Glasgow recruited 106 consecutive patients undergoing elective open AAA repair. The Glasgow Aneurysm Score (GAS), Vascular physiology only Physiological and Operative Severity Score for enUmeration of Mortality (V(p)-POSSUM), Vascular Biochemical and Haematological Outcome Model (VBHOM), Revised Cardiac Risk Index (RCRI) and Preoperative Risk Score of the Estimation of Physiological Ability and Surgical Stress Score (PRS of E-PASS) were calculated. Indices were compared using receiver operating characteristic (ROC) analysis and area under the curve (AUC) estimates. End points were all-cause mortality, Major Adverse Cardiac Events (MACE) and cardiac death. RESULTS: GAS, VBHOM and RCRI did not predict outcome. V(p)-POSSUM predicted MACE (AUC = 0.681), cardiac death (AUC = 0.762) and all-cause mortality (AUC = 0.780), as did E-PASS (AUC = 0.682, 0.821, 0.703 for MACE, cardiac death and all-cause mortality respectively). CONCLUSION: Whilst V(p)-POSSUM and E-PASS predicted outcome, the less complex RCRI and GAS performed poorly which questions the utility of decision making based on these surgical risk indices.

A pilot study on the effect of short-term consumption of a polyphenol rich drink on biomarkers of coronary artery disease defined by urinary proteomics.

Polyphenol rich diets have been associated with a reduced risk of cardiovascular disease. We examined the effect of a polyphenol rich (P-R) drink on biomarkers assessed by urinary proteomics. Thirty nine middle aged and overweight subjects were randomized to P-R drink (n = 20) or placebo (n = 19) in addition to their normal diet. After two weeks urine samples were obtained for assessment of the urinary proteome using capillary electrophoresis coupled to a mass spectrometer. A total of 93 polypeptides were found to be candidates for differential distribution with a nominal p-value <0.05, though these differences did not reach significance when multiple testing was accounted for. Sequences were determined in 19 of these demonstrating that they originate from alpha-1 antitrypsin, collagens, fibrinogen alpha and IgG kappa. Levels of 27 polypeptides were greater than 4-fold different between the two groups. Of these, 7 were previously found to be part of a coronary artery disease (CAD) specific urinary biomarker pattern. Their direction of expression was closer to the healthy state in the P-R drink group and closer to CAD state in the placebo group. Our data suggest that the P-R drink may have beneficial effects on urinary biomarkers of CAD. The data encourage the planning of future prospective studies, aimed at investigating significant effects of polyphenol rich dietary products.

Serum phosphate and outcome at one year after deceased donor renal transplantation.

Traditional risk factors do not adequately explain the increased prevalence of cardiovascular disease in renal patients. This study considered a "non-traditional" risk factor, serum phosphate and outcome in renal transplant recipients. Data from 377 patients who received a first deceased donor renal transplant between January 1, 1999, and December 31, 2008, were recorded; 10% (n=38) had diabetes, 16.7% (n=63) were smokers, and 18.8% (n=71) had a history of vascular disease. Three hundred and thirty-three patients were alive at the time of the analysis. Survivors were significantly younger, less likely to be smokers or diabetic, and had a higher estimated glomerular filtration rate at one yr post-transplantation. Serum phosphate was significantly lower in these patients (0.95 ± 0.23 vs. 1.04 ± 0.26, p = 0.031). Analysis of recipient survival, stratified by serum phosphate at one yr post-transplant, revealed that serum phosphate > 1.11 mMol/L was a significant predictor of all-cause mortality (p=0.006). Serum phosphate between 0.9 and 1.11 mMol/L afforded the best outcome. In multivariate analysis, serum phosphate remained a significant predictor of mortality (p=0.016). Serum phosphate at one yr after transplant seems to have a J-shaped relationship with mortality, and this effect is independent of traditional cardiovascular risk factors.

Renal function and cardiovascular events: relevance of eGFR and albuminuria in patients with diabetes.

Impaired renal function has been recognised as an independent cardiovascular risk factor in the general population and in patients with established cardiovascular disease. In this issue of Diabetologia, Drury et al. examined the association of two markers of renal function with cardiovascular outcome in patients with type 2 diabetes. They found that both estimated glomerular filtration rate (eGFR) and albuminuria were independent predictors, but that their incremental contribution to cardiovascular risk was modest compared with that of other risk factors. Both eGFR and albuminuria appear to integrate information from other risk factors and may be more suitable than population-based risk scores for risk prediction in individuals, but further research is required to examine whether reduced eGFR and albuminuria mainly represent generalised vascular damage or if impaired renal function directly affects vascular structure and function in patients with type 2 diabetes.

Vascular function in patients with end-stage renal disease and/or coronary artery disease: a cardiac magnetic resonance imaging study.

Decreased arterial compliance in end-stage renal disease (ESRD) is associated with increased cardiovascular risk. Our aim was to examine aortic compliance in patients with ESRD using cardiac magnetic resonance imaging (MRI) and to compare these with patients with advanced atherosclerotic disease who are known to be at high cardiovascular risk. We examined a total of 83 subjects matched for age: 24 had ESRD and were on dialysis therapy for 3+/-6 years, 24 had severe coronary artery disease (CAD), 11 had both ESRD and CAD (4+/-5 years on dialysis therapy), and 24 healthy subjects with no evidence of CAD. Vascular and cardiac function was assessed using cardiac MRI. Aortic compliance was significantly reduced in patients with CAD compared to control subjects (11.3+/-6.3 ml x 10(-3)/mm Hg vs 15.6+/-6.0 ml x 10(-3)/mm Hg, P=0.009). Patients with ESRD also exhibited significantly reduced aortic compliance compared to healthy controls (12.4+/-5.8 ml x 10(-3)/mm Hg vs 15.6+/-6.0 ml 10(-3)/mm Hg, P=0.012), whereas there was no significant difference in aortic compliance between patients with CAD and ESRD. Even in the absence of symptomatic CAD, patients with ESRD have significantly reduced aortic compliance compared to normal subjects. Patients with ESRD have equivalent aortic compliance to patients with advanced CAD. These findings suggest that a significantly reduced aortic compliance is one of many mechanisms promoting premature cardiovascular events in patients with ESRD compared to age-matched controls from the general population.

Impaired basal NO activity in patients with glomerular disease and the influence of oxidative stress.

Endothelial dysfunction has been found to be linked to and predictive of cardiovascular events. Whether endothelial function of the renal vasculature is impaired in patients with chronic glomerular disease and whether oxidative stress is of importance in this setting has not yet been determined. In this study, endothelial function of the renal vasculature was investigated in 25 patients with chronic glomerular disease and 50 control subjects matched for age and blood pressure. Renal plasma flow (RPF) and glomerular filtration rate were measured by constant infusion input clearance technique at baseline and following infusions of the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 4.25 mg/kg), the substrate of NOS L-arginine (100 mg/kg) and the antioxidant vitamin C (3 g co-infused with L-arginine 100 mg/kg). At baseline, RPF was similar in the two groups. The reduction in RPF in response to L-NMMA was less pronounced in patients with chronic glomerular disease compared to control subjects (-4.6+/-12 vs -9.8+/-9%; P=0.040), indicating reduced basal nitric oxide (NO) activity in chronic glomerular disease. Co-infusion of the antioxidant vitamin C on top of L-arginine induced a more pronounced increase in RPF in patients with chronic glomerular disease than in control subjects (21.7+/-17 vs 10.9+/-22%; P=0.036). Our findings suggest that basal NO activity of the renal vasculature is reduced in patients with chronic glomerular disease compared to age- and blood pressure-matched control subjects. This might be in part related to increased oxidative stress.

The effect of statins on angiotensin II-induced hemodynamic changes in young, mildly hypercholesterolemic men.

BACKGROUND: Angiotensin II type 1 (AT(1)) receptors are well known to mediate angiotensin II (Ang II)-induced pro-atherosclerotic effects. It has been found that hypercholesterolemia influences the expression of AT(1) receptors on vascular smooth muscle cells and that increased density of AT(1) receptors exaggerates the hemodynamic response to Ang II. We analyzed to what extent statins and AT(1) receptor antagonists diminish the vasoconstrictive response to Ang II infusion in hypercholesterolemic patients. METHODS: A total of 24 male patients with LDL cholesterol levels >130 mg/dL were enrolled in a randomized, cross-over study. After baseline evaluation, 12 patients received first cerivastatin (0.3 mg/day) and the other 12 patients initially received candesartan (8 mg/day) for 3 weeks, with subsequent cross-over of the medication for the second 3-week drug period. The vascular response was analyzed by the increase in mean arterial pressure (MAP) and total peripheral resistance (TPR) during infusion of increasing doses of Ang II at baseline and the end of each treatment period. Hemodynamic changes were also compared with those in 24 normocholesterolemic subjects without any therapy. RESULTS: At baseline, Ang II provoked a similar increase of MAP and TPR in patients and control subjects. Treatment with cerivastatin did not affect the response to Ang II compared with baseline. By contrast, treatment with candesartan attenuated significantly the response to Ang II compared with baseline and cerivastatin. CONCLUSIONS: Our hemodynamic data indicate the hypothesis that statins do not reduce the responsiveness to Ang II in resistance arteries of young, mildly hypercholesterolemic patients.

"Very delayed" graft function in a patient after living related kidney transplantation: a case report.

We report the case of a patient who experienced anuric renal transplant failure for 44 days after living related kidney transplantation. Immunosuppressive and other therapies were carefully adapted to the findings of frequent renal transplant biopsies, which ultimately led to excellent graft function.